Editorial introduction
Current Opinion in Obstetrics and Gynecology was launched in 1989. It is one of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of obstetrics and gynecology is divided into nine sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Journal’s Section Editors for this issue.
Section Editor Aydin Arici
Dr Arici received his medical degree from Istanbul Medical School in Turkey, and completed a residency in obstetrics and gynecology at Columbia University, College of Physicians and Surgeons, in New York City. His postgraduate training also included a fellowship in reproductive endocrinology and infertility at the University of Texas Southwestern Medical Center in Dallas. His is currently Professor of Obstetrics, Gynecology and Reproductive Sciences at Yale University School of Medicine in New Haven, Connecticut, and the Director of Women’s Health Department at Anadolu Foundation Health Care System in Turkey. Dr Arici is the recipient of many National Institutes of Health and pharmaceutical industry-sponsored research
grants and has trained more than 75 postdoctoral fellows. His clinical research focuses on the pathogenesis of endometriosis, and in particular the investigation of cellular and molecular mechanisms in endometrial physiology and pathology. He is a member of the Editorial Board of Journal of Clinical Endocrinology and Metabolism, Journal of Reproductive Immunology, Gynecologic and Obstetric Investigation. Guest Editor of Obstetrics and Gynecology Clinics of North America and Seminars in Reproductive Medicine, and serves as a reviewer for more than 30 scientific journals, including the New England Journal of Medicine, Science, The Lancet, Human Reproduction, Fertility and Sterility, American Journal of Obstetrics and Gynecology, Molecular and Cellular Endocrinology, Biology of Reproduction, and Journal of Clinical Investigation. More than 270 articles by Dr Arici have been published in these and other leading journals and his book chapters have appeared in such texts as Textbook of Reproductive Medicine and Reproductive Endocrinology. He is the Senior Editor of the book titled ‘Non-invasive Management of Gynecologic Disorders’. He is a frequent invited speaker and has presented at numerous national and international medical and scientific symposia. His main interests include research on infertility, hormonal problems, endometriosis, menopause and early pregnancy loss. Dr Arici is a Fellow of the American College of Obstetricians and Gynecologists and served as a clinical director of the Society for Assisted Reproductive Technology. He also serves as an ad hoc grant reviewer for the National Institutes of Health. Dr Arici is a member of 15 professional societies, including the American Society for Reproductive Medicine, the Society of Reproductive Endocrinology and Infertility, the Endocrine Society, and the European Society of Human Reproduction and Embryology.
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Does the ovarian reserve decrease from repeated ovulation stimulations? Janelle Luk and Aydin Arici Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, USA Correspondence to Dr Janelle Luk, Division of reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA Tel: +1 203 606 2689; e-mail:
[email protected] Current Opinion in Obstetrics and Gynecology 2010, 22:177–182
Purpose of review The majority of infertility patients require more than one in-vitro fertilization cycles to achieve pregnancy, which results in repeated stimulation in the ovaries. There have been raising concerns for patients about the effect of repetitive assisted reproductive technology (ART) cycles on ovarian response in subsequent cycles. Whether or not there is deterioration in ovarian response with repetitive treatment will allow clinicians to provide better counseling to patients before treatment. Recent findings The single determinant factor that has been shown in affecting ovarian reserve for patients undergoing repeated ART cycles is age. Current evidence has suggested that repetitive ovarian stimulation cycles with intrauterine insemination can be performed without clinically impairing ovarian response. Oocyte donors can be invited for at least three cycles without a negative effect on ovarian response to gonadotropins, number of mature oocytes retrieved, embryo quality, or pregnancy rates. Summary There are limited available published data on this topic. Research studies have shown that there is no detrimental effect on ovarian function of egg donors who undergo repetitive ovarian hyperstimulation. Overall findings also show that there is no significant decline in ovarian reserve in patients who undergo up to three repeated in-vitro fertilization cycles. For patients undertaking more than three cycles, the results become equivocal because age becomes a determinant factor with both pregnancy and live birth rate declining with repetitive cycles. Keywords ART cycles, donors, ovarian reserve, repeated IVF cycles Curr Opin Obstet Gynecol 22:177–182 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1040-872X
Introduction Ovulation induction and in-vitro fertilization (IVF) have become common therapies that are given to couples who have infertility problems. In the United States alone, the total number of IVF cycles undertaken in 2007 provided by Center for Disease Control numbers is 142 415, which represents data from 430 fertility clinics in operation. Data presented at the annual conference of the European Society of Human Reproduction and Embryology (ESHRE) in 2006 have also shown that more than three million babies have been born using IVF and other assisted reproductive technology (ART) since the world’s first IVF baby was born in 1978. With the continued improvements to treatment protocols, advancements in technology and refinements in scientific techniques have resulted in steadily increasing success rates for ART. Despite the improvements in the success of ART, it remains the fact that the majority of patients require more than one cycle of treatment to achieve pregnancy 1040-872X ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
and live birth. Furthermore, the use of egg donation has also helped in increasing the success rates for ART; most of the egg donors repeat more than one cycle. The question ‘Does the ovarian reserve decrease from repeated ovulation stimulations?’ has become even more important today as ART has become a worldwide phenomenon with its ever growing number of patients in need of this therapy. There have been two reviews in the last 10 years on the effect of repeated reproductive techniques on ovarian response [1,2]. However, not much progress has been accomplished since the 2005 review. Experiments and observations in humans show that in primates, early antral follicles are present in ovaries throughout the follicular as well as the luteal phase and even prior to the onset of puberty [3]. It is generally accepted that the stages of follicular development up to and including the early antral follicle are relatively independent of the pituitary gonadotropins, follicle-stimulating hormone (FSH) and DOI:10.1097/GCO.0b013e328338c165
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178 Fertility Table 1 Relevant published data on consecutive controlled ovarian hyperstimulation cycles for IVF and ovulation induction protocols
OI-HUI Diamond et al. [7] Ahmed Ebbiary et al. [8] Jacobs et al. [9] IVF Yovel et al. [14] Hoveyda et al. [13] Kolibianakis et al. [11] De Boer et al. [12] Donors Jain et al. [23] Caligara et al. [22] Opsahl et al. [24]
Number of cycles per patient
Size of the studies
ART
3–12 3–6 1–2
151 cycles 347 cycles 486 cycles
Clomiphene citrate/hMG Clomiphene citrate/nMG Clomiphene citrate/hMG
3 3 2–6 7
426 cycles 570 cycles 9379 cycles 330 cycles
IVF IVF IVF IVF
3 2–9 1–6
45 donors 284 donors 135 donors
IVF IVF IVF
hMG, human menopausal gonadotropin.
luteinizing hormone [3,4]. The main role of FSH is to stimulate the formation of a large preovulatory follicle from a preantral follicle [3]. If FSH secretion and stimulation does not occur at the appropriate time, and if maintenance of this secretion does not occur, the cohort of follicles would undergo atresia [5]. If the cohort of antral follicles has already been selected independent of the pituitary gonadotropins, the amount of FSH would only affect the development of preovulatory follicles coming from the antral pool that otherwise would be atretic due to dominant follicle selection. If so, the increase of FSH during the late luteal phase would not affect the overall number of follicles in the cohort. As a result, the repeated cycles should not affect the ovarian reserve. However, if the increase of FSH increases the number of follicles recruited into the cohort, the treatment may increase the depletion of the follicle pool by stimulating the resting follicles to grow [5]. This may result in the depletion of the number of oocytes available and may affect the overall ovarian reserve in repeated cycles. This is one way of thinking about it if one believes in the premise that germ cell production in female mammals ceases at birth. On the contrary, Johnson et al. [6] is the first group that introduces the concept of ongoing oocyte regeneration de novo postnatally within the ovary. Many studies that follow since 2004 support the idea of continuous germ cell renewal providing replenishment of oocytes in the ovary. This exerts a new way of thinking of the effects of ovarian stimulation on ovarian reserve and oocyte development. With the ever changing biological understanding of the process of folliculogenesis, the available literature concerning ovarian response in repeated ovarian stimulation cycles is, at the same time, inconclusive and limited. The first part of the review is to examine whether there is evidence in supporting that repeated cycles would decrease ovarian reserve in patients who are undergoing repetitive conservative ovarian stimulation and IVF cycles. Then, we will examine the effect of repeated ART cycles in patients with endometriosis. Finally, we
will focus on the potential long-term sequelae of multiple cycles of treatment on the well being of the ovary itself. Table 1 summarizes some of the studies mentioned in this review. The answer to the main question of this review is crucial in terms of counseling patients as well as oocyte donors about the available clinical evidence in reporting the clinical consequence of repeated ovarian stimulation.
Ovarian response to consecutive cycles of ovulation induction In this section, we would first review available clinical studies (Table 1) on whether repeated ovulation induction would deteriorate ovarian response with repetitive treatment. Secondly, we would then review the data available on the effect of IVF repetitive cycles on ovarian reserve. Ovarian stimulation combined with intra-uterine insemination (IUI) is an effective treatment of nontubal infertility but most women undergo several cycles of treatment to achieve a pregnancy. Diamond et al. [7] were one of the first groups to evaluate ovarian response in consecutive cycles of women undergoing ovulation induction with human menopausal gonadotropins (hMG) and/or clomiphene citrate. It was concluded that hMG can be administered in multiple successive cycles without clinically impairing ovarian response which, estimated by peak E2 levels and the day of hCG administration, remained similar in 3– 12 immediately successive cycles. In a prospective study of 86 women, Ahmed Ebbiary et al. [8] assessed the consistency of ovarian response and the effect of ovarian stimulation protocols (i.e. sequential clomiphene citrate or hMG stimulation, hMG-only or combined gonadotrophinreleasing hormone analog – hMG) on this consistency in consecutive cycles of ovarian stimulation and IUI in women with nonovulatory infertility. Using each patient as her own control, the study demonstrated that the ovarian response was similar in patients undergoing three to six cycles of ovarian stimulation and IUI. However, in a
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Decrease in ovarian reserve from repeated ovulation stimulations Luk and Arici 179
retrospective study of 486 cycles from 225 ovulatory infertile women undergoing hMG superovulation IUI, Jacobs et al. [9] had found a decreased ovarian response to an increased amount of stimulation, as measured by steroidogenesis and follicular recruitment with increasing age of the women. When the age variable was taken out from the analysis, there was no significant difference in the mean estradiol level per preovulatory follicle among the different age groups.
Ovarian response to consecutive cycles of in-vitro fertilization Even though there are many similarities in the process of hormonal manipulation within the cycle with conservative ovulation hyperstimulation versus IVF, the difference is marked between the two protocols. Compared to ovulation induction, IVF involves usually higher dosage of medication and also a surgical process which is the oocyte retrieval process in which the actual puncture can have destructive effect on the capillaries and follicles of the ovary, the effect of which may accumulate during repeated punctures. Repeated punctures may also induce the release of autoantigens causing a decline of the follicle pool [10]. If this is true, a decrease in the number of retrieved oocytes in women with many IVF cycles is to be expected. As a result, compared to conservative ovarian stimulation cycles combined with IUI cycles, IVF protocols appear more invasive with higher dosage of gonadotropins medication and ovarian puncture for oocyte retrieval. However, the results are found to be similar to those for conservative ovarian induction and IUI cycles. In a retrospective analysis of 3249 patients, Kolibianakis et al. [11] was one of the first groups that included 9379 cycles of IVF cycles or intracytoplasmic sperm injection (ICSI) cycles (minimum two, maximum six cycles per patient). It demonstrated that repeated ART cycles did not exert a significant effect on the mean number of cumulus oocyte complexes retrieved per attempt. Across repeated ART attempts, an increase in the mean number of ampoules used per cycle was observed which was secondary to the effect of maternal age. After controlling for the effect of maternal age, there was no decrease in the number of retrieved cumulus oocyte complexes among subsequent cycles. In a nationwide retrospective cohort study in the Netherlands with a total of 330 cycles, De Boer et al. [12] investigated whether there was a decreasing trend in the number of retrieved oocytes in women who had all undergone at least seven consecutive IVF cycles. Reassuringly, there was no significant decrease in the number of retrieved oocytes over six cycles. On adjusting for the number of ampoules and the stimulation protocol, a
significant 20% decrease in the number of retrieved oocytes between cycle numbers 1 and 6 was found but the effect was secondary to age. In a study of 190 women, Hoveyda et al. [13] assessed the results of three consecutive cycles of ovarian stimulation in the same woman. Each woman served as her own control. There were no significant differences in the number of follicles produced or the number of oocytes retrieved over the three cycles, with an average of 12 follicles and 8 oocytes produced per cycle. The number and the quality of embryos produced did not change significantly over the three cycles. To find whether age plays a role in the two age groups, they stratified and analyzed the data according to two age groups: below 35 y/o (n ¼ 112) and above 35 y/o (n ¼ 78). Both groups were noted to have significant increase in the number of ampoules of gonadotropin required per follicle over the three consecutive cycles. However, there is a significantly higher increase of ampoules of gonadotropins over the consecutive IVF cycles needed for the age group above 35 y/o compared to the younger age group. And this finding was consistent with previous studies showing an increased need for number of ampoules of gonadotropins dependent on age. Yovel et al. [14] assessed 194 women who underwent four to eight IVF cycles and the women aged from 25 to 46 years. The patients underwent from four (169 women) to eight (27 women) treatment cycles, using four established protocols for induction of ovulation. The pregnancy rates in cycles 4–8 were not statistically different with mean pregnancy rate at 16.2% per cycle. On the contrary, there were a few retrospective studies done on a large number of women in the 1990s showing that the successive IVF cycles after the third cycle decreased ovarian reserve with decreasing pregnancy and birth rate with subsequent cycles [15,16]. They included thousands of cycles to study the numerous factors that can affect the success of an IVF cycle. A large review of 36 961 cycles done by the Human Fertilisation and Embryology Authority (HFEA) who has been collecting information on all IVF cycles revealed a decline in live birth rate associated with increasing age and a decrease associated with the duration of infertility and with each subsequent cycle of treatment [16]. Even after adjustment for age, there was a significant decrease in live birth rate with increasing duration of infertility from 1 to 12 years (P < 0.001). The main goal of this database was to identify the factors that affect the outcome of IVF treatment. Even though these studies consisted of large numbers of women their treatment protocol consisted of a group of heterogeneous protocols with different dosage treatments. These studies did not assess the same group of women over consecutive IVF cycles. As a result, these
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180 Fertility
studies are not ideal to answer the main question of this review. Even though the available literature is limited, the published evidence demonstrates that repeated IVF cycles do not appear to affect the ovarian reserve with three repetitive IVF cycles. Ovarian response persists with subsequent cycles of controlled ovarian hyperstimulation in the number of oocytes retrieved and the number of embryos transferred from each stimulatory cycle. However, it appears that successive IVF cycles after the third cycle may decrease ovarian reserve, and that there is an increased gonadotropin requirement with each subsequent IVF cycle across all age groups.
Effect of repeated controlled ovarian stimulation in patients with endometriosis It has been a controversial matter on the extent to which endometriosis affects IVF outcome. It has been suggested that women with endometriosis have a lower ovarian response to ART treatment. The effect of endometriosis on pregnancy outcome after IVF-ET is controversial. Many authors have reported a detrimental effect [17,18], but not all have concurred with this finding [19,20]. Most of these studies have been relatively small or multicenter in design, and have not been able to specifically assess the impact of endometriosis stage on IVF-ET outcome. IVF is an effective infertility treatment for women with endometriosis, but most women need to undergo several cycles of treatment to become pregnant. In this case-control study, Al-Azemi et al. [21] compared outcome measures in 40 women with a history of surgically confirmed ovarian endometriosis and 80 women with tubal infertility, all of whom had at least three IVF treatment cycles. This was designed to assess how consistently women with ovarian endometriosis respond to ovarian stimulation in consecutive treatment cycles compared to women with tubal infertility. The ovarian endometriosis group had a significantly poorer ovarian response and required significantly more ampoules of FSH per cycle, a difference that became greater with each subsequent cycle. However, cumulative pregnancy (63.3 versus 62.6% by fifth cycle) and live birth (46.8 versus 50.9% by fifth cycle) rates were similar in both groups. In conclusion, despite decreased ovarian response to FSH, ovarian endometriosis does not decrease the chances of successive IVF treatment.
Effect of ovarian reserve in egg donors who undergo repeated in-vitro fertilization cycles Egg donation has become a common mode of therapy for the treatment of premature ovarian failure or recurrent unsuccessful IVF attempts. As a result, egg donation has become a common practice and egg donors who have
good track record (i.e. producing good-quality embryos and with successful pregnancy) are likely being recruited for multiple cycles. In a retrospective study of 284 donors who underwent at least two cycles with 4 donors undergoing up to nine cycles, Caligara et al. [22] studied the effect of repeated IVF cycles on the oocyte quality, assessed as fertilization, implantation and pregnancy rates. The study demonstrated that the number of retrieved oocytes was maintained during five repeated IVF cycles. Moreover, with the same dosage of stimulation used over multiple cycles, there was no difference in the oocyte quality, as shown by comparable fertilization, implantation and pregnancy rates in the recipients over multiple cycles of donation. The results from this study were confirmed by two other studies. In a retrospective chart review of 45 oocyte donors in 107 IVF cycles, Jain et al. [23] demonstrated that donors could undergo up to three stimulation cycles without a negative effect on the ovarian response to gonadotropins and the embryo quality. This finding may be due to the young age of the donors who were recruited and the relatively short interval between treatment cycles, as demonstrated by the mean age per cycle of the donors. Opsahl et al. [24] also evaluated the pregnancy rate of each IVF cycle from individual oocyte donors who underwent multiple sequential donations. Donors were grouped by the interval between cycles and the cycle number. Cumulative delivered pregnancy rates for cycles 1–6 were ranging between 51.5 and 57.6%, when the pregnancy rates did not vary by the interval between cycles. The study concluded that young healthy donors can reliably donate oocytes for at least six cycles with the expectation of consistently high pregnancy rates.
Adverse effect on ovaries with repeated cycles Preliminary studies report that ovulation-inducing medications were associated with a small increase in the risk of ovarian tumors (i.e. borderline tumors) and that the risk increased with the extended use of ovulation-inducing agents for many months [25,26]. In the study cohort of 3837 women, Rossing et al. [25] found that the risk of clomiphene citrate use was dose-dependent and the risk increased with duration of usage. After controlling for the presence of ovulatory abnormalities, the relative risk of developing ovarian tumors associated with long-term use of clomiphene citrate (12 months or more) was 11.1 [95% confidence interval (CI) 1.5–82] [24]. This was a statistically significant finding and the result was similar among gravid and nulligravid women, as well as among women with or without ovulatory abnormalities. The researchers concluded that the prolonged use of clomiphene citrate may increase the risk of a borderline or invasive ovarian
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Decrease in ovarian reserve from repeated ovulation stimulations Luk and Arici 181
tumor. The results were consistent with Whittemore et al. [26] study in which they found significant risk occurred among 13 nulligravid women who had used infertility drugs. However, no such effect was found in Mosgaard et al. [27] case control study including Danish women (below the age of 60 years) with ovarian cancer in the analysis. They compared patients who developed ovarian cancer (n ¼ 684) with an age-matched control group (n ¼ 1721) and found that there was no added risk in those with a history of fertility treatment [27]. One must wonder how infertility may also play a role in the risk of developing ovarian cancer. In a multicenter study, Ness et al. [28] pooled interviews on infertility and fertility drug use from eight case-control studies conducted between 1989 and 1999 in the USA, Denmark, Canada, and Australia. The analysis includes 5207 cases and 7705 controls [28]. It shows that the risk of ovarian cancer increased 2.67-fold among nulligravid women who attempted for more than 5 years to get pregnant compared with women who needed less than a year. Fertility drug use in nulligravid women is associated with borderline serous tumors but not with any invasive histologic subtypes. The study suggests a role for specific biologic causes of infertility, but not for infertility drugs in overall risk for ovarian cancer. Some practitioners believe that infertility itself is a more powerful risk factor for ovarian tumors than the treatment with ovulation-inducing medication. Most of these epidemiological studies on fertility drug use and risk of ovarian cancer are hampered by methodological problems, such as small study size, short follow-up time, and low prevalence of ovarian cancer. It is difficult to draw a definitive conclusion on the role of infertility in the risk of development of ovarian cancer from these studies. The most common presentation of ovarian cancer is in the sixth decade of life. The widespread availability of ovulation-inducing medication began in the 1980s; thus, we may not see the effect of ovulation-inducing medication for at least another decade. It is highly possible that the effect of fertility drug use on ovarian cancer risk has been underestimated.
suggests that successive stimulation cycles do not impair ovarian response in terms of quantity and quality of the oocytes obtained in good donors. This finding may be due to the young age of the donors who were recruited and the relatively short interval between treatment cycles, as demonstrated by the mean age per cycle of the donors reported in the studies. As for women who are undergoing IVF and ovulation induction, the results have been equivocal when they repeat more than three cycles. Overall, the finding shows that there is no significant decline in ovarian reserve in patients undertaking up to three repeated IVF cycles. Age becomes a determinant factor with both pregnancy and live birth rate declining with repetitive cycles. The consistent finding from this review is that the mean number of ampoules used per cycle increases in line with age. Consequently, an increased amount of ampoules per attempt is likely to be used in older (compared with younger) women in each ART cycle performed. Age-associated decline in ovarian reserve is known to affect the size and the activity of the cohort of follicles available to respond to gonadotropin stimulation, resulting in the increased quantity of medication needed for ovarian stimulation. Further studies into this subject are needed to better counsel patients who will be undergoing ART treatment. The potential association of repeated cycles of induction treatments and the later development of ovarian cancer has been suggested by a number of studies. However, there is no evidence-based guideline about the appropriate duration of gonadotropin administration. However limited, the current body of evidence is reassuring on this issue. Given the possibility that such agents can cause harm, it seems appropriate to use them sparingly and only with clear cut indications.
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Conclusion Repetitive fertility treatment can have a significant degree of psychological stress, with potentially important consequences for the couple and their relationship. Even with the advances in ART treatment, most couples would need to undergo more than one cycle before they can succeed. As a result, the question whether the repeated ovulation induction cycles would affect the ovarian reserve is crucial in counseling patients who are planning to undergo infertility treatments. The available data on this topic are limited. Overall, the analysis of the data
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182 Fertility Jacobs SL, Metzger DA, Dodson WC, Haney AF. Effect of age on response to human menopausal gonadotropin stimulation. J Clin Endocrinol Metab 1990; 71:1525–1530.
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Economics of assisted reproductive technologies Baris Ataa and Emre Selib a
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, McGill University, Montreal, Quebec, Canada and b Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, USA Correspondence to Emre Seli, MD, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, 310 Cedar Street, LSOG 304D, New Haven, CT 06520-8063, USA Tel: +1 203 785 7873; fax: +1 203 785 7134; e-mail:
[email protected] Current Opinion in Obstetrics and Gynecology 2010, 22:183–188
Purpose of review To give an overview of the economic aspects of assisted reproductive technologies (ART) and assess the implications of economic factors for utilization and practice of ART. Recent findings The out-of-pocket expenses for the couple seem to be the key determinant of ART utilization. Countries with reimbursement plans, which minimize out-of-pocket expenses, achieve the highest ART utilization rates. The economic burden of ART on national healthcare expenditure is modest even for countries offering the most generous reimbursement policies. Downstream costs of ART arise from multiple pregnancies and associated prematurity-related complications. These costs can outweigh the cost of ART itself. Public reimbursement plans accompanied by strict regulations for number of embryos to be transferred seem to increase not only ART utilization rates but also the uptake of single embryo transfers. Summary Although ART is expensive for individuals, it is affordable for the society, at least in the industrialized world. Public reimbursement relieves the pressure on both the physicians and the patients for achievement of pregnancy with the minimum number of treatment attempts, consequently leading to a decrease in the number of embryos transferred and in multiple pregnancies. Keywords assisted reproductive technologies, cost, cost effectiveness, economics, in vitro fertilization, utilization Curr Opin Obstet Gynecol 22:183–188 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1040-872X
Introduction Failure to conceive after 12 months of regular, unprotected intercourse is the most commonly used definition of infertility and it is a common problem estimated to affect approximately 15% couples with a more or less similar incidence all around the world [1]. Although there is a perception that the prevalence of infertility is rising and concerns exist about a possible decline in human fertility, this has not been corroborated with factual data as of yet [2–4], and at least in the United States, the prevalence of infertility has remained unchanged over the last decades, with an estimated 13% in 1965, and 14% in 1988 [5]. Among the treatment options available to infertile couples, those utilizing assisted reproductive technologies (ART) are associated with the highest success rates. Consequently, the number of patients treated using ART has been steadily increasing across the world. The International Committee for Monitoring Assisted Reproductive Technologies (ICMAART) estimated 1040-872X ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
that in the year 2002 approximately 600 000 ART cycles have been performed worldwide [6]. The number of treatment cycles reported to the European in-vitro fertilization (IVF) Monitoring Programme and the Society for Assisted Reproductive Technologies have been steadily increasing over the years [7,8]. If the growth rates are maintained consistently, it is anticipated that the total number of ART cycles per annum will reach one million by the year 2010 and two million by the year 2015 (Fig. 1).
Utilization of assisted reproductive technologies Despite the consistent increase in the number of ART cycles performed each year, the overall utilization of ART is still less than the estimated numbers had all couples in need had access to these technologies [2]. ART services require highly trained personnel and expensive equipment. Therefore, limited availability of the services and the cost of treatment can be considered major factors limiting utilization of ART. In a DOI:10.1097/GCO.0b013e3283373c13
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184 Fertility Figure 1 Current and estimated number of ART treatment cycles per year
1200000
1000000
600000
400000
United states
Number of cycles
800 000
European union Japan Australia/New Zealand Other countries
200000
0 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
Data source for the United States: Centers for Disease Control; Actual figures through 2005; projected cycles based on 4% growth rate per year. Data source for the European Union: ESHRE, ICMART; Actual figures through 2003; projected cycles based on 9% growth rate per year. Data source for Japan: Japanese Society of Obstetrics and Gynecology; Actual figures through 2004; projected cycles based on 8% growth rate per year. Data source for Australia and New Zealand: Australian and New Zealand Assisted Reproductive Database; Actual figures through 2005; projected cycles based on 9% growth rate per year. Data source for other countries: International Committee for Monitoring Assisted Reproductive Technologies; Actual figures through 2002; projected cycles based on 5% growth rate per year. Graph courtesy of James T. Poslico, Ph.D.
detailed review article on health economics of ART, infant mortality was the only healthcare measure that was significantly associated with the availability of ART services at a national level [1]. Infant mortality is regarded as an indicator of overall quality of a national healthcare system [9], and it is plausible that countries with high infant mortality rates can have priorities for other basic healthcare services rendering less resources available for ART services [1]. However, the utilization of ART in most developed countries with low infant mortality rates is still below 1500 ART cycles per million population (c.p.m.) per annum, which is considered a conservative underestimate of the actual need [1,2,10]. The observed difference in ART utilization between countries with similar low infant mortality rates seem to be partly due to differences in the availability of public reimbursement for ART. As an example, despite similar infant mortality rates, the average number of ART c.p.m. per annum ranged between 1450 and 2209 in the year 2005 in Scandinavian countries with full public reimbursement for ART [7], whereas the same figure was only 353 in Canada for the same year [11], where there was no federal government reimbursement for ART and only one province provided
partial reimbursement excluding cost of medication [10].
Cost of assisted reproductive technologies The cost of an ART treatment cycle can be categorized as direct and indirect costs. Direct costs are more or less similar for all patients in a given center and arise from physicians’ consultations, nursing services, medication, ultrasound scanning, laboratory tests, ART procedures [oocyte collection, anesthesia, sperm preparation, invitro fertilization/intracytoplasmic sperm injection (IVF/ICSI), various embryology services, and embryo transfer], hospital charges, and administrative charges. The immediate indirect costs mainly include costs associated with loss of working hours and traveling to the treatment center. The actual amount of indirect costs depends on the conditions of a particular patient rather than the center. In general, indirect costs are relatively much less than the direct costs and, therefore, considered negligible. The costs arising from the multiple pregnancies following ART, that is, hospitalization costs for women and infants, costs of neonatal complications associated with
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Economics of assisted reproductive technologies Ata and Seli
prematurity, etc. are significant downstream costs of ART and they will be discussed in detail below. The cost of an ART cycle differs widely between countries. Collins [1] estimated the average cost of a single IVF cycle in 26 countries and expressed the figures in 2002 US$. The estimates ranged from 1272 US$ in Iran and Pakistan to 6361 US$ in Hong Kong, excluding the United States where the cost at 9547 US$ was much higher than the rest of the included countries. More recently, Chambers et al. [10] reported similar information for selected developed countries; the costs as they occurred in the year 2003 were expressed in 2006 US$. Although the United States remained the most expensive country with the average cost of a standard fresh IVF cycle at 12 513 US$ (2006), the cost of a fresh IVF cycle was the lowest in Japan with 3956 US$ (2006). The cost of medication comprised a significant proportion of overall treatment cost in all countries. The proportion was highest in Canada, where medication costs were 41.5% of overall treatment cost, and the lowest in Japan, where it was 13% of overall treatment cost [10]. These differences partly arise from the different marketing price of commonly used medications, partly from differences in prescribing patterns, that is, less gonadotropins per stimulated cycle being used in one country versus another etc. It is noteworthy that the actual cost of an ART treatment cycle per se is of limited value for understanding the economic implications of treatment costs on utilization of ART. Although a single IVF cycle costs more in North America where utilization is lower, the cost of a single treatment cycle is not the lowest in Scandinavian countries or Australia where the utilization of ART is the highest [1,10].
Affordability of assisted reproductive technologies To better determine the economic burden of ART treatment on an individual couple’s budget, ART cost should be assessed relative to disposable income. For this purpose, annual household expenditures and gross national income (GNI) per capita have been used as indicators of disposable income [1,10]. When Chambers et al. [10] calculated the cost of ART treatment cycle as a percentage of GNI per capita, the figures were directly proportional to the absolute cost of ART treatment. In their study, the cost of a cycle in developed countries ranged from 10% of GNI per capita in Japan to 28% of GNI per capita in the United States. The results were similar to figures reported by Collins in a former report [1]. However, the cost of an ART treatment cycle can be greater than 50% of GNI per capita in developing countries [1]. For instance, the 1272 US$ (2002) cost of an ART cycle in Iran and Pakistan, the lowest value reported for countries
185
included in the analysis by Collins, was greater than 50% of GNI per capita in respective countries [1]. Although the number of ART c.p.m. per annum was only four in Pakistan, it was 301 in Iran, a figure greater than 126, 190 and 101 c.p.m. per annum reported for the United States, Canada and Japan in the same period. Therefore, the proportion of cost of an ART cycle to disposable income does not seem to be the only factor determining utilization.
Reimbursement of assisted reproductive technologies The regulation, provision and funding of ART services differ among countries and at times between different jurisdictions in the same country [10,12,13]. Historically, the arguments against public funding/insurance coverage for ART included lack of medical necessity, ART being regarded an experimental procedure, low effectiveness of ART procedures and resultant low cost effectiveness as a treatment option [12]. In the early days of the ART era, effectiveness of the technology has been questioned [14,15], and initial studies analyzing cost effectiveness of ART in comparison to alternative conventional therapies, that is, untreated observation, ovulation induction, and intrauterine insemination (IUI), suggested that where applicable conventional treatments were more cost effective, and the cost per additional live birth with IVF was too high to be considered feasible [16–18]. However, while the success rates of conventional treatments have remained stable [7,19], the success rates of ART have improved consistently over the years and live birth rate per treatment cycle has reached the range of 20–40% [7,8]. Currently, ART is regarded the most successful treatment modality in terms of pregnancy/live birth rates per attempt. To the contrary, the effectiveness of conventional treatments is being requestioned [19,20]. Parallel to the evolution of perception of infertility per se and of ART in both the medical and general community, an increasing number of countries are providing governmental reimbursement for ART services. However, the conditions and extent of reimbursement vary widely among countries. Although some countries provide government funding for ART treatments largely through public centers, private centers where patients pay mostly out-of-pocket remain the major service providers in others. In the United States, where no publicly funded healthcare services are available for persons in the reproductive age group, some states have mandates for fertility treatment coverage including ART by third-party payers [10,12,21]. Effect of reimbursement on the affordability of assisted reproductive technologies
Chambers et al. [10] adjusted the economic burden of an ART treatment cycle on a couple for the effect of
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186 Fertility
reimbursement policy in practice in the countries analyzed. They expressed the cost of a standard IVF cycle as the percentage of annual disposable income with and without adjusting for government subsidization. Although the figure remained unchanged at 12% in Japan, where no government subsidization exists, it was only modestly changed from 50 to 44% in the United States where reimbursement exists in different forms in some states only. On the contrary, the average cost as a percentage of annual disposable income was almost halved after adjusting for government reimbursement in Scandinavian countries and was approximately 10%. The most dramatic change was in Australia with a relative reduction by 71% from 19% to 6% of annual disposable income. Effect of reimbursement on the utilization of assisted reproductive technologies: implications on national cost of healthcare
Countries with more generous reimbursement policies minimizing the out-of-pocket expenses for the patients seem to achieve highest utilization of ART [10]. Scandinavian countries and Australia are examples reaching ART utilization rates around 1500 c.p.m. per annum with reimbursement policies that cut the cost of treatment for the couple by at least 50% [10]. These observations suggest that the out-of-pocket cost to the patient is the key determinant of the utilization of ART services. As expected, ART enjoys a larger share of the total healthcare expenditure in countries that offer reimbursement. ART treatment costs comprise only 0.06% of the total healthcare expenditure in the United States, whereas they account for 0.19% and 0.25% of total healthcare expenses in the Scandinavian countries and Australia, respectively [10]. It is noteworthy that although ART is a relatively expensive treatment with a high cost per procedure, the number of couples in need for treatment can be considered small relative to the total population, and the overall treatment cost to the society as a whole remains within reasonable limits even in countries with extensive public reimbursement and highest utilization rates. In addition, considering the relatively high cost of ART treatment for a couple, consuming a substantial proportion of their disposable income, it can be concluded that ART is expensive for the couple but easily affordable by the society. For instance, in the United States the estimated direct cost of cardiovascular diseases is 313.8 billion US$ [22], whereas the estimated direct cost of ART is less than 2 billion US$ (estimated number of treatment cycles multiplied by the average cost of an IVF cycle in the United States, including the cost of medication).
in a given society. Two ‘willingness to pay’ studies conducted in the United States and Sweden assessed how individuals value ART services [23,24]. Although the Swedish study included infertile couples, the United States study also included individuals who did not know their fertility status at the time of the study. The amounts that both study populations expressed willingness to pay exceeded the actual cost of a live birth with ART treatment. In the United States study, the amount individuals were willing to pay increased proportionally to anticipated success rate of the ART procedure [23]. Therefore, given the increased success rates with ART, it can be speculated that individuals could be expected to regard ART as better value for money today as compared with 15 years ago when these studies were conducted. The general population surveyed in the United States study expressed willingness to pay 38 US$ and 62 US$ per year in taxes for a public insurance program that would cover ART services and provide 25% and 100% chance of pregnancy with treatment, respectively. Another study found that an insurance coverage that would provide 300 c.p.m. per annum in the United States would only require 9.41 US$ premium per full time employee in the year 1995, a figure that is less than what people were willing to pay [25]. Finally, a modeling study conducted in the United States estimated that the lifetime tax contribution of a child conceived with ART to the government exceeds by 7fold the initial government subsidy for ART treatment, suggesting providing a reasonable ART coverage financially benefits the government in the long run [26]. Assisted reproductive technologies reimbursement: implications for treatment strategies
There is evidence that decisions made by the practitioners and patients during an ART treatment cycle are affected by the extent of reimbursement. Most importantly, the number of embryos transferred seems to be dependent on whether the couple is paying out-ofpocket, or they are reimbursed for the treatment. Following an initial report by Reynolds et al. [27] suggesting that insurance affects transfer practices, Jain and Gupta [28] showed that state-mandated health insurance coverage for ART services was associated with greater use of ICSI for infertility that is not attributed to male-factor condition. Most recently, Martin et al. [29] reported that states without insurance coverage for ART have a higher multiple twin live birth rate associated with more embryos transferred per cycle.
