Clin Perinatol 32 (2005) xi
Preface
Multiple Gestations Twins and other multiple births have been a fascination to popular culture since the beginning of time. Romulus and Remus were famous twins in Roman mythology. Jacob and Esau were famous twins in the Bible. Gemini is the zodiac sign of the twins. The list goes on and on. It used to be that spotting a set of twins was a rare phenomenon. Today, all one has to do is take a trip to the local mall to see that twin strollers are as commonplace as chain stores. As mentioned in many of the following chapters, the numbers of twins and higher order multiples has skyrocketed over the past several decades. Just as the number of multiple gestations has exponentially increased, so has the amount of literature pertaining to these pregnancies. The purpose of this issue of Clinics in Perinatology is to provide a comprehensive review of this topic, providing evidence-based recommendations, wherever possible. Our intention is for practitioners to use this issue as a step-by-step guide to the contemporary care and management of these pregnancies. The broutineQ care of twin pregnancies is discussed, as well as management of problems specific to multifetal pregnancies. Finally, we include a chapter on the long-term outcomes for multifetal pregnancies so that practitioners can answer questions relating to outcomes when their patients ask. We hope you enjoy reading this issue, and would like to thank the contributing authors for making it a great one. Keith A. Eddleman, MD Division of Maternal-Fetal Medicine Department of Obstetrics, Gynecology, and Reproductive Sciences Mount Sinai School of Medicine, New York, NY, USA E-mail address:
[email protected] Joanne Stone, MD Division of Maternal-Fetal Medicine Department of Obstetrics, Gynecology, and Reproductive Sciences Mount Sinai School of Medicine, New York, NY, USA E-mail address:
[email protected] 0095-5108/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.clp.2005.05.009 perinatology.theclinics.com
Clin Perinatol 32 (2005) 301 – 314
Epidemiology and Biology of Multiple Gestations Loraine Endres, MD*, Isabelle Wilkins, MD Division of Maternal–Fetal Medicine, University of Illinois Medical Center, 820 S. Wood St., MC 808, Chicago, IL 60612, USA
Twins have always aroused interest and have been represented throughout history, from Apollo and Diana in Greek mythology, to Jacob and Esau in the Bible, to Alexander Helios and Cleopatra Selene (the children of Marcus Antonius and Cleopatra), to Mary Kate and Ashley Olsen, billionaire movie stars. Conjoined twins have caused even more sensation, the best-known pair being Chang and Eng Bunker, who were born in Thailand in 1811 and inspired the term Siamese twins. Recently, higher-order multiples have caused controversy, and there has been heavy media coverage of large-number deliveries, such as the McCaughey septuplets. In this article, we review the incidence, types, and causes of multiple gestations.
Incidence In human pregnancies, twins occur with an approximate frequency of 1 in 90 births [1]. This rate is known to vary widely from country to country with the highest numbers in Nigeria and the lowest in Japan [2,3]. In the United States, the rates of twin, triplet, and higher order multiple births have increased dramatically in the last decades. From the National Vital Statistics Reports, the number of live births of twins rose 52% from 1980 to 1997. The number of triplets and higher order multiple deliveries soared with a 404% increase. During the same
* Corresponding author. E-mail address:
[email protected] (L. Endres). 0095-5108/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.clp.2005.04.002 perinatology.theclinics.com
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time period, singleton births only rose by 6%. In 1997, there were 104,137 twin births, 6148 triplet births, 510 quadruplet births, and 79 higher-order deliveries. Twins have increased to 2.7% of all births and the triplets to 0.17% [4]. In general, the number of multiple births in a population can be estimated using Hellin’s hypothesis. In 1895, Hellin demonstrated that when twins occurred once in every 89 births, then triplets occurred once in every 892, and quadruplets once in every 893 [3,5]. In 1921, Zeleny further refined the concept and wrote ‘‘if 1/N is the proportion of twin births to all births in a large population during any period, then the proportion of triplet births. . .is very near to 1/N2. . .the expected number of quadruplets is 1/N3 [3,6]. The race and age of the mothers carrying multiple gestations in the United States has also changed. Twinning used to be substantially more common in black women, but since the 1980s, the levels of twinning in white women have risen at a higher rate and have eliminated the difference. Rates among Hispanic women have increased, but still remain lower than non-Hispanic black and nonHispanic white mothers. In 1997, the twin births rates were 19.5 per 1000 births for Hispanic women, 30.0 for non-Hispanic black women, and 28.8 per 1000 for non-Hispanic white women [4]. Historically, age-specific twin birth rates rose steadily up to age 39 years, then dropped quickly. Since 1992, age-specific twin birth rates have been climbing. Women aged 45 to 49 years are three times more likely to have a twin gestation than at age 35 to 39 years; for women 50 to 54 years of age, one in every three births is a twin delivery. Triplet births have followed the same trend. Women aged 45 to 49 are 100 times more likely than a teenager to have a triplet delivery and four times more likely than women aged 35 to 39 [4]. The overall rise in multiple gestations is attributed to two major trends: older age at childbearing and increasing use of fertility-enhancing therapies. It is estimated that one third of the increase in multiple births is from the shift to older maternal age and the remaining two thirds is attributable to infertility treatment [4]. The increasing numbers of multiple gestations are having an important impact on the medical system because of higher complication rates. Luke [7] evaluated the changing pattern of births from 1973 to 1990 and found that in 1990, preterm births accounted for 9.7% of singleton births, compared with 47.9% of twin births and 87.8% of triplet and higher-order births. Because of the increasing frequency of multiples, the rates of very low and low birth weight infants were 24.2% greater among twins and 142.3% greater among triplet and higher-order births than if the multiple gestation rate had remained at the level for 1973 [7]. Other complications, such as an increased rate of anomalies and twin–twin transfusion syndrome, are discussed elsewhere in this issue. The conception rates of multiple gestations are even higher, because most statistics are reported as birth data and do not include spontaneous abortions or reductions to singleton gestations. Dickey and colleagues [8] studied the incidence of spontaneous reductions in a group of women undergoing infertility treatment. On an initial ultrasound of 7696 pregnancies, 6184 were found to have
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a single gestational sac and 726 were found to have multiple gestational sacs. Spontaneous reduction of one or more gestational sac occurred before the twelfth week of gestation in 36% of twin, 53% of triplet, and 65% of quadruplet pregnancies. In a review of 11 reports on multiple gestation loss rates without ovulation stimulation, it was estimated that 14% of multiple gestations end in abortion and 58% end in a singleton birth [9].
Types of twins There are two types of twins—monozygotic and dizygotic—that are referred to colloquially as identical and fraternal twins, respectively. Monozygotic twins develop from a single fertilized ovum that splits; therefore, they have the same genetic material. Dizygotic twins arise from more than one fertilized ovum and are only as genetically similar as any full siblings. The lay terms relate to the mechanism of the twinning but may not be accurate, because monozygotic twins may not appear as identical in cases of a large size discrepancy from twin–twin transfusion syndrome or when there is a discordant anomaly such as anencephaly in one twin. Dizygotic or fraternal twins may also look very similar, as do some other sets of siblings in families, so the scientific terms of monozygotic and dizygotic are more appropriate. Triplets and higher-order multiples are most likely to be multizygotic from superovulation. They can also be monozygotic or a combination of zygosity due to splitting of one or more zygote after multiple oocytes were fertilized. A single fertilized ovum can also split into more than two separate zygotes producing monozygotic triplets or higher-order multiples. The most famous example of this latter phenomenon is the Dionne quintuplets, who were thought to be monozygotic [10]. These combinations are also seen in other species. The ninebanded armadillo starts with a single fertilized ovum that spits after implantation to create four monozygotic quadruplets. In other species, including rodents and carnivores, multiple gestations are related to the level of follicle-stimulating hormone and are multizygotic litters from superovulation. Monozygotic pairs are thought to occur and studies in rats have shown rates up to 1%. Because conjoined twins occur sporadically in most species, this is additional proof that monozygotic twins occasionally occur [1]. While the rate of dizygotic twins varies by population, the frequency of monozygotic twins is constant throughout the world at 3.5 per 1000 and is not influenced by race, maternal age, nutrition, or other factors [11]. The rate of monozygotic twins in a group can be estimated using Weinberg’s differential method. Weinberg first developed his theory in 1901, and all that need be known is the number of like and unlike sex twins in a population [12,13]. Monozygotic twins must be the same sex, while dizygotic twins may be the same or opposite sex. Therefore, if the number of male and female fetuses conceived is assumed to be equal for dizygotic twins, out of 100 pairs there should be 50 male/female pairs, 25 male/male pairs, and 25 female/female pairs [14].
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Any increase in the number of like sex pairs can be assumed to be the number of monozygotic twins. The number can be calculated from the following formula: Monozygotic twins = (like sex pairs) (unlike sex pairs) / number of pregnancies [13] In the United States, approximately one third of twins have been monozygotic based on this formula [14]. With the dramatic increase in dizygotic twins from infertility treatment in the United States, the ratio of monozygotic to dizygotic twins is probably currently lower. Zygosity testing for twins, triplets, or any multiple gestations can be determined by way of DNA testing after birth. Presumptive diagnosis can be made from sex determination and examination of the placentas. In a twin gestation, opposite sex twins when found by ultrasound examination, karyotyping, or physical examination after delivery can be assumed to be dizygotic. Dizygotic twins should always have a dichorionic, diamniotic placenta. They can have completely separate placentas or have fused placentas with a thick ridge of membranes along the fusion plane. With rare exceptions, there should not be vascular connections across the placentas and there should always be four layers to the dividing membrane, an outer amnion on either side, and two layers of chorion in the middle. The membranes will appear as opaque as a result of a degenerated trophoblast and atrophied villi between the two chorionic layers (Figs. 1, 2) [14]. To understand the placentation of monozygotic twins, a brief review of human embryology is required. Once fertilization of the ovum occurs, a zygote is formed. As it passes along the fallopian tube, the zygote undergoes cleavage into a small number of blastomeres. On approximately day 3 after fertilization, a mass of 12 to 16 blastomeres, called a morula, enters the uterus. A cavity then forms in the morula, converting it into a blastocyst with an inner cell mass that becomes the embryo and amnion and an outer layer of trophoblast that forms the chorion and placenta. By the end of the first week, the blastocyst is superficially implanted in the endometrium. During the second week after fertilization, the
Fig. 1. The two principal types of twin placentation: diamniotic monochorionic placenta (left), which is always monozygotic, and diamniotic dichorionic placenta (right), which may be monozygotic or dizygotic. (From Benirschke K. Multiple gestation. In: Creasy RK, Resnik R, editors. Maternal-fetal medicine: principles and practice. 5th edition. Philadelphia: Saunders; 2004. p. 57; with permission.)
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Fig. 2. (A) Monozygotic placenta. (B) Dizygotic placenta.
blastocyst becomes completely implanted and the inner cell mass divides into a bilaminar embryonic disc. The amniotic cavity, amnion, yolk sac, connecting stalk, and chorion all form during this second week of development [15]. Monozygotic twins can have any form of placentation depending on the when the splitting of the zygote occurred. If the separation occurs early after fertilization, within the first two to three days before the inner cell mass forms, the placentas will be dichorionic, diamniotic with the same four layers and opaque appearance as dizygotic twins. If the splitting occurs between the third and eighth day, only the inner cell mass divides. The placentation will be monochorionic, diamniotic. The dividing membranes consist of only the two amnions and appear translucent. Almost all monochorionic twins have interfetal blood vessel connections in their placenta. If the division occurs beyond the eighth day, after the bilaminar embryonic disc and amnion have formed, the twins will be monochorionic, monoamniotic. In this case, there are no dividing membranes and the twins are in one sac. Splitting that occurs after 13 days of development results in incomplete separation of the embryonic tissue and results in conjoined twins.
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Fig. 3. Schematic representation of monozygotic twinning event superimposed on temporal events of embryogenesis. The embryonic events in the upper portion are sketched according to the publications of early human embryos by Hertig [16]. The twinning event is depicted in the lower portion with resulting placental types indicated. Di Di, diamniotic dichorionic; Di Mo, diamniotic monochorionic; Mo Mo, monoamniotic monochorionic. (From Benirschke K, Kim CK. Multiple pregnancy. N Engl J Med 1973;288:1276; with permission.)
This is rare because it becomes increasingly difficult for the rapidly growing embryo to divide into two (Fig. 3) [11,12,14–16]. Some evidence for this developmental progression of splitting comes from observations of Moneiro and colleagues on X-inactivation. They looked at buccal cell populations of dichorionic and monochorionic monozygotic twins and found that the X-inactivation pattern was more similar for monochorionic twins compared with dichorionic twins. X-inactivation occurs prior to formation of the inner cell mass so that monochorionic twins that develop from the division of the inner cell mass have more closely matched patterns of X-inactivation [17]. The rate of monozygotic twinning is thought to be fairly constant over the first 12 to 13 days of development [1]. This results in the largest number of monozygotic twins having a monochorionic, diamniotic placentation. Overall, approximately one third of monozygotic twins are dichorionic, diamniotic; two thirds are monochorionic, diamniotic; less than 4% are monoamniotic, monochorionic; and about 1 out of 400 are conjoined [12]. Like monozygotic twins, the worldwide rate of monozygotic triplets is constant at approximately 20 per million while the rate of multizygotic triplets varies by population [12]. While triplets and higher-order multiples can have a
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variety of placentations and a combination of different sexes, inspection can help determine zygosity in some cases. For example, if a set of triplets have a pair of monochorionic, diamniotic twins and an additional dichorionic, diamniotic singleton, we know that at least the twin pair is monozygotic. In multiple gestations, the placental masses can be unequally divided among the fetuses. In dizygotic or multizygotic pregnancies, the differences can be from genetic disparities. In monozygotic pregnancies, the size discrepencies can be from uneven splitting of the cells. In both, an unequal amount of villous mass may be related to a lack of space in the uterus. The placental area with a better implantation site and more maternal blood flow may be larger with a normal cord insertion while the placenta area that is crowded for room may be smaller, in an abnormal position, or have an anomalous cord insertion. This phenomenon was termed trophotropism by Strassman in 1902. He felt that this model may explain the higher incidence of placenta previa and marginal and velamentous cord insertions that are associated with the smaller placental mass [1,18]. Over the years, there has been much speculation about a potential third type of twinning referred to as polar body twinning. Danforth first published the theory in 1916 to try to explain the distribution of certain physical characteristics in twins [12,19]. Polar body twinning is based on the idea that a single ovum separates at some time during its development and is then fertilized by two different sperm. To explain polar body twinning, a brief review of the maturation of the ovum is necessary. The primary oocyte is a large cell that divides unequally during the first meiotic division. It forms a secondary oocyte that has most of the cytoplasm and a small cell called the first polar body. The secondary oocyte is held in a follicle in the ovary until ovulation. The secondary oocyte undergoes the second meiotic division to produce an ovum and a second polar body immediately before fertilization (Fig. 4). The first polar body may also divide to produce two first polar bodies. The polar bodies remain close to the ovum within the zona pellucida [12,15]. A polar body twin could occur if the primary oocyte divided equally into two secondary oocytes, if the secondary oocyte divided equally into two ovum, or if the ovum itself divided into two cells before fertilization. Depending on when the equal division occurs, the twins would be more or less like dizygotic twins, but would never be as similar as monozygotic twins because they are produced from different sperm. This is due to the chiasma that forms and the crossing-over that occurs between the chromatids of homologous chromosomes during the first meiotic division when the chromosomal number goes from diploid to haploid. Twins that develop from splitting of the primary oocyte before crossover occurs will be less genetically similar than regular siblings or dizygotic twins. Twins that develop from splitting of the secondary ooctye will be more genetically similar that siblings or dizygotic twins. Twins that result from splitting of the ovum before fertilization will have the exact same maternal genetic component, but will have different paternal genes from the different sperm. Bulmer in 1970 described all of these potential genetic combinations, but felt that they were unlikely to actually happen [12].
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Fig. 4. Diagram showing the egg during meiosis and development of the polar bodies. If fertilization of one of the polar bodies occurred, this would represent polar body twinning. (Courtesy of Adrienne Boutwell, Chicago, IL.)
Since then, there has been one case report describing a possible polar body twin pregnancy by Bieber and colleagues in 1981 [20]. They described a monochorionic, diamniotic twin gestation with one normal baby and one acardiac twin. This would have been assumed to be a monozygotic gestation based on the placentation, but the chromosome analysis of the healthy infant revealed a normal XY karyotype, while the testing of the acardiac twin showed a triploid XXX karyotype. Further histocompatibility typing and cytogentic marker studies with QFQ and C banding revealed a probable fertilization of the first polar body. In 1989, there was also a report by Fishel and colleagues [21] on the recovery of two human oocytes surrounded by a single zona pellucida. This may have represented equal splitting of the primary oocyte into two secondary oocytes that could have potentially both been fertilized. Before that in 1981, Goldgar and Kimberling [22] developed genetic models to determine if polar body twinning could be detected. They concluded that markers close to the centromere would be appropriate for testing and that there is currently no definitive evidence that polar body twins do or do not exist.
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When multiples are born, the family frequently wants to know the zygosity of the neonates, and this can have important medical implications in the future. In a study by Cameron in 1968 [23], over 50% of twin zygosity was determined by the sex of the infants and by examination of the placentas; 35% were known to be dizygotic because they were opposite sexes, and 20% were known to be monozygotic because they had a monochorionic placenta. In 1984, Segal [24] attempted to determine zygosity just by inspection of pairs of twins compared with blood typing, accurately assessing the zygosity in 94% to 96% of cases. However, when twins are going to be included in medical studies or for transplant issues, determining zygosity by physical characteristics is not appropriate. In a classic case reported by St. Clair and colleagues in 1998 [25], one brother donated a kidney to his twin. They were thought to be dizygotic based on differences in appearance. Only after 15 years of immunosuppressive therapy were they determined by way of DNA restriction fragment length polymorphisms to be monozygotic. The immunosuppressive medications were stopped and the twin did not experience rejection. This example illustrates why definitive zygosity determination is important. The original laboratory methods for zygosity determination involved complex blood typing. As early as 1977, as cytogenetic techniques improved, chromosomal banding became available as a method to elucidate zygosity. Heteromorphic areas on the chromosomes were stained and compared between sets of twins. This technique proved to be more accurate than blood typing [26–28]. By 1985, restriction fragment length polymorphisms were being used to hybridize to areas of genomic DNA. This technique had the advantage that it could be used on stored tissue or in cases of a fetal demise [29]. Currently, minisatellite DNA probes are used to determine zygosity with excellent success. Minisatellite probes consist of multiple repeated copies of a common 10 to 15 base pair sequence called a short tandem repeat. The probes can detect many highly polymorphic minisatellites at different loci in the genome and produce band patterns that are individually specific [30]. The odds that two unrelated people have the same pattern are astronomically low at Pb10 18. The chance of siblings or dizygotic twins—who should have approximately 50% matching bands—having the exact same pattern is Pb10 8. Therefore, the chance that twins would be falsely labeled monozygotic is Pb10 4 [30]. The technique has now been automated to more easily determine zygosity in multiple gestations [31].
Causes of twinning Despite the large amount of interest in multiple gestations, very little is known about the cause. In some cases of multiple gestations, the source is obvious— as in the case of a mother who has three embryos transferred after in vitro fertilization and who then becomes pregnant with triplets. But there have also been cases of assisted reproduction in which two embryos are transferred and
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the woman becomes pregnant with triplets. We do not have a clear etiology for twinning, but there are some known associations. Monozygotic twinning may actually be a teratogenic event. This is supported by the evidence that monozygotic twinning rates are stable across all ages and races. From as early as 1891, Rumpe declared that while dizygotic twinning rates increased with age, the monozygotic rate was stationary [3,32]. In 1934, Greulich looked at the age range of 6 million parturient women and found that the age distribution of those who had had monozygotic twins was not different than the controls, while the age of women who had had dizygotic twins was higher [3,33]. And while the number of twins varies by race, as early as 1936 researchers realized that the 0.43% rate of monozygotic twins was approximately the same in Japan as well as among African and Caucasian races that had higher numbers of dizygotic twins [3,34]. Another reason to conclude that monozygotic twinning may develop from a teratogenic exposure is that malformations are known to occur more frequently [35]. The incidence of congenital malformations in twins from the British Columbia Health Surveillance Registry was 6% in 1975 when published by Schinzel et al. They found the incidence of congenital anomalies to be 2.5 times higher in monozygotic twins compared with dizygotic twins or singletons [36]. Monozygotic twinning can be induced in animals from toxic exposures. In 1921, Stockard [37] developed the theory that teratogenic congenital anomalies are not based on the specific agent, but on the timing of the exposure. He worked with fish eggs because they develop outside of the mother and are easily affected by the external environment. By depriving the eggs of sea minnows and trout of oxygen and keeping them at a low temperature, he could produce twinning at an early stage and localized anomalies such as cyclopia at a later stage. In 1978, Kaufman and O’Shea [35] were able to produce monozygotic twinning in mice by exposing them to vincristine sulphate. Mice and other mammalian species normally have a very low rate of monozygotic twinning, but when they were treated with vincristine sulphate on the seventh day after conception, the rate dramatically increased. Out of 9 mice that were autopsied, there were four sets of twins, and one pair was conjoined. Stockard also felt that twinning may occur from delayed implantation, as is seen in the nine-banded armadillo. The armadillo mates in July, and the ovum develops into a blastocyst in approximately 1 week. The blastocyst then becomes quiescent until early November, when it implants and then divides into four. The four fetuses develop normally until they are delivered in March or April [12,37–39]. Stockard thought that the lack of oxygen during the long period of quiescence may be the twinning impetus. In human, the only process known to increase the rate of monozygotic gestation is assisted reproduction. Derom and colleagues [40] wrote in 1987 that artificial induction of ovulation seems to be the first identified biologic mechanism influencing the monozygotic twinning rate. From the East Flanders Prospective Twin Study from 1978 to 1985, they reported a 1.2% rate of monozygotic twins, much higher than the expected 0.45% [40]. Since then, several
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studies have also shown that during in vitro fertilization, when human embryos are transferred to the uterus during later stages of development, there is a much higher rate of monozygotic twinning. When transfer was delayed until the blastocyst stage, monozygotic rates were 5% [41,42]. This may be related to delayed implantation and oxygen deprivation, as Stockard proposed for the armadillo. It would seem logical that some of the assisted reproduction techniques that manipulate the zona pellucida such as intracytoplasmic sperm injection or assisted hatching would also cause a higher rate of monozygotic twinning. So far studies have not shown conclusively an increase in monozygotic twinning from zona pellucida micromanipulation [42–44]. It also seems plausible that genetic changes in cell adhesion molecules could result in monozygotic twinning. One study by Bamforth and colleagues [45] examined a polymorphism in the E-cadherin gene, which reduces expression of E-cadherin by 68%. They found that monozygotic twins were slightly more likely to have the polymorphism in the E-cadherin gene. They concluded that while the polymorphism alone does not explain monozygotic twinning, it may be a causative factor along with other genetic and environmental influences. Dizygotic or multizygotic pregnancies are thought to occur by more than one ova being released at the time of ovulation, an event commonly referred to as double ovulation. Although monozygotic twinning rates are not related to maternal factors, dizygotic twinning rates are known to correlate with maternal influences such as age, parity, race, and nutrition and to coital frequency [2,3,46]. These maternal characteristics are probably all related to maternal serum gonadotropin levels and the coital frequency to the opportunity for fertilization of more than one ovum. In 1926, Smith first demonstrated that gonadotropins secreted from the anterior pituitary gland controlled ovarian function. He was able to cause a cessation of ovarian function with hypophysectomy and cause function to return by implanting fresh glands [12,47]. By 1961, injecting gonadotropins into adult female animals such as rabbits, rats, sheep, and cattle was known to result in superovulation [12,48]. By 1978, the beef industry was using high doses of follicle-stimulating hormone (FSH) to achieve polyovulation and higher cattle production [11]. There is ample evidence of the same effects in humans. Many studies have shown higher rates of multiples following assisted reproduction. Collins and Bleyl [49] reported in 1990 that 94% of quadruplet pregnancies resulted from ovulation induction therapy. There are studies showing how naturally occurring different gonadotropin levels cause the age and geographical differences seen in spontaneous dizygotic twinning. As early as 1865, Duncan realized that rates of dizygotic twinning rose steadily until approximately age 40, then began falling [3,50]. Nylander wrote that the increasing incidence of dizygotic twinning with maternal age is due to rising ovarian activity under hormonal control, with the fall in incidence then being rated to exhaustion of the Graafian follicles as menopause approaches.
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Albert and colleagues did show a linear increase in urinary gonadotropins with advancing age in female rats [11,51]. Nylander also evaluated the racial differences seen in dizygotic twinning. He studied the FSH levels in Nigerian and Scottish women. The Nigerian population with a much higher rate of twinning at 50 per 1000 compared to the Scottish rate of 12 per 1000 also had significantly higher FSH levels. Within the Nigerian women, those with two prior sets of twins had higher peak FSH levels at 40 mIU/mL2 compared with those who had one set of twins at 32 mIU/mL2 and those who had singletons at 27 mIU/mL2 [2]. Soma and colleagues [52] then studied serum gonadotropin levels in Japanese women who are known to have very low rates of dizygotic twinning. They found Japanese mothers of singletons had mean peak levels of FSH of 18 mIU/mL2 compared with the Nigerian mothers at 27 and American women at 24. They concluded that the low frequency of twinning in the Japanese population may be due to low gonadotropin output. There also seem to be genetic factors that go beyond the racial differences in gonadotropin levels. Bulmer [12] wrote that daughters of women with dizygotic twins are 1.8 times more likely to have twins and sisters of women with twins are 2.6 times more likely to give birth to twins themselves. Busjahn and colleagues [53] studied a polymorphism of the PPARG gene on chromosome 3 and found a significant difference in the number of dizygotic twins with the polymorphism compared to monozygotic twins or the general population. The PPRAG gene encodes the peroxisome proliferator-activated receptor, which has effects on insulin, lipid metabolism, and body mass index, all of which can influence reproductive hormone levels. As in monozygotic twinning, dizygotic twinning is probably caused by a combination of genetic and environmental factors that have yet to be fully elucidated.
References [1] Benirschke K, Masliah E. The placenta in multiple pregnancy: outstanding issues. Reprod Fertil Dev 2001;13:615 – 22. [2] Nylander PPS. The factors that influence twinning rates. Acta Genet Med Gemellol 1981;30: 189 – 202. [3] Guttmacher AF. The incidence of multiple births in man and some of the other unipara. Obstet Gynecol 1953;2:22 – 35. [4] Martin JA, Park MM. Trends in twin and triplet births: 1980–97. National Vital Statistics Reports. Volume 47, number 24. Hyattsville (MD)7 National Center for Health Statistics; 1999. [5] Hellin D. Die Ursache der Multiparit7t der Uniparen Tiere qberhaupt und der Zwillingsschwangerschaft beim Menschen. Mqnchen7 Seitz and Schauer; 1985. [6] Zeleny CL. The relative numbers of twins and triplets. Science 1921;53:262. [7] Luke B. The changing pattern of multiple births in the United States: maternal and infant characteristics, 1973 and 1990. Obstet Gynecol 1994;84:101 – 6. [8] Dickey RP, Taylor SN, Lu PY, et al. Spontaneous reduction of multiple pregnancy: incidence and effect on outcome. Am J Obstet Gynecol 2002;186:77 – 83. [9] Little J, Thompson B. Descriptive epidemiology. In: MacGillivray I, Campbell DM, Thompson B, editors. Twinning and twins. Hoboken (NJ)7 John Wiley and Sons, Ltd; 1988. p. 37 – 42.
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[10] MacArthur JW. Genetics of quintuplets. I. Diagnosis of the Dionne quintuplets as a monozygotic set. J Hered 1938;29:323 – 9. [11] Benirschke K, Kim CK. Multiple pregnancy. N Engl J Med 1973;288:1276 – 84. [12] Bulmer MG. The biology of twinning in man. Oxford (UK)7 Clarendon Press; 1970. [13] Weinberg W. Beitr7ge zur Physiologie und Pathologie der Mehrlingsgeburten bein Menschen. Pflqgers Arch ges Physiol 1901;88:346 – 430. [14] Benirschke K. Multiple gestation. In: Creasy RK, Resnik R, editors. Maternal-fetal medicine: principles and practice. 5th edition. Philadelphia7 Saunders; 2004. p. 55 – 68. [15] Moore KL. The beginning of human development and formation of the bilaminar embryo. In: The developing human: clinically oriented embryology. 4th edition. Philadelphia: WB Saunders Company; 1988. p. 31–43, 122–26. [16] Hertig AT. Human trophoblast. Springfield (IL)7 Charles C Thomas; 1968. [17] Monteiro J, Derom C, Vlietinck R, et al. Commitment to X-inactivation precedes the twinning event in monochorionic twins. Am J Hum Genet 1998;63:339 – 46. [18] Strassmann P. Placenta praevia. Arch Gynakol 1902;67:112 – 275. [19] Danforth CH. Is twinning hereditary? J Hered 1916;7:195 – 202. [20] Bieber FR, Nance WE, Morton CC, et al. Genetic studies of an acardiac monster: evidence of polar body twinning in man. Science 1981;213:775 – 7. [21] Fishel S, Kaufman MH, Jackson P, et al. Recovery of two human oocytes surrounded by a single zona pellucida. Fertil Steril 1989;52:325 – 7. [22] Goldgar DE, Kimberling WJ. Genetic expectations of polar body twinning. Acta Genet Med Gemellol 1981;30:257 – 66. [23] Cameron AH. The Birmingham twin survey. Proc R Soc Med 1968;61:229 – 34. [24] Segal NL. Zygosity testing: laboratory and the investigator’s judgment. Acta Genet Med Gemellol 1984;33:515 – 21. [25] St. Clair DM, St. Clair JB, Swainson CP, et al. Twin zygosity testing for medical purposes. Am J Med Genet 1998;77:412 – 4. [26] Van Dyke DL, Palmer CG, Nance WE, et al. Chromosome polymorphism and twin zygosity. Am J Hum Genet 1977;29:431 – 47. [27] McCracken AA, Daly PA, Zolnick MR, et al. Twins and Q-banded chromosome polymorphisms. Hum Genet 1978;45:253 – 8. [28] Morton CC, Corey LA, Nance WE, et al. Quinacrine mustard and nucleolar organizer region heteromorphisms in twins. Acta Genet Med Gamellol 1981;30:39 – 49. [29] Derom C, Bakker E, Vlietinck R, et al. Zygosity determination in newborn twins using DNA variants. J Med Genet 1985;22:279 – 82. [30] Hill AVS. Use of minisatellite DNA probes for determination of twin zygosity at birth. Lancet 1985;276:1394 – 5. [31] Becker A, Busjahn A, Faulhaber HD, et al. Twin zygosity: automated determination with microsatellites. J Reprod Med 1997;42:260 – 6. ¨ ber einige Unterschiede Zwischen eineiigen und zweieiigen Zwillingen. Ztschr [32] Rumpe. U Geburts u Gyn7k 1891;22:344. [33] Greulich WW. Heredity in human twinning. Am J Phys Anthropol 1934;19:391 – 431. [34] Komai T, Fukuoka G. Frequency of multiple births among the Japanese and related peoples. Am J Phys Anthropol 1936;21:433 – 47. [35] Kaufman MH, O’Shea KS. Induction of monozygotic twinning in the mouse. Nature 1978;276: 707 – 8. [36] Schinzel AAGL, Smith DW, Miller JR. Monozygotic twinning and structural defects. J Pediatr 1979;95:921 – 30. [37] Stockard CR. Developmental rate and structural expression: an experimental study of twins, ‘‘double monsters’’ and single deformities, and the interaction among embryonic organs during their origin and development. Am J Anat 1921;28:115 – 277. [38] Newman HW. The biology of twins (mammals). Chicago7 University of Chicago Press; 1971. [39] Hamlett GWD. The reproductive cycle in the armadillo. Z Wiss Zool 1932;141:143 – 57.
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[40] Derom C, Vlietinck R, Derom R, et al. Increased monozygotic twinning rate after ovulation induction. Lancet 1987;8544:1236 – 8. [41] Behr B, Fisch JD, Racowsky C, et al. Blastocyst-ET and monozygotic twinning. J Assist Reprod Genet 2000;17:349 – 51. [42] Milki AA, Jun SH, Hinckley MD, et al. Incidence of monozygotic twinning with blastocyst transfer compared to cleavage-stage transfer. Fertil Steril 2003;79:503 – 6. [43] Sills ES, Moomjy M, Zaninovic N, et al. Human zona pellucida micromanipulation and monozygotic twinning frequency after IVF. Hum Reprod 2000;15:890 – 5. [44] Sills ES, Tucker MJ, Palermo GD. Assisted reproductive technologies and monozygous twins: implications for future study and clinical practice. Twin Reach 2000;3:217 – 23. [45] Bamforth F, Brown L, Senz J, et al. Mechanisms of monozygotic twinning; a possible role for the cell adhesion molecule, E-cadherin. Am J Med Genet 2003;120A:59 – 62. [46] James WH. Dizygotic twinning, marital stage and status and coital rates. Ann Hum Biol 1981; 8:371 – 8. [47] Smith PE. Ablation and transplantation of the hypophysis in the rat. Anat Rec 1926;32:221. [48] Hammond J. The physiology of reproduction in the cow. London7 Cambridge University Press; 1927. [49] Collins MS, Bleyl JA. Seventy-one quadruplet pregnancies: management and outcome. Am J Obstet Gynecol 1990;162:1384 – 91. [50] Duncan JM. In: Fecundity, fertility, sterility, and allied topics. Edinburgh (UK)7 A and C Black; 1866. [51] Albert A, Randall RV, Smith RA. Urinary excretion of gonadotropin as a function of age. In: Engle ET, Pincus G, editors. Hormones and the aging process. New York7 Academic Press; 1956. p. 49 – 62. [52] Soma H, Takayama M, Kiyokawa T, et al. Serum gonadotropin levels in Japanese women. Obstet Gynecol 1975;46:311 – 2. [53] Busjahn A, Knoblauch H, Faulhaber HD, et al. A region on chromosome 3 is linked to dizygotic twinning. Nat Genet 2000;26:398 – 9.
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Assisted Reproductive Technologies and Multiple Gestations Ellen E. Wilson, MD Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390,USA
The ideal outcome of a pregnancy, whether conceived naturally or through an infertility treatment, is a single healthy child. Infertility patients undergoing treatment with ovulation induction are at risk for multiple gestations owing to the inherent multifollicular response to fertility medications. Infertility patients undergoing treatment with assisted reproductive technology (ART) are also at increased risk for multiple gestations, primarily owing to the placement of multiple embryos into the uterus. During the past 25 years as ART procedures have increasingly been used, a rise in the multiple birth rate has occurred, producing many premature deliveries and perinatal complications. This increase in multiple pregnancies has undoubtedly taken a toll on medical, economic, and emotional reserves. Particularly in the realm of in vitro fertilization (IVF), guidelines are being formulated to help control the rate of high-order multiple gestations, and progress is now being seen in this area of ART.
History of assisted reproductive technology Rock published the first human IVF attempt in the journal Science in 1944 [1]. Subsequently, the first actual IVF pregnancy resulted in an ectopic presentation in 1976. The birth of Louise Brown in England in 1978 marked the first successful IVF attempt. The first successful IVF birth in the United States occurred in 1981 with the delivery of Elizabeth Carr [2].
E-mail address:
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Definition of assisted reproductive technology ART represents a group of therapies using the manipulation of sperm and eggs in a laboratory to facilitate a pregnancy [3]. This technology does not include procedures that stimulate ovaries to produce eggs (ie, ovulation induction alone with clomiphene citrate or gonadotropins), without the intention of having them retrieved, or procedures in which only sperm is handled (ie, intrauterine insemination). Types of ART procedures include IVF, gamete intrafallopian transfer (GIFT), and zygote intrafallopian transfer (ZIFT). Because GIFT and ZIFT are rarely performed, the term ART is often used interchangeably with IVF. Simplistically, IVF and embryo transfer entail the following: The ovaries are stimulated with fertility drugs to produce multiple mature oocytes. An egg retrieval procedure is performed. Eggs and sperm are fertilized in the laboratory. Several days of embryo culture result in cleavage. One or more embryos are placed into the uterus via a catheter through the cervix. This placement may be into the woman’s body or another person serving as a surrogate. The woman may use her own eggs or that of a donor. The embryos may be ‘‘fresh’’ (ie, newly fertilized) or ‘‘frozen’’ (used after they are thawed). Similarly, the sperm may be from the husband or partner or from a donor.
Current statistics Currently, approximately 1% of all births in the United States occur from ART [4]. A review of ART trends from 1996 to 2001 [3] reveals that the number of ART cycles performed in the United States increased from 64,724 cycles in 1996 to 107,587 cycles in 2001, and the average percentage of live births per transfer increased from 28% in 1996 to 33.4% in 2001 for fresh nondonor procedures. In 1995, 1.2 million women (2% of reproductive age) sought information on or treatment for infertility in the previous year [5]. Stephen and Chandra [6] predict that 5.4 to 7.7 million women will experience infertility by the year 2025, and that many or most of these women will undergo treatment with ART. Over the last 25 years, an increase has occurred in the incidence of twin and high-order multiple gestations (ie, triplets or more). This marked rise is due not only to the older age at childbearing but also to the use of fertility drugs to superovulate the ovaries (ie, clomiphene citrate and gonadotropins), as well as the transfer of multiple embryos during ART procedures [7,8]. When compared with natural ovulation during which one egg is normally fertilized, IVF induces
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Fig. 1. Multiple infant live births from ART cycles using fresh nondonor eggs or embryos in 2001 in the United States. (Adapted from CDC/SART Registry 2001. Assisted reproductive technology success rates: national summary of fertility clinic reports. Atlanta: US Department of Health and Human Services, Centers for Disease Control and Prevention; 2003. p. 20.)
a 20-fold increased chance of twins and a 400-fold increased chance of triplets or quadruplets [9]. In 1997, 12% of all twins were born as a result of ART, 38% of high-order gestations were due to ovulation induction, and 43% of high-order gestations were due to ART [10,11]. In 2001, of all live births that resulted from ART, 35.8% were multiple gestations and 3.8% involved triplets or more (Fig. 1).
Multiple pregnancy complications The increased morbidity and mortality among infants born from multifetal pregnancies is well recognized [12]. Congenital anomalies, cerebral palsy, intracranial hemorrhage, and blindness are some of the more common complications of twin gestations. In addition, some studies have shown that infants conceived using ART are more likely to have respiratory distress, patent ductus arteriosus, and sepsis when compared with infants not conceived with ART [12]. The increased maternal morbidity with multiple births includes hypertension, gestational diabetes, anemia, antepartum and postpartum bleeding, premature labor with required bed rest, abnormal placentation, polyhydramnios, and cesarean section [13,14].
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Follow-up studies of children conceived through IVF have suggested an increase in singletons with low birth weight, major birth defects, and neurologic problems, especially cerebral palsy [15–17]. Of note is the observation that these problems may be exacerbated as the risk of multiple gestations is increased. A critique of these studies has pointed out a lack of proper controls, bias inherent in retrospective analyses, and the fact that underlying infertility issues may have had a role in the outcomes aside from the IVF procedure [18]. Parenting stress sustained by the mothers of multiples was studied by Glazebrook et al [19]. The percentage of mothers experiencing scores representing ‘‘severe parenting stress’’ was 22% for mothers of multiples compared with 5% for mothers of IVF singletons. Glazebrook and colleagues encouraged clinicians involved in IVF to counsel patients not only on the risk for multiple gestations but also on the psychosocial burden of a multiple birth.
Multiple embryo transfer The purpose of ART has been to achieve pregnancy within ethical and reasonable guidelines with reasonable efficacy. What determines the actual success of an IVF cycle is the inherent implantation rate (ie, the chance of a single embryo implanting and leading to a pregnancy). In the past, when implantation rates ranged from 10% to 30%, it was common practice to transfer many embryos to a patient to compensate for this low rate to achieve a modestly acceptable pregnancy rate [20]. It was not unusual for a clinic to place four to six (or even more) embryos in a patient on the second or third day of cleavage stage development. For many years, the rising multiple pregnancy rates were accepted, and they were considered an unpreventable complication of a successful IVF clinic [21]. In the United States, there has never been a formal or regulated restriction on the number of embryos that a particular clinic may place in a person’s uterus. In 2001, the number of embryos transferred during ART cycles was greater than three in more than two-thirds of cycles (Fig. 2). In the United States, there is great pressure to achieve success in a minimal number of cycles for several reasons. First, a prevalent lack of insurance coverage for fertility services in the United States has encouraged clinics and patients to improve their chances at pregnancy per cycle by increasing the number of embryos transferred. This phenomenon was shown in an analysis of the 1998 Society for Assisted Reproductive Technology (SART) data [22]. IVF programs in states without insurance coverage transferred more embryos per cycle, had higher pregnancy rates, and reported higher rates of multiple gestation when compared with programs in states with IVF coverage. Second, a significant minority of infertility patients actually desire multiple gestation. Ryan et al [23] studied the proportion of infertile women who preferred a multiple birth to a singleton and found that 20.3% desired multiples. This finding was more pronounced in women who were younger than 25 years, who had a family income
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Fig. 2. Number of embryos transferred during ART cycles using fresh nondonor eggs or embryos in 2001 in the United States. (Adapted from CDC/SART Registry 2001. Assisted reproductive technology success rates: national summary of fertility clinic reports. Atlanta: US Department of Health and Human Services, Centers for Disease Control and Prevention; 2003. p. 34.)
lower than $25,000, and who generally had a lack of knowledge about the risks of multiple gestation. These investigators suggested that the increased rate of multiple births might be in part patient driven. Third, for 7 years, the Centers for Disease Control have published outcome data on infertility clinics submitted by SART. Detailed center-specific pregnancy rates are available to the public. Patients are more likely to seek out clinics with the highest pregnancy rates regardless of the multiple pregnancy rate [24]. In Europe, there has been a more stringent effort to reduce the number of high-order pregnancies. In England, the Human Fertilisation Association has sought to restrict the number of embryos transferred to a maximum of two [25]. Europe has lower rates of twin and triplets, thought to be due to the reduced number of embryos transferred at IVF. In the United States in 2001, approximately one third of IVF patients had more than three embryos transferred [3].
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In Europe, only 6.7% of patients had more than three embryos transferred [22]. In addition, insurance coverage for IVF is much greater in Europe because many countries have national health plans that cover these procedures. Patients incur lower costs and may undergo more ART procedures, lessening the drive to replace more embryos per cycle. The per capita use of ART in Europe is three times that of the United States and five to eight times higher in Scandinavia [26].
Strategies to reduce multiple gestations with assisted reproductive technology Establish guidelines for clinics As stated previously, the United States has not posed legislation to limit the number of embryos transferred in an IVF cycle. Because of the escalating rise in the number of multiple births associated with ART, in 1998 the American Society for Reproductive Medicine (ASRM) issued practice guidelines on the number of embryos to transfer [27]. After publication of the guidelines, the average number of embryos transferred decreased as shown in an analysis of IVF data collected from 1995 to 2001 [28]. In addition, between 1997 and 2001, the percentage of high-order multiples fell from 11.4% to 7.4%. Nevertheless, the percentage of total multiple births decreased only slightly from 38.4% in 1996 to 35.8% in 2001 for fresh nondonor cycles. In 2004, the ASRM updated the committee report guidelines as shown in Box 1 [29]. Emphasize age as an important factor Although implantation rates vary between patients and IVF clinics, they are highly dependent on the patient’s age. ART success rates drop as female age increases (Fig. 3). As oocytes age, embryo quality decreases along with implantation rates and pregnancy rates. Studies have demonstrated that women younger than 35 years achieve an excellent pregnancy rate with the transfer of two embryos, whereas women aged more than 35 years need more than two embryos transferred to achieve a similar success [30]. Conversely, emphasis is now being placed on transferring fewer embryos to younger patients, especially women less than 35 years of age. Improve implantation rates One method to improve implantation rates (thereby attaining a high IVF success rate with low numbers of embryos transferred) is to culture viable embryos to the blastocyst stage in the in vitro laboratory before transfer. Instead of transferring embryos on the second or third day after egg retrieval at the cleavage stage, a sequential media is used to culture embryos to 5 days after
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Box 1. Summary of Society for Assisted Reproductive Technology/ American Society for Reproductive Medicine guidelines for number of embryos to be transferred I. Programs should generate their own data on patient characteristics and embryos transferred. II. The following recommendations are based on data generated by all clinics providing ART services: a. For a female aged less than 35 years, transfer maximally two embryos. Consider transfer of one embryo if criteria exist for a favorable prognosis: i. This is the first IVF cycle. ii. There are good quality embryos by morphology. iii. There are enough good quality embryos left over to cryopreserve. iv. There was previous success with IVF. b. For a female aged between 35 and 37 years, transfer maximally three embryos. Transfer no more than two embryos if a favorable prognosis exists. c. For a female aged between 38 and 40 years, transfer no more that four embryos. Transfer no more than three embryos if a favorable prognosis exists. d. For a female aged greater than 40 years, transfer no more than five embryos. e. For poor prognosis patients, including those with two or more failed IVF cycles, additional embryos may be transferred after appropriate consultation. f. For donor egg cycles, the number of embryos transferred should be contingent on the age of the donor. III. When GIFT is performed, one more oocyte (than embryo for each category) may be transferred. Adapted from The Practice Committee of the Society for Assisted Reproductive Technology and the American Society for Reproductive Medicine. Guidelines on the number of embryos transferred. Fertil Steril 2004;82(Suppl 1):S1–2; with permission.
egg retrieval at the blastocyst stage. This practice has been proposed to enable identification of superior embryos, in essence, selecting those embryos that would have arrested at an earlier cleavage stage. The literature supports the use of blastocyst transfer to increase implantation rates, although not all investigators agree on this point [31].
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Fig. 3. Live birth rate for ART cycles using fresh nondonor eggs or embryos by age of woman in 2001 in the United States. (Adapted from CDC/SART Registry 2001 Assisted reproductive technology success rates: national summary of fertility clinic reports. Atlanta: US Department of Health and Human Services, Centers for Disease Control and Prevention; 2003. p. 22.)
Improve quality embryo selection Embryo quality is important to consider. If a patient is a poor responder and makes few eggs despite high doses of fertility medications, she is less likely to conceive than if she responds well and has a larger number of embryos available for selection [32]. Selecting the embryos to be transferred based on morphologic criteria has been shown to enhance implantation and pregnancy rates. Embryos that develop more quickly are more likely to implant [33,34]. Embryos with irregular or fragmented blastomeres are less likely to implant [35–37]. Strategies for embryo grading are being investigated to facilitate the selection of better quality embryos [38]. Nevertheless, many investigators believe that transferring embryos based solely on morphologic criteria is inefficient given that a large percentage have been found to be chromosomally abnormal. As a result, interest in preimplantation genetic diagnosis has been growing. Preimplantation genetic diagnosis Preimplantation genetic diagnosis, introduced in 1990 as an experimental procedure for patients with inherited genetic diseases, has now become a viable clinical option for many couples [39,40]. More than 1000 healthy children have been born after preimplantation genetic diagnosis worldwide. The procedure entails (1) biopsy of oocyte polar bodies or individual cells of embryos during an IVF cycle, (2) genetic analysis to identify aneuploidy, and
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(3) transfer of only aneuploid-free embryos. Some investigators predict that preimplantation genetic diagnosis may become a standard of care not just for couples at high risk for genetic disorders (ie, cystic fibrosis) but also for poor prognosis IVF patients (ie, maternal age greater than 37 years, prior IVF failures, and patients with recurrent miscarriage) [39]. As the technology advances, identification of abnormal embryos should increase IVF success rates and reduce the need for multiple embryo transfer. Barriers to greater use of this procedure include the high cost involved, the need for refinements in techniques to increase implantation rates, and the need for an increase in diagnostic precision [41,42]. Single embryo transfer The single optimal strategy to decrease the rate of multiple gestations associated with IVF is to limit the number of embryos transferred in a given cycle. Gardner et al [43] published the results of the first prospective randomized trial to determine the efficacy of single blastocyst transfer (Fig. 4). Using em-
Fig. 4. In vitro fertilization outcome after transfer of one or two blastocysts. Dark bars represent the transfer of a single blastocyst (group I). Open bars represent the transfer of two blastocysts (group II). Implantation and pregnancy rates were not statistically different between the two groups of patients. There were no twins in group I in contrast to 47.4% twins in group II. (From Gardner D. Single embryo transfer: a prospective randomized trial. Fertil Steril 2004;81:553; with permission.)
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bryo culture to the blastocyst stage, the transfer of a single embryo resulted in an ongoing pregnancy rate of 60.9% without any multiple gestations. Transfer of two embryos resulted in an ongoing pregnancy rate of 76% with a 47.4% incidence of twins. Interestingly, in this study, despite offering a single embryo transfer to all candidates in this particular program, only a small percentage agreed to volunteer. It was suggested that the patients perceived that a single embryo transfer would result in a lower pregnancy rate, and that many patients actually desired a multiple pregnancy.
Monozygotic pregnancy rate with assisted reproductive technology Most of the multiple births related to fertility treatments are dizygotic; however, there is an increased incidence of monozygotic twinning in ART-related pregnancies. The incidence of monozygotic twins following single embryo transfer in one study in Germany was 4.9%; apparent zygote splitting occurred in 4 of 82 pregnancies. This incidence is 12 times higher than the 0.4% rate of monozygotic twins in natural conceptions [44]. Derom et al [45] reported an increased incidence of monozygotic twinning in patients who were superovulated independent of IVF. Blastocyst transfer seems to increase the risk of monozygotic twinning over that seen with cleavage stage embryo transfer [46,47]. Various theories have been proposed to explain this phenomenon, including (1) the effects of ovarian stimulation on the zona pellucida; (2) exposure of the zona pellucida to biochemical or mechanical trauma (such as intracytoplasmic sperm injection and assisted hatching), which leads to herniation of the blastocyst and splitting of the zygote; and (3) altered polar gradient formation within the oocyte and early embryo [48]. Until the etiology of the increased risk of monozygotic twinning after fertility treatment is better understood, strategies to reduce the risk will be lacking.
Multiple gestation and ovulation induction The increased use of medications for ovulation induction (without ART) has led to an increase in multiple gestations in the last several decades. In fact, this use has resulted in a greater percentage of high-order multiple gestations than ART. One review cited that 7% to 18% of triplet pregnancies arise spontaneously, whereas 10% to 69% are accounted for by ovulation induction compared with 24% to 30% associated with ART [49]. This disparity in risk has become more apparent as fewer embryos are placed during an ART procedure (resulting in fewer multiple births), whereas patients undergoing ovulation induction are allowed to proceed with their cycles when multiple follicles are present. Several approaches may help to limit multiple pregnancies with ovulation induction. Lower doses of exogenous gonadotropins should be used, especially
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in patients who are known to be exquisitely sensitive to these medications (eg, women with oligo- or anovulation with polycystic ovarian syndrome or hypothalamic amenorrhea). In an ovulatory woman in a subfertile couple, one should withhold human chorionic gonadotropins (hCG) if the estradiol level is greater than 2000 pg/mL or more than four follicles greater that 17 mm in diameter are present. Ultrasound-guided aspiration of supernumerary follicles should be considered before the administration of hCG if the follicle response is excessive [50].
Intracytoplasmic sperm injection and male factors The use of intracytoplasmic sperm injection has dramatically improved treatment for male infertility. IVF clinics can often achieve adequate pregnancy rates in couples in which the man has moderate-to-severe oligospermia or even azoospermia (if sperm can be extracted from the epididymis or testis) by injecting sperm directly into an egg using a micromanipulation technique. Concerns regarding the safety of intracytoplasmic sperm injection have been raised owing to the fact that sperm selection is embryologist dependent and does not occur by natural selection. Men with compromised sperm parameters have an increase in chromosomal abnormalities. Approximately 3% to 15% of men with severe oligospermia and nonobstructive azoospermia have been found to have Y-chromosome microdeletions [51]. It is not yet clearly understood to what extent a father with a cystic fibrosis mutation, Y microdeletion, or Klinefelter’s syndrome will transmit such genotypes to his son through intracytoplasmic sperm injection. Especially when a genetic defect is discovered in a man with compromised sperm, careful genetic counseling should occur with the couple before treatment.
Birth defects after intracytoplasmic sperm injection/in vitro fertilization The largest study to date exploring the risk of major birth defects in infants conceived naturally, with IVF/intracytoplasmic sperm injection, or with IVF alone was performed in western Australia [52]. These researchers looked at 4000 randomly selected infants and found a major birth defect incidence of 4.2% in infants conceived naturally versus 8.6% in infants conceived through intracytoplasmic sperm injection and 9% conceived with IVF. The odds ratio for having a major birth defect was 2.0 for infants conceived by intracytoplasmic sperm injection or IVF when compared with controls. Various factors may have a role in the increased risk, including older parental age, the reason for intracytoplasmic sperm injection or IVF, and the effects of biologic manipulation of gametes with ART. Although most infants born as a result of ART do not have major birth defects, information on the risks should be presented to couples so that they can make an informed judgment about their treatment decision.
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Summary Since the birth of the first IVF baby in England in 1978, ART has matured significantly to become a standard practice for infertility clinics for many different reasons worldwide. Success rates have increased as the knowledge base has increased in terms of patient selection, culture media refinements, and procedural techniques and equipment. As the success rates of ART have climbed in the last 25 years, so have the multiple birth rates, primarily owing to the transfer of multiple embryos. Fertility clinics are now recognizing the need to address this risk and are placing emphasis on selecting methods to reduce the rate of multiple gestations. In the future, one can expect to see strategies such as single embryo transfer and preimplantation genetic diagnosis becoming standard practices for many, if not most, infertility patients.
References [1] Rock J, Menkin M. In vitro fertilization and cleavage of human ovarian eggs. Science 1944;100:105 – 7. [2] Jones Jr HW, Jones GS, Andrews MC, et al. The program for in vitro fertilization at Norfolk. Fertil Steril 1982;38:14 – 21. [3] CDC, American Society for Reproductive Medicine, Society for Assisted Reproductive Technology. 2001 Assisted reproductive technology success rates: national summary and fertility clinic reports. Atlanta7 US Department of Health and Human Services, Centers for Disease Control and Prevention; 2003. [4] Reynolds MA, Schieve LA, Martin JA, et al. Trends in multiple births conceived using assisted reproductive technology, United States, 1997–2000. Pediatrics 2003;111:1159 – 62. [5] Abma J, Chandra A, Mosher W, et al. Fertility, family planning, and women’s health: new data from the 1995 National Survey of Family Growth. Vital and Health Statistics, Series 23, No. 19. Hyattsville (MD)7 National Center for Health Statistics; 1997 [DHHS publication no. (PHS) 97–1995]. [6] Stephen EH, Chandra A. Updated projections of infertility in the United States: 1995–2025. Fertil Steril 2002;70:30 – 4. [7] Luke B. The changing pattern of multiple births in the United States: maternal and infant characteristics, 1973 and 1990. Obstet Gynecol 1994;84:101 – 6. [8] Rebar RW, DeCherney AH. Assisted reproductive technology in the United States. N Engl J Med 2004;350:1603. [9] Brinsden PR. Controlling the high order multiple birth rate: the European perspective. Reprod Biomed Online 2003;6:339. [10] Centers for Disease Control and Prevention. Contribution of assisted reproductive technology and ovulation inducing drugs to triplet and higher-order multiple births—United States, 1980–1997. MMWR Morb Mortal Wkly Rep 2000;49:535. [11] Wilcox LS, Kiely JL, Melvin CL, et al. Assisted reproductive technologies: estimates of their contribution to multiple births and newborn hospital days in the United States. Fertil Steril 1996;65:361. [12] Scholtz T, Bartholomaus S, Grimmer I, et al. Problems of multiple births after ARTT: medical, psychological, social and financial aspects. Hum Reprod 1999;14:2932 – 7. [13] Kinzler WL, Ananth CV, Vintzileos AM. Medical and economic effects of twin gestations. J Soc Gynecol Invest 2000;7:321 – 7.