The value of assisted reproductive technologies reimbursement
Downstream costs of assisted reproductive technologies associated with multiple births and related prematurity
Whether ART provides ‘value for money’ service for the society depends on the perception of infertility and ART
In the United States, the current success rates achieved with ART are attained in many cases through the
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Economics of assisted reproductive technologies Ata and Seli
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simultaneous transfer of multiple embryos, at the risk of multiple pregnancies. Consequently, while ART cycles account for only 1% of all births in the United States, 18% of multiple births result from ART, and 51% of all ART neonates are the products of multiple gestations [30], a frequency 15-fold–20-fold greater than with spontaneous conceptions [31]. Similar outcomes are probable in countries that demonstrate similar lack of strict regulations on the number of embryos to be transferred, although data are not readily available.
relatively modest. The trend towards using milder stimulation protocols and the actual decrease in the number of multiple pregnancies provided by transfer of fewer embryos will render ART a more cost effective treatment and can be anticipated to further decrease the costs of ART on healthcare systems. Reasonable reimbursement policies can increase not only utilization of ART treatments but also the uptake of single embryo transfers.
The increase in multiple pregnancies associated with ART treatment has significant consequences for public health. The higher rate of preterm delivery in neonates from multiple infant pregnancies compromises their survival chances and increases their risk of lifelong disability. Indeed, the incidences of infant death and cerebral palsy are increased 4–6-fold in twins and more than 15-fold in higher order pregnancies [32]. The increase in preterm delivery that results from ART-associated multiple pregnancies also has financial consequences for the society. It has been estimated that preterm births that result from ART-associated multiple pregnancies account for almost 1 billion US$ healthcare costs annually [33].
References and recommended reading
Complications associated with multiple pregnancies have led many countries to enact strict regulations with respect to IVF practice, limiting the number of oocytes fertilized and/or embryos transferred [32]. Stricter regulations have been implemented in countries where ART is reimbursed, and resulted in a significant decrease in multiple pregnancies without causing a decrease in cumulative pregnancy rates, as demonstrated by several recent studies [34,35]. Meanwhile in the United States and many other countries where ART is not reimbursed, although there are guidelines implemented by various organizations regarding the recommended number of embryos transferred, the decision is ultimately left to the individual practitioner. A reimbursement program that aligns incentives of both patients undergoing treatment and the healthcare system that pays the economic cost of multiples can prove useful in increasing the uptake of single/double embryo transfers.
Conclusion ART is the most successful treatment of infertility. However, in most parts of the world utilization of ART seems to be less than the anticipated need. ART utilization is higher in countries with reimbursement plans that substantially decrease the out-of-pocket expenses for the couple under treatment. Although the cost of an ART treatment cycle is high for individuals across the world, the overall burden of ART on national healthcare expenditures is
Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 255). 1
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ESHRE Capri Workshop Group. Social determinants of human reproduction. Hum Reprod 2001; 16:1518–1526.
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Bhattacharya S, Porter M, Amalraj E, et al. The epidemiology of infertility in the North East of Scotland. Hum Reprod 2009; 24:3096–3107.
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Joffe M. What has happened to human fertility? Hum Reprod 2010; 25:295– 307.
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Mosher W, Pratt W. Fecundity and infertility in the United States, 1965– 1988. Advance data from vital and health statistics 1990; 192:192–193.
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de Mouzon J, Lancaster P, Nygren KG, et al. World collaborative report on Assisted Reproductive Technology, 2002. Hum Reprod 2009; 24:2310– 2320.
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Nyboe Andersen A, Goossens V, Bhattacharya S, et al. Assisted reproductive technology and intrauterine inseminations in Europe, 2005: results generated from European registers by ESHRE: ESHRE. The European IVF Monitoring Programme (EIM), for the European Society of Human Reproduction and Embryology (ESHRE). Hum Reprod 2009; 24:1267–1287.
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The Society for Assisted Reproductive Technology. National Data Summary. wwwsartorg. 2007 [Accessed 15 December 2009]
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Wise PH, Pursley DM. Infant mortality as a social mirror. N Engl J Med 1992; 326:1558–1560.
10 Chambers GM, Sullivan EA, Ishihara O, et al. The economic impact of assisted reproductive technology: a review of selected developed countries. Fertil Steril 2009; 91:2281–2294. Recent analysis and comparison of economic aspects of ART in developed countries. Authors report that out-of-pocket expenses after public reimbursement is the major determinant of utilization. 11 Gunby J, Bissonnette F, Librach C, Cowan L. Assisted reproductive technologies in Canada: 2005 results from the Canadian Assisted Reproductive Technologies Register. Fertil Steril 2009; 91:1721–1730. 12 Hughes EG, Giacomini M. Funding in vitro fertilization treatment for persistent subfertility: the pain and the politics. Fertil Steril 2001; 76:431–442. 13 Brown S. Patchwork ART legislation in Europe. Focus on reproduction 2009:23. 14 Jarrell JF, Labelle R, Goeree R, et al. In vitro fertilization and embryo transfer: a randomized controlled trial. Online J Curr Clin Trials 1993;Doc No 73:[3483 words; 37 paragraphs]. 15 Soliman S, Daya S, Collins J, Jarrell J. A randomized trial of in vitro fertilization versus conventional treatment for infertility. Fertil Steril 1993; 59:1239– 1244. 16 Garceau L, Henderson J, Davis LJ, et al. Economic implications of assisted reproductive techniques: a systematic review. Hum Reprod 2002; 17:3090– 3109. 17 Karande VC, Korn A, Morris R, et al. Prospective randomized trial comparing the outcome and cost of in vitro fertilization with that of a traditional treatment algorithm as first-line therapy for couples with infertility. Fertil Steril 1999; 71:468–475. 18 Goverde AJ, McDonnell J, Vermeiden JP, et al. Intrauterine insemination or invitro fertilisation in idiopathic subfertility and male subfertility: a randomised trial and cost-effectiveness analysis. Lancet 2000; 355:13–18.
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188 Fertility 19 ESHRE Capri Workshop Group. Intrauterine insemination. Hum Reprod Update 2009; 15:265–277. 20 Practice Committee of the American Society of Assisted Reproductive Technology. Effectiveness and treatment for unexplained infertility. Fertil Steril 2006; 86:S111–S114. 21 ESHRE Data collection and consortia. http://www.eshre.com/ESHRE/ English/Data-collection-Consortia/Europe-map-reimbursement/page.aspx/ 739. [Accessed 16 December 2009] This article is an up-to-date interactive map providing detailed information about current legislation status and reimbursement policies in European countries. 22 American Heart Association. 2009 Update at a glance. Heart Disease and Stroke Statistics. 2009:33. 23 Neumann PJ, Johannesson M. The willingness to pay for in vitro fertilization: a pilot study using contingent valuation. Med Care 1994; 32:686–699. 24 Granberg M, Wikland M, Nilsson L, Hamberger L. Couples’ willingness to pay for IVF/ET. Acta Obstet Gynecol Scand 1995; 74:199–202. 25 Collins JA, Bustillo M, Visscher RD, Lawrence LD. An estimate of the cost of in vitro fertilization services in the United States in 1995. Fertil Steril 1995; 64:538–545. 26 Connolly MP, Pollard MS, Hoorens S, et al. Long-term economic benefits attributed to IVF-conceived children: a lifetime tax calculation. Am J Manag Care 2008; 14:598–604. 27 Reynolds MA, Schieve LA, Jeng G, Peterson HB. Does insurance coverage decrease the risk for multiple births associated with assisted reproductive technology? Fertil Steril 2003; 80:16–23. 28 Jain T, Gupta RS. Trends in the use of intracytoplasmic sperm injection in the United States. N Engl J Med 2007; 357:251–257.
29 Martin JR, Bromer JG, Patrizio P. Insurance coverage and IVF outcomes in USA: analysis of recent trends in patients younger than 35 years old. Fertil Steril 2009; 92 (Supplement 3):S52. Treatment outcomes are compared between states with and without mandate for assisted reproductive treatment. Number of embryos transferred and multiple pregnancy rates are lower in states with mandate for insurance coverage. Difference in overall pregnancy rates is minimal. 30 Wright VC, Chang J, Jeng G, Macaluso M. Assisted reproductive technology surveillance: United States, 2003. MMWR Surveill Summ 2006; 55:1–22. 31 Reddy UM, Wapner RJ, Rebar RW, Tasca RJ. Infertility, assisted reproductive technology, and adverse pregnancy outcomes: executive summary of a National Institute of Child Health and Human Development workshop. Obstet Gynecol 2007; 109:967–977. 32 Bromer JG, Seli E. Assessment of embryo viability in assisted reproductive technology: shortcomings of current approaches and the emerging role of metabolomics. Curr Opin Obstet Gynecol 2008; 20:234–241. 33 Bromer JG, Seli E. Preterm deliveries that result from ART-associated multiple pregnancies in the United States: a cost analysis. Fertil Steril 2008; 90 (Supplement 1):S210–S211. Modeling study assessing the cost of ART-associated multiple pregnancies and resultant prematurity. The costs are estimated to be around one billion US$ per annum, exceeding the cost of treatment itself. 34 Thurin A, Hausken J, Hillensjo T, et al. Elective single-embryo transfer versus double-embryo transfer in in vitro fertilization. N Engl J Med 2004; 351:2392– 2402. 35 Lukassen HG, Braat DD, Wetzels AM, et al. Two cycles with single embryo transfer versus one cycle with double embryo transfer: a randomized controlled trial. Hum Reprod 2005; 20:702–708.
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Cumulative live-birth rates after assisted reproductive technology Vasiliki A. Moragianni and Alan S. Penzias Boston IVF, Waltham and Division of Reproductive Endocrinology & Infertility, Department of Obstetrics & Gynecology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA Correspondence to Alan S. Penzias, MD, Director, Fellowship Program in Reproductive Endocrinology & Infertility, Beth Israel Deaconess Medical Center; Associate Professor of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, 330 Brookline Avenue KS-322, Boston, MA 02130, USA Tel: +1 781 434 6500; e-mail:
[email protected] Current Opinion in Obstetrics and Gynecology 2010, 22:189–192
Purpose of review Despite the promising success rates of IVF, many couples have to undergo several cycles before achieving live birth. In counseling patients faced with subfertility, it is important to provide cumulative live-birth rates. This review evaluates the current knowledge on cumulative rates, summarizing recently published evidence. Recent findings Existing data have been mostly presented in the form of live-birth rates per IVF cycle as a function of maternal age or reason for subfertility. Recent publications have been reporting IVF success rates in terms of cumulative live-birth rate (CLBR) per woman, thus providing a more realistic estimate that becomes applicable to individual couples. In general, CLBR following IVF has been reported between 45 and 55%. Maternal age has been shown to significantly reduce these rates, as has preimplantation genetic diagnosis. On the contrary, techniques mostly used to decrease the chance of multiple births, such as elective single embryo transfer and natural cycle IVF, do not affect CLBR while achieving a significant reduction in the rates of multiples. Summary Couples should be counseled that CLBR following IVF lies mostly around 50% and that maternal age as well as genetics of transferred embryos remain factors that influence success. Keywords assisted reproductive technology, cumulative live birth rate, IVF Curr Opin Obstet Gynecol 22:189–192 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1040-872X
Introduction Since the delivery of the first IVF baby nearly 30 years ago, significant advances have been made in the area of assisted reproductive technology (ART). Nevertheless, most subfertile couples undergo more than one treatment cycle before attaining a live delivery. An integral part of counseling these couples is educating them on the success, failure and complication rates related to each procedure they undergo with the end result of conception and live infant delivery. Traditionally, most studies have reported these rates per treatment cycle, most frequently classifying them by maternal age and cause of infertility. Such information would be useful in population-wide assessment of ART outcomes and has extensively been utilized in outcome reporting by national registries in Europe, the Middle East, North America, Australia and New Zealand [1,2]. In these registries, the term ‘cumulative’ often refers to a collection of data from different countries that are being combined and reported together. However, this method of outcome reporting has only limited applicability to any individual couple undergoing treatment. Instead, what is much more useful for both clinicians and patients and has recently been gaining 1040-872X ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
increasing attention in medical literature is the cumulative success rate per patient undergoing any number of ART cycles. More specifically, the cumulative live-birth rate (CLBR) per woman provides a more accurate depiction of treatment success and becomes directly meaningful to the subfertile couple. The aim of this review is to examine the recent medical literature on reports of CLBR following ART. These data will be first presented in general and subsequently as a factor of maternal age, the number of embryos transferred, natural cycle IVF and utilization of preimplantation genetic diagnosis (PGD).
Cumulative live-birth rates after IVF Studies from large fertility centers worldwide have been providing cumulative rates derived from longitudinal observations of cohorts of patients followed over time. In US studies, data from states such as Massachusetts have lent themselves to some of the major reported results. Not only is it one of the 14 US states offering mandated private insurance coverage for ART but it is also ranked fifth in the United States for number of ART DOI:10.1097/GCO.0b013e328338493f
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cycles and births [3,4]. Similarly, useful data are derived worldwide from national databases, such as the Copenhagen Multi-Centre Psychosocial Research Program [5].
In 2009, Malizia et al. [3 ] reported data from 6164 patients undergoing 14 248 IVF cycles in a single ART center in Massachusetts. They performed a retrospective cohort study of patients receiving treatment at their center for at least 1 year and undergoing up to six IVF cycles. The first of the cycles analyzed for each patient was always a fresh one and only subsequent cycles included in the analysis were allowed to be cryopreserved. The primary outcome measured by the authors was the delivery of single or multiple live infants, information that was obtained from the patients’ medical records. The CLBR for their population was reported between 51 and 72% in ‘conservative’ and ‘optimistic’ terms, respectively. Because it is impossible to assess the success rates of patients who interrupt treatment before attaining a pregnancy, these two approaches were used to estimate rates while still accounting for dropout patients. For the ‘conservative’ approach, it was assumed that patients who did not return for further IVF treatment had no chance of a live delivery, whereas the ‘optimistic’ approach assumed that patients not returning for IVF treatment had the same chance of a live delivery as those who did return. In a historical cohort study of 27 906 successive, linked ART cycles performed between January 2004 and December 2006, Stern et al. [4] reported the CLBR for all patients to be 53.8%. The study excluded intrauterine insemination (IUI), ovulation induction and banking cycles, as well as any cycles following the first delivery. Their analysis was based on the assumption that future treatment cycles would not result in a pregnancy and that the first cycle for each patient was the first one being reported for the study period, providing a conservative estimate overall and thus being consistent with the conservative result of the study by Malizia et al. [3]. Pinborg et al. [5] reported results from a longitudinal prospective cohort study linking the self-administered questionnaires of 1338 infertile couples with data from the National Medical Birth Register in Denmark. In their study, the cumulative rate of first live delivery following cycles of IUI, IVF, intracytoplasmic sperm injection (ICSI), frozen embryo transfer and spontaneous conceptions was 74.7% after 5 years of follow-up. However, as the authors recognize, a major weakness of the study design is positive selection bias that artificially overinflates the delivery rate, as women who delivered would be more likely to complete the questionnaire. Moreover, the authors included IUI cycles and naturally conceived pregnancies, thus further artificially inflating the overall CLBR.
Maternal age and cumulative live-birth rates with IVF When evaluating IVF outcomes, the effect of maternal age cannot be overlooked, as it affects response to infertility treatment and pregnancy outcomes. As expected, the CLBR differs significantly with advancing maternal age. Women younger than 35 years were shown by both Malizia et al. [3] and Stern et al. [4] to have conservative CLBRs more than 60%. In contrast, women older than 40 and 42 years using autologous oocytes were reported to have conservative CLBRs of 23 and 8.7%, respectively. Again overestimating rates due to study design, Pinborg et al. [5] reported a CLBR of 74.9% in women younger than 35 years, a rate that was significantly higher than that of their older cohorts. In a retrospective study of women 41–43 years of age with favorable treatment prognoses who underwent a maximum of three IVF cycles with autologous oocytes, Van Disseldorp et al. [6] reported conservative and optimistic CLBRs of 15.4 and 18.4%, respectively. Likewise, an observational study by Sundstro¨m and Saldeen [7] reported an overall 66% CLBR among 370 women who either completed a series of three fresh IVF cycles or delivered after the first or second IVF cycle. However, CLBRs were 37 vs. 17% in women younger than and older than or equal to 36 years, respectively. This evidence collectively supports the understanding that IVF can help overcome subfertility in younger patients, but the effect of age on fertility becomes progressively more refractory to treatment, especially in women older than 40 years of age [3].
Single vs. double embryo transfer One of the most significant complications resulting from ART treatment is multiple gestation and its associated morbidities, ranging from spontaneous abortion and preterm delivery to long-term neurologic sequelae. Because the number of embryos transferred during IVF is the highest predictor of this complication, it has been one of the modifiable factors targeted in order to minimize the risk of multiple births. A policy of elective single-embryo transfer (e-SET) has been instituted in many centers and numerous studies have evaluated its outcomes. A systematic review and meta-analysis of six randomized controlled trials comparing e-SET with double embryo transfer (DET) of cleavage stage embryos published by Gelbaya et al. [8] revealed CLBRs that ranged from 35.8 to 46.3% but showed no statistically significant difference between the two groups. Moreover, cumulative multiple birth rates (CMBRs) decreased significantly from 13.1– 41.2% in the DET group to 0–0.8% in the e-SET group.
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IVF cumulative live-birth rates Moragianni and Penzias 191
Similarly, a Cochrane meta-analysis [9] of five trials comparing e-SET and DET revealed no statistically significant difference in CLBR after two fresh e-SET cycles compared with one single fresh DET cycle [odds ratio (OR) 1.23, 95% confidence interval (CI) 0.56–2.69, P ¼ 0.60]. Veleva et al. [10] compared 2386 fresh cycles followed by 1272 frozen IVF cycles during an e-SET-predominant compared with a DET-predominant period in a large fertility practice. They found similar CLBRs in the two periods (48.7 vs. 45.0%, P ¼ 0.2) but significantly lower CMBRs in the e-SET period (8.9 vs. 19.6%, P < 0.0001). Furthermore, the final results of a multicenter trial of 661 patients randomized to e-SET or DET published by Thurin-Kjellberg et al. [11] once again failed to demonstrate a statistically significant difference between the CLBRs of the two groups (43.9 vs. 51.1%, P ¼ 0.08).
Natural cycle IVF Another technique that also aims at reducing the rate of multiple births from IVF while providing a patientfriendly approach and exceedingly low risk of ovarian hyperstimulation is the modified natural cycle IVF (MNC-IVF), which utilizes the one follicle that spontaneously develops during a natural cycle. To evaluate the outcomes of MNC-IVF, Pelinck et al. [12] studied a cohort of 109 patients who underwent up to nine cycles of MNC-IVF followed by controlled ovarian hyperstimulation IVF (COH-IVF) and reported CLBRs of 50% following the combination and 42.2% in COH-IVF patients alone. Of note, these patients were 18–35 years old, had no requirement for ICSI and the primary outcome measure of the study was ongoing pregnancy at 12 weeks gestational age.
Preimplantation genetic testing Preimplantation genetic testing (PGT) includes PGD and screening (PGS) and has been utilized since 1990 in an attempt to minimize the transfer of embryos affected by a known genetic aberration (in the case of PGD) or at risk for aneuploidy (in the case of PGS). Special considerations that apply to patients undergoing PGT include the potential compromise of embryos subjected to additional manipulation and biopsy, weighed against the fact that otherwise fertile couples undertake such treatment for purely genetic reasons. An assessment of CLBR in IVF cycles with PGT is, therefore, of paramount importance in the understanding of the strengths and limitations of this technology. Verpoest et al. [13] performed a prospective cohort study of 2753 fresh cycles of ICSI with PGD. The authors
report an observed CLBR of 29% compared with an expected CLBR of 62%, after a maximum of six cycles. Of note, the number of genetically unaffected embryos available for transfer, type of chromosomal abnormality being tested, fertility status of the couple, parity and mode of pituitary suppression did not influence the CLBR. However, maternal age (especially over 40 years) and number of oocytes retrieved contributed significantly and independently to the decreased rate.
Conclusion Most subfertile couples undergoing IVF treatment require a number of cycles to reach the desired outcome of a live infant delivery. The majority of studies report outcomes from IVF in terms of rates per cycle according to maternal age or cause of subfertility. Owing to its limited usefulness in this format, IVF data are alternatively being expressed as cumulative rate per woman. This review has summarized the most recent studies reporting CLBR following IVF and found the preponderance of rates to be between 45 and 75% depending on the source, with the majority of reported rates being around 50%. As predicted, advancing maternal age and PGD are both factors that decrease the success of IVF and hence CLBR. In contrast, e-SET and MNC-IVF do not affect CLBR but significantly decrease the rates of CMBR.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 255–256). 1
Nyboe Andersen A, Goossens V, Bhattacharya S, et al. Assisted reproductive technology and intrauterine inseminations in Europe, 2005: results generated from European registers by ESHRE: ESHRE. The European IVF Monitoring Programme (EIM), for the European Society of Human Reproduction and Embryology (ESHRE). Hum Reprod 2009; 24:1267–1287.
2
Gunby J, Bissonnette F, Librach C, Cowan L. Assisted reproductive technologies (ART) in Canada: 2006 results from the Canadian ART Register. Fertil Steril 2009. [Epub ahead of print]
3 Malizia B, Hacker MR, Penzias AS. Cumulative live-birth rates after in vitro fertilization. N Engl J Med 2009; 360:236–243. This is one of the largest studies to date reporting the cumulative live birth rates of IVF cycles. Stern JE, Brown MB Luke B, et al.; a SART Writing Group. Calculating cumulative live-birth rates from linked cycles of assisted reproductive technology (ART): data from the Massachusetts SART CORS. Fertil Steril. 2009. [Epub ahead of print] This study links ART cycles and evaluates the outcomes of a large database.
4
5
Pinborg A, Hougaard CO, Nyboe Andersen A, et al. Prospective longitudinal cohort study on cumulative 5-year delivery and adoption rates among 1338 couples initiating infertility treatment. Hum Reprod 2009; 24:991–999.
6
Van Disseldorp J, Eijkemans MJ, Klinkert ER, et al. Cumulative live birth rates following IVF in 41- to 43-year-old women presenting with favourable ovarian reserve characteristics. Reprod Biomed Online 2007; 14:455– 463.
7
Sundstro¨m P, Saldeen P. Cumulative delivery rate in an in vitro fertilization program with a single embryo transfer policy. Acta Obstet Gynecol Scand 2009; 88:700–706.
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192 Fertility 8
Gelbaya TA, Tsoumpou I, Nardo LG. The likelihood of live birth and multiple birth after single versus double embryo transfer at the cleavage stage: a systematic review and meta-analysis. Fertil Steril 2009. [Epub ahead of print]
Pandian Z, Bhattacharya S, Ozturk O, et al. Number of embryos for transfer following in-vitro fertilization or intra-cytoplasmic sperm injection. Cochrane Database Syst Rev 2009:CD003416. This review summarizes all studies to date evaluating the effect of e-SET on IVF outcomes.
9
10 Veleva Z, Karinen P, Toma´s C, et al. Elective single embryo transfer with cryopreservation improves the outcome and diminishes the costs of IVF/ICSI. Hum Reprod 2009; 24:1632–1639.
11 Thurin-Kjellberg A, Olivius C, Bergh C. Cumulative live-birth rates in a trial of single-embryo or double-embryo transfer. N Engl J Med 2009; 361:1812– 1813. This study substantiates existing evidence that e-SET not only significantly decreases CLBR but also significantly reduces the rate of multiple gestations. 12 Pelinck MJ, Knol HM, Vogel NE, et al. Cumulative pregnancy rates after sequential treatment with modified natural cycle IVF followed by IVF with controlled ovarian stimulation. Hum Reprod 2008; 23:1808–1814. 13 Verpoest W, Haentjens P, De Rycke M, et al. Cumulative reproductive outcome after preimplantation genetic diagnosis: a report on 1498 couples. Hum Reprod 2009; 24:2951–2959.
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The role of anti-Mu¨llerian hormone assessment in assisted reproductive technology outcome Simone L. Broera, BenWillem Molb, Madeleine Do´llemana, Bart C. Fausera and Frank J.M. Broekmansa a
Department of Reproductive Medicine, Division of Obstetrics, Neonatology and Gynecology, University Medical Center Utrecht, Utrecht and bDepartment of Obstetrics and Gynecology, Academic Medical Center, Amsterdam, The Netherlands Correspondence to Simone L. Broer, MD, University Medical Center Utrecht, Room F05.126, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands E-mail:
[email protected] Current Opinion in Obstetrics and Gynecology 2010, 22:193–201
Purpose of review The purpose of this study is to summarize the role of anti-Mu¨llerian hormone (AMH) in assisted reproductive technology (ART) treatment. Recent findings AMH is a good marker in the prediction of ovarian response to controlled ovarian hyperstimulation. In clinical practice, this means that AMH may be used for identifying poor or excessive responders. So far, studies show that AMH is not a good predictor for the occurrence of pregnancy after ART treatment. Therefore, routine screening for a poor ovarian reserve status using AMH is not to be advocated. Still, ovarian response prediction using AMH may open ways for patient-tailored stimulation protocols in order to reduce cancellations for excessive response, possibly improve pregnancy prospects and reduce costs. Summary AMH is able to predict extremes in ovarian response to controlled ovarian hyperstimulation but cannot predict pregnancy after ART treatment. Its future clinical role may be in the individualization of ART stimulation protocols. Keywords anti-Mu¨llerian hormone, assisted reproductive technology, intracytoplasmic sperm injection, in-vitro fertilization, ovarian response Curr Opin Obstet Gynecol 22:193–201 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1040-872X
Introduction Anti-Mu¨llerian hormone (AMH) has been identified as a dimeric glycoprotein and a member of the transforming growth factor beta (TGFb) family of growth and differentiation factors [1]. The human gene encoding for AMH is located on chromosome 19p13.3. Until recently, AMH was predominantly known for its role in male sexual differentiation [2,3]. AMH is produced by Sertoli cells at the time of testicular differentiation and induces regression of the Mu¨llerian ducts. In the ovaries of female fetuses, AMH can first be detected at 32 weeks of gestation [4]. The absent production of AMH from primitive granulosa cells in the early stages of female fetal development will allow the Mu¨llerian ducts to develop into the uterus, fallopian tubes and the upper part of the vagina [5,6]. In recent years, a role for AMH in postnatal ovarian function has become evident from animal studies [7]. The release of AMH from ovarian granulosa cells leads to measurable serum levels, which are proportional to the number of developing follicles in the ovaries. Therefore, AMH is considered to be a marker for the process of ovarian aging, as the number of developing follicles 1040-872X ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
decreases with age in humans [8]. The degree of ovarian aging at a given time point, referred to as an ovarian reserve, is important for the prospects in assisted reproductive technology (ART) therapy. This review focuses on the role of AMH in the prediction of outcome in ART treatment in the infertile couple.
Physiology of anti-Mu¨llerian hormone First, we would like to start with a description of AMH in ovarian folliculogenesis and an explanation of the pattern and source of AMH. The role of anti-Mu¨llerian hormone in ovarian folliculogenesis
Follicle development in the ovaries comprises initial recruitment, by which primordial follicles start to mature, and cyclic recruitment, which leads to the growth of a cohort of small antral follicles, from which the dominant follicle destined to ovulate is subsequently selected [9]. Follicle-stimulating hormone (FSH) directs the cyclic recruitment and forms the basis of the menstrual cycle. In primordial follicles, AMH expression is absent. After follicles have started to mature, AMH expression in granulosa cells of primary follicles becomes apparent. DOI:10.1097/GCO.0b013e3283384911
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194 Fertility Figure 1 Intraovarian function of anti-Mu¨llerian hormone
Intraovarian function of AMH Cycle recruitment
Initial recruitment AMH
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First, AMH has an inhibitory role in the initial recruitment and thereby aids in regulating the number of follicles remaining in the primordial pool. Second, AMH has an inhibitory effect on follicular sensitivity to FSH and could therefore play a role in the process of dominant follicle selection. AMH, antiMu¨llerian hormone; FSH, follicle-stimulating hormone.
This expression is maximal in granulosa cells of preantral and small antral follicles (up to 6 mm in diameter). Several in-vitro and in-vivo studies [10–12], using AMH knockout mice, have shown that at the larger antral follicle stages (7 mm), when follicular growth has become FSH-dependent, AMH expression diminishes and becomes undetectable. AMH is not expressed in atretic follicles or theca cells [5,13,14]. This pattern of AMH expression, from early primary follicles until the antral stages of FSH-dependent growth, supports the findings that AMH has an inhibitory role at two distinct stages of folliculogenesis. First, animal studies have indicated that AMH inhibits the transition of follicles from primordial into maturation stages, and thereby has an important role in regulating the number of follicles remaining in the primordial pool. Second, it seems that AMH has an inhibitory effect on follicular sensitivity to FSH and could therefore play a role in the process of follicular selection [7] (Fig. 1). Pattern and source of serum anti-Mu¨llerian hormone levels
Serum AMH levels are detectable at birth in the female [15,16]. In prepubertal girls, AMH values are still low, with a tendency to rise toward the onset of puberty. In adult women, serum AMH levels will decline gradually with age and become undetectable a few years before
menopause has become established [17–19]. Longitudinal studies [20,21] have demonstrated that AMH is a good predictor of the timing of menopause. Moreover, serum AMH levels have been identified as independent of the phase of the menstrual cycle [22–24], although very mild fluctuations do occur [25], especially in women with relatively high levels of AMH [26]. Even under other endocrine influences such as hormonal contraception [27,28], gonadotrophin releasing hormone agonists [29] and pregnancy [30], AMH levels have shown to be remarkably stable. The independence of menstrual cycle stage and other influences, the proportional relationship with the primordial and antral follicle cohort [31,32], and the clear relationship with reproductive age make AMH a good candidate for assessment of ovarian reserve status in the female. The source of AMH that enters the blood circulation is believed to be the cohort of ultrasonically visible antral follicles, up till the phase at which AMH expression becomes absent, that is, in follicles over 7 mm in diameter. This hypothesis has been confirmed in ovarian hyperstimulation studies, in which the majority of FSHsensitive follicles, present at a certain moment, are stimulated into dominant follicle growth. In parallel to the development of these dominant follicles, a prominent decrease in AMH levels is seen, proportional to the decrease in small antral follicles [31]. However, levels
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Role of AMH assessment in ART outcome Broer et al.
Figure 2 The source of anti-Mu¨llerian hormone that enters the blood circulation
Serum AMH is produced from the cohort of ultrasonically visible antral follicles up to 7 mm. Moreover, follicles below the sensitivity limits of ultrasonography may also contribute to serum levels. This is based on the observation that serum AMH levels do not fall to zero when FSHsensitive antral follicles (2–5 mm) are stimulated into larger, dominant follicles during ovarian hyperstimulation for IVF and interrupt their AMH production. The black line and dots represent the stages of antral follicles that contribute to serum AMH. The grey line represents the ultrasonically visible antral follicles. AMH, anti-Mu¨llerian hormone.
do not fall to zero, indicating that either at any stage of hyperstimulation, some antral follicles remain, or antral follicles with a diameter below the sensitivity limits of the ultrasound may also contribute to serum levels of AMH (Fig. 2).