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[14] Nowak E, Blickstein I, Papiernik E, et al. Iatrogenic multiple pregnancies: do they complicate perinatal care? J Reprod Med 2003;48:601 – 9. [15] Schieve LA, Meikle SF, Ferre C, et al. Low and very low birth weight in infants conceived with use of assisted reproductive technology. N Engl J Med 2002;346:731 – 7. [16] Hansen M, Kurinczuk JJ, Bower C, et al. The risk of major birth defects after intracytoplasmic sperm injection and in vitro fertilization. N Engl J Med 2002;346:725 – 30. [17] Stromberg B, Dahlquist G, Ericson A, et al. Neurological sequelae in children born after in vitro fertilization: a population-based study. Lancet 2002;359:461 – 5. [18] Kovalevsky G, Rinaudo P, Coutifaris C. Do assisted reproductive technologies cause adverse fetal outcomes? Fertil Steril 2003;79:1270 – 2. [19] Glazebrook C, Sheard C, Cox S, et al. Parenting stress in first-time mothers of twins and triplets conceived after in vitro fertilization. Fertil Steril 2004;81:505. [20] Gardner DK, Schoolcraft WB, Wagley L, et al. A prospective randomized trial of blastocyst culture and transfer in in vitro fertilization. Hum Reprod 1998;13:3434. [21] Gleicher N. Is it time to limit IVF transfers to one embryo? Contemp OB/GYN 2004;49(8):73–81. [22] Nygren KG, Andersen AN. ART in Europe, 2000. ESHRE Report No. 4. Grimbergen, Belgium7 ESHRE; 2003. [23] Ryan GL, Zhang SH, Dokras A, et al. The desire of infertile patients for multiple births. Fertil Steril 2004;81:500. [24] Alper MM. In vitro fertilization outcomes: why doesn’t anyone get it? Fertil Steril 2004; 81:514 – 6. [25] Human Fertilisation and Embryology Authority. Human Fertilisation and Embryology Association 10th Annual Report. London7 Human Fertilisation and Embryology Authority; 2001. [26] Jain T, Harlow BL, Hornstein MD. Insurance coverage and outcomes of in vitro fertilization. N Engl J Med 2002;347:661. [27] American Society for Reproductive Medicine. Guidelines on number of embryos transferred. Birmingham (AL)7 American Society for Reproductive Medicine; 1998. [28] Jain T, Missmer SA, Hornstein MD. Trends in embryo transfer practice and in outcomes of the use of assisted reproductive technology in the United States. N Engl J Med 2004; 350:1639. [29] The Practice Committee of the Society for Assisted Reproductive Technology and the American Society for Reproductive Medicine. Guidelines on the number of embryos transferred. Fertil Steril 2004;82(Suppl 1):S1–2. [30] Scheive LA, Peterson HB, Meikle SF, et al. Live-birth rates and multiple-birth risk using in vitro fertilization. JAMA 1999;282:1832. [31] Gardner DK, Schoolcraft WB, Wagley L, et al. A prospective randomized trial of blastocyst culture and transfer in in vitro fertilization. Hum Reprod 1998;13:3434 – 40. [32] Templeton A, Morris JK. Reducing the risk of multiple births by transfer of two embryos after in vitro fertilization. N Engl J Med 1998;339:573. [33] Erenus M, Zouves C, Rajamahendran P, et al. The effect of embryo quality on subsequent pregnancy rates after in vitro fertilization. Fertil Steril 1991;56:707. [34] Testart J. Cleavage stage of human embryos two days after fertilization in vitro and their developmental ability after transfer into the uterus. Hum Reprod 1986;1:29. [35] Staessen C, Janssenswillen C, Van den Abbeel E, et al. Avoidance of triplet pregnancies by elective transfer of two good quality embryos. Hum Reprod 1993;8:1650. [36] Ziebe S, Petersen K, Lindenberg S, et al. Embryo morphology or cleavage stage: how to select the best embryos for transfer after in vitro fertilization. Hum Reprod 1997;12:1545. [37] Giorgetti C, Terriou P, Auquier P, et al. Embryo score to predict implantation after in vitro fertilization: based on 957 single embryo transfers. Hum Reprod 1995;10:2427 – 31. [38] Sakkas D. Evaluation of embryo quality: a strategy for sequential analysis of embryo development with the aim of single embryo transfer. In: Gardner D, Weissman A, Howles C, et al, editors. Laboratory and clinical perspectives. London7 Martin Dunitz Press; 2001. p. 223. [39] Handyside AH, Kontogiani EH, Hardy K, et al. Pregnancies from biopsied human preimplantation embryos sexed by Y-specific DNA amplification. Nature 1990;344:768 – 70.
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[40] Verlinsky Y, Cohen J, Munne S, et al. Over a decade of experience with preimplantation genetic diagnosis: a multicenter report. Fertil Steril 2004;82:292 – 4. [41] Trounson A. Research must continue on preimplantation genetic diagnosis methodologies. Fertil Steril 2004;82:299. [42] Hill D. Ten years of preimplantation genetic diagnosis–aneuploidy screening: review of a multicenter report. Fertil Steril 2004;82:300 – 1. [43] Gardner D. Single embryo transfer: a prospective randomized trial. Fertil Steril 2004;81:551 – 5. [44] Blickstein I, Verhoeven HC, Keith LG. Zygotic splitting after assisted reproduction. N Engl J Med 1999;340:738 – 9. [45] Derom C, Vlietinck R, Derom R, et al. Increased monozygotic twinning rate after ovulation induction. Lancet 1987;1:1236 – 8. [46] Milki AA, Jun SH, Hinckley MD, et al. Incidence of monozygotic twinning with blastocyst transfer compared to cleavage-stage transfer. Fertil Steril 2003;79:503 – 6. [47] Behr B, Fisch JD, Racowsky C, et al. Blastocyst-ET and monozygotic twinning. J Assist Reprod Genet 2000;17:349. [48] Frankfurter D, Trimarchi J, Hackett R, et al. Monozygotic pregnancies from transfers of zonafree blastocysts. Fertil Steril 2004;82:483 – 5. [49] Norwitz ER. Multiple pregnancy: trends past, present, and future. Infertil Reprod Med Clin North Am 1998;9:351 – 69. [50] Practice Committee, American Society of Reproductive Medicine. Multiple pregnancy associated with infertility therapy. Fertil Steril 2004;82(Suppl):S153–7. [51] Girardi SK, Mielnik A, Schlegel PN. Submicroscopic deletions in the Y chromosome of infertile men. Hum Reprod 1997;12:1635 – 41. [52] Hansen M, Kurinczuk JJ, Bower C, et al. The risk of major birth defects after intracytoplasmic sperm injection and in vitro fertilization. N Engl J Med 2002;346:725 – 30.
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Ultrasound in Multiple Gestations: Twins and Other Multifetal Pregnancies Ana Monteagudo, MD*, Ashley S. Roman, MD, MPH Department of Obstetrics and Gynecology, NYU School of Medicine, 530 First Avenue, NB9N26-B, New York, NY 10016, USA
Routine ultrasound is an essential component of prenatal care for twin gestations and higher-order multiples. Twin pregnancies and multiples in general are at higher risk for adverse pregnancy outcomes than are singleton pregnancies [1]. Ultrasound has an important role not only in assessing amnionicity and chorionicity but also in diagnosing abnormalities and providing fetal surveillance throughout the duration of gestation. Without knowing the amnionicity and chorionicity of multifetal pregnancies, it is virtually impossible to manage them adequately. Counseling the patient (couple) regarding fetal and maternal risks is based on an accurate determination of the chorionicity and amnionicity. This determination, as well as dating the pregnancy, is most accurate during the first 12 to 14 weeks of gestation and if transvaginal sonography (TVS) is used.
Determination of amnionicity and chorionicity Monochorionic pregnancies are associated with higher perinatal morbidity and mortality than are dichorionic twin pregnancies. Perinatal mortality in monoamniotic twins has reported to be as high as 30% to 70%, but with early diagnosis and fetal surveillance, one study demonstrated a reduction in this rate to 8% [2]. Although ultrasound cannot predict zygosity with assurance, it is effective in predicting chorionicity and determining placentation.
* Corresponding author. E-mail address:
[email protected] (A. Monteagudo). 0095-5108/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.clp.2005.02.006 perinatology.theclinics.com
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Fig. 1. Using TVS, a dichorionic twin pregnancy at 5 weeks 5 days is examined. The scan reveals the two round sonolucent sacs surrounded by the brightly echogenic chorions.
The first 14 weeks (first trimester) The ideal time to determine chorionicity is during the first trimester. When examining a pregnancy in the first trimester, TVS provides better resolution and detail than transabdominal sonography (TAS), particularly in the obese patient. Attention should be given to several factors [1], including the chorionicity and [2] the number of embryos. Chorionicity of the twin or higher multiple pregnancy can be determined as early as 4 to 5 postmenstrual weeks when the chorionic sacs, which measure between 2 to 4 mm, can be counted. The chorionic sacs are round sonolucent structures with a brightly echogenic rim (chorion) that are implanted to one side of the cavity line within the thick decidua [3–6]. By simply counting the number of chorionic sacs, one can determine whether the pregnancy will be dichorionic, trichorionic, and so on; therefore, it is possible to determine precisely the chorionicity of a multifetal pregnancy by the fifth postmenstrual week of the gestation (Fig. 1).
Fig. 2. This scan reveals two chorionic sacs. In one sac, an embryo is seen with a crown rump length of 0.87 cm, consistent with 6 weeks 6 days; in the other sac, the yolk sac is imaged.
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Fig. 3. In this scan, a single chorionic sac is seen; however, within the sac, two embryos and the yolk sacs are seen. The gestational age of this pregnancy is 6 weeks 4 days.
Fig. 4. Scan shows a monochorionic diamniotic twin pregnancy at 7 weeks 4 days. (A) The two embryos are seen, each within its own amniotic cavity. A yolk sac is seen within the extra-embryonic space. (B) The same pregnancy scanned using three-dimensional (3D) sonography. The thin amniotic membrane is not appreciated using this type of sonography.
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By the time the sixth postmenstrual week arrives, the chorionic sacs are large enough that the yolk sacs and embryos can be seen within them (Figs. 2,3). At this time, the yolk sacs are very close (almost attached) to the fetal pole. The embryonic heartbeats start on day 21 after conception but become sonographically evident by the end of the fifth postmenstrual week or early sixth week. Initially, the frequency of the heartbeats is about 80 to 90 beats per minute. As the pregnancy progresses, the heart rate reaches around 150 to 160 beats per minute at around the ninth postmenstrual week. It is wise to wait until the embryonic heartbeats are visible to determine the number of fetuses in the pregnancy. The presence of cardiac activity is key to determining the number of viable fetuses. Determination of amnionicity poses several additional challenges. When multiple chorionic sacs are visualized each with a single yolk sac, a diagnosis of dichorionic diamniotic pregnancy can be made reliably by the seventh week of gestation. If a single chorionic sac is visualized and two yolk sacs are seen within this chorionic sac, determination of amnionicity is difficult to make until
Fig. 5. (A) Monochorionic diamniotic twin pregnancy at 8 weeks 4 days. At this gestational age, there is a sufficient amount of amniotic fluid to determine clearly the amnionicity of the pregnancy. (B) Three-dimensional scan of trichorionic triamniotic triplet pregnancy at 8 weeks.
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the eighth week of pregnancy. Before the eighth postmenstrual week, the amnion rests too close to the fetus to make a reliable diagnosis. With increasing amniotic fluid at about the eighth week, the amnion separates from the fetal body and becomes easier to image. A study by Bromley and Benacerraf [7] demonstrated that, before the eighth week, the amniotic membrane could only be identified in 50% of patients (Figs. 4–6). Nevertheless, the number of yolk sacs visualized at approximately 6 weeks’ gestation correlates highly with the number of amnions. In monoamniotic twins, the number of yolk sacs seen is variable. A single yolk sac, a partially divided yolk sac, or two yolk sacs may be present depending on the timing of cell division. By approximately 10 weeks’ gestation, chorionicity can be determined by visualizing the junction between the two amniotic sacs and the chorion or uterus. In pregnancies with a single fused placenta, the junction between the two placentas will appear to be thick and wedge-shaped (‘‘lambda sign’’ or ‘‘twin peak sign’’), confirming dichorionicity (Fig. 7). If this junction appears thin and
Fig. 6. (A) Monochorionic monoamniotic twin pregnancy at 9 weeks. Note the single amniotic sac surrounding both fetuses. (B) This 3D scan of a trichorionic triamniotic triplet pregnancy at 9 weeks clearly depicts the three chorionic sacs, each containing a fetus.
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Fig. 7. (A) Dichorionic diamniotic twin pregnancy with a single fused placenta. The junction between the two placentas depicts the delta or twin peak sign. (B) In this dichorionic diamniotic twin pregnancy, the placentas are not fused; therefore, there is no twin peak sign seen. (C) Threedimensional scan of the same pregnancy in B.
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Fig. 8. At 11 weeks, this monochorionic diamniotic twin pregnancy demonstrates the T-shaped junction between the chorionic sac and the two amniotic sacs.
T-shaped and meets the uterine wall at a 90-degree angle, the pregnancy is monochorionic (Fig. 8). This criteria can also be used in higher-order multiples with mixed chorionicity (Figs. 9,10). Multiple studies have confirmed the accuracy of these sonographic techniques in predicting chorionicity. As confirmed by pathologic findings, first-trimester sonography has 100% accuracy in determining chorionic and amniotic type [6,8].
Beyond the 15th week (second and third trimesters) Determination of chorionicity and amnionicity in the patient who is diagnosed with a twin gestation during the second trimester is more problematic. Although first-trimester sonography has up to 100% accuracy in determining chorionicity, second-trimester sonography is less accurate, approximately 90% [9]. The following findings can assist in making an accurate diagnosis [10]: Fetal gender: Determination of fetal gender is an important component of assessing chorionicity. Twins of different genders in the vast majority of cases indicates dichorionicity; however, in approximately 50% of dichorionic diamniotic (Di-Di) twin pregnancies, like-sex twins will be present. When like-sex twins are imaged, further evaluation is needed, namely, scrutinizing the placentas to make the diagnosis of chorionicity. Number of placental masses: The location of each placental mass should be noted. Separate placental sites are also an indicator of dichorionicity (Fig. 11); however, this finding has limitations, because only approximately one third of all twin gestations will have placentas that are widely separated from each other. The sensitivity of two placental sites is 32% with a predictive value of 100% [11]. In cases of concordant sex and a single placental mass, further evaluation is necessary [12].
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Intertwin membrane: a. Thickness: When chorionicity is inconclusive by evaluating fetal gender and placental mass, the intertwin membrane thickness can be measured. In the setting of monochorionic diamniotic twins, the dividing membrane consists of two layers of amnion. Usually, this membrane is very thin and hairlike. In the setting of Di-Di twins, the dividing membrane consists of four layers—two layers of amnion and two layers of chorion (Figs. 12,13). A dichorionic dividing membrane will be thicker when measured by ultrasound. Winn and colleagues [9] reported that membrane thickness of less than 2 mm in the second and third trimester predicted monochorionicity accurately 90% of the time. After magnification of the image, measurements should be taken close to the placenta (b3 cm). Although overall accuracy is high, intraobserver and interobserver reproducibility of measurements has been shown to be poor [13]. b. Counting the layers of the intertwin membrane: Counting the latter two layers can be achieved by ‘‘zooming in’’ the picture for better imaging. A thick membrane is composed of four layers (amnion-chorion-chorionamnion), a reliable sign of Di-Di twin pregnancy (Fig. 14). In contrast, a thin membrane measuring less than 2 mm is composed of two layers (amnion-amnion), also a reliable sign of monochorionic diamniotic twin pregnancies. The predictive value of looking at the membrane layers has been reported to be 98.5% with an accuracy of 100% for dichorionic placentation [14]. c. Looking at the membrane origin or ‘‘take-off’’: Of the three markers, the most useful and reliable (when seen) is the membrane take-off. If triangular shaped, the marker is named the twin peak or lambda sign (both terms are used interchangeable in the literature) (Fig. 14B). When seen, it is a consistent marker of dichorionicity. The accuracy of this sign in determining chorionicity has been reported to be 100% [15]. When the take-off has a T shape or the membrane approaches the placenta at or close to 90 degrees, this becomes a dependable sign of monochorionicity. At times, if the single placenta is posterior and the pregnancy is advanced, the view of the take-off of the membranes may be obscured by the fetus. Given the current limitations of second- and third-trimester ultrasound in predicting chorionicity and amnionicity, the optimal time for determining these characteristics is during the first trimester of pregnancy. All patients suspected of carrying a multiple gestation should be imaged sonographically during the first trimester.
Fetal anatomic survey Twin gestations are inherently at higher risk of anomalies and chromosomal aneuploidy. This risk of congenital anomaly is approximately twice as high as
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Fig. 9. (A) A quadruplet pregnancy at 9 weeks 2 days. Each chorionic sac contains a single fetus; therefore, this is quadchorionic quadamniotic pregnancy. (B) A quintuplet pregnancy at 7 weeks 3 days. (C) A quintuplet pregnancy at 7 weeks 4 days imaged using three-dimensional ultrasound.
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Fig. 10. (A) A TAS scan of a dichorionic triplet pregnancy at 11 weeks 1day. The intertwin membrane in the monochorionic twins is thinner when compared with the membrane between the two chorionic sacs. (B) The same triplet pregnancy scanned using TVS. The difference in caliber between the intertwin membrane between A and B when compared with triplet C is obvious.
in singleton pregnancies. In one study, the rate of malformations was 2.12% for twins compared with 1.05% for singletons [16]. Kato and Fujiki [1] reported that twins had a 2.17% congenital malformation rate compared with 1.47% in singletons. In monochorionic twins, the perinatal mortality and morbidity is threefold to tenfold higher than in dichorionic twins owing to their common vascular architecture, high rate of discordant fetal growth and growth restriction, and congenital abnormalities [17]. Furthermore, monozygotic twins appear to be at higher risk for structural malformation than are dizygotic twins, with a 50%
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Fig. 11. At 21 weeks, the posterior placenta of twin A is evident when compared with the anterior placenta of twin B.
greater anomaly rate [18,19]. In monozygotic pregnancies, there is a 15% concordance rate for the detected anomaly, that is, when an anomaly is detected in one monozygotic fetus, the other fetus will also have the anomaly 15% of the time [20,21]. In addition to the higher rate of structural abnormalities in twin gestations when compared with singletons, twin pregnancies are at risk for defects unique to multifetal gestations, especially in monochorionic pregnancies. Cord entanglement Cord entanglement can occur with monoamniotic twins. The reported incidence is relatively high, with rates ranging from 22.6% to 57% [22,23]. Cord entanglement usually is present from the first trimester; the diagnosis is made when a mass of cord is seen between the two fetal bodies [24]. Adding color
Fig. 12. Arrow points to the thin two-layer intertwin membrane of a monochorionic diamniotic twin pregnancy.
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Fig. 13. When compared with Fig. 12, the intertwin membrane in this dichorionic diamniotic twin pregnancy appears thick and measures 2.8 mm.
Fig. 14. (A) By zooming in, the four-layer intertwin membrane can be seen in this dichorionic diamniotic twin pregnancy. (B) This scan demonstrates a fused single anterior placenta with the twin peak sign, as well as a thick intertwin membrane.
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Fig. 15. In this monochorionic monoamniotic twin pregnancy at 12 weeks 2 days, the cords are already entangled.
and performing a Doppler study on the umbilical cord mass can assist in the diagnosis. In cases of cord entanglement, the Doppler waveform obtained from the cord mass will show differing fetal heart rate patterns in the same direction (Figs. 15,16) [25]. Conjoined twins Conjoined twins occur at a rate of 1 in 50,000 pregnancies in the general population [26]. Conjoined twins result from a postimplantation division of the zygote between day 13 and 16 after conception [27]. The most common types of conjoined twins are thoracoomphalopagus (28%), thoracopagus (18%), omphalopagus (10%), incomplete duplication (10%), and craniopagus (6%) [28]. The diagnosis can be made by 8 weeks’ gestation. There is a single amniotic sac with what appears to be a bifid fetal pole that moves as one; the fetuses remain in the same position relative to each other despite changes in position. During the second trimester, sonography can delineate the area where the fetuses are joined and can determine which organs are shared (Fig. 17). Twin reversed arterial perfusion The twin reversed arterial perfusion (TRAP) sequence or acardiac twins occurs in 1 in 35,000 pregnancies and can be a more difficult diagnosis to make. This abnormality occurs in 1% of monozygotic twins. The normal fetus maintains perfusion in the acardiac fetus through arterial-to-arterial and venous-to-venous anastomoses such that the circulation of the acardiac fetus is reversed. The acardiac fetus may have no heart or may have an abnormal heart with two chambers. The TRAP sequence is associated with a 35% mortality rate owing
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to cardiac failure and high rates of long-term neurologic impairment for the ‘‘normal’’ twin, if it survives. On ultrasound, the acardiac fetus may resemble a teratoma, that is, a tissue mass with heterogeneous echogenicity, or a fetus that has undergone intrauterine demise (Fig. 18); therefore, the TRAP sequence may be mistakenly diagnosed as an intrauterine fetal demise of one twin. Although there are several case reports in which the TRAP sequence has been diagnosed in the first trimester using Doppler study [29,30], it is more commonly diagnosed during the second trimester. In one recent series [31], an experience with six cases of TRAP sequence was reported. All cases had been mistakenly diagnosed as intrauterine fetal demise during the second trimester by outside clinics.
Fig. 16. (A) During the initial scan of this monochorionic monoamniotic twin pregnancy at 15 weeks 3 days, bunched-up umbilical cords were seen between the two fetuses, which never changed position even after repeated follow-up scans. (B) Using color, the entanglement of the cords became more obvious. (C) The widely open sample volume includes and records simultaneously the Doppler flow velocity waveforms of both cords of the twins in the area of the suspected cord entanglement. By carefully examining the simultaneous heart rates obtained from both umbilical cords, often a clear differential heart rate can be obtained, serving as proof of entanglement. (D) The three orthogonal planes and the reconstructed three-dimensional color Doppler study of the entangled cord of a 25 weeks 6 days monochorionic twin pregnancy reveals the degree of knotting in this cord.
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Fig. 16 (continued).
Ultrasound diagnosis of the TRAP sequence was ultimately made in these cases using color Doppler study of umbilical vessel flow. Given the higher rate of anomalies in twin pregnancies, screening for fetal structural anomalies with second-trimester ultrasound is recommended by the American College of Obstetrics and Gynecology and the American Institute of Ultrasound in Medicine. Although routine ultrasound surveillance in low-risk singleton pregnancies is debated owing to its low sensitivity and negative predictive value [32], ultrasound screening of twin pregnancies has been shown
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Fig. 17. (A) Conjoined (thoracopagus) twin pregnancy at 19 weeks. The fetuses are conjoined starting at the heart. (B) Cephalothoracopagus syncephalus at 22 weeks 5 days. The scan reveals two spines leading to a single neck. (C) The single head is large, and the brain architecture is abnormal. (D) The fused livers are seen. (E) The fused pelvises with two separate urinary bladders are seen.
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Fig. 17 (continued).
to have high accuracy in detecting congenital anomalies. Edwards and colleagues [19] reported 82% sensitivity, 100% specificity, a 100% positive predictive value, and a 98% negative predictive value in detecting major congenital anomalies. In this study, the anatomic surveys were performed between 16 and 20 weeks. The mean gestational age at the first survey was 17.1 weeks, but the mean gestational age at anomaly diagnosis was 22.3 weeks. Given the finding that most structural abnormalities in twins are found after 20 weeks’ gestation, it is the policy at the authors’ center to perform two anatomic surveys in twin pregnancies. One survey is performed at 14 to 15 weeks’ gestation when the majority of structures for both fetuses can be seen with a high-frequency transvaginal probe, and a second study is performed at 20 to 22 weeks [30] when structures such as the heart and brain can be visualized more completely.
Fetal surveillance Once twin pregnancy has been diagnosed, ultrasound has an important role in routine fetal surveillance for the remainder of pregnancy.
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Fig. 18. (A) Monochorionic diamniotic twins at 19 weeks. The acardiac twin appears relatively well formed; however, it has multiple abnormalities, including a cleft lip and palate, ascites, and hydrops. (B) Transverse section through the neck showing the cystic hygroma that presented in this acardiac twin.
Fetal growth assessment Twin pregnancies regardless of chorionicity are at higher risk for fetal growth abnormalities than are singleton pregnancies. Although some overlap occurs, two different types of growth abnormalities should be recognized: (1) fetal growth restriction (estimated fetal weight [EFW] b 10th percentile for gestational age) in one or both fetuses, and (2) discordant growth. As is true for singleton pregnancies, fetal growth restriction is associated with increased perinatal morbidity and mortality, such as respiratory complications, sepsis, and hyperbilirubinemia [33]. Growth discordance is defined as a 20% difference in birthweight between the fetuses. It is calculated by dividing the difference in EFW between the fetuses
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by the EFW of the larger twin. The mean intertwin birthweight difference is 10.3%, with 5% of twin pregnancies having a 25% or greater discordance. Discordant growth is associated with increased perinatal morbidity, such a respiratory complications and hyperbilirubinemia, even if the individual EFWs are greater than the 10th percentile [34]. Under normal situations, twin fetuses grow at the same rate as singleton fetuses until approximately 30 to 34 weeks’ gestation. According to birthweight data, twin fetuses grow more slowly than singleton fetuses after this gestational age [35]. Ultrasound studies have confirmed these findings [36]. Studies performing ultrasonography on twin gestations have shown that this difference in birthweight is primarily caused by smaller biparietal diameters and abdominal circumferences after 30 weeks in twins when compared with a singleton cohort. Fetal growth should be estimated by measuring the head circumference, biparietal diameter, abdominal circumference, and femur length at 3- to 4-week intervals. Jensen and colleagues [37] demonstrated that ultrasonographic calculation of fetal weight in twin pregnancies correlated well with actual weights of the fetuses. Ultrasound predicted weight below the 10th percentile with 85% sensitivity, an 80% positive predictive value, and 87% specificity. Furthermore, ultrasound predicted discordance with 64% sensitivity, 91% specificity, and a 64% positive predictive value. For 72% of all weights, the actual weight deviated less than 10% from the estimated weight.
Cervical length The mean gestational age at delivery for twin gestations is 35.8 weeks [38]. Seventy-five percent of twin preterm deliveries result from preterm labor or preterm premature rupture of membranes [39]. A shortened cervical length in the midtrimester is a strong predictor of preterm delivery in twin gestations. Between 14 and 25 weeks’ gestation, the median cervical length in twin pregnancies is between 3.7 and 4 cm [40–42]. There is strong evidence supporting an increased incidence of preterm delivery with a cervical length of 2.5 cm or less before 24 weeks in twin gestations. Souka et al [40] reported that a cervical length of 2.5 cm or less at 23 weeks’ gestation had a sensitivity of 100% in predicting delivery before 28 weeks. Goldenberg et al [43] demonstrated that a cervical length of 2.5 cm or less at 24 weeks had a positive predictive value of 53.9% in predicting delivery before 35 weeks and a positive predictive value of 26.9% for delivery before 32 weeks. Although a normal cervical length reassures the patient and physician that preterm birth is unlikely, the major limitation of following cervical length in twin pregnancies is that there is no known effective intervention to prevent preterm birth in patients with cervical shortening. Cervical cerclage has been proposed as one means to prevent preterm delivery, but it has not been shown to be effective in twin pregnancies [44].
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Problems unique to multiple gestations: special role for ultrasound Ultrasound also has an important role in the diagnosis and surveillance of several conditions unique to multiple gestations. Twin-twin transfusion syndrome Twin-twin transfusion syndrome (TTTS) occurs in 10% to 20% of monochorionic pregnancies. It is thought to be caused by unequal distribution of blood flow to the fetuses owing to vascular connections in the placenta. As a result, blood is shunted to one twin, leading to overperfusion of this recipient twin and underperfusion of the donor twin. The diagnosis of TTTS is made by ultrasound and is characterized by discordance in fetal size and amniotic fluid volumes in the two sacs. Although the diagnosis of TTTS has been reported as early as the first trimester [45], it is more commonly made during the second trimester (Fig. 19). Hallmarks of the diagnosis in the second trimester are a single placenta, concordant gender, greater than 20% growth discordance between the fetuses, and discordant amniotic fluid volume between the sacs (oligohydramnios or b 2 cm maximal vertical pocket in one sac, with polyhydramnios or N 8 cm maximal vertical pocket in the other) (Fig. 20) [26]. A discrepancy in the diameter of the umbilical cords, an abnormal umbilical artery on Doppler study (such as absent or reversed umbilical artery end-diastolic flow, absent or reversed ductus venosus flow, and umbilical vein pulsations), and fetal hydrops may also been seen with the disorder. When there is anhydramnios or no measurable amniotic fluid pocket around one fetus, the situation is called a ‘‘stuck’’ twin. A stuck twin can be difficult to differentiate from monoamniotic twins when no prior ultrasound examinations have been
Fig. 19. Monochorionic diamniotic twin pregnancy at 14 weeks 1 day. Twin A is seen freely moving within its amniotic cavity; however, twin B has severe oligohydramnios and is stuck to the uterine wall.
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performed on the patient. In the stuck twin scenario, the dividing membrane is ‘‘shrink-wrapped’’ against the fetus, making it difficult to visualize. Unlike in monoamniotic twins, the stuck twin does not move freely within the amniotic cavity; with changes in maternal position, it appears stuck in the same place. TTTS is not the only cause of a stuck twin, and a careful anatomic survey should be performed to evaluate for genitourinary abnormalities in these fetuses. Quintero et al [46] have proposed an ultrasound staging system for diagnosing and counseling these patients (Table 1). The association between the stage at diagnosis and the prognosis has been inconsistent in several studies [47]. A
Fig. 20. (A) TAS of a monochorionic diamniotic twin pregnancy. Twin B is seen attached to the anterior abdominal area under real-time sonography. The movements of this fetus were restricted. (B) A zoomed-up view shows that the amniotic membrane is present and is essentially tethering the fetus to the anterior abdominal wall. Severe oligohydramnios is present. (C) The discrepancy in the size of the twins is evident. (D) Twin A has a large bladder. Doppler studies were normal using the Quintero staging system [46]. This pregnancy was classified as a stage II twin-twin transfusion syndrome.
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Fig. 20 (continued).
change in stage, that is, progression to a more severe stage, has been correlated with an adverse outcome [48]. For this reason, this system remains a valuable tool in the surveillance of patients with TTTS and is an important factor in determining the timing of surgical intervention, such as laser ablation of communicating vessels in the placenta or endoscopic cord ligation. Table 1 Quintero staging system for twin-twin transfusion syndrome Stage
Polyhydramnios/ oligohydramnios
Absent bladder in donor
Critically abnormal Doppler studies
Hydrops
Death
I II III IV V
+ + + + +
+ + + +
+ + +
+ +
+
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Intrauterine demise of one twin The demise of one twin during the first trimester, the ‘‘vanishing twin,’’ is a relatively common event. It is estimated that only 71% of twin pregnancies diagnosed before 7 weeks’ gestation result in two liveborn neonates [49]. In general, the loss of one fetus in a twin pregnancy during the first trimester does not seem to be associated with an adverse outcome, although a case of neurologic sequelae in a surviving fetus has been reported [50]. Intrauterine demise of one fetus in a twin pregnancy is reported to occur during the second or third trimester in 2% to 5% of twin pregnancies [26]. The demise of one fetus in a monochorionic pregnancy is associated with serious morbidity and mortality [51] for the surviving fetus. It is postulated that at time of the demise of one twin the loss of vascular tone and hypotension in the dead fetus results in transient but severe hypotension in the surviving fetus that can lead to neurologic impairment, multi-organ dysfunction, and death [51–53]. The areas of the brain most susceptible to hypotensive or ischemic injury are the watershed areas just superolateral to the lateral ventricles. The characteristic finding on imaging these fetuses or neonates is cystic periventricular leukomalacia, which has been reported in as many as 40% to 50% of twin pregnancies where there has been one demise [54]. Uterine anomalies and multiple gestations Uterine malformations occur in 0.1% to 3% of all women [55,56]. They range from an arcuate uterus to a bicornuate uterus to a didelphic uterus. Pregnancy in the setting of uterine malformation carries high rates of pregnancy loss, preterm labor, and preterm premature rupture of membranes depending on the type of malformation. Patients with a bicornuate uterus and a singleton gestation have a miscarriage rate of up to 40%, a preterm delivery rate of up to 40%, and a live birth rate of 57%. These risks are theoretically heightened when carrying a multiple gestation. There are multiple reports in the medical literature of multiple gestations in the setting of uterine malformation. Some of the more unusual studies report twin pregnancies with one fetus in each horn of a bicornuate uterus. The authors have reported their experience with a patient carrying a quadruplet pregnancy with two fetuses in each horn of a septate uterus [57]. As is true when diagnosing a multiple gestation in general, the best time to identify a uterine malformation during pregnancy is during the first trimester.
Summary Ultrasound has a critical role in the management of twin pregnancies (and multiple pregnancies in general) in all three trimesters. In twin pregnancies, even if they present late for prenatal care, the assessment of chorionicity and
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amnionicity can and should be attempted. Usually, this attempt will be successful. The diagnosis of chorionicity and amnionicity is essential, because the degree of fetal surveillance during the pregnancy is determined by this finding. During the first trimester, the diagnosis of chorionicity and amnionicity by ultrasound can be made with an extremely high degree of accuracy. During the early second trimester, ultrasound is used to detect malformations and provide guidance for invasive procedures. In the late second and third trimesters, antenatal surveillance of the pregnancy, such as growth studies, Doppler studies, and cervical length assessment, is made possible.
References [1] Kato K, Fujiki K. Multiple births and congenital anomalies in Tokyo Metropolitan Hospitals, 1979–1990. Acta Genet Med Gemellol (Roma) 1992;41(4):253 – 9. [2] Rodis JF, McIlveen PF, Egan JF, et al. Monoamniotic twins: improved perinatal survival with accurate prenatal diagnosis and antenatal fetal surveillance. Am J Obstet Gynecol 1997;177(5): 1046 – 9. [3] Goldstein S, Snyder J, Watson C, et al. Very early pregnancy detection with endovaginal ultrasound. Obstet Gynecol 1988;72:200 – 4. [4] Goldstein S. Early pregnancy scanning with the endovaginal probe. Contemp Obstet Gynecol 1988;31:54. [5] Warren W, Timor-Tritsch I, Peisner D, et al. Dating the pregnancy by sequential appearance of embryonic structures. Am J Obstet Gynecol 1989;161:747 – 53. [6] Monteagudo A, Timor-Tritsch IE, Sharma S. Early and simple determination of chorionic and amniotic type in multifetal gestations in the first fourteen weeks by high-frequency transvaginal ultrasonography. Am J Obstet Gynecol 1994;170(3):824 – 9. [7] Bromley B, Benacerraf B. Using the number of yolk sacs to determine amnionicity in early first trimester monochorionic twins. J Ultrasound Med 1995;14(6):415 – 9. [8] Copperman AB, Kaltenbacher L, Walker B, et al. Early first-trimester ultrasound provides a window through which the chorionicity of twins can be diagnosed in an in vitro fertilization (IVF) population. J Assist Reprod Genet 1995;12(10):693 – 7. [9] Winn HN, Gabrielli S, Reece EA, et al. Ultrasonographic criteria for the prenatal diagnosis of placental chorionicity in twin gestations. Am J Obstet Gynecol 1989;161(6 Pt 1):1540 – 2. [10] Monteagudo A, Timor-Tritsch IE. Second- and third-trimester ultrasound evaluation of chorionicity and amnionicity in twin pregnancy: a simple algorithm. J Reprod Med 2000;45(6): 476 – 80. [11] Mahony BS, Filly RA, Callen PW. Amnionicity and chorionicity in twin pregnancies: prediction using ultrasound. Radiology 1985;155(1):205 – 9. [12] Timor-Tritsch IE, Fleischer A, Monteagudo A, et al. Monochorionic quadramniotic quadruplets: sonographic workup. Fetal Diagn Ther 1997;12(6):363 – 7. [13] Stagiannis KD, Sepulveda W, Southwell D, et al. Ultrasonographic measurement of the dividing membrane in twin pregnancy during the second and third trimesters: a reproducibility study. Am J Obstet Gynecol 1995;173(5):1546 – 50. [14] D’Alton ME, Dudley DK. The ultrasonographic prediction of chorionicity in twin gestation. Am J Obstet Gynecol 1989;160(3):557 – 61. [15] Finberg H. The ‘‘twin peak’’ sign: reliable evidence of dichorionic twining. J Ultrasound Med 1992;11:571 – 7. [16] Kohl SG, Casey G. Twin gestation. Mt Sinai J Med 1975;42(6):523 – 39. [17] Pasquini L, Wimalasundera RC, Fisk NM. Management of other complications specific to monochorionic twin pregnancies. Best Pract Res Clin Obstet Gynaecol 2004;18(4):577 – 99.
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[18] Coleman BG, Grumbach K, Arger PH, et al. Twin gestations: monitoring of complications and anomalies with US. Radiology 1987;165(2):449 – 53. [19] Edwards MS, Ellings JM, Newman RB, et al. Predictive value of antepartum ultrasound examination for anomalies in twin gestations. Ultrasound Obstet Gynecol 1995;6(1):43 – 9. [20] Timor-Tritsch IE, Monteagudo A, Horan C, et al. Dichorionic triplet pregnancy with the monoamniotic twin pair concordant for omphalocele and bladder exstrophy. Ultrasound Obstet Gynecol 2000;16(7):669 – 71. [21] Schinzel AA, Smith DW, Miller JR. Monozygotic twinning and structural defects. J Pediatr 1979;95:921 – 30. [22] Roque H, Gillen-Goldstein J, Funai E, et al. Perinatal outcomes in monoamniotic gestations. J Matern Fetal Neonatal Med 2003;13(6):414 – 21. [23] Sau AK, Langford K, Elliott C, et al. Monoamniotic twins: what should be the optimal antenatal management? Twin Res 2003;6(4):270 – 4. [24] Sebire NJ, Souka A, Skentou H, et al. First trimester diagnosis of monoamniotic twin pregnancies. Ultrasound Obstet Gynecol 2000;16(3):223 – 5. [25] Overton TG, Denbow ML, Duncan KR, et al. First-trimester cord entanglement in monoamniotic twins. Ultrasound Obstet Gynecol 1999;13(2):140 – 2. [26] D’Alton ME, Simpson LL. Syndromes in twins. Semin Perinatol 1995;19(5):375 – 86. [27] Benirschke K, Kim CK. Multiple pregnancy. 1. N Engl J Med 1973;288(24):1276 – 84. [28] Romero R, Pilu G, Jeanty P, et al. Conjoined twins. In: Prenatal diagnosis of congenital anomalies. Norwalk (CT)7 Appleton & Lange; 1988. p. 405 – 9. [29] Shalev E, Zalele Y, Ben Ami M, et al. First trimester ultrasonic diagnosis of twin reversed arterial perfusion sequence. Prenat Diagn 1992;2:21 – 2. [30] Lindhal S, Balwin V, Wakeford J. Early diagnosis of an acardiac acephalus twin by ultrasound. Med Ultrasound 1984;8:105 – 7. [31] Weisz B, Peltz R, Chayen B, et al. Tailored management of twin reversed arterial perfusion (TRAP) sequence. Ultrasound Obstet Gynecol 2004;23(5):451 – 5. [32] DeVore GR. The Routine Antenatal Diagnostic Imaging with Ultrasound Study: another perspective. Obstet Gynecol 1994;84(4):622 – 6. [33] Luke B, Minogue J, Witter FR. The role of fetal growth restriction and gestational age on length of hospital stay in twin infants. Obstet Gynecol 1993;81(6):949 – 53. [34] Amaru RC, Bush MC, Berkowitz RL, et al. Is discordant growth in twins an independent risk factor for adverse neonatal outcome? Obstet Gynecol 2004;103(1):71 – 6. [35] Ananth CV, Vintzileos AM, Shen-Schwarz S, et al. Standards of birth weight in twin gestations stratified by placental chorionicity. Obstet Gynecol 1998;91(6):917 – 24. [36] Senoo M, Okamura K, Murotsuki J, et al. Growth pattern of twins of different chorionicity evaluated by sonographic biometry. Obstet Gynecol 2000;95(5):656 – 61. [37] Jensen OH, Jenssen H. Prediction of fetal weights in twins. Acta Obstet Gynecol Scand 1995; 74(3):177 – 80. [38] Alexander GR, Kogan M, Martin J, et al. What are the fetal growth patterns of singletons, twins, and triplets in the United States? Clin Obstet Gynecol 1998;41(1):114 – 25. [39] Gardner MO, Goldenberg RL, Cliver SP, et al. The origin and outcome of preterm twin pregnancies. Obstet Gynecol 1995;85(4):553 – 7. [40] Souka AP, Heath V, Flint S, et al. Cervical length at 23 weeks in twins in predicting spontaneous preterm delivery. Obstet Gynecol 1999;94(3):450 – 4. [41] Guzman ER, Walters C, O’Reilly-Green C, et al. Use of cervical ultrasonography in prediction of spontaneous preterm birth in triplet gestations. Am J Obstet Gynecol 2000;183(5):1108 – 13. [42] Yang JH, Kuhlman K, Daly S, et al. Prediction of preterm birth by second trimester cervical sonography in twin pregnancies. Ultrasound Obstet Gynecol 2000;15(4):288 – 91. [43] Goldenberg RL, Iams JD, Miodovnik M, et al. The preterm prediction study: risk factors in twin gestations. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Am J Obstet Gynecol 1996;175(4 Pt 1):1047 – 53. [44] Newman RB, Krombach RS, Myers MC, et al. Effect of cerclage on obstetrical outcome in twin gestations with a shortened cervical length. Am J Obstet Gynecol 2002;186(4):634 – 40.
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[45] Berg C, Baschat AA, Geipel A, et al. First trimester twin-to-twin transfusion syndrome in a trichorionic quadruplet pregnancy—a diagnostic challenge. Fetal Diagn Ther 2002;17(6):357 – 61. [46] Quintero RA, Morales WJ, Allen MH, et al. Staging of twin-twin transfusion syndrome. J Perinatol 1999;19(8 Pt 1):550 – 5. [47] Quintero RA, Dickinson JE, Morales WJ, et al. Stage-based treatment of twin-twin transfusion syndrome. Am J Obstet Gynecol 2003;188(5):1333 – 40. [48] Taylor MJ, Govender L, Jolly M, et al. Validation of the Quintero staging system for twin-twin transfusion syndrome. Obstet Gynecol 2002;100(6):1257 – 65. [49] Sampson A, de Crespigny L. Vanishing twins: the frequency of spontaneous fetal reduction of a twin pregnancy. Ultrasound Obstet Gynecol 1992;2:107 – 9. [50] Weiss JL, Cleary-Goldman J, Tanji K, et al. Multicystic encephalomalacia after first-trimester intrauterine fetal death in monochorionic twins. Am J Obstet Gynecol 2004;190(2):563 – 5. [51] Fusi L, Gordon H. Twin pregnancy complicated by single intrauterine death: problems and outcome with conservative management. Br J Obstet Gynaecol 1990;97(6):511 – 6. [52] Fusi L, McParland P, Fisk N, et al. Acute twin-twin transfusion: a possible mechanism for braindamaged survivors after intrauterine death of a monochorionic twin. Obstet Gynecol 1991; 78(3 Pt 2):517 – 20. [53] D’Alton ME, Newton ER, Cetrulo CL. Intrauterine fetal demise in multiple gestation. Acta Genet Med Gemellol (Roma) 1984;33(1):43 – 9. [54] Pharoah PO, Adi Y. Consequences of in-utero death in a twin pregnancy. Lancet 2000; 355(9215):1597 – 602. [55] Rock JA, Schlaff WD. The obstetric consequences of uterovaginal anomalies. Fertil Steril 1985; 43(5):681 – 92. [56] Sanfilippo JS, Wakim NG, Schikler KN, et al. Endometriosis in association with uterine anomaly. Am J Obstet Gynecol 1986;154(1):39 – 43. [57] Monteagudo A, Strok I, Greenidge S, et al. Quadruplet pregnancy: two sets of twins, each occupying a horn of a septate (complete) uterus. J Ultrasound Med 2004;23(8):1107 – 11 [quiz, 1112–3].
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Invasive Procedures in Multifetal Pregnancies Meredith Rochon, MD*, Keith A. Eddleman, MD, Joanne Stone, MD Division of Maternal-Fetal Medicine, Mount Sinai Medical Center, 5 East 98th Street, Box 1171, New York, NY 10029, USA
The increased use of assisted reproductive techniques and delayed childbearing have resulted in a veritable epidemic of multiple pregnancies in the past decade, particularly those of higher order. As the number of multiple pregnancies has increased, so has the frequency with which invasive procedures are performed in these gestations. Techniques such as amniocentesis and chorionic villus sampling (CVS), first performed in singletons, are now commonly performed in multiple gestations. Multifetal pregnancy reduction and selective termination are procedures unique to multiple pregnancies and were developed to cope with their sequelae. This review discusses the various invasive techniques currently performed in multiple pregnancies.
Amniocentesis Amniocentesis is commonly performed in singleton and multiple gestations. In this invasive procedure, amniotic fluid is removed from the uterine cavity for diagnostic or therapeutic purposes. Indications for diagnostic amniocentesis include chromosomal or genetic analysis, evaluation for a neural tube or abdominal wall defect, documentation of fetal lung maturity, and testing for intrauterine infection. Each fetus of a multizygotic pregnancy is genetically unique; there-
* Corresponding author. E-mail address:
[email protected] (M. Rochon). 0095-5108/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.clp.2005.02.002 perinatology.theclinics.com
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fore, when prenatal diagnostic studies are performed, each fetus must be individually tested. Most operators also test each fetus in a monochorionic pair because, although the fetuses are usually genetically identical, rarely they can be discordant for genetic disorders owing to postzygotic mutations [1]. The relative positions of the fetal sacs should be well documented at the time of the procedure. If any of the test results are abnormal, one must be able to distinguish between fetuses.
Technique Amniocentesis is an outpatient office procedure. After the abdomen is prepared with Betadine, a 20- or 22-guage needle is inserted into the amniotic cavity under continuous ultrasound guidance. The amount of fluid removed depends on the indication; in general, it should not exceed 1 mL per week of gestation (typically, 10 to 30 mL). After extracting the necessary fluid, 1 mL of indigo carmine is injected through the same needle into the sac of the tested fetus. The needle is then withdrawn, and the procedure is repeated with the next fetus. Alternatively, a single-needle insertion technique is performed in which both fetuses are sampled with one needle by passing from one sac into the other through the dividing membrane [2]. Injection of indigo carmine ensures that each sac is tested only once. If the needle is inadvertently inserted into the same sac a second time, the fluid withdrawn will be blue, and the operator will know immediately that he or she is in the wrong sac. When high-order multiple pregnancies are sampled, each sac should be marked in succession with indigo carmine. Indigo carmine has not been associated with any fetal risk [3]. The use of methylene blue, another common dye agent, is contraindicated because of associated fetal risks, including skin staining, intestinal atresia, hemolytic anemia, and fetal death [4,5]. Whenever possible, the operator should avoid going through the placenta, because transplacental entry has been suggested in one retrospective review of multifetal amniocentesis to increase the loss rate when compared with transamniotic entry [6]. Increased numbers of needle sticks have been associated with higher loss rates in singletons [7]. Although this effect has not been evaluated in multiple gestations, it seems prudent to limit the number of attempts to two per sac. The use of antibiotic prophylaxis is not necessary. Although the risk of Rh sensitization is low, particularly without transplacental needle passage, RhoGAM should be administered for all women at risk for Rh sensitization. Genetic amniocentesis is typically performed between 15 and 22 weeks’ gestation, whereas amniocentesis for other diagnostic and therapeutic indications can be performed at any time during pregnancy. Early amniocentesis performed before 15 weeks has been described in twins [8]. When compared with amniocentesis performed after 15 weeks, early amniocentesis is associated with increased rates of fetal loss, failed procedures, multiple needle insertions, amniotic fluid leakage, failed culture, and fetal talipes equinovarus in randomized trials
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[9]. For these reasons, early amniocentesis is no longer recommended in twin or singleton pregnancies. Success and contamination Multifetal amniocentesis is feasible in nearly all pregnancies. Rarely, relative sac position or maternal characteristics such as morbid obesity or large fibroids may present a significant technical challenge to the operator. Fibroids should be avoided whenever possible because going through them is painful and renders needle manipulation difficult. When one sac completely overlies the other, the single-needle technique should be considered, although little is known regarding loss or contamination rates following this technique. The use of indigo carmine makes cross-contamination between fetuses unlikely, because it is obvious when a particular fetus is being inadvertently tested a second time. Maternal contamination can occur but is rare. Postprocedural loss rates The American College of Obstetricians and Gynecologists estimates that the loss rate after second-trimester singleton amniocentesis is 1 in 200 [10]. The limited data available on multifetal amniocentesis are for twins. Postprocedural loss rates after twin amniocentesis have been reported to range from 2.3% to 8.1% [11–16]. Given the background pregnancy loss rate for twins before 24 weeks’ gestation of approximately 6% [17], it is unclear whether the increased loss rate (above the 0.5% rate for singletons) is attributable to the twin pregnancy or the procedure. Yukobowich et al compared three retrospective cohorts: 476 twin pregnancies undergoing amniocentesis, 489 women with singletons who had amniocentesis, and 477 women with twins who presented for ultrasound studies at a similar gestational age but who did not have an invasive procedure [11]. The loss rate within 4 weeks of the procedure was significantly higher in the twin amniocentesis group (2.7%) than in the exposed singletons (0.6%) or unexposed twins (0.6%). Other studies have not confirmed a higher loss rate associated with twin amniocentesis over the background loss rate of twins [12,14]. For example, in a retrospective case-control study, Ghidini et al compared 101 twins undergoing amniocentesis with 108 twin controls and found no difference in fetal loss rates between the two groups [14]. Risk factors associated with increased loss rates after multifetal amniocentesis have not been well characterized. Data describing these risks for singleton amniocentesis have been characterized and include maternal age, vaginal bleeding in the current pregnancy, and a history of abortion [18]. Other factors associated with increased loss rates include an increased number of attempts [7], the presence of green or brown pigmented amniotic fluid [19,20], and elevated maternal serum alpha-fetoprotein (MSAFP) as the indication for amniocentesis [21]. Operator experience does not seem to affect the loss rate in singleton amniocentesis [21], although this has not been investigated in twins.
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Amniocentesis for fetal lung maturity or infection Close to term it is not necessary to test both sacs, and the fetus sampled should be the one less likely to be mature, for example, the male fetus when fetuses are discordant for gender. At earlier gestational ages, discordance in lung maturity status is more likely, particularly for twins discordant for gender [22,23]; therefore, it seems reasonable to test both fetuses in pregnancies less than 36 weeks’ gestation. When evaluating for intrauterine infection, only the lower most sac (fetus A) should be sampled, because infection generally ascends from the vagina. If clinical suspicion is high and the fluid from sac A does not show evidence of infection, amniocentesis of other fetuses can be considered.
Chorionic villus sampling Chorionic villus sampling is an invasive procedure in which placental villi are obtained for performing prenatal diagnostic studies in women at increased risk for fetal chromosomal or genetic abnormalities. It is usually performed at 10 to 12 weeks’ gestation. Technique Chorionic villus sampling can be performed using a transabdominal or transcervical approach. When testing multiple pregnancies, a combination of both routes is often used. The approach is chosen based on operator experience and the relative locations of the fetal sacs and placentas. Dichorionic fetuses are each tested separately. Monochorionic fetuses share one placenta; therefore, they must be tested together with only a single sample. Whether using a transabdominal or transcervical approach, CVS is performed under continuous ultrasound guidance using an aseptic technique. The transabdominal approach uses a 20-gauge needle that is inserted into the placenta. Chorionic villi are then aspirated as the needle is moved back and forth within the placenta under negative pressure. When testing multiple fetuses via the transabdominal approach, separate needle insertions with fresh needles are performed to avoid cross-contamination of the specimens. The transcervical approach is usually performed with an aspiration catheter. A biopsy forceps can also be used [24]. The instrument is passed through the cervix and into the placenta under ultrasound guidance, and villi are aspirated similar to the transabdominal technique. Typically, only one fetus in a multifetal pregnancy can be tested using the transcervical approach. Antibiotic prophylaxis is not necessary. RhoGAM should be administered as indicated. A detailed written description of the relative sac positions and placental locations should accompany any multifetal CVS. The relative filling of the bladder should also be noted, because it may change the appearance of the sac
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and placental locations within the uterus. The operator must be able to identify each sac correctly at a later date, particularly in the setting of an affected fetus. Success and contamination Multiple fetuses can be sampled successfully by CVS in more than 99% of cases when performed by an experienced operator [6,24–28]. Contamination of fetal samples is a real concern, although, in experienced centers, this probably occurs in less than 2% of CVS procedures [6,24–29]. Contamination is a risk because separate placentas are often fused, and, unfortunately, there is no way to mark each placenta as it is tested, as can be done with indigo carmine during multifetal amniocentesis. Several strategies are employed to minimize the risk of contamination. The operator should fully evaluate placental positions before testing. A placenta may appear anterior in some views and posterior in others, particularly if the bladder is emptied or filled. Separate needles and catheters should be used for each fetus. The tip of the aspirating device should be placed close to the umbilical cord insertion site on each placenta to minimize the risk of testing the wrong fetus. Postprocedural loss rates Few studies have investigated outcomes of CVS in multifetal pregnancies, and those that have are small and provide data primarily on twins. Brambati et al reviewed 208 multiple pregnancies undergoing CVS in the first trimester (198 sets of twins and 9 sets of triplets) and compared the pregnancy outcomes of the dichorionic/diamniotic twin cohort with that of a control population of 63 sets of twins undergoing no invasive procedure [26]. There were no total pregnancy losses in either group and no differences in fetal and perinatal losses between the study and control populations [26]. Other series also report acceptably low loss rates (0.6% to 4.2%) [6,25,28] comparable with the background loss rate of twins of approximately 6% [17]. Furthermore, more than half of the losses reported after multifetal CVS occur more than 4 weeks after the procedure at a time when it is difficult to attribute the pregnancy loss to the procedure [30]. Chorionic villus sampling versus amniocentesis Once a patient has decided to have an invasive procedure, the decision to choose one procedure over another should be based on a combination of patientspecific factors, such as the likelihood of proceeding to multifetal pregnancy reduction, the gestational age at presentation, and the experience of the operator, as well as technical factors, such as the relative position of the sacs and maternal body habitus. The indication for invasive testing is also influential. The more likely the fetus is to be affected, the stronger CVS should be considered.
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The chief advantage of CVS is that it is performed at an earlier gestational age than amniocentesis, typically between 10 and 12 weeks’ gestation versus greater than 15 weeks. If the fetus is affected, a selective termination can be performed at an earlier gestational age for a substantially lower emotional impact and perhaps a lower rate of loss after selective termination [6,29]. Conversely, if the fetus is normal, peace of mind can be achieved earlier in the pregnancy, thereby enhancing maternal-fetal bonding [31] and lowering parental stress regarding the pregnancy. Finally, the early gestational age at which CVS can be performed enables fetuses to be tested before multifetal pregnancy reduction, ensuring that the nonreduced fetuses are chromosomally normal. A potentially higher postprocedural loss rate has been widely quoted as a disadvantage of CVS when compared with amniocentesis. Nevertheless, few studies have compared these procedures in multiple gestations. Wapner et al [32] evaluated the outcome of 161 twin pregnancies undergoing CVS and 81 twin pregnancies undergoing amniocentesis and found no differences in fetal loss rates or total pregnancy loss rates. Similarly, in a more recent retrospective review, Antsaklis et al compared pregnancy outcomes of 347 twin pregnancies undergoing amniocentesis with 69 twin pregnancies undergoing CVS and found no differences in the total pregnancy loss rate before 24 weeks (4.18% versus 4.54%), the rate of preterm delivery before 32 weeks (11.8% versus 16.7%), or the total fetal loss rate (8.8% versus 10.2%) [6]. In experienced hands, CVS seems to be as safe as amniocentesis in twin pregnancies. Another disadvantage of CVS is the higher contamination rate and increased need for an additional invasive procedure, required in 5% of CVS cases compared with 0.3% of amniocentesis cases in one series [29]. Additional procedures are primarily performed for evaluation of sampling error or to confirm confined placental mosaicism [30]. Identification of confined placental mosaicism may represent an advantage of CVS, because it identifies pregnancies at increased risk of perinatal morbidity [33] that may deserve increased fetal surveillance. Chorionic villus sampling is a procedure that is not as widely available as amniocentesis, primarily because it is more difficult. Furthermore, it has been shown with singleton CVS that, unlike in amniocentesis, postprocedural loss rates decrease with operator experience [34]. Multifetal CVS represents a technically challenging procedure, and the availability of experienced operators should factor into the decision of whether to undergo amniocentesis or CVS.
Multifetal pregnancy reduction Multifetal pregnancy reduction refers to the nonselective reduction of one or more fetuses of a multifetal pregnancy. The purpose is to reduce the risk of complications associated with multifetal pregnancies and to optimize the chance of carrying and delivering one or several healthy infants. It is done by reducing the actual number of fetuses in the uterus. Multifetal pregnancy reduction should be considered by any woman with three or more fetuses.
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Chorionicity Knowledge of chorionicity is crucial before performing multifetal pregnancy reduction. The traditional technique described herein assumes multichorionic placentation in which there are none of the interfetal placental vascular anastomoses commonly found with monochorionic fetuses. If two fetuses have a shared circulation and one is injected with a toxin, there is a high likelihood that the toxin will get into the co-twin’s circulation and cause fetal death [35]. In addition, acute adverse hemodynamic changes in the survivor may occur owing to blood loss into the low-pressure vascular system of the dead fetus. For this reason, as well as the risk of pregnancy complications inherent to monochorionic twins, the monochorionic pair of a multifetal pregnancy are often preferentially reduced. Reduction of a single fetus in a monochorionic pair can be done but requires special techniques with much higher complication rates. Because of this difficulty, reduction of a single fetus in a monochorionic pair is usually only considered when one of the fetuses is anomalous (selective termination) or in the setting of twin-to-twin transfusion syndrome. Chorionicity is best established by ultrasound in the first trimester by identification of the presence or absence of the lambda sign. The lambda sign is a triangular projection of echodense tissue between two sacs representing two chorions and two amnions. Before 13 weeks, chorionicity can be correctly established by the presence or absence of the lambda sign in 100% of cases [26].