Anti-Mu¨llerian hormone in the prediction of assisted reproductive technology outcome It has been long known that with increasing chronologic age, female fecundity – the ability to produce offspring – decreases. This has been clearly demonstrated by the age dependency of success rates in ART [33–35]. Agerelated female infertility [36,37] is mainly based on changes in ovarian reserve, defined as the number and quality of the remaining follicles and oocytes in the ovaries at a given age. Decline in follicle numbers determines the occurrence of irregular cycles and menopause, whereas quality decay of the oocytes results in decreasing fecundity [38]. Much like the substantial individual variation in the onset of menopause (mean age 51 years, range 40–60 years) [39,40], the rate of decline in fertility may vary considerably between women of the same age. For ovarian reserve testing prior to ART, female age remains the predictor of first choice. However, in view of the variation in the ovarian aging process, a test capable of providing reliable information regarding a woman’s individual ovarian reserve within a certain age category would enable the clinician to provide an individually tailored treatment plan. For
195
instance, in older women, the finding of a normal ovarian reserve may justify the decision to allow ART treatment, whereas in young women with exhausted reserve either early application, refusal of ART or choosing for egg donation could be the consequence. Ovarian reserve can be considered normal when stimulation for ART by exogenous gonadotropins results in the retrieval of some 6–14 healthy oocytes at follicle puncture [41–43]. With such a yield, the chances of producing a live birth through IVF are considered optimal [44], whereas in the case of producing less than six oocytes, prospects become increasingly poor. The preferred outcome in studies on the value of ovarian reserve testing would be live birth after a series of ART cycles as an expression of a couple’s fertility potential. However, other outcome measures [especially oocyte yield or follicle number and pregnancy after one IVF/intracytoplasmic sperm injection (ICSI) cycle] are in fact the most common. Also, ovarian reserve tests mainly relate to the size of the follicle cohort that is at any time responsive to FSH. This focus on quantity prohibits high expectations on the relation to oocyte quality and pregnancy as outcome. Ovarian reserve test evaluation should imply the assessment of predictive accuracy and clinical value of the test. Predictive accuracy refers to the degree by which the outcome condition (pregnancy or poor/excessive response) is predicted correctly and is expressed by the sensitivity and specificity [45,46]. Using the sensitivity and specificity for a range of cut-off levels, a receiver operating characteristic (ROC) curve can be drawn. The area under this curve (AUC) represents the overall predictive accuracy of the test. Values of 1.0 imply perfect and 0.5 completely absent discrimination. Assessment of the clinical value of the test is a complex process through which the applicability in daily practice should become clear. The overall accuracy represented by the ROC curve, the rate of abnormal tests at the cutoff used, the valuation of false-positive and false-negative test results, the consequence for patient management of an abnormal test, and finally the cost and patient burden of carrying out the test all need to be incorporated in the decision process [47]. Anti-Mu¨llerian hormone and the prediction of poor ovarian response
A certain proportion of women (2–30%) undergoing ovarian hyperstimulation will experience a poor response [44,48–50]. In updates of the initial systematic review by Broekmans et al. [51], the accuracy and clinical value of AMH as a prognostic factor for the occurrence of a poor response after IVF/ICSI treatment have been analyzed and compared with the antral follicle count (AFC) [52,53–70]. The ROC curves have revealed that
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196 Fertility Figure 3 The predictive accuracy of anti-Mu¨llerian hormone for the occurrence of poor response and nonpregnancy after ovarian hyperstimulation for IVF in comparison to the antral follicle count
(a) Sensitivity
Accuracy poor response prediction
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Accuracy non pregnancy prediction 1
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The individual combinations of sensitivity/specificity as extracted from the individual studies, as well as the summary ROC curves are shown. (a) The ROC curves for both AMH and the AFC run toward the upper left, indicating a good capacity to discriminate between normal and poor responders at certain cut-off levels. (b) The ROC curves for both tests run almost parallel to or even cross the X ¼ Y line, indicating that the test will not perform better than flipping a coin in predicting who will become pregnant. The test is, then, considered useless for nonpregnancy prediction. AFC, antral follicle count; AMH, anti-Mu¨llerian hormone; ROC, receiver-operating characteristic.
AMH has an adequate capability to predict a poor responder to ovarian hyperstimulation, with an area under the ROC curve (ROC-AUC) of approximately 0.90. The predictive accuracy for the AFC appeared not clearly different (ROC-AUC 0.89) (Fig. 3a). Since the emergence of these meta-analyses, several additional studies have been published on the role of AMH in the prediction of a poor response [71,72,73–75], with results that are in line with the initial meta-analyses [52,53]. The findings in these studies have been depicted in Table 1 ([54,56–71,72,73–75,76,77]). Both the methodology and patient selection, as well as the reported sensitivity and specificity combinations (range 0.40–0.97 and 0.41–1.00, respectively) completely fit within the findings of the earlier reports. Therefore, in Fig. 3(a), the summary ROC curve for the prediction of a poor response represents the full range of published studies to date. It can be stated that, from the published literature, AMH presents itself as a reliable predictor of poor response to ovarian stimulation for IVF/ICSI. Although direct comparisons have been carried out only in a limited number of studies, AMH has demonstrated to be a better marker in the prediction of poor response than basal FSH, but equally well compared to the AFC. Anti-Mu¨llerian hormone and the prediction of excessive ovarian response
An excessive ovarian response to hyperstimulation may lead to a potentially life-threatening condition, the ovar-
ian hyperstimulation syndrome (OHSS). The risk of OHSS is highly linked to an exaggerated ovarian response to gonadotrophin stimulation. The syndrome may lead to severe illness requiring hospitalization and intensive care, with thromboembolism or multiple organ failure as potential life-threatening complications. Mild and moderate forms of OHSS may occur in 15–20% of all ovarian stimulation cycles, whereas the severe form of the syndrome has been reported as frequent as 1–3% [78]. Specific risk factors for OHSS include young age, low BMI, signs of polycystic ovarian syndrome and previous history of OHSS [79,80]. The main factor for preventing OHSS is the recognition of risk factors for OHSS leading to an individualized FSH stimulation protocol. Excessive response prediction by the use of ovarian reserve tests may also be a promising tool for treatment tailoring. The association between excessive response and higher serum levels of AMH [54,58,62,63,81] has prompted systematic research on the predictive value of AMH for the occurrence of an excessive response [67,74,76,77]. The results of the five studies identified from the literature search are shown in Table 1. The reported sensitivities varied between 0.57 and 0.93, and the specificities between 0.62 and 0.96, at varying cut-offs for an abnormal test. The accuracy values expressed by the ROC-AUC’s have shown to be very promising. Moreover, from a number of studies [72,76,77], it has been demonstrated that AMH was a better predictor of an excessive response than other patient factors such as female age, BMI, basal FSH or inhibin B. Still, much like for poor ovarian
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Role of AMH assessment in ART outcome Broer et al.
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Table 1 Sensitivity and specificity values of the studies in the prediction of ovarian response and pregnancy References Poor response prediction Muttukrishna et al. [56] van Rooij et al. [54] van Rooij et al. [54] van Rooij et al. [54] Penarrubia et al. [57] Ebner et al. [63] Tremellen et al. [58] Ficicioglu et al. [61] La Marca et al. [62] La Marca et al. [62] McIlveen et al. [60] Kwee et al. [66] Kwee et al. [66] Kwee et al. [66] Kwee et al. [66] Kwee et al. [66] Freour et al. [65] Smeenk et al. [64] Nakhuda et al. [68] Nelson et al. [67] Nelson et al. [67] New studies Barad et al. [75] Jayaprakasan et al. [73] Jayaprakasan et al. [73] Jayaprakasan et al. [73] Jayaprakasan et al. [73] Jayaprakasan et al. [73] Riggs et al. [72] Nardo et al. [74] Gnoth et al. [71] Excessive response prediction Lee et al. [76] Lee et al. [76] Nelson et al. [67] Nelson et al. [67] Riggs et al. [72] Nardo et al. [74] Aflatoonian et al. [77] Nonpregnancy prediction van Rooij et al. [54] van Rooij et al. [54] van Rooij et al. [54] Penarrubia et al. [57] Ebner et al. [63] Eldar-Geva et al. [59] Smeenk et al. [64] Kwee et al. [66] Lekamge et al. [69] Elgindy et al. [70] New studies Gnoth et al. [71] Barad et al. [75]
Cutoff AMH (ng/ml)
Cycles (n)
Sensitivity
Specificity
PPV
NPV
LRþ
0.10 0.10 0.20 0.30 0.69 1.66 1.13 0.25a 0.50 0.75 1.25 0.80 1.00 1.20 1.40 1.60 1.30 1.40 0.35 0.14 0.70
69 119 119 119 80 141 75 44 48 48 84 104 104 104 104 104 69 80 66 340 340
0.76 0.49 0.54 0.60 0.40 0.69 0.80 0.91 0.83 0.83 0.58 0.54 0.64 0.68 0.75 0.79 0.44 0.62 0.91 0.38 0.70
0.88 0.94 0.90 0.89 0.92 0.86 0.85 0.91 0.83 0.92 0.75 0.93 0.93 0.88 0.86 0.78 1.00 0.73 0.82 0.99 0.91
0.68 0.77 0.70 0.70 0.62 0.63 0.67 0.77 0.63 0.77 0.76 0.75 0.78 0.68 0.66 0.56 1.00 0.31 0.71 0.87 0.58
0.92 0.81 0.83 0.84 0.82 0.89 0.92 0.97 0.94 0.94 0.57 0.85 0.88 0.88 0.90 0.91 0.92 0.91 0.95 0.90 0.94
6.63 8.16 5.70 5.60 4.80 4.86 5.50 10.00 5.00 10.00 2.33 8.14 9.77 5.73 5.18 3.51 – 2.29 5.00 36.10 7.42
0.50 0.59 0.70 0.80 0.90 0.99 0.83 1.00 1.26
76 135 135 135 135 135 123 165 132
0.87 0.53 0.60 0.73 0.87 0.94 0.82 0.87 0.97
0.84 0.93 0.90 0.86 0.80 0.73 0.79 0.67 0.41
0.85 0.47 0.43 0.39 0.35 0.33 0.27 0.21 0.36
0.86 0.94 0.95 0.96 0.98 0.99 0.98 0.98 0.98
5.50 7.11 6.00 5.18 4.33 3.48 3.82 2.60 1.66
1.99 3.36 2.10 3.50 1.59 3.50 4.83
262 262 314 316 123 165 159
0.90 0.62 0.88 0.57 0.84 0.88 0.93
0.62 0.87 0.79 0.96 0.67 0.70 0.78
0.42 0.58 0.26 0.52 0.53 0.24 0.63
0.95 0.88 0.99 0.97 0.90 0.98 0.97
2.38 4.64 4.10 13.80 2.56 2.90 4.26
0.10 0.20 0.30 Not stated 1.66 2.52 1.40 1.40 1.96 2.70
106 106 106 80 132 56 80 110 126 29
0.22 0.27 0.28 0.62 0.19 0.67 0.38 0.31 0.50 0.82
0.89 0.85 0.81 0.56 0.69 0.69 0.73 0.79 0.71 0.83
0.85 0.84 0.81 0.73 0.39 0.71 0.58 0.84 0.78 0.88
0.28 0.28 0.28 0.43 0.45 0.64 0.54 0.24 0.42 0.77
1.94 1.79 1.50 1.40 0.63 2.17 1.36 1.51 1.75 4.94
1.80 1.00
119 76
0.83 0.75
0.34 0.62
0.58 0.84
0.63 0.48
1.25 1.96
AMH, anti-Mu¨llerian hormone; NPV, negative predictive value; PPV, positive predictive value. a Value in pg/ml.
response prediction, the AFC may produce the same level of predictive accuracy [77]. It can be concluded that the accuracy of AMH as a predictor of excessive response prior to initiating ovarian hyperstimulation may be clearly sufficient to open ways of preventing such event by adaptation of the stimulation protocol.
Anti-Mu¨llerian hormone and prediction of pregnancy
A number of authors have tried to identify cut-off levels for AMH that are able to distinguish between patients who do or do not become pregnant after ART. The results of these studies have been summarized in the updates of the initial meta-analysis on ovarian reserve testing [51]. It has become clear from these updates that for the prediction of the outcome pregnancy, AMH is
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198 Fertility
quite a poor performer, as demonstrated by the shape of the ROC curve in Fig. 3(b) [52,53]. The lack of sufficient overall predictive accuracy implies that the test will have only very limited value for daily clinical practice. Only when cut-off levels are chosen that lead to sensitivity– specificity combinations in the lower left corner of the ROC diagram, few nonpregnant cases can be identified, without wrongly accusing too many cases that do become pregnant. Cut-off levels will then be so extreme that only very low percentages of abnormal tests will be found, making the impact of applying the test only marginal. Several additional studies [75,82,83] have appeared on the prognostic value of AMH in the prediction of ongoing pregnancy, as summarized in Table 1. The results of the recently published studies are also very much in line with the previously mentioned meta-analyses. The reported sensitivity varied between 0.19 and 0.83, and the reported specificity between 0.34 and 0.89. The summary ROC curve of the studies depicted in Fig. 3(b), containing the sensitivity–specificity points of all published studies to date for the prediction of a nonpregnancy, therefore represents the current best estimate of predictive accuracy. Only one study [67] has been published relating AMH levels to live birth rate after IVF. In this prospective study in 340 patients, it was shown that the live birth rate dramatically increased with increasing AMH levels. Also, AMH appeared to be a better predictor of live birth (AUC ¼ 0.62) than either female age or FSH. However, after adding oocyte yield into a multivariable analysis, oocyte yield was the only variable that predicted live birth. These findings show that it is probably through the correlation with ovarian response that AMH is capable of predicting the occurrence of live birth. A possible new approach stems from the use of AMH follicle fluid levels and their relation to the probability of pregnancy. Fanchin et al. [84] have demonstrated that AMH measured in the follicular fluid is significantly associated with clinical pregnancy rates and embryo implantation rates, in contrast to other parameters such as patient age, the AFC and serum AMH. The study by Wunder et al. [82] has confirmed this finding by showing that AMH in follicular fluid was significantly increased in women who conceived as compared to those who did not. One of the complicating issues in pregnancy prediction is the fact that the vast majority of studies limit the observation of pregnancy occurring to one cycle per couple only. This may be not the proper way to relate a couple’s potential to become pregnant to a test result. A better way could be studying a series of cycles per couple. Hendriks et al. [85] have analyzed the predictive capacity of several ovarian reserve tests for the occurrence of ongoing pregnancy after three cycles. They have found that age
and AMH were the only significant predictors for ongoing pregnancy in three cycles. However, AMH failed to add any predictive power to the effect of knowing female age. This implies that female age is a very strong predictor of outcome pregnancy, and that the ovarian reserve tests relating to quantitative aspects will fail to provide additional information. Another way of getting information about chances of becoming pregnant is by predicting the quality of the oocytes and or the embryo. Several studies [63,64,84,86,87] have analyzed the relationship between serum AMH and characteristics of oocytes and/or embryo quality. Lie Fong et al. [87] demonstrated that there was no consistent correlation between serum AMH and embryo morphology and embryo aneuploidy rates, a finding that was confirmed by Smeenk et al. [64]. In contrast, Ebner et al. [63] and Silberstein et al. [86] did find a significant positive relationship between AMH levels and oocyte quality and embryo morphology. In view of such inconsistency, research on the relationship between AMH and surrogate measures of pregnancy seems not the way forward.
Anti-Mu¨llerian hormone and the clinical value in patient-tailored treatment The accuracy of AMH in the prediction of a nonpregnancy is poor. In clinical practice, this means that the rate of false positives would be too high, that is, too many patients would be falsely categorized in the nonpregnancy group. Therefore, AMH can only be used as a counseling regarding pregnancy chances, but it may not be the factor for the decision whether or not to treat a patient. More appropriate decisive factors would be the response in a first ART treatment or a combination of AMH with other prognostic factors, especially female age. If ovarian response was the endpoint of interest, then the clinical value of AMH as an ovarian reserve test could be considered highly satisfactory. Unfortunately though, no proven strategy to prevent the occurrence of poor response is currently known. Also, a poor response may not always imply a poor prognosis, especially in younger women [88]. The same may be true for ‘poor’ responders after the application of mild stimulation protocols [89]. In poor responders, in a first IVF cycle, it has become increasingly known that not any adaptation in the treatment protocol in a second cycle will improve the subsequent response or the prognosis for pregnancy if randomized trials are concerned [90,91]. This may indicate that in predicted poor responders, the expectations of adapted management may be marginal. Only few studies exist on the effect of adapting the dosage of FSH based on ovarian reserve tests in order
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Role of AMH assessment in ART outcome Broer et al.
to obtain an optimal number of oocytes and improved prospects for pregnancy. Klinkert et al. [50] have shown that predicted poor responders, based on an AFC of below 5, did not benefit from a higher starting dosage of gonadotrophins in the first IVF treatment cycle. Also, Lekamge et al. [92], in a pseudo-randomized design, have demonstrated that there is no proven clinical value of increasing the dosage of FSH in patients with predicted low ovarian reserve. In contrast, in a study by Popovic-Todorovic et al. [42], an individualized dose regimen in IVF cases with normal basal FSH levels did increase the proportion of appropriate ovarian responses during controlled ovarian hyperstimulation. Even a higher ongoing pregnancy rate in the individualized dose group was reported. These findings together implicate the need for larger studies providing the final answer to the question whether a predicted poor responder will or will not benefit from the use of higher dosages of FSH. Regarding excessive response prediction, a comprehensive review and meta-analysis of the published literature will allow for final conclusions on the clinical value of AMH. To date, excessive responders in a first cycle may benefit from dose adaptation in a subsequent cycle, but there exist no comparative trials on this issue. The effect of individualized dose regimens on prior predicted excessive responders has been demonstrated by the results of the CONsistency in r-FSH Starting dOses for individualized tReatmenT (CONSORT) study [93]. On the basis of an algorithm for individualizing the FSH dosage using FSH, BMI, age and the AFC, excessive responses could be clearly prevented, without an obvious reduction in pregnancy prospects. Although AMH is a most consistent predictor of ovarian response, it has hardly been studied in patient-tailoring the stimulation protocol. Only one observational study [94] has individualized FSH dosage on the basis of prior measured AMH. It has been shown that the use of AMH to individualize the stimulation protocol could result in a reduced risk of OHSS, decreased treatment burden and maintained pregnancy rates. Prospective randomized studies on the true effects of preventive management in AMH-predicted poor/excessive responders are highly needed to confirm these results.
Conclusion Serum AMH is released from the granulosa cells of the antral follicle cohort that is visible at ultrasound. It highly correlates with the follicle numbers and therefore constitutes an important marker for individual ovarian reserve assessment. The cycle stability and operator independency make AMH a most attractive single predictor of both poor and excessive ovarian response to
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controlled ovarian hyperstimulation in ART treatment. Similar to other ovarian reserve tests, such as the AFC and FSH, AMH is not a good predictor of pregnancy. Whether adapted treatment based on AMH testing will eventually lead to improved outcome, higher safety and improved cost efficiency of ART must be further established.
Acknowledgements Dr F.J. Broekmans is a member of the external advisory board for Ferring Pharmaceuticals, Hoofddorp, The Netherlands. He receives no monetary compensation. Professor B.C. Fauser has received fees and grant support from the following companies (in alphabetic order): Andromed, Ardana, Ferring, Genovum, Merck Serono, Organon, Pantharei Bioscience, PregLem, Schering, Schering Plough, Serono, and Wyeth.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 256). 1
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Ectopic pregnancy after assisted reproductive technology: what are the risk factors? Hye Jin Changa,b and Chang Suk Suhb,c a Health Promotion Center, bDepartment of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam, Gyeonggi and cDepartment of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, South Korea
Correspondence to Chang Suk Suh, MD, PhD, Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, 300 Gumi, Bundang, Seongnam, Gyeonggi 463-707, South Korea Tel: +82 31 787 7251; fax: +82 31 787 4054; e-mail:
[email protected] Current Opinion in Obstetrics and Gynecology 2010, 22:202–207
Purpose of review This review discusses recent publications that investigate risk factors associated with ectopic pregnancy after IVF. Recent findings Data on the risk factors for developing ectopic pregnancy after IVF are still inconsistent. Between fresh nondonor IVF and embryo transfer cycles, the significant risk factor for ectopic pregnancy was tubal factor infertility, and endometriosis, rather than male factor infertility. Higher ectopic pregnancy rate could be associated with zygote intrafallopian transfer, assisted hatching, large embryo transfer volume, deep fundal transfer, and frozen embryo transfer. The supraphysiologic progesterone level may decrease uterine contractility and enhance implantation in the uterine cavity in fresh embryo transfer compared with frozen embryo transfer cycles. Although recent results suggest reassurance in risk of ectopic pregnancy with frozen transfer, clinicians should be remembering this possibility while performing a frozen embryo transfer. Higher implantation potential per embryo at the blastocyst stage may increase the risk of ectopic pregnancy than cleavage stage. Especially, according to numbers of embryos transferred, different risk of ectopic pregnancy after IVF was noted. Summary Different hormonal milieu, the reproductive health characteristics of infertile women such as distorted tubal function, technical issues of IVF procedures, and the estimated embryo implantation potential are possible risk factors. How each factor contributes to the risk of occurring ectopic pregnancy after assisted reproductive technology is uncertain and needs further investigation. Keywords assisted reproductive technology, ectopic pregnancy, IVF and embryo transfer, risk factor Curr Opin Obstet Gynecol 22:202–207 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1040-872X
Introduction Ectopic pregnancy is a well known risk of IVF. The rate of ectopic pregnancy is higher in pregnancies resulting from assisted reproduction technologies (ARTs) than in spontaneous pregnancies. Society of Assisted Reproductive Technology (SART) guidelines for outcomes reporting documented that ectopic pregnancy was defined as the presence of an extrauterine gestation documented by ultrasound or salpingectomy, and heterotopic pregnancy was defined as ectopic pregnancy coexisting with a synchronous intrauterine pregnancy (IUP) [1]. Several possible theories for this finding have been proposed, including direct injection of embryos in transfer media to the fallopian tubes and migration of embryos via reflux expulsion from uterine contraction [2,3]. The majority of information on ectopic pregnancy after IVF stems from case reports or case series. There were a few studies with denominator data. However, the sample 1040-872X ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
size was considerably smaller and thus unable to evaluate sufficiently the risk of ectopic pregnancy by subgroup analysis. And when counting ectopic pregnancies, a heterotopic pregnancy was included in several studies and excluded in other studies. Because the incidence of heterotopic pregnancy has increased with the widespread use of ART and its frequency is as high as 1 : 500 to 1 : 100 [4,5], the heterotopic pregnancy included in ectopic pregnancy count may cause as certain bias. Therefore, it is difficult to understand specific factors in ART that may affect the rate of ectopic pregnancy. This review discusses recent publications that investigate the epidemiology and risk factors of ectopic pregnancy after IVF.
Epidemiology The incidence of ectopic pregnancy after IVF generally ranges from 2.1 to 8.6% of all clinical pregnancies [6,7], DOI:10.1097/GCO.0b013e32833848fd
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Ectopic pregnancy after ART Chang and Suh 203
but in selected groups with tubal factor infertility, it is as high as 11% [8] compared with the estimated rate of 2.0 per 100 pregnancies for the general US population in 1990–1992 [9]. In 2007, SART [1] reported a decrease in the incidence of ectopic pregnancy to 1.6% of clinical pregnancies as compared with 2.0% in 2000. However, the incidence of ectopic pregnancy per transfer was similar: 0.8 vs. 0.7%, respectively. It compares favorably with the estimated overall incidence of ectopic pregnancy in the USA of 2% per reported pregnancy. This finding was attributable to the decrease in the proportion of couples with tubal factor infertility undergoing IVF procedure and a concomitant increase in couples with male factor infertility. The dominant adverse effect of female factor on outcomes was corroborated, whereas male factor infertility now appears to have a limited effect on outcomes because of the availability of intracytoplasmic sperm injection.
Risk factors Risk factors for ectopic pregnancy after natural conception, including previous ectopic pregnancy, pelvic inflammatory disease (PID), tubal disease or surgery, and smoking, have been well described [3]. However, data on the risk factors for developing ectopic pregnancy after IVF are still inconsistent. Theoretically, differences between natural conception and conception via ART may affect the risk of ectopic pregnancy. The four point views are important in assessing the risk of ectopic pregnancy after IVF: different hormonal milieu, the reproductive health characteristics of infertile women, technical aspects of IVF procedures, and the estimated embryo implantation potential. Different hormonal milieu
One of the differences between natural conception and IVF and embryo transfer (IVF-ET) cycles might be hormonal milieu at the time of embryo transfer. Higher hormone levels may affect tubal peristalsis and egg or zygote transport. Some insisted progesterone contributes to uterine quiescence [10]. Increased uterine contractility may allow decreased implantation within the uterine cavity and favor migration of the embryos into the fallopian tubes. In IVF-ET cycles supraphysiologic progesterone concentrations are produced by multiple corpus lutea and supplemented by luteal support. Thus, the progesterone level of IVF-ET cycle could exceed the level of normal conception and may result in more uterine relaxation in IVF-ET, whereas there is another effect of the high estradiol levels in IVF cycles on tubal peristalsis through the control of tubal smooth muscle contractility and ciliary activity [11]. However, Pyrgiotis et al. [12] did not demonstrate a difference in estradiol levels on the day of human chorionic gonadotropin administration between IVF-ET patients with and without ectopic
pregnancy. The possible relation between risk of ectopic pregnancy and estrogen–progesterone level at the time of embryo transfer should be further investigated. Reproductive health characteristics of infertile women
Infertile women who undergone IVF-ET procedures have different health characteristics compared with general population, and it may result in increased risk of ectopic pregnancy. Distorted tubal anatomy could be a strong predisposing factor due to any reasons such as previous tubal surgery, PID, endometriosis, and peritubal adhesion. We could also be able to investigate the association between risk of ectopic pregnancy and women’s reproductive health status, according to the comparison nondonor IVF and donor IVF/gestational surrogate. Tubal factor infertility, previous pelvic inflammatory disease, and endometriosis
A number of different tubal damages have been associated with varying results of IVF-ET. Hydrosalpinx, PID, and bacterial infection, as well as smoking habits are known to be negative factors to normal pregnancy [3]. As with naturally occurring pregnancy, tubal factor infertility has been identified as the most prominent risk factor for ectopic pregnancy after IVF. And a previous ectopic pregnancy and tubal surgery also affect the fertility of women. Several studies [2,7,12] have extensively suggested that the presence of damaged tubes does confer a higher risk for ectopic pregnancy in IVF. Clayton et al. [7] have recently analyzed the risk of ectopic pregnancy among 94 118 patients who conceived with ART procedures in US clinics between 1999 and 2001. Out of 94 118, 2009 (2.1%) were ectopic pregnancies. They found that women with tubal factor infertility had a two-fold increase in risk [odds ratio (OR) 2.0, 95% confidence interval (CI) 1.7–2.4; reference group is ART for male factor], and women with female factor infertility except tubal factors or with endometriosis had a 30–40% increased risk of ectopic pregnancy. And risk for ectopic pregnancy was significantly decreased among women with a previous live birth. The tubal damage was also reported among women with ectopic pregnancies who had used IVF because of endometriosis or unexplained infertility [8]. The increased risk of ectopic pregnancy in women with endometriosis or unexplained infertility might be related to tubal damage, that is, tubal disorder in those was less likely to be diagnosed. Keegan et al. [13] reported lower ectopic pregnancy rates (0.9%; 24/2688 pregnancies) compared with the national rate consistently reported by SART/American Society for Reproductive Medicine for USA clinics (2.1–2.2%). They insisted that their aggressive practice of documented tubal disease with salpingectomy might help prevent ectopic pregnancy after IVF. Although it is still unclear whether surgical management of tubal disease prevents chances of
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204 Fertility
ectopic pregnancy with IVF, a randomized controlled trial of salpingectomy in women with clinically diagnosed tubal disorder could be considered to find advantage of their practice. To evaluate the prognosis for the patient who becomes pregnant after infertility treatment, Tomazevic and Ribic-Pucelj [14] analyzed the occurrence of ectopic pregnancy following 474 reconstructive microsurgical operations and 2119 stimulated IVF-ET for tubal infertility. The results presented that the ratio of patients who had repeated ectopic pregnancies to the number of operations was 12%, and to all pregnancies after surgery was 28%. In IVF-ET cycles for tubal infertility, ectopic pregnancy represented 2.8% of all pregnancies and 3% of all transfers. Although the risk for ectopic pregnancy after IVF-ET is much lower than the risk after tubal surgery, it is still rather high compared with the risk in the normal population. In the patients with severe tubal lesions, IVFET is preferable to tubal surgery considering ectopic pregnancy when deciding upon treatment. And, the results indirectly imply that a direct tubal damage by surgery is important role for occurring ectopic pregnancy rather than IVF-ET procedure itself. In respect to tubal surgery, another retrospective study [15] of 640 IVF-ET cycles in the tubal factor group showed that 359 cycles were performed in patients who had prior tubal reconstructive surgery; tubal pregnancies comprised 15.6% of the clinical pregnancies. In the remainder of the tubal factor group with no prior tubal surgery, 281 embryo transfer cycles yielded a tubal pregnancy rate of only 5.5% (P < 0.05). Women with prior reconstructive surgery for distal tubal disease are at highest risk of developing tubal pregnancy after IVF. It is possible that proximal occlusion or salpingectomy after failed distal tubal surgery may be a predisposing factor to tubal pregnancy after IVF-ET. Overall, in consideration of recent publications, distorted tubal anatomy could be a strong predisposing factor from any reasons such as previous tubal surgery, PID, endometriosis, and peritubal adhesion. The likelihood that women with tubal factor infertility have a greater risk than women with other factors has suggested an important role of tubal anatomy. Previous ectopic pregnancy history
Numerous investigators thought ‘tubal factors’ as a common reason for sterility and as an affecting factor on the rate of ectopic pregnancy [2,12,14]. Weigert et al. [16] investigated the influence of the condition of the fallopian tubes in women who experienced a tubal ectopic pregnancy in a previous pregnancy, on the incidence of a repeated tubal pregnancy in an IVF-ET cycle. Women with a prior tubal ectopic pregnancy significantly increased the risk per pregnancy for a further ectopic
pregnancy even in IVF-ET (8.95 vs. 0.75%, P < 0.001), especially if they are smoking. However, the number of tubal ectopic pregnancy events was too low, further analysis of effects of different subgroups on the risk for a tubal ectopic pregnancy could not be performed. Donor IVF vs. nondonor IVF
In comparison with the ectopic rate (2.2%) among pregnancies conceived with fresh, nondonor IVF-ET, the ectopic rate was significantly decreased when donor oocytes were used (1.4%) or when a gestational surrogate carried the pregnancy (0.9%) [7]. It means that embryo implantation potential is associated with risk because oocyte donors are young women without an infertility factor. Previous studies suggested that chromosomal abnormalities might play a role in the cause of ectopic pregnancy. The results were inconsistent, and limited by small sample size [17–19]. The characteristics of embryos in infertile women required further study to find whether they are related or not to the risk of ectopic pregnancy. In addition, the incidence of tubal disease in the donor egg population is thought to be significantly lower than in the fresh nondonor IVF population because the diminished ovarian reserve is the main cause of infertility in donor egg recipients [20]. Therefore, donor IVF might benefit from lower ectopic pregnancy rates compared with the fresh nondonor IVF. And low ectopic pregnancy rate of gestational surrogate represents that an anatomical factor of uterus and tube is also important in causing ectopic pregnancy after IVF. Technical aspects of IVF procedures
A technical problem of IVF procedures also may increase risk of ectopic pregnancy after IVF. Higher ectopic pregnancy rate might be associated with zygote intrafallopian transfer (ZIFT), assisted hatching, higher embryo transfer volume, deep fundal transfer, and frozen embryo transfer. Zygote intrafallopian transfer
Clayton et al. [7] have observed a significant increase in the risk of ectopic pregnancy after ZIFT (3.6%) compared with fresh nondonor IVF-ET cycles (2.2%) (OR 1.65, 95% CI 1.13–2.40). It is somewhat intuitive because embryos are transferred into the fallopian tubes in ZIFT. However, this effect was not observed in gamete intrafallopian transfer (GIFT) procedures, there was no increase in ectopic pregnancy risk (2.4%). The investigation whether ZIFT or GIFT has an effect on ectopic pregnancy risk is limited by small sample size. Small sample size excluded analysis of specific treatment risk factors among ZIFT pregnancies. The power may not be sufficient to detect such small statistical difference.