Chorionic villus sampling before multifetal pregnancy reduction One or more fetuses can be tested by CVS before multifetal pregnancy reduction. This testing is desirable for several reasons. First, patients who are considering multifetal pregnancy reduction are often at high risk for carrying a fetus with aneuploidy owing to maternal age and desire invasive testing. Second, noninvasive means for assessing aneuploidy risk have lower sensitivity and specificity for multifetal pregnancies than for singletons, and some of those that are available (second-trimester serum analyte screens or ‘‘quad’’ screens) are not reliable after multifetal pregnancy reduction owing to falsely elevated AFP [36]. CVS before multifetal pregnancy reduction provides the patient and provider with the assurance that chromosomally normal fetuses are being left intact. Several studies have shown that performing CVS before multifetal pregnancy reduction does not increase the postprocedural pregnancy loss rate above that of multifetal pregnancy reduction alone [25,37,38]. An accurate verbal description and a diagram of the relative positions of the gestational sacs and placentas must be carefully recorded so that if an abnormal karyotype is found, it can be correctly matched to the affected fetus. This description should also include the relative fullness of the bladder, because filling or emptying of the bladder can change the intrauterine appearance.
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Technique Multifetal pregnancy reduction is performed as an outpatient procedure in the office. At the authors’ center, the patient and her partner undergo significant pre-procedure counseling, usually on a day separate from the day of the procedure. Ultrasound examination is performed to confirm chorionicity. The relationship of the gestational sacs to each other is carefully noted. If CVS has been performed before multifetal pregnancy reduction, care is taken to identify correctly each fetus that has been tested. Each fetus is measured, the fluid level in each sac is assessed, and the anatomy of each fetus is examined to identify any gross abnormalities. Although multifetal pregnancy reduction is usually performed at the end of the first trimester, a time before which a comprehensive anatomic survey is likely to reveal any abnormalities, a limited assessment of the anatomy and nuchal translucency can be performed to determine the risk for aneuploidy or structural abnormality. In general, the fetuses that are reduced are selected for technical reasons and are usually those closest to the anterior uterine wall or fundus. The fetus above the cervix is avoided whenever possible because of a hypothetical increased risk of infection or uterine irritability if that fetus were reduced. Fetuses with a lagging crown-rump length, decreased fluid, increased nuchal translucency, or an obvious anomaly are preferentially reduced. If CVS has been performed before multifetal pregnancy reduction, fetuses that are known to be chromosomally normal are left intact, and abnormal or untested fetuses are preferentially reduced. After identification of the fetus to be reduced, the abdomen is prepared with Betadine. Under continuous ultrasound guidance, a 22-gauge spinal is inserted into the fetal thorax, and approximately 5 mEq of potassium chloride (2 mEq/mL) is injected. Asystole is usually seen within 1 minute of injection of potassium chloride; the needle is left in place until asystole has been observed for 2 minutes and then withdrawn. Additional fetuses can be reduced by directing the needle into a different sac or, more commonly, by using a separate needle stick. Antibiotic prophylaxis can be given and RhoGAM administered as indicated. An ultrasound 1 hour after the procedure is recommended to confirm asystole in the reduced fetuses and the presence of cardiac activity in the nonreduced fetuses. The fetuses are left in situ and, over a period of weeks to months, are resorbed. Natural history of multifetal pregnancies Multifetal pregnancy reduction was developed as a technique to optimize the pregnancy outcome of high-order multifetal pregnancies. Any discussion of whether multifetal pregnancy reduction improves these pregnancy outcomes requires an appraisal of their natural history. Multiple gestations are at higher risk for fetal, neonatal, and maternal complications when compared with singleton pregnancies. Total pregnancy loss rates (before 24 weeks) rise with an increasing number of fetuses and have been estimated to be 6% for twins [17], 11.5% for triplets [39,40], and 16.7%
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for quadruplets and quintuplets [41,42]. Similarly, mortality rates are significantly higher than for singletons and increase with the number of fetuses. As calculated from 152,233 twin, 5356 triplet, 362 quadruplet, and 36 quintuplet births in the United States from 1995 to 1997, early mortality rates (death from 20 weeks’ gestation to the first year of life) were 4.8% for twins, 8.6% for triplets, 10.8% for quadruplets, and 28.9% for quintuplets [43]. There is also a concomitant increase in associated morbidities. For example, a 47-fold increase in cerebral palsy in triplet pregnancies and an eightfold increase in twins when compared with singletons has been observed, primarily owing to high rates of prematurity [40]. In one series, 44% of 94 couples with triplets had at least one significantly impaired child [44]. Similarly increased rates are seen in other types of morbidities. The increased rate of fetal complications associated with multiple pregnancies is primarily attributable to high rates of prematurity. Furthermore, mean gestational age at delivery and birthweight decrease as the number of fetuses increases, with average gestational ages at delivery for twins, triplets, and quadruplets estimated to be 35, 33, and 31 weeks [39]. Multifetal pregnancy reduction was developed to cope with these high rates of morbidity and mortality, primarily by decreasing rates of prematurity and total pregnancy loss. Pregnancy outcomes after multifetal pregnancy reduction Observational data from the largest published single center series of 1000 cases of multifetal pregnancy reduction report an unintended pregnancy loss rate, defined as the unintended loss of the entire pregnancy before 24 weeks, of 5.4% [45], which is comparable with the loss rate of nonreduced twins and lower than the loss rate of nonreduced triplets. The largest collaborative series of more than 3500 cases from 11 centers in five countries reported an unintended loss rate of 9.6% [46]. The lower loss rate seen in the single center series is most likely explained by the inherent differences of a multicenter experience versus that of a single center with a small number of operators and a well-established protocol [30]. Furthermore, the collaborative series included some transvaginal and transcervical procedures, which have been associated with higher loss rates, whereas the single center series only used the transabdominal approach. Most of the losses in both series occurred many weeks after the procedure, making it hard to attribute these losses to multifetal pregnancy reduction. For example, Stone et al found that more than 55% of total pregnancy losses occurred more than 8 weeks after the reduction. These losses may be more reflective of the multifetal pregnancy (most reductions in this series were to twins) than of the procedure. The total pregnancy loss rate within 4 weeks of the procedure in this series was only 0.8% and accounted for 14.8% of the total losses observed [45]. Both series found that loss rates decreased with a lower starting number and finishing number of fetuses [45,46]. For example, data collected by Stone et al showed that loss rates were lowest when twins were reduced to singletons (2.5%), remained stable (approximately 5%) when the starting number was three, four, or
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five fetuses, and increased to 12.9% when the starting number was six or more [45]. There was a trend toward lower loss rates when the pregnancy was reduced to a singleton (3.5%) versus twins (5.5%), although a limited number of reductions to a singleton prevented this from being statistically significant [45]. Loss rates were significantly higher when the pregnancy was reduced to triplets (16.7%) [45]. The loss rates observed approximate those of naturally occurring twins and triplets. Loss rates in both series decreased with operator experience [45,46]. The mean gestational ages at delivery for finishing numbers of one, two, and three fetuses were 37.9, 35.3, and 33.5 weeks [45]. Multifetal pregnancy reduction improves the outcome of multifetal pregnancies above and beyond a reduction in total pregnancy loss rates. This effect is clearly illustrated in the results of a recently published meta-analysis comparing twins reduced from triplets with nonreduced triplets, which are summarized in Table 1. Multifetal pregnancy reduction significantly reduces the risk of severe prematurity and perinatal mortality while increasing the ‘‘take home baby rate.’’ The outcome of pregnancies reduced to twins seems to be comparable with that of nonreduced twins. Yaron et al compared 143 triplet pregnancies reduced to twins with 812 nonreduced twins [17]. Total pregnancy loss rates before 24 weeks were similar between reduced twins (6.2%) and nonreduced twins (5.8% to 6.3%), as was gestational age at delivery (approximately 35 weeks in both groups) and mean birthweights. Other studies have reported similar findings [30,47], although some have suggested that the mean birthweight of twins after multifetal pregnancy reduction is decreased when compared with that of nonreduced twins [48,49], particularly with increased starting numbers [45]. Psychologic impact of multifetal pregnancy reduction Despite improved pregnancy outcomes after multifetal pregnancy reduction, there is a significant psychologic impact on the parents. Most patients with highorder multiples conceive with assisted reproductive techniques, usually after many years of infertility. The decision to terminate wanted, usually normal, fetuses can be agonizing, and couples may later regret the decision to undergo the
Table 1 Meta-analysis of published studies of reduced and nonreduced triplets from 1984 to 2001 Parameter
Reduced triplets (3 to 2) (n = 2230)
Nonreduced triplets (n = 604)
Odds ratio
P
Pregnancy loss b 24 weeks Delivery b 28 weeks Delivery b 32 weeks Perinatal mortality Take home baby rate
5.1% 2.9% 10.1% 26.6/1000 93%
11.5% 8.4% 20.3% 92.2/1000 78.6%
0.45 0.35 0.5 0.3 0.3
b .001 .0001 b .0001 b .0001 .002
(0.3–0.6) (0.2–0.6) (0.37–0.66) (0.2–0.5) (0.2–0.7)
Adapted from Wimalasundera RC, Trew G, Fisk NM. Reducing the incidence of twins and triplets. Best Prac Res Clin Obstet Gynaecol 2003;17:309–29.
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procedure regardless of pregnancy outcome [50]. Patients should be counseled that parents of multiples also sustain extreme psychologic stress. Even if all of the infants are healthy, which high-order multiples usually are not, taking care of multiple infants at the same time is extremely draining physically and emotionally, not to mention economically burdensome. With the added risk of one or more infant experiencing prolonged NICU stays, the need for complex medical care, and significant deficits, the stress could be overwhelming. In a prospective study comparing patients undergoing multifetal pregnancy reduction with those who did not reduce their triplet pregnancy, mothers who underwent multifetal pregnancy reduction had less anxiety and depression and more satisfactory relationships with their children [51]. Although many women in the multifetal pregnancy reduction group expressed sadness and guilt 1 year later, the majority reported a significant reduction in emotional pain at 2 years [51].
Selective termination Selective termination is a procedure in which one anomalous fetus in a multifetal pregnancy is terminated. When one or more fetuses in a multifetal pregnancy are found to be anomalous, the patient has three choices. The first is to manage the pregnancy expectantly; the second is to terminate the entire pregnancy; and the third is to terminate selectively the affected fetus. Selective termination can be performed for a chromosomal, structural, or genetic abnormality, usually identified by ultrasound or an invasive prenatal diagnostic test such as CVS or amniocentesis. It can be performed at any time from the time of diagnosis (generally after 10 weeks) up to the legal limit of termination. The legal limit for termination in most states is 24 weeks; third-trimester selective termination can be performed legally in certain US states and in some other countries [52]. Selective termination was initially developed to prevent the survival of a severely affected infant [53]. As experience with selective termination increased with a concomitant improvement in procedural outcomes, it became increasingly offered for lethal anomalies to reduce the emotional impact of giving birth to a child who would not live [53]. It is theorized that, in some cases, termination of the anomalous twin may optimize the outcome of the normal fetus. For example, anencephaly is often complicated by polyhydramnios owing to impaired fetal swallowing, which invariably results in preterm labor. Selective termination of this fetus may decrease the rate of preterm labor and the effects of prematurity on the normal co-twin [30]. Technique As is true for multifetal pregnancy reduction, the traditional technique for selective termination can only be used if the fetuses are multichorionic. As
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discussed previously, chorionicity is usually determined by the presence or absence of the lambda sign on first-trimester ultrasound. If the pregnancy is already in the latter half of the second trimester, it may be more difficult to determine chorionicity. Fetuses discordant for gender or that appear to have separate placentas are obviously dichorionic. Specialized genetic tests such as quantitative fluorescent polymerase chain reaction assays and polymorphic small tandem repeats can be used for rapid determination of zygosity [54,55] for pregnancies with uncertain chorionicity. Another vital preprocedure consideration is correct identification of the anomalous fetus. If the fetuses are discordant for gender or a structural anomaly, the affected fetus can be determined visually at the time of the procedure by ultrasound. If the anomaly cannot be identified on ultrasound (eg, in many genetic diseases), the operator must rely on previously documented fetal and placental positions, underscoring the importance of a precise detailed description of the location of each fetus at the time of an invasive diagnostic procedure. Correct identification of the affected fetus can be challenging if several weeks have passed since the invasive diagnostic procedure, because growth of the uterus and fetuses may alter the appearance of their relative positions. Usually, the affected fetus is readily identifiable. If there is any doubt, rapid determination of karyotype by fluorescent in situ hybridization should be performed and the results obtained before selective termination [30]. Documentation of the karyotype of the terminated fetus at the time of the procedure by amniocentesis or fetal blood is recommended to confirm the correct fetus has been terminated [30]. Once the fetus to be terminated has been correctly identified, the procedure is performed in a manner similar to multifetal pregnancy reduction. Under ultrasound guidance, potassium chloride is injected into the thorax of the affected fetus via a transabdominal route and the needle left in place until asystole is observed for 2 minutes. The amount of potassium chloride required will depend on the gestational age/size of the fetus. Prophylactic antibiotics are usually given and RhoGAM administered as indicated. The fetus is left in situ while the pregnancy continues. If performed in the late first trimester or early second trimester, the fetus may be resorbed. At later gestational ages, the fetus will not be completely resorbed, but, over a period of weeks to months, the amniotic fluid around the fetus will disappear, and the fetal tissue will become significantly condensed. The reduced fetus is typically delivered with the placenta and is usually too macerated for any meaningful evaluation. Pregnancy outcome after selective termination The overall pregnancy loss rate, defined as the unintended total pregnancy loss rate before 24 weeks, was 4.0% in the largest single center series of 200 patients [56] and 7.5% in the largest collaborative experience of 402 patients [57]. The lowest loss rate (2.4%) after selective termination is observed with a starting number of two [56]. This rate increases significantly to 11.1% when starting with three or more fetuses and is highest when more than one fetus is terminated
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(42.9%) [56]. In continuing pregnancies, the outcome after selective termination is generally favorable, with low rates of prematurity and few maternal complications. For women not experiencing a pregnancy loss or electively terminating their pregnancy, the median gestational age at delivery was 37.1 weeks in one series [56]. Data from early studies suggested that rates of pregnancy loss and preterm delivery increased with increasing gestational age at the time of selective termination [57,58]. More recent data suggest that there is no advantage to performing selective termination at earlier gestational ages [56]. In fact, in one series, there was a trend toward a higher rate of pregnancy loss in patients undergoing selective termination at or before 20 weeks’ gestation when compared with selective termination after 20 weeks (5.9% versus 1.3%, P = .09) [56]. Patients and physicians should be reassured that selective termination in experienced hands is safe at any gestational age. Selective termination of a monochorionic fetus Monochorionic fetuses can occasionally be discordant for anomalies, and it may be desirable to terminate the affected co-twin. Interfetal anastomoses via the placenta prohibit the use of potassium chloride. As a result, many alternative techniques have been tried. The majority of these focus on occlusion of the cord of the affected fetus. A review of these techniques appears elsewhere in this issue.
Percutaneous umbilical blood sampling Percutaneous umbilical blood sampling (PUBS) is typically performed for special diagnostic and therapeutic indications, such as an evaluation for hydrops or infection, or to perform specialized studies that cannot be accomplished by amniocentesis or CVS. It can also be performed when an abnormality is suspected late in pregnancy for a more rapid diagnosis. PUBS is an invasive procedure in which fetal blood is sampled from the umbilical vein, usually at the placental umbilical cord insertion site. An anemic or thrombocytopenic fetus can also be transfused through the same needle if indicated. Percutaneous umbilical blood sampling is a technically challenging procedure and is considerably more invasive than other diagnostic studies, because the needle enters the fetal circulation. The procedure-related fetal loss rate following PUBS in singletons is higher than with CVS and amniocentesis and is estimated to be 1% to 2% [59]. The risk is recognized to vary with the indication, with ‘‘healthy’’ fetuses having the lowest risk (eg, those undergoing genetic studies) and ‘‘sick’’ fetuses having significantly higher risk (eg, a fetus with hydrops or severe thrombocytopenia). There is only one published study describing this technique in multiple gestations. Antsaklis et al retrospectively reviewed 89 cases of fetal blood
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sampling procedures in twin pregnancies performed from 1977 to 2000 [59]. The vast majority of these procedures were performed on unimpaired fetuses for the purpose of genetic diagnosis. The mean gestational age at the time of the procedure was 20.3 weeks. All of the fetuses (178) were successfully sampled. Seventeen pregnancies were subsequently terminated, 12 underwent selective termination, and 5 were lost to follow-up, leaving a final cohort of 55 pregnancies (110 fetuses). The overall procedure-related fetal loss rate, defined in this series as miscarriage or fetal death within 2 weeks of the procedure, was 8.2% (9/110) [59]. Because of the high loss rate and considerable technical challenge PUBS presents in multifetal pregnancies, this procedure has few true indications.
Summary Several invasive procedures are now commonly performed in multifetal pregnancies. Techniques for prenatal diagnosis performed in multifetal pregnancies, such as amniocentesis and CVS, present specific technical challenges when compared with their performance in singletons and are best performed by experienced operators to increase the success of the procedure, reduce contamination, and minimize postprocedure complications. Procedures developed to cope with the sequelae specific to multifetal pregnancies, such as multifetal pregnancy reduction and selective termination, are also commonly performed with generally good outcomes. The moral and psychologic issues associated with these procedures are extensive and complex for the patient and the physician, but it is clear that pregnancy outcomes of high-order multiples (triplets and up) are improved by multifetal pregnancy reduction. It is hope that with better regulation of assisted reproductive techniques, the need for these specialized procedures will become obsolete.
References [1] Gonsoulin W, Copeland KL, Carpenter RJ, et al. Fetal blood sampling demonstrating chimerism in monozygotic twins discordant for sex and tissue karyotype (46,XY and 45,X). Prenat Diagn 1990;10(1):25 – 8. [2] Jeanty P, Shah D, Roussis P. Single-needle insertion in twin amniocentesis. J Ultrasound Med 1990;9:511 – 7. [3] Cragan JD, Martin ML, Khoury MJ, et al. Dye use during amniocentesis and birth defects [letter]. Lancet 1993;341:1352. [4] Vincer MJ, Allen AC, Evans JR, et al. Methylene blue–induced hemolytic anemia in a neonate. CMAJ 1987;136:503 – 4. [5] Kidd SA, Lancaster PA, Anderson JC, et al. Fetal death after exposure to methylene blue dye during mid-trimester amniocentesis in twin pregnancy. Prenat Diagn 1996;16:39 – 47. [6] Antsaklis A, Souka AP, Daskalakis G, et al. Second-trimester amniocentesis vs chorionic villus sampling for prenatal diagnosis in multiple gestations. Ultrasound Obstet Gynecol 2002;20: 476 – 81.
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[7] Midtrimester amniocentesis for prenatal diagnosis: safety and accuracy. JAMA 1976;236: 1471 – 6. [8] Jorgensen C, Andolf E. Amniocentesis before the 15th week in single and twin gestations: complications and quality of genetic analysis. Acta Obstet Gynecol Scand 1998;77:151 – 4. [9] Johnson JM, Wilson RD, Singer J, et al. Technical factors in early amniocentesis predict adverse outcome: results of the Canadian early (EA) versus mid-trimester (MA) amniocentesis trial. Prenat Diagn 1999;19:732 – 8. [10] American College of Obstetricians and Gynecologists Committee on Practice Bulletins— Obstetrics. ACOG Practice Bulletin. Clinical management guidelines for obstetriciangynecologists: prenatal diagnosis of fetal chromosomal abnormalities. Obstet Gynecol 2001; 97(5 Pt 1):S1 – 12. [11] Yukobowich E, Anteby EY, Cohen SM, et al. Risk of fetal loss in twin pregnancies undergoing second trimester amniocentesis. Obstet Gynecol 2001;98:231 – 4. [12] Antsaklis A, Daskalakis G, Papantoniou N, et al. Genetic amniocentesis in multifetal pregnancies reduced to twins compared with nonreduced twin gestations. Fertil Steril 2000;74:1051 – 2. [13] Ko TM, Tseng LH, Hwa HL. Second-trimester genetic amniocentesis in twin pregnancy. Int J Gynecol Obstet 1998;61:285 – 7. [14] Ghidini A, Lynch L, Hicks C, et al. The risk of second-trimester amniocentesis in twin gestations: a case-control study. Am J Obstet Gynecol 1993;169:1013 – 6. [15] Anderson RL, Goldberg JD, Golbus MS. Prenatal diagnosis in multiple gestation: 20 years’ experience with amniocentesis. Prenat Diagn 1991;11:263 – 70. [16] Pruggmayer M, Baumann P, Schutte H, et al. Incidence of abortion after genetic amniocentesis in twin pregnancies. Prenat Diagn 1991;11:637 – 40. [17] Yaron Y, Bryant-Greenwood PK, Dave N, et al. Multifetal pregnancy reductions of triplets to twins: comparison with nonreduced triplets and twins. Am J Obstet Gynecol 1999;180:1268 – 71. [18] Papantoniou NE, Daskalakis GJ, Tziotis JG, et al. Risk factors predisposing to fetal loss following a second trimester amniocentesis. Br J Obstet Gynecol 2001;108:1053 – 6. [19] Zorn EM, Hanson FW, Greve LC, et al. Analysis of the significance of discolored amniotic fluid detected at midtrimester amniocentesis. Am J Obstet Gynecol 1986;154:1234 – 40. [20] Hess LS, Anderson RL, Golbus MS. Significance of opaque discolored amniotic fluid at secondtrimester amniocentesis. Obstet Gynecol 1986;67:44 – 6. [21] Tabor A, Philip J, Madsen M, et al. Randomised controlled trial of genetic amniocentesis in 4606 low-risk women. Lancet 1986;1:1287 – 93. [22] Whitworth NS, Magann EF, Morrison JC. Evaluation of fetal lung maturity in diamniotic twins. Am J Obstet Gynecol 1999;180:1438 – 41. [23] Mackenzie MW. Predicting concordance of biochemical lung maturity in the preterm twin gestation. J Matern Fetal Neonatal Med 2002;12:50 – 8. [24] Casals G, Borrell A, Martinez JM, et al. Transcervical chorionic villus sampling in multiple pregnancies using a biopsy forceps. Prenat Diagn 2002;22:260 – 5. [25] Eddleman KA, Stone JL, Lynch L, et al. Chorionic villus sampling before multifetal pregnancy reduction. Am J Obstet Gynecol 2000;183:1078 – 81. [26] Brambati B, Tului L, Guercilena S, et al. Outcome of first-trimester chorionic villus sampling for genetic investigation in multiple pregnancy. Ultrasound Obstet Gynecol 2001;17:209 – 16. [27] Pergament E, Schulman JD, Copeland K, et al. The risk and efficacy of chorionic villus sampling in multiple gestations. Prenat Diagn 1992;12:377 – 84. [28] De Catte L, Liebaers I, Foulon W. Outcome of twin gestations after first trimester chorionic villus sampling. Obstet Gynecol 2000;96:714 – 20. [29] van den Berg C, Braat AP, Van Opstal D, et al. Amniocentesis or chorionic villus sampling in multiple gestations? Experience with 500 cases. Prenat Diagn 1999;19:234 – 44. [30] Rochon M, Stone J. Invasive procedures in multiple gestations. Curr Opin Obstet Gynecol 2003;15:167 – 75. [31] Caccia N, Johnson JM, Robinson GE, et al. Impact of prenatal testing on maternal-fetal bonding: chorionic villus sampling versus amniocentesis. Am J Obstet Gynecol 1991;165:1122 – 5.
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[32] Wapner RJ, Johnson A, Davis G, et al. Prenatal diagnosis in twin gestations: a comparison between second-trimester amniocentesis and first-trimester chorionic villus sampling. Obstet Gynecol 1993;82:49 – 56. [33] Stipoljev F, Latin V, Kos M, et al. Correlation of confined placental mosaicism with fetal intrauterine growth retardation: a case control study of placentas at delivery. Fetal Diagn Ther 2001;16:4 – 9. [34] Wijnberger LD, van der Schouw YT, Christiaens GC. Learning in medicine: chorionic villus sampling. Prenat Diagn 2000;20:241 – 6. [35] Benson CB, Doubilet PM, Acker D, et al. Multifetal pregnancy reduction of both fetuses of a monochorionic pair by intrathoracic potassium chloride injection of one fetus. J Ultrasound Med 1998;17:447 – 9. [36] Grau P, Robinson L, Tabsh K, et al. Elevated maternal serum alpha-fetoprotein and amniotic fluid alpha-fetoprotein after multifetal pregnancy reduction. Obstet Gynecol 1990;76:1042 – 5. [37] Brambati B, Tului L, Baldi M, et al. Genetic analysis prior to selective fetal reduction in multiple pregnancy: technical aspects and clinical outcome. Hum Reprod 1995;10:818 – 25. [38] De Catte L, Camus M, Bonduelle M, et al. Prenatal diagnosis by chorionic villus sampling in multiple pregnancies prior to fetal reduction. Am J Perinatol 1998;15:339 – 43. [39] Stone J, Eddleman K. Multifetal pregnancy reduction. Curr Opin Obstet Gynecol 2000;12:491 – 6. [40] Wimalasundera RC, Trew G, Fisk NM. Reducing the incidence of twins and triplets. Best Prac Res Clin Obstet Gynaecol 2003;17:309 – 29. [41] Skrablin S, Kuvacic I, Pavicic D, et al. Maternal neonatal outcome in quadruplet and quintuplet versus triplet gestations. Eur J Obstet Gynecol Reprod Biol 2000;88:147 – 52. [42] Francois K, Alperin A, Elliott JP. Outcomes of quintuplet pregnancies. J Reprod Med 2001; 46:1047 – 51. [43] Salihu HM, Aliyu MH, Rouse DJ, et al. Potentially preventable excess mortality among higherorder multiples. Obstet Gynecol 2003;102:679 – 84. [44] Strauss A, Bettina WP, Genzel-Boroviczeny O, et al. Multifetal gestation: maternal and perinatal outcome of 112 pregnancies. Fetal Diagn Ther 2002;17:209 – 17. [45] Stone J, Eddleman K, Lynch L, et al. A single center experience with 1000 consecutive cases of multifetal pregnancy reduction. Am J Obstet Gynecol 2002;187:1163 – 7. [46] Evans MI, Berkowitz RL, Wapner RJ, et al. Improvement in outcomes of multifetal pregnancy reduction with increased experience. Am J Obstet Gynecol 2001;184:97 – 103. [47] Hwang JL, Pan HS, Huang LW, et al. Comparison of the outcomes of primary twin pregnancies and twin pregnancies following fetal reduction. Arch Gynecol Obstet 2002;267:60 – 3. [48] Alexander JM, Hammond KR, Steinkampf MP. Multifetal reduction of high-order multiple pregnancy: comparison of obstetrical outcome with nonreduced twin gestations. Fertil Steril 1995;64:1201 – 3. [49] Leondires MP, Ernst SD, Miller BT, et al. Triplets: outcomes of expectant management versus reduction for 127 pregnancies. Am J Obstet Gynecol 2000;183:454 – 9. [50] Berkowitz RL, Lynch L, Stone J, et al. The current status of multifetal pregnancy reduction. Am J Obstet Gynecol 1996;174:1265 – 72. [51] Garel M, Stark C, Blondel B, et al. Psychological reactions after multifetal pregnancy reduction: a 2-year follow-up study. Hum Reprod 1997;12:617 – 22. [52] Lipitz S, Shalev E, Meizner I, et al. Late selective termination of fetal abnormalities in twin pregnancies: a multicentre report. Br J Obstet Gynaecol 1996;103:1212 – 6. [53] Bush MC, Eddleman KE. Multifetal pregnancy reduction and selective termination. Clin Perinatol 2003;30:623 – 41. [54] Chen CP, Chern SR, Wang W. Rapid determination of zygosity and common aneuploidies from amniotic fluid cells using quantitative fluorescent polymerase chain reaction following genetic amniocentesis in multiple pregnancies. Hum Reprod 2000;15:929 – 34. [55] Cirigliano V, Canadas P, Plaja A, et al. Rapid prenatal diagnosis of aneuploidies and zygosity in multiple pregnancies by amniocentesis with single insertion of the needle and quantitative fluorescent PCR. Prenat Diagn 2003;23:629 – 33.
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[56] Eddleman KD, Stone JL, Lynch L, et al. Selective termination of anomalous fetuses in multifetal pregnancies: two hundred cases at a single center. Am J Obstet Gynecol 2002;187:1168 – 72. [57] Evans MI, Goldberg JD, Horenstein J, et al. Selective termination for structural, chromosomal, and mendelian anomalies: international experience. Am J Obstet Gynecol 1999;181:893 – 7. [58] Lynch L, Berkowitz RL, Stone J, et al. Preterm delivery after selective termination in twin pregnancies. Obstet Gynecol 1996;87:366 – 9. [59] Antsaklis A, Daskalakis G, Souka AP, et al. Fetal blood sampling in twin pregnancies. Ultrasound Obstet Gynecol 2003;22:377 – 9.
Clin Perinatol 32 (2005) 373 – 386
Down Syndrome Screening in Twins Melissa C. Bush, MDa,*, Fergal D. Malone, MD, FRCSIb a
Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of California, Irvine, 101 The City Drive, Orange, CA 92868, USA b Department of Obstetrics and Gynecology, The Rotunda Hospital, Parnell Square, Dublin, Ireland
Down syndrome (DS) is the most common single pattern of human malformation and one of the most common serious congenital abnormalities found at birth. The prevalence of DS is known to increase with maternal age, as does the prevalence of spontaneous and iatrogenic multiple gestations. Because many women who use assisted reproductive technology (ART) have spent considerable time trying to become pregnant, their age-related risk of aneuploidy is often significant by the time they finally conceive. These factors place patients with multiple gestations at higher risk for aneuploidy than are age-matched controls. Prenatal diagnosis of DS in twins was first reported using amniocentesis in 1978 [1,2]. Prenatal screening for DS in twins is a more recent development. Prenatal screening and diagnosis in twins presents unique challenges. The performance of DS biochemical screening is altered, invasive testing is more complex, and there are unique ethical and counseling challenges [3]. Current recommendations for offering invasive testing to all women of advanced maternal age (35 years at the expected date of delivery) [4] do not take into account factors specific to a given pregnancy, including the number of fetuses. No clear standards exist for DS screening in multifetal pregnancies, and, currently, many centers do not offer screening for aneuploidy for patients with multiple gestations. Meyers et al [5] have calculated that a 31-year-old woman with twins of unknown zygosity has the same risk of having at least one affected fetus as a 35-year-old woman carrying a singleton (approximately 1:270 at midtrimester). This calculation has been criticized, because the actual prevalence
* Corresponding author. Saddleback Memorial Hospital, 24411 Health Center Drive, Suite 300, Laguna Hills, CA 92653. E-mail address:
[email protected] (M.C. Bush). 0095-5108/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.clp.2005.03.001 perinatology.theclinics.com
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of DS in twins is lower than that predicted. Another researcher has concluded, ‘‘Until there is a more precise estimate of these rates it is probably best to assume that the prior term risk for twins does not differ from that of singletons’’ [6]. The latest American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin suggests that a pregnancy carrying twins at age 33 years has the same risk as a singleton pregnancy in a 35-year-old [7]. One may interpret the Meyers’ article to mean that if maternal age alone is used as the criterion for offering invasive testing, patients with twins should be offered such testing if they will be 31 years of age or older at their estimated delivery date [5,8]. Nevertheless, the sensitivity for DS using maternal age alone is approximately 30%, with a 5% false-positive rate in singletons [8]. The techniques presented herein may serve to modify this approach by evolving toward a more precise pregnancy-specific risk and ultimately a fetus-specific risk rather than an age-specific risk for aneuploidy. Such information would be of great benefit to parents, who could then decide to undergo invasive testing and consider selective termination of an aneuploid fetus [9]. Many patients agonize over the decision to accept prenatal diagnostic procedures for fear of procedure-related loss rates, especially if the pregnancy was achieved via ART. Some of these patients desire screening but will proceed to invasive procedures only if their individual risk assessment is sufficiently high. Patients should be counseled appropriately regarding their options for screening versus diagnostic tests. For patients who will not accept any possible chance of DS, invasive procedures to provide a definitive diagnosis represent the only option. Amniocentesis and chorionic villus sampling (CVS) are commonly reported as being associated with a 0.5% to 1% procedure-related risk of pregnancy loss. These risks may be increased in twins [3], but a recent review suggests that loss rates are acceptable in experienced hands [10]. Patients carrying twins who are offered prenatal diagnosis for DS must be aware of the three options if fetal aneuploidy is confirmed: (1) continue the pregnancy with both normal and abnormal fetuses; (2) terminate the entire pregnancy; or (3) selectively terminate the abnormal fetus. Significant psychologic stress can be experienced by couples facing such difficult decisions [9].
Second-trimester ultrasound screening For many years, the mainstay of screening for DS in multiple gestations has been second-trimester sonography to evaluate for major structural malformations or ‘‘soft markers’’ that may be associated with aneuploidy. Several such soft markers have been described, which when present may increase the risk of an individual fetus for DS [11]. Conversely, the absence of these markers may decrease the a priori risk from age or biochemical screening. When a major structural malformation is discovered, the decision regarding an invasive diagnosis is straightforward. When one or more soft markers are noted, a fetus-specific
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down syndrome screening in twins Table 1 Likelihood ratios for Down syndrome and isolated soft markers in singleton gestations Sonographic marker
Nyberg 1998 [12]
Nyberg 2001 [11]
Smith-Bindman 2001 [44]
Nuchal thickening Hyperechoic bowel Short humerus Short femur Echogenic focus Renal pyelectasis
18.6 5.5 2.5 2.2 2 1.5
11 6.7 5.1 1.5 1.8 1.5
17 6.1 7.5 2.7 2.8 1.9
Data from Nyberg DA, Souter VL, El-Bastawissi A, et al. Isolated sonographic markers for detection of fetal Down syndrome in the second trimester of pregnancy. J Ultrasound Med 2001;20(10): 1053–63.
risk can be calculated using likelihood ratios. Likelihood ratios for DS associated with isolated soft markers have been calculated by Nyberg et al [12] and include 11 for nuchal thickening, 6.7 for an echogenic bowel, 5.1 for a short humerus, 1.5 for a short femur, 1.8 for an echogenic intracardiac focus, and 1.5 for pyelectasis (Table 1). The a priori risk is multiplied by the appropriate likelihood ratio to yield a final fetus-specific risk for DS, and an objective decision regarding an invasive diagnosis is made. Additionally, following a genetic sonogram, if no soft markers are visible, the fetus-specific risk for DS can be reduced by 50% to 70% depending on which set of likelihood ratios is used. An advantage of second-trimester ultrasound screening is that it can provide an estimation of fetus-specific risk, whereas serum screening is limited to a pregnancy-specific risk. The likelihood ratio for nuchal thickening in the second trimester should be used with caution to modify a first trimester–based risk assessment, because firstand second-trimester nuchal measurements are not independent of each other.
Second-trimester biochemical screening In singleton pregnancies, the triple screen (alpha-fetoprotein [AFP], human chorionic gonadotropin [hCG], and unconjugated estriol [uE3]) can identify 60% to 70% of DS pregnancies with a 5% false-positive rate. The addition of inhibin-A (quad screen) increases the sensitivity to 77% at a 5% false-positive rate [13]; however, in twin pregnancies, midtrimester serum screening has been of limited value, with triple screening estimated to detect 44% of DS pregnancies and quad screening estimated to detect 47% at a 5% false-positive rate [14]. These detection rates represent significant reductions when compared with the relative screening performance in singleton pregnancies. These disparities are due to the unaffected co-twin masking the abnormal maternal serum levels associated with an aneuploid fetus [6]. Furthermore, even if screening suggests an affected fetus is present, biochemical markers cannot specify which twin is abnormal. In one study of 420 patients with twins, only 50% of the eight patients discordant for DS were identified using maternal serum AFP and free b-hCG for
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a 5% false-positive rate [15]. Using the triple screen in another cohort of 274 known twin pregnancies, 15 (5.5%) screened positive [16]. In that series, 9 of the 14 viable screen-positive pregnancies underwent amniocentesis, and all were found to be euploid. There were no cases of DS identified in this particular population. Nevertheless, mathematical modeling was used to estimate that 73% of monozygotic twin pregnancies and 43% of dizygotic twin pregnancies with DS (overall 53% detection rate) could be identified at a 5% false-positive rate [17]. Second-trimester biochemistry is not as sensitive in twins in a comparison with singleton gestations, although its use still represents an improvement when compared with screening based on age alone, which has a significantly higher false-positive rate at any given detection rate. Pseudorisk calculation A complicating factor when screening for DS in multiple gestations is zygosity. In multiple gestations, the probability of aneuploidy is directly related to zygosity. There is no definitive noninvasive method of determining the zygosity of twins concordant for gender. Chorionicity is strongly related to zygosity; all monochorionic twins are monozygous, and up to 90% of dichorionic twins may be dizygous [17]. Between 10 and 14 weeks’ gestation, chorionicity can reliably be determined via ultrasound by the presence or absence of the twin peak (lambda) sign at the intertwin membrane when there is one placental mass. Pregnancies are classified as dichorionic if there is discordance for gender, if there are two separate placentas, or if there is a single placental mass with the twin peak sign present [18]. Nevertheless, it can be difficult to assign zygosity with certainty using ultrasonography; therefore, much of the data on multiple gestation screening with biochemical markers are based on theoretical performances. Each fetus in a dizygotic pregnancy has an independent risk of aneuploidy, such that the pregnancy has approximately twice the risk that at least one fetus is affected when compared with the risk for a singleton. Monozygotic twins almost always have the same karyotype, and the risk of an affected fetus approximates the maternal age risk of a singleton. If zygosity is unknown, the risk of having at least one aneuploid fetus can be approximated as somewhat less than double, because monozygous twins will generally be concordant for DS, reducing the overall risk [6]. Among twin pregnancies affected with DS, both fetuses are affected in about 17% of cases [17]. In normal twin pregnancies, second-trimester biochemical markers are on average twice as high as those in singleton pregnancies of the same gestational age (Table 2). The exception is estriol, which is, on average, 1.67 times as high in twin pregnancies when compared with singleton gestations. Based on standard Gaussian distributions, the apparently lower estriol values seen in twins would increase the computed risk for DS in this setting. Wald et al [19] demonstrated that the distributions of second-trimester serum analytes in unaffected twin and singleton pregnancies are not different; therefore, it is theoretically possible to predict aneuploidy risk in twin pregnancies by dividing the values of the analytes
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Table 2 Median second-trimester marker levels (multiples of the median) in twin pregnancies estimated using the median levels in singleton pregnancies Unaffected
All twin pregnancies
AFP uE3 Total hCG Free b-hCG Inhibin-A
2.13 1.67 1.84 1.90 1.99
Affected
Monochorionic
Dichorionic
AFP uE3 Total hCG Free b-hCG Inhibin-A
1.53 1.20 3.68 4.22 3.56
1.83 1.44 2.76 3.06 2.78
[19] [19] [19] [44] [45]
[46] [46] [46] [46] [11,47]
[46] [46] [46] [46] [11,47]
From Wald NJ, Rish S, Hackshaw AK. Combining nuchal translucency screening and serum markers in prenatal screening for Down syndrome in twin pregnancies. Prenat Diagn 2003;23:588–92; with permission.
by the corresponding medians for singletons [19]. This screening result, known as a pseudorisk, is interpreted as if the pregnancy were a singleton gestation. This policy is designed to yield a similar false-positive rate in singleton and twin pregnancies [19].
First-trimester biochemical screening Like second-trimester markers, first-trimester serum markers are on average twice as high in normal twin gestations when compared with normal singleton pregnancies. For singleton gestations, studies totaling 300 DS cases have shown that the median level of free b-hCG is 1.83 multiples of the median (MoM) and the median level of pregnancy-associated plasma protein A (PAPP)-A 0.38 MoM [20]. Existing data on the behavior of biochemical markers in unaffected twin pregnancies are limited but suggest that free b-hCG and PAPP-A may be elevated twofold (Table 3). Differences in the levels of free b-hCG between monochorionic and dichorionic twins have been hypothesized to be due to vascular disturbances, more frequent in monochorionic twins, which could induce placental hypoxia, increasing hCG production [21]. Published data on first-trimester markers in affected twin pregnancies are limited to 12 cases. Noble et al [22] studied ten discordant and two concordant sets of twins for DS. The median level of maternal serum free b-hCG was significantly higher than in 136 normal twin pregnancies, 1.60 versus 1.00 MoM. Nevertheless, Noble and colleagues concluded that because only one case was above the 95th percentile, free b-hCG was not capable alone of distinguishing
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Table 3 Median first-trimester marker levels (multiples of the median) in twin pregnancies estimated using the median levels in singleton pregnancies Unaffected
All twin pregnancies
Nuchal translucency PAPP-A Free b-hCG
1.0 1.86 [39] 2.10 [39]
Affected
Monochorionic
Dichorionic
Nuchal translucency PAPP-A Free b-hCG
2.02 [48,49] 0.80 [50] 3.76 [50]
2.02 [49] 1.33 [50] 2.93 [50]
From Wald NJ, Rish S, Hackshaw AK. Combining nuchal translucency screening and serum markers in prenatal screening for Down syndrome in twin pregnancies. Prenat Diagn 2003;23:588–92; with permission.
between DS and euploid pregnancies; therefore, it would have limited utility in the prediction of fetal DS in twins at 10 to 14 weeks’ gestation [22].
Impact of assisted reproduction technology and ethnicity on first- and second-trimester serum markers in twins Midtrimester serum AFP and free b-hCG have also been compared in spontaneously conceived twin pregnancies versus those that have resulted from ART. In 145 in vitro fertilization (IVF) unaffected twin pregnancies, midtrimester free b-hCG levels were significantly higher (2.20 median MoM) than in spontaneous twins (1.83 median MoM), whereas no significant difference was found in midtrimester AFP levels (2.30 median MoM versus 2.18 median MoM in IVF and spontaneous twins, respectively) [23]. This increase in free b-hCG may result in higher false-positive rates when DS screening is performed in ART pregnancies compared with spontaneous pregnancies. Another reason for increased false-positive rates in ART pregnancies is that standard screening algorithms include maternal age. Maymon and Jauniaux [24] also hypothesized that changes in the fetoplacental endocrinologic metabolism in ART pregnancies contribute to the higher false-positive rates. The issue of first-trimester markers and ART is unresolved. One study reported that first-trimester free b-hCG levels were significantly (21%) increased in 411 singleton pregnancies achieved by assisted reproduction [25]. Another study compared first-trimester serum markers in 30 ART twins versus 150 spontaneous twin controls and found no such differences [26]. Larger studies are needed to resolve this question. In the meantime, patients undergoing ART should be counseled about the possibility of higher false-positive rate for firsttrimester screening. In singleton pregnancies, Asians and African Americans have higher values for AFP, hCG, and uE3 than do whites and Hispanics [27]. Evaluation of these
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same analytes in 4443 twin pregnancies has shown the same pattern of ethnic variation [28]. Although triple screening takes into account maternal ethnicity in singleton gestations, ethnicity has not yet been included in the estimation of DS risk in twins in the centers that perform second-trimester biochemical screening. Additionally, no data have been published on twins in ethnically diverse populations.
First-trimester nuchal translucency sonographic screening Nuchal translucency measurement combined with maternal age may detect up to 77% of DS in singleton pregnancies, with a 6% false-positive rate [29]. Nuchal translucency evaluation in twins is feasible, and the median measurements obtained in unaffected twins have been found to be similar to those in singleton age-matched controls [30]. The major advantage of nuchal translucency assessment in multiple gestations is that it can provide an accurate fetus-specific risk for DS. Nuchal translucency measurement has been used in twins to guide the selection of invasive tests for prenatal diagnosis, with those at increased risk being offered CVS and those at lower risk being offered amniocentesis [31]. It has also been used to help select fetuses for multifetal pregnancy reduction [32]. Additionally, if the parents opt for selective termination of an abnormal fetus, the increased nuchal translucency aids in the correct identification of the abnormal fetus. One difficulty with nuchal translucency risk assessment in twins is the issue of chorionicity. In a dizygous twin pregnancy, the risk of DS for each fetus is independent of each other, whereas in a monozygous twin pregnancy, the risk for one fetus should be the same as the risk for the other. In dizygous twin pregnancies, the risk for each fetus based on the individual nuchal translucency measurements is calculated, the two fetus-specific risks are added together, and the contribution of the serum markers is incorporated. In monozygous twin pregnancies, the two fetus-specific nuchal translucency measurements are averaged before the risk is calculated and before the contribution of the serum markers is incorporated. The geometric mean is calculated, because nuchal translucency measurements are logarithmically distributed [19]. The main limitation with this approach is the difficulty in many cases of twins of assigning zygosity, as opposed to chorionicity, with certainty. A significant number of monozygous twin gestations are dichorionic; therefore, zygosity cannot be assumed on the basis of chorionicity. Because of the difficulty of combining information from serum marker levels and nuchal translucency measurements in twin pregnancies, some screening centers ignore the serum marker results and rely on nuchal translucency only. This practice has the disadvantage of discarding potentially useful screening information [17]. A recent study [21] suggested that pseudorisk calculation has become outdated because it is theoretical, and an approach based on the actual distribution of markers in twins is now available. Screening via secondtrimester biochemistry is more valuable than using maternal age alone.
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A concern with nuchal translucency screening in twin pregnancies is that the false-positive rate of the test is higher than in singleton pregnancies. This increase is thought to be due to a higher prevalence of increased nuchal translucency measurements in chromosomally normal fetuses from monochorionic gestations. In a cohort of 448 twin fetuses, the nuchal translucency was above the 95th percentile in 7.3% of all fetuses and in seven of eight (88%) of those with trisomy 21. Sensitivity for trisomy 21 is similar to that in singleton pregnancies, but the specificity may be lower because nuchal translucency measurements may also be increased in chromosomally normal monochorionic twin pregnancies [33]. It has been hypothesized that increased fetal nuchal translucency may be an early manifestation of complications arising from the shared placental circulation in monochorionic pregnancies, such as twin-to-twin transfusion syndrome (TTTS). Subsequent reports have found that the median nuchal translucency measurement in unaffected monochorionic fetuses is not significantly different from the median nuchal translucency in unaffected singleton fetuses [34,35]. A study of 303 sets of monochorionic twins, of which 15% developed severe TTTS, found that fetal nuchal translucency was greater than the 95th percentile in 8.2% of fetuses. The prevalence of increased nuchal translucency was 17.4% in the pregnancies that developed TTTS compared with 6.6% in those that did not [35]. Another study also showed a higher incidence of increased nuchal translucency greater than the 95th percentile in at least one fetus in 7 of 30 (23%) pairs of monochorionic twins versus 10 of 70 (14.3%) of dichorionic twins [36]. In a study of 11 monochorionic twins, TTTS developed in the two pregnancies in which a fetus had increased nuchal translucency and abnormal ductus venosus flow [37]. Nuchal translucency evaluation on its own is likely to be a powerful maker for fetal aneuploidy in multiple gestations, although specificity may be decreased owing to the impact of monochorionicity. Larger studies are needed to determine whether, in the calculation of risk for trisomy 21 in monochorionic pregnancies, the nuchal translucency of the fetus with the largest or the smallest measurement (or the average of the two measurements) should be considered [38].
Combined nuchal translucency and first-trimester serum screening In singleton gestations, the combination of maternal age, nuchal translucency thickness, and first-trimester assays of free b-hCG and PAPP-A detects 82% of DS cases, with a 5% false-positive rate [30]. In twin pregnancies, interpreting nuchal translucency and serum markers together is problematic, because the concentration of each serum marker necessarily relates to the pregnancy, whereas nuchal translucency measurement is specific to each fetus [16]. Individual nuchal translucency measurements can be used separately to obtain fetus-specific risks or used together to obtain a pregnancy-specific risk, whereas serum markers can only be used to obtain a pregnancy-specific risk. One calculates a risk based on age and nuchal translucency, and then incorporates the serum markers. Likelihood ratios are
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calculated using the univariate or multivariate Gaussian distributions of the screening markers in unaffected and DS pregnancies [16]. Two examples of this calculation using a 29-year-old patient are presented in the next sections, one assuming monochorionic twins and the other assuming dichorionic twins. The patient’s first-trimester screening results for fetus 1 included a nuchal translucency of 1.35 MoM. Fetus 2 had a nuchal translucency of 1.98 MoM, PAPP-A of 0.93 MoM, and free b-hCG of 3.36 MoM. For monochorionic twins Step 1. The geometric mean of the two nuchal translucency measurements is 1.63 MoM, yielding a likelihood ratio of 2.25. Step 2. Multiply the likelihood ratio by the patient’s age-related risk: 2.25 1:1000 = 1:440. Step 3. Divide the markers by the median MoM in twins to give the singleton MoM equivalent. These MoMs are 1.86 for PAPP-A (Table 3) and 2.10 for free b-hCG. For PAPP-A, this is 0.93/1.86 and for free b-hCG, 3.36/2.10. This gives a likelihood ratio of 2.0. Step 4. Multiply the serum combined likelihood ratio by the age and nuchal translucency–related risk: 2.0 1:440 = 1:220. For dichorionic twins Step 1. The likelihood ratios for each fetus based on nuchal translucency of 1.35 and 1.98 are 0.7 and 11, respectively. Step 2. Multiply the likelihood ratios by half the patient’s age-related risk: 1/2 1:1000 = 1:2000. For fetus 1: 0.7 1:2000 = 1:2700. For fetus 2: 11 1:2000 = 1:180. Half the age-related risk is used because the background risk of each fetus in a twin pregnancy being affected with DS is, on average, half that of a singleton fetus. Step 3. Add the risks calculated in step 2 to obtain the pregnancy-related risk based on age and nuchal translucency: 1:2900 + 1:180 = 1:170. Step 4. Multiply the serum combined likelihood ratio by the age and nuchal translucency–related risk: 2.0 1:170 = 1:85. From the previous examples, it can be seen that the overall risk in dichorionic twins is higher owing to the higher chance of discordant karyotypes. The combination of nuchal translucency and the first-trimester serum markers free b-hCG and PAPP-A has been evaluated in a study of 159 twin pregnancies, 57 prospectively and 102 retrospectively [39]. The researchers simulated the impact of screening twin pregnancies discordant (one aneuploid and one euploid) and concordant (both aneuploid) for DS using biochemical parameters only, nuchal translucency alone, and the combined serum-sonographic screen. The underlying assumption in twins is that each fetus contributes 50% of the analyte level found in the maternal serum. In this model, it was estimated that 79.7% of
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Table 4 Modeled and actual detection rates in twin pregnancies for various marker combinations after correction of the biochemical parameters for the presence of a twin pregnancy (detection rates quoted at a fixed 5% false-positive rate) Marker combination Nuchal translucency and maternal age [39] Free b-hCG, PAPP-A, and maternal age [39] Nuchal translucency, free b-hCG, PAPP-A, and maternal age [39] Nuchal translucency, free b-hCG, PAPP-A, and maternal age [41]
Discordant for DS, detection rate (%)
Concordant for DS, detection rate (%)
75.2
75.2
51.5
55.4
79.7
81.3
75
No cases
twins discordant for DS and 81.3% of twins concordant for DS would be detected by the combined first-trimester screening (Table 4); however, further data are required in normal and affected twin pregnancies to make the algorithm for combining serum and sonographic risk assessment in twins more robust. The first case of a prospective diagnosis of DS in twins via prenatal firsttrimester combined nuchal translucency and serum screening was published in 2000 [40]. The same researchers then published a prospective series of 206 twin pregnancies undergoing first-trimester screening. Using a 1 in 300 risk cut-off, 28 of 412 (6.9%) fetuses screened positive [41]. Overall, 19 of 206 (9.2%) twin pregnancies had at least one fetus with an increased risk, and 12 of these 19 accepted invasive testing. There were four cases of DS, three of which (75%) were identified by first-trimester screening. All of the patients with twins discordant for DS underwent selective termination with subsequent normal delivery of the surviving twin. Although the study was based on small numbers, the detection rate of 75% is in line with theoretical projections based on pseudorisk calculations (Table 4). Nevertheless, it was not possible to provide meaningful measures of sensitivity, specificity, and false-positive rates, or to evaluate the contribution of nuchal translucency versus biochemical markers.
First- versus second-trimester screening Limited data are available directly comparing the efficacy of first- and secondtrimester screening for DS in twins. A 1999 series compared nuchal translucency measurement with second-trimester serum triple screening in 60 twin and 120 singleton pregnancies [30]. There were no significant differences in nuchal translucency thickness between singleton and twin pregnancies. Serum screening results showed that 15% of twin pregnancies were screen positive (risk of DS, 1 in 380 or higher) compared with 6% of singleton pregnancies. It was concluded that conflicting first- and second-trimester risk estimates and high false-positive
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rates would be problematic for counseling patients, and that further studies were needed to determine the preferable approach for screening in twins.
Higher order multiples Maymon et al [42] studied 79 fetuses in 24 patients, 10 of who subsequently underwent multifetal pregnancy reduction. Nuchal translucency measurement was feasible in higher order multiple gestations, and the distributions of the measurements obtained were found to be similar to those from singleton age-matched controls [42]. Because obtaining meaningful data from biochemical screening is impractical, nuchal translucency screening is the only method other than maternal age for screening for aneuploidy in higher order multiple gestations. Although some centers are offering CVS before multifetal pregnancy reduction [43], many others are not skilled in multifetal pregnancy CVS procedures and offer nuchal translucency screening as an alternative.
Summary Available methods for screening for DS in twin gestations include maternal age, first-trimester nuchal translucency, first-trimester combined screening, second-trimester genetic sonography, second-trimester quad screening, and combinations of tests across different gestational ages (Table 5). Biochemical screening is generally associated with DS detection rates at least 15% less than in singleton pregnancies. Nuchal translucency measurement may help close that gap, but the best available modeling data show approximately 75% to 85% detection rates, with a 5% false-positive rate. The performance of nuchal transTable 5 Estimated screening performance in twin pregnancies according to test used and chorionicity (detection rate for a 5% false-positive rate) Twin pregnancy Monochorionic (ie, concordant for DS) Dichorionic (nearly always discordant for DS) All twinsc Singletons a
Nuchal translucency (%)
Combined testa (%)
Integrated testb (%)
73
84
93
68
70
78
69 73
72 85
80 95
Maternal age, nuchal translucency, free b-hCG, and PAPP-A at 10–13 weeks. Maternal age, nuchal translucency, and PAPP-A at 10–13 weeks; and AFP, uE3, free b-hCG, and inhibin-A at 14–22 weeks (using total hCG instead of free b-hCG gives similar results). c Using the observation that 17% of affected twin pregnancies are monochorionic. From Wald NJ, Rish S, Hackshaw AK. Combining nuchal translucency screening and serum markers in prenatal screening for Down syndrome in twin pregnancies. Prenat Diagn 2003;23:588–92; with permission. b
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lucency combined with biochemical screening has not yet been fully evaluated in twins.
References [1] Filkins K, Kushnick N, Diamond N, et al. Prenatal diagnosis of Down syndrome in one of dizygotic twins. Am J Obstet Gynecol 1978;131(5):584 – 5. [2] Heller RH, Palmer LS. Trisomy 21 in one of twin fetuses. Pediatrics 1978;62(1):52 – 3. [3] Jenkins TM, Wapner RJ. The challenge of prenatal diagnosis in twin pregnancies. Curr Opin Obstet Gynecol 2000;12:87 – 92. [4] American College of Obstetricians and Gynecologists. ACOG Practice Bulletin Number 27. Prenatal diagnosis of fetal chromosomal abnormalities. Washington, DC7 ACOG; May 2001. [5] Meyers C, Adam R, Dungan J, et al. Aneuploidy in twin gestations: when is maternal age advanced? Obstet Gynecol 1997;89:248 – 51. [6] Cuckle H. Down’s syndrome screening in twins. J Med Screen 1998;5:3 – 4. [7] American College of Obstetricians and Gynecologists. ACOG Practice Bulletin Number 56. Multiple gestation: complicated twin, triplet and high-order multifetal pregnancy. October 2004. Washington, DC7 ACOG; 2004. [8] Odibo AO, Lawrence-Cleary K, Macones GA. Screening for aneuploidy in twins and higherorder multiples: is first-trimester nuchal translucency the solution? Obstet Gynecol Surv 2003; 58(9):609 – 14. [9] Evans MI, Goldberg JD, Dommergues M, et al. Efficacy of second-trimester selective termination of fetal abnormalities: international collaborative experience among the world’s largest centers. Am J Obstet Gynecol 1994;171:90 – 4. [10] Rochon M, Stone J. Invasive procedures in multiple gestations. Curr Opin Obstet Gynecol 2003; 16:167 – 75. [11] Nyberg DA, Souter VL, El-Bastawissi A, et al. Isolated sonographic markers for detection of fetal Down syndrome in the second trimester of pregnancy. J Ultrasound Med 2001;20(10): 1053 – 63. [12] Nyberg DA, Luthy DA, Resta RG, et al. Age-adjusted ultrasound risk assessment for fetal Down’s syndrome during the second trimester: description of the method and analysis of 142 cases. Ultrasound Obstet Gynecol 1998;12(1):8 – 14. [13] Wald NJ, Densem JW, George L, et al. Prenatal screening for Down’s syndrome using inhibin-A as a serum marker. Prenat Diagn 1996;16:143 – 53. [14] Cuckle H. Improved parameters for risk estimation in Down’s syndrome screening. Prenat Diagn 1995;15:1057 – 65. [15] Spencer K, Salonen R, Muller F. Down’s syndrome screening in multiple pregnancies using alpha fetoprotein and free beta hCG. Prenat Diagn 1994;14:537 – 42. [16] Neveux LM, Palomaki GE, Knight GJ, et al. Multiple marker screening for Down syndrome in twin pregnancies. Prenat Diagn 1996;16:29 – 34. [17] Wald NJ, Rish S, Hackshaw AK. Combining nuchal translucency screening and serum markers in prenatal screening for Down syndrome in twin pregnancies. Prenat Diagn 2003;23:588 – 92. [18] Sepulveda W, Sebire NJ, Hughes K, et al. The lambda sign at 10–14 weeks gestation as a predictor of chorionicity in twin pregnancies. Ultrasound Obstet Gynecol 1996;7:421 – 3. [19] Wald N, Cuckle H, Wu T, et al. Maternal serum unconjugated oestriol and human chorionic gonadotropin levels in twin pregnancies: implications for screening for Down’s syndrome. Br J Obstet Gynaecol 1991;98:905 – 8. [20] Canick JA, Kellner L. First trimester screening for aneuploidy: serum biochemical markers. Semin Perinatol 1999;23:359 – 68. [21] Muller F, Dreux S, Dupoizat H, et al. Second-trimester Down syndrome maternal serum screening in twin pregnancies: impact of chorionicity. Prenat Diagn 2003;23:331 – 5.
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[22] Noble PL, Snijders RJM, Abraha HD, et al. Maternal serum free beta hCG at 10 to 14 weeks of gestation in trisomic twin pregnancies. Br J Obstet Gynaecol 1997;104:741 – 3. [23] Raty R, Virtanen A, Koskinen P, et al. Maternal midtrimester serum AFP and free b-hCG levels in in vitro fertilization twin pregnancies. Prenat Diagn 2000;20:221 – 3. [24] Maymon R, Jauniaux E. Down’s syndrome screening in pregnancies after assisted reproductive techniques: an update. Reprod Biomed Online 2002;4:285 – 93. [25] Liao AW, Heath V, Kametas N, et al. First-trimester screening for trisomy 21 in singleton pregnancies achieved by assisted reproduction. Hum Reprod 2001;10:1501 – 4. [26] Orlandi F, Rossi C, Allegra A, et al. First trimester screening with free beta-hCG, PAPP-A and nuchal translucency in pregnancies conceived with assisted reproduction. Prenat Diagn 2002; 22(8):718 – 21. [27] O’Brien JE, Dvorin E, Drugan A, et al. Ethnic and racial specific variation in multiple marker biochemical screening (MMBS): hCG and uE3 also require separate databases. Obstet Gynecol 1997;89:355 – 8. [28] O’Brien JE, Dvorin E, Yaron Y, et al. Differential increases in AFP, hCG and uE3 in twin pregnancies: impact on attempts to quantify Down syndrome screening calculations. Am J Med Genet 1997;73:109 – 12. [29] Malone FD, Dalton ME. First-trimester sonographic screening for Down syndrome. Obstet Gynecol 2003;102:1066 – 79. [30] Maymon R, Dreazen E, Rozinsky S, et al. Comparison of nuchal translucency measurement and second-trimester serum screening in twin versus singleton pregnancies. Prenat Diagn 1999;19: 727 – 31. [31] Sebire NJ, Noble PL, Psarra A, et al. Fetal karyotyping in twin pregnancies: selection of technique by measurement of fetal nuchal translucency. Br J Obstet Gynaecol 1996;103: 887 – 90. [32] Maymon R, Jauniaux E. Down’s syndrome screening in pregnancies after assisted reproductive techniques: an update. Reprod Biomed Online 2002;4:285 – 93. [33] Sebire NJ, Snijders RJM, Hughes K, et al. Screening for trisomy 21 in twin pregnancies by maternal age and fetal nuchal translucency thickness at 10–14 weeks of gestation. Br J Obstet Gynecol 1996;103:999 – 1003. [34] Spencer K. Screening for trisomy 21 in twin pregnancies in the first trimester: does chorionicity impact on maternal serum free b-hCG or PAPP-A? Prenat Diagn 2001;14:319 – 20. [35] Sebire NJ, Souka A, Skentou H, et al. Early prediction of severe twin-to-twin transfusion syndrome. Hum Reprod 2000;15:2008 – 10. [36] Monni G, Zoppi MA, Ibba RM, et al. Nuchal translucency in multiple pregnancies. Croat Med J 2000;41:266 – 9. [37] Matias A, Montenegro N, Areias JC. Anticipating twin-twin transfusion syndrome in monochorionic twin pregnancy: is there a role for nuchal translucency and ductus venosus blood flow evaluation at 11–14 weeks? Twin Res 2000;3(2):65 – 70. [38] Nicolaides KH. Nuchal translucency and other first-trimester sonographic markers of chromosomal abnormalities. Am J Obstet Gynecol 2004;191:45 – 67. [39] Spencer K. Screening for trisomy 21 in the first trimester using free b HCG and PAPP-A combined with fetal nuchal translucency thickness. Prenat Diagn 2000;20:91 – 5. [40] Spencer K, Nicolaides KH. First trimester prenatal diagnosis of trisomy 21 in discordant twins using fetal nuchal translucency thickness and maternal serum free b-hCG and PAPP-A. Prenat Diagn 2000;20:683 – 4. [41] Spencer K, Nicolaides KH. Screening for trisomy 21 in twins using first trimester ultrasound and maternal serum biochemistry in a one-stop clinic: a review of three years experience. BJOG 2003;110:276 – 80. [42] Maymon R, Dreazen E, Tovbin Y, et al. The feasibility of nuchal translucency measurement in higher order multiple gestations achieved by assisted reproduction. Hum Reprod 1999;14(8): 2102 – 5. [43] Eddleman KA, Stone JL, Lynch L, et al. Chorionic villus sampling before multifetal pregnancy reduction. Am J Obstet Gynecol 2000;183:1078 – 81.
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[44] Smith-Bindman R, Hosmer W, Feldstein VA, et al. Second-trimester ultrasound to detect fetuses with Down syndrome: a meta-analysis. JAMA 2001;285:1044 – 55. [45] Wald NJ, Densem JW. Maternal serum free b-human chorionic gonadotropin levels in twin pregnancies: implications for screening for Down syndrome. Prenat Diagn 1994;14:319 – 20. [46] Watt HC, Wald NJ, George L. Maternal serum inhibin-A levels in twin pregnancies: implications for screening for Down’s syndrome. Prenat Diagn 1996;16:927 – 9. [47] Wald NJ, Densem JW, Smith D, et al. Four-marker serum screening for Down’s syndrome. Prenat Diagn 1994;14:707 – 16. [48] Wald NJ, Densem JW, George L, et al. Inhibin-A in Down’s syndrome pregnancies: revised estimate of standard deviation. Prenat Diagn 1997;17:285 – 90. [49] Nicolaides KH, Snijders RJM, Cuckle HS. Correct estimation of parameters for ultrasound nuchal translucency screening. Prenat Diagn 1998;16:29 – 34. [50] Wald NJ, George L, Smith D, et al. Serum screening for Down’s syndrome between 8 and 14 weeks of pregnancy. Br J Obstet Gynaecol 1996;103:407 – 12.
Clin Perinatol 32 (2005) 387 – 402
Management of High-Order Multiple Gestation John P. Elliott, MDa,b,c,* a
Phoenix Perinatal Associates, a Division of Obstetrix Medical Group, 1331 N. 7th Street, Suite 275, Phoenix, AZ 85006, USA b Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Banner Good Samaritan Medical Center, 1111 E. McDowell Road, Phoenix, AZ 85006, USA c Department of Obstetrics and Gynecology, University of Arizona Health Sciences Center, 1501 N. Campbell Avenue, Tucson, AZ 85724, USA
Human reproduction is most efficient when there is a singleton fetus. Each additional fetus affects the outcome of the pregnancy by reducing the gestational age at delivery by approximately 3.5 weeks (Table 1). There is a corresponding effect on the birth weight of fetuses in a multiple gestation. This is influenced both by prematurity and also an increased incidence of nutritionally challenged fetuses in multiple gestation pregnancies. These facts are illustrated in Table 2 summarizing data from Barbara Luke on outcomes of multiple births from the University Consortium in multiple births compared with national data for singleton gestations. Table 2 also illustrates the cost of medical care for the mother and her babies. The challenge of improving outcome for multiple gestations involves overcoming the factors that predispose to prematurity and low birth weight.
Evolution of the problem High-order multiple gestation (HOM) refers to triplet and quadruplet pregnancies. Quintuplets and more are called grand-multiple gestations. The incidence of multiple gestation has increased dramatically since approximately 1985. There are various reasons for the increase, including delayed childbearing, but the dominant driving force is advances in reproductive endocrine technologies. * Phoenix Perinatal Associates, a Division of Obstetrix Medical Group, 1331 N. 7th Street, Suite 275, Phoenix, AZ 85006. E-mail address:
[email protected] 0095-5108/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.clp.2005.04.001 perinatology.theclinics.com
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Table 1 Gestational age at delivery No. of live born babies
Mean age at delivery
Singleton Twins (spontaneous) Twins (Reduced) Triplets Quadruplet Quintuplet
40 weeks 36.5 weeks 35.5 weeks 33 weeks 29.5 weeks 29 weeks
Spontaneous high-order multiple gestations can be approximated using Hellen’s Rule, which starts with the twin rate in a population and then squares that to give the triplet rate and cubes the twin rate to give the occurrence of quads, and so forth. Thus, in the United States, with the twin rate at 1:83, the number of spontaneous triplets would be 1:832 or 1:6889, and the number of spontaneous quadruplets would be 1:833 or 1:571,787. This would predict about eight spontaneous quadruplet pregnancies in the United States per year (4,000,000 births). Table 3 compares the incidence of HOM gestations in 1997 with that of 2002. The number of quadruplet and quintuplet pregnancies has decreased slightly, while triplets continue to increase. Twins now represent over 3% of pregnancies. There is a higher perinatal mortality rate in HOM gestation (51.5/1000 for triplets and 127/1000 for quadruplets) [1]. Long-term morbidity is also increased in multiple gestations. Yokoyama and colleagues [2] estimate the long-term handicap risk in Table 4.
Solutions for the problem Clearly, no couple undergoes infertility therapy hoping to conceive an HOM gestation, although twins are sometimes considered an economically beneficial outcome. HOM pregnancies are usually unanticipated consequences of the ef-
Table 2 University Consortium on multiple Births Gestation Singleton
a
39.3 wk
a
Birth weight a
3358 g
Twins (2,939)
35.4 wk
2279 g
Triplets (178)
32.6 wk
1725 g
Quadruplets (10)
30.5 wk
a
1267 g
Length of stay 3.2 3.2 14.2 6.3 26.0 13.7 39.0 21.0
b
d db days days days days days days
Cost $1,892 $5,940b $22,729 $8,688 $65,771 $14,704 $95,007 $31,637
National average. University of Michigan average in 2001; mean of vaginal + cesarean births. Courtesy of B. Luke, University of Miami School of Medicine, Miami, Florida. b
Both b
$7.932b $54,146 $212,017 $441,665
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management of high-order multiple gestation Table 3 Incidence of high-order multiple gestation (National Vital and Health Statistics Report) 1997 Twins Triplets Quadruplets Quintuplets
104,137 6,148 510 79
2002 (2.6%) (0.2%) (0.01%) (0.001%)
125,134 6,898 434 69
(3.1%) (0.2%) (0.01%) (0.001%)
fort to produce a singleton gestation. The advent of blastocyst implantation has improved the success rate for in vitro procedures but has created some additional problems for some successful pregnancies. There is an increased identical twinning rate in IVF pregnancies. The consequences of monozygotic twinning depend on the age of the embryo at the time of the split. Early (b 3 days) events result in dichorionic/diamniotic (di/di) identical twins, but later (N day 3, b day 8) splitting causes monochorionic/diamniotic (mo/di) placentation. With blastocyst transfer, the embryos are at day 5 of life, thus any twinning event will produce mo/di twins, which creates a 5% to 30% risk of developing acute twin-twintransfusion syndrome (TTTS). The improved success of blastocyst transfer has allowed infertility specialists to transfer fewer embryos with a higher success rate [3] but has complicated some pregnancies. This strategy of implanting fewer embryos will reduce the rate of HOM gestation. Once an HOM gestation has occurred, life has changed for the parents. What was expected to be a joyous discovery that pregnancy has occurred turns into a shocking reality that 3 or more embryos are developing. The parents are presented with three options. The first is to abort the entire pregnancy, which is virtually impossible for an infertility couple to do considering the cost of infertility treatments and the fact that life has been created. The second option is to selectively reduce one or more embryos. This generally leaves a twin gestation, which is considered to be at increased, but acceptable risk, compared with a singleton gestation [4,5]. Selective reduction is an unwanted option for all infertility patients faced with the problem of an HOM gestation. It is chosen only as a perceived ‘‘lesser of two evils.’’ Counseling by reproductive specialists is often directive; patients are told that they cannot successfully carry an HOM gestation, that they will have ‘‘brain-damaged babies,’’ and that the only way to reduce that risk is to selectively reduce to twins. This approach is wrong. Table 4 Risk of long-term morbidity
Singleton Twin Triplet Quadruplets and quintuplets
Per baby
Per pregnancy
2% 4% 9% 11%
2% 7% 22% 50%
Data from Yokoyama Y, Shimizu T, Hayakawa K. Incidence of handicaps in multiple birth and associated factors. Acta Genet Med Gemellol 1995;44:881–91.
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Counseling should be nondirective. A perinatologist should be involved in the discussion and the risks and benefits of both selective reduction and carrying the HOM gestation presented to the parents. Outcome data are important for the couple to make an informed decision. It is also helpful for the couple to speak with other families that have chosen both to reduce and to carry. After considering the medical/obstetric/neonatal risks and the psychosocial/moral/ economic impact on their family, each couple must decide on carrying their HOM gestation or selective reduction. The best solution to the problem is to not create an HOM gestation. Once the problem occurs, the challenge for the health care team is to obtain the best outcome possible for these families that choose to carry an HOM gestation.
Factors affecting outcome in high-order multiple gestations The mean gestational age at delivery of a multifetal pregnancy is strongly correlated with the number of ‘‘living’’ fetuses in the uterus. Table 1 is based on delivering two, three, four, or more live babies. This fact is illustrated by a report by Collins and Bleyl [6] that gave outcome data on 71 quadruplet pregnancies. The mean gestational age at delivery was reported to be 31.4 weeks, but if all pregnancies that did not deliver four live babies were removed from the analysis, the mean gestational age at delivery dropped to 29.7 weeks. The other pregnancies delivered at an age that corresponded to the number of live babies. A second factor influencing outcome is the placentation of the HOM gestation. As previously mentioned, blastocyst transfer will produce mo/di twins that can then be incorporated in an HOM pregnancy. Anytime there is one or more monochorionic placentas, the risk of TTTS is added to those of an HOM pregnancy. Acute severe TTTS resulting in severe oligohydramnios in the donor twin (stuck twin syndrome) occurs in 5% to 30% of mo/di twins. Heyborne and colleagues [7] reported a diagnosis of TTTS in 3 of 96 (3.1%) mo/mo twin pregnancies. In our experience, although TTTS occurs in HOM pregnancies, there appears to be some modulation afforded by the other fetuses present in the uterus (placenta plus amniotic fluid volume). The cases we have seen develop later (22–27 weeks) and respond more favorably to intervention with therapeutic amniocentesis than cases of TTTS developing in mo/di twins. Treatment of TTTS in an HOM gestation should be similar to that in a mo/di twin gestation. Early diagnosis is crucial to be able to initiate appropriate therapy in a timely manner, which will improve outcome. Ultrasound surveillance of pregnancies with monochorionic placentas should occur at 2-week intervals from 16 to 26 weeks. Any trend toward discordancy in fetal size or amniotic fluid volume should prompt more frequent ultrasound assessment. Intervention in patients with early TTTS (stage I or II in the Quintero staging system [8]) is generally initiated with aggressive therapeutic amniocentesis [9]. There are no reports of selective laser photocoagulation of communicating vessels in HOM gestations. Therapeutic amniocentesis should be initiated immediately when the deepest
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vertical pocket around the recipient baby is 8 cm or more [10] and the intent of treatment is to remove as much amniotic fluid as possible (even leaving oligohydramnios). Failure to remove adequate fluid decreases the therapeutic benefit of the procedure. Repeat therapeutic amniocentesis should be done as soon as the deepest pocket reaccumulates to 8 cm or more. A very significant factor in outcome for any multiple gestation is the parity of the mother. Patients with a history of one or more term deliveries have an advantage in carrying an HOM gestation. Elliott and Radin [1] reported that in 57 quadruplet pregnancies parous patients delivered at a greater gestational age than nulliparous by 1.4 weeks. Ron-El and colleagues [11] also noted that observation with parity extending the age at delivery by 2 weeks over first time pregnant patients. Other reports support this observation [12,13]. A recent report by Aina-Mumuney and colleagues [14] documents a 3-week benefit favoring parity over nulliparity. Maternal height is the final factor influencing outcome. Blickstein and colleagues [15] reported that nulliparous women taller than 165 cm delivered triplets at a heavier birth weight and were at a lower risk of delivering very low birth weight triplets. Unpublished data from our practice also support a longer gestational age at delivery for patients 5V 3W or taller compared with 5V 2W or shorter.
Strategies to improve outcome in high-order multiple gestation Our approach to HOM pregnancies has evolved over the last 20 years. It is an aggressive proactive management style that anticipates problems and attempts to avert the consequences rather than react to the circumstances once a complication starts to happen. The most serious risks in an HOM gestation include: preterm labor (PTL), which occurs in 76% to 90% of HOM gestations [16,17]; pregnancy-induced hypertension (PIH) (35% of triplets [16], 72% of quadruplets [17]); preterm premature rupture of the membranes (20%) [16,17]; anemia (25%) [16,17]; gestational diabetes (7% of triplets, 19% of quadruplets) [16,17]; and incompetent cervix (14%) [6]. Small for gestational age (SGA) (birth weight below the 10th percentile for a single gestation) and intrauterine growth restriction (IUGR) (birth weight below the 3rd percentile for a singleton gestation) occur in approximately 20% and 9%, respectively, of triplets [18] and 10%, and 1%, respectively, of quadruplets [17]. Our aggressive proactive approach to care involves reducing the occurrence of these complications or minimizing their effect on the pregnancy.
Presenting the management plan to the patient The patient and her family are frequently sophisticated and knowledgable about their pregnancy. They are aware that there are significant risks involved
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in carrying an HOM gestation. Most of them will have already gathered a lot of information from the internet or from support groups. I encourage patients to be as knowledgeable as possible and if they have not contacted one of the National support groups, I will suggest that they do so immediately. Mothers of Supertwins can be reached at (631) 859-1110 and
[email protected]; the Triplet Connection can be reached at (209) 474-0885 and tripletconnection.org. Besides providing a large packet of information, the parents are given names of other parents of HOM in their area that can provide a reality check for the family for the hundreds of practical questions about carrying an HOM gestation and then caring for the family after delivery. The patient wants her doctor to outline a strategy for her of how the problems of HOM pregnancy will be handled. A ‘‘game plan’’ is practical and psychologically reassuring for the patient. I have found that the attitude and determination of the mother are critical to the success of the pregnancy. Although it cannot be measured, the willingness of the mother to endure the physical and psychological challenges of her HOM gestation affect outcome. Every organ system of her body will be affected. Early in the pregnancy she will experience nausea and vomiting, although true hyperemesis gravidarum occurs in only 10% of cases and the need for parenteral nutrition is infrequent [17]. Uterine distention occurs early and becomes extreme beyond 30 weeks. Backache, pressure, constant fetal movement, sleeplessness, heartburn, constipation, hemorrhoids, headaches, leg cramps, urinary frequency, inability to be comfortable in any position, difficulty walking, and itching all make the mother miserable. The psychologic stress of an HOM gestation is equally a problem for the family. Anxiety about the risk to her babies, guilt about not performing her usual work or household activities, inability to care for other children, depression, and sleep deprivation can be a burden to the mother and affect her attitude. I tell parents that their lives will change carrying their HOM gestation. If the result of the pregnancy is three or four or five healthy ‘‘normal’’ children, they will be blessed; however, if one or more of their children die or have long-term handicaps, their lives will be challenged forever. This is the ultimate motivation.
Events in the first trimester The first trimester is really one of adjustment in an HOM pregnancy. It should be a time of acquiring knowledge and enduring the nausea. Prenatal vitamins and folic acid are continued from preconception. At week 12 to 15, we prescribe 81 mg/d baby aspirin and 2000 mg/d supplemental calcium (4 Tums tablets have 2000 mg of calcium), which may lower the risk of PIH [19]. We recommend that each patient purchase Dr. Barbara Luke’s book When You’re Expecting Twins, Triplets, or Quads [20]. Weight gain needs to be 2 to 3 lbs/wk to achieve an ideal weight gain of 50 to 75 lbs for a triplet pregnancy and 75 to 100 lbs for a quadruplet gestation. It is crucial to stress that 75% of this weight gain should
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be achieved by 24 to 26 weeks. Luke and colleagues [21] documented the association between fetal growth and length of gestation in triplet pregnancies. Adequate weight gain by 24 weeks gestation is shown to be an important factor affecting fetal growth and length of gestation. Following these guidelines for weight gain and nutrition, Francois and colleagues [17] reported neonatal outcomes of 30 quadruplet pregnancies in our practice. The mean weight gained was 66.3 F 21 lbs. The mean birth weight for 120 babies was 1542.2 F 384 g. The incidence of SGA (below the 10th percentile) was 10% and IUGR was 0.8%. The lack of significant SGA in our patients contributed to the excellent outcome.
The second trimester Aggressive assessment of the HOM pregnancy begins in the second trimester. Targeted ultrasound assessment is performed at 18 weeks to identify any congenital malformations. If there is monochorionic placentation, ultrasound is done every 2 weeks from 16 to 26 weeks to assess fetal size and amniotic fluid volume (AFV) discordancy. If each fetus has its own placenta and amnion, growth ultrasounds are done every 3 to 4 weeks. Vaginal ultrasound to assess cervical length and funneling should be performed at 18 weeks and every 1 to 2 weeks through 24 weeks to assess for risk of incompetent cervix. Although not reported in the literature, it is our experience that approximately 5% of twins and 12% of HOM will have an incompetent cervix. If the cervical length is 3.0 cm or more, ultrasound can be done every 2 weeks; however, if it is less than 3 cm, ultrasound should be done weekly or more frequently. Even nulliparous patients with an HOM gestation are at risk of a functionally incompetent cervix. This is probably due to increased levels of relaxin, a hormone that causes softening and dilation of the cervix [22], rather than a structural weakness in the cervical collagen matrix. Cervical shortening should prompt careful assessment for contractions. If contractions are occurring, tocolysis should be considered. It is our experience that PTL is more often the cause of cervical change than an incompetent cervix. If uterine activity is not occurring, strong consideration should be given to placing a cervical cerclage [23]. Cervical length between 2.5 cm and 3 cm prompts contraction assessment and usually a repeat cervical length ultrasound in 4 to 7 days. Stable cervical lengths can be followed clinically. When the cervical length decreases to 2.0 to 2.5 cm in an asymptomatic patient, consideration is given to placing a cerclage. At cervical lengths shorter than 2.0 (in the absence of PTL), a cerclage is almost always indicated if the gestational age is 18 to 26 weeks. In our practice, cervical cerclage is a necessary therapeutic intervention in approximately 12.5% of HOM gestations. Prophylactic cervical cerclage has not been shown to be helpful in HOM gestations [24].
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Prevention of preterm labor Preterm labor detection and treatment is the single most important aspect of the prenatal care of an HOM gestation. PTL occurs in approximately 76% of triplets [16] and 90% of quadruplets [17]. PTL occurs early in HOM pregnancies, frequently in the second trimester. The mean gestational age for PTL to occur in our quadruplets was 23.1 F 6.9 weeks [2]. This emphasizes the need to initiate aggressive surveillance to facilitate early diagnosis of PTL. It is extremely difficult in singleton gestations to detect PTL in a timely manner and is even more difficult in an HOM pregnancy. Capable, educated, motivated women are able to accurately detect approximately 15% of uterine contractions [25,26]. Education is given to all patients about the signs and symptoms of PTL, including: cramping, dull lower backache, pelvic pressure, change in vaginal discharge, spotting, pressure in the inner thighs, intestinal cramping, and an overall feeling that things just aren’t right. They are instructed to report these symptoms immediately. Because self-reporting of signs and symptoms of PTL is not adequate to allow reliable early detection of PTL, we use home contraction monitoring (Matria Health Care Corporation, Marietta, GA) [27]. As a general principal, we manage our HOM gestations at home. It is psychologically better when a patient is in familiar surroundings, and nutritionally she will eat better, too. Knowledge of uterine activity is critical to making a diagnosis of PTL and managing that complication when it occurs. We start home uterine activity monitoring at 18 weeks in quadruplets and quintuplets and 20 weeks in triplets.
Background uterine activity An important concept in the detection and prevention of PTL is the understanding of background uterine activity. The uterus is smooth muscle, which has the capability of contracting. It is well known that the pregnant uterus contracts early in the first trimester until delivery and well into the postpartum period. Braxton-Hicks contractions are an example. It is my opinion that background uterine activity is important in determining which patient will develop PTL and when that will occur. Background uterine activity can be assessed by way of home uterine activity monitoring. Two hours of uterine activity are generally recorded each day in separate 1-hour sessions. The number of contractions occurring over a week of monitoring is averaged so that a background contraction assessment is available as the number of contractions per hour per week (ctx/hr/wk). This average is updated each week to give the clinician an idea of the current status of the uterus. If PTL involves contractions with some frequency (eg, 8/hr) and cervical change, it is my contention that a uterus that is already contracting more frequently will respond to some stimulus (which causes increased contractions acutely) by developing PTL, compared with a uterus that is relatively quiet (low background contractile activity) that may respond to the same stimulus by simply increasing contractions, but not to the level causing
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cervical change. For example, let us consider two hypothetical patients—one who has a background uterine contraction frequency of 1.5 ctx/hr/wk, and another who is having 4.3 ctx/hr/wk. If we superimpose an event on both of these patients, such as a urinary tract infection that will cause 5 ctx/hr to occur, the first patient increases to 6.5 ctx/hr and is unlikely to change her cervix, but the second patient is now at 9.3 ctx/hr and is in danger of cervical change and a diagnosis of preterm labor. Many factors affect this background uterine activity; some will increase contractions, while others will decrease contractions. Among the influences that will increase background uterine contractions is gestational age. As gestation increases, so do the number of contractions in a normal pregnancy [28,29]. Time of day influences contractions with an increase from about 5 pm to 3 am due to normal diurnal release of cortisol from the adrenal gland [28]. Endogenous hormone activity also affects contractions, with estrogen increasing contractions (estriol surge) [30] and progesterone decreasing contractions [31]. For HOM gestations, the size of the uterus at any gestational age affects contractions, with each additional fetus increasing background activity [32,33]. Physical activity will increase contractions [34], and contractile activity is decreased by bed rest. Infections (cystitis, pyelonephritis, and appendicitis [35]) all can increase contractions, and certainly early chorioamnionitis is associated with PTL. Stress has long been thought to increase uterine activity, and we have documented that anxiety and emotional influences can generate contractions, probably as a result of the elaboration of hormones (epinephrine and norepinephrine). Medications will also affect contractions, with some causing an increase (eg, oxytocin, prostaglandin preparations, Cytotec [misoprostol], and ergot derivatives) while others will cause a decrease (eg, magnesium sulfate [MgS04], beta sympathomimetic drugs [terbutaline, ritodrine, and so forth], prostaglandin synthetase inhibitors [indomethacin, Motrin (ibuprofen), Toradol (ketorolac tromethamine), and so forth], and calcium channel blockers [nifedipine]). Steroids may cause an increase in contractions when administered to pregnancies at risk of preterm delivery. Betamethasone caused an increase in contractions and PTL in HOM gestations when given to enhance pulmonary maturity [36]. Why do some patients with a high risk of PTL go into PTL, while others do not? For example, why don’t all patients with triplets or quadruplets develop PTL? It is my belief that the background contractions are the answer.
The concept of threshold of contractions Although there have been no studies to formally establish threshold values for the level of background contractions that increases the risk of PTL, Garite and colleagues [32] established the mean uterine activity 48 hours before the onset of PTL was 3.5 ctx/hr, which increased to 5.3 ctx/hr 24 hours before PTL. Elliott and Radin [37] independently observed that a background uterine activity
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of 3.5 ctx/hr was an important dividing line that illustrates this principal. Betamethasone given to HOM gestations increased the rate of uterine contractions. In those patients whose baseline uterine activity was less than 3.5 ctx/hr for the 48 hours before the first dose of betamethasone, there was a statistically increased number of ctx/hr, but no patients developed cervical change and no patients delivered. However, if the baseline contractions were greater than 3.5/hr, labor with cervical change was more frequent, and delivery occurred in four patients. Thus, if the uterine activity is low when a stimulus occurs that will result in an increase in contractions, labor may not occur; however, if the uterus is more active when the same stimulus occurs, labor may develop with possible preterm delivery. We have arbitrarily selected 3.5 ctx/hr as a meaningful threshold of background uterine activity.
Prevention of preterm labor in high-order multiple gestation I believe that in HOM gestations it is important to measure the background uterine activity and then to use available therapies to maintain the uterine activity below 3.5 ctx/hr/wk. The possible interventions that could reduce contractions include: decreased activity (bed rest), psychologic reassurance, and tocolytic drugs. Although bed rest has not been shown to be beneficial as a ‘‘stand-alone’’ treatment of PTL, it is my opinion that it is beneficial, because it can reduce background contractions, which may make it more difficult for any given stimulus to start PTL. Biofeedback techniques may also help decrease psychologic tension and anxiety. We start our HOM gestations on modified bed rest at 20 weeks, where the patient is requested to be off her feet and preferably recumbent (bed, couch, recliner or chaise lounge). Tocolytic drugs are the main intervention in our aggressive prophylactic approach to PTL prevention in HOM gestations. It is relatively well established that tocolytic medications will work for a minimum of 48 hours in singleton pregnancies; efficacy beyond that time is limited in the literature due mainly to decreasing dosage of the drug or switching to an oral agent which is less effective. Elliott JP [38] established in a large number of singleton and twin pregnancies the efficacy of magnesium sulfate as a tocolytic agent. PTL in an HOM gestation is a very difficult process to control with tocolytic drugs. It is frequently necessary to use multiple drugs (MgS04, terbutaline, indomethacin) in maximum dosages to arrest PTL, and there is always the possibility of failure, which would result in a premature delivery. Aggressive use of tocolytic therapy is associated with a risk of complications, most commonly pulmonary edema. It is our opinion that prevention is preferable to treatment. Our drug of choice for prophylaxis is a terbutaline pump. We reported our successful use of this form of tocolysis in an attempt to keep the background uterine activity less than 3.5 ctx/hr [39]. Of 15 triplet and quadruplet pregnancies that received prophylactic terbutaline pump tocolysis, 5 (33%) eventually developed PTL. This is in contrast to the 75% to 90% rate of PTL in
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other publications [1,16]. It is important to note that higher initial doses of terbutaline (basal infusion rate of 0.066-0.076 mg/hr, approximately 16% greater than singleton pregnancies) were needed in HOM gestations due to increased renal clearance of the drug. Some pregnancies required basal infusion doses of 0.15 mg/hr. This physiology is also a factor when treating HOM patients who develop true PTL. Elliott and Radin [40] published data showing that higher doses of MgS04 had to be administrated to achieve therapeutic serum levels in HOM gestations compared with singleton pregnancy. It is important to remember that therapeutic serum levels are necessary for the tocolytic drug to be successful. Frequently, too little drug is administered to achieve a therapeutic effect and when contractions don’t stop, the drug is declared a failure and is discontinued, when in reality the dosage only needed to be increased to successfully tocolyse the patient.
The third trimester We perform routine fetal fibronectin testing in our HOM gestations starting at 24 weeks. This is repeated every 2 weeks until 32 weeks. Peaceman and colleagues [36] demonstrated a preterm delivery rate of less than 1% within 2 weeks of a negative fetal fibronectin test, whereas there was approximately a 17% risk of delivery in the next 2 weeks with a positive test. Unpublished data from our practice for HOM gestations show a 6% risk of delivery in the 2 weeks following a negative test and an approximately 50% delivery rate in the 2 weeks following a positive test. A positive fetal fibronectin test prompts us to administer corticosteroids (if not already given) and weekly office visits with a cervical examination. Very close attention should be paid to contractions with aggressive tocolysis initiated early when contractions increase or labor begins. Routine testing is done for gestational diabetes, which occurs in approximately 20% of quadruplet gestations [17]. I am not very aggressive with initiation of insulin therapy, because I believe that a small increase in maternal blood glucose is probably beneficial for fetal nourishment and growth. Antepartum fetal assessment is technically challenging with the fetal monitor, so biophysical profile testing is used when indicated. Elliott and Finberg [41] established that routine testing should start at 32 weeks and earlier testing should be done when there is either PIH or one or more SGA fetuses at a gestational age compatible with delivery if fetal jeopardy is established with the biophysical profile. PIH is frequent in HOM gestations, and often HELLP syndrome is present. We will aggressively use dexamethasone to treat HELLP syndrome when it develops in our HOM pregnancies. Heller and Elliott [42] reported the successful use of steroids to treat HELLP syndrome in these circumstances. Although the therapy is not 100% successful, days to many weeks can be gained using this treatment, and any gestational gain affects three or four babies, emphasizing the importance of any lengthening of gestation.
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The grande finale Delivery represents the final obstetrical report card for an HOM gestation. We deliver our HOM pregnancies by way of cesarean section, as has been documented to occur in over 90% of patients with triplets [43]. Although vaginal delivery is not inherently a more risky alternative, cord prolapse and placental abruption may complicate attempted vaginal delivery. Our goal is an elective delivery. We choose 35 weeks no days for delivery of triplets and 34 weeks no days for quadruplets and quintuplets. The reason for this is respect for the physical and psychologic well-being of the mother and the excellent neonatal outcome of babies born at that gestational age, although we do not advocate elective earlier delivery of HOM gestations or other pregnancies solely because of overall excellent neonatal outcome. In general, it is not appropriate to deliver a patient unless the dangers of leaving the patient pregnant exceed the risk to the fetus in the nursery. A delivery at 36 weeks is better for a baby than a delivery at 35 or 34 or 33 weeks [44]. In our quadruplets, elective delivery occurred in 22.7% of our patients, which was second to PIH (40.3%) as the reason for delivery [17].
Results of our management strategy In the last 20 years, we have cared for over 500 triplet pregnancies, over 70 quadruplets, and 4 quintuplets. Francois and colleagues [45] reported our Table 5 Maternal morbidity and obstetrical complications of quadruplet pregnancy Variable Antepartum hospitalization Hyperemesis gravidarum Hyperemesis gravidarum, TPN required Gestational diabetes mellitus A1 Gestational diabetes mellitus A2 Anemia (Hct b30%), no antepartum transfusion required Anemia (Hct b30%), antepartum transfusion required Antepartum bleeding Placenta previa Pre-eclampsia HELLP syndrome Preterm premature rupture of the membranes Preterm labor Twin-to-twin transfusion syndrome Chorioamnionitis
Incidence (%) 100 9.4 3.1 18.8 3.1 25 15.6 3.1 0 71.9 12.5 18.8 90.6 3.1 6.3
Abbreviation: TPN, total parenteral nutrition. Data from Francois K, Sears C, Wilson R, et al. Maternal morbidity and obstetrical complications of quadruplet pregnancy: twelve years experience at a single institution [abstract]. Am J Obstet Gynecol 2001;184:S174.
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management of high-order multiple gestation Table 6 Neonatal outcomes of quadruplet pregnancy Variable Intrauterine growth restriction Small for gestational age Chromosomal abnormalities Congenital malformations Respiratory distress syndrome Transient tachypnea of the newborn Apnea Suspected or culture-proven sepsis Necrotizing enterocolitis Intraventricular hemorrhage, grades III/IV Periventricular leukomalacia Gastroesophageal reflux Retinopathy of prematurity Neonatal seizures Pulmonary hypertension Neonatal death
Incidence (%) 0.8 10 0 1.7 32.5 12.5 1.7 7.5 1.7 0 0.8 12.5 6.6 0.8 1.6 0.8
Data from Francois K, Sears C, Wilson R, et al. Neonatal outcomes of quadruplet pregnancies: twelve-year experiences at a single institution [abstract]. Am J Obstet Gynecol 2001;184:S174.
outcome with 32 nonconsecutive, nonselected quadruplet pregnancies. Maternal morbidity is given in Table 5, and neonatal outcome is presented in Table 6. The mean gestational age at delivery was 32.1 weeks (F2.1 weeks) with a range of 26.7 to 34.1 weeks. Six pregnancies (20%) were delivered between 30 and 32 weeks, and 18 (60%) were delivered between 33 and 34 weeks. There was 1 death in these 120 babies, for a perinatal mortality rate of 8.3/1000. Major neonatal morbidity was rare, with necrotizing enterocolitis in 1.7%, intraventricular hemorrhage grades III or IV in 0%, periventricular leukomalacia in 0.8%, and retinopathy of prematurity grade II to III in 6.6%. This low rate of morbidity certainly reflects the large number of babies born after 32 weeks. Garite and colleagues [46] have provided data that document that the outcome of babies in a multiple gestation is similar to singletons born prematurely at each week after viability. Thus it is clear that delivery at a more advanced gestational age is the key to successful pregnancy outcome in multiple gestation. Poor outcome in HOM gestation is a possible result, but it is not even a common result with our approach to management.
Summary This article provides an overview of HOM gestation and our suggestions for management. Based on our outcomes, we advocate an aggressive approach to HOM pregnancy management. Adequate weight gain will help reduce the
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incidence of low birth weight and IUGR fetuses. In my opinion, aggressive manipulation of background uterine contractions with bed rest, psychologic reassurance, and tocolysis with a terbutaline pump will decrease the incidence of true PTL, and aggressive tocolysis with MgS04 and other drugs will decrease preterm delivery from PTL. Treatment of HELLP syndrome with dexamethasone will prolong pregnancy in those patients developing PIH/HELLP. Management is directed at delaying delivery until 34 or 35 weeks if at all possible.
References [1] Elliott JP, Radin TG. Quadruplet pregnancy: contemporary manangement and outcome. Obstet Gynecol 1992;80:421 – 4. [2] Yokoyama Y, Shimizu T, Hayakawa K. Incidence of handicaps in multiple birth and associated factors. Acta Genet Med Gemellol 1995;44:881 – 91. [3] Templeton A. The multiple gestation epidemic: the role of the assisted reproductive technologies. Am J Obstet Gynecol 2004;190:894 – 8. [4] Pinborg A, Loft A, Schmidt L, et al. Morbidity in a Danish National Cohort of 472 IVF/ICSI twins, 1132 non-IVF/ICSI twins and 634 IVF/ICST singletons: health related and social implications for the children and their families. Hum Reprod 2003;18:1234 – 43. [5] Scheb AI, Petterson B, Blair E, et al. The risk of mortality or cerebral palsy in twins: a collaborative population based study. Pediatr Res 2002;52:671 – 81. [6] Collins MS, Bleyl JA. Seventy-one quadruplet pregnancies: management and outcome. Am J Obstet Gynecol 1990;162:1384 – 92. [7] Heyborne KD, Porreco RP, Garite TJ, et al. Improved perinatal survival of monoamniotic twins with intensive inpatient monitoring. Am J Obstet Gynecol 2005;192:96–101. [8] Quintero R, Morales W, Allen M, et al. Staging of twin-twin-transfusion syndrome. J Perinatol 1999;19:550 – 5. [9] Quintero RA, Dickinson JE, Morales WJ, et al. Stage-based treatment of twin-twin transfusion syndrome. Am J Obstet Gynecol 2003;188:1733 – 40. [10] Elliott JP, Urig MA, Clewell WH. Aggressive therapeutic amniocentesis for treatment of twintwin transfusion syndrome. Obstet Gynecol 1991;77:537 – 40. [11] Ron-El R, Caspi E, Schreyer P, et al. Triplet and quadruplet pregnancies and management. Obstet Gynecol 1981;57:458 – 63. [12] Gonen R, Heyman E, Asztalos EV, et al. The outcome of triplet, quadruplet, and quintuplet pregnancies managed in a perinatal unit: obstetric, neonatal, and follow-up data. Am J Obstet Gynecol 1990;162:454 – 9. [13] McKeown T, Record RG. Observations on foetal growth in multiple pregnancy in man. J Endocrinol 1952;8:360 – 400. [14] Aina-Mumuney AJ, Rai KK, Taylor MY, et al. Nulliparity and duration of pregnancy in multiple gestation. Obstet Gynecol 2004;104:110 – 3. [15] Blickstein I, Jacques DL, Kieth LG. Effect of maternal height on gestational age and birth weight in nulliparous mothers of triplets with a normal pregravid body mass index. J Reprod Med 2003;48:335 – 8. [16] Malone FD, Kaufman GE, Chelmow D, et al. Maternal morbidity associated with triplet pregnancy. Am J Perinatol 1998;15:73 – 7. [17] Francois K, Sears C, Wilson R, et al. Maternal morbidity and obstetrical complications of quadruplet pregnancy: twelve years experience at a single institution [abstract]. Am J Obstet Gynecol 2001;184:S174. [18] Angel JL, Kaltr CS, Morales WJ, et al. Aggressive perinatal care for high-order multiple
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gestation: does good perinatal outcome justify aggressive assisted reproductive techniques? Am J Obstet Gynecol 1999;181:253–9. Hauth JC, Goldenberg RL, Parker CR, et al. Low-dose aspirin therapy to prevent preeclampsia. Am J Obstet Gynecol 1993;168:1083 – 93. Luke B, Eberlein T. When you’re expecting twins, triplets, or quads. New York7 Harper Collins; 2004. Luke B, Nugent C, VandeVen C, et al. The association between maternal factors and perinatal outcomes in triplet pregnancies. Am J Obstet Gynecol 2002;187:752 – 7. Vogel I, Salvig JD, Secher NJ, et al. Association between raised serum relaxin levels during the eighteenth gestational week and very preterm delivery. Am J Obstet Gynecol 2001;184:390 – 3. Althuis SM, Dekker GA, Hummel P, et al. Final results of the Cervical Incompetence Prevention Randomized Cerclage trial ‘‘CIPRACT’’: therapeutic cerclage with bedrest vs bedrest alone. Am J Obstet Gynecol 2001;185:1106 – 12. Mordel N, Zajicek G, Benshushan A, et al. Elective suture of uterine cervix in triplets. Am J Perinatol 1993;10:14 – 6. Newman RB, Gill PJ, et al. Maternal perception of prelabor uterine activity. Obstet Gynecol 1986;68:765 – 9. Beckmann CA, Beckmann CR, Stanziano GJ, et al. Accuracy of maternal perception of preterm uterine activity. Am J Obstet Gynecol 1995;174:672 – 5. Morrison JC, Martin JN, Martin RW, et al. Prevention of preterm birth by ambulatory assessment of uterine activity: a randomized study. Am J Obstet Gynecol 1987;156:536 – 43. Moore TM, Iams JD, Creasy RK, et al. Diurnal and gestational patterns of uterine activity in normal human pregnancy. Obstet Gynecol 1994;83:517–23. Main DM, Grisso IA, Wold J, et al. Extended longitudinal study of uterine activity among lowrisk women. Am J Obstet Gynecol 1991;165:1317 – 22. McGregor IA, Jackson GM, Lachelin GC, et al. Salivary cstriol as a risk assessment for preterm labor: a prospective trial. Am J Obstet Gynecol 1995;173:1337–42. Keirse MJNC, Grant A, King JF. Preterm labor. In: Chalners I, Enkin M, Keirse MJNC, editors. Effective care in pregnancy and childbirth. New York7 Oxford University Press; 1989. p. 694 – 745. Garite TJ, Bentley DL, Hamer CA, et al. Uterine activity characteristic in multiple gestations. Obstet Gynecol 1990;76:S56 – 9. Newman RB, Gill PJ, Campion S, et al. The influence of fetal number on antepartum uterine activity. Ostet Gynecol 1989;73:695 – 9. Spinnewijn WEM, Lirgerubg FK, Struijk PC, et al. Fetal heart rate and uterine contractility during maternal exercise at term. Am J Obstet Gynecol 1996;174:43–8. Mourad J, Elliott JP, Erickson L, et al. Appendicitis in pregnancy: new information that contradicts long held clinical belief. Am J Obstet Gynecol 2000;182:1027 – 9. Peaceman AM, Andrews WW, Thorp JM, et al. Fetal fibronectin as a predictor of preterm birth in patients with symptoms: a multicenter trial. Am J Obstet Gynecol 1993;169:1595 – 8. Elliott JP, Radin TB. The effect of corticosteroid administration on uterine activity and preterm labor in high order multiple gestations. Obstet Gynecol 1995;85:250 – 4. Elliott JP. Magnesium sulfate as a tocolytic agent. Am J Obstet Gynecol 1983;147:277 – 82. Elliott JP, Flynn M, Kaemmerer EL, et al. Terbutaline pump tocolysis in high order multiples. J Reprod Med 1997;42:687 – 93. Elliott JP, Radin TG. Serum magnesium levels during magnesium sulfate tocolysis in high order multiple gestations. J Reprod Med 1995;40:450 – 2. Elliott JP, Finberg HJ. Biophysical profile testing as an indicator of fetal well being in high order multiple gestations. Am J Obstet Gynecol 1995;172:508 – 12. Heller CS, Elliott JP. The use of corticosteroids to prolong gestation to high order multiple pregnancies complicated by HELLP syndrome. J Reprod Med 1997;42:743 – 6. Dommergues M, Mahieu-Caputo D, Dumez Y. Is the route of delivery a meaningful issue in triplets and higher order multiples? Clin Obstet Gynecol 1998;41:25 – 9.
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[44] Elliott JP, Istwan NB, Rhea D, Stanziano G. Indicated and non-indicated preterm delivery in twin gestations: impact on neonatal outcome and cost. J Perinatol 2005;25:4–7. [45] Francois K, Sears C, Wilson R, et al. Neonatal outcomes of quadruplet pregnancies: twelve-year experiences at a single institution [abstract]. Am J Obstet Gynecol 2001;184:S174. [46] Garite TJ, Clark RH, Elliott JP, Thorp JA. Twins and triplets: the effect of plurabity and growth on neonatal outcome compared to singletons. Am J Obstet Gynecol 2004;191:700–7.
Clin Perinatol 32 (2005) 403 – 429
Nutrition in Multiple Gestations Barbara Luke, ScD, MPH, RD School of Nursing and Health Studies, University of Miami, 5801 Red Road, Coral Cables, FL 33143-3850, USA
In 2002 there were 132,535 infants of multiple pregnancies born in the United States, the highest number ever recorded [1]. The number of multiple births has risen dramatically since 1980, with an 83% increase in twins and a 454% increase in triplet and higher-order births (quadruplets and quintuplets). Although triplets and higher-order multiples are increasing at a faster rate, twins account for 94% of all multiple births each year. The rise in multiple births that began in the last decades of the twentieth century and continues today may be one of the underlying reasons for the stagnation in progress toward meeting national health objectives [2,3]. Although infants of multiple births comprise only 3% of all live births, they are disproportionately represented among preterm (13%), early preterm (15%), low birthweight (21%), and very low birthweight (25%) infant populations [1,4–7]. The average birthweight and gestational age is 3332 g at 38.8 weeks for singletons compared with 2347 g at 35.3 weeks for twins, 1687 g at 32.2 weeks for triplets, 1309 g at 29.9 weeks for quadruplets, and 1105 g at 28.5 weeks for quintuplets [1]. Women pregnant with multiples are nearly six times more likely to be hospitalized during pregnancy and more than twice as likely to be admitted to the intensive care unit when compared with women pregnant with singletons [8–14]. Maternal length of stay during the birth admission is 60% to 70% higher for multiple versus singleton births, and, even when matched for gestational age, the hospital costs for the mother’s birth admission are 37% higher, primarily owing to more complications before and after delivery [15].
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Because of these factors, the risk of dying before their first birthday is nearly seven times greater for twins and almost 20 times greater for triplets, and the survivors are at higher risk for perinatally related mental and physical handicaps [16–19]. It is estimated that twin pregnancies produce a child with cerebral palsy twelve times more often than do singleton pregnancies, and that one fifth of all triplet pregnancies and one half of all quadruplet pregnancies result in at least one child with a major handicap [20,21]. Even when matched for gestational age, at 1 year of age, infants of multiple births have nearly three times the risk for cerebral palsy [22]. Several prenatal factors have been linked to the increased risk of handicap among multiples, including preeclampsia, preterm premature rupture of membranes (PPROM), fetal death of a sibling in utero, and delivery at less than 32 weeks [21]. Growth-retarded premature infants, regardless of their plurality, have a significantly higher risk of morbidity and mortality than do appropriately grown infants [23–25], and the survivors have an excess of developmental problems during childhood [26,27]. When matched for gestational age, appropriately grown twins and singletons do not differ in their morbidity or associated costs [23,24,28], and, at earlier gestational age, multiples consistently have a survival advantage [16–19,24,29–31]. Although there are numerous nonmodifiable factors that may contribute to low birthweight and prematurity (ie, maternal age, ethnicity, parity, and prior obstetric history), the most promise may lie in the nutritional factors that are modifiable during pregnancy [32–34]. The Guidelines for Perinatal Care (5th edition, 2002) [35] acknowledge that nutrition counseling is an integral component of perinatal care, and that it is most effectively accomplished by referral to a nutritionist or registered dietitian. These recommendations, which were issued jointly by the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists for singleton pregnancies only, cover preconception care, nutrition in pregnancy, postpartum guidelines, and neonatal nutrition. In reality, nutrition counseling and interventions are often overlooked in the prenatal care of multiples, with few studies citing specific nutrition interventions [36–42]. This lack of counseling is unfortunate, because nutrition may provide a powerful mechanism by which to improve intrauterine growth and the length of gestation in these highrisk pregnancies.
Effect of plurality on maternal risk factors The effect of some maternal factors, positive and negative, may be magnified in multiple pregnancies. For example, an estimated 12% to 14% of women in the United States smoke during pregnancy, a known risk factor for low birthweight, very low birthweight, early preterm birth, and placental complications [1,43]. The population-attributable risk for low birthweight for twins versus singletons is 122.9 versus 55.3 per 1000 smokers, 32.8 versus 4.3 for very low birthweight, and 32.6 versus 7.9 for birth at less than 33 weeks’ gestation [44].
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Likewise, for placenta previa and abruptio placenta, major causes of maternal morbidity and mortality, the risks are 40% and 106% higher, respectively, for twin versus singleton pregnancies and are further magnified by higher parity and older maternal age [45,46]. It is well established in singleton pregnancies that a prior history of a good outcome (term birth of a non–low birthweight infant) conveys a reproductive advantage in subsequent pregnancies, with a strong tendency to repeat gestational age and birthweight [47]. This positive effect has recently been demonstrated when the subsequent pregnancy is with twins [48] or triplets [49]. When compared with nulliparas, women with a prior good outcome had longer gestations (by 6.3 days for twins and 7.9 days for triplets) and higher mean birthweights (+ 228 g for twins and + 153 g for triplets). Similarly, a history of an adverse pregnancy outcome has a negative effect on subsequent pregnancies, although few data are available on multiple pregnancies. It is estimated that the attributable risk in a subsequent pregnancy owing to a history of prematurity is 12.5% and the risk owing to low birthweight 20% [47]. Follow-up studies have shown that women with a history of adverse pregnancy outcomes experience excess metabolic and cardiovascular morbidity and mortality in later life [50–54]. Gestational diabetes, preeclampsia, low birthweight, and preterm delivery have each been linked to subsequent alterations in lipids, vascular function, and fasting insulin concentrations and a higher risk for metabolic or cardiovascular disease years or even decades postpartum. There have been no long-term follow-up studies of mothers of multiples.
Effect of assisted conception on maternal risk factors Recent studies have suggested that multiple births from assisted reproductive technology may experience excess morbidity, including a greater likelihood of being low birth weight and premature [55], although these findings are not consistent in all studies [56,57]. Older maternal age in singleton pregnancies is a well-established risk factor for increased perinatal and infant mortality, but, as shown recently, maternal age may have a different implication for multiple gestations [58,59]. The proportion of women who use donor eggs in pregnancies conceived by assisted reproductive technology increases exponentially after age 40 years (b 5% of cycles among women b 37 years of age to N 70% of cycles among women age N 46 years) [60]. The live birth rate is much higher with donor eggs than with a woman’s own eggs after about age 35 years. Older maternal age has a different meaning in pregnancies conceived by assisted reproductive technology when compared with those conceived spontaneously. Even with donor eggs, there is a concern that older maternal age may be associated with an increase in obstetric complications in these women, secondary to a higher incidence of underlying medical disease, decreased cardiovascular reserve, and a diminished ability to adapt to the physical stress that may accompany aging. The twin and the triplet and higher-order rate for pregnancies conceived by
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assisted reproductive technology is estimated to be 14-fold and 54-fold higher, respectively, than for the United States as a whole [61].
Nutritional factors and diet therapy Maintenance of stable blood glucose levels Stress (from infection, inflammation, trauma, or psychologic distress) raises plasma glucose concentrations by increasing the contrainsulin hormones (eg, cortisol and placental growth hormone). Scholl et al [62] suggest that higher but seemingly normal maternal plasma glucose concentrations are associated with very preterm delivery by predisposing to, or acting as, a marker for placental inflammation and subclinical infection, and that insulin resistance might be an underlying cause of very preterm delivery. Subclinical infection associated with very preterm delivery is manifested as a systemic inflammatory response that is otherwise asymptomatic. There is a growing body of literature suggesting that, in adults, insulin resistance is an indicator of inflammation driven by interleukin-1b (IL-1b), interleukin-6 (IL-6), and tumor necrosis factor-a [63,64]. Overweight and obese women are more likely to be insulin resistant. In his analysis of data from the Collaborative Perinatal Project, Naeye [65] reported that an increased risk of very preterm delivery was associated with acute chorioamnionitis among obese gravidas. Adipose tissue expresses and releases the proinflammatory cytokine IL-6, potentially inducing low-grade systemic inflammation in overweight and obese individuals. The acute phase C-reactive protein (CRP) is a sensitive marker for systemic inflammation. In an analysis of the Third National Health and Nutrition Examination Survey (NHANES), Visser et al [66] reported that the body mass index (BMI) was associated with raised CRP levels in women, particularly those with a higher waist-to-hip ratio, because abdominal adipose tissue releases more IL-6 than does subcutaneous adipose tissue [67]. These findings suggest that a state of low-grade systemic inflammation is present in overweight and obese individuals. CRP concentrations are independent of pregnancy and gestational age and do not cross the placenta. Elevated CRP levels are more often found in patients who are refractory to tocolysis, suggesting an underlying infectious morbidity. A positive association has also been reported between elevated CRP levels and histologic evidence of placental infection [68]. Elevated plasma glucose concentrations during pregnancy have also been linked to the development of preeclampsia. Hsu et al [69] reported that, among pregnant women with insulin-dependent diabetes mellitus, those with elevated hemoglobin A1c values (N8%) between 16 and 20 weeks’ gestation had a significantly higher incidence of preeclampsia when compared with women whose mean hemoglobin A1c level was normalized during this stage of gestation (46% versus 26%). Hyperglycemia-induced inflammation may be part of the causal pathway through which obesity predisposes to preeclampsia.