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Ectopic pregnancy after ART Chang and Suh 205
Assisted hatching
In a retrospective analysis of 623 clinical pregnancies conceived after IVF, a 5.4% ectopic pregnancy rate (14/258 clinical pregnancies) was found in women in whom assisted hatching was performed compared with 2.2% (8/365) in the group without assisted hatching [21]. Embryos that have undergone assisted hatching have been reported to implant earlier compared with unhatched embryo [22,23]. A different finding was also reported that the assisted hatching did not increase the risk of ectopic pregnancy [7]. In a prospective randomized study [24] to evaluate the effect of assisted hatching on IVF outcome, there was no increase of ectopic pregnancy in the assisted hatching group compared with the unhatching embryo and blastocyst group. National data reported to SART and the Centers for Disease Control and Prevention or larger multicenter series should be analyzed in an attempt to elucidate the effect of assisted hatching on ectopic pregnancy. Embryo transfer volume
Knutzen et al. [25] performed a mock embryo transfer using 40 ml of radio-opaque dye; the dye was seen in the fallopian tube in 38% of all transfers. This suggests that with a transfer volume not much higher than what is commonly used by IVF programs, there is significant likelihood for the embryos to reach the fallopian tubes. Higher transfer volume had been associated with higher ectopic pregnancy risk [4]. Although in which type of fluid or media the embryo should be transferred has also been a matter of debate, in usual practice, the volume of media transferred is 15–20 ml. Deep fundal transfer
A randomized prospective study [6] was performed to compare the effects of a midfundal vs. a deep fundal transfer technique on subsequent intrauterine and ectopic pregnancy rates after IVF. This study [6] showed that the clinical pregnancy rate after the deep fundal transfer was 12.4% of IUPs per cycle with a 1.5% ectopic pregnancy rate (12.2%/clinical pregnancy), vs. 14.2% IUPs per cycle with a 0.4% ectopic pregnancy rate (3%/clinical pregnancy), after midfundal transfer. As a result of this study, deep fundal embryo transfer could be associated with an increased risk of ectopic pregnancy. Frozen embryo transfer vs. fresh embryo transfer
There may be a concern for a higher ectopic pregnancy rate in cryopreserved embryo transfers compared with fresh transfers as suggested by some reports in the literature [12,26,27]. There are several possible theories that explain these findings. Progesterone appears to play a role in reducing uterine contractility during the luteal phase of the menstrual cycle. Decreased uterine contractility may allow enhanced implantation in the uterine cavity as opposed to migration of the embryo into the
fallopian tubes. In fresh IVF cycles, the supraphysiologic progesterone concentrations produced by multiple corpora lutea in addition to exogenous progesterone supplementation far exceed the level of progesterone in frozen transfers and may result in better uterine relaxation in fresh transfer [10,28]. And, the developmental delay of thawed embryos may lead to a longer lag time before implantation in the uterus, increasing the opportunity for migration to the extrauterine space [27]. In addition, uterine dimensions could be different according to the ovarian stimulation. High estrogen level may lead to increase the uterine dimension larger than nonstimulated frozen cycle. There could be a tendency to transfer embryos to the same depth from external os during fresh and frozen embryo transfers, resulting in the injection of embryos closer to the fallopian tubes. However, Jun and Milki [29] recently reported that the rate of ectopic pregnancy is not significantly increased after the transfer of frozen thawed blastocysts compared with fresh blastocyst transfer (2.8 vs. 1.8%). We also performed a meta-analysis [30] to investigate the effect of frozen embryo transfer on rate of ectopic pregnancy. A meta-analysis was performed of data from seven comparative studies including 13 059 pregnancies that resulted from nondonor IVF cycles. The ectopic pregnancy rate was 2.31% (49/2125 pregnancies) for frozen embryo transfer and 1.48% (162/10 934 pregnancies) for fresh IVF-ET. These rates were statistically not different when assessed by random effect model (OR 1.66, 95% CI 0.62–4.41). These findings are in line with another large series by Check et al. [31] who noted no increase in ectopic pregnancy rate after day 3 frozen embryo transfer, by showing the same to be true after frozen blastocyst transfer. Although recent results suggest reassurance in risk of ectopic pregnancy with frozen transfer, clinicians should consider this possibility while performing a frozen embryo transfer. It may be helpful to use ultrasound guidance with emphasis on the distance away from the fundus, considering previous data in the literature and theoretical mechanisms. Estimated embryo implantation potential
The association between ectopic pregnancy risk and embryo implantation potential, based on the two indicators we were able to assess, varied according to the day of embryo transfer (day 3 vs. day 5) and number of embryos transferred. Day 3 vs. day 5
Generally, there has been a belief that blastocyst embryo transfer may reduce the ectopic pregnancy rate [28]. If this is true, ectopic pregnancy rate in a certain group will be altered according to a relative proportion of blastocyst
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206 Fertility Table 1 Factors associated with ectopic pregnancy among pregnancies conceived using fresh nondonor IVF and embryo transfer, USA, 1999–2001 No. of embryos transferred related to estimated embryo implantation potential 3 embryos transferred D3 culture and no extra embryos cryopreserved D3 culture and extra embryos cryopreserved D5 culture and no extra embryos cryopreserved D5 culture and extra embryos cryopreserved 1–2 embryos transferred D3 culture and no extra embryos cryopreserved D3 culture and extra embryos cryopreserved D5 culture and no extra embryos cryopreserved D5 culture and extra embryos cryopreserved
AOR
95% CI
Reference 1.04 1.04 0.96
Reference 0.91–1.20 0.79–1.36 0.69–1.34
0.93 0.67 0.56 0.55
0.76–1.12 0.52–0.87 0.41–0.77 0.43–0.71
AOR, adjusted odds ratio; CI, confidential interval; D3, day 3; D5, day 5; IVF-ET, in-vitro fertilization and embryo transfer. Data from [7].
embryo transfer. On the contrary, the available literature does not support the idea that blastocyst embryo transfer lowers the ectopic pregnancy rate. There has been a study [32] demonstrating that blastocyst embryo transfer does not reduce the ectopic pregnancy rate compared with cleavage stage embryo transfer (3.9 vs. 3.5%, P ¼ 0.8). Moreover, a significant increase in the ectopic pregnancy rate was noted in blastocyst embryo transfer in a subsequent study [13] (1.6 vs. 0.5%, P ¼ 0.006). Rosman et al. [20] also reported that, of 4186 clinical pregnancies, the rate of ectopic pregnancy was 0.4% from day 3 transfer and 1.3% from day 5 transfer; this difference was statistically different (P ¼ 0.002). It has been proposed that decreased uterine contractility later in the luteal phase and the larger diameter of the blastocyst would interfere with its ability to reflux through ostium, protecting against tubal implantation. However, higher implantation potential per embryo at the blastocyst stage than cleavage stage may negate these effects. The number of embryos transferred
The risk of ectopic pregnancy among pregnancies in which three or more embryos had been transferred was 2.4–2.5%. However, when only less than two embryos were transferred, ectopic pregnancy rates varied according to embryo implantation potential indicators: 2.2% with neither indicator present, 1.6% when extra embryos had been available and cryopreserved, 1.4% when embryos were cultured for 5 days rather 3 days, and 1.4% when both of these conditions were met. These latter three rates were significantly different from the referent group. More than three embryos transferred with neither indicator for higher implantation potential (Table 1) [7]. After the logistic regression analysis, the transfer of two embryos or fewer was protective among three subgroups of women with at least one indicator of higher embryo implantation potential (ORs 0.6–0.7). Transfer of higher estimated embryo implantation potentials was associated with a decreased ectopic risk when two or fewer embryos were transferred, but not when three or more embryos were transferred. And these similar protective effects also could be observed among donor oocyte procedure, further supporting the
hypothesis that embryo implantation potential is associated with risk of ectopic pregnancy.
Conclusion The potential interfering factor in interaction of tubal function and transferred embryo is different hormonal milieu at the time of embryo transfer from hyperstimulation protocols. High level of progesterone and estradiol could affect tubal peristalsis, egg transport, and uterine relaxation. And distortion of normal anatomy of tube is a predisposing factor. The likelihood that women with tubal factor infertility have a greater risk than women with other factors has suggested an important role of tubal anatomy. Higher ectopic pregnancy rate may be associated with ZIFT, assisted hatching, high embryo transfer volume, deep fundal transfer, and frozen embryo transfer. Although recent results suggest reassurance in risk of ectopic pregnancy with frozen transfer, clinicians should consider this possibility while performing a frozen embryo transfer. The ectopic rate was significantly decreased when donor oocytes were used, and higher implantation potential per embryo at the blastocyst stage may increase the risk of ectopic pregnancy than cleavage stage. Transfer of higher estimated embryo implantation potentials was associated with a decreased ectopic risk when two or fewer embryos were transferred, but not when three or more embryos were transferred. Therefore, when transfer of blastocyst embryo is planned, it is better to restrict the number of embryos transferred for decreasing ectopic pregnancy rate.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 257). 1
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20 Rosman ER, Keegan DA, Krey L, et al. Ectopic pregnancy rates after in vitro fertilization: a look at the donor egg population. Fertil Steril 2009; 92:1791– 1793. A retrospective study compared the rates of ectopic pregnancy in fresh embryo transfer between nondonor IVF patients and donor egg recipients over a period of 8 years in a single institution. The rate of ectopic pregnancy was 0.9% for fresh IVF and 0.6% for donor IVF, which was not statistically different.
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21 Jun SH, Milki AA. Assisted hatching is associated with a higher ectopic pregnancy rate. Fertil Steril 2004; 81:1701–1703. 22 Liu HC, Cohen J, Alikani M, et al. Assisted hatching facilitates earlier implantation. Fertil Steril 1993; 60:871–875. 23 Mandelbaum J. The effects of assisted hatching on the hatching process and implantation. Hum Reprod 1996; 11 (Suppl 1):43–50; discussion 51– 55. 24 Hagemann AR, Lanzendorf SE, Jungheim ES, et al. A prospective, randomized, double-blinded study of assisted hatching in women younger than 38 years undergoing in vitro fertilization. Fertil Steril 2010; 93:586–591. 25 Knutzen V, Stratton CJ, Sher G, et al. Mock embryo transfer in early luteal phase, the cycle before in vitro fertilization and embryo transfer: a descriptive study. Fertil Steril 1992; 57:156–162. 26 Kashyap S, Chung P, Kligman I, et al. 7 year descriptive summary of ectopic pregnancies occurring after fresh and frozen IVF cycles [abstract]. Fertil Steril 2002; 78:S137.
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13 Keegan DA, Morelli SS, Noyes N, et al. Low ectopic pregnancy rates after in vitro fertilization: do practice habits matter? Fertil Steril 2007; 88:734–736.
28 Fanchin R, Ayoubi JM, Righini C, et al. Uterine contractility decreases at the time of blastocyst transfers. Hum Reprod 2001; 16:1115–1119.
14 Tomazevic T, Ribic-Pucelj M. Ectopic pregnancy following the treatment of tubal infertility. J Reprod Med 1992; 37:611–614.
29 Jun SH, Milki AA. Ectopic pregnancy rates with frozen compared with fresh blastocyst transfer. Fertil Steril 2007; 88:629–631.
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Is there a benefit in follicular flushing in assisted reproductive technology? Micah J. Hill and Eric D. Levens Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA Correspondence to Eric D. Levens, MD, Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Building 10, CRC, Room E1-3140, 10 Center Drive, Bethesda, MD 20892, USA Tel: +1 301 496 5800; fax: +1 301 402 0884; e-mail:
[email protected] Current Opinion in Obstetrics and Gynecology 2010, 22:208–212
Purpose of review Follicular flushing utilizing double-lumen retrieval needles attempts to increase oocyte yield during transvaginal retrieval. The original work on this topic, now more than 2 decades old, examined its utility in normal-responding assisted reproductive technologies (ART) patients. Newer studies examining its utility have focused on special populations expected to demonstrate benefit: poor responders, natural cycle and minimal stimulation ART, and in-vitro maturation cycles. This review assesses the current evidence regarding the effectiveness of ovarian follicular flushing in improving oocyte yield. Recent findings Follicular flushing offers no substantive benefit in oocyte yield, fertilization rates, or pregnancy outcomes for normal and poor-responding ART patients. Patients undergoing natural cycle or minimal stimulation ART may benefit from follicular flushing resulting in more mature embryos but unclear effects on cycle outcome. Summary Randomized controlled trials consistently demonstrate no benefit and increased procedural time with follicular flushing in both normal and poor-responding ART patients. Nonrandomized data suggest a possible role for follicular flushing in natural cycle or minimal stimulation ART and in those undergoing in-vitro maturation IVF cycles; however, randomized controlled trials are needed to verify this finding. Presently, there is insufficient evidence to recommend the routine use of follicular flushing. Keywords assisted reproductive technologies, double-lumen retrieval needle, oocyte retrieval, ovarian follicle flushing, poor responders Curr Opin Obstet Gynecol 22:208–212 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1040-872X
Introduction Prior to the early 1980s, oocyte retrieval was performed via laparoscopy, a cumbersome and expensive process requiring general anesthesia [1,2]. Laparoscopy was soon replaced by transvaginal retrieval under ultrasound guidance as the primary route to obtain oocytes for assisted reproductive technologies (ART) due to its safety, effectiveness, and the avoidance of general anesthesia [3–6]. The conversion to a transvaginal retrieval approach was followed by refinements in the oocyte retrieval needle design in an effort to maximize recovery and minimize patient discomfort [7–9]. Double-lumen needles (one channel to withdraw follicular fluid and another to instill isotonic saline into the follicle) were developed to allow for simultaneous or intermittent flushing and aspiration of ovarian follicles, a process that could not be accomplished with single-lumen retrieval needles [10]. A survey of ART clinics in 2001 reported that more than 50% performed follicular flushing in addition to direct aspiration of follicu1040-872X ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
lar fluid [11]. Proponents of follicular flushing have contended that greater oocyte yield may be achieved by obtaining oocytes that might otherwise be retained within the follicle following direct aspiration, resulting in a higher potential for pregnancy [10,12]. This notion was supported by initial reports of improved oocyte recovery when performing follicular flushing compared with direct aspiration, thus fueling speculation that pregnancy outcomes may likewise be improved [13]. This article sets out to assess the current state of evidence regarding the effectiveness of ovarian follicular flushing in improving oocyte yield and the resulting benefits in ART cycle outcome in both an unselected ART population as well as populations with limited follicle development.
Unselected assisted reproductive technologies population Over the years, there have been several studies examining the utility of ovarian follicular flushing. The results of DOI:10.1097/GCO.0b013e3283373bfe
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Benefits of follicular flushing Hill and Levens 209 Table 1 Summary of prospective, observational studies evaluating oocyte recovery in the initial aspirate and subsequent follicle flushes Oocytes obtained (%)
Author (year) Waterstone et al. [13] el Hussein et al. [14] Bagtharia et al. [15]
Follicles Oocytes Patients aspirated retrieved (n) (n) (n) 50 96 141
720 1181 1489
538 1046 1231
Direct aspirate (%)
1st flush (%)
2 flushes (%)
446 (83) 75 (14) 17 (3) 854 (82) 143 (14) 49 (5) 501 (40) 30 (3) 700 (57)
Pregnancy rates (%)
Fertilization rates (%)
Direct 1st 2 Direct 1 aspirate flush flushes aspirate flush (%) (%) (%) (%) (%) 56 62 55
43 66 58
24 36 NR
NR NR 26
NR NR 20
Procedure time (min) NR 25.8 11.1 NR
Percentage of the overall number of oocytes as obtained in each group; lower than the fertilization rate of the aspirate group (P < 0.05); lower this study performed up to six flushes. Only the results for the aspirate than the fertilization rate of both the aspirate and 1st flush groups (P < 0.01); and first two flushings reported in this Table.
the three prospective, observational studies performed to date have been summarized in Table 1 [13–15]. Although there were no control or comparison groups in these studies, the initial aspiration would be expected to approximate the yield obtained with direct aspiration using a single-lumen retrieval needle. Combined, these studies included 291 patients undergoing ART resulting in the aspiration of 2815 oocytes. Sixty-four percent of the oocytes were obtained in the initial follicle aspirate. The proportion of fertilized oocytes obtained in the second flush was significantly lower in the two studies reporting this proportion as compared with those obtained by aspiration [13,14]. The study by el Hussein et al. [14] reported an overall pregnancy rate of 28%, but had no resultant pregnancies from cycles that utilized embryos derived from oocytes obtaining from ovarian-follicle flushing. These findings suggested that while oocyte yield was increased, pregnancy outcomes were not affected by repetitive follicle aspirations. Another study reported aspirating all follicles at least 14 mm that were present at the time of oocyte retrieval [15]. The authors reported flushing each follicle up to six times. A notable drawback of this study was that the authors did not delineate the process by which follicles were selected for repetitive aspiration. This omission significantly undermined the conclusions drawn from this study. Nevertheless, the authors concluded that up to four follicle flushes allowed for the maximum number of oocytes to be retrieved, whereas not significantly impacting operating or anesthetic time. A large observational study of 2398 patients undergoing ART in Australia was performed when the authors’ practice protocol changed from routine flushing in all patients to direct aspiration alone [11]. The authors compared outcomes in patients from a time period immediately preceding and following the protocol change. During this time the ART protocol for the two groups was otherwise unchanged. The baseline characteristics including age, BMI, diagnosis of infertility, and peak estradiol levels between the two groups were
similar. The fertilization rates between groups did not differ whether ICSI, GIFT, or IVF was utilized. Recognizably not free from bias, the authors noted an increase in oocytes retrieved (direct: 8.8 oocytes, flushing: 8.2 oocytes) and in pregnancy rates (direct: 23%, flushing: 21%) with aspiration alone; however, the differences were limited and not statistically significant. Moreover, this study was unable to demonstrate a benefit in terms of clinical outcomes with follicular flushing and further provided evidence that follicular flushing might be detrimental to ART cycle outcome. Remarkably, there has been a paucity of randomized trials comparing follicle flushing to direct aspiration. To date, four trials including a total of 214 patients have been conducted that compare follicular flushing to direct aspiration in the normal-responding population [10,16– 18]. Unexpectedly, in these randomized studies, there were more oocytes retrieved in the aspiration only groups than among those undergoing follicle aspiration (direct: 8.9 oocytes, flushing: 7.5 oocytes) (Table 2). In addition, follicular flushing was associated with significantly longer retrieval times, accounting for approximately 15 min of additional procedural time [16,17]. The total number of pregnancies were similar between the two groups (direct: 15, flushing: 16) [16]. In both reports the authors reported total number of pregnancies, but not pregnancy rates nor specific P-values. In total, follicular flushing appears to offer no advantage over direct aspiration alone. Without a noted benefit, it remains difficult to justify the longer retrieval times associated with follicular flushing. As a result, we recommend that follicular flushing not be routinely performed in the normal-responding ART population.
Poor responders Women demonstrating a poor response to gonadotropin stimulation comprise approximately 10% of the total ART population and have significantly lower pregnancy outcomes as a result of limited follicular development
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210 Fertility Table 2 Summary of studies directly comparing follicular aspiration alone to follicular aspiration with flushing Patients (n) Author Cohort Knight et al. [11] Randomized trials Haines et al. [10] Tan et al. [16] Kingsland et al. [17] Scott et al. [18] Average
Mean oocytes retrieved (n)
Fertilization rate (%) Aspirate
Flushing
Procedure time (minutes)
Aspirate
Flushing
Aspirate
Flushing
P value
1139
1139
8.25.1
8.85.6
NS
56
54
NS
18 50 16 22 106
18 50 18 22 108
0.22 NS NS NS
70 56 60 66 63
64 60 64 64 63
0.60 NS NS NS
6.8 11 8.5 6.3 8.9
5.6 9 7 5.9 7.5
P value
Aspirate
Flushing
–
–
– 15 20 – 17.5
– 30 35 – 32.5
P-value – – <0.001 <0.01 –
Specific P values not reported.
[19,20]. Maximizing oocyte recovery among these patients may have significant clinical importance. Although follicular flushing may result in slightly better oocyte recovery among patients with a normal response, a definitive improvement in overall pregnancy outcomes has been difficult to demonstrate. However, in the setting of a poor ovarian response, the recovery of additional oocytes may represent a significant proportion of the total retrieved and thus may offer an increased opportunity to improve pregnancy outcomes. This has led some to hypothesize that follicular flushing may have its greatest utility in this population [13,15]. A recent randomized controlled trial compared follicular flushing to aspiration alone in poor-responding patients with 4–8 follicles at least 12 mm and at least two follicles at least 16 mm [21]. As expected, the mean age of the population was older than previous studies examining follicle flushing in an unselected population; however there were no differences in the age of participants between the study groups (direct: 37.1 years, flushing: 36.2 years; P ¼ 0.48). This study demonstrated a small increase in the number of oocytes retrieved with follicular flushing, yet this difference was not statistically significant (direct: 5.9 oocytes, flushing: 6.5 oocytes; P ¼ 0.38). Moreover, oocytes obtained from follicular flushing did not affect the fertilization rate. Interestingly, follicular flushing resulted in lower implantation and ongoing pregnancy rates (direct: 40%, flushing: 20%; P ¼ 0.43), but due to the limited sample size, these differences were not statistically significant. As observed in normal-responding patients, follicular flushing doubled the procedural time. Nonetheless, due to the limited number of follicles requiring flushing, the incremental increase was a mere 3 min (direct: 186 s, flushing: 366 s; P < 0.001). Despite its rigorous study design, this trial was hampered by a relatively small sample size with 15 patients in each arm. A post-hoc analysis suggested that 162 poor-responding patients would need to be randomized to provide sufficient power to demonstrate an improvement of one oocyte retrieved. Similar results were observed in another recent observational study [22]. Patients were enrolled into this cohort,
if they had a history of poor response in a previous cycle or the potential for a poor response based on abnormal baseline screening. Initially direct aspiration of the follicle was performed and only when there were no oocytes recovered from an individual follicle was follicular flushing performed (up to four flushes). The authors noted similar fertilization and clinical pregnancy rates among those undergoing direct aspiration or additional follicular flushing. In contrast to the previous randomized trial [21], this study observed an improvement in the number of top quality embryos (direct: 41%, flushing: 59%; P ¼ 0.01) and implantation rates (direct: 20%, flushing: 34%; P ¼ 0.04) among those undergoing follicular flushing [22]. In the end, there remains limited available evidence upon which to support a specific recommendation as to whether to perform follicular flushing in poor-responding patients. At present, it appears unlikely that follicular flushing will provide a substantial improvement in oocyte yield. It is important to note that the only randomized trial examining this question was adequately powered to detect a two oocyte difference in recovery between groups. Moreover, even if there were an improvement of one or two oocytes in this population, it remains unclear as to whether the outcome of ultimate interest (clinical pregnancy) would be impacted. On the contrary, unlike in normal-responding patients, the incremental increase in procedure time was insignificant (3 min). It is our opinion that clinical discretion should be employed as to when to utilize follicle flushing in the poor-responding patient population. However, in the absence of evidence of significant benefit, direct aspiration alone can be justified.
Semi-natural/minimal stimulation cycle assisted reproductive technologies The utility of follicular flushing has also been evaluated in patients undergoing a minimal stimulation ART protocol [23]. The patients underwent ultrasound and estradiol monitoring until the lead follicle exceeded 12 mm. At this time, daily gonadotropins and a gonadotropin-releasing
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Benefits of follicular flushing Hill and Levens 211
antagonist were administered. Human chorionic gonadotropin was given for oocyte maturation when the lead follicle was more than 16 mm in diameter and oocyte retrieval was performed 34 h later. Although the majority of the outcomes were similar between oocytes derived from flushing and aspiration only, the flushing group demonstrated increased top quality embryos and implantation rates of embryos derived from oocytes obtained from follicular flushing. The authors defined top quality embryos as day 2 embryos having no multinucleated blastomeres, 4–5 blastomeres, and less than 20% anucleated fragments. Although the pregnancy rates were higher among those undergoing follicle flushing, the results were not statistically significant between the two groups (direct: 14%, flushing: 23%; P ¼ NS). The same group performed another study utilizing a similar study design. In this study, there were no statistically significant differences between the groups in regard to fertilization and pregnancy rates [22]. However, there was the suggestion of improved embryo quality (flushing group: 37%, aspiration group: 28%) and implantation rates (flushing group: 44%, aspiration group: 24%). Nevertheless, neither of the results were statistically significant. The main findings were that 37% of the total oocytes were recovered from flushing and 53% of the pregnancies resulted from oocytes recovered from flushing. The authors concluded that oocytes obtained by follicular flushing were of the same quality as those obtained by aspiration and that semi-natural ART cycles may benefit from follicular flushing. In both studies, all patients underwent follicular aspiration without flushing. Patients who had no oocyte recovered from aspiration alone were changed to the flushing group. Patients who still had no oocyte after aspiration and flushing were not included in the analysis. Such an experimental design makes definitive conclusions difficult and highlights the need for randomized controlled trials. However, these data suggest a potential for benefit with follicular flushing in patients undergoing seminatural or minimal stimulation ART.
of four patients showed 100% oocyte recovery in three patients and 71% oocyte retrieval in the fourth patient. The authors argued that follicular flushing might help to maximize oocyte yield in IVM cycles, though it is difficult to draw definitive conclusions from such small numbers.
Quality of oocytes obtained from follicular flushing The ostensible purpose of follicular flushing is to increase oocyte yield. Theoretically, oocytes which are less mature may be less likely to detach from the follicle and, therefore, follicular flushing may result in obtaining oocytes of lower maturity. Immature oocytes are associated with lower fertilization rates and are less likely to produce blastocyst stage embryos [25]. Decreased fertilization, cleavage rates, and viability of oocytes obtained from follicular flushing have been demonstrated and may represent the retrieval of immature oocytes [13,14]. However, this is in contrast to the majority of the literature, which shows no difference between oocytes obtained by flushing or aspiration in regards to fertilization rates and mature oocytes [10,11,15–17,21,22,26]. Interestingly, one paper evaluating poor-responding patients undergoing minimal stimulation ART found that follicular flushing might recover better quality oocytes [23]. In this paper, follicular flushing produced more top quality embryos (flushing: 59%, direct aspiration: 41%) and had a higher implantation rate (flushing: 34%, direct aspiration: 20%). The authors concluded that follicular flushing recovered oocytes of optimal reproductive competence. Mechanisms proposed for this finding included oocytes recovered by aspiration alone representing an early hCG reaction and being over-matured [27]. Oocytes achieved secondarily by flushing might have benefited from longer contact with cumulus cells [28]. Although there are theoretical benefits for follicular flushing, only a single study has identified increased oocyte competence in oocytes recovered by flushing and this may represent mechanisms unique to poor responders or minimal stimulation ART protocol rather than the retrieval methodology.
In-vitro maturation cycles Oocyte retrieval in in-vitro maturation (IVM) cycles can be challenging as this technique targets antral follicles only 8–12 mm in diameter [24]. As smaller follicles contain oocytes of lesser maturity, it is possible that they are less likely to release from the follicle during traditional aspiration. For this reason follicular flushing has been theorized to increase the oocyte yield in IVM cycles. Only one abstract was identified evaluating the use of follicular flushing in IVM cycles [24]. This small report
Conclusion Despite theoretical and suggested benefits in observational studies, randomized-controlled trials in unselected ART populations have failed to demonstrate a benefit of follicular flushing, while demonstrating an increase in procedural time. Furthermore, there has been a suggestion of a possible reduction in oocytes recovered with follicular flushing, though the difference has been small. Ultimately, current evidence provides little to support the routine use of ovarian-follicle flushing. In the setting of limited follicle development (e.g. poor responders,
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212 Fertility
minimal stimulation, or natural cycle ART protocols), there may continue to be a role for follicular flushing as it may yield improved recovery in these subpopulations. However, definitive conclusions regarding follicular flushing in these populations cannot be made at the present time. There is a need for adequately powered, randomized, controlled trials in the populations most likely to benefit from an increased oocyte yield, including poor responders, IVM, minimal stimulation, and natural cycle ART patients.
Acknowledgements The authors would like to thank Mary Ryan, MLS at the National Institutes of Health Library for her valuable assistance with the literature search in the preparation of this manuscript. There are no conflicts of interest. This work was supported, in part, by the Program in Reproductive and Adult Endocrinology, NICHD, NIH, Bethesda, MD.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 257–258).
11 Knight DC, Tyler JP, Driscoll GL. Follicular flushing at oocyte retrieval: a reappraisal. Aust N Z J Obstet Gynaecol 2001; 41:210–213. 12 Aziz N, Biljan MM, Taylor CT, et al. Effect of aspirating needle calibre on outcome of in-vitro fertilization. Hum Reprod 1993; 8:1098–1100. 13 Waterstone JJ, Parsons JH. A prospective study to investigate the value of flushing follicles during transvaginal ultrasound-directed follicle aspiration. Fertil Steril 1992; 57:221–223. 14 el Hussein E, Balen AH, Tan SL. A prospective study comparing the outcome of oocytes retrieved in the aspirate with those retrieved in the flush during transvaginal ultrasound directed oocyte recovery for in-vitro fertilization. Br J Obstet Gynaecol 1992; 99:841–844. 15 Bagtharia S, Haloob AR. Is there a benefit from routine follicular flushing for oocyte retrieval? J Obstet Gynaecol 2005; 25:374–376. 16 Tan SL, Waterstone J, Wren M, et al. A prospective randomized study comparing aspiration only with aspiration and flushing for transvaginal ultrasound-directed oocyte recovery. Fertil Steril 1992; 58:356– 360. 17 Kingsland CR, Taylor CT, Aziz N, et al. Is follicular flushing necessary for oocyte retrieval? A randomized trial. Hum Reprod 1991; 6:382– 383. 18 Scott RT, Hofmann GE, Muasher SJ, et al. A prospective randomized comparison of single- and double-lumen needles for transvaginal follicular aspiration. J In Vitro Fert Embryo Transf 1989; 6:98–100. 19 Mohamed KA, Davies WA, Allsopp J, et al. Agonist ‘flare-up’ versus antagonist in the management of poor responders undergoing in vitro fertilization treatment. Fertil Steril 2005; 83:331–335. 20 Ulug U, Ben-Shlomo I, Turan E, et al. Conception rates following assisted reproduction in poor responder patients: a retrospective study in 300 consecutive cycles. Reprod Biomed Online 2003; 6:439–443. 21 Levens ED, Whitcomb BW, Payson MD, et al. Ovarian follicular flushing among low-responding patients undergoing assisted reproductive technology. Fertil Steril 2009; 91:1381–1384. This randomized controlled trial evaluating follicular flushing found no improvement in oocytes retrieved, mature oocytes, implantation rates, or ongoing pregnancy rates among poor-responding patients.
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22 Lozano DH, Fanchin R, Chevalier N, et al. Optimising the semi natural cycle IVF: the importance of follicular flushing. J Indian Med Assoc 2006; 104:423– 427.
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23 Mendez Lozano DH, Brum Scheffer J, Frydman N, et al. Optimal reproductive competence of oocytes retrieved through follicular flushing in minimal stimulation IVF. Reprod Biomed Online 2008; 16:119–123. This comparative study evaluated the benefits of follicular flushing in poorresponder patients. Embryos derived from oocytes obtained from follicular flushing showed improved implantation rates and more top quality embryos. No difference was noted in the clinical pregnancy rate between the two groups.
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Wiseman DA, Short WB, Pattinson HA, et al. Oocyte retrieval in an in vitro fertilization-embryo transfer program: comparison of four methods. Radiology 1989; 173:99–102.
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24 Uzelac PS, Christensen GL, Nakajima ST. Follicular flushing avoids multiple vaginal punctures and may aid in oocyte recovery in in vitro maturation (IVM). Fertil Steril 2009; 91:S5. This is the only study to evaluate follicular flushing for patients undergoing IVM. As the paper is limited by a very small sample size, the authors noted acceptable oocyte yield from mid-sized follicles and the avoidance of multiple vaginal punctures with follicular flushing.
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Awonuga A, Waterstone J, Oyesanya O, et al. A prospective randomized study comparing needles of different diameters for transvaginal ultrasounddirected follicle aspiration. Fertil Steril 1996; 65:109–113.
25 Lin YC, Chang SY, Lan KC, et al. Human oocyte maturity in vivo determines the outcome of blastocyst development in vitro. J Assist Reprod Genet 2003; 20:506–512.
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26 Peeraer K, Spiessens C, De Jaegher N, et al. Correlation between the number of follicular flushings, oocyte/embryo quality and pregnancy rate for IVF: a prospective study. Hum Reprod 2007; 22:i168.
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10 Haines CJ, Emes AL, O’Shea RT, et al. Choice of needle for ovum pickup. J In Vitro Fert Embryo Transf 1989; 6:111–112.
27 Bomsel-Helmreich O, Huyen LV, Durand-Gasselin I, et al. Timing of nuclear maturation and cumulus dissociation in human oocytes stimulated with clomiphene citrate, human menopausal gonadotropin, and human chorionic gonadotropin. Fertil Steril 1987; 48:586–595. 28 Goud PT, Goud AP, Qian C, et al. In-vitro maturation of human germinal vesicle stage oocytes: role of cumulus cells and epidermal growth factor in the culture medium. Hum Reprod 1998; 13:1638–1644.
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Update on the role of leukemia inhibitory factor in assisted reproduction Lusine Aghajanova Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, California, USA Correspondence to Lusine Aghajanova, MD, PhD, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, 513 Parnassus Avenue, HSW 1671, Box 0556, San Francisco, CA 94143, USA Tel: +1 415 476 2039; fax: +1 415 502 7866; e-mail:
[email protected] Current Opinion in Obstetrics and Gynecology 2010, 22:213–219
Purpose of review To review the recent literature on the involvement and importance of leukemia inhibitory factor (LIF) in the human implantation process, and the attempts using LIF-based interventions to improve assisted reproductive technologies (ARTs) outcome in women with recurrent implantation failure. Recent findings High LIF expression is an indicator of receptive endometrium in fertile women. However, in infertile individuals, the data on endometrial LIF expression and secretion are controversial. Even after ruling out other causes of infertility, such as tubal, endocrine, male factor, and endometriosis, LIF-only detection is not sufficient for assessment of implantation potential in women with unexplained infertility. This is obviously in contrast to evidence of the crucial role of LIF in mouse endometrial physiology. In a large multicenter study, recombinant human LIF failed to improve the outcome of IVF treatment in women with recurrent implantation failure. Summary A better comprehension of the mechanisms underlying endometrial receptivity and implantation should guide clinicians through proper management and treatment of infertility and implantation failure, and may eventually enable widespread adherence to single embryo transfer practices. Keywords endometrial receptivity, implantation, in-vitro fertilization, leukemia inhibitory factor Curr Opin Obstet Gynecol 22:213–219 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1040-872X
Introduction
Embryo–endometrial interactions
Assisted reproductive technologies (ARTs) increase a couple’s chance for conception from 15 to 20% in a fertile natural cycle to around 32.5% (cumulative pregnancy rates for 2007 fresh embryo transfer across all age groups) in an ART cycle [1]. This is a great improvement in the care for infertile couples; however, why cannot we do better? There are two essential constituents of the establishment of pregnancy: viable healthy embryo and receptive endometrium. Oocyte aneuploidy and chromosomal abnormalities of the embryo are the main causes of implantation failure [2,3]. Yet, in cases when highest quality embryo(s) are transferred and no pregnancy occurs it is unclear what the reasons may be. In such cases, embryo abnormality not detected by conventional screening methods (morphology, development) or implantation failure is obvious possibility. Implantation failure is defined as the failure of an embryo to implant during an IVF cycle, and many agree that it can be called so after two-to-three failed cycles [4].
A series of sequential events should happen in a complex and consecutive way in order for implantation to occur – a seemingly easy, but in fact unbelievably multifarious process.