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Carbohydrate metabolism Pregnancy is a state of accelerated starvation, resulting in lower fasting glucose levels and an exaggeration of the insulin response to eating. In twin pregnancies, these changes are magnified, particularly during the second half of pregnancy, with significantly lower maternal serum glucose and insulin concentrations and higher plasma concentrations of b-hydroxybutyrate when compared with the maternal concentrations in singleton pregnancies, indicating more rapid depletion of glycogen stores and resultant metabolism of fat between meals and during an overnight fast [70]. Both fasting and ketonuria have been linked to an increase in preterm labor and preterm delivery, a phenomenon termed the ‘‘Yom Kippur effect’’ [71,72]. In animal studies, fasting results in higher plasma levels of prostaglandin metabolites, with resultant increases in uterine contractions, preterm labor, and birth [73–75]. An exaggeration of this effect may be partially responsible for the increased incidence of early preterm births in multiple pregnancies. A reduced glucose stream from the mother to fetus results in slower fetal growth, smaller birth size, and an increased risk of fetal growth restriction [76,77]. Irregular food intake during pregnancy has been associated with other adverse short- and long-term effects. Siega-Riz et al [78] reported a 30% higher risk of preterm delivery among women who ate fewer than three meals and two snacks per day. Women who fasted for 13 or more hours tended to be at the extremes of income (b $20,000 or N $70,000), to have more than three children, to work one or two jobs, to be black, to smoke, and to be at the extremes of prepregnancy weights (underweight or obese) [79]. They tended to have diets significantly lower in calories, carbohydrate, folate, vitamin C, and calcium. The adverse effects of maternal ketonemia extend beyond premature birth. Studies of women with diabetes during pregnancy have shown significant correlations between second- and third-trimester glycemic regulation and neurobehavioral deficits in the neonates [80]. These alterations in neurodevelopment have been demonstrated in the children of diabetic women through 9 years of age [80–82]. Although similar studies have not been conducted on women pregnant with multiples, the alterations are similar to those seen in diabetic pregnancies and may explain a component of the excess handicap observed among children of multiple pregnancies.
Supplementation with calcium, magnesium, and zinc In addition to being the nutrients most often lacking in women’s diets, calcium, magnesium, and zinc have been identified as having the most potential for reducing pregnancy complications and improving outcomes [83–85]. A review by the World Health Organization concluded that these nutrients should be evaluated rigorously, because these interventions may have effects on impaired fetal growth and preterm delivery [84].
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Calcium During pregnancy, there is an increased physiologic demand for calcium such that a full-term infant accretes about 30 g, primarily in the third trimester, when there is active ossification of the fetal skeleton. Prenatal diets low in calcium have been associated with increased blood pressure because of heightened smooth muscle reactivity, resulting in an increased risk of pregnancy-induced hypertension and preterm delivery. Results of calcium supplementation trials among high-risk women have been promising, with significant reductions in preterm deliveries among teenagers (7.4% versus 21.1%, P b.007) and significantly longer mean gestations among women with very low dietary calcium intakes (37.4 versus 39.2 weeks, P b.01) [86–88]. Other studies have shown inconsistent results in lowering the rates of pregnancy-induced hypertension, or no effect on preterm delivery and small-for-gestational age births [89,90]. Calcium supplementation trials among high-risk women (teenagers in Baltimore and women with very low calcium intakes in Quito, Ecuador) were promising in decreasing the rate of preterm delivery. Among teenagers (aged 16 years) in Baltimore with similar overall dietary calcium intakes, the calcium-supplemented group had a lower incidence of preterm delivery when compared with the placebo group (7.4% versus 21.1%, P b.007) [86]. Life-table analysis demonstrated an overall shift to a higher gestational age in the calcium-supplemented group. In Ecuador, the length of gestation was increased from 37.4 to 39.2 weeks for the calciumsupplemented group versus the placebo group [87,88]. On the other hand, a large calcium supplementation trial including more than 1000 adult women from Argentina showed a decrease in pregnancy-induced hypertension but no effect on preterm delivery [89], and a multicenter trial in the United States of calcium supplementation with more than 4500 adult women showed no difference in pregnancy-induced hypertension, preterm deliveries, or small-for-gestational age births [90]. The ability of supplemental calcium to decrease the risk of preterm delivery may be confined to high-risk populations in which there is a severe dietary restriction of calcium or, as true in adolescents and multiple pregnancy, there is an increased demand for this nutrient. Prenatal calcium supplementation may have effects beyond pregnancy. Beliza`n et al [91] evaluated blood pressure in 7-year-old children whose mothers had received calcium supplementation during pregnancy. They reported significantly lower systolic blood pressure and lower risk of high systolic blood pressure (relative risk [RR], 0.59; 95% confidence interval [CI], 0.39–0.90), particularly among children in the highest quartile of BMI (weight/[height]2) (RR, 0.43; 95% CI, 0.26–0.71).
Magnesium Magnesium supplementation trials have also reported inconsistent results [92–94]. These inconsistencies may have been caused by differences in study design, study populations, and the concurrent use of other medications such as b-sympathomimetic agents [94]. Clinical studies have demonstrated that magnesium is not only effective as therapy for and prophylaxis against eclampsia but
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is safe and potentially beneficial for the neonate [95,96]. In a case-control study examining the risk of cerebral palsy in premature infants exposed to magnesium in utero, Nelson and Grether [96] reported a protective effect (odds ratio [OR], 0.14; 95% CI, 0.05–0.51), regardless of whether the magnesium had been given for preeclampsia or as treatment for preterm labor. In a population-based cohort study of prenatal magnesium exposure among children who had been very low birthweight, Schendel et al [97] also reported a protective effect against cerebral palsy (OR, 0.11; 95% CI, 0.02–0.81) and possibly against mental retardation (OR, 0.30; 95% CI, 0.07–1.29). Magnesium therapy, as prenatal supplementation or as therapy for preeclampsia or preterm labor, may have a neuroprotective role.
Zinc During pregnancy, plasma zinc concentrations decline by 20% to 30% when compared with nonpregnant values, reflecting the transfer of zinc from the mother to fetus and the normal expansion of the maternal plasma volume [98,99]. Plasma zinc concentrations and available zinc intakes are significantly correlated, with zinc supplementation increasing maternal plasma levels [100,101]. Using plasma zinc as an indicator of zinc status, Neggers et al [100] found a positive correlation between the duration of gestation and the zinc concentration at entry to prenatal care. A randomized trial of zinc supplementation of women with plasma zinc levels below the median showed that zinc supplementation resulted in an increase in gestation duration by approximately 0.5 weeks and an increase in birthweight [102]. Plasma zinc levels in the lowest quartiles are associated with a significantly greater frequency of maternal complications, including infection [103,104]. Maternal zinc nutriture, as a composite index of zinc measured from maternal whole blood, hair, and colostrum, has been shown to be related to the risk of PROM [104]. Women with PROM were found to have significantly lower levels of zinc when compared with women who gave birth at term. Scholl and Hediger [105] evaluated the association between dietary zinc intake and pregnancy outcome in a cohort of 818 low-income, mostly minority women in Camden, New Jersey. A low zinc intake during pregnancy (b 6 mg/day or b 40% of the Recommended Daily Allowance [RDA] for pregnancy) was associated with an increased incidence of iron-deficiency anemia at entry to care, a lower use of prenatal supplements during pregnancy, and a higher incidence of inadequate weight gain during pregnancy. Even after adjusting for other confounding variables (eg, energy intake, maternal age, ethnicity, cigarette smoking), a low dietary intake of zinc was associated with a twofold increase in the risk of low birthweight (adjusted OR, 2.10; 95% CI, 1.19–3.67), a nearly twofold increase in preterm delivery (adjusted OR, 1.86; 95% CI, 1.11–3.09), and a threefold increased risk of early preterm birth (b 33 weeks’ gestation) (adjusted OR, 3.46; 95% CI, 1.04 –11.47). In addition, there was a joint effect of iron-deficiency anemia at entry to care and a low zinc intake during pregnancy. When both were present, there was a fivefold increased risk of preterm delivery (adjusted OR, 5.44; 95% CI, 1.58 –18.79).
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Dietary factors to improve endothelial function The n-3 fatty acids, found in seafood, canola, and olive oils, decrease the expression of adhesion molecules on the endothelium and decrease leukocyteendothelium interactions. They also improve endothelium-dependent relaxation and hemostatic factors associated with endothelial function. The antioxidant vitamins E and C reduce oxidative stress, cell adhesion molecule expression, and monocyte adhesion, as well as improving endothelium-dependent vasodilation and endothelial function [106,107]. Folic acid reduces concentrations of plasma homocysteine, which adversely affects the endothelium by increasing adhesion molecule expression and platelet aggregation and decreasing nitric oxide production. Zinc is vital to vascular endothelial cell integrity, and a deficiency can result in impairment of endothelial barrier function. Recent studies of women at risk for preeclampsia have reported improvements in plasma markers of vascular endothelial activation and placental insufficiency, as well as a reduced recurrence of the disease with vitamin C and E supplementation [106,107]. Summary of recommendations for vitamin and mineral supplementation The following recommendations for multiple gestations for vitamin and mineral supplementation can be made: Take one multivitamin daily with 100% of the nonpregnant RDA for the first trimester (including 400 mg of folate). Double the dose for the second and third trimesters. Take 3 g of calcium per day. Take 1.2 g of magnesium per day. Take 45 mg of zinc per day. Consider supplementation with an additional 1 g of vitamin C and 400 IU of vitamin E for a possible reduction in the risk for preeclampsia.
Maternal pregravid weight and gestational weight gain Singletons The factors most strongly correlated with the length of gestation and birthweight are maternal height, pregravid or early pregnancy body weight, maternal fat deposition, and gestational weight gain. Although each factor independently influences birthweight and the length of gestation, their effects are neither equal nor additive. The landmark studies in this area are from the Collaborative Perinatal Project, which was conducted between 1959 and 1964 [108–111]. Based on term singleton pregnancies, these studies demonstrated that (1) a progressive increase in weight gain was paralleled by an increase in mean birthweight and a decline in the incidence of low birthweight infants; (2) increasing
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pregravid weight diminishes the effect of weight gain on birthweight; (3) there is an inverse relationship between weight gain and perinatal mortality with gains up to 30 pounds; and (4) higher gestational weight gains are related to higher birthweights and better growth and development during the first postnatal year. As a result of these and subsequent studies, in 1990 the Institute of Medicine issued pregravid BMI-specific weight gain guidelines for singleton pregnancies [112]. Many investigators have subsequently confirmed these associations, including the link between a low prepregancy weight and prematurity and intrauterine growth retardation, with reported increased risks ranging from 1.7 to 3.0 depending on the study population [113]. The population-attributable risk for early preterm birth (b 32 weeks) with low prepregnancy weight is as much as 31% to 43% depending on race and ethnicity [114]. Low maternal weight gain has also been significantly associated with intrauterine growth retardation and preterm birth, with reported risks ranging from 2.1 to 4.3 [112,115–118]. Significant interaction has also been documented between a low pregravid weight and low weight gain on the risk of preterm birth (adjusted OR, 5.63; 95% CI, 2.35–13.8) [116].
Weight gain in twin pregnancies In its 1990 report, the Institute of Medicine suggested a range of maternal weight gain of 35 to 45 pounds for term (38–41 weeks) twin pregnancies [112]. The consensus among researchers who have evaluated these guidelines for twins is that total weight gain should be at least 40 to 45 pounds, with an emphasis on adequate weight gain before 24 weeks’ gestation [119–129]. Recent research has demonstrated a ‘‘ripple’’ effect of maternal weight gain on twin fetal growth, with gains before 20 weeks and between 20 and 28 weeks affecting fetal growth from 20 to 28 weeks and 28 weeks to delivery [128]. Before 20 weeks, the only factors affecting fetal growth are monozygosity and smoking; both are negative factors. For twins, an average birthweight of 2500 g or greater is associated with maternal weight gains of 40 to 45 pounds (18.2–20.5 kg), with 24 pounds by 24 weeks [123,124]. A low rate of gain before 24 weeks (b 0.85 lb/week), regardless of the rate of gain after 24 weeks, is significantly associated with poor intrauterine growth and higher morbidity [124]. Luke and Leurgans [125] reported that the advised weight gain for twin gestations averaged 30 pounds, whereas actual gains averaged 40 to 45 pounds. Their study also evaluated the Institute of Medicine recommendations of 35 to 45 pounds for twin pregnancies and concluded that weight gains above this range were associated with twin birthweights of 2500 to 2800 g at 35 to 38 weeks, the optimal birthweight for gestational age for these pregnancies. Several studies on twin gestations have clearly established the importance of maternal weight gain before 20 weeks’ gestation on twin birthweight [121,126,128]. The first study, based on 646 twin pregnancies at three study sites, demonstrated that twin birthweight was significantly associated with
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weight gain before 20 weeks in underweight women, before 20 weeks and after 28 weeks in overweight women, and during all three gestational periods in normal weight women [126]. The second study, based on 1564 twin pregnancies, confirmed and expanded the earlier findings and showed that early maternal weight gain (before 20 weeks) and midpregnancy weight gain (between 20 and 28 weeks) significantly affected the rates of fetal growth between 20 and 28 weeks and 28 weeks to birth [128]. It is clear that by improving weight gain early in pregnancy, fetal growth can be enhanced and, by extension, gestation lengthened. Based on these studies, Luke et al [130] have proposed BMI-specific weight gain guidelines for twin pregnancies. These guidelines were modeled using multiple regression for the gestational periods of 0 to 20 weeks (early pregnancy), 20 to 28 weeks (midpregnancy), and 28 weeks to delivery (late pregnancy). The guidelines were based on achieving optimal rates of fetal growth (between the twin and singleton 50th percentiles between 20 and 28 weeks and between the twin 75th and 90th percentiles between 28 and 36 weeks) and average birthweights between the singleton 50th percentile and the twin 90th percentile at 36 weeks (2700–2800 g). Optimal rates of fetal growth and optimal birthweights were associated with rates of maternal weight gain (lbs/week) (Table 1). The pattern of maternal weight gain has been shown to be as important as total weight gain in its effect on birthweight in singleton and twin pregnancies. Although the increase in fetal weight is greatest during the third trimester (after 28 weeks), gains during midgestation (second trimester or 20 to 28 weeks) have the strongest association with birthweight [116,131–139]. In singletons, Abrams and Selvin [134] demonstrated that birthweight increased in each trimester by 18, 33, and 17 g, respectively, per kilogram per week of maternal weight gain. Scholl et al [136] reported that weight gains to 20 weeks and to 28 weeks were most strongly related to birthweight, contributing 22 to 24 g to birthweight per kilogram per week of maternal weight gain. In addition, a low rate of weight gain or a poor pattern of weight gain was associated with an increased risk of preterm birth [116,139,140]. Studies on twins performed by the author’s research team have shown similar results, with low weight gains consistently associated with reduced birthweights. Early and midgestation weight gains seem to exert an
Table 1 Recommended patterns of maternal weight gain in twin pregnancy Gestational period BMI group
Early
Mid
Late
Total gain
Underweight (b20) Normal weight (20–25) Overweight (26–30) Obese (N30)
1.25–1.75 1.00–1.50 1.00–1.25 0.75–1.25
1.50–2.0 1.25–2.0 1.00–1.5 1.00
1.25 1.00 1.00 0.75
47–61 38–54 36–45 29–39
lbs lbs lbs lbs
Data from Luke B, Min L, Hediger ML, et al. Body mass index–specific weight gains associated with optimal birth weights in twin pregnancies. J Reprod Med 2003;48:217–24.
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even greater effect on twin birthweights, with gains to 20 weeks, between 20 and 28 weeks, and from 28 weeks to birth increasing birthweights by 65, 37, and 16 g, respectively, per kilogram per week of maternal weight gain [124,126,128]. In addition, we have shown that inadequate early weight gain may be associated with the development of preeclampsia in twin gestations [141]. Weight gain in triplet pregnancies In their analysis of 1138 triplet pregnancies, Elster et al [37] reported several factors that were predictive of higher average fetal weight for a given gestational age, including male gender, older maternal age, maternal height, pregravid weight and weight gain, and parity. These investigators also reported that the length of gestation correlated with maternal age, parity, and weight gain. Maternal weight gain was even more strongly associated with outcomes in triplets than in twins, and gains in different periods of gestation affected birthweight, birthweight for gestation (birthweight z score), and the length of gestation in a study of 144 triplets by Luke et al [142]. Regression analyses indicated that the most significant periods of maternal weight gain for average triplet birthweight were from conception to 20 weeks and between 20 and 28 weeks (158 g/lb/week, P = .001, and 111 g/lb/week, P = .001, respectively). For the average triplet birthweight z score, the most significant periods were between 20 and 28 weeks (0.53 standard deviation [SD] units/lb/week, P b.0001) and for the length of gestation from 28 weeks to delivery (4.6 days/lb/week, P b.0001). The effect of higher weight gain before 20 or 24 weeks on twin and triplet birthweight is most pronounced among infants of underweight gravidas [121,124]. This early weight gain may reflect the acquisition of maternal nutrient stores, particularly the deposition of body fat [143]. In addition, levels of fat-mobilizing hormones, such as follicle-stimulating hormone (FSH) and human placental lactogen (hPL), may be higher in normal weight and overweight women and in women with dizygotic twin pregnancies [144]. Underweight women with low early weight gain may be lacking appropriate nutrient reserves (including maternal stored fat) as well as adequate levels of hormones to mobilize the nutrient stores that are available, resulting in a high incidence of birthweights equal to or less than the 10th percentile in their infants. Higher early gains may be particularly important in multiple pregnancies for two reasons. First, pregnancy is usually much shorter for multiple gestations by as much as 4 to 12 weeks, shortening the period for intrauterine growth. As shown by Williams et al [145], the peak rate of growth in weight for multiples occurs at about 31 weeks compared with 33 weeks for singletons. Second, higher gains during early gestation may influence the structural and functional development of the placenta [146]. In multiple pregnancies, the placenta ages more quickly, shortening the gestational period during which it can most effectively transfer nutrients to the developing fetuses. Higher gains during early gestation may initially benefit placental structure and function and subsequently augment fetal growth through more effective placental function and the transfer of a higher level of nutrients.
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Monitoring anthropometric changes Singletons A substantial portion of gestational weight gain is maternal body fat, which, when measured as the triceps skinfold thickness or mid-upper arm circumference (MUAC), increases in the first two trimesters and decreases in the third, reflecting the early accretion of maternal body fat and the subsequent use in late gestation to meet increasing energy needs. The components of maternal weight gain, particularly changes in body fat, may be more important determinants of pregnancy outcome than absolute weight gain. Prior studies of well-nourished women based on deuterium oxide and underwater weighing [147–150] and anthropometric measures [151–153] have reported a pattern of small gains in maternal body fat early in pregnancy, rapid accumulation between 20 and 30 weeks’ gestation, and a leveling off between 30 weeks and delivery. A consistent finding in studies with diverse ethnic and racial groups is the correlation between triceps skinfold or MUAC measures during the second trimester and birthweight, with the loss of upper arm fat or the failure to accrue maternal fat during the second trimester associated with poor fetal growth and subsequent lower birthweights [151–155]. Examining the components of weight gain in pregnancy, Hediger et al [156] demonstrated that, for teenagers and adults whose pregravid weights were above the 25th percentile for age, the loss of subcutaneous fat (N 6.4 cm2) from 28 weeks through 4 to 6 weeks postpartum (measured at the mid-upper arm) was associated with a higher birthweight (+144 g, P b.01). At the same time there appeared to be a mobilization of fat stores, there was an increase in arm muscle area. When pregravid weight was below the 25th percentile for age, a loss of upper arm fat was associated with a lower birthweight ( 339 g, P b.01), suggesting that the nutrient stores of these women may have been relatively depleted. Continued weight gain and increases in upper arm fat area (N5 cm2) accompanied by a loss of upper arm muscle were also associated with a lower birthweight ( 123 g, P b.02). These observations suggest that a change in upper arm fat is a significant predictor of variation in infant birthweight. Serial monitoring by arm anthropometry and maternal weight may help determine the risk for intrauterine growth retardation.
Multiples Changes in arm anthropometry have also been used to determine the risk of intrauterine growth retardation in twin pregnancies [157]. Serial data on the MUAC and maternal weight gain were collected on 72 women pregnant with twins. MUAC changes were determined from 20 to 34 weeks, that is, subsequent to the early gestational weight gains strongly associated with fetal growth in twins (b 20 weeks) but before the later onset of edema. Over this interval, MUAC
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should increase, reflecting, initially, maternal fat and lean body mass (LBM) increases and, after 28 to 30 weeks, increases in LBM alone. The baseline MUAC measured at 20 weeks averaged 29.7 F 3.8 cm. From 20 to 34 weeks, there was no net change in MUAC ( 0.002 F 0.16 cm/week) but a highly significant correlation between weight gain at 20 weeks and subsequent change in MUAC (r = 0.41, P b.001). The cutoff for change in the MUAC that was most closely associated with twin birthweight was determined to be 0.2 cm/week ( 2 mm/week). Women with a change in MUAC of less than 0.2 cm/week differed in that they were significantly shorter, heavier, and had lower weight gain. In models adjusted for gestation, race, the number of males/sibship, chorionicity, and baseline MUAC at 20 weeks, the decrement in total twin birthweight attributable to a change in MUAC of less than 0.2 cm/week was 446 F 97 g (P b.03) and the decrement in average birthweight z score, 0.53 F 0.23 SD units (P b.03). Changes in the MUAC from 20 to 34 weeks were significantly associated with fetal growth in twin pregnancies. Serial measures of MUAC that indicated a loss of more than 0.2 cm/week from 20 to 34 weeks were significantly associated with a smaller twin birthweight and reduced fetal growth. Such a loss of MUAC may indicate that dietary intake or nutrient stores are inadequate. These findings also raise the possibility that serial measurements of MUAC, a simple but relatively precise measure of change in maternal body composition, in obese women in whom weight gain guidelines are less clear could be used as a proxy for weight gain to determine risk for poor fetal growth.
Effect of parity It is well known that changes in body composition occur with pregnancy, with parous women generally being heavier and having a higher proportion of body fat when compared with nulliparous women. This difference is particularly important in multiple pregnancies. Luke et al [126,128] reported that multiparity significantly increased the sum of twin pair birthweights by 231 to 368 g and significantly increased the rate of the sum of twin pair fetal growth between 20 and 28 weeks by 8.13 g and between 28 and 36 weeks by 11.72 g. In their study of 144 triplet pregnancies, Luke et al [142] reported primiparity to be significantly associated with lower average birthweight ( 124 g, P = .005) and lower average birthweight z score ( .615 SD units, P = .001). Crowther and Hamilton [158] reported that triplet perinatal mortality was significantly higher in primigravidas when compared with grand multigravidas (P b.001) (mean gestation of 31.1 F 5.2 versus 34.0 F 3.4 weeks, or a difference of about 20.3 days). Gonen et al [159] reported that multiparous women with triplet and higher-order pregnancies delivered about 1 week later than nulliparous women. Among triplet pregnancies, Ron-El et al [160] reported mean gestations that were about 10 days longer for multiparas versus nulliparas (240 days versus 230 days).
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Hemodynamics and iron status Iron-deficiency anemia diagnosed at 12 weeks (first trimester), 16 to 18 weeks (second trimester), or 25 to 32 weeks (early third trimester) is significantly associated with preterm delivery (OR ranging from 1.29–1.68, 2.7–4.3, and 1.8–3.5, respectively) [161–165]. Conversely, high hemoglobin levels in the first or second trimesters are associated with an increased risk for small-forgestational-age (SGA) births (OR ranging from 1.27 in the first trimester to 1.79 in the second trimester) [165], as well as stillbirths, particularly those that are preterm and SGA [166]. Serum ferritin, which is considered to be the most reliable marker of maternal iron status [167], is lowered with iron deficiency and elevated in the presence of infection and has also been linked to prematurity. Extremes of maternal serum ferritin levels measured early in the second trimester (15–17 weeks), as well as elevated levels at 24, 26, or 28 weeks, have been associated with preterm birth [168–173]. When elevated third-trimester serum ferritin levels reflect a failure to decline from entry to care, they are significantly associated with preterm and very preterm birth (adjusted OR, 8.77; 95% CI, 3.9–19.7 and adjusted OR, 3.81, 95% CI, 1.93–7.52, respectively), with irondeficiency anemia and poor maternal nutritional status underlying the relationship [173]. In a study of women at high-risk for fetal growth restriction, Hou et al [174] reported that serum ferritin in the highest quartile at 25 or 36 weeks was significantly associated with asymmetric fetal growth restriction (adjusted OR, 3.4; 95% CI, 1.6–7.2, and adjusted OR 2.7; 95% CI, 1.3–5.8, respectively). The lowest quartile of serum ferritin at 36 weeks was significantly associated with a risk for symmetric fetal growth restriction (adjusted OR, 2.2; 95% CI, 1.01–4.6). Chronic inflammation also suppresses erythropoiesis, underusing iron and increasing the store of iron. Hou et al [174] have suggested that high serum ferritin and asymmetric fetal growth restriction may reflect a noninfectious vascular inflammatory response or chronic subclinical infection. Scholl and Hediger [161] reported that iron-deficiency anemia, indicated by a low serum ferritin at entry to prenatal care, was significantly associated with an increased risk of inadequate maternal weight gain (adjusted OR, 2.67; 95% CI, 1.13–6.30), preterm delivery (adjusted OR, 2.66; 95% CI, 1.15–6.17), and low birthweight (adjusted OR, 3.10; 95% CI, 1.16–4.39) in singleton pregnancies. The few studies that have evaluated iron status in multiple pregnancies have reported lower hemoglobin levels in the first and second trimesters, higher rates of iron-deficiency anemia, and even residual iron-deficiency anemia in the infants up to 6 months of age [175–177]. We have evaluated the relationships among maternal iron status, maternal weight gain, and fetal growth in twin pregnancies [178]. Average third-trimester ferritin levels were at the usual cutoff for irondeficiency anemia (12 mg/L) and were even lower with higher maternal weight gains to 24 weeks ( 0.37 F 0.07 lb per mg/L, P = .009), averaging 15.3 mg/L with birthweights of 2379 g for women who gained less than 20 lbs by 24 weeks versus 10.3 mg/L with birthweights of 2609 g for women who gained more than 34 lbs by 24 weeks ( P b.01). Hemoglobin levels did not differ at varying levels
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of maternal gain to 24 weeks. These findings indicate that, although most mothers of twins may have serum ferritin levels in the third trimester consistent with iron deficiency, unlike for singletons, this finding may actually be a clinical indicator of better fetal growth as iron stores are used to support the growth of two fetuses. Iron status during pregnancy has also been linked to fetal programming and the development of chronic disease. Low maternal hemoglobin is strongly related to the development of a large placenta and a high placental/birthweight ratio, which is seen as predictive of long-term programming of hypertension and cardiovascular disease. Because the iron demands of pregnancy may exceed 1 g, with nearly half this amount in the red cell mass increase in blood volume, the maternal preconceptional and early pregnancy iron status is extremely important. Severe maternal iron-deficiency anemia leads to placental adaptive hypertrophy, a fall in the cortisol-metabolizing system, and an increased susceptibility to hypertension in later life.
Patient education and model of care The Public Health Service’s Expert Panel on the Content of Prenatal Care Report in 1989 [179] recommended specific types of advice or counseling during pregnancy, including nutrition, vitamin use, smoking cessation, alcohol and drug use cessation, breastfeeding, and maternal weight gain. Subsequent studies have reported that only 10% to 50% of women indicate receiving this recommended advice [180–182]. Women who reported not receiving the recommended advice were 38% to 50% more likely to have a low birthweight baby and were twice as likely to be hospitalized during pregnancy for complications when compared with women receiving the optimal level of advice [181,183,184]. In addition, studies have reported that certain subgroups, such as low-income, African-American or Pacific Islanders, women 30 years of age or older, multigravidas, or those with the least education, tend to receive less advice or counseling [185–188]. The US Preventive Services Task Force recommends ‘‘providing pregnant women with specific nutritional guidelines to enhance fetal and maternal health’’ [189]. One of the most successful national programs to date in this area is the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC), which provides food assistance and dietary counseling for pregnant women, nursing mothers, and preschool children who are considered to be at health risk because of inadequate nutrition and low income. WIC participation has been shown to reduce significantly the prevalence of low birthweight and very low birthweight infants, prematurity, inadequate prenatal care, and infant mortality [190–193]. All income-eligible women in our pilot program have also been enrolled in the WIC program, which provides specific foods for pregnant and nursing women and their children, including milk, cheese, beans, eggs, peanut butter, tuna fish, fruit juices, and cereals. Ironically, low-income women are more likely to receive nutrition counseling through the WIC program than are middle- or upper-income
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women through care at private physicians’ offices. Other programs that have augmented usual prenatal care have also reported improved outcomes. Several states have reported reductions in low birthweight with expanded Medicaid prenatal services [194–196]. Programs that have targeted special groups, such as HIV-infected women [197] or Medicaid-eligible African-American women [198], have also reported improvements, including more smokers quitting during pregnancy and reductions in rates of low birthweight and prematurity.
Specialized prenatal programs for multiples Several researchers have attempted to improve outcomes in multiple pregnancies by promoting programs of specialized prenatal care, all of which have included a maternal nutrition component. These studies have demonstrated fewer antenatal hospitalizations, early preterm births, and very low birthweight infants [36,39,41,199–202]. There have only been two specific prenatal nutrition programs for multiples [38,42]. The Higgins Nutrition Intervention Program in Montreal, Canada, which recommends an additional 1000 calories and 50 g of protein to baseline singleton dietary recommendations, has demonstrated an 80-g improvement in twin birthweight and a 15% reduction in preterm births (b 37 weeks) (from 47% to 40%) in their analysis of 177 program twin pregnancies versus 343 nonprogram twin pregnancies [38]. The other prenatal nutrition program for multiples was at the University of Michigan [42]. The study population included all live twin births at the University of Michigan Health Systems delivered between 1996 and 2002. Excluded were pregnancies in which the mother had been transferred emergently with pregnancy complications from outlying hospitals at the time of delivery, pregnancies with monochorionic placentation, and pregnancies complicated by fetal death or major congenital anomalies of one or both twins. The study sample included 190 program pregnancies and 339 nonprogram pregnancies. Women were referred to the program by any member of the health care team, as well as by self-referral, and were not randomly assigned to program versus nonprogram status. All prenatal care for twin pregnancies was given by attending and resident physicians, including generalists and maternal-fetal medicine specialists. The study was approved by the Institutional Review Board at the University of Michigan Medical School. The program included twice-monthly prenatal visits to a registered dietitian and nurse practitioner team in addition to regular prenatal visits with the woman’s primary care physician, additional maternal education, modification of maternal activity, individualized dietary prescription, multimineral supplementation, and serial monitoring of nutritional status. Patient education for the program group and nonprogram group included discussions on environmental and work hazards, physical activity, signs of preterm labor, and travel. Program visits also included discussions on diet, signs and symptoms of preeclampsia, fetal growth and development, and an exploration of
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any problems or symptoms. Work leave was recommended by 24 weeks’ gestation or sooner with stressful physical or mental work or antenatal complications, as well as decreasing stair climbing and strenuous lifting or carrying and limiting recreational activities to walking or swimming. Each program participant received a dietary assessment on entry to the program based on a 24-hour dietary recall. If needed, recommendations were made to bring the diet to 3000 to 4000 kcal per day, depending on pregravid BMI, as 20% calories from protein, 40% calories from carbohydrate, and 40% calories from fat. At each subsequent program visit, the dietary assessment was repeated, and additional recommendations were made as needed. Based on the system of diabetic exchanges, this diet translated into three meals and three snacks per day. For women with nausea and vomiting, antiemetics were prescribed, and guidelines were given to maintain hydration and avoid ketosis, resuming a full diet as soon as possible. Program participants were advised to include a daily mineral supplement of calcium and magnesium with zinc, totaling 3 g of calcium carbonate, 1.2 g of magnesium oxide, and 45 mg of zinc oxide, in three equally divided doses at breakfast, dinner, and bedtime. In addition, program participants were advised to include a multivitamin containing 100% of the nonpregnant RDAs, increasing to two pills per day after 20 weeks’ gestation. Participants were questioned regarding compliance and use of the correct dosage at each visit. Each program visit included measurements of maternal weight, blood pressure, MUAC, and fundal height and fetal heart tones, and a urinary assessment for leukocytes, protein, ketones, and glucose. Ultrasonographic measures of fetal growth were obtained at 18 to 20 weeks and again at 24, 28, and 32 weeks’ gestation. Participants were instructed to call the program staff the following day when laboratory samples were drawn or ultrasound examinations performed to discuss the results. Each program participant was given her own personal prenatal record on which all of her clinical and laboratory data, dietary recommendations, and mineral supplement guidelines were listed. This prenatal record also included intermediate and total weight gain goals and the 50th percentile of singleton fetal weight for each week of gestation as goals for twin growth. The emphasis was on achieving and maintaining fetal growth as close as possible to the singleton 50th percentile. On entry to the program, target goals were discussed with each participant, including weight gain goals to 20 weeks, 28 weeks, and 36 to 38 weeks (term for twins); an average twin pair birthweight greater than 2500 g; and gestation to 36 weeks or greater. Program mothers were less likely to experience PPROM, preterm labor, or preeclampsia, complications owing to deliver before 32 weeks’ gestation, or very low birthweight or low birthweight infants. Program mothers were more likely to meet the BMI-specific weight gain goals, particularly by 20 and 28 weeks’ gestation, the periods most strongly associated with fetal growth and subsequent birthweight (adjusted OR, 1.73; 95% CI, 1.13–2.64, and adjusted OR, 1.53; 95% CI, 1.02–2.33, respectively). Likewise, infants of program mothers were significantly less likely to require medical interventions and to be diagnosed with a range of neonatal conditions, particularly those associated with prematurity. Adjusted analyses showed that
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program participation increased the length of gestation by 7.6 days, increased birthweight by 220 g per twin, and reduced newborn hospitalization by 5.3 days and costs by $14,023 per twin. The risk of rehospitalization during the first 3 years after birth was significantly lower for program children (adjusted OR, 0.31; 95% CI, 0.11–0.91) and higher for nonprogram children (adjusted OR, 2.81; 95% CI, 1.11–7.25). Program children were better grown at birth, with significantly higher birthweights, birth lengths, and head circumferences, and continued to grow more rapidly through 8 months of age. Although there was no significant difference in absolute weight, length, or head circumference at 8 months and 18 months and in weight and length at 3 years of age, nonprogram children generally demonstrated more catch-up growth during these periods. At each age, program and nonprogram children did not differ significantly in their mental and motor development, but, overall, program children scored better. Overall, 11.3% of assessments of nonprogram twins were scored as delayed compared with 7.6% of program twins, for an adjusted OR of 1.55 (95% CI, 1.04–2.31). Conversely, program children were one-third less likely to be scored as delayed when compared with nonprogram children (adjusted OR, 0.65; 95% CI, 0.44–0.96). The components of this prenatal program have been developed into a comprehensive book for the patient as well [203].
Prenatal antecedent of childhood and adult health Recently, there has been growing interest in the possible link between prenatal growth and subsequent childhood and adult health and disease, termed metabolic imprinting or programming [204]. Barker et al provided the first direct evidence that certain adult-onset diseases could originate from intrauterine growth retardation, reporting an association between essential hypertension and low birthweight [205]. Data from the British National Study of Children born in 1946 provide additional evidence for the link between low birthweight and the subsequent development of hypertension and insulin resistance [206]. The fetal adaptations to uteroplacental insufficiency, particularly decreased DNA synthesis in the myocardium [207], might be the basis for the association between intrauterine growth retardation and the subsequent risks of cardiovascular disease in adult life. Poor maternal nutritional status as determined by triceps skinfold at 18 and 28 weeks’ gestation has been correlated with the subsequent development of higher blood pressure in the children at age 11 years [208]. Conversely, prenatal interventions to improve prenatal nutrition may have far-reaching positive effects on health beyond the perinatal period. For example, Beliza`n et al [91] demonstrated that 7-year-old children whose mothers had received calcium supplementation prenatally had significantly lower systolic blood pressures and a lower risk of high systolic blood pressure (RR, 0.59; 95% CI, 0.39– 0.90). This effect was particularly evident among children in the highest quartile of BMI (RR, 0.43; 95% CI, 0.26– 0.71). Currently, understanding of the biologic
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mechanisms underlying metabolic programming is limited. Multiple pregnancy provides a unique model to evaluate the relative effects of an exaggerated nutrient drain versus nutrient enhancement on prenatal and postnatal growth.
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luke anemic women: pregnancy unfavorably affected by maternal iron excess. Hum Reprod 2000; 15:1843 – 8. Holzman C, Katnik R, Jetton J, et al. Do maternal serum ferritin levels have a role in predicting preterm delivery [abstract]? Am J Epidemiol 1996;143:S73. Tamura T, Goldenberg RL, Johnston KE, et al. Serum ferritin: a predictor of early sponta neous preterm delivery. Obstet Gynecol 1996;87:360 – 5. Goldenberg RL, Tamura T, DuBard M, et al. Plasma ferritin and pregnancy outcome. Am J Obstet Gynecol 1996;175:1356 – 9. Goldenberg RL, Mercer BM, Miodovnik M, et al. Plasma ferritin, premature rupture of membranes, and pregnancy outcome. Am J Obstet Gynecol 1998;179:1599 – 604. Goepel F, Ulmer HU, Neth RD. Premature labor contractions and the value of serum ferritin during pregnancy. Gynecol Obstet Invest 1988;26:265 – 73. Scholl TO. High third-trimester ferritin concentration: associations with very preterm delivery, infection, and maternal nutritional status. Obstet Gynecol 1998;92:161 – 6. Hou J, Cliver SP, Tamura T, et al. Maternal serum ferritin and fetal growth. Obstet Gynecol 2000;95:447 – 52. Spellacy WN, Handler A, Ferre CD. A case-control study of 1253 twin pregnancies from a 1982–1987 prenatal data base. Obstet Gynecol 1990;75:168 – 71. Blickstein I, Goldchmit R, Lurie S. Hemoglobin levels during twin vs singleton pregnancies. J Reprod Med 1995;40:47 – 50. Ben Miled S, Bibi D, Khalfi N. Iron stocks and risk of anemia in twins. Archs Inst Pasteur Tunis 1989;66:221 – 41. Hediger ML, Luke B. Hemodynamics and maternal weight gain in twin pregnancies. Presented at the meeting of the American Public Health Association, Chicago, November 9–11, 1999. Public Health Service. Caring for our future: the content of prenatal care. A report of the Public Health Service’s Expert Panel on the content of prenatal care. Washington (DC)7 US Government Printing Office; 1989. Kogan MD, Alexander GR, Kotelchuck M, et al. Comparing mothers’ reports on the content of prenatal care received with recommended national guidelines for care. Public Health Rep 1994;109:637 – 46. Sable MR, Herman AA. The relationship between prenatal health behavior advice and low birth weight. Public Health Rep 1997;112:332 – 9. Peoples-Sheps MD, Hogan VK, Ng’andu N. Content of prenatal care during the initial workup. Am J Obstet Gynecol 1996;174:220 – 6. Kogan MD, Alexander GR, Kotelchuck M, et al. Relation of the content of prenatal care to the risk of low birth weight. JAMA 1994;271:1340 – 5. Haas JS, Berman S, Goldberg AB, et al. Prenatal hospitalization and compliance with guidelines for prenatal care. Am J Public Health 1996;86:815 – 9. Cogswell ME, Scanlon KS, Fein SB, et al. Medically advised, mother’s personal target, and actual weight gain during pregnancy. Obstet Gynecol 1999;94:616 – 22. Taffel SM, Keppel KG. Advice about weight gain during pregnancy and actual weight gain. Am J Public Health 1986;76:1396 – 9. Kogan MD, Kotelchuck M, Alexander GR, et al. Racial disparities in reported prenatal care advice from health care providers. Am J Public Health 1994;84:82 – 8. Yu SM, Jackson RT. Need for nutrition advice in prenatal care. J Am Diet Assoc 1995;95: 1027 – 9. US Preventive Services Task Force. Guide to clinical preventive services. 2nd edition. Baltimore7 Williams & Wilkins; 1996. p. 625. Owen AL, Owen GM. Twenty years of WIC: a review of some effects of the program. J Am Diet Assoc 1997;97:777 – 82. Stockbauer JW. WIC prenatal participation and its relation to pregnancy outcomes in Missouri: a second look. Am J Public Health 1987;77:813 – 8.
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[192] Moss NE, Carver K. The effect of WIC and Medicaid on infant mortality in the United States. Am J Public Health 1998;88:1354 – 61. [193] Brown HL, Watkins K, Hiett AK. The impact of the Women, Infants, and Children Food Supplement Program on birth outcome. Am J Obstet Gynecol 1996;174:1279 – 83. [194] Griffin JF, Hogan JW, Buechner JS, et al. The effect of a Medicaid managed care program on the adequacy of prenatal care utilization in Rhode Island. Am J Public Health 1999;89: 497 – 501. [195] Long SH, Marquis MS. The effects of Florida’s Medicaid eligibility expansion for pregnant women. Am J Public Health 1998;88:371 – 6. [196] Baldwin L-M, Larson EH, Connell FA, et al. The effect of expanding Medicaid prenatal services on birth outcomes. Am J Public Health 1998;88:1623 – 9. [197] Turner BJ, Newschaffer CJ, Cocroft J, et al. Improved birth outcomes among HIV-infected women with enhanced Medicaid prenatal care. Am J Public Health 2000;90:85 – 91. [198] Klerman LV, Ramey SL, Goldenberg RL, et al. A randomized trial of augmented prenatal care for multiple-risk, Medicaid-eligible African American women. Am J Public Health 2001; 91:105 – 11. [199] Vergani P, Ghidini A, Bozzo G, et al. Prenatal management of twin gestation: experience with a new protocol. J Reprod Med 1991;36:667 – 71. [200] Gardner MO, Amaya MA, Sakakini J. Effects of prenatal care on twin gestations. J Reprod Med 1990;35:519 – 21. [201] Papiernik E, Mussy MA, Vial M, et al. A low rate of perinatal deaths for twin births. Acta Genet Med Gemellol 1985;34:201 – 6. [202] O’Connor MC, Arias E, Royston JP, et al. The merits of special antenatal care for twin pregnancies. Br J Obstet Gynaecol 1981;88:222 – 30. [203] Luke B, Eberlein T. When you’re expecting twins, triplets or quads: a complete resource. 2nd edition. New York7 HarperCollins; 2004. [204] Waterland RA, Garza C. Potential mechanisms of metabolic imprinting that lead to chronic disease. Am J Clin Nutr 1999;69:179 – 97. [205] Barker DJ, Bull AR, Osmond C, et al. Fetal and placental size and risk of hypertension in adult life. BMJ 1990;301:259 – 62. [206] Fall CHD, Osmond C, Barker DJP, et al. Fetal and infant growth and cardiovascular risk factors in women. BMJ 1995;310:428 – 32. [207] Gagnon R, Rundle H, Johnston L, et al. Alterations in fetal and placental deoxyribonucleic acid synthesis rates after chronic fetal placental embolization. Am J Obstet Gynecol 1995;172: 1451 – 8. [208] Clark PM, Atton C, Law CM, et al. Weight gain in pregnancy, triceps skinfold thickness, and blood pressure of offspring. Obstet Gynecol 1998;91:103 – 7.
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Maternal Complications of Multifetal Pregnancy Cynthia Gyamfi, MD*, Joanne Stone, MD, Keith A. Eddleman, MD Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, Mount Sinai School of Medicine, The Mount Sinai Hospital, 5 East 98th Street, 2nd floor, Box 1171, New York, NY 10029, USA
The numbers of multiple gestations have increased significantly in the past two decades, now accounting for up to 3% of all live births in the United States [1,2]. This change can be attributed to an increase in the use and success of assisted reproductive technologies. Because perinatal morbidity and mortality are increased in multiple gestations, practitioners of obstetrics should familiarize themselves with these complications and their management and prevention [2]. This article reviews the common maternal complications encountered in multifetal gestations.
Maternal adaptation In general, the adaptations that maternal physiologic systems undergo in multifetal pregnancies are similar to those in singleton pregnancies but occur to a greater degree [3]. Pritchard [4] published most of the original studies on maternal adaptations in pregnancy in the 1960s. In 1965, he showed that blood volume at term in normal women is 40% to 45% higher when compared with nonpregnant levels. It would follow that this increase in blood volume, and subsequently in cardiac output, would be higher in multiple gestations. Veille et al [5] performed echocardiograms in 20 twin and 32 singleton pregnancies to support this hypothesis. They looked for changes in cardiovascular status and * Corresponding author. E-mail address:
[email protected] (C. Gyamfi). 0095-5108/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.clp.2005.02.004 perinatology.theclinics.com
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found that the cardiac output in twin gestations was increased over that in singleton pregnancies in the second and third trimesters. Blood volume and maternal red blood cell volume are greater, cardiac output is higher, and heart rate is increased. Although cardiovascular changes are among the earliest noted, the respiratory system undergoes adaptations as well. Because uterine distention occurs earlier and more rapidly in twin gestations, respiratory symptoms such as shortness of breath occur earlier and are more frequent. Tidal volume and oxygen consumption are also increased, evidenced by a higher degree of alkalosis in arterial pH [1]. In addition to cardiovascular and respiratory changes, hormonal changes occur as well. There is an increase of steroid and protein hormones from the fetoplacental unit in multiple gestations [6]. Maternal serum levels of progesterone, estradiol, human chorionic gonadotropin (hCG), and alpha-fetoprotein are higher in multiple gestations. This hormonal increase has several potential manifestations. For example, the increase in beta-hCG over that in singleton pregnancies can lead to an increase in nausea and vomiting during pregnancy. Another example of significant hormonal increases can be seen when screening multiple gestations for Down syndrome or trisomy 18. The increase in estriol will alter the results; therefore, the health care provider should specify the number of fetuses before sending off this screening test. ‘‘Physiologic anemia’’ describes the relative anemia occurring in pregnancy owing to a 40% to 45% increase in blood volume with a corresponding increase in red blood cell volume of only one third. This anemia is more pronounced in twin gestations [3]. In addition, at term, the average estimated blood loss (935 mL) for vaginal delivery is greater than that in singleton pregnancies [3]. Because of the increased requirements of iron and folic acid for the second fetus in addition to the other changes mentioned, maternal anemia in twin pregnancies can be severe. Nutritional requirements are increased as well. Women pregnant with twins have decreased glucose and insulin concentrations. This deficit leads to more a more rapid break down of glycogen stores and a state of ‘‘accelerated starvation’’ [7]. The body enters a fasting-like state, which has been linked to preterm labor in animal studies owing to a resulting increase in prostaglandins [7]. Luke et al have made recommendations for daily caloric intake for twin and triplet pregnancies based on body mass index (BMI). The recommendations range from 3000 kcal/day in obese patients (BMI N 29.0) to 4000 kcal/day in underweight patients (BMI b 19.8) [7]. Higher rates of iron-deficiency anemia have been noted in twin gestations when compared with singletons [7–9]. Spellacy and colleagues [8] reviewed 1253 twin pregnancies, comparing them with singleton controls, and found higher rates of iron-deficiency anemia in the twin group. Blickstein et al [9] reported similar findings when comparing singleton pregnancies with twin pregnancies in the first and second trimesters. Nevertheless, in the third trimester, only the subgroup of multiparous patients with twins continued to have statistically
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greater levels of anemia when compared with their nulliparous twin and all singleton counterparts. Folate levels are decreased remarkably in twin gestations when compared with singletons, and supplementation should be considered. Although Campbell showed that examination of a peripheral smear for megaloblastic anemia was helpful in making the diagnosis, when these smears were compared in twin and singleton pregnancies, the actual incidence of anemia in twins was lower than expected [6].
Antepartum management Antepartum management of twins is different from that of singletons. There are studies in the literature supporting specialized twin clinics to optimize perinatal outcome. Luke and colleagues [10] showed a reduction in preeclampsia, preterm premature rupture of the membranes (PPROM), delivery at less than 36 weeks, low birth weight, and neonatal morbidity when mothers with twin gestations were enrolled into specialty twin clinics. These clinics included twicemonthly visits to a registered dietician and nurse practitioner, in addition to the regular prenatal visits to the woman’s primary care physician. The clinic visits included discussions on diet, signs and symptoms of preeclampsia, fetal growth and development, and a query as to any problems the patient was experiencing [10]. Other studies evaluating specialized prenatal care for twins have shown similar results [11,12]. Ultrasound has become fundamentally important in the antepartum management of multiple gestations. Most authorities scan twins and higher-order multiples every 3 to 4 weeks from around 18 weeks’ gestation for growth, and more frequently if growth restriction is noted [2]. Measurement of cervical lengths can also be performed to predict preterm labor. Bed rest has been evaluated as an intervention to improve outcome in multiple gestations. Currently, there is ample evidence to suggest that it is not only unnecessary but also potentially harmful [3,13]. Crowther and colleagues [14] randomized 118 women with uncomplicated twin gestations in Zimbabwe to bed rest or regular activity at 28 to 30 weeks. They found no difference in the rates of preterm delivery or neonatal morbidity; however, they did note an increase in birthweight with fewer small for gestational age infants in the bed rest group. Goldenberg et al reviewed the MEDLINE database for all literature regarding bed rest in pregnancy up to a date of publication of 1994 and found little proof as to the effectiveness of this intervention [13]. They also noted several potential complications, including an increased risk for thromboembolic disease, muscle atrophy, bone demineralization, and calcium depletion. In addition, costs associated with bed rest included lost wages, hospitalization, and lost domestic productivity [13]. Crowther [15] performed a Cochrane review looking specifically at hospitalization and bed rest in multiple gestations. She found
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that routine bed rest did not decrease the incidence of preterm birth or perinatal mortality. Although there was a trend toward a decreased number of lowbirthweight infants in the bed rest group, this was not statistically significant. In fact, women in the bed rest group had a statistically significant increase in preterm birth at less than 34 weeks’ gestation (odds ratio [OR], 1.84; 95% confidence interval [CI], 1.01 to 3.34). An analysis of triplet gestations in the same review also showed no significant change in outcomes in the bed rest and regular activity groups. The conclusion of the Cochrane review was that routine bed rest should not be offered for multiple gestations until further evidence is available [15].
Pregnancy complications and management Preterm labor Preterm labor is defined as regular uterine contractions leading to cervical change before the completion of 37 weeks’ gestation [16]. Approximately 45% of twins deliver before 37 weeks [17]. When higher-order multiples are included in the paradigm, this rate increases to more than 60% [18]. The average gestational age at delivery in multiple gestations decreases with an increasing number of fetuses. The mean gestational age at delivery is 36 weeks for twins, 33.5 weeks for triplets, and 31 weeks for quadruplet gestations [3]. Mechanical forces from increasing uterine size are the likely etiology. Preterm labor is the most common complication of multiple gestations and has a direct effect on perinatal morbidity and mortality [1,19]. For many years, obstetricians have been trying to identify accurately which patients are at increased risk for preterm labor. The American College of Obstetricians and Gynecologists (ACOG) identified several promising biologic markers for preterm birth in their review of risk factors for preterm delivery [16]. Among these were fetal fibronectin, salivary estriol, bacterial vaginosis, home uterine activity monitoring, and cervical ultrasonography. Of these factors, the most promising have been fetal fibronectin and cervical ultrasonography [16]. Fetal fibronectin is a protein in the basement membrane that serves as an adhesion binder of the placenta and membranes to the decidual layer [16]. It is present in the cervix until about 16 to 20 weeks’ gestation. It then reappears at about 35 weeks or with the onset of preterm labor. In patients from 24 weeks 0 days to 34 weeks 6 days gestation with symptoms of preterm labor, the negative predictive value for delivery within 7 days was 99.5% and within 2 weeks 99.2%. The positive predictive value for delivery within 7 days was 13.4% and within 2 weeks 16.2% [20]. The study included multiple gestations. Goldenberg and colleagues [21] evaluated risk factors for preterm delivery in twins and found that fetal fibronectin was predictive of preterm birth at less than 32 weeks if assayed at 28 weeks.
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Several studies have demonstrated that it is possible to predict preterm labor in twins by measurement of cervical length [21–23]. As part of the Preterm Prediction Study, Goldenberg et al evaluated possible risk factors for preterm delivery in twin gestations [21]. They found that a cervical length of less than or equal to 25 mm at 24 weeks was the best predictor of preterm birth at less than 32 weeks, less than 35 weeks, and less than 37 weeks. Souka and colleagues [22] showed that a cervical measurement of less than 25 mm in twins at 23 weeks was highly sensitive in predicting preterm delivery. Skentou et al [22] also found that measurement of the cervix in twin gestations at 23 weeks predicted preterm birth. The use of cerclage to prevent preterm delivery in twins was first evaluated in 1982. Dor and colleagues [24] randomized 50 twin gestations conceived after ovulation induction to cerclage versus no intervention. The preterm delivery rate was similar in both groups, that is, 45.4% and 47.8%, respectively. Even in the presence of cervical shortening, Newman and colleagues [25] showed that cerclage placement did not change perinatal outcome. The management of preterm labor in multiple gestations is similar to the management of preterm labor in singletons with one important caveat. Women carrying multiple gestations are at increased risk for pulmonary edema than their singleton counterparts owing to a greater increase in plasma volume, decreased colloid osmotic pressure, and more severe anemia [19]. Commonly used treatments such as intravenous hydration, magnesium sulfate, and beta-adrenergic agonists should be used with careful monitoring of input and output of fluids. Other commonly used treatments in singletons such as indomethacin or calciumchannel blockers can also be used in multiples [20]. Few data support the use of combination tocolytic therapy in singleton or multiple gestations [26]; however, magnesium sulfate should not be used in conjunction with nifedipine. Nifedipine can potentiate the neuromuscular blocking action of magnesium, causing significant neuromuscular blockade [27]. If other combination tocolytic therapy is used in these patients, they should be monitored closely for complications such as pulmonary edema or hypotension. Recently, progesterone has been re-introduced to the discussion of preterm delivery. Although there is no demonstrated role of progesterone in the management of active preterm labor, Meis et al [28] demonstrated that weekly injections of 17 alpha-hydroxyprogesterone caproate could decrease the rate of preterm delivery in patients with singleton pregnancies who were at increased risk for this complication. Similar results were seen with the use of vaginal progesterone in a randomized study by da Fonseca and colleagues [29] of singleton pregnancies at increased risk for preterm delivery. Currently, a multicenter trial is underway to evaluate the use of progesterone to prevent preterm delivery in twins and triplets. There have been no effective long-term tocolytics for the prevention of preterm delivery in multiple gestations. Such agents include oral or subcutaneous infusion of terbutaline, oral nifedipine, or rectal indomethacin [2,20]. Although the role of corticosteroids for fetal lung maturity has not been supported by scientific evidence in twins, it is still recommended for multiple gestations at 24 to 34 weeks with impending delivery [3].
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Preterm premature rupture of the membranes The management of PPROM in multiples is essentially similar to that in singletons. These pregnancies are managed expectantly, given some combination of antibiotics that usually involves a penicillin, and delivered for signs and symptoms of chorioamnionitis or at 32 to 36 weeks (whichever is the institutional standard). Mercer et al [30] compared outcomes of PPROM in 99 twin pregnancies versus 99 matched singletons. They found that PPROM was twice as common in twins as in singletons (7.4% versus 3.7%; P b.001; OR, 2.1). They also noted that the latency to delivery in twins was 1.1 days (P = 0.03), whereas with singletons it was 1.7 days. Membrane rupture usually occurs in the presenting sac and can be diagnosed with a sterile speculum examination assessing for pooling of amniotic fluid, ferning, and a positive nitrazine test [31]. It is more difficult to evaluate for PPROM in a nonpresenting sac. These patients usually present with intermittent leakage of fluid. The incidence of PPROM in the nonpresenting twin pair is unknown [31]. Rupture of the separating membrane in a twin gestation seems to be unique to monochorionic diamniotic pairs. Gilbert and colleagues [32] reviewed eight cases of intrauterine rupture of the dividing membrane and found that the twins subsequently developed all of the complications of a monochorionic monoamniotic pair. The perinatal mortality rate was 44% (7/16), and the mean gestational age at delivery was 29 weeks. Some potential causes for this rare complication were an invasive procedure during the pregnancy, intra-amniotic infection, trauma caused by the fetus, and developmental disturbances [32].
Delayed delivery of second twin (asynchronous delivery) Delayed or asynchronous delivery of the second twin refers to delivery of one fetus of a multiple gestation that is not followed promptly by delivery of the next fetus or fetuses [2,3]. Although this scenario is rare, it is usually seen when one of the fetuses is delivered very preterm, and uterine contractility ceases. The next twin may deliver days to weeks later. This management should be reserved for cases of extreme prematurity. In addition, monochorionicity, chorioamnionitis, suspected abruption, and pre-existing preeclampsia should be considered contraindications to this management [3]. Zhang and colleagues [33] recently reviewed 200 twin pregnancies in which the first twin was delivered between 17 and 29 weeks, and the second twin was delivered at least 2 days later. They compared these twins with 374 matched twin controls in which the second twin was delivered on the same day or on the next calendar day. The mean gestational age at delivery in each group was 23 weeks, and the median duration of delay in the study group was 6 days. Additionally, more of the delayed second twins survived to 1 year (56%) than in the nondelayed group (24%) (P b.001).