1040-872X ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Leukemia inhibitory factor (LIF) is a pleiotropic cytokine able to exert various effects on a wide variety of tissues and cell types throughout the body (reviewed in [5,6]), and has been extensively studied throughout the years. LIF has been shown to act at different levels of the reproductive axis (Fig. 1), as will be discussed in following paragraphs. Embryo–endometrial interactions start before the embryo even attaches to the endometrial epithelial surface through the secretion by the embryo of several ligands to receptors present in luminal and glandular epithelium, such as fucosylated oligosaccharides, ghrelin, and LIF, and also by endometrial ligands to receptors DOI:10.1097/GCO.0b013e32833848e5
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214 Fertility Figure 1 Involvement of leukemia inhibitory factor in the function and expression by the organs of hypothalamo-hypophyso-gonadalend organ axis
Hypothalamus Pituitary
Placenta
Leukemia inhibitory factor
Embryo
Adrenals Ovaries
Fallopian tubes
Uterus (endometrial epithelium and stroma, uNK cells)
uNK cells, uterine natural killer cells.
expressed by the early embryo [LIF, heparin-binding epidermal growth factor-like growth factor (HB-EGF), insulin-like growth factor]. Following these early interactions continues a complex cascade of cell-to-cell and paracrine interactions between the embryo and maternal endometrial surface. In humans, implantation is achieved only during a very specific short time in mid-secretory phase, called window of implantation (WOI), when complex interactions between numerous factors create a receptive-stage endometrium, hospitable for blastocyst implantation [7–9,10]. Identifying markers of human implantation can serve a purpose in fertility regulation, which goes two ways: correction of implantation failure and prevention of implantation (contraception).
Leukemia inhibitory factor and the neuroendocrine regulation of reproductive function LIF is a pleiotropic-secreted cytokine able to exert various effects on the wide variety of tissues and cell types throughout the body. LIF acts through binding to the LIF cell-surface receptor (LIFR), consisting of two subunits, the specific low-affinity LIFRb and the shared gp130 receptor, common for different members of IL-6 family cytokines. Binding of LIF to LIFRb induces a conformational change causing the heterodimerization of LIFRb and gp130, which creates a high-affinity receptor–ligand complex able to activate the intracellularsignaling pathways JAK/STAT, MAPK, and PI3K/AKT [5,11,12]. Negative regulation on LIF is exerted via the suppressors of cytokine signaling (SOCS), which negatively regulate JAK/STAT pathways by interacting with JAKs [6,13,14] (Fig. 2).
ability to regulate the migration of gonadotropin-releasing hormone (GnRH) neurons during fetal development, the fundamental process for the development of normal reproductive function [15]. In that study, LIF was shown to stimulate the migration of GN-11 cells (immortalized highly migratory GnRH neurons), which retain many characteristics of migrating GnRH neurons, as well as activate the main signaling pathways known to be coupled to LIFR (JAK/STAT, MAPK, and PI3K/ AKT). Moreover, it was also shown that LIF is expressed prenatally in nasal regions where from the GnRH neurons originate and start migrating, supporting the role of this cytokine in GnRH neuron motility and migration [15]. Further, studies from the same group on GT1-7 cells (immortalized hypothalamic GnRH-secreting neurons) demonstrated that LIF may exert its neuroendocrine effect, acting through its receptors, by directly stimulating GnRH release at nanomolar concentrations [16]. In additional evidence on the involvement of LIF in neuroendocrine function, Watanobe and Yoneda [17] demonstrated the ability of LIF to participate in the generation of luteinizing hormone (LH) and prolactin surges in the rat [17].
Leukemia inhibitory factor and the ovaries In the human ovary, LIF is expressed in ovarian stroma, granulosa cells, and present in follicular fluid where its levels correlate with estrogen production and embryo quality [18]. In mice, LIF increased the growth, but not maturation, of cultured preantral follicles, acting as a proliferative factor for granulosa and theca cells [19].
Leukemia inhibitory factor and the embryo It was demonstrated recently that LIF is involved in the central regulation of reproductive function due to its
Interaction between fucosylated oligosaccharides expressed by endometrium and their ligand L-selectin
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Update on role of LIF in assisted reproduction Aghajanova 215 Figure 2 Leukemia inhibitory factor-signaling pathway
LIFR
Plasma membrane
LIF gp130
SOCS1 protein
JAK JAK
SHP2
PI3K
P
AKT
STAT3 MAPK P
mTOR MEF2 c-Fos CREB
STAT3 P
STAT3
SOCS1 mRNA
DNA binding and gene expression
P
STAT3
P
STAT3
Nucleus
LIFR, leukemia inhibitory factor receptor b; JAK, janus kinase; STAT, signal transducer and activator of transcription; SHP2, Src homology 2-domaincontaining tyrosine phosphatase; PI3K, phosphatidylinositol-3-kinase; AKT, serine-threonine protein kinase (v-akt murine thymoma viral oncogene homolog 1); MAPK, mitogen-activated protein (MAP) kinase; mTOR, mammalian target of rapamycin; SOCS, suppressors of cytokine signaling; MEF2, myocyte enhancer factor-2; c-Fos, FBJ murine osteosarcoma viral oncogene homolog; CREB, cAMP responsive element binding protein; P, phosphorylated. Solid line represents direct and dotted line represents indirect relationship.
produced by the embryo is crucial for adhesion of the blastocyst during the implantation window [20]. In the mouse embryo, LIF upregulates the expression of both sialyl Lewis X (sLex), and fucosyltransferase VII, a key enzyme of sLex oligosaccharide fucosylation, thereby regulating development of the embryo and its adhesive potential [21]. Human preimplantation embryos are known to express LIF and both of its receptors (reviewed in [5,22]). It was shown recently that LIF induced cumulus expansion in human and mouse oocytes during in-vitro maturation and, together with recombinant follicle-stimulating hormone, improved oocyte competence in mice as shown by increased cleavage rate, blastocyst development, and pregnancy rate [23].
trium [25]. Agrin has been suggested to relate to aggregation of acetylcholine receptors not only at neuromuscular junctions in the uterus but also in endometrium [25]. In ovine uterus, LIFRb and gp130 has been shown to be stimulated by interferon tau and progesterone in a stagespecific and cell-specific manner in endometrium and during early pregnancy [26]. Interaction between interferon tau and LIF pathways in human endometrium has not been reported yet. Pleiotropic protein prokineticin 1, expressed in the epithelium of receptive endometrium and during early pregnancy, induces human chorionic gonadotropin-mediated upregulation of LIF in human and baboon endometrium [27]. Of note, endometrial LIF expression can be regulated not only by the embryo and/ or endometrial microenvironment but also by seminal plasma [28].
Leukemia inhibitory factor and the uterus LIF action is complex and not entirely understood, yet extensively studied (reviewed in [5,6,10]) Recently, Carino et al. [12] reported that leptin upregulated LIF and LIF receptors’ expression in benign and cancerous human endometrial epithelial cell lines, acting via JAKsignaling, PI3K-signaling, and mTOR-signaling pathways, confirming an earlier report [24]. Spatiotemporal expression of the heparan sulfate proteoglycan agrin has been shown to be regulated by LIF in murine endome-
LIF plays a role in both adhesive and invasive phases of implantation due to its anchoring effect on the trophoblast and regulation of trophoblast differentiation [29]. It is expressed in first trimester decidua, chorionic villi, decidual leukocytes, and uterine natural killer cells (reviewed in [5,6]). LIF has been shown to modulate trophoblast invasiveness and affect immune tolerance by controlling human HLA-G expression of invasive cytotrophoblast cells during implantation [30].
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216 Fertility
Today’s reproductive physicians and scientists are challenged not only to identify the marker(s) of endometrial receptivity but also exploring noninvasive methods for assessing such markers. Aspiration and flushing of the uterine cavity has been used in several studies to identify markers of endometrial receptivity and has been shown to not have a detrimental effect on pregnancy rates if performed in the peri-implantation period, as compared to endometrial biopsy [30]. LIF was detected in uterine flushings 2 days after ovulation. The amount of LIF in uterine flushings was reported to be highly predictive for the pregnancy in subsequent menstrual cycles [31]. However, a recent study demonstrated that secretory LIF levels in uterine flushings in healthy female volunteers did not correlate with endometrial dating of tissue maturation and serum progesterone levels [30].
(mid-secretory phase) have a greater probability of getting pregnant than those with weaker expression, thus supporting a predictive value of LIF in IVF practice. Interestingly, that was true in the situation when LIF expression was analyzed in a previous unstimulated cycle, and even though it is well known that endometrial maturation pattern differs in stimulated versus natural cycles, strong endometrial LIF immunoreactivity was nonetheless predictable of successful pregnancy in a subsequent cycle. Furthermore, the same group showed that a successful implantation after an IVF cycle is associated with a claudin-4(tight junction protein)/LIFþ endometrium [35]. On the basis of these data, the authors speculated that therapeutic intervention for compensating low endometrial LIF expression may positively affect IVF outcomes, as has been proposed earlier [36].
Studies of endometrial maturity and receptivity during IVF treatment cycle by analyzing endometrial secretions are likely to be more clinically informative than assessment in the previous cycle, as there can be intrapatient variations from cycle to cycle. However, it seems even more valuable to perform such assessments of endometrial functionality during the time of ovulation (sample obtained right before oocyte retrieval). In this way, cases of immature or advanced endometrium could be corrected by timely addition of exogenous hormones, embryo transfer could be conducted only when a high-implantation prediction rate is assessed, or otherwise cancelled and embryos frozen rather than transferred to a suboptimally receptive uterus.
Allegra et al. [37] choose a different approach to identify genes required for successful human implantation. They analyzed endometrial mid-secretory gene expression in previous cycles of women who became pregnant in subsequent intracytoplasmic sperm injection cycles using a panel of 43 genes chosen based on published microarray studies of WOI gene expression. They hypothesized that the genes that have homogenous expression among 15 subsequently pregnant individuals are the ones crucial for the implantation process and discovered that only six genes were similarly expressed, with LIF being one of them, showing positive correlation between endometrial LIF expression and pregnancies [37].
Leukemia inhibitory factor involvement in the implantation process A receptive endometrium is characterized by distinct changes in cell morphology and molecular function, as determined by the formation of pinopodes, and the production of numerous growth factors, cytokines, and adhesion molecules. Pinopodes, the ectoplasmic protrusions of the apexes of epithelial cells, were shown to release LIF-containing vesicles into uterine lumen [32]. This LIF is necessary for a cross-talk with the implanting embryo, which expresses LIF receptors, facilitating the adhesion process. Ji et al. [33] showed that the implantation site of a human oviduct with ectopic gestation expresses significantly higher amounts of LIF protein compared to nonimplantation site of the same tube, or to the normal healthy tube [33]. They also demonstrated that women with salpingitis have significantly higher tubal LIF expression, compared to the normal fallopian tube, potentially triggered by the inflammatory cytokines, thus conceivably increasing the susceptibility of these patients for tubal pregnancy [33].
Leukemia inhibitory factor and infertility Serafini et al. [34] showed that women with stronger endometrial LIF immunoreactivity during the WOI
Makker et al. [38] studied LIF immunoexpression in fertile and infertile women. No effect of a selective estrogen receptor modulator (SERM, ormeloxifene) on endometrial LIF expression was reported, even though expression of estrogen receptors and progesterone receptors was altered in SERM treated endometrium [38]. Moreover, there was no difference in LIF expression between fertile and infertile (primary and secondary infertility) individuals, even though the majority of all (fertile and infertile) endometrial samples were ‘out of phase’ histologically [38]. As LIF has been shown to increase aromatase expression in adipose tissue [39], it may be one of the factors affecting estrogen synthesis in reproductive tissues, such as the ovarian follicle and endometrium. Interestingly, no defects in eutopic endometrium LIF mRNA and secreted protein levels were detected in infertile women with endometriosis [40], indicating that an altered secretion of this cytokine cannot account for the infertility of these patients with minimal endometriosis. Tumor suppressor p53 was shown to be involved in murine reproduction by transcriptional regulation of LIF (p53 knockout mice experience implantation failure
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Update on role of LIF in assisted reproduction Aghajanova 217
due to decreased uterine LIF expression, and LIF injections can rescue the impaired implantation) [10,41]. In humans, Kang et al. [42] found that single-nucleotide polymorphisms (SNPs) for the p53 codon 72 had a significant impact of LIF expression levels and correlated with implantation potential [42]. LIF levels are lower in cells with the p53 allele encoding proline (P) at codon 72, compared to cells with the allele encoding arginine (R) at this codon. The P72 codon was enriched in IVF patients of less than 35 years old and served as a risk factor for implantation failure after IVF in this population, suggesting that LIF plays a major role in implantation failure in this group, compared to older patients [42]. Moreover, the frequency of P72 codon was significantly higher in women with recurrent implantation failure after IVF [43]. Interestingly, environmental stresses such as cold winter temperature and UV radiation select the more active p53 R72 allele, which increases the activation of LIF (and some other genes), promoting therefore more efficient metabolism and embryo implantation in strenuous conditions [44]. Analyzing p53 SNPs in IVF populations may provide another way of identifying cohorts of patients that could potentially benefit from therapy with recombinant human (r-h) LIF.
Leukemia inhibitory factor and unexplained infertility Altmae et al. [45] were the first to perform a large-scale microarray analysis on endometrium from well characterized individuals with unexplained infertility. Surprisingly, several molecules with an established role in endometrial receptivity and the embryo implantation process (LIF, HOXA10, L-selectin, HB-EGF, and others) did not pass the three-fold cutoff threshold. As endometrial tissue biopsy samples contain several cell populations, interpretation of mass array data is complex and more difficult due to different cell types present in the tissue [45]. We recently showed in endometria from fertile women that high levels of LIFR and gp130 immunostaining correlated to low SOCS1 immunostaining, whereas the same inverse relationship was not observed in endometria from women with unexplained infertility [13]. Moreover, this study showed that LIF signaling may be impaired in some, but not all, women with unexplained infertility and/or implantation failure [13]. The potential involvement of LIF gene mutations in implantation failure has been studied. Earlier studies of women with unexplained infertility and with recurrent failure of implantation after IVF treatment did not support the hypothesis that LIF gene mutations may decrease the biological activity of LIF in endometrium and cause an implantation failure [5,46,47]. However,
Novotny et al. [48] demonstrated that LIF gene mutation can have a negative impact on pregnancy achievement by women with unexplained infertility or endometriosis undergoing IVF [48]. Because LIF gene mutation is not a frequent finding in infertile women, larger sample size is needed for further investigations.
Recombinant human leukemia inhibitory factor in clinical trials as the first treatment for implantation failure The European Society of Human Reproduction and Embryology 2003 meeting was highlighted by the promising report on the usage of recombinant LIF in pure female factor infertility patients with unexplained recurrent implantation failure after fresh IVF (reviewed in [10]). Subsequently, a large multicenter, randomized, double-blinded, placebo-controlled study was performed [36]. Patients (aged 21–37 years old) with at least two failed ART cycles after transfer of at least 1 fresh grade A or B embryos, with normal BMI, normal early follicular phase (basal) FSH levels, and normal semen analysis of male partner were started on long GnRH agonist protocol. r-hLIF was administered at 150 mg s.c. twice daily for seven days, immediately after embryo transfer. Patients in treatment and placebo groups were matched for demographic, disease characteristics and ART cycle details [36]. However, very unfortunately, this extended study failed to demonstrate that r-hLIF s.c. administration in the luteal phase after embryo transfer improved implantation and pregnancy rates compared with placebo in women with recurrent implantation failure [36]. Consequently, the questions arise: shall we give up on the LIF as an important implantation molecule and focus our research and potential treatment on finding a new promising target? Or, shall we reassess the study and continue with LIF after careful selection of the study groups, way of administration and/or duration of treatment? One potential improvement could be the selection of the proper study groups, consisting of women with LIF deficiency. These should most probably include the very carefully selected women with unexplained infertility (not tubal factor infertility or endometriosis), as in tubal infertility no LIF deficiency was reported, and reports on LIF expression in endometriosis are quite contradicting ([33] and above). Advanced maternal age with the associated decreased ovarian reserve, as well as premature ovarian failure, should probably be also excluded as a factor, thus including only patients with normal FSH and E2 basal levels and normal antral follicle count. Another potential modification can be a way of r-hLIF administration, aiming on the local endometrial delivery of the drug rather than systemic.
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218 Fertility
The failure of this trial, however, should not discourage the physicians and scientists who favor LIF as an implantation marker, because the compensation for LIF was never performed with the prior assessment of its expression in a given patient. Moreover, the ideal treatment pattern would be the controlled administration of LIF followed by the normalization of endometrial expression, allowing balanced and appropriate cytokine supplementation. This being said, exogenous LIF administration throughout the early pregnancy (very much like supplementation with estradiol and progesterone) may have a potential to improve chances of not only achieving, but also maintaining the pregnancy.
Summary LIF is a cytokine that is able to modulate reproductive function at different levels. It acts during embryonic development by regulating the migration of GnRH neurons, it acts as a permissive molecule on GnRH release in adults, and it even regulates LH and prolactin secretion by the pituitary. On peripheral tissue level, LIF-deficient mice have impaired implantation. Whether LIF deficiency is a local uterine phenomenon, or it is present in the other parts of hypothalamo-pituitary-gonadal-end organ levels, warrants further investigation. However, although the role of LIF in the human implantation process is proved to be important, it is not crucial, because the significance of increased occurrence of LIF gene mutations in infertile women is not proved yet, and the endometrium from infertile women is not always LIF-deficient. High LIF expression is an indicator of a receptive endometrium in fertile women. However, in infertile individuals, the data on endometrial LIF expression and secretion are controversial. Even after ruling out other causes of infertility, such as tubal, endocrine, male factor and endometriosis, LIF-only detection is not proved to be sufficient for assessment of implantation potential in women with unexplained infertility. Therapy with r-hLIF promised an efficient pathogenesisbased treatment of implantation failure. However, in a large multicenter study, r-hLIF failed to improve the outcome of IVF treatment in women with recurrent implantation failure. Nevertheless, giving up on LIF as a target for therapeutic interventions may be preliminary, and with certain modifications the cytokine may be able to get another chance to prove its viability as a therapeutic in clinical medicine.
Conclusion A better comprehension of the mechanisms underlying endometrial receptivity and implantation should guide clinicians through proper management and treatment of
infertility and implantation failure, and may eventually enable widespread adherence to single embryo transfer practices. The latter will undoubtedly decrease maternal and perinatal complications associated with multiple pregnancy and birth after ART treatment, as well as decrease medical costs.
Acknowledgement Special thanks to Dr Irwin J. C. (UCSF) for critical reading of the manuscript.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 258). 1
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Update on role of LIF in assisted reproduction Aghajanova 219 16 Dozio E, Ruscica M, Galliera E, et al. Leptin, ciliary neurotrophic factor, leukemia inhibitory factor and interleukin-6: class-I cytokines involved in the neuroendocrine regulation of the reproductive function. Curr Protein Pept Sci 2009; 10:577–584. 17 Watanobe H, Yoneda M. A significant participation of leukemia inhibitory factor in regulating the reproductive function in rats: a novel action of the pleiotropic cytokine. Biochem Biophys Res Commun 2001; 282:643–646. 18 Arici A, Oral E, Bahtiyar O, et al. Leukaemia inhibitory factor expression in human follicular fluid and ovarian cells. Hum Reprod 1997; 12:1233–1239. 19 Haidari K, Salehnia M, Rezazadeh Valojerdi M. The effect of leukemia inhibitory factor and coculture on the in vitro maturation and ultrastructure of vitrified and nonvitrified isolated mouse preantral follicles. Fertil Steril 2008; 90:2389– 2397. 20 Genbacev OD, Prakobphol A, Foulk RA, et al. Trophoblast L-selectinmediated adhesion at the maternal-fetal interface. Science 2003; 299:405– 408. 21 Zhang Q, Liu S, Zhu Z, Yan Q. Regulating effect of LIF on the expression of FuT7: Probe into the mechanism of sLe(x) in implantation. Mol Reprod Dev 2009; 76:692. 22 Wanggren K, Lalitkumar PG, Hambiliki F, et al. Leukaemia inhibitory factor receptor and gp130 in the human Fallopian tube and endometrium before and after mifepristone treatment and in the human preimplantation embryo. Mol Hum Reprod 2007; 13:391–397. 23 De Matos DG, Miller K, Scott R, et al. Leukemia inhibitory factor induces cumulus expansion in immature human and mouse oocytes and improves mouse two-cell rate and delivery rates when it is present during mouse in vitro oocyte maturation. Fertil Steril 2008; 90:2367–2375. 24 Gonzalez RR, Rueda BR, Ramos MP, et al. Leptin-induced increase in leukemia inhibitory factor and its receptor by human endometrium is partially mediated by interleukin 1 receptor signaling. Endocrinology 2004; 145:3850–3857.
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Mental health of parents of twins conceived via assisted reproductive technology Sirpa Vilskaa and Leila Unkila-Kalliob a
Students’ Health Service and bDepartment of Obstetrics and Gynaecology, Helsinki University Central Hospital, Helsinki, Finland Correspondence to Dr Sirpa Vilska, MD, Students’ Health Service, To¨o¨lo¨nkatu 37 A, 00260 Helsinki, Finland Tel: +358 400 649 415; e-mail:
[email protected] Current Opinion in Obstetrics and Gynecology 2010, 22:220–226
Purpose of review To review recent knowledge on mental health of parents of twins conceived via assisted reproductive technology (ART). Recent findings Mental health of mothers and fathers of twins conceived via ART is impaired when compared with that of ART singletons. Summary Existing studies are mainly cross-sectional and most of them focus on maternal mental health. It is evident that twin parenthood is the main factor impairing the mental health in parents with ART twins. This aspect should be taken into account when counseling the couples and deciding the number of embryos for transfer in ART. Well conducted prospective longitudinal studies are needed on both maternal and paternal mental health with twins conceived via ART from transition to parenthood to and beyond toddler age covering later life with school-aged and adolescent twins. Keywords anxiety, assisted reproduction, depression, infertility, pregnancy Curr Opin Obstet Gynecol 22:220–226 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1040-872X
Introduction Assisted reproductive technology (ART) [1], especially IVF and intracellular sperm injection (ICSI), is an effective treatment of infertility. Successful ART treatments were first achieved by multiple embryo transfers but with the consequence of increased number of multiple births. The evolution of ART, including the development of a well functioning cryopreservation system, contributes to the current policy that not more than two embryos [2] or electively a single embryo is recommended to transfer [3,4]. However, data from recent ART registries continue to show high rates of iatrogenic multiple and twin births even these days. In Europe, in 2005, the proportions of triplet and twin births via ART were 0.8 and 21.0%, respectively [5], but in the United States, twins accounted for 44.1% of ART infants in 2006 [6]. Twin birth rate after ART is still in clear contrast with natural twin birth rate that is around 1%.
Psychological aspects of infertility and of assisted reproductive technology on twin parenthood The emotional burden of infertile couples is affected by the experience of being infertile, but also by many kinds of losses. Achieving an ongoing pregnancy after ART often follows years of stress, uncertainty and multiple treatment failure. Increased levels of depression, anxiety 1040-872X ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
and lower self-esteem are seen among ART parents of singletons in some studies, but not in all [7]. Caring and parenting twins or multiples induces both physical and psychological strain, and may be emotionally more demanding than parenting singletons, especially so for previously infertile couples [8]. Further, first-time motherhood may be an additional stressor for mental health in parents of ART twins [9]. In a large population-based study [10] with adjustment for many demographic and socioeconomic characteristics, but not infertility, mothers of multiple births had around 40% increased risk of having moderate/severe depressive symptoms 9 months postpartum than mothers of singletons. Every fifth to every third infertile couple show positive attitudes towards a twin birth [11,12]. Long infertility with failed treatments, young age, nulliparity and low family income together with insufficient knowledge on the risks of a multiple gestation make the couple more prone to prefer double or even multiembryo transfer to fulfill their desire to have children irrespective of the potential risks to their or the child’s health [13,14]. Further, obstetric and perinatal complications such as prematurity, very low birth weight and health problems in the child may predispose the infertile parent to mental health problems [8,10,15]. Out of the ART pregnancies, 96% of higher order multiples, 57% of twins but only 9% of singletons were low birth weight and the respective DOI:10.1097/GCO.0b013e3283384952
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Mental health of parents of ART twins Vilska and Unkila-Kallio
rates for preterm birth were 97, 65 and 14% [6]. When compared with spontaneously conceived twins of unlike sex, the ART twins had a higher risk for prematurity and low birth weight [16]. In addition, the ART twins were more frequently admitted to a neonatal intensive care unit (NICU) and also hospitalized during their first 3 years than the spontaneously conceived twins. However, in a meta-analysis [17], mortality of ART twins was found to be lower than that of spontaneously conceived twins. The ART providers’ responsibility for education of couples for risks and consequences of multiple births has been emphasized [11,18]. The later study by Ryan et al. [19] showed that adding written education on the risks of twin and singleton pregnancies and births to standard counseling before ART decreased the couple’s desire of twins. The technical development of infertility treatments during the existence of ART has been huge. However, concerning the psychosocial dimensions of infertility, more appropriate research on psychosocial consequences of both successful and unsuccessful treatments is required [7,20]. The aim of this review is to focus on recent research on mental health of mothers and fathers of twins conceived via ART. Unfortunately, only one recent study focused solely on mental health of parents of twins conceived via ART, and therefore, a short overview on previous studies is added.
General aspects of studies on parental mental health of twins conceived via assisted reproductive technology Transition to parenthood from infertile status is a demanding, dynamic process especially for parents of twins. However, the body of research on mental health and psychosocial wellbeing of parents of twins conceived via ART is very limited. Some data exist from transition to parenthood and from toddler to preschool age, but no data exist on parental mental health of school age and adolescent twins. Infertile couples proceeding into ART represent norm population with low rate of clinically significant psychiatric morbidity, thus increasing the challenges of measuring mental health. Questionnaires are commonly used in the research setting to study mental health, as they are simple to use in large populations. They give a fairly reliable view of the existence of psychological symptoms in a population. However, they have also restrictions as they produce information mainly on conscious processes and ideas. Further, self-reports may be vulnerable to social desirability and especially so among couples undergoing infertility treatments.
221
Longitudinal measurements increase the reliability of the information and are of special importance when the differences between groups are not supposed to be great, as in normative samples. Further, follow-up enables evaluation of the direction of the development both within and across the groups with advanced statistical analysis. A big problem with the longitudinal setting is to reach a relevant full response rate, especially regarding parents of twins. Many of the published cross-sectional studies [21–23, 24,25] comparing mental health of parents of ART twins with that of parents of singletons (Table 1) include methodological inconsistencies that complicate the relevance of the results and the between-study comparisons. Another problem is that measures on mental health vary a lot, making the comparisons of the results very confusing for a clinician. The largest study by Olivennes et al. [24] focuses solely on mental health of mothers of twins conceived via ART. In all the other studies [21– 23,25], twins and triplets are included in the same study group. However, triplet parenthood is demanding [26]. Further, each additional multiple birth child has been shown to increase the risk of maternal depression [23]. Thus, results of studies assessing parental mental health of twins and triplets in the same series do not reliably refer to mental health associated with twin parenthood. Fathers of twins were included in only one [25] of these five cross-sectional studies. Another confusing factor is that parents treated with own and donated gametes are combined in the same study group [21,22,25]. To an infertile couple, third-party reproduction, including conception with donated sperm, oocytes or embryos, is a unique and demanding issue, as the genetic link between at least one of the parents and the offspring is missing. Considering the particular character of third-party reproduction, mental health of parents conceived via gamete or embryo donation necessitates a separate investigation. The cross-sectional studies comparing mental health of parents of twins conceived via ART with other parents of twins are presented in Table 2 ([9,27–29]). The selection of control groups is confusing, as three studies out of four include both fertile and previously infertile couples as controls, although infertility is a known life stressor. Furthermore, sample sizes are mostly relatively small. Important and commendable is that both mothers and fathers are included in three of the four studies. The only longitudinal study [30] on mental health of parents of twins conceived via ART is a recent one (Table 3). It has a large study group of unselected, consecutive parents with ART twins conceived with own gametes and three control groups, all recruited
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M, first time M
Glazebrook et al. [22]
Ellison et al. [23]
M and F
Roca de Bes et al. [25]
37 twins, 9 triplets
111 twins, 10 triplets 344 twins
51 twins, 8 triplets
49 twins, 7 triplets
n
OI, IVF/ICSI; IUI, including donated gametes
IVF/ICSI
IVF, including donated gametes OI, IVF/ICSI
IVF, including donated gametes
Conception
77
344, matched
OI, IVF/ICSI; IUI
IVF/ICSI
spontaneous OI, IVF/ICSI
129 128, matchedb c
IVF
IVF
Conception
95
115
n
Singletons
Twins/triplets
6 months–4 years
2–5 years
1–2 years
1 year
6 weeks
Age of children at time of data collection
EPDS (clinically significant symptoms of depression) GHQ-12 (psychiatric disorder) CES-D (clinical depression) EPDS (levels of depression) CES-D, Radloff’s Spanish version (clinical depression)
Measures (dimension of mental health)
ND
$
ND $
" $
ND
ND
"
"
Father
Mother
Resultsa
CES-D, Center for Epidemiological Studies Depression Scale; EPDS, The Edinburgh Postnatal Depression Scale; F, father; GHQ, General Health Questionnaire; IUI, intrauterine insemination; M, mother; OI, ovulation induction. a Results compared with controls: " increased, # decreased, $ no difference and ND: no data available. b Matched for maternal age, parity and children’s year of birth. c Matched for age and sex of children. Families with disabled child/children were excluded.
M
Olivennes et al. [24 ]
M, first time
Sheard et al. [21]
Reference
Study participants – mother, father
Control couples
Study couples
Table 1 Cross-sectional studies assessing mental health of parents of twins conceived via assisted reproductive technology with comparison to couples with singletons according to the age of children at time of data collection
222 Fertility
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M and F
M and F
M
Colpin et al. [9]
Munro et al. [28]
Tully et al. [29]
121
40
24
37
n
IVF, IUI GIFT OI
IVF
IVF, AIH
ART
Conception
54 25 25 15 121 matchedb
38
n
Twins
Twins
Spontaneous Hormonally induced Spontaneous After infertility work up Spontaneous
Spontaneous
Conception
11.8 months (range 10–13) 6 months–5 years 8 months 5 years
8.5 months, SD 4.9
Age of children at time of data collection
MHI (depression, emotional ties, general positive affect, loss of behavioral emotional control) GHQ-30 (anxiety, and depression) GHQ-60 (psychiatric caseness) DIS (DSM-IV criteria for depression)
Measures (dimension of mental health)
Father $
$ $ ND
Mother $
$ $ $
Resultsa
AIH, artificial insemination by husband; ART, assisted reproduction technology; DIS, Diagnostic Interview Schedule; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders; F, father; GHQ, General Health Questionnaire; GIFT, gamete intrafallopian transfer; IUI, intrauterine insemination; M, mother; MHI, Mental Health Inventory; OI, ovulation induction. a Results compared with controls: $ no difference and ND: no data available. b Matched for sex, zygosity and ethnicity of twins; family income and occupation; relationship status of parents; twin’s birth order and birth weight; mother’s age; number of children in the family. Mothers of child/children with cerebral palsy excluded.
M and F
Baor et al. [27]
Reference
Study participants – mother, father
Control couples
Study couples
Table 2 Cross-sectional studies assessing mental health of parents of twins conceived via assisted reproductive technology with comparison to couples with twins according to the age of children at time of data collection
Mental health of parents of ART twins Vilska and Unkila-Kallio 223
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
$ $ $ $ $ $
# $
$ $
$ $ $ $
Comparison group, n
Mothers Depression Anxiety
$ $ $ $
$ $
$ $
– – – –
– –
ART < control –
Main effects
$ $ $ $
$ $
$ $
Control twins, 15
72
" $ $ "
$ $
" $
ART singletons, 324
Two months postpartum
$ $ $ $
$ $
$ $
Control singletons, 304
Twin > singleton – – Twin > singleton
– –
Twin > singleton Twin > singleton
Main effects
$ $ $ $
$ $
# #
Control twins, 11
55
" " $ $
$ $
" $
ART singletons, 270
With 1-year-old children
" " $ $
$ $
$ $
Control singletons, 251
Twin > singleton Twin > singleton Twin > singleton
Twin > singleton Twin > singleton ART < control – –
Main effects
ART, assisted reproductive technology; ", symptoms increased in mothers/fathers of ART twins; #, symptoms decreased in mothers/fathers of ART twins; $, no difference. Waller Duncan post-hoc analyses, analysis of covariance, main effects: group $ART/control, parenthood $twin/singleton. All analyses were adjusted for the child’s birth weight. Data modified from Vilska et al. [30].
Sleeping difficulties Social dysfunction Fathers Depression Anxiety Sleeping difficulties Social dysfunction
$ $
Control twins, 20
Control singletons, 379
91
ART couples with twins, n ART singletons, 367
The second trimester of pregnancy
Data collection time
Table 3 Mental health symptoms (General Health Questionnaire – 36) of parents of twins conceived via assisted reproductive technology compared with parents of twins conceived spontaneously (control twins), parents of singletons conceived via assisted reproductive technology (assisted reproductive technology singletons) and parents of singletons conceived spontaneously (control singletons) and the overall effect of assisted reproductive technology and twin parenthood on mental health symptoms
224 Fertility
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Mental health of parents of ART twins Vilska and Unkila-Kallio
within the same year. The control groups include a large number of couples with singletons conceived via ART as well as fertile couples with spontaneous singletons and smaller control group of fertile couples with spontaneous twins. Mental health was assessed in four dimensions – symptoms of depression, anxiety, social dysfunction and sleeping difficulties – at three time points: in the second trimester of pregnancy, 2 months after delivery and when the children were 1 year old. The full response rate was well satisfactory for statistical analysis for all other groups (60–73.6%) apart from the couples with spontaneously conceived twins (55%, n ¼ 11). Thus, the comparisons between parents with ART and spontaneously conceived 1-year-old twins have to be cautiously interpreted. However, this longitudinal setting with three control groups allowed an advanced statistical approach with multivariate analysis of covariance to evaluate the effect of ART and twinning on mental health. The previous study from the same material on parental mental health of singletons conceived via ART or spontaneously showed that successful ART did not predict impaired mental health during the transition to parenthood [31].
Maternal mental health during twin pregnancy achieved via assisted reproductive technology Data on maternal mental health during ART twin pregnancy exist only from the second trimester of pregnancy [30]. The symptoms of depression, anxiety as well as sleeping difficulties and social function in mothers of twins conceived via ART were comparable to mothers of singletons irrespective of the way of conception. However, when compared with mothers with spontaneously conceived twins, the mothers of twins conceived via ART had fewer symptoms of depression (Table 3).
Maternal mental health and twin parenthood following assisted reproductive technology Mothers of twins conceived via ART have more symptoms of depression at 2 months postpartum and with 1-year-old children than the mothers of singletons conceived via ART [30] (Table 3). The symptoms of anxiety were comparable. Further, in another large study [24], mothers of 2-year-old to preschool-aged twins conceived via IVF or ICSI had increased levels of depression when compared with matched mothers of singletons (Table 1). Similarly, clinical depression was more frequent in mothers of 1–2-year-old twins or triplets when compared with matched mothers of singletons [23]. However, the most recent, but small study [25] could not repeat this finding. Interestingly, first-time mothers were studied in a study of both twins and triplets and these mothers of multiples
225
conceived via ART had significantly more symptoms of depression than the counterpart mothers of singletons [21]. However, with 1-year-old children, no differences existed as regards the psychiatric disorders [22]. When comparing mental health of mothers with twins according to way of conception, similar mental health between ART and spontaneous conception has been found in different settings [9,27–29] (Table 2) except in the study by Vilska et al. [30]. Mothers with toddlerage twins conceived via ART had fewer symptoms of depression and anxiety than spontaneously conceived mothers of twins (Table 3). Taken together, mothers of ART twins have more symptoms of impaired mental health when compared with mothers of singletons conceived via ART. Mothers of twins conceived via ART have similar or better (one study) mental health than mothers of spontaneously conceived twins.
Paternal mental health during the partner’s twin pregnancy achieved via assisted reproductive technology Fathers of ART twins show similar mental health during their partner’s mid-pregnancy as fathers of singletons irrespective of the way of conception and fathers of spontaneously conceived twins [30] (Table 3).
Paternal mental health and twin parenthood following assisted reproductive technology The effect of twin parenthood on paternal mental health after successful ART has been studied in the recent study [30]. The fathers of twins conceived via ART had significantly more symptoms of depression and social dysfunction than fathers of singletons conceived via ART when the children were 2 months old (Table 3). With 1-year-old twins, the fathers who had experienced ART had more symptoms of depression and anxiety than the fathers of singletons irrespective of the way of conception. The recent small study [25] found no difference in clinical depression between fathers of twins or singletons conceived via ART and other infertility treatments. Way of conception, that is, ART, does not affect paternal mental health based on four studies [9,27,28,30] with series from 2-month-old to 5-year-old twins (Tables 2 and 3). In all, twin parenthood, not ART, is a risk factor for paternal mental health, especially with toddler-age twins.
Conclusion Existing data on mental health of parents with twins conceived via ART are very limited. ART twin pregnancy does not impair parental mental health during
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226 Fertility
mid-pregnancy. However, it is evident that at postpartum and at toddler to preschool age of children, parental mental health is better with singletons than with twins conceived via ART. Twin birth rate after ART is high due to transfer of multiple embryos. ART personnel are encouraged to counsel infertile couples prior ART on the known medical and psychosocial consequences of twin births. More data from large, well conducted prospective longitudinal studies on parental, not only maternal, mental health are needed from families with twins conceived via ART. Studies covering also later life with school-aged and adolescent twins are desired.
Acknowledgement We thank Maija Tulppala, MD, PhD, for her professional comments and help during the preparation of the manuscript.
11 Ryan GL, Zhang SH, Dokras A, et al. The desire of infertile patients for multiple births. Fertil Steril 2004; 81:500–504. 12 Hojgaard A, Ottosen LD, Kesmodel U, et al. Patient attitudes towards twin pregnancies and single embryo transfer: a questionnaire study. Hum Reprod 2007; 22:2673–2678. 13 Pinborg A, Loft A, Schmidt L, et al. Attitudes of IVF/ICSI-twin mothers towards twins and single embryo transfer. Hum Reprod 2003; 18:621–627. 14 Child TJ, Henderson AM, Tan SL. The desire for multiple pregnancy in male and female infertility patients. Hum Reprod 2004; 19:558–561. 15 Singer LT, Salvator A, Guo S, et al. Maternal psychological distress and parenting stress after the birth of a very low-birth-weight infant. JAMA 1999; 281:799–805. 16 Hansen M, Colvin L, Petterson B, et al. Twins born following assisted reproductive technology: perinatal outcome and admission to hospital. Hum Reprod 2009; 24:2321–2331. This large study considering zygosity compared health of twins conceived spontaneously or by ART during the first 3 years of children. Higher risk for adverse perinatal outcome, admission to NICU and hospitalization in ART twins was found. 17 Helmerhorst FM, Perquin DA, Donker D, et al. Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies. BMJ 2004; 328:261. 18 D’Alton M. Infertility and the desire for multiple births. Fertil Steril 2004; 81:523–525; discussion 526.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 257). Zegers-Hochschild F, Adamson GD, de Mouzon J, et al. The International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) Revised Glossary on ART Terminology, 2009. Hum Reprod 2009; 24:2683–2687. This study reports internationally accepted standardized terminology in medically assisted reproduction to be used also in infertility research.
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Thurin A, Hausken J, Hillensjo T, et al. Elective single-embryo transfer versus double-embryo transfer in in vitro fertilization. N Engl J Med 2004; 351:2392– 2402.
Pandian Z, Bhattacharya S, Ozturk O, et al. Number of embryos for transfer following in-vitro fertilisation or intra-cytoplasmic sperm injection. Cochrane Database Syst Rev 2009:CD003416. This Cochrane Database systematic review updates the evidence of effectiveness of the embryo transfer policies.
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Nyboe Andersen A, Goossens V, Bhattacharya S, et al. Assisted reproductive technology and intrauterine inseminations in Europe, 2005: results generated from European registers by ESHRE: ESHRE. The European IVF Monitoring Programme (EIM), for the European Society of Human Reproduction and Embryology (ESHRE). Hum Reprod 2009; 24:1267–1287. Sunderam S, Chang J, Flowers L, et al. Assisted reproductive technology surveillance: United States, 2006. MMWR Surveill Summ 2009; 58:1–25.
Hammarberg K, Fisher JR, Wynter KH. Psychological and social aspects of pregnancy, childbirth and early parenting after assisted conception: a systematic review. Hum Reprod Update 2008; 14:395–414. This is a comprehensive review of research on psychosocial aspects of transition to parenthood after successful ART. The authors highlight methodological differences and inconsistencies in current evidence. The challenges of future research of the topic are discussed.
7
19 Ryan GL, Sparks AE, Sipe CS, et al. A mandatory single blastocyst transfer policy with educational campaign in a United States IVF program reduces multiple gestation rates without sacrificing pregnancy rates. Fertil Steril 2007; 88:354–360. 20 Schmidt L. Social and psychological consequences of infertility and assisted reproduction: what are the research priorities? Hum Fertil (Camb) 2009; 12:14–20. 21 Sheard C, Cox S, Oates M, et al. Impact of a multiple, IVF birth on postpartum mental health: a composite analysis. Hum Reprod 2007; 22:2058–2065. 22 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; 81:505–511. 23 Ellison MA, Hotamisligil S, Lee H, et al. Psychosocial risks associated with multiple births resulting from assisted reproduction. Fertil Steril 2005; 83:1422–1428. 24 Olivennes F, Golombok S, Ramogida C, et al. Behavioral and cognitive development as well as family functioning of twins conceived by assisted reproduction: findings from a large population study. Fertil Steril 2005; 84:725–733. This large study with relevant study design compares levels of depression in mothers of preschool-age twins and singletons conceived via ART. 25 Roca de Bes M, Gutierrez Maldonado J, Gris Martinez JM. Psychosocial risks associated with multiple births resulting from assisted reproduction: a Spanish sample. Fertil Steril 2009; 92:1059–1066. 26 Garel M, Salobir C, Lelong N, et al. Mothers of triplets and their children: course from 4 to 7 years after birth. Gynecol Obstet Fertil 2000; 28:792– 797. 27 Baor L, Bar-David J, Blickstein I. Psychosocial resource depletion of parents of twins after assisted versus spontaneous reproduction. Int J Fertil Womens Med 2004; 49:13–18. 28 Munro JM, Ironside W, Smith GC. Psychiatric morbidity in parents of twins born after in vitro fertilization (IVF) techniques. J In Vitro Fert Embryo Transf 1990; 7:332–336. 29 Tully LA, Moffitt TB, Caspi A. Maternal adjustment, parenting and child behaviour in families of school-aged twins conceived after IVF and ovulation induction. J Child Psychol Psychiatry 2003; 44:316–325.
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Klock SC. Psychological adjustment to twins after infertility. Best Pract Res Clin Obstet Gynaecol 2004; 18:645–656.
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Colpin H, Munter AD, Nys K, et al. Parenting stress and psychosocial well being among parents with twins conceived naturally or by reproductive technology. Hum Reprod 1999; 14:3133–3137.
30 Vilska S, Unkila-Kallio L, Punamaki RL, et al. Mental health of mothers and fathers of twins conceived via assisted reproduction treatment: a 1-year prospective study. Hum Reprod 2009; 24:367–377. In this prospective, longitudinal study, mental health of mothers and fathers of twins conceived via ART is assessed by General Health Questionnaire-36 over the transition to parenthood by comparisons with parents of ART singletons and with parents of spontaneously conceived twins and singletons.
10 Choi Y, Bishai D, Minkovitz CS. Multiple births are a risk factor for postpartum maternal depressive symptoms. Pediatrics 2009; 123:1147–1154. This large population-based well conducted study shows clearly the association of multiple births and maternal depressive symptoms 9 months after delivery.
31 Repokari L, Punama¨ki R-L, Poikkeus, et al. The impact of successful assisted reproduction treatment on female and male mental health during transition to parenthood: a prospective controlled study. Hum Reprod 2005; 20:3238– 3247.
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Borderline ovarian tumors and fertility Joo-Hyun Nam Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea Correspondence to Joo-Hyun Nam, MD, PhD, Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, #388-1 Poongnap-2 Dong, Songpa-Gu, Seoul 138-736, Republic of Korea Tel: +82 2 3010 3633; fax: +82 2 476 7331; e-mail:
[email protected] Current Opinion in Obstetrics and Gynecology 2010, 22:227–234
Purpose of review Borderline ovarian tumors (BOTs) are a distinct diagnostic category of epithelial ovarian tumors, distinguished from both benign and invasive epithelial ovarian tumors. Because they affect young women of childbearing age, are diagnosed at an early stage, and are associated with excellent prognosis, fertility-sparing options are often used. In this review, we discuss recent findings on the outcomes of fertility-sparing treatments in patients with BOTs. Recent findings Reports on the use of fertility-sparing surgery in patients with advanced-stage BOTs and on the application of laparoscopy in fertility-sparing surgery are increasing. As potential alternative, experiences on ovarian tissue cryopreservation have been reported. Summary Fertility-sparing surgery is the best option to preserve childbearing capacity in young patients with BOTs. Fertility-sparing surgery is well tolerated not only in patients with early-stage BOTs but also in patients with advanced-stage BOTs with noninvasive extraovarian implants, if these implants can be resected completely. After fertilitysparing surgery, pregnancy outcomes are promising and most pregnancies are achieved spontaneously. There are few complications associated with pregnancy, and subsequent pregnancy seems to have little impact on disease course. Fertility drugs are well tolerated in patients with infertility after fertility-sparing surgery for early-stage BOTs, but caution should be exercised when using these drugs after surgery in patients with advanced-stage BOTs. If fertility-sparing surgery is technically not feasible owing to extensive tumor involvement of both ovaries, recent artificial reproductive technologies can be considered, including embryo, oocyte, and ovarian tissue freezing; use of donor oocytes; and surrogacy, but more experience with these options is required. Keywords borderline ovarian tumor, fertility, fertility-sparing surgery Curr Opin Obstet Gynecol 22:227–234 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1040-872X
Introduction Borderline ovarian tumor (BOT) is a distinct diagnostic category of epithelial ovarian tumor, distinguished from both benign epithelial ovarian tumor and invasive epithelial ovarian cancer [1,2]. BOTs account for 5% of all epithelial ovarian tumors and 15% of all epithelial ovarian cancers [3]. Pathologically, BOTs are characterized by features of malignant epithelial ovarian tumors, including stratification of the epithelial lining of the papillae, formation of microscopic papillary projections or tufts arising from the epithelial lining of the papillae, epithelial pleomorphism, atypicality, and mitotic activity, but do not demonstrate invasion of the underlying stroma [4]. Although uncommon, metastatic noninvasive or invasive implants may occur in patients with BOTs. Clinically, BOTs are distinct from invasive epithelial ovarian cancer in that more than 80% of BOTs are diagnosed as stage I 1040-872X ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
disease, they often affect young women who wish to preserve their fertility, and they have low potential for malignancy, including indolent behavior, longer patient survival, and later recurrence [5]. Nearly, all series have reported a 5-year survival rate of 100% for patients with stage I and IIA tumors [6]. Even when the tumor involves the pelvis or abdomen, the 5-year survival rate is about 80% [6]. BOTs are diagnosed at an early stage and in young women who wish to preserve their fertility, and are associated with excellent prognosis; hence, patients with BOTs are good candidates for fertility-preserving treatments. Fertility-sparing surgery has shown increased safety and efficacy in patients with BOTs, and outcomes have been reported for other fertility-preserving options in patients for whom fertility-sparing surgery is not applicable. DOI:10.1097/GCO.0b013e3283384928
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228 Fertility
based on disease extent and the presence of factors associated with poor prognosis, including microinvasion, a micropapillary pattern, and invasive or noninvasive implants. Among the variables to consider during surgery are the type of adnexal surgery (cystectomy, oophorectomy, or salpingo-oophorectomy), the performance of wedge biopsy of the normal appearing contralateral ovary, and the use of a laparoscopic approach.
Text of review Of several options to preserve fertility, fertility-sparing surgery is the best option.
Fertility-sparing surgery Surgical removal of BOTs is the mainstay of patient management. Although the extent of surgery has been debated, the standard surgical procedures include total hysterectomy; bilateral salpingo-oophorectomy and peritoneal staging procedures, including peritoneal washings, multiple peritoneal biopsies, and resection of implants; omentectomy; and appendectomy (in patients with mucinous BOTs) [7]. Lymphadenectomy is usually not indicated owing to the rarity of lymph node metastasis and questions regarding the prognostic role of lymph node metastasis [8–11]. Because of recent changes in attitudes toward radical oncologic surgery, benefits are evaluated not only with respect to disease control but also to functional end results that may affect the patient’s quality of life. Preservation of fertility during surgery is regarded as one of the most important quality-of-life issues in younger patients with BOTs. Most studies, including this review, have defined fertility-sparing surgery as the preservation of the uterus and ovarian tissue in one or both adnexa in women of reproductive age, and defined radical surgery as approaches that include total hysterectomy, bilateral salpingo-oophorectomy, or both.
Early stage (International Federation of Gynecology and Obstetrics stage I)
Fertility-sparing surgery was initially performed in patients with early-stage or International Federation of Gynecology and Obstetrics (FIGO) stage I BOTs. Therefore, most studies compared the oncologic safety of fertility-sparing surgery and radical surgery in patients with early-stage BOTs (Table 1 [12–18,19,20]). Although recurrence rates were similar to or slightly higher in patients undergoing fertility-sparing surgery than in those undergoing radical surgery, fertility-sparing surgery did not compromise survival. Most recurrent lesions in patients who underwent fertility-sparing surgery were borderline tumors, which could be cured with complete surgical procedures at recurrence, similar to recurrences in patients who underwent radical surgery. Thus, fertility-sparing surgery was considered well tolerated in patients with early-stage BOTs. However, the patterns of recurrence were somewhat different in the two groups of patients. Fertility-sparing surgery was associated with lower rates of abdominal and pelvic recurrences than radical surgery. Rather, the most common type of recurrence in patients who underwent fertility-sparing surgery was isolated recurrence in the remaining ovary. This has important clinical implications
Oncologic safety
Because fertility-sparing surgery should not compromise the survival of patients with BOTs, this surgical approach should be reserved for young women who wish to preserve their fertility. The radicality of surgery should be
Table 1 Comparison of the outcome of fertility-sparing surgery with radical surgery in patients with early-stage borderline ovarian tumor Reference Ji et al. [12] Gotlieb et al. [13] Zanetta et al [14] Morice et al. [15] Romagnolo et al. [16] Donnez et al. [17] Fauvet et al. [18] Park et al. [19] De Iaco et al. (2009) [20]
Surgical management
Number of patients
Follow-up time (months, median)
Recurrence, n (%)
Radical Fertility-sparing Radical Fertility-sparing Radical Fertility-sparing Radical Fertility-sparing Radical Fertility-sparing
70 25 26 49 150 189 125 49 60 53
55 88 57
3 (4) 4 (16) 2 (8) 4 (8) 7 (5) 35 (19) 6 (5) 9(18) 4 (7) 9 (17)
Radical Fertility-sparing Radical Fertility-sparing Radical
59 16 194 164 176
NR NR 65
0 3 14 23 9
Fertility-sparing Radical Fertility-sparing
184 83 95
60 NR NR
9 (5) 5 (6.0) 22 (23)
70 109 NR NR 75
(0) (19) (7) (14) (5)
Location of recurrent disease at first recurrence 2, abdomen; 1, omentum 3, ovary; 1, abdomen 2, pelvis 2, ipsilateral ovary; 2, contralateral ovary NR NR NR 1, both ovary; 6, contralateral ovary; 2, NR 3, pelvis; 1, NR 2, pelvis; 3, ipsilateral ovary; 3, contralateral ovary; 1, NR 3, ovary NR NR 1, ovary; 1, ovary, pelvis; 1, pelvis; 2, pelvis, pelvic lymph nodes; 4, peritoneal seeding 7, ovary; 1, ovary, lung; 1, lung, pericardium 5, pelvis 20, ovary; 1, ovary, peritoneum; 1, peritoneum
NR, not reported.
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Borderline ovarian tumors and fertility Nam 229
because isolated ovarian recurrences can be cured by secondary surgery, including a second round of fertility-sparing surgery in patients who wish to preserve their fertility. Several studies [19,20,21] have shown that a second round of fertility-sparing surgery was both well tolerated and effective. Advanced stage (International Federation of Gynecology and Obstetrics stages II–IV): extraovarian invasive or noninvasive implants
Recently, the application of fertility-sparing surgery has expanded to include patients with advanced-stage disease by noninvasive extraovarian implants. Implant invasiveness is an important factor when considering fertilitysparing surgery in patients with advanced-stage disease because invasiveness is the most important prognostic factor in these patients. Although several studies have reported the outcomes of fertility-sparing surgery in patients with advanced-stage BOTs (Table 2 [14,19, 20,22–24,25,26]), the number of study participants was too small to draw definitive conclusions. However, the overall survival of patients with noninvasive implants was excellent, with most patients who died after fertilitysparing surgery having had invasive implants [27,28,29]. Therefore, fertility-sparing surgery can be a viable treatment option in patients with noninvasive implants if the implants can be resected completely. Further evaluation is required to confirm these findings.
high, but only one patient with an extraovarian implant died of disease [36]. Although definitive conclusions are limited by the small sample size, the authors of this study suggested that fertility-sparing surgery could be safely proposed to a majority of patients with micropapillary BOTs who are carefully followed up [36]. Further evaluation, however, is warranted. Infrequently, microscopic foci of invasion of the stroma by single cells and nests of moderately atypical cells are found in patients with BOTs. If such foci measure less than 3 mm in the longest linear dimension and are 10 mm2 or less in area, the tumors are designated BOTs with microinvasion. Although studies [22,37] have suggested that the prognosis of patients with BOTs with microinvasion is similar to that of patients with BOTs without microinvasion, several recent studies have suggested that microinvasion ultimately has an impact on recurrence rate, survival, or both [24,38]. Few studies have addressed the outcome of fertility-sparing surgery in patients with BOTs with microinvasion, but a recent study [39] included 10 such patients with microinvasion but without micropapillary pattern. Although five of these patients had recurrent disease, all lesions developed on the remaining ovary and all patients with recurrence were salvaged successfully [39]. This suggests that fertility-sparing surgery may be well tolerated in patients with BOTs with microinvasion, but further evaluation is required.
Micropapillary pattern and microinvasion
BOTs with a micropapillary pattern [30,31] have been associated with more common bilateral ovarian involvement, extraovarian implants, and invasive implants [22,32]. Although some studies [31,32,33] have reported an increased risk of recurrence in patients with micropapillary type tumors, other studies [34,35] have not found this association. Few studies have evaluated the outcomes of fertility-sparing surgery in patients with micropapillary BOTs, although a recent study [36] included 15 such patients. The rates of bilateral ovarian involvement, extraovarian implants, and recurrence were
Type of adnexal surgery
Oophorectomy or salpingo-oophorectomy as fertilitysparing surgery in patients with BOTs has been reported to be associated with better oncologic safety because lessextensive surgery has been associated with higher recurrence rates. In some patients, however, cystectomy as fertility-sparing surgery may be the only viable option owing to previous history of unilateral oophorectomy or salpingo-oophorectomy or bilateral involvement of BOTs. Although limited data are currently available on the safety and outcomes of cystectomy in patients with
Table 2 The outcome of fertility-sparing surgery in patients with advanced-stage borderline ovarian tumor Reference
Type of implants
Zanetta et al. [14]
Noninvasive Invasive Noninvasive Invasive Noninvasive Invasive Noninvasive Invasive NR NR Noninvasive Noninvasive Invasive
Prat and De Nictolis [22] Camatte et al. [23] Longacre et al. [24] De Iaco et al. [20] Vigano et al. [25] Park et al. [19] Uzan et al. [26]
Number of patients
Recurrence
Death
18 7 9 1 14 3 21 0 21 10 3 38 3
5 5 2 1 7 2 5 0 4 6 1 20 2
0 0 0 1 0 0 0 0 NR 0 0 1 0
NR, not reported.
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230 Fertility
BOTs, a recent retrospective study comparing the outcomes in 40 patients who underwent unilateral salpingooophorectomy with those in 22 patients who underwent cystectomy found that the recurrence rates were 22.7 and 27.5%, respectively. A recent prospective randomized controlled trial comparing the safety of bilateral cystectomy and unilateral oophorectomy along with contralateral cystectomy in patients with bilateral BOTs found no significant differences between the two groups. In addition, several retrospective studies have suggested that bilateral adnexectomy in patients with bilateral BOTs was associated with only an insignificant increase in recurrence rate. Taken together, these findings indicate that cystectomy is well tolerated for patients with BOTs, but that cystectomy should be limited to patients with a previous history of unilateral adnexectomy or bilateral BOTs.
Integration of laparoscopic surgery
Wedge biopsy of normal appearing contralateral ovary
Fertility outcomes
The rates of bilateral involvement of BOTs have been reported to be 25–50% for serous-type tumors and 5– 10% for mucinous-type tumors [4,5], suggesting the need for histopathologic evaluation of the contralateral ovary during fertility-sparing surgery. However, wedge biopsy of the remaining ovary may cause mechanical infertility or ovarian failure [15,40]. A study of 14 patients who underwent wedge biopsy of the contralateral ovary found that none was positive, and one patient with normal results had recurrent disease in the remaining ovary [15]. These findings indicate that histopathologic evaluation of the normal appearing contralateral ovary is not helpful in reducing the risk of recurrence in the remaining ovary. In a recent retrospective study [19] of 22 patients who underwent wedge biopsy of the normal appearing contralateral ovary, none was positive for BOTs, whereas 11 of the 22 patients who underwent cystectomy to remove benign-appearing cysts of the contralateral ovary had BOTs on the contralateral ovary. Thus, careful inspection of the surface of the contralateral ovary and biopsies of suspicious lesions or cysts should be adequate for screening.
Because most previous studies have been retrospective in design, information on baseline ovarian function and fertility status before surgery, postoperative ovarian function, and menstrual function was not available. In addition, information on pregnancy outcomes was also limited because only some of these previous studies reported pregnancy outcomes and some omitted some of the details of pregnancy outcomes. However, pregnancy outcomes seem promising because pregnancy rates ranged from 32 to 100% (Table 4 [9,12–14,16–18,19,26,44,46–51]). Most patients conceived spontaneously without infertility treatment and few patients suffered from infertility (Table 4). The rates of complications associated with pregnancy, including ectopic pregnancy, miscarriage, preterm delivery, and fetal anomaly, were not significant (Table 4).
Laparoscopic surgery has several advantages over laparotomy in the management of adnexal tumors. Owing to advances in laparoscopic instruments and surgical techniques, the use of laparoscopic surgery is continuously increasing in the surgical management of patients with BOTs and invasive epithelial ovarian cancers. It is now possible to perform all surgical staging procedures for BOTs and epithelial ovarian cancers laparoscopically [41,42]. Studies [41,42] have suggested the feasibility, safety, and accuracy of laparoscopic surgery for patients with early-stage epithelial ovarian cancer. Recurrence rates were found to be similar in patients undergoing laparoscopy or laparotomy, fertility-sparing surgery for BOTs (Table 3 [16–18,19,43,44,45]), indicating that laparoscopic surgery is a reasonable alternative to laparotomy in the surgical management of patients with BOTs.
The appropriate time to try to conceive after fertilitysparing surgery has not been determined, although successful pregnancies have been achieved as early as 3 months after surgery [26,44]. Because pregnancies complicated by recurrent disease during this early
Table 3 Comparison of laparoscopic and laparotomic fertility-sparing surgery in patients with borderline ovarian tumor Reference
Surgical approach
Donnez et al. [17]
Laparoscopy Laparotomy Laparoscopy Laparotomy Laparoscopy Laparotomy Laparoscopy Laparotomy Laparoscopy Laparotomy Laparoscopy Laparotomy Laparoscopy Laparotomy
Maneo et al. [43] Fauvet et al. [18] Boran et al. [44] Romagnolo et al. [16] Park et al. [19] Total
Number of patients 3 13 30 32 149 209 56 6 53 61 48 136 399 457
Recurrence (%) 3 0 11 7 18 19 4 0 7 6 2 7 45 39
(100) (0) (36.7) (21.9) (12.1) (9.1) (7.1) (0) (13.2) (9.8) (4.2) (5.1) (11.3) (8.5)
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95 82 79 518 19 339 27 25 75 142 360 249 113 101 360 41
25 39 15 43 19 189 12 25 16 62 162 38 53 37 184 41
19 NR NR 24 10 NR 12 6 11 25 65 NR 12 NR 31 NR
9 (47) 15 6 12 (50) 6 (60) 44 6 (60) 6 (100) 7 (64) 10 (45) 21 (32) 3 7 (58) 13 27 (87) 14
NR 22 10 25 6 44 6 6 12 13 30 4 8 13 33 18
NR NR NR NR 6 NR NR 4 12 13 27 4 7 13 33 9
NR NR NR NR 0 NR NR 1b 0 0 3d 0 0 0 0 5f
NR NR NR 14a 0 NR NR 2c 0 0 8 NR 0 0 0 8g
NR, not reported. a Five patients had infertility before surgery. b Ovulation induction. c One patient had infertility before surgery. d Ovulation induction with intrauterine insemination in one patient, and in-vitro fertilization and embryo transfer in two patients. e Elective termination for personal reason in eight patients. f Ovulation induction in two patients and in-vitro fertilization with embryo transfer in three patients. g Ovulation induction in three patients and in-vitro fertilization with embryo transfer in five patients. h Including one molar pregnancy.
Ji et al. [12] Gotlieb et al. [13] Papadimitriou et al. [46] Morris et al. [47] Seracchioli et al. [48] Zanetta et al. [14] Demeter et al. [49] Chan et al. [50] Donnez et al. [17] Boran et al. [44] Fauvet et al. [18] Rao et al. [51] Romagnolo et al. [16] Camatte et al. [9] Park et al. [19] Uzan et al. [26]
Reference NR 0 NR NR NR 3 NR 1 0 3 8e 0 1 0 0 0
NR 0 NR NR 0 0 NR 0 0 0 0 0 0 0 0 4h
NR 3 NR NR 0 0 NR 0 0 0 0 0 0 NR 0 0
NR 0 NR NR 0 0 NR 0 0 0 0 0 0 NR 0 0
NR 19 NR NR 6 41 NR 4 12 10 17 4 7 NR 33 14
NR 0 NR NR 0 NR NR 0 0 0 0 0 0 NR 0 0
NR 0 5 1 0 NR NR 0 1 1 5 NR 2 0 0 NR
No. of No. of No. of patients Recurrence Total patients pregnancy No. of Pregnancy patients Ectopic Ongoing Preterm Term Fetal after no. of Conservative pregnancy achieved pregnancy Spontaneous with assisted fertility patients surgery attempt (%) achieved pregnancy reproduction treatment Abortion pregnancy pregnancy birth birth anomaly pregnancy
Table 4 Pregnancy outcome after fertility-sparing surgery in patients with borderline ovarian tumor
NR NR NR NR 24.5 15.7 NR NR NR NR 13.7 (3–36) 28.6 24.6 NR NR 39 NR 13.5 (3–183)
Mean time interval to pregnancy (months)
NR NR NR NR NR 11 NR NR NR NR NR NR NR NR 0 1
Radical surgery after completion of family planning
Borderline ovarian tumors and fertility Nam 231
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232 Fertility
follow-up period would be problematic, many physicians are reluctant to recommend that patients conceive within 1 or 2 years after fertility-sparing surgery. However, this delay may negatively influence pregnancy outcomes. In addition, because BOTs tend to recur later than invasive epithelial ovarian cancer, it is not reasonable to delay pregnancy until after a sufficient follow-up period. Therefore, married patients should try to conceive from 3 to 6 months after surgery. Although the influence of pregnancy on disease course has not been fully evaluated, recurrence rates after pregnancy were not high and there have been few reports of recurrences complicated by pregnancy (Table 4). If patients are unmarried, periodic follow-up with cancer antigen-125 and ultrasonography of the remaining ovary after 3–6 months is recommended before trying to conceive owing to the high rate of recurrence in the remaining ovary during the follow-up period. It is also not clear whether radical surgery, including hysterectomy and salpingo-oophorectomy, should be performed after patients complete their families. Although most studies have not reported the number of patients who underwent radical surgery after family completion (Table 4), most patients remained disease-free after a long followup period without radical surgery [14,19,26]. Most recurrent lesions were borderline tumors and were located in the remaining ovary; thus, these patients were salvaged successfully by secondary surgery. Therefore, it may be reasonable to delay radical surgery until recurrence. Because the preservation of ovarian function is another important goal of fertility-sparing surgery, it may also be reasonable to delay complete surgery until after menopause. The effect of infertility treatment, particularly ovulation induction, on the disease course after fertility-sparing surgery is unclear. Retrospective case–control studies [52,53] have suggested a link between the use of fertility drugs and ovulation induction with clomiphene citrate and the occurrence of epithelial ovarian cancer. One mechanism explaining the link between ovulation induction and the development of epithelial ovarian cancer may be the direct action of gonadotropins on ovarian epithelial cells [54]. However, a recent in-vitro study [55] using BOT and invasive epithelial ovarian cancer cell lines found that high doses of estrogens or gonadotropins did not induce tumor cell proliferation. In addition, a recent retrospective multicenter study [56] found that four of 25 early-stage BOT patients who underwent ovulation induction had recurrent disease, but all recurrent lesions were borderline tumors and all patients were salvaged successfully. These findings indicate that infertility drugs can be used safely in patients who experience infertility after fertility-sparing surgery of early-stage BOTs. However, induction of ovulation in some patients
with advanced-stage BOTs has been found to induce recurrences as rapidly progressive invasive carcinomas [26,57], although other patients did not experience recurrence [47,56,58]. Therefore, caution should be exercised regarding ovulation induction in patients with advanced-stage BOTs.
Other potential options to preserve fertility Patients ineligible for fertility-sparing surgery because the normal ovarian portion cannot be preserved due to massive bilateral ovarian involvement and only the uterus can be preserved have several alternative options for fertility preservation. These include embryo freezing, oocyte freezing, and ovarian tissue freezing. Embryo freezing is routinely used in infertility clinics and has a good success rate of 20–30% [59]. It can be considered for BOT patients before definitive surgery [60]. However, a life partner or sperm donor is required, and patients must delay cancer treatment for 2–6 weeks. Oocyte freezing is also a viable option for fertility preservation in patients with BOTs. More than 230 pregnancies from frozen oocytes have been reported worldwide, with live-birth rates per oocyte thawed of 1.9–4.6% [61]. To our knowledge, however, oocyte freezing has not yet been attempted in patients with BOTs. Although oocyte freezing does not require a life partner or sperm donor, it does require a 2–6-week delay in cancer treatment. Moreover, these two fertility preservation options are costly and both must be planned and performed before surgery. Thus, they are not applicable for most patients with BOTs because BOTs are usually diagnosed during surgery by frozen biopsy. Another option to preserve fertility is ovarian tissue freezing, which can be performed during surgery. To our knowledge, however, only three pregnancies from ovarian tissue freezing have been reported in the literature [62–64]. Delay in cancer treatment and a life partner or sperm donor are not required. A large number of immature oocytes can be frozen using this technique. Although several studies have reported a restoration of endocrine function and embryo development from this technique, it is still experimental, and cancer cells may be transmitted [65]. This technique has been used recently in patients with BOTs, but, to our knowledge, the cryopreserved fragments have not been reimplanted [66]. Donor oocytes can also be used [67,68], if none of these methods is feasible. Surrogacy can also be considered for patients who require hysterectomy, but this does not constitute fertility preservation.
Conclusion Fertility-sparing surgery is the best option to preserve childbearing capacity in young patients with BOTs. It can be safely performed not only in patients with early-stage BOTs but also in patients with advanced-stage BOTs
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Borderline ovarian tumors and fertility Nam 233
who have noninvasive extraovarian implants if these implants can be resected completely. Recurrence is more common in patients who undergo fertility-sparing surgery than those who undergo radical surgery. However, most recurrent lesions are borderline tumors and located in the remaining ovary. Hence, most patients with recurrent disease can be salvaged successfully by secondary surgery, and second-round fertility-sparing surgery may be feasible for patients who still wish to preserve their fertility. Pregnancy outcomes after fertility-sparing surgery are promising and most pregnancies are achieved spontaneously. The rate of pregnancy-associated complications is low and subsequent pregnancy has little impact on disease course. Fertility drugs are well tolerated in patients with early-stage BOTs who experience infertility after fertility-sparing surgery, but caution is warranted in patients with advanced-stage BOTs. If fertility-sparing surgery is technically not feasible due to extensive tumor involvement of both ovaries, other potential options can be considered, including embryo freezing, oocyte freezing, ovarian tissue freezing, use of donor oocytes, and surrogacy, but more experience with these options is required.