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When reviewing the options for management, careful counseling is paramount. The patient should be watched closely for signs and symptoms of chorioamnionitis or sepsis. In an earlier study by Zhang et al [34], delaying delivery of the second twin caused a rate of intrauterine infection of 36%, with 5% of mothers experiencing sepsis. Death of one twin The death of one fetus in a multiple gestation is a rather common event when it occurs in the first trimester. Only 50% of twin gestations diagnosed by first-trimester ultrasonography result in the delivery of two live infants [30]. The ‘‘vanishing twin’’ phenomenon, occurring in 21% to 25% of patients, was described with increasing use and resolution of ultrasound [35,36]. When death occurs in the first trimester, it does not seem to affect the overall pregnancy outcome. When the demise of one fetus occurs in a multiple gestation in the second or third trimester, there is a higher potential for significant morbidity and mortality in the remaining fetus or fetuses [2]. This risk is especially true for a monochorionic twin pair. A literature review of 119 monochorionic twin gestations complicated by the demise of one fetus found that 9% of the surviving fetuses died in utero, 10% died in the neonatal period, and 24% of the survivors had significant neurologic injury [37]. The risk of neurologic injury is not increased in a dichorionic twin pair [2]. Overall, demise of one fetus in the second or third trimester is less common than in the first trimester, occurring in 2% to 5% of twin pregnancies and 14% to 17% of triplets [2].
Complications that are increased in multiple gestations Preeclampsia Hypertensive disorders of pregnancy are more common in multiple gestations. Because the underlying pathophysiology of preeclampsia and gestational hypertension is not entirely clear, it is difficult to determine the cause of the increase in these phenomena in multifetal pregnancies. In a review of 3407 twin and 8287 singleton pregnancies by Coonrad and colleagues [38], a twin gestation carried a fourfold increase in preeclampsia independent of race and parity. A nulliparous patient with a twin pregnancy was 14 times more likely to experience preeclampsia than was her parous singleton counterpart. Mastrobattista et al [39] reviewed 53 triplet pregnancies and compared them with age-, parity-, and race-matched twin pregnancies. They found that severe preeclampsia was nearly five times as common in the triplet pregnancies than in their twin counterparts (OR, 4.9; 95%CI, 1.2–23.5; P = .02). Studies like these suggest that fetal number and placental mass are somehow involved in the pathogenesis of preeclampsia.
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Treatment of preeclampsia in multifetal pregnancies is similar to that in singletons. Once again, because of the decreased colloid osmotic pressure and increased plasma volume when compared with singleton pregnancies, magnesium sulfate should be employed with caution, and the input and output of all fluids should be monitored. The risk for recurrence of preeclampsia in twins and singletons was also recently compared. Trogstad and colleagues [40] reviewed a population-based registry of 550,218 patients that included first and second pregnancy outcomes. The risk of recurrence of a particular disease, in this case preeclampsia, helped to determine the mode of inheritance. They hypothesized that, because twin gestations were predisposed to preeclampsia (most likely owing to fetal number and placental size), the rate of recurrence should be less than in a singleton gestation without a similar predisposition. Their findings supported this hypothesis. For women with a first time singleton pregnancy, the recurrence rate was 14.1% compared with a rate of 6.8% for those with a first time twin pregnancy ( P b.001). Recently, several case reports in the literature have described the selective termination of a diamniotic dichorionic pregnancy for the treatment of severe preeclampsia when a placental disorder was thought to be affecting one of the fetuses. Most of the cases referred to the Ballantyne syndrome or ‘‘mirror syndrome.’’ This syndrome describes the association of fetal hydrops or placentomegaly with maternal fluid retention and preeclampsia [41,42]. Heyborne and Porreco [43] reviewed three cases of second-trimester preeclampsia associated with a lethal condition in one twin. Selective termination was employed in an effort to resolve the preeclampsia and was successful in all three patients. Two of the patients went on to deliver at term, and the third delivered at 34 weeks and 4 days after PPROM and preterm labor.
Fatty liver of pregnancy Multiple gestations are a risk factor for fatty liver in pregnancy. Of the reported cases, 14.5% are in twin gestations [2]. This diagnosis should be kept in the differential when working up a twin gestation near term for malaise, nausea, and vomiting until it is ruled out. Davidson and colleagues [44] reviewed three biopsy-documented cases of fatty liver of pregnancy in three triplet gestations. They theorized that increased placental mass might be a factor. Each of the patients in their series presented with vague complaints of malaise, nausea, vomiting, and epigastric pain. It was noted that the initial physical examination of patients with acute fatty liver of pregnancy is usually unremarkable. The more commonly associated signs and symptoms, such as profound hypoglycemia, severe liver dysfunction, and coagulopathy, develop later in the disease course. Davidson and colleagues delivered the patients based on the results of liver biopsies and recognized early liver biopsy as increasing the suspicion for acute fatty liver [44].
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Recently, the association of acute fatty liver of pregnancy with fetal fatty acid oxidation defects has been demonstrated [45]. Maternal liver disease, namely, acute fatty liver and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome, has been detected in women who carry long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficient fetuses. It may be prudent to evaluate the neonates of mother with fatty liver or HELLP syndrome for LCHAD deficiency. Gestational diabetes There are conflicting data evaluating the association of gestational diabetes with pregnancy. Association with the placental hormone human placental lactogen (hPL) and gestational diabetes has been established [1]. Theoretically, because of increased placental mass, more hPL is available to induce gestational diabetes. Devine et al reviewed the literature on gestational diabetes and found that this was not true; however, the data are conflicting. Schwartz and colleagues [46] reviewed 29,644 singleton pregnancies and found 1245 (4.2%) that had gestational diabetes. Of the 429 twin pregnancies during that same time period, 33 (7.7%) had gestational diabetes. This number was statistically more than in the singleton group (P b.05). Other maternal complications Other complications associated with multiple gestations include urinary tract infections, maternal intervertebral disease, and anemia [1,2]. Increased urinary tract infections result from an increased progesterone effect, with an increase in stasis. The pathophysiology behind anemia was discussed earlier. Multiple gestations should be supplemented from the first trimester with at least 60 mg of elemental iron and 1 mg of folic acid [2]. Luke et al have demonstrated the utility of nutritional supplementation in multiple gestations [10].
Triplets The general consensus on triplets and higher-order multiples is that maternal complications are increased, even over that occurring in twin pregnancies [1]. The most common complication is preterm labor, occurring from 60% to 90% of the time [1,18]. The most frequent medical complication in triplets is hypertension, but the actual incidence is difficult to describe because the specific parameters for definition of hypertension were not included in many studies. Anemia is more severe, not only during the pregnancy but also because of the increased risk of blood loss at delivery owing to the increased likelihood of a cesarean delivery [1]. Many of the studies looking at triplet gestation are observational, with few using twins or singletons as a control. Never-
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theless, studies with a twin control group still show an increase of preterm labor [1,47].
Improving pregnancy outcome As discussed previously, the use of specialized ‘‘twin clinics’’ improves pregnancy outcome, and, certainly, this specialization can be extrapolated to higher-order multiples. A recent questionnaire survey by Cleary-Goldman and colleagues [48] to evaluate practice patterns by obstetricians when managing multiple gestations showed that, although the majority thought they were adequately trained, there were ‘‘gaps’’ in knowledge, specifically regarding chorionicity. Additionally, although the importance in demonstrating chorionicity for the subsequent management of a multiple gestation has been established, less than half of practicing obstetricians (48%) performed a first-trimester ultrasound for this indication. Some level of involvement with a maternal-fetal medicine specialist may fill in knowledge gaps specific to the management of multiples. In addition, the reduction of fetal number by selective termination, in the presence of one anomalous fetus, or by multifetal pregnancy reduction has been shown to improve pregnancy outcome. These topics are covered in detail elsewhere in this issue.
Summary There are many complications of multiple gestations. Preterm labor is the most common complication, and its definitive treatment has not been established. In addition to preterm labor, preeclampsia, gestational hypertension, PPROM, and anemia are significant problems encountered frequently in multiple gestations. The number of complications can be reduced by early and regular prenatal care by a staff familiar with these challenges.
References [1] Devine PC, Malone FD. Maternal complications associated with multiple pregnancy. Clin Obstet Gynecol 2004;47:227 – 36. [2] Malone FD, D’Alton ME. Multiple gestation. In: Creasy RK, Resnik R, editors. Maternal-fetal medicine. 5th edition. Philadelphia7 Saunders; 2004. p. 513 – 36. [3] Cunningham FG, Gant NF, Leveno KJ, et al, editors. Williams obstetrics. 21st edition. New York7 McGraw-Hill; 2001. [4] Pritchard JA. Changes in the blood volume during pregnancy and delivery. Anesthesiology 1965;26:393 – 9. [5] Veille JC, Morton MJ, Burry KJ. Maternal cardiovascular adaptations to twin pregnancy. Am J Obstet Gynecol 1985;153:261 – 3. [6] Campbell DM. Maternal adaptation in twin pregnancy. Semin Perinatol 1986;10:14 – 8.
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[7] Luke B. Improving multiple pregnancy outcomes with nutritional interventions. Clin Obstet Gynecol 2004;47:146 – 62. [8] Spellacy WN, Handler A, Ferre CD. A case-control study of 1253 twin pregnancies from a 1982–1987 perinatal database. Obstet Gynecol 1990;75:168 – 71. [9] Blickstein I, Goldschmit R, Lurie S. Hemoglobin levels during twin vs. singleton pregnancies: parity makes the difference. J Reprod Med 1995;40:47 – 50. [10] Luke B, Brown MB, Misiunas R, et al. Specialized prenatal care and maternal and infant outcomes in twin pregnancy. Am J Obstet Gynecol 2003;189:934 – 8. [11] Ellings JM, Newman RB, Hulsey TC, et al. Reduction in very low birth weight deliveries and perinatal mortality in a specialized, multidisciplinary twin clinic. Obstet Gynecol 1993;81: 387 – 91. [12] Vergani P, Ghidini A, Bozzo G, et al. Prenatal management of twin gestation: experience with a new protocol. J Reprod Med 1991;36:667 – 71. [13] Goldenberg RL, Cliver SP, Bronstein J, et al. Bed rest in pregnancy. Obstet Gynecol 1994;84: 131 – 6. [14] Crowther CA, Verkuyl DA, Neilson JP, et al. The effects of hospitalization for rest on fetal growth, neonatal morbidity and length of gestation in twin pregnancy. Br J Obstet Gynecol 1990;97:872 – 7. [15] Crowther CA. Hospitalisation and bed rest for multiple pregnancy. Cochrane Database Syst Rev 2000;(4):CD000110. [16] ACOG practice bulletin, No. 31. Assessment of risk factors for preterm birth. Washington, DC7 American College of Obstetricians and Gynecologists; 2001. [17] Vital and Health Statistics. Health and demographic characteristics of twin birth: United States, 1988. Series 21: Data on natality, marriage, and divorce, No. 50. Washington, DC7 US Department of Health and Human Services; 1992. [18] National Center for Health Statistics. Final natality data. http://www.marchofdimes.com/peristats/ level1.aspx?reg=99&top=3&stop=188&lev=1&slev=1&obj=1. Accessed August 31, 2004. [19] ACOG educational bulletin, No. 253. Special problems of multiple gestation. Washington, DC7 American College of Obstetricians and Gynecologists; 1998. [20] Peaceman AM, Andrews WW, Thorp JM, et al. Fetal fibronectin as a predictor of preterm birth in patients with symptoms: a multicenter trial. Am J Obstet Gynecol 1997;177:13 – 8. [21] Goldenberg RL, Iams JD, Miodovnik M, et al for the National Institute of Child Health Human Development Maternal-Fetal Medicine Units Network. The preterm prediction study: risk factors in twin gestations. Am J Obstet Gynecol 1996;175:1047 – 53. [22] Souka AP, Heath V, Flint S, et al. Cervical length at 23 weeks in twins in predicting spontaneous preterm delivery. Obstet Gynecol 1999;94:450 – 4. [23] Skentou C, Souka AP, To MS, et al. Prediction of preterm delivery in twins by cervical assessment at 23 weeks. Ultrasound Obstet Gynecol 2001;17:7 – 10. [24] Dor J, Shalev J, Mashtach S, et al. Elective cervical suture of twin pregnancies diagnosed ultrasonically in the first trimester following induced ovulation. Gynecol Obstet Invest 1982; 13:55 – 60. [25] Newman RB, Krombach RS, Myers MC, et al. Effect of cerclage on obstetrical outcome in twin gestations with a shortened cervical length. Am J Obstet Gynecol 2002;186:634 – 40. [26] Hill WC. Treatment of preterm labor in multiple gestations. Clin Obstet Gynecol 2004;47: 216 – 26. [27] Snyder SW, Cardwell MS. Neuromuscular blockade with magnesium sulfate and nifedipine. Am J Obstet Gynecol 1989;161:35 – 6. [28] Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alphahydroxyprogesterone caproate. N Engl J Med 2003;348:2379 – 85. [29] da Fonseca EB, Bittar RE, Carvalho MHB, et al. Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study. Am J Obstet Gynecol 2003;188:419 – 24. [30] Mercer BM, Crocker LG, Pierce WF, et al. Clinical characteristics and outcome of twin gesta-
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gyamfi et al tion complicated by preterm premature rupture of the membranes. Am J Obstet Gynecol 1993; 168:1467 – 73. Graham G, Simpson LL. Diagnosis and management of obstetrical complications unique to multiple gestations. Clin Obstet Gynecol 2004;47:163 – 80. Gilbert WM, Davis SE, Kaplan C, et al. Morbidity associated with prenatal disruption of the dividing membrane in twin gestations. Obstet Gynecol 1991;78:623 – 30. Zhang J, Hamilton B, Martin J, et al. Delayed interval delivery and infant survival: a populationbased study. Am J Obstet Gynecol 2004;191:470 – 6. Zhang J, Johnson CD, Hoffman M. Cervical cerclage in delayed interval delivery in a multifetal pregnancy: a review of seven case series. Eur J Obstet Gynecol Reprod Biol 2003;108: 126 – 30. Landy HJ, Weiner S, Corson SL, et al. The ‘‘vanishing twin’’: ultrasonographic assessment of fetal disappearance in the first trimester. Am J Obstet Gynecol 1986;155:14 – 9. Corson SL, Dickey RP, Gocial B, et al. Outcome in 242 in vitro fertilization-embryo replacement or gamete intrafallopian transfer-induced procedures. Fertil Steril 1989;51:644 – 50. Nicolini U, Poblete A. Single intrauterine death in monochorionic twin pregnancies. Ultrasound Obstet Gynecol 1999;14:297 – 301. Coonrod DV, Hickok DE, Zhu K, et al. Risk factors for preeclampsia in twin pregnancies: a population-based cohort study. Obstet Gynecol 1995;85:645 – 50. Mastrobattista JM, Skupski DW, Monga M, et al. The rate of severe preeclampsia is increased in triplet as compared to twin gestations. Am J Perinatol 1997;14:263 – 5. Trogstad L, Skrondal A, Stoltenberg C, et al. Recurrence risk of preeclampsia in twin and singleton pregnancies. Am J Med Genet 2004;126A:41 – 5. Heyborne KD, Chism DM. Reversal of Ballantyne syndrome by selective second-trimester fetal termination. J Reprod Med 2000;45:360 – 2. Vidaeff AC, Pschirrer ER, Mastrobattista JM, et al. Mirror syndrome: a case report. J Reprod Med 2002;47:770 – 4. Heyborne KD, Porreco RP. Selective fetocide reverses preeclampsia in discordant twins. Am J Obstet Gynecol 2004;191:477 – 80. Davidson KM, Simpson LL, Knox TA, et al. Acute fatty liver of pregnancy in triplet gestation. Obstet Gynecol 1998;91:806 – 8. Ibdah JA, Yang Z, Bennett MJ. Liver disease in pregnancy and fetal fatty acid oxidation defects. Mol Genet Metab 2000;71:182 – 9. Schwartz DB, Daoud Y, Zazula P, et al. Gestational diabetes mellitus: metabolic and blood glucose parameters in singleton versus twin pregnancies. Am J Obstet Gynecol 1999;181:912 – 4. Santema J, Bourdrez P, Wallenburg H. Maternal and perinatal complications in triplet compared with twin pregnancy. Eur J Obstet Gynecol Reprod Biol 1995;60:143 – 7. Cleary-Goldman J, Morgan MA, Robinson JN, et al. Multiple pregnancy: knowledge and practice patterns of obstetricians and gynecologists. Obstet Gynecol 2004;104:232 – 7.
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Antepartum Management of Multifetal Pregnancies Alisa B. Modena, MD, Vincenzo Berghella, MD* Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Jefferson Medical College of Thomas Jefferson University, 834 Chestnut Street, Suite 400, Philadelphia, PA 19107, USA
The incidence of multifetal pregnancies has increased significantly during the past 20 years, now accounting for 3% of all pregnancies [1]; therefore, their antepartum management has become increasingly important to the general obstetrician/gynecologist and maternal-fetal medicine specialist. Because of their higher rates of perinatal and maternal morbidity and mortality, these pregnancies present a challenge to the practitioner.
Maternal and fetal risks Of the well-established increase in fetal morbidity and mortality in multiple gestations, prematurity and growth restriction pose the most frequent risks to the pregnancy. Other threats include increased rates of spontaneous abortion, congenital anomalies, intrauterine fetal demise, and perinatal death. Neonates of multifetal pregnancies have an increased perinatal mortality rate when compared with their gestational age–matched singleton counterparts [2]. The increase in fetal morbidity and mortality is matched by the uniformly increased maternal risk. Hypertension, anemia, and abruption all occur more frequently in women with more than one fetus [3]. In a prospective study of twin and singleton pregnancies, Sibai et al [4] found that the rates for gestational
* Corresponding author. E-mail address:
[email protected] (V. Berghella). 0095-5108/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.clp.2005.02.003 perinatology.theclinics.com
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hypertension and preeclampsia and for adverse neonatal outcomes in these pregnancies were significantly higher for women carrying twins. The characteristics of the hypertension, if present, tend toward earlier development, increased severity, and atypical presentation [5]. These increased risks of maternal and neonatal complications necessitate close observation of multifetal pregnancies during the antepartum period.
Diagnosis Recognition of a multifetal pregnancy is a crucial component to the implementation of an antepartum management strategy. In geographical areas where first-trimester ultrasound is not routine, the early diagnosis of multiples depends on maintaining a high index of suspicion. A uterine size clinically estimated to be greater than expected, a history of assisted reproduction, or an elevated maternal serum alpha-fetoprotein (MSAFP) value warrant further investigation. If multifetal gestation is suspected, ultrasound should be performed at the earliest possible gestational age. Ultrasound is very sensitive for this purpose, with detection rates approaching 99.3% [6]. In the Routine Antenatal Diagnostic Imaging with Ultrasound (RADIUS) trial, 129 multifetal pregnancies were studied. Those screened by ultrasound were consistently diagnosed earlier than those not screened [7]. Ultrasonographic study of multifetal pregnancies is crucial not only for determining the fetal number but also for determining placentation, amnionicity, and chorionicity. Determination of amnionicity and chorionicity is most easily established in the first trimester and becomes more difficult and less accurate as the gestation matures secondary to progressive thinning of the membrane and fetal crowding. This ascertainment is important because monochorionic pairs, which account for 20% to 33% of twin gestations, have a relative risk of perinatal mortality of 2.5 [8]. This diagnosis also incurs the increased threat of neurologic morbidity associated with twin-twin transfusion syndrome and demise of a co-twin in utero [9]. Dichorionicity is established by visualization of two separate placentas or gender discordancy. If these characteristics are not apparent, a piece of chorionic tissue projecting between the layers of the dividing membrane, the lambda or twin-peak sign [10,11], demonstrates dichorionicity and its absence, monochorionicity. Thickness of the intertwin membrane has been reported as a predictor of chorionicity but is less reliable [12]. If chorionicity cannot be reliably established, consideration needs to be given to invasive testing for chorionicity assignment [13]. Monoamnionicity is ruled out by visualization of a membrane between the fetuses. Ultrasonography must also be used in the detection of fetal anomalies. The rates of malformations in monozygotic and dizygotic twins are 3.7% and 2.5%, respectively [14]; therefore, careful surveillance of fetal anatomy must be done.
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Prenatal diagnosis Because every fetus carries a risk for congenital anomalies, the presence of more than one increases the chance that the gravida is carrying an abnormal fetus. This concept, along with the association that exists between twinning and maternal age, is important to consider when deciding to refer a patient for prenatal diagnosis and genetic counseling. Genetic counseling should make apparent to the patient the risk of a chromosomal abnormality, the potential complications of any procedure, the possibility of discordant results, the need to obtain a sample from each fetus, and the ethical concerns surrounding a pregnancy with one abnormal fetus. In 1997, Meyers et al [15] calculated the risk for chromosomal aneuploidy in multifetal pregnancies at various maternal ages. In the population studied, they found that a 31-year-old woman pregnant with twins had a risk of chromosomal aneuploidy of 1 in 190, similar to a 35-year-old carrying a singleton. Furthermore, monozygotic twins are not necessarily concordant for chromosomal abnormalities owing to the phenomenon of postzygotic nondisjunction resulting in heterokaryotypic twins.
First- and second-trimester screening In 1996, Sebire et al [16] investigated trisomy 21 screening by fetal nuchal translucency in twin pregnancies, combining measurement of nuchal translucency thickness and maternal age. They measured nuchal translucency between 10 and 14 weeks’ gestation in 448 twin pregnancies and found that the sensitivity of fetal nuchal translucency was similar to that in singleton pregnancies, with a lower specificity. The researchers found an 88% detection rate for Down syndrome and a 7.3% screen-positive rate. Based on these data, the authors recommend offering fetal nuchal translucency measurement in the first trimester as a screening test for Down syndrome in pregnancies with twin gestation, as long as the center has adequate training and experience. First-trimester screening tests that include maternal serum analyte measurement have been adjusted for multifetal pregnancy; however, these adjustments have not been studied adequately, making their interpretation difficult. The authors do not recommend the use of these tests in this population. Second-trimester MSAFP can be used in multifetal pregnancies to screen for fetal neural tube defects. The definition of an elevated MSAFP level for a twin gestation accounts for the increased fetal tissue mass and larger placental volume. A value of 4.5 multiples of the median in an uncomplicated twin gestation is abnormal for most laboratories and requires further testing. This value gives a detection rate of 50% to 85% based on a false-positive rate of 5% [17]. Secondtrimester screening for Down syndrome by maternal serum analyte levels combined with maternal age in 4443 twin pregnancies was shown to be inconsistent [18]. This screening test should not be offered to patients in this population.
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Amniocentesis of both gestational sacs for genetic determination can be performed successfully in most patients with an ultrasound-guided, doubleneedle approach. Instillation of 1 to 2 mL of indigo carmine dye into the first amniotic sac, followed by removal of clear fluid with a different needle from the second sac, ensures an adequate sample of both sacs. If the twins are without question monozygotic by ultrasound findings, only one sac can be sampled. The rate of pregnancy loss after genetic amniocentesis in twins is considered similar to that in singletons [19]. Chorionic villous sampling under ultrasound guidance performed between 10 and 13 weeks is an alternative to amniocentesis in multiple gestations [20]. In experienced centers, twin-twin contamination occurs in 4% to 6% of samples [17].
Preterm labor/birth Fifty-seven percent of twin gestations deliver before 37 weeks and 12% at less than 32 weeks [1]. Several management approaches, including patient education, specialized antepartum clinics, home uterine activity monitoring, serial cervical evaluation, cervical cerclage, and maintenance tocolytics, have been used with varying results to predict and prevent preterm birth in multiple gestations. The presence of an anomalous fetus in a twin gestation increases the risk of preterm delivery of both twins when compared with the risk for nonanomalous twin gestations [21]. Determining which patients with multifetal pregnancy will deliver early is an active area of maternal-fetal medicine research. Cervical length on ultrasound and cervicovaginal fetal fibronectin detection have been evaluated in multifetal pregnancies to predict preterm labor. Of significance, a cervical length of less than 25 mm at 24 weeks’ gestation was associated with preterm delivery before 32 weeks (odds ratio, 7.7). Similarly, a positive cervicovaginal fetal fibronectin at 28 weeks was associated with preterm delivery before 32 weeks (odds ratio, 9.4) [22]. Prediction of preterm labor with a scoring system based on cervical length minus internal os dilation has been proposed [23]. This system is associated with a positive predictive value of 75%. Bivins et al [24] studied the ability of weekly digital examinations of the cervix to predict preterm labor. These examinations were not successful in predicting preterm labor, nor could they predict adverse maternal or fetal outcome. A short cervix on ultrasound does identify some twin pregnancies at risk for preterm birth, but the 60% positive predictive value does not predict preterm birth significantly more than history alone [25]. Because no interventions have been shown to decrease preterm birth once a short cervix on ultrasound or a positive fetal fibronectin has been detected, the routine use of these screening tests in multifetal pregnancies cannot be recommended. Routine prophylactic cervical cerclage has not been shown to improve the risk of preterm birth in multiple gestations [26,27]. Elimian et al [28] looked at prophylactic cerclage in triplet pregnancies versus those managed expectantly
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and found no difference in the mean age at delivery or the incidence of perinatal complications. Its use is not recommended for this purpose. Activity reduction or bed rest is often recommended for the prevention of preterm delivery in multifetal pregnancies. Numerous studies have failed to show an advantage from activity reduction in decreasing the incidence of preterm delivery, lengthening gestation, or improving neonatal morbidity [29,30]. Likewise, there is no evidence to suggest that bed rest delays preterm delivery in this population. Antepartum activity reduction and bed rest should be used with caution and recommended only for the same complications of pregnancy that it would be used in singleton gestations. Home uterine activity monitoring has been proposed as a method for detecting preterm labor. A meta-analysis of six randomized trials involving twins showed no benefit to neonatal outcome with the use of this modality [31]. Maintenance tocolytics, including oral terbutaline, nifedipine, indomethacin, and subcutaneous terbutaline infusion, have been advocated to prevent preterm labor in multifetal pregnancies; however, data do not support the use of these agents for this purpose [32,33]. Increasing evidence in the literature supports the use of supplemental progesterone in preventing preterm delivery in singleton gestations [34]. At this time, there are no data to support its use in multifetal pregnancies. Skill in managing preterm labor is crucial for the practitioner treating women with multifetal pregnancies. As is true for singleton gestations, the diagnosis of preterm labor is confirmed by regular uterine contractions that cause the cervix to change from its nonlaboring state. Once preterm labor is diagnosed, numerous agents are available for its inhibition. These agents include beta-adrenergic agents, magnesium sulfate, indomethacin, calcium channel blockers, and atosiban. Close monitoring for maternal and fetal complications from these medications, particularly for pulmonary edema, is needed. The increased incidence of pulmonary edema is due to the higher blood volume, lower colloid osmotic pressure, and anemia in these patients. Women who are of advanced maternal age are also at an increased risk for myocardial ischemia and cardiac arrhythmias from tocolytic therapy. Induction of fetal lung maturity should be undertaken with corticosteroids in women with multiple gestations who are expected to deliver at less than 34 weeks’ gestation [35]. Therapy with 12 mg of betamethasone given in two doses 24 hours apart may be beneficial not only by reducing the prevalence, severity, and complications of respiratory distress syndrome but also by decreasing neonatal cystic periventricular leukomalacia and neonatal mortality. Preterm rupture of membranes (PROM) occurs more frequently in multiple gestations than in singletons. In 1993, Mercer et al [36] showed that labor ensued significantly earlier in twins after PROM. The frequency of chorioamnionitis in the presenting twin is significantly higher than in the nonpresenting twin in dichorionic pregnancies [37]. The management of pregnancies with multiple gestations complicated by preterm PROM depends on the gestational age, number of fetuses, and the presence of maternal or fetal complications. Delivery is indicated if there is demonstration of fetal lung maturity, or if preterm labor,
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chorioamnionitis, or nonreassuring testing occurs. Otherwise, expectant management before 34 weeks consists of antibiotics, usually ampicillin and erythromycin, together with corticosteroid therapy for fetal lung maturity. Rarely, prolongation of the pregnancy after premature rupture of the membranes and delivery of the presenting twin may be considered in a clinically stable patient. The most recent review from 1999 presents 48 cases of asynchronous delivery in multiple gestations, demonstrating a survival rate of 42% [38]. The largest series from a single center reported on 24 consecutive patients with asynchronous delivery. The average latency period achieved was 36 days, and the survival rate for the first infant born was 0/18 at less than 24 weeks and 4/9 (45%) after 24 weeks. The overall survival rate for the second born infant was 12/24 (50%) [39].
Antepartum surveillance Serial sonography to assess fetal weight and growth in multifetal pregnancies is an important aspect of antepartum management. In 2002, Hartley et al [40] showed that growth restriction confers a worse perinatal outcome in twins when compared with singletons. Sonographic assessment should be done every 3 to 4 weeks from 18 to 20 weeks until delivery. Fetal growth in this population mirrors singleton growth until 28 to 32 weeks, at which time twin fetal growth decelerates [41,42]. Some advocate the use of twin growth charts in the third trimester. If growth discordance (N20% to 30%, calculated as a percentage of the larger twin’s weight) or growth restriction (10%) is discovered, ultrasound assessment every 2 weeks is suggested. Fetal growth deceleration leading to discordancy is optimally detected between 20 and 28 weeks [43]. The detection of intrauterine growth restriction is more predictive of poor perinatal outcome than is discordance alone. Discordant twins who are both above the tenth percentile in estimated weight generally have good outcomes. In 10,683 discordant twins studied by Blickstein and Keith [44], the neonatal mortality rate was significantly higher among pairs in which the smaller twin weighed less than or equal to the tenth percentile. If the diagnosis of fetal weight discordance with intrauterine growth restriction of one or more fetuses is made, intensive fetal monitoring should begin, including twice-weekly nonstress testing and weekly umbilical artery Doppler velocimetry measurements. Doppler testing has been validated in multifetal gestations; the values and patterns of change in vascular resistance are the same as for singletons [45]. If testing indicates worsening fetal status before 34 weeks, corticosteroid therapy followed by delivery is a valid option. Deteriorating testing in one fetus prompting delivery of the entire pregnancy is a decision that should be made in conjunction with the maternal-fetal medicine specialist, neonatologist, and the parents of the affected fetuses. Weekly surveillance with nonstress testing or a biophysical profile for all multifetal pregnancies has not been validated in prospective studies. Surveillance
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with nonstress testing or a biophysical profile for pregnancies complicated by abnormal fluid volumes, pregnancy-induced hypertension, fetal anomalies, growth abnormalities, monoamnionicity, or other standard obstetric indications is as reliable in multiple gestations as in singleton gestations [46]. Quantifying amniotic fluid volume in multiple gestations by measuring the deepest vertical pocket in each sac is probably the most accurate method to measure actual amniotic fluid volume [47]. Because of the synchronous nature of pulmonary maturation in twins, assessment of fetal lung maturity in a multifetal pregnancy can generally be performed accurately from one sac only [48]. Under certain circumstances, including preterm labor, ruptured membranes, diabetes mellitus, growth restriction, or growth discordance, both sacs should be sampled, because it is difficult to predict which fetus will have the higher lung maturity with these conditions.
Unique complications associated with multiple gestations Twin-twin transfusion syndrome occurs in 10% to 15% of monochorionic pregnancies. It is believed to be secondary to an imbalance of blood flow through vascular communications in the placenta. This imbalance leads to overperfusion of one twin, who sustains polycythemia and is at risk for hydrops from circulatory overload, and underperfusion of the co-twin, who becomes anemic and may become growth restricted. The cause seems to be a paucity of placental anastomoses, which interferes with the placenta’s ability to regulate blood flow equally between the twins. The most frequently used criteria for the diagnosis of twin-twin transfusion syndrome is polyhydramnios (fluid pocket 8) of one twin, with oligohydramnios (fluid pocket 2) of the other twin in a monochorionic diamniotic pregnancy. Twin-twin transfusion syndrome typically presents in the midtrimester before 26 weeks. Other ultrasonographic criteria commonly associated with twin-twin transfusion syndrome include the presence of a single placenta, gender concordance, significant growth discordance, a discrepancy in amniotic fluid volume, a discrepancy in the size of the umbilical cords, and the presence of fetal hydrops or congestive cardiac failure [49]. Ultrasonographic evaluation of the pregnancy should include Doppler velocimetry and fetal echocardiography, and amniocentesis should be performed to rule out chromosomal abnormalities or intraamniotic infection. In 2000, Taylor et al [50] demonstrated that absent or reversed end-diastolic flow in the donor umbilical artery, abnormal pulsatility of the venous system of the recipient, and absence of an arterioarterial anastomosis predict poor survival in twin-twin transfusion syndrome when present at the initial diagnosis. The prognosis for pregnancies complicated by twin-twin transfusion syndrome is extremely poor. Generally, the earlier in the pregnancy the twin-twin transfusion syndrome is diagnosed, the worse the prognosis. The survival rate for twins diagnosed at less than 26 weeks without treatment is only 30% [51].
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Therapy for twin-twin transfusion syndrome is controversial. A recent multicenter trial from Europe randomized women to endoscopic laser coagulation versus serial amnioreduction. The trial was stopped early when it was determined that the infants from the endoscopic laser group had significantly improved survival of at least one twin at 28 days and a decreased incidence of cystic periventricular leukomalacia and were more likely to be free of neurologic complications at 6 months [52]. Because this is the only trial on this subject, and because laser therapy has significantly increased prematurity and other complications, the accepted first-line therapy for most centers worldwide, especially for mild or moderate disease, remains serial amnioreduction, which has an overall survival rate of 78% [53]. The optimal treatment of this disorder has not been identified. The twin reversed arterial perfusion (TRAP) sequence, also known as acardiac twinning, is a rare (1/35,000 births, 1% of monochorionic twin pregnancies) complication of monochorionic pregnancies. This sequence consists of a nonanomalous donor twin that develops features of cardiac failure and a recipient twin with the absence of organs, including the heart, above the umbilicus. The goal of antepartum management is to maximize survival in the donor twin. Without treatment, the donor twin succumbs in 50% to 75% of cases [54]. In utero treatment is aimed at interrupting the vascular connections between the twins based on the donor twin size formula published by Moore et al [54]. Expectant management with serial ultrasound evaluations may also be offered. Conjoined twins are a subset of monozygotic twin gestations in which incomplete embryonic division occurs 13 to 15 days after conception. This defect results in varying degrees of fusion of the two fetuses and occurs in approximately 1 in 50,000 births. Ultrasound evaluation is critical not only in the diagnosis of conjoined twins but also in evaluating the shared anatomy. Antepartum management includes serial fetal ultrasonography and possibly MR imaging to delineate the exact range of union and to assist in neonatal surgical planning. Cesarean delivery is the delivery method of choice to minimize maternal and fetal trauma [49].
Death of one twin Death of one twin in utero occurs with a frequency of 2% to 7% in spontaneously conceived pregnancies and a frequency as high as 25% in multiple gestations arising from assisted reproductive technologies. Once a single fetal demise is diagnosed, the gestational age and chorionicity of the pregnancy will determine the correct course of clinical management. At term, delivery of the surviving twin is warranted. The most common time for the demise of one twin is the first trimester, although it can occur at any time in the pregnancy. Dickey et al [55] studied 549 twin pregnancies with an initial ultrasound examination between 3.5 and
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4.5 weeks. They showed spontaneous reduction of one sac, the vanishing twin phenomenon, in 36% pregnancies at less than 7 weeks’ gestation. In monochorionic pregnancies, demise after the first trimester confers a higher incidence of morbidity and mortality in the surviving twin than does demise in a dichorionic pregnancy. If demise of one monochorionic twin occurs after the first trimester, the incidence of intrauterine fetal demise in the second twin is approximately 10%, and the risk of neurologic abnormalities is approximately 20% [56]. Multicystic encephalomalacia, which leads to profound neurologic handicap, occurs in approximately 12% of surviving fetuses after the death of a co-twin as early as 18 weeks [49]. These neurologic injuries most likely stem from hypotension at the time of the demise and are not likely to be altered by immediate delivery; therefore, it is reasonable to manage these patients expectantly until 37 weeks, or the time of fetal lung maturity. For monochorionic and dichorionic twin gestations, it has been observed that loss of a twin after the first trimester increases the incidence of intrauterine growth restriction, preterm labor, and perinatal mortality [57]. Preterm demise dictates increased fetal surveillance of the affected pregnancy. In the past, it had been speculated that retention of a dead fetus might increase the risk of disseminated intravascular coagulation in the mother secondary to the release of thromboplastic material into the maternal circulation. Recently, this phenomenon has been shown to have little clinical significance; therefore, coagulation studies of the maternal serum are unnecessary.
Timing of delivery Multiple gestations should be delivered by 39 weeks owing to the rising perinatal mortality at that time. In 2002, Sairam et al [58] reported that the rate of intrauterine fetal demise in multiple gestations increased after 39 weeks, surpassing the risk of a singleton at 42 weeks. In 2001, Hartley et al [59] studied 8150 twin pregnancies to determine the gestational age at which the perinatal mortality rate was the lowest and the hospital stay length the shortest. They found that the optimal time of delivery for twin gestations was between 37 and 38 weeks, and that twin pregnancies should not go beyond 39 weeks’ gestation owing to the higher risks of perinatal death and longer hospital stays.
References [1] Martin J, Hamilton B, Ventura S. et al. Births: final data for 2001. National Center for Health Statistics. National Vital Statistics Reports, vol. 51(2);2002. [2] Hamilton E, Platt R, Morin L, et al. How small is too small in a twin pregnancy? Am J Obstet Gynecol 1998;179(3):682 – 5. [3] Spellacy W, Handler A, Ferre C. A case-control study of 1253 twin pregnancies from a 1982–1987 perinatal data base. Obstet Gynecol 1990;75:168 – 71.
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[4] Sibai B, Hauth J, Caritis S, et al. Hypertensive disorders in twin versus singleton gestations. Am J Obstet Gynecol 2000;182:938 – 42. [5] Hardardottir H, Kelly K, Bork M. Atypical presentation of preeclampsia in high-order multifetal gestations. Obstet Gynecol 1996;87:370. [6] Carroll S, Soothill P, Abdel-Fattah S, et al. Prediction of chorionicity in twin pregnancies at 10–14 weeks of gestation. Br J Obstet Gynecol 2002;109:82. [7] Ewigman B, Crane J, Frigoletto F, et al for the RADIUS group. Effect of prenatal ultrasound screening on perinatal outcome. N Engl J Med 1993;329:821 – 7. [8] Dube J, Dodds L, Armson A. Does chorionicity or zygosity predict adverse perinatal outcomes in twins? Am J Obstet Gynecol 2002;186:579 – 83. [9] Adegbite A, Castille S, Ward S, et al. Neuromorbidity in preterm twins in relation to chorionicity and discordant birth weight. Am J Obstet Gynecol 2004;190:156 – 63. [10] Sepulveda W, Sebire N, Hughes K, et al. Evolution of the lambda or twin-chorionic peak sign in dichorionic twin pregnancies. Obstet Gynecol 1997;89:439 – 41. [11] Wood S, St. Onge R, Conners G, et al. Evaluation of the twin peak or lambda sign in determining chorionicity in multiple pregnancy. Obstet Gynecol 1996;88(6):6 – 9. [12] Stagiannis K, Sepulveda W, Southwell D. Ultrasonographic measurement of the dividing membrane in twin pregnancy during the second and third trimesters: a reproducibility study. Am J Obstet Gynecol 1995;173:1546. [13] D’Alton M, Dudley D. The ultrasonographic prediction of chorionicity in twin gestation. Am J Obstet Gynecol 1989;160:557. [14] Cameron A, Edwards J, Derom R, et al. The value of twin surveys in the study of malformations. Eur J Obstet Gynecol Reprod Biol 1983;14:347. [15] Meyers C, Adam R, Dungan J, et al. Aneuploidy in twin gestations: when is maternal age advanced? Obstet Gynecol 1997;89:248 – 51. [16] Sebire N, Snijders R, Hughes K, et al. Screening for trisomy 21 in twin pregnancies by maternal age and fetal nuchal translucency thickness at 10–14 weeks of gestation. Br J Obstet Gynaecol 1996;103(10):999 – 1003. [17] Wapner R. Genetic diagnosis in multiple pregnancies. Semin Perinatol 1995;19:351. [18] O’Brien J, Dvorin E, Yaron Y. Differential increases in AFP, hCG and uE3 in twin pregnancies: impact on attempts to quantify Down syndrome screening calculations. Am J Med Genet 1997; 73:109. [19] Ghidini A, Lynch L, Hicks C. The risk of second-trimester amniocentesis in twin gestations: a case-control study. Am J Obstet Gynecol 1993;169:1013. [20] Wapner R, Johnson A, Davis G, et al. Prenatal diagnosis in twin gestations: a comparison between second-trimester amniocentesis and first-trimester chorionic villus sampling. Obstet Gynecol 1993;82:49 – 56. [21] Malone F, Craigo S, Chelmow D, et al. Outcome of twin gestations complicated by a single anomalous fetus. Obstet Gynecol 1996;88:1 – 5. [22] Goldenberg R, Iams J, Miodovnik M. National Institute of Child Health and Human Development, Maternal-Fetal Medicine Units Network. The preterm prediction study: risk factors in twin gestations. Am J Obstet Gynecol 1996;175:1047. [23] Newman R, Godsey R, Ellings J. Quantification of cervical change: relationship to preterm delivery in the multifetal gestation. Am J Obstet Gynecol 1991;165:264. [24] Bivins H, Newman R, Ellings J, et al. Risks of antepartum cervical examination in multifetal gestations. Am J Obstet Gynecol 1993;169(1):22 – 5. [25] Yang J, Kuhlman K, Daly S, et al. Prediction of preterm birth by second trimester cervical sonography in twin pregnancies. Ultrasound Obstet Gynecol 2000;15:288. [26] Dor J, Shalev J, Mashiach S, et al. Elective cervical suture of twin pregnancies diagnosed ultrasonically in the first trimester following induced ovulation. Gynecol Obstet Invest 1982; 13:55. [27] Newman R, Krombach R, Myers M, et al. Effect of cerclage on obstetrical outcome in twin gestations with a shortened cervical length. Am J Obstet Gynecol 2002;186:634.
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[28] Elimian A, Figueroa R, Nigam S, et al. Perinatal outcome of triplet gestation: does prophylactic cerclage make a difference? J Matern Fetal Med 1999;8:119. [29] Adams D, Sholl J, Haney E, et al. Perinatal outcome associated with outpatient management of triplet pregnancy. Am J Obstet Gynecol 1998;178:843. [30] Crowther C. Hospitalization and bed rest for multiple pregnancy. Cochrane Database Syst Rev 2001;(1):CD000110. [31] Colton T, Kayne H, Zhang Y. A meta-analysis of home uterine activity monitoring. Am J Obstet Gynecol 1995;173:1499. [32] Keirse M, Grant A, King J. Preterm labour. In: Chalmers I, Enkin M, Keirse M, editors. Effective care in pregnancy and childbirth. New York7 Oxford University Press; 1989. p. 644. [33] Ashworth M, Spooner S, Verkuyl D, et al. Failure to prevent preterm labour and delivery in twin pregnancy using prophylactic oral salbutamol. Br J Obstet Gynaecol 1990;97:878 – 82. [34] Meis P, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alphahydroxyprogesterone caproate. N Engl J Med 2003;348:2379. [35] Gilstrap L, Clewell W, D’Alton M, et al. Antenatal corticosteroids revisited: repeat courses. NIH Consensus Statement 2000;17(2):1 – 18. [36] Mercer B, Crocker L, Pierce W, et al. Clinical characteristics and outcome of twin gestation complicated by preterm rupture of the membranes. Am J Obstet Gynecol 1993;168:1467 – 73. [37] Phung D, Blickstein I, Goldman R, et al. The Northwestern Twin Chorionicity Study. I. Discordant inflammatory findings that are related to chorionicity in presenting versus nonpresenting twins. Am J Obstet Gynecol 2002;186:1041 – 5. [38] Platt J, Rosa C. Delayed interval delivery in multiple gestations. Obstet Gynecol Surv 1999; 54(5):343 – 8. [39] Farkouh L, Sabin E, Heyborne K, et al. Delayed-interval delivery: extended series from a single maternal-fetal medicine practice. Am J Obstet Gynecol 2000;183(6):1499 – 503. [40] Hartley R, Hitti J, Emanuel I. Size-discordant twin pairs have higher perinatal mortality rates than nondiscordant pairs. Am J Obstet Gynecol 2002;187:1173 – 8. [41] Alexander G, Kogan M, Martin J, et al. What are the fetal growth patterns of singletons, twins, and triplets in the United States? Clin Obstet Gynecol 1998;41:114. [42] Grumbach K, Coleman B, Arger P. Twin and singleton growth patterns compared using ultrasound. Radiology 1986;158:237. [43] Gonzalez-Quintero V, Luke B, O’Sullivan M, et al. Antenatal factors associated with significant birth weight discordancy in twin gestations. Am J Obstet Gynecol 2003;189:813 – 7. [44] Blickstein I, Keith L. Neonatal mortality rates among growth-discordant twins, classified according to the birth weight of the smaller twin. Am J Obstet Gynecol 2004;190:170 – 4. [45] Akiyama M, Kuno A, Tanaka Y, et al. Comparison of alterations in fetal regional arterial vascular resistance in appropriate-for-gestational-age singleton, twin, and triplet pregnancies. Hum Reprod 1999;14:2635. [46] Newman R, Ellings J. Antepartum management of the multiple gestation: the case for specialized care. Semin Perinatol 1995;19:387 – 403. [47] Magann E, Chauhan S, Whitworth N, et al. Determination of amniotic fluid volume in twin pregnancies: ultrasonographic evaluation versus operator estimation. Am J Obstet Gynecol 2000; 182(6):1606 – 9. [48] Whitworth N, Magann E, Morrison J. Evaluation of fetal lung maturity in diamniotic twins. Am J Obstet Gynecol 1999;180(1):1438 – 41. [49] D’Alton M, Simpson L. Syndromes in twins. Semin Perinatol 1995;19:375. [50] Taylor M, Denbow M, Duncan K, et al. Antenatal factors at diagnosis that predict outcome in twin-twin transfusion syndrome. Am J Obstet Gynecol 2000;183:1023 – 8. [51] Berghella V, Kaufmann M. Natural history of twin-twin transfusion syndrome. J Reprod Med 2001;46(5):480 – 4. [52] Senat M, Deprest J, Boulvain M, et al. Endoscopic laser surgery versus serial amnioreduction for severe twin-to-twin transfusion syndrome. N Engl J Med 2004;351:136 – 44. [53] Mari G, Roberts A, Detti L, et al. Perinatal morbidity and mortality rates in severe twin-
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twin transfusion syndrome: results of the International Amnioreduction Registry. Am J Obstet Gynecol 2001;185(3):708 – 15. Moore T, Gale S, Benirschke K. Perinatal outcome of forty-nine pregnancies complicated by acardiac twinning. Am J Obstet Gynecol 1990;163(3):907 – 12. Dickey R, Taylor S, Lu P, et al. Spontaneous reduction of multiple pregnancy: incidence and effect on outcome. Am J Obstet Gynecol 2002;186(1):77 – 83. Pharoah P, Adi Y. Consequences of in-utero death in a twin pregnancy. Lancet 2000;355:1597. Prompeler H, Madjar H, Klosa W. Twin pregnancies with single fetal death. Acta Obstet Gynecol Scand 1994;73:205. Sairam S, Costeloe K, Thilaganathan B. Prospective risk of stillbirth in multiple-gestation pregnancies: a population-based analysis. Obstet Gynecol 2002;100:638 – 41. Hartley R, Emmanuel I, Hitti J. Perinatal mortality and neonatal morbidity rates among twin pairs at different gestational ages: optimal delivery timing at 37 to 38 weeks’ gestation. Am J Obstet Gynecol 2001;184(3):451 – 8.
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Intrapartum Management of Twins: Truths and Controversies Andrew J. Healy, MD, Sreedhar Gaddipati, MD* Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Columbia University, PH16-66, New York, NY 10032, USA
Although the delivery of twins is similar to that of singletons, managing physicians must recognize the increased risks associated with twin pregnancies. These risks include pre-eclampsia, preterm labor, premature rupture of membranes, and hemorrhage. For these reasons, certain issues must be addressed when a women with a twin gestation presents to the labor suite. The patient should have adequate intravenous access placed and blood sent for an evaluation of hematocrit and platelets, as well as a request to the blood bank to have blood available on-call to the labor suite. Additional laboratory tests may be required based on the clinical history. A vital component to successful intrapartum management includes the immediate presence of requisite professional staff. These personnel include experienced obstetricians (two at minimum), nurses, anesthesiologists, operating room technicians, and pediatricians. Although labor progression may occur safely in a labor, delivery, and recovery room, twin delivery should be performed in an operating room. Accurate assessment of intrapartum fetal well being should be accomplished by continuous simultaneous electronic fetal monitoring, either by external monitoring or, when the recording of separate fetal heart rates is in question, by using an internal monitor for Twin A and an external monitor for Twin B. Sonography also comprises an essential component of the intrapartum management of twin gestations. On presentation to the labor suite, ultrasound examination should be performed to confirm viability, placental location, and fetal presentation. Sonographic evaluation of the heart rate and lie of the second twin following delivery of the first twin can facilitate a safe conclusion to a
* Corresponding author. E-mail address:
[email protected] (S. Gaddipati). 0095-5108/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.clp.2005.02.001 perinatology.theclinics.com
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delivery. In addition, evaluation of fetal size is important if weights have not been obtained within the previous 14 days. The knowledge of estimated fetal weights is essential because many of the recommendations on delivery management are based on birthweight [1–3].
Labor characteristics in twin gestations The overall duration of labor in twin pregnancies in comparison with singletons remains controversial. Literature from the 1960s suggests that the overall labor duration is the same; however, when the components of labor are addressed individually, several differences become apparent. Among these differences is an increase in the frequency of uterine activity. Newman and colleagues studied 18 twin and 22 singleton pregnancies, all of which were delivered at 36 weeks’ or greater gestation. Uterine activity was present in both groups as early as 23 weeks’ gestation; however, with twins, significant increases in frequency were seen as the gestation progressed. In contrast, with singleton gestations, a significant increase in uterine activity did not occur until after 36 weeks’ gestation [4]. Friedman in 1964 noted paradoxical findings in his study of 184 twin gestations. The duration of the latent phase was significantly foreshortened and culminated in a more dilated cervix in twin pregnancies when compared with their singleton counterparts. Nevertheless, the progression of active labor was protracted in twins [5]. This observation is even more evident in nulliparous patients and has been attributed to ‘‘uterine inertia’’ as well as malpresentation. The former is believed to result from an overdistended uterus, characterized by an increased frequency of less intense uterine contractions [6]. The result of this phenomenon, as observed by Friedman, was a significant increase in dysfunctional labor patterns. More recently, Schiff and colleagues examined twin gestations delivered between 1984 and 1996 and matched these pregnancies with singleton gestations with respect to parity and maternal age. Included in this study were patients who delivered at 37 weeks’ or greater gestation and who had Twin A in the vertex presentation with a birthweight of 2500 g or greater. To study the natural history of the labor, patients were excluded from the study if they required induction or augmentation of labor, if they presented with cervical dilatation of more than 6 cm on admission, or if they had received tocolysis within 2 weeks of labor. In addition, patients with hypertension, diabetes, or maternal stature less than 150 cm were excluded. Schiff and colleagues chose to define the first stage as the interval between 4 and 10 cm, acknowledging this as the active phase of labor. Nulliparous women carrying twins had a shorter first stage of labor when compared with similar women carrying singletons (3.0 F 1.5 hours in twins versus 4.0 F 2.6 hours in singletons). In the study population, there were no differences in the length of the second stage [7]. These observations have implications in the management of twin labor, particularly when considering the decision to perform cesarean section. Nevertheless, the standard for these la-
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boring patients has not yet been determined. In the meantime, obstetricians should rely on the standards established for singleton gestations.
Induction and augmentation techniques Numerous induction techniques have been developed in the effort to initiate labor. Among these techniques are various forms of prostaglandins and mechanical dilators used to promote cervical ripening and medications to stimulate uterine contractions. Although these methods have been tested thoroughly in singleton pregnancies, the data pertaining to their safety and efficacy in twin pregnancies are limited. Harle and Brun [8] performed a case-control study of 81 patients with uncomplicated twin gestations managed by induction or expectant care after 36 weeks’ gestation. Induction techniques used included oxytocin (18), vaginal prostaglandins (6), and intrauterine balloon catheters (12). No significant differences were observed in mean labor times, the rate of maternal infection, fetal distress, vaginal delivery, operative vaginal delivery, and cesarean section. There were also no significant differences in neonatal outcomes as assessed by 5-minute Apgar scores less than 7 and admissions to the neonatal intensive care unit (NICU). Harle and Brun concluded that the induction of labor might be performed after 36 weeks’ gestation without increasing maternal-fetal morbidity. Price and Marivate [9] published a series evaluating the safety and efficiency of the induction of labor in high-risk twin pregnancies. The investigation compared 32 patients with twin gestations with a control group of patients matched for maternal age, parity, and gestational age. Indications for induction included hypertension (11), prolonged pregnancy (8), intrauterine growth restriction/ placental insufficiency (6), premature rupture of the membranes (5), and other causes (2). All pregnancies were greater than 34 weeks’ gestational age and were induced via artificial rupture of membranes and intravenous oxytocin infusions. Patients were monitored with an internal electrode on Twin A, intermittent external cardiotocographic monitoring of Twin B, and an intrauterine pressure catheter in the presenting sac. No significant differences were observed in the duration of labor (induced, 7.0 F 3.3 hours versus spontaneous, 6.3 F 2.1 hours) or the success rate of vaginal delivery (induced, 83% versus spontaneous, 75%). There was no significant difference in arterial cord pH between the two groups despite a trend toward a lower Apgar score (7) in the second twin irrespective of their group. The main problem throughout the study was technical difficulty in monitoring the second twin, especially during the second stage. Despite this issue, no abnormal cord pH was discovered. A single perinatal death occurred in a thanatophoric dwarf and was unrelated to the method of delivery. The study included patients in whom Twin A was in the breech presentation (spontaneous group, 11; induction group, 8) who were permitted an attempt at vaginal delivery. Local prostaglandins have been associated with a greater risk of uterine hyperstimulation. This concern may emanate from the increased uterine activity
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observed in twin pregnancies; however, no case reports documenting this phenomenon have been published [10]. The use of extra-amniotic balloon placement devices has been associated with an increased risk of malpresentation of the presenting twin [11]; however, this risk also remains a theoretical concern, because no corroborating publications can be found. Manor and colleagues [12] published a case series including 17 patients with twin gestations who underwent induction of labor between 36 to 42 weeks using an intrauterine balloon catheter. Indications for induction included pre-eclampsia (10), discordance (3), suspected fetal distress (2), and postdates (2). All of the patients had Bishop scores less than 5, and Twin A in the vertex presentation. Balloon devices were inflated with 80 to 100 mL of sterile normal saline. Vaginal delivery occurred in 15 of 17 patients (88%), with 12 of 15 (80%) delivering within 24 hours of balloon insertion. Two patients underwent cesarean delivery for failure to progress and suspected fetal distress, respectively. Four patients required oxytocin infusion. All neonates had 5-minute Apgar scores of 10, and no complications were observed. It was concluded that the use of an intrauterine device for the induction of labor in twin gestations was safe and effective. Fausett and colleagues [13] reviewed oxytocin, perhaps one of the oldest induction agents. In a retrospective case-control review, 62 gravidas with twin gestations greater than 32 weeks requiring oxytocin for induction or augmentation were matched with 62 women carrying singletons by parity, gestational age, maximum oxytocin dose, and cervical dilatation at the initiation of the oxytocin. Although the numbers were small, there were no differences in the rates of adverse events (perinatal deaths, arterial cord pH b 7.00, time to delivery, or NICU admissions). There was a statistically significant lower frequency of fetal heart rate abnormalities and hyperstimulation in twins when compared with singletons. Although numerous techniques for labor induction are employed regularly in twin gestations, the data supporting the safety and efficacy in this particular population are limited and largely extrapolated from singleton pregnancies.
Vertex-vertex twins: the optimal presentation The optimal route of delivery for twin pregnancies requires consideration of numerous variables. These factors include the presentation of the fetuses, estimated fetal weights, the presence of discordance, operator experience, the availability of ultrasound, and gestational age. The selected route of delivery should minimize maternal and fetal risks while maximizing neonatal outcome. In a summary of publications from 1982 to 2002 by Robinson and Chauhan, twin pregnancies presented as vertex-vertex (45%), vertex-nonvertex (34%), and nonvertex-other (21%) [3]. Only the first two categories of patients should be considered as candidates for vaginal delivery in viable pregnancies. Despite trends demonstrating an increase in elective cesarean section, vertexvertex twins may be regarded as the optimal candidates for vaginal delivery [14].