Acknowledgement There is no conflict of interest.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 256). 1
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234 Fertility 33 Chang SJ, Ryu HS, Chang KH, et al. Prognostic significance of the micro papillary pattern in patients with serous borderline ovarian tumors. Acta Obstet Gynecol Scand 2008; 87:476–481. In this study, the presence of micropapillary pattern was significant prognostic factor in patients with BOT. 34 Slomovitz BM, Caputo TA, Gretz HF 3rd, et al. A comparative analysis of 57 serous borderline tumors with and without a noninvasive micropapillary component. Am J Surg Pathol 2002; 26:592–600. 35 Winter WE 3rd, Kucera PR, Rodgers W, et al. Surgical staging in patients with ovarian tumors of low malignant potential. Obstet Gynecol 2002; 100:671– 676. 36 Laurent I, Uzan C, Gouy S, et al. Results after conservative treatment of serous borderline tumors of the ovary with a micropapillary pattern. Ann Surg Oncol 2008; 15:3561–3566. This study included 15 patients with micropapillary BOT who underwent fertilitysparing surgery. 37 Kennedy AW, Hart WR. Ovarian papillary serous tumors of low malignant potential (serous borderline tumors). A long-term follow-up study, including patients with microinvasion, lymph node metastasis, and transformation to invasive serous carcinoma. Cancer 1996; 78:278–286. 38 Ren J, Peng Z, Yang K. A clinicopathologic multivariate analysis affecting recurrence of borderline ovarian tumors. Gynecol Oncol 2008; 110:162– 167. In multivariate analysis including 234 patients with BOT, surgical procedure, cyst rupture, stage of disease, microinvasion, and peritoneal implants were independent prognostic factors for disease-free survival. 39 Laurent I, Uzan C, Gouy S, et al. Results after conservative treatment of serous borderline tumours of the ovary with stromal microinvasion but without micropapillary pattern. BJOG 2009; 116:860–862. This study included 18 patients who underwent fertility-sparing surgery for BOT with stromal microinvasion but without micropapillary pattern. 40 Weinstein D, Polishuk WZ. The role of wedge resection of the ovary as a cause for mechanical sterility. Surg Gynecol Obstet 1975; 141:417–418. 41 Park JY, Bae J, Lim MC, et al. Laparoscopic and laparotomic staging in stage I epithelial ovarian cancer: a comparison of feasibility and safety. Int J Gynecol Cancer 2008; 18:1202–1209. 42 Park JY, Kim DY, Suh DS, et al. Comparison of laparoscopy and laparotomy in surgical staging of early-stage ovarian and fallopian tubal cancer. Ann Surg Oncol 2008; 15:2012–2019. 43 Maneo A, Vignali M, Chiari S, et al. Are borderline tumors of the ovary safely treated by laparoscopy? Gynecol Oncol 2004; 94:387–392. 44 Boran N, Cil AP, Tulunay G, et al. Fertility and recurrence results of conservative surgery for borderline ovarian tumors. Gynecol Oncol 2005; 97:845–851. 45 Tinelli R, Malzoni M, Cosentino F, et al. Feasibility, safety, and efficacy of conservative laparoscopic treatment of borderline ovarian tumors. Fertil Steril 2009; 92:736–741. This is a comprehensive review on the role of laparoscopic surgery in fertilitysparing management for young women with BOT. 46 Papadimitriou DS, Martin-Hirsch P, Kitchener HC, et al. Recurrent borderline ovarian tumours after conservative management in women wishing to retain their fertility. Eur J Gynaecol Oncol 1999; 20:94–97. 47 Morris RT, Gershenson DM, Silva EG, et al. Outcome and reproductive function after conservative surgery for borderline ovarian tumors. Obstet Gynecol 2000; 95:541–547. 48 Seracchioli R, Venturoli S, Colombo FM, et al. Fertility and tumor recurrence rate after conservative laparoscopic management of young women with earlystage borderline ovarian tumors. Fertil Steril 2001; 76:999–1004. 49 Demeter A, Csapo Z, Szantho A, et al. A retrospective study of 27 ovarian tumors of low malignant potential. Eur J Gynaecol Oncol 2002; 23:415–418.
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Stem cells and reproduction Hongling Dua and Hugh S. Taylora,b a
Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine and bMolecular Cellular and Developmental Biology, Yale University, New Haven, Connecticut, USA Correspondence to Hugh S. Taylor, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University, P.O. Box 208063, 333 Cedar St, New Haven, CT 06520, USA Tel: +1 203 785 4005; e-mail:
[email protected] Current Opinion in Obstetrics and Gynecology 2010, 22:235–241
Purpose of review To review the latest developments in reproductive tract stem cell biology. Recent findings In 2004, two studies indicated that ovaries contain stem cells which form oocytes in adults and that can be cultured in vitro into mature oocytes. A live birth after orthotopic transplantation of cyropreserved ovarian tissue in a woman whose ovaries were damaged by chemotherapy demonstrates the clinical potential of these cells. In the same year, another study provided novel evidence of endometrial regeneration by stem cells in women who received bone marrow transplants. This finding has potential for the use in treatment of uterine disorders. It also supports a new theory for the cause of endometriosis, which may have its origin in ectopic transdifferentiation of stem cells. Several recent studies have demonstrated that fetal cells enter the maternal circulation and generate microchimerism in the mother. The uterus is a dynamic organ permeable to fetal stem cells, capable of transdifferentiation and an end organ in which bone marrow stem cells may differentiate. Finally stem cell transformation can be an underlying cause of ovarian cancer. Summary Whereas we are just beginning to understand stem cells, the potential implications of stem cells to reproductive biology and medicine are apparent. Keywords bone marrow, endometriosis, endometrium, oocyte, reproduction, stem cells Curr Opin Obstet Gynecol 22:235–241 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1040-872X
Introduction Stem cells are defined as undifferentiated cells that are capable of reproducing themselves (self-renewal) and differentiating into many different cell types, which can produce at least one type of highly differentiated descendant. Embryonic stem cells are derived from the inner cell mass of the blastocysts. They were first isolated from mouse in 1981 and these cells have the developmental potential to form trophoblast and derivatives of all three germ layers in vitro [1,2]. Due to these characteristics of embryonic stem cells, research on embryonic stem cells raises the possibility of ‘designer’ tissue and organ engineering. However, ethical considerations question the instrumental use of embryos for the isolation of stem cells, even if those embryos are surplus to requirements for assisted reproduction and destined for destruction. One alternative is to explore the use of adult stem cells; however, their full potential remains to be determined. Nearly all postnatal organs and tissues contain populations of stem cells, which have the capacity for renewal after damage or ageing. In the past several years, studies on adult stem cell plasticity show that adult stem cells are 1040-872X ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
able to differentiate into other cell types in new locations, in addition to their usual progeny in their organ of residence [3,4]. Bone marrow derived stem cells can differentiate into skeletal myoblasts, endothelium, cardiac myoblasts, renal parenchymal, hepatic and biliary duct epithelium, lung, gut and skin epithelia, and neuroectodermal cells [5]. These studies show that bone marrow-derived stem cells may be involved in the regeneration of damaged tissue. The concept of plasticity of stem cells also opens up the possibility of repairing an individual’s failing organ by transplanting. The adult stem cells are responsible for the growth, homeostasis and repair of many tissues. How can they balance self-renewal with differentiation, and make the proper lineage determination? In normal adult tissues, stem cells are ultimately controlled by the integration of intrinsic factors (such as nuclear transcription factors) and extrinsic factors (growth factors, cell–cell contact or external influences). In 1978, Schofield [6] proposed the stem cell niche hypothesis, which hypothesized that stem cells reside within fixed compartments, or niches. This physiological microenvironment, consisting of specialized cells, secretes signals and provides cell surface molecules to control the rate of stem cell DOI:10.1097/GCO.0b013e328338c152
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236 Fertility
proliferation, determine the fate of stem cell progeny, and protect stem cells from death. Mammalian stem cells niches have been described in the hematopoietic, neural, epidermal, and intestinal systems [7]. Recent work has revealed that the interactions between stem cells and their niches may be more dynamic than originally believed. For example, hematopoietic stem cells (HSCs) may occupy two anatomically and physiologically distinct niches, an osteoblast niche and a vascular niche, and shuttle between them [8,9]. The vascular niche might explain stem cell survival in extramedullary haematopoietic sites, such as the liver and spleen, in which HSCs exist throughout adulthood without osteoblasts.
Germline stem cells in the postnatal ovary in mammal Germline stem cells (GSCs) are the self-renewing population of germ cells that serve as the source for gametogenesis. GSCs in Drosophila females maintain oocyte production in adult ovaries [10]. However, it was believed that ovaries of some vertebrates, especially those of mammals, did not contain self-renewing stem cells in adults. A long-held dogma in ovarian biology in mammals is that females are born with a finite population of nongrowing primordial follicles; oocyte numbers decline throughout postnatal life, eventually leaving the ovaries devoid of germ cells [11,12]. In humans, the decline in oocytes numbers is accompanied by exhaustion of the follicle pool and menopause before the end of life [13]. In 2004, Johnson et al. [14] provided evidence to challenge this doctrine. They demonstrated the existence of proliferative GSCs that give rise to oocytes and follicle production in the postnatal period of mammalian ovary [14]. In these experiments, the numbers of healthy (nonatretic) and degenerating (atretic) follicles in ovaries of C57BL/6 mice were counted; the numbers of nonatretic quiescent (primordial) and early-growing (primary) prenatal follicles in single ovaries were higher than expected, and the rate of depletion in the immature ovary was less than anticipated. In the same year, Bukovsky et al. [15] also claimed to identify GSCs and formation of new primary follicles in adult human ovaries. This group showed that cytokeratin-positive mesenchymal cells in ovarian tunica albuginea differentiate into ovarian surface epithelium (OSE) cells by a mesenchymal–epithelial transition. Germ cells can originate from surface epithelial cells which cover the tunica albuginea. The data also indicate that the pool of primary follicles in adult human ovaries may not represent a static, but rather a dynamic population of differentiating and regressing structures. These studies suggested the existence of proliferative germ cells that sustain oocyte and follicle production in the postnatal mammalian ovary, and indicate that oocytes are continuously formed in the adult. However, subsequent work has not demonstrated
offspring from donor-derived oocytes. The function of these ‘oocytes’ remains to be determined.
Origin of germ cells in adult ovary The origin of oocytes (and primary follicles) in ovaries of adult mammalian females has been disputed for over 100 years. In the 19th century, Weismann’s theory assumed that, before embryonic cells become committed along specific pathways, a set of germ cells is set aside, which are destined to give rise to the gametes. This theory was not questioned until the 1970s. In the early 2000s, evidence confirmed that functional mouse oocytes and sperm can be derived from mouse embryonic stem cells in culture [16–18]. Toyooka et al. [16] reported embryonic stem cells can form germ cells in vitro, and Geijsen et al. [17] found that injecting these cultured haploid male gametes into unfertilized egg led to embryo development to the early blastocyst stage. Hubner et al. [18] reported that mouse embryonic stem cells in culture can develop into oogonia that enter meiosis and recruit adjacent cells to form follicle-like structures and later developed into blastocysts. More than 10 years ago, Bukovsky et al. [19] proposed that in adult human females, the OSE was a source of germ cells. As mentioned before, in 2005, this group demonstrated that new primary follicles differentiated from the OSE, which arises from cytokeratin-positive mesenchymal progenitor cells residing in the ovarian tunica albuginea. OSE cells in-vitro culture confirmed their in-vivo observations that in adult human ovaries, the OSE is a bipotent source of oocytes and granulosa cells [20]. In 2005, Johnson et al. [21] reported that mammalian oocytes originate from putative germ cells in bone marrow and are distributed through peripheral blood to the ovaries. Their data showed that bone marrow transplantation restores oocyte production in wild-type mice sterilized by chemotherapy, as well as in ataxia telangiectasia-mutated gene-deficient mice, which are otherwise incapable of making oocytes. Donor-derived oocytes are also observed in female mice following peripheral blood transplantation. It was suggested that bone marrow is a potential source of germ cells that could sustain oocyte production in adulthood. In 2007, the same group reported that bone marrow transplantation generates immature oocytes and rescues long-term fertility in a preclinical mouse model of chemotherapy-induced premature ovarian failure [22]. However, these studies are challenged by some. To test directly the physiological relevance of circulating cells for female fertility, Wagers’ team established transplantation and parabiotic mouse models to assess the capacity of circulating bone marrow cells to generate ovulated oocytes, both in the steady state and after induced damage. Their studies showed no evidence that bone marrow cells, or any other normally circulating cells,
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Stem cells and reproduction Du and Taylor 237
contribute to the formation of mature, ovulated oocytes. Instead, cells that travelled to the ovary through the bloodstream exhibited properties characteristic of committed blood leukocytes [23]. So far, the origin of germ cells in female mammals is still an open issue. Controversy will be sure to stimulate further research on GSCs.
Ovarian tissue transplantation Ovarian transplantation has a long history, traced back 200 years. However, there was little progress until the middle of the 20th century. More recently Oktay and Karlikaya [24] have reported that ovulation occurred after laparoscopic transplantation of frozen-thawed ovarian tissue to the pelvic side wall in a 29-year-old patient who had undergone salpingo-oophorectomy. In 2004, the same group reported another case in which a four-cell embryo was obtained from 20 oocytes retrieved from tissue transplanted beneath the skin in a patient who had chemotherapy-induced menopause [25]. The same year, a live birth after ovarian tissue transplant was reported in a nonhuman primate [26]. Later in 2004, a successful pregnancy and live birth after orthotopic transplantation of cryopreserved ovarian tissue was reported by Donnez et al. [27]. In that case, a patient whose ovaries were damaged by cancer chemotherapy received frozenthawed ovarian tissue transplantation. These findings give new hope for fertility preservation, including immature oocyte retrieval, in-vitro maturation of oocytes, oocyte vitrification or embryo cryopreservation. However, one major concern over orthotopic auto-transplantation is the potential risk that the frozen-thawed ovarian cortex might harbor malignant cells. There is the potential that such cells could induce a recurrence of disease after re-implantation. Some studies have suggested that ovarian tissue transplantation in Hodgkin’s disease is well tolerated [28,29]. However, Shaw and colleagues [30] reported that ovarian grafts from a lymphoma prone strain of mice could transfer lymphoma to recipient animals. In 2005, Silber et al. [31] reported that a 24-year-old woman gave birth after a transplant of ovarian cortical tissue from her monozygotic twin sister. This patient had premature ovarian failure at the age of 14 years, whereas her sister had normal ovaries and three naturally conceived children. After unsuccessful egg-donation therapy, the sterile twin received a transplant of ovarian cortical tissue from her sister. About 1 year later, she delivered a healthy-appearing female infant. In 2007, Donnez et al. [32] reported another case of successful allograft of ovarian cortex between two genetically nonidentical sisters. In this case, the patient presented with beta-thalassemia major and underwent chemotherapy and total body irradiation before bone marrow transplantation (BMT) about 16 years ago. The treatment resulted in premature ovarian failure. After excision of ovarian cortical fragments from an
HLA-compatible sister, these fragments were immediately sutured to the ovarian medulla of the patient. Restoration of ovarian function was achieved after six months. In 2007, Silber et al. [33] reported 10 more successful ovary transplants in monozygotic twins after premature ovarian failure in one twin; two healthy babies have been delivered, and another three pregnancies are ongoing. Ovarian tissue transplantation not only brings hope to cancer patients, but also to those with ovarian dysgenesis or premature ovarian failure.
Stem cells in the uterus The uterine endometrium in mammals is one of the most dynamic human tissues and consists of a glandular epithelium and stroma that are completely renewed in each monthly menstrual cycle. Endometrial stem cells were thought to reside in the basalis layer and serve as a source of cells that differentiate to form the endometrium. Under systemic hormonal changes, such as the cyclic increase in the serum level of estradiol, stem cells migrate and give rise to a group of progenitor cells that become committed to specific types of differentiated cells, for example epithelial, stromal and vascular, within a certain microenvironment. These endogenous stem cells allow the rapid regeneration of the endometrium necessary to support pregnancy. There was no direct evidence to confirm this hypothesis until 2004. In that year, two studies from different labs provided evidence for the origin of this cyclic renewal [34,35]. A team led by Gargett demonstrated that human endometrium contains small populations of epithelial and stromal stem cells responsible for cyclical regeneration of endometrial glands and stroma and that these cells exhibited clonogenicity. The results showed that small numbers of epithelial (0.22%) and stromal cells (1.25%) initiated colonies in serum-containing medium and exhibit high proliferative potential [34]. In 2006, Gargett’s team used label-retaining cell (LRC) approach to identify somatic stem/progenitor cells and their location. The results demonstrated the presence of both epithelial and stromal LRC in mouse endometrium, which suggests that these stem-like cells may be responsible for endometrial regeneration [36]. Later on, another group also demonstrated that the human endometrium contains a low number of cells with the characteristics of endometrial stromal stem/ progenitor cells, which seem to belong to the family of the mesenchymal stem cells (MSCs) [37]. Our laboratory found that bone marrow is an exogenous source of endometrial cells [35]. In a 2004 study, we provided evidence of endometrial regeneration in bone marrow transplant recipients who received marrow from a single-HLA antigen mismatched donor BMT for leukemia. Donor-derived endometrial epithelial cells and stromal cells were detected in endometrial samples
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238 Fertility
of bone marrow recipients by RT-PCR and immunohistochemistry. These cells appeared histologically to be endometrial epithelial and stromal cells and also express appropriate markers of endometrial cell differentiation. Cyclic mobilization of bone marrow-derived stem cells may be a normal physiologic process. In 2007, our group also reported that after BMT, male donor-derived bone marrow cells were found in the uterine endometrium of female mice, and, although uncommonly (<0.01%), these cells can differentiate into epithelial cells [38]. Later, another study confirmed that bone marrow progenitor cells contribute to the uterine epithelium, and the population of cells may include CD45þ cells [39]. Further, in 2008, a new study showed that bone marrow-derived endothelial progenitors contribute to the formation of new blood vessels in the endometrium [40]. Last year, a group from Japan also reported that bone marrow-derived cells from human male donors can compose endometrial glands in female transplant recipients [41]. We also generated experimental endometriosis in a mouse model by ectopic endometrial implantation in the peritoneal cavity and detected LacZ expressing cells in the wild-type ectopic endometrium after BMT from LacZ transgenic mice [38]. The result showed that bone marrow-derived cells also contribute endometriosis. It was suggested that the repopulation of endometrium with bone marrow-derived stem cells may be important to normal endometrial physiology and also may help to explain the cellular basis for the high long-term failure of conservative alternatives to hysterectomy. The endometrium may regenerate after resection or ablation from a stem cell source outside of the uterus. Disorders of the uterine endometrium are common, leading to abnormal uterine bleeding, infertility, pregnancy complications, miscarriage, endometriosis and cancer. These findings have potential implications for the treatment of uterine disorders. Finally these data support a new theory for the cause of endometriosis, which may have its origin in ectopic transdifferentiation of stem cells. In 2007 two studies determined the existence of a small population of multipotent stem cells in endometrium [42,43]. The Gargett lab collected human endometrial tissue from reproductive-aged women, and prepared human endometrial stromal cell cultures. Then endometrial stromal cells were incubated with adipogenic, osteogenic and myogenic differentiation induction media for 4 weeks. The results showed that a subset of endometrial stromal cells differentiate into cells of adipogenic, osteogenic, myogenic and chondrogenic cell lineages [42]. Wolff et al. [43] from our laboratory also collected endometrial tissue from reproductive-aged women and monolayer endometrial stromal cell (ESC), myometrial, fibroid, fallopian tube, and uterosacral ligament tissue cultures were generated. These cells were cultured in a
defined chondrogenic media containing dexamethasone and transforming growth factor for 21 days and then were analyzed for markers of human articular cartilage, including sulfated glycosaminoglycans and type II collagen. Cultured endometrial derived stem cells (EDSCs) contain cells that can be differentiated into chondrocytes [43]. Finally, the Taylor group has recently reported that EDSCs can be differentiated into neurons which produce dopamione and have the potential to treat Parkinson’s disease. Since endometrium can easily be obtained, it may represent a new potential source of pluripotent cells. Regenerative medicine holds tremendous potential to treat many forms of human disease. Endometrial biopsy could become an important source of stem cells for future cell-based therapies.
Placenta and stem cells Over the last 30 years, colonization has been a longaccepted theory which proposes that the yolk sac was the sole source of hematopoiesis in the mammalian embryo. It was believed the embryonic yolk sac-derived HSCs colonized fetal liver to initiate definitive hematopoiesis and subsequently colonize bone marrow at the neonatal stages to support adult hematopoiesis. However, in the 1990s, accumulating evidence located hematopoiesis to another site in the aorta-gonad-mesonephros (AGM) of mouse embryos [44]. A 2003 study indicated that the placenta contains a high frequency of multipotential clonogenic progenitors including CFU-GMs, CFUGEMMs, BFU-Es and HPP-CFCs [45]. The study results suggest that the placenta may function as a hematopoietic organ during development. In 2005, two studies simultaneously reported that HSCs activity can be detected in the mid-gestation placental labyrinth region [46,47]. The onset of HSC activity in the placenta coincides with that in the AGM region and the yolk sac. The HSC pool size in the placenta is 15-fold greater than in the AGM. The expansion of the HSC pool in the placenta occurs prior to and during the initial expansion of HSCs in the fetal liver. The size of the placental HSC pool diminished, whereas the HSC pool in the fetal liver continues to expand. These data suggest that placenta is another site contributing to the establishment of the mammalian definitive hematopoietic system. Further, in 2004, three groups also identified and isolated cells with MSC-like potency in human placenta [48–50]. In the last couple of years, the Huang group reported that placenta-derived multipotent cells can differentiate into hepatocyte-like cells, neuronal and glial cells when the cells cultured under appropriate conditions in vitro [51,52]. The placenta may be another source of multipotent stem cells.
Stem cell transfer from the fetus The presence of fetal cells in maternal circulation has now been confirmed by many investigators [53]. Several
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Stem cells and reproduction Du and Taylor 239
studies reported that microchimeric cells of fetal origin have been identified in the peripheral blood of patients with the autoimmune disease systemic sclerosis (SSc) [54]. However, it has not been determined if these cells are integrally involved in the pathogenesis of SSc, or if fetal microchimeric cells are just a marker of inflammation. Increased numbers of microchimeric fetal cells have been identified in some diseases of pregnancy, for example preterm labor, preeclampsia and aneuploidy [55]. However, there is speculation that the increased number of fetal microchimeric cells in the maternal circulation is a reflection of the abnormalities within the structure of the placenta, and not directly related to the disease process. In 2001, a team led by Bianchi discovered that male cells were seen in thyroid sections in women, presumably from their sons [56]. They reported that male cells were seen individually or in clusters in all thyroid disease from which biopsies were examined; they were not restricted to inflammatory thyroid diseases. In one patient with a progressively enlarging goiter, they noted fully differentiated male thyroid follicles closely attached to and indistinguishable from the rest of the thyroid. Later on, this team reported that XYþ microchimeric cells in maternal tissue, acquired most likely through pregnancy, express leukocyte, hepatocyte and epithelial markers [57]. The results suggest that pregnancy may result in the physiologic acquisition of a fetal cell population with the capacity for multilineage differentiation. The study also showed that hepatocytes of fetal stem cell origin were identified in liver tissue of one woman with liver injury and another woman following hepatic transplantation. In other studies, rats that had been bred to GFP males sustained directed injury to the liver and kidney of postpartum females. They found that fetal cells were engrafted into the bone marrow with resulting detection of these cells in the peripheral blood of the rats [58]. This study also demonstrated that the engrafted GFP-positive fetal cells gave rise to hepatocytes in the liver and tubular epithelial cells in the kidney. The GFP-positive cells were not found in the organs of the rats that were not injured. These findings suggest that in a state in which the tissue injury is chronic, fetal cell microchimerism may be established more frequently, or more easily and also suggests that microchimeric cells are involved in tissue repair. In 2008, two groups reported interesting studies describing the contribution of fetal stem cells to cancer. One group investigated microchimeric fetal cells clustered at sites of tissue injury in the lung decades after known male pregnancy; male cells were identified in lung/thymus tissue from all women with sons. The male cells in the lung were clustered in tumors rather than in surrounding healthy tissues. These male presumed-fetal cells were identified in pathological postreproductive tissues, in which they were more likely to be located in diseased
tissues at several-fold higher frequency than normal tissues. It is suggested that fetal cells are present at sites of tissue injury and may be stem cells, either recruited from marrow or having proliferated locally [59]. Since breast carcinomas associated with pregnancy display a high frequency of inflammatory types, multifocal lesions and lymph node metastasis, another group from France questioned whether fetal stem cells are involved in this disease process. They analyzed women presenting with carcinomas who were pregnant with male fetuses. The results showed that the presence of fetal cells in pregnancy-associated breast carcinoma is a frequent phenomenon. These cells were predominantly part of the tumor stroma and could contribute to the poorer profile of these carcinomas [60].
Cancer stem cells in reproductive tract Cancer stem cells (CSCs) are defined as a rare cell population in cancer with indefinite potential for selfrenewal, and they are proposed to be the cancer-initiating cells responsible for tumorigenesis and contribute to cancer resistance. Alteration of self-renewal pathways seems to be an important mechanism underlying CSC formation. The best known and most comparable pairs of somatic and CSCs are HSCs and leukemic stem cells (LSCs) [61,62]. Recently CSCs have been positively identified and successfully isolated from a large number of cancers [63]. Ovarian cancer is an extremely aggressive disease. The cellular mechanisms underlying the increasing aggressiveness associated with ovarian cancer progression are poorly understood. Although epithelial ovarian cancers (EOCs) have been thought to arise from the simple epithelium lining the ovarian surface or inclusion cysts, the major subtypes of EOCs show morphologic features that resemble those of the mu¨llerian duct-derived epithelia of the reproductive tract. HOX genes, which normally regulate mu¨llerian duct differentiation, are not expressed in normal OSE, but are expressed in different EOC subtypes according to the pattern of mullerian-like differentiation of these cancers [64–66]. Ectopic expression of Hoxa9 in tumorigenic mouse OSE cells gave rise to papillary tumors resembling serous EOCs. In contrast, Hoxa10 and Hoxa11 induced morphogenesis of endometrioid-like and mucinous-like EOCs, respectively. Hoxa7 showed no lineage specificity, but promoted the abilities of Hoxa9, Hoxa10, and Hoxa11 to induce differentiation along their respective pathways. Although those findings indicate roles for Hoxa7 and Abd-B-like HOX genes in aberrant differentiation, their roles in OSE transformation have yet to be defined. Stem cell transformation may be the underlying mechanism leading to ovarian cancer [67]. The study showed
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240 Fertility
that a single tumorigenic clone was isolated among a mixed population of cells derived from the ascites of a patient with advanced ovarian cancer. During the course of the study, another clone underwent spontaneous transformation in culture, providing a model of disease progression. Both the transformed clones possess stem cell-like characteristics and differentiate to grow in an anchorage-independent manner in vitro as spheroids, although further maturation and tissue-specific differentiation was arrested. Significantly, tumors established from these clones in animal models are similar to those in the human disease in their histopathology and cell architecture. Furthermore, the tumorigenicclones,evenonserialtransplantation,continue to establish tumors, thereby confirming their identity as tumor stem cells. These findings suggest that stem cell transformation can be the underlying cause of ovarian cancer and continuing stochastic events of stem and progenitor cell transformation define the increasing aggression that is characteristically associated with the disease. Many types of stem cells use a multidrug resistance (MDR) pump to rid themselves of chemicals, including nuclear dyes. This property facilitates fluorescenceactivated cell sorting of those rare cells capable of nuclear dye exclusion, which have been termed side-population cells. This in turn has led to the finding that side-population cells exhibit many stem cell-like properties [68,69]. In 2006, a group claimed to identify and characterize a stem cell-like subpopulation of ovarian cancer cells from two distinct genetically engineered mouse ovarian cancer cell lines [70]. This study identified a rare population of verapamil-sensitive side-population cells in mouse ovarian cancer cell lines that have clonogenic properties in vitro and form tumors in vivo. In contrast, non-side-population cells derived from the same cancer cell lines do not exhibit clonogenic or tumor-forming properties. Similarly a 2008 study identified an endometrial cancer (EnCa) stem cell population; in that study the investigators tested relative tumor formation activity of the side-population and nonside-population fractions. Only the side-population fraction was tumorigenic. And this rare subset of cells is capable of initiating tumor formation in NOD/SCID mice [71]. Later on, another study reported that expression of the adult stem cell marker Musashi-1 was increased in endometriosis and endometrial carcinoma [72]. Musashi-1 is a RNA-binding protein associated with maintenance and asymmetric cell division of neural stem cells. These results are consistent with the hypothesis that EnCa contain a subpopulation of tumor-initiating cells with stem-like properties, and support the concept of a stem cell origin of endometriosis and endometrial carcinoma.
Conclusion We are just beginning to understand stem cells, and many key questions remain. The potential advantages of stem
cells in reproductive biology and medicine are apparent. Stem cells may play an important role in normal uterine and ovarian physiology. They likely are involved in the response of these tissues to injury and disease. The potential for these processes to be exploited for medical treatment is of great promise. Additionally, stem cells likely play a role in pathology of the reproductive tract. Stem cells give rise to cancers and endometriosis. A better understanding of stem cell biology may prove helpful in the treatment of these conditions. Finally the fetus, placenta and even the endometrium are all sources of stem cells. Endometrial-derived stem cells may provide an immunologically matched source of multipotent stem cells for tissue engineering and regenerative medicine.
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Impact of previous uterine artery embolization on fertility Nadia Berkanea,b and Constance Moutafoff-Borieb a
UPMC University Pierre et Marie Curie Paris 6 and Department of Gynecology and Obstetrics and Reproductive Medicine, Tenon Hospital, AP-HP, Paris, France
b
Correspondence to Dr Nadia Berkane Tel: +33 1 56 01 61 03; fax: +33 1 56 01 64 03; e-mail:
[email protected] Current Opinion in Obstetrics and Gynecology 2010, 22:242–247
Purpose of review To describe data on the effects of uterine artery embolization (UAE) on fertility. Recent findings UAE is used to treat postpartum hemorrhage (PPH) and fibroids. This effective therapy is replacing surgery in many cases. One of the main goals of UAE is to preserve the uterus and therefore fertility (pregnancies, menses and ovarian reserve). Pregnancies after this technique have been described. The main complications encountered during these pregnancies are not only PPH but also miscarriages and cesarean deliveries after UAE for fibroids. Conflicting results varying from completely well tolerated to serious complications such as definitive negative effect on endometrium and ovary function have been reported. Nevertheless, the series differ in that they included women of different ages and used different material for vessel occlusion (definitive microparticles of varying sizes, temporary pledgets of gelatine sponge, etc.). We discuss the impact of these differences on uterus vascularization and fertility. Summary UAE is an effective treatment for PPH and fibroids. Pregnancy is possible after UAE. Recurrent PPH is a serious and frequent complication. Synechia is also a potential complication. Desire of childbearing should be considered when choosing embolization or surgery and, in case of embolization, the choice of material used. Further studies on future fertility after UAE are needed as well as information on fertility after surgery. Keywords embolization, fibroids, postpartum hemorrhage, pregnancy Curr Opin Obstet Gynecol 22:242–247 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1040-872X
Introduction
Embolization for postpartum hemorrhage
Uterine artery embolization (UAE) is a vascular radiological technique used to treat postpartum hemorrhage (PPH) [1–3] and uterine myomas [4,5]. It constitutes a conservative treatment designed to keep the uterus intact. Now, it remains to demonstrate that fertility is really preserved after treatment. This step must take into account that different embolic materials are used depending on the type of treatment: temporary embolotherapy (pledgets of absorbable gelatine sponge, or nonbovine sponge, etc.), and definitive vascular occlusion (microparticules of several sizes, coils, etc.). These materials could potentially have a different impact on uterine and ovarian vascularization.
PPH is one of the first causes of maternal mortality [27]. Once the woman’s life is no longer in danger, if bleeding persists the medical goal is obviously to stop the hemorrhage while preserving the uterus. Obstetricians can opt for conservative surgical options and/or UAE. Although there are no randomized trials comparing these options, embolization of the uterine or other local arteries seems to be highly effective [1–3] and to have substantial advantages over surgery.
Literature reports conflicting results on preservation of fertility after UAE [6–26]. The goal of our discussion is therefore not only to collect published results but also to point out study limitations which could introduce biases and give misleading conclusions and possibly explain the disputed results. 1040-872X ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Techniques Embolization of pelvic arteries needs a trained radiologist [2,3,24]. A unilateral right femoral approach is used and a 4 or 5-French femoral arterial introducer inserted. Initial aorto-iliac angiography is performed to detect the site of bleeding from the pelvic arteries and contralateral internal iliac angiography is then performed. The ipsilateral internal iliac artery and uterine artery are catheterized with the same catheter and via the same puncture DOI:10.1097/GCO.0b013e328338c179
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Impact of previous uterine artery embolization on fertility Berkane and Moutafoff-Borie 243
site. Highly selective catheterization of vaginal or ovarian arteries is performed when necessary. Artery occlusions are performed with pledgets of absorbable gelatine sponge or nonbovine sponge, or in few cases with definitive material.
found in the literature [18,32]. Moreover, uterine artery Doppler waveforms were evaluated in two series [12,21] and were normal. Menses
Boulleret et al. [11] reported that 91% of the 23 contacted women resumed normal menses and Salomon et al. [10] and Eriksson et al. [31] reported that all the women resumed normal menses but authors [10,11,31] did not indicate if the patients were taking oral contraceptives or not. In the series by Chauleur et al. [18], eight women who used levonorgestrel-releasing intrauterine device or levonorgestrel contraception reported less abundant or more irregular menses, whereas the 33 others resumed normal cycles and menses though we do not know if they were taking estroprogestative contraception. Fiori et al. [21] reported regular menses in 30 out of 33 patients (91%) and 14 of whom were on oral hormonal contraception, 6 had an intrauterine device, 1 had an etonorgestrel implant and 9 no contraception. Results from the series of Sentilhes et al. [24] were different as 15 cases (22%) of amenorrhea or decreased flow of menstruation were found in the 68 women, 11/58 in the group UAE alone and 4/10 in the UAE and surgical devascularization group. Synechia was found in 8 of the 15 cases. Gaia et al. [23] found that 23 women out of 107 reported oligomenorrhea and 6 amenorrhea, 3 of whom had been embolized using Curaspon powder for UAE for PPH. It is worth noting that the two last authors used micoparticles and microcoils for Sentilhes [24] and, for Gaia et al. [23], Curaspon powder. Gaia et al. [23] noted a link between these materials and the occurrence of synechiae. The 11 women who could not conceive in the Gaia et al. [23] series had synechia and/or oligomenorrhea.