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Controversial exclusion criteria such as fetal weights and twin discordance are less applicable in these patients, because each presenting vertex acts to dilate the cervix sufficiently for the remainder of the respective after-coming fetal body. Following delivery of the first twin, the cord is clamped and cut. The presentation of the second twin should be confirmed with ultrasound or the operator’s vaginal hand. The advantage of the former is direct visualization of the fetal heart rate, allowing the operator to confirm reassuring fetal status. The vertex should be gently guided into the pelvis using a vaginal and an abdominal hand. The assistance of a skilled partner can facilitate this process. The amniotic sac should be ruptured only after engagement of the fetal head in an effort to minimize the risk of cord prolapse. A fetal scalp electrode may be placed at this time for optimal heart rate monitoring. The operator must closely monitor the patient for evidence of adverse events, including a nonreassuring fetal heart rate and evidence of abruption or cord prolapse. In addition, spontaneous version has been reported to occur following delivery of the first twin in 2% of vertex-vertex twins [3]. Any evidence of nonreassuring maternal-fetal status should be followed by expeditious delivery with vaginal assistance or cesarean section. The usual obstetric indications apply to facilitate the delivery of the second twin. Successful vaginal delivery of vertex-vertex twins occurs in 70% to 86% of patients [15,16]. Kurzel and colleagues published a retrospective series including 541 sets of twins delivered at a single institution, including 231 sets in the vertex-vertex presentation. Of these cases, vaginal delivery occurred in 86.2% of pregnancies. Thirty-two (13.8%) patients required abdominal delivery, including 12 (5%) patients who underwent cesarean section following the successful vaginal delivery of Twin A. The indications for the combined procedure included cord prolapse (7), a change in presentation (3), fetal distress (1), and abruption (1) [16]. Robinson and Chauhan reviewed five studies that collectively included 592 sets of vertex-vertex twins. Successful vaginal delivery of both twins was achieved in 73% of patients. An additional eight (2%) patients delivered vaginally but required internal podalic version for the delivery of Twin B. The cesarean section rates for Twin B only and both twins were 6% and 19%, respectively [3]. These studies demonstrate not only the anticipated success rates but also the possible complications that may occur in a patient undergoing a trial of labor. The obstetrician must be prepared with the necessary assistants and skills to manage each scenario. Although vaginal delivery of both twins is the most likely outcome, appropriate counseling of patients should include the possibility of a combined vaginal-cesarean delivery. Delivery time interval between twins The optimal time interval between the delivery of each twin is uncertain. Lengthy intervals increase the risk in the second twin for complications such as umbilical cord prolapse, abruption, and malpresentation. Nevertheless, maneu-
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vers to expedite delivery can also result in fetal injury. Early studies before the advent of electronic fetal monitoring suggested that an interval beyond 30 minutes increased the fetal risk for hypoxemia and asphyxia [17–19]. This historical tenet is supported by a recent study by Leung and colleagues [20]. In their series of 118 concordant uncomplicated twin gestations greater than 34 weeks, all of the first twins were delivered vaginally, with the majority spontaneous deliveries (64.4%) and the remainder (35.6%) by operative means. For second twins, 39% were delivered vaginally, 16.1% were delivered by operative vaginal assistance, 28% were assisted breech deliveries, and 16.9% required cesarean section. The median twin-to-twin delivery interval was 16.5 minutes. The findings indicated that longer intervals correlated with poorer cord gas results. When the arterial cord pH of the second twin was compared with the delivery interval, a decline in pH of 0.00529 per minute was observed. No second twins possessed an arterial pH less than 7.00 if delivered within 15 minutes, whereas 5.9% and 27% of second twins had a pH less than 7.00 for delivery intervals of 16 to 30 minutes and greater than 30 minutes, respectively. In addition, in the subgroup of second twins with a delivery interval beyond 30 minutes, there was a 73% incidence of cardiotocographic evidence of fetal distress. In a second article by Leung and colleagues detailing 51 cases, a statistically significant steeper decline was noted in arterial cord pH for the Twin B’s second stage when compared with Twin A’s second stage (0.00155 per minute versus 0.00495 per minute, P = 0.038). The length of Twin A’s second stage did not influence the cord gas results of Twin B’s individual second stage [21]. Rayburn and colleagues [22] performed a retrospective analysis of 115 sets of live-born twins delivered vaginally at 34 weeks’ or greater gestation. The mean twin-to-twin interval was 21 minutes (range, 1–134), with 70 (61%) of second twins delivered within 15 minutes of their older sibling. Combined vaginal-cesarean delivery increased significantly when the twin-to-twin interval exceeded 15 minutes (2/70 versus 8/45, P b.02). With respect to neonatal outcome, 5-minute Apgar scores were greater than 7, and no increase was seen in admission to the NICU for all 17 second twins delivered following intervals greater than 30 minutes. Per institutional protocols, in addition to the use of continuous external monitoring, the second twins were monitored frequently with ultrasound for the assessment of fetal status and presentation. Adam and colleagues [23] reviewed 397 sets of twins weighing 1000 g or greater in which Twin A was in the vertex presentation. The twins lacked anomalies and were delivered at a single institution over an 8-year period. Twinto-twin delivery intervals were less than 15 minutes for 245 patients (76%), 16 to 30 minutes for 54 patients (17%), and exceeded 30 minutes in 24 cases (7%). Ninety percent of vertex and 97% of nonvertex second twins were delivered within 30 minutes of their older sibling. No increase occurred in the frequency of Apgar scores less than 7 as the delivery interval increased from less than 15 minutes to 15 to 30 minutes. Although a few second twins were delivered after 30 minutes, no increase in morbidity was identified in this group.
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Persad and colleagues performed a retrospective analysis of all twins delivered at their institution over a 20-year period in an effort to uncover risk factors for combined vaginal-cesarean deliveries. A total of 1565 patients, including second twins in the vertex and nonvertex presentations, were included. Perinatal outcomes evaluated included a composite of respiratory distress, acidosis, 5-minute Apgar scores less than 3, birth asphyxia, intraventricular hemorrhage, trauma, and other complications of prematurity. Although the delivery interval was not associated with an increase in perinatal morbidity for the second twin, intervals beyond 60 minutes were associated with an eightfold higher risk of cesarean section. Furthermore, these combined deliveries were associated with a significant increase in maternal infection, length of hospitalization, and use of general anesthesia [14]. Prolongation of the delivery interval beyond 30 minutes may be reasonable in the context of a reassuring fetal status, progressive descent, and stable maternal condition. This prolongation should be accompanied by the obstetrician’s recognition that the cervix may have reconstituted, making breech delivery more complicated. Oxytocin should be employed judiciously to decrease the uterine component of this interval.
Vertex-nonvertex twins Although choices for the optimal mode of delivery of vertex-vertex twins seem straightforward, twins in vertex-nonvertex presentation represent an area of controversy, with the vast amount of evidence supporting practice derived from retrospective studies. A recommendation for cesarean delivery Although there are articles offering observations and recommendations from the 1950s onward, several articles from the 1970s recommended that second twins in a nonvertex presentation should be delivered by cesarean section after noting depressed Apgar scores or increased perinatal morbidity and mortality [17,19,24–26]. Ware reported that the first-born twin was more likely to have a 1-minute Apgar score ranging from 7 to 10 when compared with the second twin. Farooqui and colleagues in their review of the literature acknowledged the controversy by citing articles from the 1950s noting an increased mortality for second twins undergoing breech extraction or internal podalic version, and articles from the 1960s suggesting no difference or a difference that was influenced by prematurity. They concluded from a review of their institution’s experience that breech delivery led to an increase in mortality. Kauppila and colleagues, Ho and Wu, and Kohl and Casey published some of the larger studies in the 1970s in which they reported similar findings when reviewing twin deliveries at their respective institutions. Taylor summarizes this opinion in an editorial comment on the article by Kauppila and colleagues, recommending that ce-
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sarean section be used to improve neonatal outcomes in twin gestations when one of the fetuses is nonvertex [27]. Cetrulo later supported this position in a review of the literature and the outcomes at his institution [15,28]. Safety of vaginal delivery for nonvertex second twins In the 1980s, articles began to be published that challenged this conclusion. Acker and colleagues [29] reviewed deliveries from 1977 to 1980, comparing 74 twins that were electively delivered by cesarean section with 76 second twins delivered vaginally from the breech presentation, all with birthweights of 2000 g or more. No difference was noted in neonatal mortality or low Apgar scores. No neonatal deaths occurred with birthweights of 1500 g or greater; however, deaths occurred in both groups when the birthweight was under 1500 g (4/11 in the cesarean group versus 2/6 in the vaginal group). In reviewing data on 4728 twins from the Obstetrical Statistical Cooperative delivered between 1970 and 1977, Kelsick and Minkoff [30] compared 839 breech second twins delivered vaginally with 173 breech second twins delivered by cesarean section. No difference was noted in neonatal mortality regardless of the mode of delivery. Chervenak and colleagues [31] published several articles addressing the controversy. In 1984, they reported no neonatal deaths or intraventricular hemorrhage in 60 vaginally delivered vertex-nonvertex twins with a birthweight of 1500 g or greater. Among 16 twins with a birthweight less than 1500 g, 7 deaths were noted for Twin A and 6 for Twin B, with intraventricular hemorrhage occurring equally in each group. They concluded that neonatal death did not occur in the group of the infants weighing1500 g or more, because 93% of the twins were antenatally diagnosed, leading to improved intrapartum monitoring. This conclusion was expanded in their next article reviewing data from a pool of 385 twin deliveries. Although they acknowledged that outcome variables were underpowered, they noted that when breech second twins were compared with vertex second twins, there was no statistical difference in the rates of neonatal death, respiratory distress syndrome, intraventricular hemorrhage, or 5-minute Apgar scores less than 7. This result was noted for infants above and below the 1500 g birthweight. Nevertheless, in citing literature linking increased morbidity to vaginally delivered singletons in breech presentation weighing less than 1500 g, Chervenak and colleagues recommended that only if the estimated fetal weight of the second twin was greater than 2000 g should they be considered candidates for vaginal breech delivery [32]. This recommendation accounts for the error associated with sonographic estimations of birthweight. A 1987 study by Blickstein and colleagues [33] with smaller numbers also suggested that vertex breech twins were not an indication for cesarean delivery, although they did not address a weight limitation. In 1993, Fishman and colleagues [34] evaluated whether nonvertex second twins were at increased risk for perinatal mortality when compared with vertex second twins. A total of 207 vertex second twins were compared with 183 breech second twins in an assessment of 5-minute Apgar scores, NICU stay, NICU
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admission, and neonatal death. Even after stratification by weight, no differences were noted. The study was powered sufficiently to assess a 2.5-fold difference in outcome variables but was underpowered for assessing low-birthweight infants. Greig and colleagues [35] evaluated the second twin in an analysis of presentation and the mode of delivery. Using data on 416 sets of twins delivered from 1985 to 1990, the second twin was categorized as to whether it was vertex or nonvertex and whether delivery was vaginal or cesarean. The groups were also stratified by weight. Five-minute Apgar scores, mean arterial and venous pH values, NICU stay, and intraventricular hemorrhage rates were not statistically different among the four groups. Although the group weighing less than1500 g was small, Greig and colleagues suggested that the outcome was not related to the mode of delivery, and no cases of head entrapment were noted in 21 infants weighing less than 2000 g. Caukwell and Murphy [36] analyzed 422 sets of twins aged 24 weeks or greater at gestation that were vaginally delivered between 1990 and 1997. In this analysis, all Twin A fetuses were in vertex presentation; morbidities of 237 vertex versus 185 nonvertex presenting Twin B fetuses were compared. With a power analysis to detect an odds ratio of 1.5, they noted no difference in low 5-minute Apgar scores or admissions to the NICU at all gestational ages for the nonvertex second twin, even after controlling for the clinical condition of Twin A. The rates of seizures and perinatal death were not different between the two groups. When 30 infants in the 24 to 31 weeks’ gestational group were analyzed separately, all odds ratios crossed 1 (no statistical differences) with respect to Apgar scores, admission to the NICU, respiratory distress syndrome, the need for ventilation, and perinatal death. A call for randomized trials Many of the articles cited previously and others reviewed but not included have called for further study to settle this question. The only randomized trial addressing management of the nonvertex second twin was reported in 1987 by Rabinovici and colleagues. Sixty vertex-nonvertex twins aged 35 weeks or greater who were delivered between 1983 and 1985 were randomized to vaginal delivery versus cesarean delivery. Although rates of neonatal morbidity were low, a comparison between cesarean second twins and vaginal second twins revealed no differences in morbidity [37,38]. Hogle and colleagues [39] conducted a metaanalysis of four articles selected from 67 identified in a MEDLINE and EMBASE search of articles published from 1980 to 2001. These articles were chosen to include twins for which both birthweights were 1500 g or greater, or the pregnancy was 32 weeks’ or greater gestation. These studies were included if the objective clearly included a comparison of planned cesarean versus planned vaginal delivery. With the exception of a statistically significant higher rate of decreased 5-minute Apgar scores for second twins presenting breech and delivered by planned cesarean delivery, analysis of the 1932 infants collected from the four articles could not provide a conclusive recommendation for a preferred
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method of delivery for vertex breech twins. The call for a randomized trial has been heeded by the Canadian Institutes for Health Research by launching the Twin Birth Study. This international trial started in December 2003 and is randomizing twins satisfying the following criteria: (1) gestational age from 32 to 38 weeks, (2) Twin A in vertex presentation, and (3) birthweights of 1500 g or greater [39,40]. Until well-designed randomized trials are completed, the American College of Obstetricians and Gynecologists (ACOG) and the Society of Obstetricians and Gynecologists of Canada (SOGC) support delivery of nonvertex second twins weighing 1500 to 4000 g as long as criteria for vaginal breech delivery are met [41,42].
Intrapartum external cephalic version Owing to its relative success with minimal perinatal morbidity in singletons, external cephalic version (ECV) has also been used in nonvertex second twins; however, data supporting its success and safety are variable. In 1983, Chervenak and colleagues [43] reported their experience with ECV in malpresenting second twins from 1977 to 1981. Successful version and vaginal delivery was accomplished in 10 of 14 fetuses in transverse lie and 8 of 11 in breech presentation. Two other ECVs were successful, but vaginal delivery was not accomplished, resulting in an overall success rate of 72% for ECV and a 90% success rate of vaginal delivery if ECV was successful. In their series, two version attempts were not successful when the weight of Twin B was 500 g or greater compared with Twin A. Successful ECV was not associated with parity, gestational age, or birthweight. Similar results were reported by Tchabo and Tomai [44] in 1992 in a review of twins delivered between 1983 and 1989 who were 35 weeks’ or greater gestation. Successful ECV and vaginal delivery was noted in 11 of 12 fetuses in transverse lie and 16 of 18 fetuses in breech presentation. The largest series suggesting success and safety was reported by Kaplan and colleagues in 1995 [45]. During 1988 to 1992, 142 sets of vertexnonvertex twins weighing 1500 g or greater presented for management. As per protocol, ECV was always attempted; if unsuccessful, vaginal breech delivery was accomplished if possible. Of the 142 sets of twins, Twin A was delivered vaginally in 96. Among the 96 Twin Bs, ECV was successful in 72 (75% success rate). Of the remaining 22, 20 were delivered vaginally as a breech twin, and 2 required cesarean delivery. Other studies have reported a lower success rate. Gocke and colleagues [46] studied 136 vertex-nonvertex twins all weighing1500 g or greater who underwent ECV, breech extraction, or primary cesarean delivery based on physician preference. Successful ECV leading to vaginal delivery occurred less often than successful breech extraction (19/41 or 46% versus 53/55 or 96%, respectively). Moreover, a failed ECV was more likely to result in a cesarean delivery when compared with a failed breech extraction. Although no differences in neonatal
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morbidities were noted, ECV was associated with a higher failure rate. Similar results were noted in series reported by Wells and Maudlin [47,48]. Chauhan reviewed 11 publications from 1983 to 1998 describing outcomes with ECV of Twin B. Overall successful ECV occurred in 67% of cases (212/325), and 63% (204/325) were delivered vaginally in a vertex presentation. Complications, which included fetal distress, cord prolapse, and abruption, occurred at a rate of 7% (22/325). In a summary of five of the more recent articles from 1989 to 1998 in which breech extraction was compared with ECV, 42% of patients required cesarean delivery if EVC was attempted compared with 2% if breech extraction was attempted [3]. Based on the available literature and from the view of safety for the fetus, all methods seem reasonable to employ and require that the obstetrician assess his or her skills in accomplishing a safe delivery. Without prospective trials to confirm retrospective data, it seems that attempting ECV may lead to a higher risk for cesarean delivery when compared with attempting breech extraction.
Does prematurity alter the route of delivery? As mentioned previously, most studies when looking at their complete population of twins readily admitted that the number of twin pairs weighing less than 1500 g was too small to apply anything more than descriptive statistics. Nevertheless, several studies specifically attempted to look at the lowbirthweight infant. Barrett and colleagues [49] performed a retrospective study of 99 sets of twins with birthweights less than 2000 g to evaluate the relationship between the route of delivery and perinatal outcome. Data on concordant twins between 26 and 36 weeks’ gestation were collected from 1976 to 1981; only those twins for which intrapartum electronic fetal monitoring was employed for both were included for analysis. Neonatal outcomes assessed included the rates of hyaline membrane disease, patent ductus arteriosus, and death. The outcome of each twin was compared with his or her respective co-twin as a control. A comparison between vaginally delivered versus cesarean delivered second twins was not performed. For 14 sets of twins delivered vaginally with birthweights of 601 to 999 g, there was an increased frequency of death in the second twin when compared with the first twin (twin A, 5 deaths versus twin B, 11 deaths; P = .054); no other rates of complications were disparate. In 19 sets of twins with birthweights between 1000 and 1499 g, a significant increase was observed in the rates of hyaline membrane disease and patent ductus arteriosus in second twins delivered vaginally. This disparity in outcomes between co-twins was not present in 20 sets of twins in the same weight class delivered by cesarean section. Similarly, no disparity was noted in the higher-weight class for vaginally delivered or cesarean born twins. Based on these findings, Barrett and colleagues concluded that cesarean section was the optimal route of delivery for all twins expected to have birthweights less than 1500 g. Reviewer’s comments and
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criticisms published along with the manuscript suggested that the study’s conclusions were limited by the use of co-twins as controls, by biases inherent in a retrospective review, and by the researchers’ data analysis. Morales and colleagues [50] analyzed 156 sets of concordant twins born between 1981 and 1986 with a birthweight less than 1500 g to assess the impact of birth order, presentation, and the mode of delivery. Their data support the concept that vertex-vertex twin gestations do not have an improvement in outcome with routine cesarean section. In fact, in their series, an increase in respiratory distress syndrome was noted in the infants delivered by cesarean section. In the assessment of the effect of presentation and method of delivery, some morbidities were noted to be increased in a univariate analysis, but after controlling for birthweight discrepancies between comparison groups, no differences were noted in intraventricular hemorrhage, respiratory distress syndrome, or bronchopulmonary dysplasia. In 1990, Rydhstrfm [51] reviewed the records of 862 twins weighing less than 1500 g identified from the Medical Birth Registry in Sweden starting in 1973, and examined periods from 1973 to 1976 (group I), 1977 to 1980 (group II), and 1981 to 1983 (group III). Although there are limitations to this retrospective analysis, Rydhstrfm observed that, despite an increase in the cesarean section rate (7.7%, 40.5%, and 68.9% in groups I, II, and III, respectively) and a decrease in the neonatal and intrapartum mortality rate (51.7%, 40.5%, and 29.1%, respectively), the rates of cerebral palsy or mental retardation at follow-up 8 or more days after delivery were similar (8.8% versus 8.0% in group I versus II), regardless of presentation. The researchers were forthcoming regarding numerous inherent biases in their study, including the possibility that cesarean section may have been performed only in patients with ‘‘viable pregnancies,’’ and the fact that more than 50% of vaginally delivered twins were diagnosed less than 1 day before delivery compared with less than 15% of twins delivered by cesarean section. Nevertheless, one would have suspected that such factors would have falsely supported the benefit of cesarean section. In a second publication, Rydhstrfm performed a retrospective analysis of 91 sets of twins weighing between 1500 and 2499 g [52]. The Medical Birth Registry database was searched from 1973 to 1983 for pregnancies in which one or both twins died during labor or within the first 28 days of life. Two controls matched for birth weight and year of delivery were selected for each case. The cesarean section rate increased more than threefold during the study interval, and mortality decreased from 73 (2.9%) during the first 4 years to 6 (0.3%) during the last 3 years of the interval. Nevertheless, analysis of the data demonstrated that delivery by cesarean section was not a major factor related to improved outcome; rather, improved survival was attributed to the use of fetal monitoring, ultrasonography, improved prenatal care, and improved neonatal care. Similarly, Davison and colleagues [53] during the period from 1979 to 1990 compared the outcomes of 54 breech extracted second twins with those of 43 second twins delivered by elective cesarean section owing to malpresentation. All twins in this cohort weighed between 750 and 2000 g. Based on this data set,
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there were no differences in the rates of intraventricular hemorrhage, necrotizing enterocolitis, respiratory distress syndrome, and mortality. Nevertheless, the study was underpowered given the small differences in the rates of the morbidities cited (eg, a rate of intraventricular hemorrhage of 9.3% versus 12%; respiratory distress syndrome, 63% versus 62%; and necrotizing enterocolitis, 6.5% versus 5.8% for the vaginal versus cesarean groups, respectively). Two recent studies also focused on this question during an era in which betamethasone was used for fetal benefit in cases of preterm delivery and advances in NICU care occurred. Winn and colleagues [54] reviewed the records of twins born between 1994 and 1999 at 24 weeks’ or greater gestation when Twin B was in nonvertex presentation. Three groups were analyzed: group I, cesarean delivery and no labor; group II, cesarean delivery in labor; and group III, vaginal delivery of Twin B as a breech. The analysis was also separated by birthweight less than 1500 g and birthweight greater than or equal to 1500 g. For the group weighing 1500 g or more, the study was sufficiently powered to state reliably that there were no differences in cord arterial and venous parameters of pH, pCO2, pO2, and base deficit. For the group weighing less than 1500 g, although there was a statistically significant but not clinically important difference in arterial base deficit and venous pH values, owing to small numbers, the study was underpowered to answer adequately the question of safety in this weight class. Similarly, Ziadeh and Badria [55] performed a retrospective analysis of 108 sets of twins aged 28 weeks’ or greater at gestation and weighing less than 1500 g delivered at a single institution. Data on the pregnancies were also collected between 1994 and 1999, and included 41 vertex-vertex, 40 vertex-nonvertex, and 27 nonvertex–other sets of twins. Intrapartum fetal heart monitoring was used for both twins, and fetal presentations were established by ultrasound. Neonatal outcome measures included Apgar scores, rates of respiratory distress syndrome, and mortality. In the vertex-vertex twin pregnancies, no improvement in neonatal outcome was conferred by cesarean section. The researchers actually demonstrated a significant increase in respiratory distress syndrome in the twins delivered by cesarean section (cesarean section, 66% versus vaginal delivery, 42%; P = .02). When an attempt at vaginal delivery of the second twin failed and cesarean delivery was required (4.6% of cases), an increase in neonatal mortality was observed in comparison to twins born vaginally. When outcomes were assessed by birth order, irrespective of the route of delivery, second twins experienced lower 1- and 5-minute Apgar scores (P = .01 and .04, respectively) and an increase in respiratory distress syndrome (Twin A, 70% versus Twin B, 82%; P = .02). Based on their analysis, Ziadeh and Badria concluded that cesarean section did not confer a benefit for vertex-vertex twin gestations. Although they acknowledged that their data suggested that cesarean delivery might decrease neonatal mortality if one of the fetuses were nonvertex, they stated that the data were limited to addressing long-term morbidities. Many institutions have experienced an increase in the use of cesarean section for preterm vertex-vertex twin gestations. Despite this change in practice, few
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publications have attempted to address the effect, if any, of cesarean delivery on the perinatal outcomes in preterm twins. The applicability of the aforementioned studies to current obstetric practice is somewhat limited by the years in which the data were collected. Several of the studies preceded the widespread use of antenatal steroids to promote fetal/neonatal well being. The remaining and more recent studies do not comment on the use of antenatal steroids, which may have substantially affected rates of respiratory distress syndrome/hyaline membrane disease and neonatal mortality. In addition, technologies such as ultrasonography were limited, if even present, during some of the periods. Review of the published literature provides little if any evidence to support the use of cesarean section in vertex-vertex presenting preterm twins solely to improve neonatal outcome. Although the practice of cesarean delivery may be appropriate in preterm cases when one of the fetuses is in nonvertex presentation, the evidence does not support the implementation of cesarean delivery in preterm twins as a universal practice.
The nonvertex first twin: is the management choice clear? Although vaginal delivery of vertex breech presentation is controversial, the nonvertex presenting Twin A seems to have a more clear management plan. For a viable Twin A presenting as a transverse lie, there is general agreement that cesarean delivery is necessary for optimal fetal outcome and prevention of maternal injury. For the presentation of breech-vertex twins, the greatest concern is the occurrence of interlocking twins. There is a complete literature covering a classification system, outcomes of pregnancies complicated by this clinical scenario, and maneuvers to relieve the complication, ranging from abdominal intervention to the extreme of decapitation of one fetus to save the other [56–58]. In effort to update the 1 in 1000 incidence of locked twins reported in 1888, Cohen and colleagues analyzed twins from the Obstetrical Statistical Cooperative from 1950 to 1960. They discovered one case of interlocking twins in a series of 817 twin pregnancies, and 1 in 87.7 twin gestations when the presentation was breech-vertex. Because of this rare but potentially catastrophic clinical situation, the vast majority of practicing obstetricians have been trained to avoid the complication entirely by recommending cesarean delivery [58]. The ACOG acknowledges that, although the possibility of locked twins exist, the incidence is rare. The College also states that, ‘‘In general, cesarean delivery is the method of choice when the first twin is nonvertex. . .’’ [41]. Other complications associated with Twin A delivered as a vaginal breech have been reported. In the meta-analysis by Hogle and colleagues, nonvertex Twin A infants were noted to have poorer 5-minute Apgar scores [39]. Similarly, in the review by Kelsick and Minkoff of the Obstetrical Statistical Cooperative, which included 450 breech-breech and breech-vertex twins delivered between 1970 and 1977, neonatal mortality was significantly higher for vaginally delivered
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breech Twin A when compared with those delivered by cesarean section (4.6% versus 2.4%, respectively) [30]. In a more recent study by Blickstein and colleagues [59], 239 breech vertex twins delivered vaginally were compared with 374 similarly presenting twins delivered by cesarean section between 1990 and 1997. The analysis in this retrospective case-control study was also subdivided into two groups with a birthweight less than 1500 g or greater than or equal to 1500 g. A higher death rate was noted in the less than 1500 g group for vaginal versus cesarean born breech first twins (44.7% versus 7.8%, respectively), suggesting that this group should undergo cesarean section if neonatal outcome is to be optimized. For the 1500 g or greater group, there were no differences with regards to 5-minute Apgar scores less than 7 or neonatal deaths. Because cases were obtained from multiple centers that may have had differing NICU practices, neonatal morbidities were not reported. In an effort to minimize the complication of interlocking heads associated with the breech vertex presentation, Essel and Opai-Tetteh [60] examined 41 twins delivered vaginally versus 27 twins undergoing cesarean section. Both groups contained twins who were either breech-breech or breechtransverse. Because there were no differences in neonatal mortality or low Apgar scores between the two groups, it was concluded that vaginal delivery of these presentations was acceptable if the estimated weights were between 1500 and 3500 g and other criteria for breech vaginal birth were met. One interesting report described two cases in which ECV was used for the breech Twin A. In appropriately selected patients (minimal effort needed, unengaged breech for Twin A), it was suggested that ECV may be a reasonable option but should be evaluated by appropriate studies [61]. Although some data suggest that breech first twins do not need cesarean section, the numbers are small and require further study. Recommendations from within the field of obstetrics by authoritative sources, the literature from the management of singleton breech pregnancies, the lack of a randomized trial or studies investigating neonatal morbidities, and diminished exposure during training to all types of breech presentations have resulted in the practice of cesarean section in this type of presentation, except in rare circumstances.
Vaginal birth after cesarean delivery The practice of vaginal birth after cesarean delivery (VBAC) continues to be controversial. The pendulum of management has swung widely from the style represented by the often quoted, ‘‘Once a cesarean, always a cesarean,’’ to a policy of encouraging VBAC to a temperance of enthusiasm, with recent data suggesting that prostaglandin use can contribute to infrequent but catastrophic morbidity and mortality for the mother and neonate when the uterus is scarred [62]. With respect to twin pregnancies, several studies have provided retrospective data to support its practice. Strong and colleagues [63] reviewed 56 twin gestations delivered between 1982 and 1986, comparing 31 undergoing elective
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repeat cesarean delivery with 25 undergoing attempted vaginal delivery. Of the latter group, 18 (72%) experienced a successful vaginal delivery, with 1 patient experiencing a uterine scar dehiscence. This patient had two previous cesarean sections before VBAC and received oxytocin augmentation, resulting in a 4-cm defect noted after delivery. This 4% dehiscence rate compared favorably with the institution’s 2% dehiscence rate in singleton gestations. In 1996, Miller and colleagues [64] reviewed 210 twin gestations in women with a history of a previous cesarean delivery. A total of 118 women underwent elective repeat cesarean delivery, whereas 92 underwent a trial of labor during the period from 1985 to 1994. Of those attempting VBAC, 64 (70%) successfully delivered both infants vaginally, 15 required cesarean delivery for both infants, and 13 required cesarean delivery for the second twin only. One uterine dehiscence was seen in each group, which was defined as a scar separation not requiring operative intervention. In contrast, although no uterine ruptures were noted in the group undergoing VBAC, two were noted in the elective repeat group. Uterine ruptures were defined as full-thickness separations associated with laparotomy to control hemorrhage, hysterectomy or repair of the uterus or bladder, extrusion of any fetal part, placenta, or cord, or the need for cesarean delivery for distress. No differences in neonatal morbidities were seen with respect to NICU admission rates, respiratory distress syndrome, intraventricular hemorrhage, seizures, 5-minute Apgar scores less than 7, or neonatal deaths. Since this publication, others have also been reported, albeit, with smaller numbers, each contributing to the literature to support safety in VBAC [65–69]. With respect to the position of the ACOG, the data are insufficient to assess safety but suggest that obstetricians ‘‘should select the delivery technique with which they are most comfortable’’ [62].
Summary The management of twin gestations continues to be challenging, and it is incorrect to assume that the intrapartum phase of twins is devoid of controversy. Although the maternal safety of cesarean section has given the obstetrician a way to expedite the arrival of twins, further research, especially in the form of randomized trials, is needed to demonstrate its judicious use for the benefit of the mother and her infants.
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[60] Essel JK, Opai-Tetteh ET. Is routine caesarean section necessary for breech-breech and breechtransverse twin gestations? S Afr Med J 1996;86:1196 – 200. [61] Bloomfield MM, Philipson EH. External cephalic version of Twin A. Obstet Gynecol 1997;89: 814 – 5. [62] American College of Obstetricians and Gynecologists. Induction of labor for vaginal birth after cesarean section. ACOG Committee Opinion 271. Washington (DC)7 ACOG; 2002. [63] Strong TH, Phelan JP, Ahn MO, et al. Vaginal birth after cesarean section in the twin gestation. Am J Obstet Gynecol 1989;161:29 – 32. [64] Miller DA, Mullin P, Hou D, et al. Vaginal birth after cesarean section in twin gestation. Am J Obstet Gynecol 1996;175:194 – 8. [65] Odeh M, Tarazova L, Wolfson M, et al. Evidence that women with a history of cesarean section can deliver twins safely. Acta Obstet Gynecol Scand 1997;76:663 – 6. [66] Wax JR, Philput C, Mather J, et al. Twin vaginal birth after cesarean. Conn Med 2000;64:205 – 8. [67] Myles TD, Miranda R. Vaginal birth after cesarean delivery in the twin gestation. Obstet Gynecol 2000;95:S65. [68] Myles T. Vaginal birth of twins after a previous cesarean section. J Matern Fetal Med 2000; 10:171 – 4. [69] Sansregret A, Bujold E, Gauthier RJ. Twin delivery after a previous caesarean: a twelve-year experience. J Obstet Gynaecol Can 2003;25:294 – 8.
Clin Perinatol 32 (2005) 475 – 494
Monochorionic Twin Pregnancies Thomas Trevett, MD, Anthony Johnson, DO* Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of North Carolina, CB#7516, 214 MacNider Building, Chapel Hill, NC 27599-7516, USA
The National Vital Statistics Report (NVSS) from 2000 indicated that the rate of twin births in the United States increased over the past two decades by 55% from 19 per 1000 live births to 29 per 1000 live births [1]. Although this report did not provide sufficient epidemiologic information to determine the etiology for the increase, the most likely causes include delayed childbearing and the use of assisted reproductive technology (ART). Both are associated with increased rates of dizygotic (DZ) twinning, the fertilization of two separate ova. ART has also been associated with a threefold to tenfold increased incidence in the rate of monozygotic (MZ) twinning, the fertilization of one ovum that divides into two similar and hopefully equal embryos [2]. The report by Murphy and Hey [3] suggests that factors other than ART must exist to explain the 30% increase in the rate of MZ twins seen in the United Kingdom, because the observation spans 50 years. Cziezel and Vargha [4] recently reported an increase in the incidence of twinning with pre- and postconceptional supplementation of a high dose of folic acid and multivitamins. Although zygosity was not reported, it was speculated that the increased prevalence of twins with folic acid/multivitamin supplementation might reflect a population-specific reduction in anomalies and early fetal loss associated with homocysteine metabolism. When compared with the rates for DZ twins, the perinatal mortality and morbidity rates for MZ twins are increased threefold to tenfold [5]. These increased rates seem to be related to the timing of the embryonic division and subsequent chorionicity and not zygosity [6]. Before day 3 of pregnancy, twinning results in complete and hopefully equal separation of the chorion and eventually two separate placentas and gestational sacs. This dichorionic diamniotic (DCDA)
* Corresponding author. E-mail address:
[email protected] (A. Johnson). 0095-5108/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.clp.2005.02.007 perinatology.theclinics.com
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Table 1 Monozygotic twins by chorionicity, amnionicity, and timing Parameter
25%–30%
70%–75%
1%–2%
Chorion Amnion Time (days)
Dichorionic Diamniotic 0–3
Monochorionic Diamniotic 4–7
Monochorionic Monoamniotic 8–14
twinning is phenotypically indistinguishable from DZ twins. Embryonic division in MZ twins after day 3 results in a single shared placenta, known as monochorionic (MC) twinning. If the division is between day 3 and 7, there will be separate gestational sacs or monochorionic diamniotic (MCDA) twinning. After day 7, the fetuses will share a placenta and gestational sac, forming monoamniotic (MCMA) twins. If division occurs between day 13 and 15, incomplete division will occur, forming conjoined twins. This rare phenomenon is seen in 1 in 50,000 to 1 in 100,000 pregnancies (Table 1). Thirty percent of twins are MZ, with 75% of these MC. The incidence of twinning in the NVSS report was at least 1 in 300 pregnancies; therefore, 1 in 150 viable fetuses will develop with an MC placentation.
Perinatal mortality and morbidity Perinatal mortality and neurologic morbidity are markedly different in MC and DC twins [7]. With few exceptions, perinatal loss rates in MC twins are twofold to threefold higher than in DC twins. A report by Sebrie et al [8] notes that, if losses before viability are included, the risk may actually be increased sixfold (12.2% for MC twins versus 1.8% for DC twins). MC twins are associated with an increased risk of low birth weight (odds ratio [OR], 3.0), preterm delivery (OR, 3.8), and neurologic morbidity (OR, 6.0) [9,10]. Adegbite et al [11] compared MC and DC twins born between 24 and 34 weeks’ gestation and found that MC placentation was associated with significant increases in the incidence of cerebral palsy (8% versus 1%) and neurologic morbidity (15% versus 3%). Impaired neurodevelopment in the MC twins was significantly increased when associated with discordant growth (42%), twin-twin transfusion syndrome (TTTS) (37%), or co-twin death (60%) in a comparison with MC twins with concordant growth (8%). Discordant growth had a greater impact than TTTS on the incidence of cerebral palsy in MC infants when compared with DC infants. Congenital anomalies occur more frequently in twin gestations. In a recent international registry of 12 million births with 260,865 twin pairs, the ratio of malformations between twins and singleton pregnancies at birth was 1.25 (95% confidence interval [CI], 1.21–1.28) [12]. This study confirmed the association involving twinning with an increased risk of structural defects of the heart, central nervous system (CNS), anterior wall defects, and open neural tube defects, specifically anencephaly. Twinning was also identified as a risk factor for malformations in all systems, a finding that had not been previously reported. Un-
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fortunately, as is true in most reports, the registry data failed to delineate findings by zygosity or chorionicity. In DZ twins, the risk of a congenital anomaly in one fetus is independent of the risk in the co-twin; therefore, the risk is twice the population background risk of a singleton. Many reports have suggested that the incidence of congenital anomalies in MZ twins is twofold to threefold the background risk [13]. Discordance is the rule for congenital anomalies in MZ twins, with less than 15% of abnormal twins being concordant for any malformation. Schinzel et al [14] suggested that structural malformations in MZ twins should fall into one of three categories: (1) early malformations involving midline structural defects related to the twinning process, including cloacal anomalies, open neural tube defects, ventral wall defects, alimentary tract anomalies (tracheo-esophageal fistula, CNS malformation such as holoprosencephaly), conjoined twins, and acardiac twinning; (2) vascular disruptions resulting in cardiac defects, limb reduction defects, microcephaly, or periventricular leukomalacia secondary to hypoperfusion following a co-twin’s death; and (3) constriction deformations such as congenital hip dislocation, clubfoot, or craniosynostosis. The first two categories are unique to the MC twin gestation, whereas the last category may be seen in DZ and MZ twinning. There are numerous reports of discordance in the expression of X-linked traits, autosomal recessive disorders, and chromosomal abnormalities in MZ twins as well. Various mechanisms have been postulated to explain these observations, which as in early malformations may have a role in the etiology or teratogenicity of the twinning process. These mechanisms include skewed X inactivation, genomic imprinting, loss of imprinting, uniparental disomy, a change in chromosome number, mitochondrial mutations, and telomeric crossover [15]. In light of these observations, genetic and phenotypic discordance should not be discounted in all cases of MZ and more specifically MC twins.
Chorionicity determination Accurate and early determination of the chorionicity is a critical component in the management of twin pregnancies and should be a standard component in ultrasound evaluation of multifetal pregnancies. The first determinant of chorionicity is fetal gender. A twin pregnancy with discordant fetal gender associated with separate placentas is almost certain to be DC. At times, gender cannot be determined confidently in the first and early second trimester. As pregnancy advances, separate placentas may ‘‘fuse’’ or abut each other. When separate placental masses cannot be distinguished, caution should be exercised in basing chorionicity on discordant gender alone owing to the increased risk of genital ambiguity associated with MC twinning [7]. If one considers that all MZ twins and 50% of DZ twins will be concordant for sex, gender determination will not be diagnostic in two thirds of twin pregnancies with fused placentas.
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Fig. 1. Dividing membrane in DCDA twin gestation. Three layers are seen: two outer thin amnion and a thick inner combined chorion.
Measuring the thickness of the membrane is associated with some success. The dividing membrane in DCDA pregnancies is composed of four layers, that is, two layers each of amnion and chorion (Fig. 1). In an MCDA pregnancy, the dividing membrane includes two layers of amnion. Using a 2-mm cut-off in the second and third trimester, Bracero and Byrne [16] reported a 75.7% and 85% sensitivity and specificity, respectively, for the detection of DC placentation. Others have noted significant biologic as well as inter- and intraobserver variability when using membrane evaluation as a determinate of chorionicity [17]. The most accurate diagnosis of chorionicity can be made between 10 and 14 weeks by detecting the presence of the lambda or twin peak sign. The lambda sign is an echogenic triangular projection of tissue into the base of the transitional zone between the intertwin membranes in DC placentas (Fig. 2). A lambda sign will be seen in 95% to 97% of DC placenta at 10 to 14 weeks. The absence of the lambda or the ‘‘T’’ sign has been reported in 91% to 100% of MC placentas in the late first trimester [18,19].
Fig. 2. Lambda sign. Arrow indicates echogenic triangular projection of tissue into the base of the transitional zone between the intertwin membranes of DC placentas.
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Complications specific to monochorionic twinning Twin-twin transfusion It is estimated that 15% to 25% of MC pregnancies are associated with TTTS [20]. This rate is most likely an underestimate owing to the underreporting of pregnancies that experience an early loss of one twin [21]. Many questions remain regarding the etiology of TTTS. The syndrome does not occur in DCDA twins of DZ or MZ origin. The disease is clearly related to the placental angioarchitecture that is unique to MC twinning. Three types of vascular communications have been identified in MC twins by postpartum placental injection studies [22], Doppler velocimetry [23], and direct visualization during fetoscopic surgery [24]. Arteriovenous (AV) anastomoses are deep within the placenta with arterial perfusion from one twin to a shared cotyledon and venous drainage to the co-twin. Superficial anastomoses may be venovenous (VV) or arterioarterial (AA). These bidirectional communications allow direct flow depending on the pressure gradients between the fetuses. It is generally believed that, unless there is compensation in the reverse direction by another AV or superficial anastomoses, unidirectional flow through the AV anastomoses will eventually result in TTTS [24,25]. In their study of the angioarchitecture of MC placentas, Denbow et al [26] found no difference in the number of AV and VV anastomoses between MC pregnancies affected with and without TTTS; however, there was a significant reduction in the number of AA anastomoses in affected pregnancies. Perinatal survival correlated with placental angioarchitecture. The absence of AV anastomoses was associated with a perinatal survival rate of 94%. When AV anastomoses were present, survival rates were higher with accompanying AA anastomoses when compared with the survival without the anastomoses, 87% versus 67%, respectively (P = .19). These findings suggest that AA anastomoses are at least part of the essential components in maintaining equilibrium in the pressure gradients between the two circulations in MC placentas. In the study by Diehl et al using direct fetoscopic visualization of the placental vascular topography in 126 severe TTTS pregnancies, at least one AV anastomosis was found in all cases, with a mean of five (range, 1–14). Unidirectional flow in these anastomoses was always ‘‘donor to recipient.’’ Superficial AA and VV anastomoses were present in 31% and 12% of cases, respectively [24]. These in vivo findings confirm the significance of the imbalance in AV anastomoses as a prerequisite for the development of TTTS. The occurrence of TTTS is rare in MCMA twins. Again, this observation seems to be related to the number and type of placental vascular communications. In a comparison of dye injection studies of placentas from uncomplicated MCMA and MCDA pregnancies, Bajoria [27] found a greater number of anastomoses overall and for each of the different types (AA, VV, and AV) in MCMA pregnancies. It was speculated that the abundance of anastomoses was the primary mitigating factor responsible for TTTS in MCMA pregnancies. Comparing the
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angioarchitecture of MCMA and MCDA twin pregnancies, Umur et al [28] found a significant difference in the anastomoses pattern between the two groups. AA anastomoses were seen in 100% of MCMA twins versus 80% of MCDA twins (P = .013), whereas AV anastomoses occurred less frequently in MCMA twins (50% versus 83%, P = .002). There was no difference in the prevalence of VV anastomoses between the two groups. These findings provide further support for the concept that AA anastomoses are an essential component in maintaining hemodynamic equilibrium in MC twinning. Not all studies have confirmed these observations. Denbow et al found no difference in the angioarchitecture following placental injection studies of MCMA and MCDA pregnancies with and without TTTS [26]. The pathophysiology of TTTS remains elusive at this time. One postulate that has long been considered the basis for the phenotypic observations in TTTS is the transfusion of blood from the donor to the recipient. Various reports have suggested that this simplistic concept is unlikely, with only 25% of TTTS cases demonstrating a difference in hemoglobin levels greater than 15% at birth [29], and no difference found in erythropoietin or iron levels between the twins [30,31]. Bajoria et al [32] have provided evidence suggesting that the presence of an endocrine mediator, namely, vasopressin (AVP), is part of the mechanism regulating fetal circulating volumes. Nevertheless, it is unclear whether the imbalance of AVP in the twins is causative or a secondary response to the development of hypovolemia in the donor twin. Additional reports have implicated other hormones and proteins as potential contributors to the yet undefined pathologic process, including insulin-like growth factors (IGF-2) [33], leptin [34], atrial natriuretic peptide [32], and renin/angiotensin levels [35]. A recent report suggests a possible molecular etiology with the finding of increased expression of the water transporter gene Aquaporin 1 in cell free mRNA from amniotic fluid samples of recipient twins [36]. Although the initiating mechanisms and downstream sequence of events remain to be unraveled, the consequences of this cascade are well established. In the absence of intervention, reduced vascular volume will result in vasoconstriction, oliguria, oligohydramnios, reduced growth rate, end-organ damage, longterm neurologic morbidity, and, often, fetal death in the donor fetus. The co-twin will experience volume overload with the development of persistent megacystis, hydramnios, accelerated growth, cardiomegaly with cardiac decompensation, hydrops, and similar perinatal morbidity and mortality. The diagnosis of TTTS rests on ultrasound findings that can be visualized as early as the first trimester. Early markers include nuchal translucency greater than the 95th percentile [37] and folding of the intertwin membrane at 15 to 17 weeks’ gestation [38,39] (Fig. 3), with an OR of 3.5 (95% CI, 0.9–6.2) and 4.2 (95% CI, 3.0–6.0), respectively. The hallmark of TTTS is a the presence of an MC placentation and discordant amniotic fluid volumes, with a maximum vertical pool (MVP) less than 2 cm in the donor twin and greater than 8 cm in the recipient twin, the so-called ‘‘oligohydramnios-polyhydramnios’’ sequence. With disease progression, the donor twin’s bladder will not be visualized secondary to
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Fig. 3. Folding of the intertwin membrane in MCDA pregnancy.
decreased renal perfusion. Discordant growth is common but not an absolute finding, and may be a delayed manifestation. Except in rare instances, such as heterokaryotic twining, the fetuses are concordant for sex. Once the diagnosis is confirmed or suspected, the severity of the disease should be established. In an attempt to create a formal ultrasound-generated classification of TTTS, Quintero et al [40] introduced a staging system including criteria such as the presence or absence of the bladders and stomach, abnormal Doppler velocimetry of fetal and umbilical vessels, and the presence of hydrops or in utero death. The staging system has been adapted by many investigators as a means of quantifying observations at the time of diagnosis of TTTS and subsequent ultrasound. Because the syndrome does not necessarily follow an orderly pattern, a prognostic value of the disease stage at any one observation in determining perinatal outcome has not been shown. Wee and Fisk [41] postulate that, although the stage at diagnosis is useful, the progression to more advanced stages is a better indicator of outcome. Treatment In the absence of intervention, mortality rates ranging from 80% to 100% [40,42–44] can be expected when TTTS is diagnosed before 24 weeks’ gestation. The therapeutic interventions in this disorder are all invasive, with success and complications rates related to the gestational age and severity of the disease at the time of intervention. The procedures include amniocentesis, septostomy, laser photocoagulation of placental anastomoses, and umbilical cord occlusion by diathermy or ligation. Because of the dearth of controlled trials, there continues to be ongoing debate as to which intervention is most appropriate at various points in the disease spectrum. Amnioreduction and septostomy Serial amniocenteses or amnioreductions with or without septostomy will provide symptomatic relief and prevent preterm delivery from uterine distention
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owing to polyhydramnios in the recipient twin [45] and may improve uteroplacental perfusion [46]. Amnioreduction is widely performed, requiring minimal technical skills and expense. In general, the procedure is performed when the MVP in the recipient twin exceeds 10 cm. The volume removed will vary with the ultimate goal to normalize the MVP of the recipient twin. Most cases of TTTS will require more than one procedure, because amniotic fluid reaccumulates rapidly in the recipient fetus [43]. Rarely, a single procedure early in the disease may ablate the process. In general, procedures are performed under local anesthesia for the skin and deep muscle. An 18-gauge spinal needle is introduced under ultrasound guidance through a placental-free window into the amniotic cavity with polyhydramnios. An extension tubing is connected to the needle, and the distal end is attached to suction to drain actively the amniotic fluid. Fluid is removed until the deepest vertical pocket is less than or equal to 6 cm, or a total of 3 L is removed. Ultrasound assessment of amniotic fluid is repeated weekly. A repeat amnioreduction is undertaken when the MVP again exceeds 10 cm. If the fetal karyotype has not been determined previously, such testing should be offered so that an aliquot of fluid can be obtained at the outset for cytogenetic analysis. If amnioreduction is the sole intent of the intervention, needle placement should be away from the donor twin in an attempt to avoid the dividing membrane. The risk of procedure-related complications has been reported to be 15% [44]. Survival rates of at least one fetus following amnioreduction have ranged from 18% to 83% in small case series [47]. The perinatal mortality rate in the international registry of 223 affected pregnancies [44] and the national Australian registry involving 112 pregnancies was 60% [44,48]. Mari et al noted a small but significant difference in the rates of survival for recipients (65%) versus donors (55%). In the presences of hydrops in the recipient or absent end-diastolic blood flow in the umbilical artery of either twin, survival rates were 40% and 35%, respectively [44]. The rate of neurologic morbidity following amnioreduction has been reported to 5% to 58% [47]. The goal of septostomy is to reduce the amniotic fluid volume in the recipient sac by amnioreduction and to puncture intentionally the intertwin membrane to allow equilibration of the amniotic fluid volumes between the gestational sacs. In theory, this maneuver should ultimately improve uteroplacental perfusion and promote fetal swallowing in the donor. Collectively, these events should correct hypovolemia, improve renal blood flow, and increase urinary output in the donor. The collective survival rate of 64% from small case series has been similar to that for amnioreduction. The report from the international multicenter randomized controlled trial found no difference in the perinatal survival rates for amnioreduction and septostomy; however, there was frequently an advantage of requiring only a single procedure with septostomy (60%) as compared with the performance of serial amnioreductions in the treatment of severe TTTS (30%) (P = .04) [49]. Other authorities have stated that septostomy should have no role in the management of TTTS. These arguments are based on several factors. First, the
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amniotic fluid pressures are already equal despite the large discordance in volume between the donor and recipient. Second, correction of the amniotic fluid volume in the donor sac does not improve urinary output and removes one of the critical criteria for monitoring TTTS progression. Third, in the event there is disease progression, creation of an undulating dividing membrane will severely reduce the success of a secondary procedure such as laser photocoagulation [50]. Fourth, iatrogenic septostomy sites may extend, creating a pseudomonoamniotic pregnancy, resulting in cord entanglement and loss of one or both twins [51].
Laser photocoagulation of chorioangiopagus Proponents of laser ablation argue that, unlike amnioreduction or septostomy, laser photocoagulation should be the preferred therapy for severe TTTS because it addresses the underlying pathophysiology by disrupting the vascular anastomoses. In theory, the procedure should be relatively straightforward. Performed under general inhalational or regional anesthesia or conscious sedation with local anesthesia, an appropriately sized operating trocar sheath that will accommodate a 2- to 3-mm endoscope is inserted through a placental-free window into the amniotic cavity of the recipient twin. Once the targeted vessels have been identified, a 400- to 600-mm neodymium:yttrium-aluminum-garnet (Nd:YAG) or diode laser fiber with 30 to 60 W of laser energy is used to obliterate the anastomotic vessels. At the completion of the laser photocoagulation, amnioreduction is performed to normalize the MVP to less than 6 cm. Early reports described procedures in which the operator simply targeted all vessels crossing the dividing membrane without confirmation of anastomoses, so-called ‘‘nonselective’’ laser ablation [52]. Often, the partition is not the true division of the vascular territory; rather, it is more likely that the membranes have been deviated from the true equator by the disparate fluid volumes. Nonselective occlusion can lead to loss of multiple donor vessels not involved in the transfusion process, placental insufficiency, and further compromise and death of the donor twin. Quintero et al [53] introduced the concept of selective laser photocoagulation, a process of mapping the placental topography to identify and number the causative vessels. Comparing selective versus nonselective occlusion, these investigators demonstrated improved outcome, with survival rates of least one twin of 83% versus 61%, respectively, using selective laser photocoagulation. Maternal morbidity and procedure failure have been related to placentation. In most cases, access to posterior and lateral placentas has been achieved percutaneously with small skin incisions and a single instrument. Anterior placentas, present in approximately one third of cases, have proved to be a challenge owing to the limitation of endoscopic instrumentation presently available in the United States. Flexible endoscopes provide access but limit visualization and increase procedure failure rates. Rigid endoscopes require a two-puncture technique or laparotomy to exteriorize the uterus to allow access to the communicating vessels [52,54]. Pending approval by the US Food and Drug Administration,
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these issues should be reduced significantly with the availability of small semirigid endoscopes (fetoscopes) that have been developed through collaboration with European colleagues and private industry [47]. Transient hydropic states after laser ablation may be seen in the donor owing to an acute hypervolemia, which resolves spontaneously over a few days [55]. Abnormal umbilical artery Doppler velocimetry has been found to normalize in as many as 50% of cases within the first week following laser occlusion [56]. Since the original report by De Lia et al [57] in 1990, numerous uncontrolled case series of laser ablation of placental vessels have been published with survival rates ranging from 55% to 69% and neurologic compromise in 5% to 11% [47]. Preliminary evidence from controlled trials suggested an improved outcome with laser photocoagulation when compared with amnioreduction. Hecher et al found no difference in overall survival rates of 61% versus 51% in the laser and amnioreduction groups, respectively; however, a greater percentage of cases had at least one survivor in the laser treated group, 79% versus 60% (P = .03). Only 2% of laser cases required more than one intervention compared with 81% in the amnioreduction group ( P = .03). Additionally, the laser group had a mean gestational age at delivery greater than the amnioreduction group, 33.7 versus 30.7 weeks, respectively, and a lower incidence of abnormal ultrasonographic findings after delivery, 6% versus 18% [43]. Similarly, Quintero at al [58] reported a greater overall survival of at least one neonate, 83% versus 67%, and reduced neurologic morbidity following selective laser photocoagulation. Although the findings in these reports suggested an improved outcome with laser photocoagulation, Roberts et al [59] stated in their Cochrane Database Review that, in the absence of randomized trials, there was no evidence available to ascertain which intervention was most appropriate in the management of TTTS. At the time of the report, 2001, three randomized trials were underway— the Eurofetus Study, a quasi-randomized trial sponsored by St. Joseph’s Women’s Hospital in Tampa, Florida, and the National Institute of Health (NIH) sponsored Twin-Twin Transfusion Syndrome Study. The Eurofetus trial was a randomized controlled study of women presenting with severe TTTS between 15 and 26 weeks’ gestation for selective laser photocoagulation or amnioreduction. The original study design called for 172 women to be enrolled into each arm. At the second interim analysis, the study was terminated owing to the finding of a significantly higher rate of survival of at least one twin in the laser group when compared with the amnioreduction group. At that point, 142 women had been enrolled, 72 to selective laser photocoagulation and 70 to amnioreduction. The laser group had a higher likelihood of survival of at least one neonate, 76% versus 56% (P = .002); a later mean gestational age at delivery, 33 versus 29 weeks (P = .004); a lower incidence of periventricular leukomalacia, 6% versus 15% (P = .02); and were more likely to be free of neurologic morbidity at 6 months of age, 52% versus 31% (P = .003), when compared with the amnioreduction group. An improved outcome with laser photocoagulation versus amnioreduction was seen in all Quintero stages of TTTS. From these results, it was concluded that selective laser photocoagulation
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was a more effective first-line treatment than amnioreduction for TTTS diagnosed before 26 weeks’ gestation [47]. Fisk and Galea [60] in an accompanying editorial called into question the conclusion that laser photocoagulation was a more effective first-line treatment. They pointed to the fact that, in the laser and amnioreduction groups, adverse perinatal outcome was much lower than in previous uncontrolled studies from the general population. This difference may reflect the fact that the Eurofetus cases were more severely affected than those in previous reports; however, the lack of standardization of prenatal care may have had a role as well. Following intervention, patients were returned to their private obstetrician for the balance of their care. Fisk and Galea stressed the need for formal neurologic evaluation of the surviving infants. The reported improved neurologic outcome in the laser group was based on imaging ultrasounds performed during the first 2 weeks of life. Fisk and Galea concluded that, although the Eurofetus trial suggested the real possibility of benefit, further studies were needed with longterm neurologic development as the primary endpoint before the laser could be considered as first-line therapy in all stages of TTTS. Readers were referred to the ongoing NIH-sponsored randomized trial comparing laser photocoagulation and amnioreduction. At the time of the submission of this article, the quasi-trial had been discontinued, with no information available regarding case enrollment or outcome. The NIH-sponsored TTTS study is ongoing, with 11 amniocentesis and 3 laser centers in the country. Patients or physicians interested in obtaining more information about the trial are referred to the study Web site, accessed at http:// fetalsurgery.chop.edu. One of the previously mentioned researchers (N.M. Fisk) is a medical consultant to the NIH trial. Selective reduction In the only randomized controlled trial published to date, only one third of cases had two healthy survivors; therefore, the option of selective reduction must be considered. Because of the presence of vascular anastomoses in TTTS, selective reduction requires occlusion at the level of the umbilical cord of one of the twins. The use of embolic coils, thrombotic or sclerosing agents, and laser photocoagulation of the umbilical cord has been fraught with high failure and pregnancy loss rates [61]. Endoscopic directed cord ligation has been found to be a successful technique; however, with technical challenges and the risk of premature rupture of membranes (PROM) approaching 30%, few centers rely on ligation as a primary technique for cord occlusion. Bipolar diathermy is the most commonly used technique for selective reduction in complicated MC twins. With over 200 procedures performed, the rates of survival of the remaining co-twin and PROM before 30 weeks’ gestation and the mean gestational age at delivery have been 80%, 22%, and 35 weeks, respectively. Debate continues in regards to which twin should be reduced in the absence of an accompanying structural defect anomaly. Because of the finding of growth restriction and abnormal blood flow studies, it has been suggested that the donor fetus should be reduced if
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selective reduction is requested. Although, intuitively, this approach may seem correct, reports have shown no difference in perinatal survival and neurology morbidity with cord occlusion of the donor or recipient [62,63]. Currently, the decision of which twin to reduce should rest primarily on the complexity of access to the umbilical cords. Patients should be advised that there is no report addressing the long-term neurologic outcome in survivors following selective reduction in pregnancies affected by severe TTTS. Twin reversed arterial perfusion Twin reversed arterial perfusion, the TRAP sequence, has an incidence of 1 in 35,000 pregnancies and complicates approximately 1% of all MC twins. It can complicate DA or MA monochorionic twin gestations. Prenatal diagnosis is made by ultrasound based on the finding of a viable twin, or pump twin, and a recipient twin with a variety of forms, including deficient development of the head, upper extremities, and thorax. Three criteria are necessary for the diagnosis of TRAP: (1) an MC placenta; (2) reversed perfusion through AA anastomoses in the umbilical vessels; and (3) discordant development in the acardiac twin, including complete or partial absence of the heart [64]. It is unclear whether the TRAP sequence is a primary defect of cardiac embryogenesis, a malformation of twinning, or a secondary deformation owing to severe TTTS resulting in hypoxia and secondary atrophy of the heart [65]. The reversed flow is generally of low velocity and may be difficult to visualize through the pelvic vessels of the acardiac twin. The TRAP sequence places the ‘‘pump’’ twin at significant risk owing to the additional burden of perfusing the acardiac twin, leading to cardiac hypertrophy, failure, hydrops, and, ultimately, in utero demise. Management is directed at ensuring the well being of the viable twin. Moore et al [66] reported an overall perinatal mortality rate of 55% primarily from prematurity associated with polyhydramnios and congestive heart failure (P = .01). Increasing acardiac growth with a viable/acardiac weight ratio greater than 70% was associated with rates of prematurity, polyhydramnios, and congestive heart failure of 90%, 40%, and 30%, respectively. Although some would dispute the need for aggressive active intervention in the TRAP sequence, there is evidence to suggest that early intervention will improve perinatal outcome. In the review by Tan and Sepulveda [67], an overall survival rate of 76% was reported in 74 cases of TRAP sequence in which in utero intervention was performed, with a median gestational age at delivery of 36 weeks. When interstitial laser ablation was compared with bipolar diathermy for umbilical cord occlusion, the laser was associated with a later gestational age at delivery, 37 versus 32 weeks; a lower failure rate, 13% versus 35%; and a lower rate of PROM, 23% versus 58%. The improved outcome with interstitial laser treatment is mostly likely reflective of the difference in instrumentation for the two procedures. The interstitial laser uses a 17- to 18-gauge needle for access compared with a 3.3-mm trocar for bipolar diathermy.
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Sullivan et al [68] presented 10 cases of the TRAP sequence managed expectantly. The perinatal mortality rate of 10% suggests that some cases can be managed conservatively with success. Nevertheless, any sonographic finding suggesting compromise in the viable twin, including hydramnios, persistent megacystis, or cardiac failure before 28 weeks’ gestation, would certainly require in utero intervention to prevent unacceptable rates of perinatal morbidity and mortality. In utero death of co-twin In MC twin gestations, because of the omnipresence of vascular anastomoses, the intrauterine fetal death of one twin places a significant risk of morbidity and mortality on the co-twin. The incidence of neurologic morbidity in the surviving co-twin has ranged from 12% to 50%. In a report by Nicolini and Poblete [69] on 119 MC twin pregnancies with a single intrauterine fetal death, there were 57% healthy survivors, 20% perinatal deaths, and 24% with serious sequelae. The last group had complications owing to prematurity or anomalies specifically related to the death of the co-twin, that is, hypoperfusion including porencephaly, multicystic encephalomalacia, cerebral or cerebellar infarcts, renal cortical necrosis, and small bowel atresia. The risk for the surviving co-twin is dependent on the gestational age at the time of intrauterine fetal death. The rate of a compromised co-twin is increased sevenfold if the demise occurs in the second and third trimester as compared with the first. The interval from ‘‘death to delivery’’ does not seem to increase the risk of morbidity for the survivor. The collective experience from two recent reports suggests that fetal blood sampling and intrauterine transfusion within 24 hours of a single intrauterine fetal death in MC twinning, so-called ‘‘intrauterine rescue,’’ provides prognostic information and may reduce long-term morbidity in the surviving co-twin [70,71]. In 9 of 22 (41%) cases, the surviving co-twin was nonanemic, with an uneventful pregnancy with normal neurologic outcome. Intrauterine transfusion was performed in 13 of 22 (59%) anemic fetuses. Six (46%) had a normal neurologic outcome, whereas seven (54%) had a poor perinatal outcome. These preliminary findings provide support for in utero evaluation and possible therapy for the surviving co-twin to avoid acute intrauterine fetal death and extreme prematurity. The management of single intrauterine fetal death in MC twins should be dictated by two criteria: (1) the interval from demise to detection and (2) the gestational age. In the rare event that acute demise is detected remote from delivery, fetal blood sampling (FBS) may be considered, whereas near term, delivery should proceed. More often then not, the timing of intrauterine fetal death will not be possible. It is unlikely that immediate delivery will prevent morbidity at the time of death of the co-twin if the intrauterine fetal death occurred greater than 24 hours previously. Preterm delivery may add an unnecessary risk with no potential benefit to the co-twin in such situations [72]. In the absence of a nonreassuring fetal status, conservative management is rec-
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ommended, with intensive fetal well-being and growth assessments for the balance of the pregnancy. Ultrasound imaging or MR imaging of the fetal brain of the surviving co-twin 3 to 5 weeks after intrauterine fetal death to assess for the presence of intracranial lesions may provide valuable information to counsel the parents in regards to the neurodevelopmental outcome [73].
Selective fetal growth lag Severe fetal growth discordance or a greater than 25% difference in estimated fetal weights occurs more frequently and is associated with greater morbidity when present in MC twin pregnancies as compared with DC twins [74]. A possible explanation for the increased incidence in MC twins may reflect the twining process, with unequal sharing of blastomeres at the time of twinning [75]. Alternative explanations include disparate sharing of the placental mass, the presence and quantity of anastomotic placental vessels, and eccentric or velamentous cord insertion. The perinatal mortality rate for the growth-restricted fetus is reported to be 25%, with a further 25% experiencing loss of both twins [61]. Management options for selective fetal growth lag include conservative management with intensive monitoring of the twins for evidence of impending fetal death, or selective reduction of the growth-restricted twin by cord occlusion. The latter approach would decrease the risk of morbidity and mortality in the surviving twin related to intrauterine fetal death of the smaller fetus. The utility of Doppler velocimetry as part of the monitoring paradigm remains in question. In singletons, identification of absent and reversed end-diastolic umbilical artery flow has been associated with a reduction in perinatal mortality [76]. The same cannot be said in regards to the growth-restricted MC twin. The presence of large AA anastomoses, present in about 80% of MC twin placentas, can produce intermittent reversed end-diastolic flow patterns in twins discordant for growth [77]; therefore, other indices of fetal well being must be taken into account in the surveillance of these pregnancies, including amniotic fluid MVP and biophysical profiles. Corticosteroids should be administered at the time of diagnosis if it occurs greater than 24 weeks’ gestation, with delivery for a nonreassuring fetal status. Quintero et al [78] have suggested the possibility of a third option in such cases—the creation of a ‘‘functionally dichorionic’’ placenta by selective laser ablation of superficial vascular anastomoses in the placenta. In a cohort of 28 MC pregnancies with selective fetal growth lag, 17 were followed expectantly, and 11 underwent laser coagulation of the superficial AV anastomoses. No difference was seen in the survival rate of at least one fetus, 82% versus 72%. Nevertheless, the finding of neurologic compromise in 3 of 22 (13.6%) of the surviving neonates from the expectantly managed group as compared with 0 of 12 in the laser group led the researchers to conclude that ‘‘unlinking’’ the placental circulations would improve neonatal morbidity. Although this is an interesting observation, the therapy may increase rates of preterm PROM, preterm labor, and
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infection without offering a significant improvement in overall outcomes and should be viewed as an experimental therapy at this time. Monoamniotic twins One percent of MZ twinning is complicated by MCMA placentation. Historically, the perinatal mortality rate has been reported to range from 30% to 70%; however, with advances in ultrasound diagnosis and fetal monitoring, it may be significantly reduced. Recent reports by Rodis et al and Allen et al suggest that a perinatal mortality rate as low as 8% to 10% may be achievable [79,80]. After diagnosis and confirmation of normal fetal anatomy, the management of MCMA twins focuses on achieving a reasonable gestational age before elective preterm delivery, which is undertaken to prevent loss of one or both twins. In all cases, some form of intensive monitoring after reaching viability is required. The type of monitoring varies greatly among centers. Some admit patients at 24 weeks for continuous external fetal monitoring, whereas others recommend only twice weekly outpatient nonstress testing. Regardless of the monitoring technique, cord entanglement is ubiquitous and can result in fetal death even in the presence of a recently reassuring nonstress test [80]. The timing of delivery for MCMA twins is controversial. Demaria et al did not report any in utero deaths between 32 and 36 weeks [81]; however, a metaanalysis by Roque et al demonstrated a stable per week perinatal mortality rate of 2% to 4% between 25 and 32 weeks’ gestation, increasing to 11% at 33 to 35 weeks and 22% at 36 to 38 weeks [82]. At the authors’ center, patients are admitted at the time of viability and undergo thrice-daily nonstress testing, with elective delivery at 32 weeks following corticosteroid administration. Conjoined twins Twinning that occurs between day 13 to15 may result in the incomplete division of the inner cell mass, leading to conjoined twins. This event is rare, occurring in 1 in 50,000 pregnancies. The diagnosis can be made readily with ultrasound. The exact nature of the connection between the fetuses must be determined to counsel the parents fully in regards to the likely perinatal outcome. Conjoined twins are classified by the region of the connection. The majority (70% to 75%) are thoracopagus with a common sternum, liver, and diaphragm, among other organs. Seventy percent of thoracopagus twins have a common heart. In other types, the connection between the twins is less critical and may allow for a successful pregnancy outcome and postnatal separation. Accurate prenatal delineation of shared anatomy may be assisted by the use of MR imaging. In cases in which termination is not requested by the parents, delivery by classic cesarean section is often required, with vaginal delivery reserved for extremely premature twins that can be delivered without significant maternal trauma [83].
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Antepartum management and surveillance With the knowledge that MC pregnancies are more likely to be complicated by preterm PROM, preterm delivery, fetal growth lag, and intrauterine fetal death, increased antenatal surveillance is warranted over that for an uncomplicated DC twin. Growth and fetal well-being assessments should be performed by ultrasound every 3 to 4 weeks and possibly more frequently in the presence of significant discordance or severe TTTS. MC twins are more likely to be delivered early for nonreassuring biophysical profiles as well as abnormal Doppler measurements [74]. When discordance is identified, the etiology must be sought. Increased surveillance with weekly Doppler assessments of the smaller twin should be performed, including examination of the umbilical and middle cerebral arteries and ductus venosus. As noted previously, caution must be exercised when interpreting umbilical artery waveform results in the presence of placental vascular anastomoses.
Summary The MC placenta should be considered a developmental malformation and, as such, represents one of the most common birth defects. Great strides are being made to unravel the progression of nature’s successful attempt at human cloning through fission [84]. Critical to any strategy to reduce the perinatal morbidity and mortality associated with MC placentas is early detection. Intense surveillance in at risk pregnancies will provide a better understanding of their natural progression, improve prognosis with early intervention, and ultimately provide the key to prevent many of the complications unique to the MC placenta.
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[55] Gratacos E, Van Schoubroeck D, Carreras E, et al. Transient hydropic signs in the donor fetus after fetoscopic laser coagulation in severe twin-twin transfusion syndrome: incidence and clinical relevance. Ultrasound Obstet Gynecol 2002;19:449 – 53. [56] Zikulnig L, Hecher K, Bregenzer T, et al. Prognostic factors in severe twin-twin transfusion syndrome treated by endoscopic laser surgery. Ultrasound Obstet Gynecol 1999;14:380 – 7. [57] De Lia JE, Cruikshank DP, Keye Jr WR. Fetoscopic neodymium:YAG laser occlusion of placental vessels in severe twin-twin transfusion syndrome. Obstet Gynecol 1990;75:1046 – 53. [58] Quintero RA, Dickinson JE, Morales WJ, et al. Stage-based treatment of twin-twin transfusion syndrome. Am J Obstet Gynecol 2003;188:1333 – 40. [59] Roberts D, Neilson JOP, Weindling AM. Interventions for the treatment of twin-twin transfusion syndrome. Cochrane Database Syst Rev 2001;1:CD002073. [60] Fisk NM, Galea P. Twin-twin transfusion—as good as it gets? N Engl J Med 2004;351(2): 182 – 4. [61] Lewi L, Schoubroeck DV, Gratacos E, et al. Monochorionic diamniotic twins: complications and management options. Curr Opin Obstet Gynecol 2003;15:177 – 94. [62] Nakata M, Chmait RH, Quintero RA. Umbilical cord occlusion of the donor versus recipient fetus in twin-twin transfusion syndrome. Ultrasound Obstet Gynecol 2004;23:446 – 50. [63] Taylor MJ, Shalev E, Tanawattanacharoen S, et al. Ultrasound-guided umbilical cord occlusion using bipolar diathermy for stage III/IV twin-twin transfusion syndrome. Prenat Diagn 2002; 22:70 – 6. [64] Fisk NM, Ware M, Stanier P, et al. Molecular genetic etiology of twin reversed arterial perfusion sequence. Am J Obstet Gynecol 1996;174:891 – 4. [65] Weisz B, Peltz R, Chayen B, et al. Tailored management of twin reversed arterial perfusion (TRAP) sequence. Ultrasound Obstet Gynecol 2004;23:451 – 5. [66] Moore TR, Gale S, Benirschke K. Perinatal outcome of forty-nine pregnancies complicated by acardiac twinning. Am J Obstet Gynecol 1990;163:907 – 12. [67] Tan TY, Sepulveda W. Acardiac twin: a systematic review of minimally invasive treatment modalities. Ultrasound Obstet Gynecol 2003;22:409 – 19. [68] Sullivan AE, Varner MW, Ball RH, et al. The management of acardiac twins: a conservative approach. Am J Obstet Gynecol 2003;189:1310 – 3. [69] Nicolini U, Poblete A. Single intrauterine death in monochorionic twin pregnancies. Ultrasound Obstet Gynecol 1999;14:297 – 301. [70] Senat MV, Bernard JP, Loizeau S, et al. Management of single fetal death in twin-to-twin transfusion syndrome: a role for fetal blood sampling. Ultrasound Obstet Gynecol 2002;20:360 – 3. [71] Tanawattanacharoen S, Taylor MJ, Letsky EA, et al. Intrauterine rescue transfusion in monochorionic multiple pregnancies with recent single intrauterine death. Prenat Diagn 2001;21: 274 – 8. [72] Fusi L, McParland P, Fisk N, et al. Acute twin-twin transfusion: a possible mechanism for braindamaged survivors after intrauterine death of a monochorionic twin. Obstet Gynecol 1991;78: 517 – 20. [73] Pasquini L, Wimalasundera RC, Fisk NM. Management of other complications specific to monochorionic twin pregnancies. Best Pract Res Clin Obstet Gynaecol 2004;18:577 – 99. [74] Victoria A, Mora G, Arias F. Perinatal outcome, placental pathology, and severity of discordance in monochorionic and dichorionic twins. Obstet Gynecol 2001;97:310 – 5. [75] Machin GA. Some causes of genotypic and phenotypic discordance in monozygotic twin pairs. Am J Med Genet 1996;61:216 – 28. [76] Karsdorp VH, van Vugt JM, van Geijn HP, et al. Clinical significance of absent or reversed end diastolic velocity waveforms in umbilical artery. Lancet 1994;344:1664 – 8. [77] Wee LY, Taylor MJ, Vanderheyden T, et al. Transmitted arterio-arterial anastomosis waveforms causing cyclically intermittent absent/reversed end-diastolic umbilical artery flow in monochorionic twins. Placenta 2003;24:772 – 8. [78] Quintero RA, Bornick PW, Morales WJ, et al. Selective photocoagulation of communicating vessels in the treatment of monochorionic twins with selective growth retardation. Am J Obstet Gynecol 2001;185:689 – 96.
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[79] Allen VM, Windrim R, Barrett J, et al. Management of monoamniotic twin pregnancies: a case series and systematic review of the literature. BJOG 2001;108:931 – 6. [80] Demaria F, Goffinet F, Kayem G, et al. Monoamniotic twin pregnancies: antenatal management and perinatal results of 19 consecutive cases. BJOG 2004;111:22 – 6. [81] Rodis JF, McIlveen PF, Egan JF, et al. Monoamniotic twins: improved perinatal survival with accurate prenatal diagnosis and antenatal fetal surveillance. Am J Obstet Gynecol 1997;177: 1046 – 9. [82] Roque H, Gillen-Goldstein J, Funai E, et al. Perinatal outcomes in monoamniotic gestations. J Matern Fetal Neonatal Med 2003;13:414 – 21. [83] D’Alton ME, Simpson LL. Syndromes in twins. Semin Perinatol 1995;19:375 – 86. [84] Tong S, Caddy D, Short RV. Twinning rates. Lancet 1997;349:1398 – 9.
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Long-Term Outcomes in Multiple Gestations Larry Rand, MD*, Keith A. Eddleman, MD, Joanne Stone, MD Maternal Fetal Medicine, Mount Sinai School of Medicine, 5 East 98th Street, Second floor, New York, NY 10029, USA
One of the most pressing dilemmas parents confront when faced with the prospect of a multiple gestation is the long-term outcome. Children born from a multiple gestation are at increased risk for cerebral palsy (CP), learning disability, and language and neurobehavioral deficits [1]. Traditionally, these long-term adverse outcomes have been thought to be a consequence of zygosity/chorionicity or the increased rate of prematurity in multiples; however, this relationship does not appear to be true. Mounting evidence shows that adverse long-term outcomes are more prevalent in children of multiple gestations independent of their gestational age at birth and, to a lesser extent, zygosity [1]. With the increased incidence of multiple pregnancies and use of assisted reproductive technology (ART), these issues increasingly are causing difficulty for parents. Long-term outcomes are a critical part of preconceptual and early pregnancy counseling for parents faced with a multiple gestation or considering ART, and the provider should be well versed on the issues surrounding zygosity, gestational age, higher-order multiples, and the effects of options such as multifetal pregnancy reduction.
Paucity and limitations of data Some of the data that have been available from previous studies for use in counseling have been flawed epidemiologically. Few of these studies are population based, with most being case series. Most of the studies lack long-term follow-up of both (or all) children, a critical feature. Many lack vital prenatal * Corresponding author. E-mail address:
[email protected] (L. Rand). 0095-5108/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.clp.2005.03.002 perinatology.theclinics.com
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information such as the gestational age at the time of diagnosis of multiple pregnancy and chorionicity. Significant confounders often not accounted or corrected for include sex, race, and gender, as well as the maternal use of medication or antenatal steroid exposure. The presence of intrauterine growth restriction (IUGR), which is independently associated with an excess of neurodevelopmental abnormalities [2–4], or the use of ART, which may increase the background rate of monochorionicity [5], is frequently not accounted for. Furthermore, obstetric issues such as the mode of delivery and the impact of birth order are rarely addressed. It is not surprising that long-term outcomes in multiple gestations have been difficult to study. The nature of a long-term outcome alone becomes an obstacle to follow-up. Moreover, an outcome such as neurologic handicap, one of the most prevalent issues in multiple pregnancies, is often not diagnosed until years after birth, with the time lag creating a further impediment to the accuracy of long-term follow-up. Neurologic handicaps occur within a spectrum that is wide and variable and, to a degree, subjective. A major handicap such as cerebral palsy is clearly different from a minor learning or behavioral disability. It is challenging to attribute accurately or confidently the true causal factor for a minor or subtle neurologic handicap in any offspring, whether from a singleton or multiple pregnancy. Further confounding adverse long-term outcomes in multiple pregnancies are the myriad socioeconomic and cultural issues present in any family unit. Variety in schooling and education, specific family situations, and even nutrition may all independently affect subtle neurologic or developmental findings in children. It is easy to understand why the data examining these outcomes must be examined critically before their use in counseling patients.
Prematurity, birth weight, and mortality Twins, triplets, and higher-order multiples carry a greater risk of prematurity and subsequent higher morbidity and mortality. In 2002, the average gestational age at delivery for twins, triplets, and quadruplets was reported as 35.3, 32.2, and 29.9 weeks, respectively. The average birth weight was 2347, 1687, and 1309 g for the same [6]. Infants from multiple pregnancies are at increased risk for cerebral palsy, learning disabilities, slow language development, and behavioral difficulties [7], as well as chronic lung disease, neuromuscular developmental delay, and death. This excess neonatal and long-term morbidity and mortality in multiples has traditionally been attributed to the higher incidence of prematurity and, by extension, birth weight in multiples; however, prematurity may, in fact, not be the sole etiologic factor [8–10]. As discussed herein, recent data suggest that twins are at greater risk for death and severe morbidity than are singletons in excess of the risk attributable to their greater prematurity [1].
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Current data are conflicting regarding mortality rates (neonatal and infant) associated with multiple gestations. Buekens and Wilcox [11] studied over 230,000 infants in Belgium born between 1983 and 1984. In their analysis, twins had a higher mortality rate in all birth weight categories [11]. The National Institute of Child Health and Development (NICHD) neonatal network, including 12 prominent regional neonatal centers in the United States, analyzed data from a large sample of very low birth weight (VLBW) infants, 19% of which were twins. There was no difference in overall mortality in VLBW twin infants when compared with VLBW singletons. The VLBW twin group sustained a greater incidence of respiratory distress syndrome, but there were no differences in chronic lung disease or the incidence of severe intraventricular hemorrhage [12]. Mothers of twins were more likely to have received antenatal steroids and to have undergone cesarean delivery. Kiely [13] studied time trends in perinatal morbidity in New York City between 1968 and 1986 and showed that, although overall mortality rates fell, singleton rates fell much faster than those for twins, implying a higher constant mortality rate in the latter. Synnes et al [14] looked at extremely premature infants born at a single center. When adjusted for gestational age, mortality was significantly higher in 24-week twins when compared with 24-week singletons but declined with advancing gestational age. There was no difference between the groups by 28 weeks’ gestation [14]. The differences in mortality rates were limited to these susceptible high-risk premature subsets rather than applying to all premature infants. The birth order of multiples has been studied as a prognostic factor because of the increased incidence of operative delivery, hypoxia, and malpresentation in second twins [15–17]. Most complications specific to second twins have been minimized in contemporary obstetric practice. Chen et al [18], Ghai and Vidyasagar [19], and Lee et al [20] found no differences in perinatal morbidity and mortality between first and second born twins at any gestational age or birth weight.
Neurologic outcomes Neurologic impairment is by far the most significant and concerning long-term outcome variable in surviving twins. This impairment includes cerebral palsy and its variants and extends to severe learning and cognitive disabilities. The disability spectrum is broad and relatively undefined, owing primarily to the aforementioned confounding variables that apply. Although a condition such as cerebral palsy is clinically evident and clear to identify, it can prove difficult to define causality when examining relatively mild (but individually significant) learning disabilities in infants and children. A propensity toward selection bias when looking prospectively or cross-sectionally at this range of neurodevelopmental delay in infants of multiple gestations must be accounted for, and every effort to use comparison groups must be made.
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In 1992, Laplaza et al [21] reviewed 12 relevant studies and concluded that the proportion of cerebral palsy cases that were from twin pregnancies ranged from 5.4% to 10.4%, citing cerebral palsy as being fivefold to tenfold more frequent than in singletons. Nevertheless, all of the studies they reviewed were case series and lacked population denominators. Newer population-based cerebral palsy registers have now been established that allow the comparison of prevalence rates of cerebral palsy in twins and singletons that are also birth weight and, to a lesser extent, gestational age specific [8,22]. Pharoah [1] has shown that by combining all three of these population-based studies [8,22,23] from Western Australia, the North East Thames region of the United Kingdom, and the Mersey region of the United Kingdom, it can be seen that, overall, twins have an approximately fivefold increased risk of cerebral palsy when compared with singletons, whereas triplets have a 17-fold increased risk of cerebral palsy when compared with singletons [23]. When the cerebral palsy prevalence was stratified by birth weight, no statistically significant difference in the prevalence was seen between twins and singletons among lower birth weight groups (b1500 g or between 1500 and 2499 g). Statistical significance was gained when twins weighing over 2500 g were compared with singletons. This finding is most likely explained by the combination of a higher proportion of low birth weight infants among twins and a significantly higher prevalence of cerebral palsy in normal birth weight twins [1]. Overall rates of cerebral palsy were significantly higher in twins versus singletons at VLBWs (b1500 g) when compared with the rates for infants weighing more than 2500 g (73.7% and 69.4% versus 3.9% and 1.1%, respectively) (Table 1). As shown by several case series and reports, the surviving twin after a co-twin death is at a significantly high risk for cerebral palsy, with the majority of these twins in monozygotic/monochorionic pregnancies. Newer population-based studies have confirmed this high risk. In two such studies by Pharoah et al and Grether et al, 4 of 33 and 6 of 63 twin survivors of a co-twin fetal death had cerebral palsy, bringing the risk of cerebral palsy in this clinical situation (mostly monozygotic/monochorionic) to 1 in 10 [8,9]. An important confounding issue in studying these phenomena is the inability to analyze monozygosity versus dizygosity separately because zygosity was not a registered variable in these population studies. Table 1 Birth weight-specific cerebral palsy prevalence in twins and singletons (combined Western Australia, North East Thames and Mersey UK region cerebral palsy registers) Birth weight group
Twins
Singletons
Twin-singleton difference (95% CI); P value
b 1500 g 1500 –2499 g N = 2500 g All
73.7 8.8 3.9 9.7
69.4 9.4 1.1 1.9
4.1 ( 16.3–38.4); P = 0.7 (NS) 0.6 ( 3.2–2.5); P = 0.7 (NS) 2.8 (1.5–4.7); P b 0.0001 7.8 (6.2–9.7); P b 0.0001
Abbreviation: NS, not significant. Data from Pharoah POD. Neurological outcome in twins. Semin Neonatol 2002;7:225.
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Some studies that do not contain information on zygosity use a surrogate tool to estimate zygosity by comparing like- versus unlike-sex twins. Like-sex twins include monozygotic and dizygotic twins, whereas unlike-sex twins must be dizygotic. When looking at each birth weight group, like-sex twins are always more likely to be at risk for cerebral palsy when compared with unlike-sex twins (Table 2). Although the combined prevalences of cerebral palsy for the likeand unlike-sex co-twin survivors of a fetal death are similar as found in the aforementioned cerebral palsy registry data (82.2 per 1000 infant survivors), for each birth weight group, the like-sex twins are at greater risk for cerebral palsy than are unlike-sex twins [1]. In addition to analyzing the surviving twin after the death of a co-twin in utero, the risk for cerebral palsy in a surviving twin when both twins are born alive but one subsequently dies in infancy has also been assessed [24]. This analysis is referred to as the co-twin infant death. When stratified by birth weight, the prevalence of cerebral palsy in these extremely low birth weight co-twins (b1000 g) is high, although not statistically significantly different in like- or unlike-sex twins, with one in every five survivors sustaining cerebral palsy. In Pharoah et al’s ‘‘moderately low birth weight’’ group (weighing between 1000 and 2499 g), the prevalence of cerebral palsy was higher in like- (122.6 per 1000) versus unlike-sex (14.7 per 1000) twins and was high overall (131 per 1000 in the 1000 to 1499 g group and 45.9 per 1000 in the 1500 to 2499 g group) (Table 3). Cerebral palsy is not the only neurodevelopmental risk these children face. In the surviving twin after the demise of a co-twin in utero, the prevalence of neurologic impairment apart from cerebral palsy was 111 in 1000 in like-sex infants and 118 in 1000 in unlike-sex infants. Neurologic impairment was evaluated by questionnaire rather than examination and, when found not to be cerebral palsy, was classified as ‘‘other.’’ This diagnostic analysis may be criticized as imprecise; however, it was still considered an impairment of sorts, and the incidence was high [24]. In addition, a population-based study from the Collaborative Perinatal Project of the National Institute of Neurological Disorders Table 2 Birth weight-specific cerebral palsy prevalence in co-twin survivors of a fetal death (England and Wales, 1993–1995)
Birth weight
Like-sex twins
Unlike-sex twins
CP/number of infant CP prevalence survivors per 1000
CP/number of infant survivors
CP prevalence in CP prevalence like- and unlike-sex per 1000 twins combined
0/11 2/16 2/37 0/47 4/111
0 125.0 54.1 0 36.0
b1000 g 1/20 1000–1499 g 13/62 1500–2499 g 10/110 2500 g 3/74 All birth weights 27/266
50.0 209.7 90.9 40.5 101.5
32.3 192.3 81.6 24.8 82.2
Mantel–Haenszel weighted relative risk comparing like- with unlike-sex twins, 2.17 (95% Cl, 0.81 to 5.79). Data from Pharoah POD. Neurological outcome in twins. Semin Neonatol 2002;7:225.
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Table 3 Birth weight-specific cerebral palsy prevalence in co-twin survivors of an infant death (England and Wales, 1993–1995) Like-sex twins
Birth weight
Unlike-sex twins
CP/number CP/number of infant CP prevalence of infant CP prevalence survivors per 1000 survivors per 1000
b1000 g 17/84 1000–1499 g 14/80 1500–2499 g 5/75 2500 g 0/51 All birth weights 36/290
202.4 175.0 66.7 0 124.1
9/42 1/34 0/34 0/26 10/136
214.3 29.4 0 0 73.5
CP prevalence in like- and unlike-sex twins combined 206.3 131.6 45.9 0 107.9
Mantel–Haenszel weighted relative risk comparing like- with unlike-sex twins, 1.66 (95% Cl, 0.88 to 3.29). Data from Pharoah POD. Neurological outcome in twins. Semin Neonatol 2002;7:226.
and Stroke showed that twins contributed disproportionately to the group of children with moderate-to-severe learning disability, even when excluding those with cerebral palsy and controlling for birth weight [25]. This finding was inclusive of all twins, independent of death in utero or infant death. It is unlikely that cerebral palsy in the surviving co-twin after an infant death is secondary to the effects of prematurity. It seems more likely to be a consequence of an early antenatal etiology, attributable potentially to monochorionicity. It is also clear that extremely low birth weight (b1000 g) like-sex twins have a higher mortality rate when compared with unlike-sex twins of similar birth weight (490 versus 397 per 1000) (95% confidence interval [CI], 35.5–149.0; P = .001) [24]. Theoretically, this increased mortality in like-sex twins may be due, in part, to antenatal cerebral pathology that, when combined with severe prematurity, diminishes their survival capabilities to a much greater extent than in unlike-sex twins [24]. Ultimately, it is clear that the co-twin survivor after the death of a twin in utero or at infancy has a much greater risk for cerebral palsy than if both twins remain alive through infancy. Nonetheless, when both twins remain alive, the overall risk for cerebral palsy in normal birth weight twins is greater than the risk for singletons [26], with a trend toward a higher prevalence in like- versus unlikesex twins (difference not statistically significant) [27]. Williams et al showed this in a logistic regression analysis on a large sample of twins and singletons in England [22] when it was found, after a correction for relevant confounding variables, that being a twin was an independent risk factor for cerebral palsy (Table 4). In contrast to Pharoah’s findings, Monset-Couchard et al [28] found only a minimally increased rate of cerebral palsy in twin sets in a study evaluating the long-term outcome of IUGR versus appropriate for gestational age co-twins and triplets. This difference may be explained by the survival of both twins in the study set. Many of the documented childhood cases of cerebral palsy have been traced back to the death of a co-twin in utero, especially in a monochorionic pregnancy or one affected by twin-twin transfusion syndrome.
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Table 4 Birth weight specific cerebral palsy prevalence when both twins survive infancy (England and Wales, 1994–1995)
Birth weight
Like-sex twins
Unlike-sex twins
CP/number of infant CP prevalence survivors per 1000
CP/number of infant survivors
CP prevalence in CP prevalence like- and unlike-sex per 1000 twins combined
2/63 3/227 7/2523 4/3174 16/5987
31.7 13.2 2.8 1.3 2.7
b1000 g 3/128 1000–1499 g 4/610 1500–2499 g 23/5725 N = 2500 g 13/6001 All birth weights 43/12464
23.4 6.6 4.0 2.2 3.4
26.2 8.4 3.6 1.9 3.2
Mantel–Haenszel weighted relative risk comparing like- with unlike-sex twins, 1.24 (95% Cl, 0.68 to 2.30); not significant. Data from Pharoah POD. Neurological outcome in twins. Semin Neonatol 2002;7:226.
The twin survivor with cerebral palsy has been shown to display a wide variety of anatomic abnormalities, particularly if the co-twin’s death occurs in utero. These defects include white matter infarction, hydrocephalus, multicystic encephalomalacia, cortical atrophy, ventriculomegaly, holoprosencephaly, polymicrogyria, and periventricular heterotropia [29–31]. The type of anatomic abnormality correlates with the timing of the damaging event. White matter infarction and multicystic encephalomalacia correlate with third-trimester events, whereas second-trimester events lead to neuronal migrational abnormalities (eg, polymicrogyria). Not surprisingly, seizure disorders are more commonly seen in twins when compared with singletons, even when controlled for or not associated with cerebral palsy or another learning disability. This risk was particularly emphasized as affecting monochorionic twins over all others [32].
Zygosity and chorionicity Galton is traditionally credited with suggesting the notion of using twins to compare nature versus nurture (ie, genetics versus environment) to better understand long-term outcomes in offspring. With this mindset, any differences between monozygotic twins should be due to environmental factors alone, whereas outcome differences in dizygotic twins might be inferred as occurring as a result of genetic or environmental differences or both. This thinking has been used in many studies spanning a range from congenital anomalies to the adult onset of psychiatric and physiologic disease states. Many twin registries have been analyzed based on this assumption. Nevertheless, it remains clear that the determination of zygosity can be challenging and should not be made by a morphologic comparison of features alone but rather by supplementation with biochemical and genetic testing.
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Zygosity seems to have a significant and prominent role in the long-term outcome issues of multiple gestations. All dizygotic twins and one third of monozygotic twins (when splitting occurs at b3 days) will become dichorionic. Two thirds of monozygotic twins are monochorionic (splitting occurring during the early blastocyst stage, between 5 and 7 days). This differentiation is vital because much of the long-term morbidity and mortality occurs in monochorionic placentation. Monozygozity, by virtue of its inherent risk of monochorionicity, carries the risk of twin-twin transfusion syndrome and, even in its clinical absence, the potential subclinical effect of placental anastomoses. As is described in this report, monochorionic twins are at greater risk for poor short-term and long-term outcomes when compared with dizygotic (and monozygotic/dichorionic) twins. In a developmental biology article on twinning, Hall [33] pointed out that monozygotic twins live off the cytoplasm of one ovum until they implant, the same amount of cytoplasm intended for a singleton. Implantation and early embryonal stages have vital nutritional requirements for growth, oxygen tension, and gene regulatory mechanisms that help establish normal physiology in a timely matter. Monozygotic twinning may affect this process and may alter signaling among the mother, placenta, and twins that may, in turn, affect future gestational growth. Depending on the initial differences in the number of cells at the time of separation, differences in vascular flow, and the attachment to the placenta, potential vascular compromise could lead to an increased risk of disruptive and significant anomalies or possibly more subtle imprinting that could affect one (preferentially) or both infants later in life [33]. In 1961, Bernischke [34] published a case report of a twin with cerebral and renal cortical necrosis and splenic infarcts in the setting of a demised and macerated co-twin. The findings were postulated to be thromboplastic in etiology, with the thrombotic material passing from the dead to the still living twin via the placental anastomoses and ultimately causing disseminated intravascular coagulopathy. Since then, this pathologic theory has been implicated in findings such as multicystic encephalomalacia, splenic and renal infarcts, and renal cortical necrosis [35,36]. In the vast majority of cases, emboli are not verifiable pathologically or in the surviving twin. The emerging theory suggested by Fusi and Gordon [37] became one of acute hemodynamic change and resulting ischemia, essentially an acute twin-twin transfusion syndrome at the time of the death of one twin. A rapid fall in blood pressure of the dead twin leads to a relative exsanguination of the surviving twin, with the development of severe hypotension and ischemic damage to the heart, brain, kidneys, and gastrointestinal tract. The timing of these events is most likely immediate; therefore, the untoward potential adverse effects on the remaining fetus are likely unavoidable unless the event occurs under realtime observation and immediate delivery of a viable co-twin is feasible. In 2000, Mari et al [38] studied the long-term outcome in monozygotic twins with twin-twin transfusion syndrome who were treated with aggressive serial amnioreduction. Based on 33 pregnancies in their study set, they concluded that if the infants were born after 27 weeks without malformations and survived the
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neonatal period, there were no additional handicaps. Serial amnioreductions did not improve the outcomes in a twin-twin transfusion pregnancy when one of the twins had absent end-diastolic flow or hydrops. Despite clear evidence as to the various mechanisms by which a monochorionic pregnancy incurs risk by virtue of the twin-twin transfusion syndrome or death in utero (resulting in hemodynamic changes and potential thrombotic events), there is some suggestion that anastomoses may occur in dichorionic placentas early in gestation that subsequently disappear (with some found, rarely, in the term placenta) [39]. This observation may offer the slightest bit of insight into how similar findings of cerebral palsy and other long-term neurologic sequelae are seen in dizygous and monozygous nonmonochorionic placentations. Again, studies that rely on the estimation of chorionicity or zygosity by using like- and unlike-sex grouping implicitly may be fraught with error not only in terms of actual chorionicity but also by incorrect sex assignment or failure to note an early fetal loss in a multiple pregnancy. As discussed previously, adverse neurologic effects are not limited to pregnancies in which when one co-twin dies in utero. Long-term poor neurologic outcomes are also seen in live-born twins when one of the twins subsequently dies in infancy. The surviving infant is still more likely to develop neurologic impairment or cerebral palsy, despite the lack of an in utero death. This observation implies that it is not necessarily the death in utero but the monochorionic placentation that may be responsible for the cerebral lesions [40]. It has been difficult to discern the chronologic order of events in twinning and long-term neurologic dysfunction. Does the process of twinning, particularly that of monozygous twins, innately confer an in utero risk of cerebral injury that somehow leads to premature birth with its ensuing issues, or does the preterm birth that is more prevalent in twinning lead to vulnerability of the immature neurologic system and ultimately the long-term morbidity risk? These evolutionary theories have proved difficult to tease apart and remain elusive. Although neurologic outcomes dominate the literature and are the least obvious to diagnose when compared with outcomes seen in the short-term or immediate neonatal period, there are other implicated issues in multiples that are of interest. Congenital anomalies lead this list and may be a result of an ischemic insult owing to the death of a co-twin in utero. These types of anomalies are more common among monozygotic compared with dizyogotic twins or multiples and singletons. Associated congenital anomalies include agenesis of one or both kidneys (Potter’s syndrome), duodenal atresia, cardiac anomalies, and aplasia cutis. Overall, the most commonly noted defects are cardiac, renal, and gastrointestinal anomalies. When these anomalies are present in monozygotic twins, they are usually discordant [41]. As is true for neurologic deficits, these anomalies may be due to transient bouts of ischemia during twin-twin transfusion syndrome, occurring during crucial embryologic events. Early anastomoses are present even before the placenta fully takes over, and these channels may be implicated even during the embryologic period [22,34,35,42–48]. It has been postulated that similar anomalies and adverse neurologic sequelae arising in
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singletons might be due to the very early demise of a co-twin, also referred to as the ‘‘vanishing-twin syndrome.’’ Although some reports have denied any adverse effect on the surviving twin when the co-twin dies in early gestation [49,50], there have been numerous reports of cerebral palsy in the surviving twin following second-trimester [42,51,52] and first-trimester [53] loss of a co-twin. Because earlier and more common use of ultrasound has become part of clinical practice, the vanishing twin phenomenon is seen more frequently, with the observation of more than one sac in early gestation but ongoing pregnancy and delivery of a singleton. Given that normal birth weight twins are at a considerably higher risk of cerebral palsy when compared with singletons and the more frequently reported occurrence of a vanishing twin, it has been hypothesized that most cases of cerebral palsy in apparently singleton fetuses may, in fact, be attributable to early fetal loss of a twin [53]. Factors that may affect this hypothesis include whether the diagnosis of a vanishing twin was made from visualization of a sac or embryo, and at what gestational age the loss occurred. Again, the morbidities linked with twin or multiple gestations are not always associated with the (known) death of a co-twin.
Intrauterine growth restriction and multiples Regardless of their plurality, growth-restricted infants have a significantly higher risk of morbidity and mortality when compared with appropriately grown infants of comparable gestational age, including significant neurodevelopmental defects [2–4]. More than half of all triplet and higher-order multiple gestations are complicated by IUGR [54]. Given the predisposition for low birth weight infants in multiple gestations, the long-term effects of being born small for gestational age (SGA) or having been IUGR in utero are intriguing. Recently, Monset-Couchard et al [28] set out to determine whether extremely low birth weight (b1000 g) infant co-twins actually remain small or have adverse neurologic sequelae when compared with appropriate for gestational age co-twins or triplets. These researchers had previously shown that long-term neurologic follow-up in multiples revealed a deficit in academic performance with age, related, in part, to socioeconomic and cultural issues as confounders [55]. To analyze these outcomes ideally, these confounders would need to be standardized or corrected. Multiples who met the criteria for IUGR/SGA while their co-twins remained appropriate for gestational age made perfect study candidates for long-term follow-up. The IUGR infants were part of a twin or triplet set and were selected for follow-up whenever the entire set was born alive and survived; therefore, they constituted a natural match. They were equal for gestational age, family setting, and socioeconomic milieu, food quality and quantity, education, and the same age at follow-up. Monset-Couchard and colleagues studied 783 extremely low birth weight infants born between January 1981 and December 1999 who were admitted to,
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and taken care of, in a single neonatal intensive care unit (NICU). Of these infants, 353 were IUGR (defined as b10th percentile), and 267 survived. Fiftyfour of the infants were from twin or triplet sets. Seven neonates were similar in size, and 11 remained single survivors, leaving 36 study sets of twins. The infants were observed for growth, neurodevelopmental outcome, and school performance for a period ranging from 3 to 17 years. Although the infants were raised in a similar environment, the growth-restricted/extremely low birth weight infants remained smaller and had more behavioral problems as well as visual and speech difficulty, but most of them were able to maintain school grade level with their appropriate for gestational age co-twins with adequate assistance. Ultimately, more growth-restricted children eventually repeated a grade, depending somewhat on the level of stimulation in the home environment [55]. Additionally, Karlberg and Luo in 2000 [56] showed that growth in utero is a significant predictor of postnatal growth, even when genetic stature is taken into account (as estimated by target height). A significant proportion of the growthrestricted co-twins/triplets who failed to catch up, and even those that did catch up, remained shorter and lighter. This observation warrants consideration of the long-term stunting effect of IGUR.
Higher-order multiples With the current state of ART use, the incidence of higher-order multiples has gained new significance, and knowledge of the potential adverse effects and longterm outcomes may be significantly beneficial to parents considering the option of fetal reduction. Most reports on the outcomes of higher-order multiples are based on small samples, usually a reflection of a single neonatal unit taking care of a small number of higher-order multiples at any given time. In addition, these single-center reports are often inclusive of long periods of time and feature various treatment protocols without adequately correcting for confounding variables [57]. None of these studies were controlled. Yokoyama et al investigated the risk of handicaps in twins, triplets, quadruplets, and quintuplets in Japan. The study sample was taken from the Kinki University Twin and Higher Order Multiple Birth Registry and consisted of 705 pairs of twins, 96 sets of triplets (287 triplets excluding 1 infant death), 7 sets of quadruplets (27 quadruplets excluding 1 infant death), and 2 sets of quintuplets. All of the patients in the study sample were born after 1977. The incidence of long-term neurologic deficits, including cerebral palsy, was 3.7% in twins, 8.7% in triplets, 11.1% in quadruplets, and 10.0% in quintuplets. The risk of producing at least one handicapped child was approximately 20% in triplets and 50% in quadruplets. Twins had a 7.4% risk for a handicap in one child (1 in 13 pairs of twins). When compared with the expected incidence of long-term neurologic deficits in this population, there was a significant clustering of handicaps in twins and triplets. Four significant risk factors were reported for such
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handicap, demonstrated by logistic regression: gestation number, young gestational age, premature rupture of the membranes, and preeclampsia. In their analysis of twins and triplets in the cerebral palsy registry of Western Australian births between 1980 and 1990, Petterson et al [23] found that cerebral palsy occurred 17 times more often in triplet pregnancies than in singletons. A confounding factor to these numbers is the incidence of IUGR, which, as mentioned previously, occurs in half or more of all triplet and quadruplet pregnancies [58]. A small number of controlled or partly controlled studies have compared the outcomes between higher-order multiples and twins or singletons. Based on US birth statistics between 1983 and 1988, Luke [59] performed a population-based analysis of all live births and fetal deaths between 1983 and 1988, including over 9000 triplets. Fetal mortality was compared by categories of birth weight and gestational age for twins and triplets versus singletons. After correcting for gestational age, triplets had a higher mortality rate (ranging from 5- to 20-fold depending on birth weight) [59]. Similar results were reported in a Swedish registry of infants born between 1973 and 1988 [60]. By comparison, two recent single-center studies found no difference in the mortality rates for premature singletons, twins, and higher-order multiples when corrected for gestational age [61,62]. In these studies, triplets did exhibit a higher incidence of short-term morbidities such as respiratory distress syndrome, patent ductus arteriosus, intraventricular hemorrhage, and retinopathy of prematurity. These studies examined neonatal outcome alone and did not include long-term follow-up. Ultimately, it seems that higher-order multiples may be at increased risk for short- and long-term adverse outcomes, but further controlled populationbased studies are needed to quantify adequately their risks.
Assisted reproductive technologies In population-based studies of naturally conceived children, twins have an approximately fourfold higher risk of cerebral palsy when compared with singletons [63]. Nevertheless, the literature specifically addressing long-term outcome morbidity in twins born after assisted reproductive intervention is limited. A Swedish registry study has shown an increased risk of cerebral palsy in children born after assisted reproductive intervention but attributed this risk primarily to the high rate of twinning and higher-order multiples [64]. To better study the long-term effects of in vitro fertilization (IVF) techniques on twins, Pinborg et al [65] established a database on all singletons and twins born after assisted conception in Denmark between 1995 and 2000. The prevalence of neurologic sequelae in singletons born after assisted conception was compared with that in twins born after assisted reproductive conception and then compared with the findings in twins born by natural conception. Pinborg and colleagues assessed any differences in neurologic outcomes in children conceived after IVF versus those conceived by intracytoplasmic sperm injection (ICSI).
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There were 3393 twins and 5130 singletons conceived by ART, whereas 10,239 twins were naturally conceived. The children were followed up to a minimum of 2 years of age and a maximum of 7 years. Neurologic and psychiatric diagnoses were not determined by first-hand interview or examination of the children but rather by data from the national patients’ registry and the Danish psychiatric central registry. Neurologic sequelae were defined and classified as cerebral palsy, mental retardation, severe mental developmental disturbances, and retarded psychomotor development. The crude prevalence rates of adverse long-term neurologic outcomes in assisted reproduction twins and singletons were 8.8 and 8.2 cases per 1000, whereas the rate in naturally conceived twins was 9.6 cases per 1000. The prevalence of cerebral palsy in the three groups was 3.2, 2.5, and 4.0 cases per 1000, respectively. When comparing each of the twin groups, the odds ratios of neurologic deficits and cerebral palsy (adjusted for year of birth and child sex) were 0.9 and 0.8, respectively. Comparing ART twins with singletons, the corresponding odds ratio was 1.1 for any neurologic deficit and 1.3 for cerebral palsy specifically. Comparing children conceived by ICSI with those conceived by IVF, the odds ratio was 0.9. It was concluded that naturally conceived twins and their ART counterparts, as well as singletons, had a similar risk of long-term neurologic deficits. Similarly, children born as a result of IVF had the same neurologic risks as those born as a result of ICSI [65]. Other recent studies have shown higher risks of adverse outcomes, including a doubled rate of intrauterine death [66–72]. Short-term adverse consequences (including the aforementioned intrauterine death) are still very real, and the lack of a difference in long-term neurologic deficits should not preclude good judgment when considering embryo number for replacement in a population apt toward multiples. Many studies have compared reproductively assisted twins with naturally conceived twins and then compared both groups with singletons to help elucidate the effects ART might have. For example, when ART conceived twins are compared with naturally conceived twins, they essentially have equivocal longterm risks, but these risks are different than those for singletons conceived via ART, who have been shown to have a 2.6-fold higher incidence of low birth weight when compared with their naturally conceived peers [73]. Because the use of ART, when successful, increases the risk of multiple births and the risk of low birth weight, Schieve et al [69] compared rates of low birth weight among ART-associated births in the United States between 1996 and 1997 with rates in the general population. That year, 137,000 procedures were attempted, and 23% of them resulted in live births. In the 57% of the pregnancies that resulted in multiple births at the time of delivery, low birth weight was common, as expected, but no more common than in multiples conceived naturally in the general population. In singletons, there was actually an increase in the risk of low birth weight among those who were preterm when compared with the general population (6.5% vs 2.5%), that is, the 2.6-fold risk referred to previously. There was no
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difference in the maternal health or pregnancy profile of the mothers who delivered the infants of lower birth weight. It was suggested that ART was a likely attributable factor. In considering other potential effects ART may have on the long-term outcomes of multiple gestations, it is prudent to keep a watchful eye on the emerging data questioning the higher risks of birth defects in offspring born from ART. Moreover, the use of assisted conception techniques increases the frequency of monozygotic twinning and related pathology, essential to the impact of these long-term outcomes. The issue of birth defects and their incidence in ART-associated pregnancies has been more difficult to study, primarily owing to difficulty in collecting data. Past studies have been limited by theoretical over- or underreporting of infants conceived with ART and by a dearth of comparison groups. Hansen et al [73] changed this approach by combining data from three registries in Western Australia—a compulsive ART registry, a delivery registry, and a birth defect registry. The same data sources were used for all three groups studied. By one year of age, 9% of ART infants had a confirmed birth defect compared with 4.2% of the naturally conceived infants. There was no difference in the groups of infants who were conceived by IVF versus ICSI. The excess defects were confirmed in multiple and singleton births. The birth defect differences were most significant for musculoskeletal and cardiovascular defects. Hansen used an independent pediatrician to identify defects, eliminating the bias of excess detection owing to increased surveillance in a risk group. The importance of both groups’ findings is their potential implications on the long-term outcomes of infants born via ART, the use of which is a high-risk factor for multiple pregnancy. The use of ART may double the risk of a term infant with low birth weight (but does not seem to affect multiples), as well as doubling the risk of a major birth defect. Although the relative risk is elevated, the absolute risk remains low, and most parents facing significant obstacles getting pregnant will find these numbers acceptable. Neither these studies nor previous studies have been able to postulate or identify explanations for these increased risks. Nevertheless, the drugs taken and resultant hormone levels have been implicated, as has the underlying cause of infertility. This becomes relevant if the underlying cause is, in fact, infertility, and the addition of the drugs and procedures of ART do not cause additive risk. Other factors that might affect the rate of birth defects in these infants include the advanced age of infertile couples and the factors associated with the procedures themselves, such as freezing and thawing of embryos, the potential for polyspermic fertilization, and the impact of breaking the zona pellucida. Multiple pregnancies conceived by ovarian stimulation alone have not been shown to have an altered long-term infant outcome. Kallen et al [74] looked at outcomes including birth defects, low birth weight, and infant death in 420 women who delivered between 1995 and 1999 after ovarian stimulation and compared them with 438,582 women who had no assisted technique. The year of birth, maternal age, parity, and length of subfertility before pregnancy were all
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controlled. In the study group, there was a twinning and triplet rate of 5.2% and 0.5%, respectively, compared with 1.2% and 0.02% in the naturally conceived control group. Interestingly, the study group had a nearly doubled rate of monozygotic twinning when compared with the control group. The excess number of low birth weight infants in the study group was mainly explained by the confounding variables of maternal age, parity, and subfertility, as were the slightly increased rates of congenital malformations and perinatal deaths.
Maternal (and paternal) long-term impacts Although the long-term effects of early mother-twin relationships have yet to be fully established, a recent study comparing preterm twins with singletons found that mothers of twins had fewer initiatives and responses to positive and negative (ie, crying) signals. Mothers of twins tended to lift, hold, touch, or pat their babies less often and talked to them less frequently when compared with the mothers of singletons. When followed up at 18 months in the same study, the cognitive development of the twins was less advanced that that of the singleton controls [75]. These findings may be due in part to the enormous stresses a mother of premature twins sustains. Many preterm deliveries of multiples are complicated by medical illness and NICU stays, requiring separation from the mother for significant periods. This care entails daily or twice daily NICU visits or, in some cases, a transfer to a hospital with tertiary care that is separate from the delivering hospital or far from home. The infants may become separated depending on their individual medical circumstances. The father may find himself in the midst of a logistic nightmare trying to see and care for his partner and the infants in myriad locations and in varying states of recovery. There is a particular emotional strain if one baby is sicker than the other. The mother will involuntarily tend to be more attracted to the healthier infant [76]. Because mothers want to devote equal affection to all of their offspring, such skewed attraction is followed by ensuing guilt. Not to be underestimated are the parental stress of bereavement in the event of an infant’s death, or the stress of having a special needs child, especially if children of the same age have very different needs. Parents who have lost an infant born from a multiple gestation but who also have a survivor may find that their bereavement is underestimated by peers and family and masked by the presence of the surviving child. This situation, combined with the parents’ natural preoccupation with the survivor, can significantly inhibit the grieving process and lead to long-term resentment or sorrow. Higher-order births have an added set of psychologic parental stressors. Insight into the lives of these parents was provided by a population-based study of more than 300 families with higher-order births in 1980 and 1982 through 1985 in the United Kingdom. The United Kingdom National Study of Triplets and Higher Order Births covered medical and social aspects of these families
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from the time of conception until the children where in school [77]. The study highlighted often overlooked aspects of parenting triplets or more. For example, no mother can carry three babies at once; with overwhelming difficulty, can she transport or feed them on her own. Mothers find that they cannot practically leave the home and become housebound and isolated. Help for these families tends to be inadequate and begins too late, usually not until the parents become ill or exhausted. A study by the Australian Multiple Births Association showed that 197.5 hours per week were required to care for 6-month-old triplets while carrying out necessary household tasks (there are only 168 hours in the week) [78]. Parents in higher socioeconomic brackets, often found among the ART populations, benefit greatly from hired help immediately upon bringing the infants home. This help does not alleviate the aforementioned stresses of preterm delivery, illness, death of a multiple, or neurologic handicap. In terms of the children born from a multiple pregnancy, it is clear that the siblings of twins are more likely to sustain behavioral problems [79]. Not emphasized enough are the difficulties of the single surviving twin and the unaffected co-twin of a disabled child, especially when in the same household. These groups of children undergo complex long-term psychologic reactions ranging from anger, guilt, grief, and abandonment, often mirrored from parental reactions. Unfortunately, the parental stress has been demonstrated by the higher incidence of maternal depression and child abuse in multiple birth families [80]. An unexpected finding is the potential for increased marital solidification as parents cope with the inordinate stresses of multiple births.
Summary Children born from multiple pregnancies face difficulty socializing, behavioral difficulties, and developmental delays, whereas their parents risk exhaustion, depression, and anxiety. Parents must deal with their children’s health challenges, unmet family needs, social stigma, and the potential of compounded losses. Clearly, multiple births present significant potential long-term medical risks to offspring and have a long-term psychologic impact on parents. Despite what is currently known, given the paucity and limitations of the current literature, more long-term follow-up research on outcomes with higher-order multiples is needed. This information will prove essential in the prenatal and preconceptual counseling of these patients, especially in light of the continued increased use of ART and the greater availability of options such as multifetal pregnancy reduction.
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