Indications The main indications [28,29] of UAE are PPH after vaginal deliveries, persistent mild bleeding after caesarean and late bleeds [30] as well as some cases of vaginal and cervical trauma when local surgery fails to stop bleeding [28]. Nevertheless, not all patients can benefit from embolization therapy as hospitals with maternities are not always equipped with the necessary specific radiological materials and a vascular radiologist is not always available. Cases of massive hemorrhage with severe shock status [28] and most hemorrhages occurring during caesareans must be treated by surgical procedures.
Efficacy With a high success rate [1–3], surgery after embolization failure is a rare entity, whereas radical surgery following ineffective conservative surgical therapy is a regular second step. For these reasons, there is now a growing body of literature promoting embolization techniques over surgery except for contraindicated situations [2,28,29].
Fertility after uterine artery embolization for postpartum hemorrhage Some medical teams have contacted their patients who underwent UAE for PPH to determine whether they desired further pregnancies, the occurrence of pregnancies and sometimes information of the presence and quality of menses.
Embolization for uterine myomas Uterine myomas (fibroids) are common benign tumors often found in women of childbearing age. Their location, number, and kind of complications require care and determine the therapeutic strategy. Hormonal treatment and/or surgery were the cornerstone of treatment up to 1995.
Pregnancies
The main publications on pregnancies are listed in Table 1. The most frequent reported complications in pregnancies following UAE are PPH [10–12,18,21,23, 24,31]. Only three cases of fetal growth restriction were
Table 1 Pregnancies after uterine artery embolization (UAE) for postpartum hemorrhage (PPH)
Studies Ornan et al. [9] Salomon et al. [10] Boulleret et al. [11] Descargues et al. [12] Eriksson et al. [31] Chauleur et al. [18] Gaia et al. [23] Fiori et al. [21] Sentilhes et al. [24]
Number of Number of Number Number Number patients treated contacted desiring to of pregnant of pregnancies with UAE women conceive women (all) 28 28 35 31 41 113 56 68a
17 23 25 20 37 107 34
6 6 9 16 29 2 infertile 13
6 5 3 7 4 16 18 13 17
6 6 3 10 7 19 19 20 26
Number of pregnancies with babies
Number of abortions
6 4 2 6 5 þ 2 premature 18 (2 twin) 18 12 19
2 2M 1VA 3M þ 1VA 0 1M 1M 4VA þ 3M þ 1EP 2VA þ 4M þ 1EP
Number of recurrent PPH 0 2 0 0 0 1 3 1 6
EP, ectopic pregnancy; M, miscarriage; VA, voluntary abortion. a Including 10 UAE associated with surgical devascularization.
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244 Fertility
However, medical treatments have limited effects, and conservative surgery weakens the uterus and delays time of conception. Embolization has thus since emerged as a preferred option and constitutes a new and ‘elegant’ treatment to replace or delay surgery [4,6–8,33,34].
Techniques The main difference between the various protocols currently practiced resides in the choice of material used to obstruct the vessels. Initially, after identifying the uterine vessels by angiography, they were obstructed by nonresorbable microparticles of various sizes [5,16,20,22]. The problem is that these small particles can enter the endometrial arteries causing ischemia with risk of amenorrhea, synechia or, even ovarian failure if they pass into the uteroovarian anastomoses [5,13,25,26,33,35–37]. Some teams have therefore recently been using other nonresorbable materials composed of microspheres (Embospheres) which are greater than 500 mm [20,22], to better preserve endometrial and ovarian vascularization. Others prefer to use resorbable materials [38]. Whatever the technique used, embolization causes fibroid ischemia and often leads to pain which has to be treated with pain relief, locoregional anesthesia and sometimes hospitalization.
information on menstruation patterns and hormonal follow-up tests. Pregnancies
As a measure of precaution women presenting with fibroids who have a desire for children are not generally eligible for embolization [34]. Thus, there are few studies reporting on subsequent pregnancies. Moreover, it is sometimes difficult to know how many women in these series wanted children. The main studies are reported in Table 2. One large study [13] compiled data from 53 pregnancies after UAE and 139 pregnancies after myomectomy by laparoscopy and showed a higher risk of preterm delivery, malpresentation and caesarean delivery in the UAE group. Menses, ovarian preservation
Uterine fibroids can cause metrorragia or menorragia, or pelvic-compression symptoms [39]. These signs might necessitate UAE therapy if medical treatment fails. However, the theoretical or real alteration of endometrial vascularization cast doubts on the risk of secondary infertility and, until recently, a desire of childbearing was a contraindication for embolization [34,40] even though it was still performed in these women. In addition, submucous fibroids surgically accessible by endoscopy are still not an indication for embolization [39]. Similarly, subserous fibroids constitute a contraindication for embolization due to the risk of septic necrobiosis.
One case of endometrial atrophy after use of 150–250 mm microparticles was reported by Tropeano et al. [25]. Hehenkamp et al. [26] compared 88 women after UAE and 89 after hysterectomy (H) with a follow-up of 24 months. He measured anti-Mullerian hormone (AMH) and follicle-stimulating hormone (FSH). FSH levels (n ¼ 88 UAE–86 H) increased significantly in the two groups, whereas AMH values (n ¼ 30 UAE–33 H) decreased until 6 weeks after treatment. In the surgery group they then recovered to expected values and remained that way until the end of the follow-up, whereas in the UAE group AMH values remained significantly low after a slight initial recovery. Tropeano et al. [41] evaluated 36 women by hormonal testing after UAE. He reported only one case of changes in menstrual characteristics: irregular cycles (in a woman aged 38 years) and a significant increase in FSH and estradiol levels but not significantly more than hormonal follow-up of a group of 36 matched control women. Mara et al. [42] evaluated FSH levels in 30 women at between 6 and 17 months after UAE, and compared the values with those of 33 women having undergone myomectomy. He found no difference between the two groups.
Efficacy
Discussion
Considering the different materials used and the varying indications and contraindications applied by one team and another, caution must be applied when comparing published success rates. Furthermore, follow-up is most often short. However, results tend to demonstrate at least the short-term efficacy of embolization in the treatment of fibroids [4,5,19].
With a 90–100% [1–3] success rate in stopping bleeding in women with PPH, the effectiveness of UAE is indisputable. It has largely replaced conservative surgery which only has a proximal action (in ligaturing hypogastric arteries) or semi-distal (other techniques of arterial ligatures). Surgery for fibroids can weaken the uterine wall, whereas UAE for fibroids is effective [4–8,34] and even if efficacy might only be temporary it should allow enough time for pregnancy before surgery. However, UAE could also have a negative impact on further fertility. An important point which differs from study to study, is the material used and this has a strong impact: the smaller the particles the higher the risk of occlusion of the
Indications
Fertility after uterine artery embolization for myomas We have done a literature search on pregnancies following UAE for myomas, and we have also looked for
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In the few studies evaluating fertility after UAE the number of pregnancies is low [6,7,9–17,19–24,31]. It is likely, however, that the real number of pregnancies is underestimated. Indeed, the ideal evaluation of fertility is the number of subsequent pregnancies and, for various reasons, most women included in the studies mentioned above did not want to become pregnant. One obvious reason is that women with fibroids who desire children are not eligible for UAE [34]. Finally, women having experienced PPH requiring embolization and extensive medical management are generally deeply affected by the possible risks that they entail by subsequent pregnancies and thus hesitate before becoming pregnant again.
50 100 NK 1 3M (27.3%), 2M (13.3%)
50 72 3 6
endometrial and ovarian arteries. Indeed, smallest polyvinyl alcohol particle emboli have been identified within the cervix, uterine body and adnexa after some cases of radical surgery following UAE [43]. The probable cut-off for material size is 500 mm. For temporary material, Curaspon powder could have the same impact as smallest microparticles [23].
AP, abnormal placentation; EP, ectopic pregnancy; M, miscarriage; NK, not known; VA, voluntary abortion.
NK 23 Pinto Pabon et al. [20] Firouznia et al. [22]
100 102
500–1200 500–700
11/10 15/14
18, 4 FGR, 3AP 33 and 2 still births 1 FGR, 6AP 6 preterm 8 13 24/21 56/33 NK 108 355–500 NK 555 1200 Pron et al. [16] Walker and McDowell [17]
Studies
4M (16.7%), 2VA, 17M (29.8%), 3VA, 1EP,
Cesarean rate (%) Particle size
Number desiring to conceive Number of patients treated with UAE
Table 2 Pregnancies after uterine artery embolization (UAE) for fibroids
Number of pregnancies (all)/number of pregnant women
Number of pregnancies with babies
Number of abortions
Number of recurrent PPH
Impact of previous uterine artery embolization on fertility Berkane and Moutafoff-Borie 245
This means that teams wishing to evaluate fertility need to adopt an indirect approach by enquiring about the abundance and regularity of the menses. Most studies report no change in menses or cycles [10,11,18]. However, they do not provide any details of estroprogestative contraception making it likely that a certain number of cases are due to withdrawal bleeding rather than real menses and it is thus difficult to draw any conclusions as to the possible presence of ovarian failure. Reported pregnancies after UAE for PPH are often described as normal until delivery. Two series underlined that uterine artery Doppler waveforms were normal during the pregnancies [12,21], and few cases of fetal growth retardation have been reported [18,32]. One frequent complication after UAE for PPH is the risk of PPH with sometimes serious consequences [10,18,21,23,24]. The risk of infertility after UAE for fibroids is not known. The few pregnancies obtained after UAE for fibroids seem to be complicated by miscarriages, preterm deliveries, abnormal placentation, cesarean deliveries and PPH [16,17,20,22], though these are complications which could also be expected with a myomatous uterus even without treatment [40]. Nevertheless, as these complications could be a consequence of the procedure they must be clearly evaluated in further prospective trials. Several authors have described synechia as a complication of UAE most often after placenta accreta, and/or the use of the smaller microparticles or Curaspon powder [23–25]. All these materials can potentially reach and obstruct endometrial vessels due to their size. Synechia is
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246 Fertility
suspected to cause amenorrhea, oligomenorrhea and infertility. This opens the question of a systematic diagnostic hysteroscopy a few months after UAE to check the integrity of the uterine cavity. We would suggest that a diagnostic hysteroscopy should be performed in the case of amenorrhea, oligomenorrhea, but also before pregnancy as synechia could be a risk factor for secondary PPH. Some series evaluated ovarian reserve after UAE for fibroids by hormonal testing before and after UAE but the results are conflicting and the series have limitations [19,26,36,37,41,44]. There are some reassuring conclusions despite the use of particles smaller than 250 mm but with a short follow-up [42], and without measuring AMH which is more sensitive than FSH. Other results are more worrying [26] as they show loss of ovarian reserve in a population of women with a mean age of 44 years at UAE. However, a more recent study by Tropeano et al. [41] did not demonstrate negative effects of UAE on ovarian reserve in a population of younger women (mean: 35 years). It is important to note that particles greater than 500 mm were used in cases of visible ovarian artery anastomosis in these two series ruling out the effect of the material used [26,41]. The patient’s age is often high, close to 40–44 years, with possible natural disturbances of menses. The hypothesis found in literature is that UAE could precipitate menopause in women aged over 40 or already in a premenopausal status [36,42,44]. Moreover, authors who compared UAE to surgery on the effects of ovarian reserve underlined that surgery has also negative effects [41,42]. This point should be taken into account when interpreting the negative impact of UAE. It is therefore possible that the impact of UAE on fertility is no more negative than that of surgery when appropriate sized particles are used to avoid endometrial lesions. However, even if it has been demonstrated theoretically that UAE for fibroids using particles greater than 500 mm preserves fertility, there is insufficient evidence to confirm this hypothesis. The use of a solid temporary material such as Curaspon or gelatin sponge for fibroid treatment by UAE could be safer for patients who desire to have children. We would like to stress though that, in all cases of UAE for PPH, the vascular radiologist should avoid using microparticles as the emergency context leaves no room for a meaningful discussion with the patient about further pregnancies.
Conclusion Recurrent PPH is one of the most serious and frequent complications of pregnancies after UAE. Synechia is a potential complication particularly in case of placenta accreta and, the use of small particles or of Curaspon powder. Therefore, we recommend systematic diagnostic
hysteroscopy in case of menses disorder or before starting a pregnancy. Microparticles could induce a real risk of occlusion of endometrial and ovarian vessels. For this reason, except in prospective trials with a fully informed patient, their use is still inappropriate for women with a desire of childbearing. Due to the small size of published series, further studies on future fertility after UAE but also on fertility after surgery are needed to refine these conclusions.
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Bariatric surgery and fertility Divya K. Shah and Elizabeth S. Ginsburg Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, Boston, Massachusetts, USA Correspondence to Elizabeth S. Ginsburg, MD, Associate Professor of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02215, USA Tel: +1 617 732 6660x33905; e-mail:
[email protected] Current Opinion in Obstetrics and Gynecology 2010, 22:248–254
Purpose of review Bariatric surgery is the most reliable way to sustain weight loss in the morbidly obese. Reproductive age women comprise the majority of bariatric patients, and many may be interested in conceiving after surgery. The purpose of this review is to synthesize the recent literature on bariatric surgery and fertility to assist providers in patient counseling. Recent findings Obesity adversely impacts fecundability and IVF outcomes through a variety of mechanisms. The body of literature on reproductive outcome after bariatric surgery is sparse and of mixed quality. Bariatric surgery has been shown to improve menstrual cyclicity in anovulatory women, but little is published on the impact of surgical weight loss on spontaneous or IVF-treatment-related pregnancy rates. The increased risk of miscarriage in obese women may decline after bariatric surgery. There are currently insufficient data to support recommendations regarding the ideal timing for pregnancy after bariatric surgery. Summary Obesity has been shown to adversely impact fertility, and weight loss is associated with significant improvement in many parameters of reproductive function. Further research is required as to the specific impact of surgical weight loss on pregnancy and miscarriage rates, as well as the optimal timing of pregnancy after bariatric surgery. Keywords bariatric surgery, infertility, obesity, overweight Curr Opin Obstet Gynecol 22:248–254 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1040-872X
Introduction Obesity and its associated health consequences have become a global epidemic. The World Health Organization (WHO) projects that more than 700 million adults will be obese by 2015 [1]. In the United States, recent estimates from the National Center for Health Statistics reveal that more than 66% of Americans are overweight, and over 30% of those meet criteria for obesity [2]. Although obesity treatment has traditionally focused on caloric restriction and increased physical activity, lifestyle changes often yield modest results and regaining weight is common [3,4]. Bariatric surgery has emerged as the most reliable way to sustain weight loss in the morbidly obese [5,6]. A 1991 National Institutes of Health (NIH) consensus panel recommends bariatric surgery for individuals with a BMI of at least 40 kg/m2, or over 35 kg/m2 with associated co-morbidities such as diabetes mellitus, sleep apnea, or cardiovascular disease, or for those who fail more conservative therapies [7]. Bariatric surgery can be categorized into restrictive, malabsorptive, and mixed procedures [8,9–11,12]. 1040-872X ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Restrictive procedures, such as the vertical banded gastroplasty or adjustable gastric banding, promote early satiety by reducing gastric capacity. Adjustable gastric banding places a silicon band around the proximal stomach that can be inflated or deflated through a subcutaneous port to create a variably sized gastric pouch. Malabsorptive procedures constrain nutrient absorption by bypassing a large section of the small intestine and are rarely used secondary to associated nutritional deficiencies. Mixed procedures limit gastric intake while promoting malabsorption. The Roux-en-Y gastric bypass is a mixed procedure, creating a small gastric pouch that empties directly into the distal jejunum, bypassing the remaining stomach, duodenum, and most of the proximal jejunum. Roux-en-Y gastric bypass and adjustable gastric banding, both of which are increasingly performed laparoscopically, represent the most widely utilized bariatric surgical procedures [13]. American women are nearly twice as likely to be morbidly obese as American men, and comprise a majority of bariatric patients [10,14]. Women account for 83% of patients undergoing bariatric surgery between the ages of 18 and 45 [10,15]. In a recent observational study of DOI:10.1097/GCO.0b013e3283373be9
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Bariatric surgery and fertility Shah and Ginsburg 249
reproductive age women undergoing bariatric surgery, 30% of participants stated that future pregnancy was important to them, with 32% of those intending to conceive within 2 years following surgery [16]. Despite these trends, research on fertility after bariatric surgery is relatively sparse. The purpose of this review is to provide a synthesis of the recent literature on bariatric surgery and fertility to assist providers in counseling patients.
Obesity and fertility Over 50% of women with polycystic ovarian syndrome (PCOS) and associated oligo-anovulation are overweight or obese [17,18]. The ovulatory dysfunction in many PCOS patients is mediated by insulin resistance and hyperinsulinemia, which is augmented by the degree of obesity (Fig. 1, [19]). Insulin stimulates androgen production by ovarian theca cells and inhibits hepatic synthesis of sex-hormone-binding-globulin (SHBG), resulting in an androgen-dominant environment that inhibits normal follicular maturation [20,21].
Obesity has also been shown to adversely impact fecundability in ovulating women [22–24]. The mechanism of this effect is unknown but may be related to altered pulsatile gonadotropin secretion. In a large study of 674 ovulatory perimenopausal women, Santoro et al. [25] found a significant association between BMI and menstrual cycle length, with overweight (BMI > 25 kg/m2) women demonstrating longer follicular phases (P < 0.0001) and shorter luteal phases (P ¼ 0.006) than normal-weight controls. Overweight women were also found to have reduced urinary LH, FSH, and luteal phase pregnanediol glucuronide (Pdg, a progesterone metabolite) excretion, suggesting an adverse impact of obesity on corpus luteum function. Jain et al. [26] similarly demonstrated reduced LH pulse amplitude and lower levels of luteal urinary Pdg in 18 morbidly obese ovulatory premenopausal women compared with eumenorrheic normal-weight controls. Elevated levels of leptin, an adipokine secreted by white adipose tissue, provide another mechanism for the decreased fertility observed in obese women
Figure 1 Hormonal interaction between obesity and female fertility
(a) Nutrition is linked to the female reproductive system through the effects of leptin and insulin. The increase in body fat during normal adolescence is associated with insulin resistance and a compensatory increase in insulin secretion. Hyperinsulinemia results in reduction of sex-hormone-bindingglobulin (SHBG) with consequent elevations in free estrogens and androgens. Leptin influences secretion of GnRH, thereby stimulating secretion of gonadotropins. Insulin can also function directly on the ovary. (b) In overweight women and/or those with polycystic ovarian syndrome (PCOS), increased adiposity results in elevated leptin levels, leading to a preferential increase in LH, but not FSH, levels. The net effect is to stimulate the partial development of follicles that secrete supranormal levels of testosterone, but which rarely ovulate (hence low progesterone). These changes are exacerbated by insulin-induced reduction in SHBG, which amplifies ovarian testosterone production/action. Adapted from [19].
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250 Fertility
[16,27]. Serum leptin concentration is proportional to total body adiposity and leptin receptors are present on human granulosa and theca cells as well as the endometrium [28]. Excess leptin has been shown to inhibit ovarian steroidgenesis and inhibit follicular growth in both human and animal models [29,30]. A small body of evidence suggests that obesity may be correlated with diminished ovarian reserve. The ovarian reserve markers Mullerian-inhibiting substance (MIS) and inhibin B have been shown to be significantly lower in obese perimenopausal women [31]. In a study of 16 reproductive age women undergoing bariatric surgery, mean MIS concentrations were found to decrease by 23.9% 2–3 months after surgical weight loss (P ¼ 0.034 as compared with preoperative levels) in women under the age of 35 [32]. The authors speculate that this decrease may be either a transient expression of postoperative stress or a permanent effect of surgery on MIS gene expression, although it could also theoretically reflect an acute depletion of the follicular pool. Observational studies have noted associations between body fat distribution and infertility. In a prospective study of 500 obese women undergoing donor insemination, central obesity had a significant impact on the probability of conception. Women with a waist–hip ratio of 0.8 or more were 30% less likely to conceive than those with a ratio of 0.7 or less [22]. Additionally, a recent survey of 1500 reproductive age women undergoing bariatric surgery observed an increased risk of PCOS and infertility among women who were self-reportedly obese before the age of 18 than those who became obese later in life [16].
Bariatric surgery and fertility Although the literature suggests improvement in spontaneous pregnancy rates after bariatric surgery, most studies are observational, poorly controlled, and do not differentiate between ovulatory and anovulatory obese women. A retrospective survey of 783 women after biliopancreatic diversion reported spontaneous postoperative conception (mean BMI ¼ 30 kg/m2) in 47% of patients who were unable to become pregnant preoperatively (mean BMI ¼ 47 kg/m2) [33]. In a small retrospective case series by Bilenka et al. [34], eight of nine patients conceived spontaneously after vertical banded gastroplasty as compared to one out of six who attempted pregnancy before undergoing surgery. Martin et al. [35] reported five spontaneous pregnancies after gastric banding in nulligravid women who were previously unable to conceive. Neither study had a separate control group or specified the ovulatory status of participants. A retrospective cohort study reported a higher rate of fertility treatment in diabetic patients following bariatric surgery
(21.4%) as compared with those who had not undergone surgery (5.5%; P < 0.001) [36,37]. Although controlling for patient age, obesity, and parity, the study did not adjust for ovulatory status or cause of infertility, making it difficult to form conclusions from these data. The impact of weight loss on anovulatory infertility has been studied extensively in women with PCOS, with several studies demonstrating improvements in insulin sensitivity, menstrual cyclicity, and ovulation rates with even modest weight loss [38–40]. Recent studies have specifically addressed the impact of bariatric surgery on anovulatory infertility. In a retrospective survey of reproductive age women who had undergone bariatric surgery, 71% of 98 patients who were anovulatory preoperatively regained menstrual cyclicity after surgery. The patients who regained ovulatory function had a greater average weight loss than those who remained anovulatory (61.4 vs. 49.9 kg; P ¼ 0.02) [41]. A survey of 109 morbidly obese women who lost greater than 50% of their excess body weight with bariatric surgery also demonstrated fewer menstrual irregularities (40.4% preoperatively vs. 4.6% postoperatively; P < 0.001) [42]. A third retrospective study of 24 morbidly obese oligomenorrehic women with PCOS revealed resumption of normal menstrual cycles after a mean of 3.4 2.1 months in all women [43]. Hyperandrogenism in women with PCOS has also been shown to improve after bariatric surgery. A prospective study of 17 women with PCOS showed decreased levels of hirsuitism, testosterone, androstenedione, and dehydroepiandrosterone sulfate (DHEA-S), as well as normalization of menstrual cycles after bariatric surgery [44]. Comparatively little is known about the impact of bariatric surgery on fertility in ovulatory obese women. A single study by Rochester et al. [45] looked at urinary hormone excretion in eumenorrheic morbidly obese women after bariatric surgery. Levels of urinary LH and Pdg during the luteal phase increased significantly after surgical weight loss (Fig. 2). Although postoperative luteal phase urinary LH levels were comparable to those seen in normal-weight women, luteal Pdg levels remained below that seen in controls, indicating only partial recovery of luteal function after bariatric surgery. The adipokines leptin and adiponectin have been postulated to adversely impact ovulation in obese women [46]. Leptin concentrations decrease with weight loss on low-calorie diets [47] or after bariatric surgery [48]. Murine models demonstrate reversal of subfertility with reduction of leptin levels after dietary modification [49]. Unlike most adipokines, adiponectin concentrations are lower in obesity and insulin-resistant states. Plasma adiponectin increases with significant weight loss following bariatric surgery [48], but not after more modest weight loss from caloric restriction [47]. The cytokines
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Bariatric surgery and fertility Shah and Ginsburg 251 Figure 2 Reproductive hormone changes after bariatric surgery
Recent studies have described a number of hormonal alterations in women after bariatric surgery. Decreased adipose tissue results in lower levels of estradiol, which stimulates hypothalamic release of GnRH and gonadotropin secretion by the pituitary. Urinary metabolites such as peak LH and luteal Pdg have been shown to increase as a result. Surgical weight loss also lowers insulin levels, resulting in increased sex-hormone-binding-globulin (SHBG) and decreased peripheral testosterone secretions. MIS levels have also been shown to decrease after bariatric surgery. Adapted from [12].
interleukin-6 (IL-6) and plasminogen activator inhibitor1 (PAI-1) are increased in obese individuals, in whom they may contribute to ovulatory dysfunction (IL-6) [50] or implantation failure (PAI-1) [51]. Bariatric surgery has been shown to decrease levels of IL-6 [52] and PAI-1 [53]. Although the literature on adipokines and bariatric surgery is expanding, studies have yet to identify a specific role for these hormones in the treatment of obesity-related reproductive failure.
retrieved in addition to requiring higher doses of gonadotropins. Data from 48 682 IVF cycles presented at the American Society of Reproductive Medicine (ASRM) 2009 annual meeting reveal that odds of pregnancy decreased with increasing BMI in obese women and the odds of live birth decreased with increasing BMI in both overweight and obese women [64]. When IVF outcomes using donor oocytes were evaluated, there was no difference in pregnancy rates between obese, overweight, or normal-weight women, suggesting an adverse impact of obesity on oocyte quality or number [65].
Bariatric surgery and IVF outcomes Obesity has been shown to adversely impact IVF outcomes, although the data are inconsistent regarding which parameters are affected [54]. Recent literature demonstrates associations between obesity and decreased mature oocyte yield, need for increased gonadotropin stimulation, and increased cycle cancellation rates [55–57,58,59]. Although many studies also report decreased clinical pregnancy and live birth rates among obese or morbidly obese women [58,60,61], others have not [57,62]. A large retrospective study by Dokras et al. [57] demonstrated no difference in clinical pregnancy or live birth rates between obese or morbidly obese women and normal-weight controls. A systematic review by Maheshwari et al. [63] reported that women with a BMI of 25 kg/m2 or more have lower pregnancy rates and reduced numbers of oocytes
Little is published on the impact of surgical weight loss on IVF outcomes. A case report revealed empty follicle syndrome at the time of oocyte retrieval in a previously morbidly obese woman who had lost 175 lbs. after gastric bypass. Intramuscular hCG was used in a subsequent cycle with retrieval of 19 oocytes and successful pregnancy [66].
Bariatric surgery and miscarriage Obesity is associated with increased risk of miscarriage in ovulation induction cycles [67], with IVF-ICSI [59,68], as well as in morbidly obese women using donor oocytes [69]. These findings are supported by a recent metaanalysis demonstrating an increased risk of miscarriage in
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252 Fertility
women with a BMI 25 kg/m2 or more as compared with normal-weight controls (odds ratio 1.67, 95% confidence interval 1.10–2.09), regardless of mode of conception [70]. This association persisted in subgroup analyses of women undergoing oocyte donation and ovulation induction, but there was no evidence for increased miscarriage rates after IVF-ICSI. A few studies have shown no detrimental impact of obesity on first trimester pregnancy failure [71,72]. The discrepancy in the data is likely related to variance in the definition of obesity. There may be a decline in miscarriage rates after bariatric surgery. A small cohort study of nine patients showed decreased miscarriage rates after gastric banding (six of 18 pregnancies ended in miscarriage prior to surgery as compared to one of 13 after) [34]. Friedman et al. [73] compared pregnancy outcomes in 1136 women before and after biliopancreatic diversion and found a 17% miscarriage rate before surgery as compared to 11% after it. A retrospective survey study of 700 women, however, showed no difference in self-reported miscarriage rates before and after biliopancreatic diversion [33].
Bariatric surgery and male fertility There are minimal data on surgical weight loss and male infertility. Obesity is associated with increased estrogen and reduced total testosterone in men [74,75]. A cohort study of 22 morbidly obese men after Roux-en-Y gastric bypass showed decreased serum estradiol and increased total and free testosterone as compared to 42 morbidly obese controls [76]. Interestingly, a case series of six morbidly obese men of proven fertility who presented with secondary infertility after Roux-en-Y gastric bypass suggested a negative impact of bariatric surgery on male fertility. Semen analysis and testicular biopsy revealed secondary azoospermia with complete spermatogenic arrest in all six men, despite normal sex hormone profiles. The authors speculate whether postoperative nutrient absorption was insufficient for spermatogenesis [77].
Timing of bariatric surgery relative to conception Because patients generally undergo a period of rapid weight loss after bariatric surgery, there is a theoretical concern that maternal or fetal nutrition may be compromised by a pregnancy in the immediate postoperative period [78]. Some bariatric surgery centers advocate nutritional monitoring for up to 2 years after surgery, finding that 30–50% of patients require supplementation of calcium, iron, or vitamin B12 [79]. Small studies comparing pregnancies within 12–18 months of bariatric surgery with later pregnancies found no difference in cesarean delivery rate, low birth weight, or congenital abnormalities [80,81]. A recent prospective cohort study
of 26 women stratified by time to conception after laparoscopic Roux-en-Y gastric bypass, however, did show a 50% rate of preterm delivery in pregnancies that occurred within the first 12 months (two out of four pregnancies) as compared with a 20% rate among those occurring more than 2 years postoperatively (two of 10 pregnancies) [82]. The general consensus is that pregnancy should be delayed 12–18 months after surgery to avoid nutritional deficiencies and promote weight loss [35,83,84], However, in their 2008 systematic review, Maggard et al. [15] conclude that there are insufficient data to support recommendations regarding the ideal timing for pregnancy after bariatric surgery.
Conclusion Obesity has been shown to adversely impact male and female fertility through a variety of mechanisms. Bariatric surgery is the most reliable way to achieve and sustain weight loss in the morbidly obese. Although bariatric surgery is associated with significant improvement in many parameters of reproductive function, the American College of Obstetricians and Gynecologists does not recommend it as a treatment for infertility [84]. Our practice is to recommend consultation with a bariatric surgeon for all morbidly obese infertile patients. Morbidly obese patients are also required to meet with maternal– fetal medicine specialists to discuss the increased risk of obstetrical complications such as gestational diabetes, preeclampsia, and cesarean delivery that are well established in this population [78,84,85]. It is worth noting that many obese infertile women chose not to undergo bariatric surgery secondary to the recommended postoperative delay in conception [86] or concerns about surgical complications. When counseling patients, the potential improvements in obstetrical outcome and pregnancy rates with weight loss must be balanced against the decreased likelihood of conception with increasing maternal age. Further studies are needed to determine the optimal timing of bariatric surgery relative to pregnancy and whether the benefits of preconception weight loss outweigh the higher risk of age-related infertility with delay of fertility treatment.
Acknowledgement There are no conflicts of interest.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 257). 1
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Bibliography Current World Literature This bibliography is compiled by clinicians from the journals listed at the end of this publication. It is based on literature entered into our database between 1 February 2009 and 31 January 2010 (articles are generally added to the database about two and a half months after publication). In addition, the bibliography contains every paper annotated by reviewers; these references were obtained from a variety of bibliographic databases and published between the beginning of the review period and the time of going to press. The bibliography has been grouped into topics that relate to the reviews in this issue.
Contents Fertility 255 Economics of assisted reproductive technologies 255 Cumulative live-birth rates after assisted reproductive technology
Vol 22 No 3 June 2010
258 Does the ovarian reserve decrease from repeated ovulation stimulations? 258 Update on the role of leukemia inhibitory factor in assisted reproduction 258 Are first-trimester screening markers altered in ART pregnancies?
256 The role of anti-Mu¨llerian hormone assessment in assisted reproductive technology outcome 256 Borderline ovarian tumors and fertility 256 Stem cells and reproduction 256 Impact of male age in reproduction
Papers considered by the reviewers to be of special interest Papers considered by the reviewers to be of outstanding interest The number in square brackets following a selected paper, e.g. [7], refers to its number in the annotated references of the corresponding review. Current Opinion in Obstetrics and Gynecology 2010, 22:255–258 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 1040-872X #
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257 Impact of previous artery embolization on fertility 257 Fertility in congenital adrenal hyperplasia 257 Ectopic pregnancy after assisted reproductive technology: what are the risk factors? 257 Mental health of parents of twins conceived via assisted reproductive technology 257 Bariatric surgery and fertility 257 Is there a benefit in follicular flushing in assisted reproductive technology?
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Simon C. European funding for reproduction research-A multinational perspective. Nat Med 2008; 14:1222. Strauss JF, De Paolo LV. Funding for the reproductive sciences in the US. Nat Med 2008; 14:1214–1217. Vayena E, Peterson HB, Adamson D, Nygren KG. Assisted reproductive technologies in developing countries: are we caring yet? Fertil Steril 2009; 92:413– 416. Veleva Z, Karinen P, Tomas C, Tapanainen JS, et al. Elective single embryo transfer with cryopreservation improves the outcome and diminishes the costs of IVF/ICSI. Hum Reprod 2009; 24:1632–1639. Wechowski J, Connolly M, Schneider D, McEwan P, et al. Costsaving treatment strategies in in vitro fertilization: a combined economic evaluation of two large randomized clinical trials comparing highly purified human menopausal gonadotropin and recombinant folliclestimulating hormone alpha. Fertil Steril 2009; 91:1067– 1076.
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Impact of previous artery embolization on fertility
Ectopic pregnancy after assisted reproductive technology: what are the risk factors? Review: (pp. 202–207)
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