JOURNAL OF WOMEN’S HEALTH Volume 24, Number 2, 2015 ª Mary Ann Liebert, Inc. DOI: 10.1089/jwh.2014.4999
Oocyte Donation Is an Independent Risk Factor for Pregnancy Complications: The Implications for Women of Advanced Age Johnny S. Younis, MD,1,2 and Neri Laufer, MD 3,4
Abstract
Maternal age at first pregnancy and age-related infertility are steadily increasing, and the demand for assisted reproductive technologies (ART) to treat age-related infertility is also on the rise. The latest registry findings from Europe and the United States show that the meager results of ART in women above 43 years of age have not improved much over the past 10 years. The latest evidence shows that the demand for oocyte donation (OD) is steadily increasing. Contrary to previous belief—attributing increased perinatal complications in OD recipients to advanced maternal age and multifetal pregnancy—accumulating evidence from the past few years suggests that OD itself is a significant and independent risk factor for pregnancy complications, mostly for preeclampsia. The increased rate of chronic maternal disease and medical complications in pregnancy observed in advanced maternal age, coupled with the growing demand for OD, with its independent association with preeclampsia, create an urgent need to adopt a clear policy taking these risks into account. We present recent evidence showing that OD is an independent risk factor for pre-eclampsia and suggest recommendations for women approaching OD treatment in advanced age.
Introduction
P
arallel to the steadily increasing average age of mothers at first birth in Western societies,1 the demand for assisted reproductive technologies (ART) to treat age-related infertility is also on the rise.2 Reproductive potential declines as female age advances, and current technology using autologous oocytes remains limited by the ovarian ‘‘biological clock.’’ According to the most recent registry statistics from Europe and the United States, ART results in women older than 43 years have not improved much over the past 10 years.3,4 The cumulative live-birth rate following ART has also been shown to be poor in women ‡ 43 years of age treated with autologous oocytes. By the third cycle, the conservative and optimal estimates of live-birth rates decline, from 63.3% and 74.6%, respectively, for women younger than 31 years of age, to 6.6% and 11.3% for those 43 years of age or older.5 Oocyte donation (OD), originally developed to treat premature ovarian failure in young women, is currently more commonly applied to treat age-related low ovarian reserve
infertility. High-quality evidence shows that the demand for OD is steadily increasing.6 It is now estimated that about 100,000 cycles of OD are performed annually worldwide,7 the majority for age-related infertility. Until recently, the prevailing notion was that increased perinatal complications in donated-oocyte recipients could be attributed to advanced maternal age and multifetal pregnancy.8–11 However, accumulating evidence from the past few years suggests that OD itself is a significant and independent risk factor for pregnancy complications, mostly for pre-eclampsia.12–17 The increased rate of chronic maternal disease (chronic hypertension and pregestational diabetes mellitus), medical complications in pregnancy (especially pre-eclampsia and gestational diabetes mellitus), higher Cesarean-section rate, postpartum maternal complications, and neonatal morbidity observed in advanced maternal age,18 coupled with the growing demand for OD,6 with its independent association with pre-eclampsia, create an urgent need to adopt a clear policy addressing these risks. This article presents recent
1
Reproductive Medicine Unit, Department of Obstetrics and Gynecology, Poriya Medical Center, Tiberias, Israel. Faculty of Medicine in Galilee, Bar-Ilan University, Safed, Israel. 3 Reproductive Medicine Unit, Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Ein-Karem, Jerusalem, Israel. 4 Hadassah Medical School, Hebrew University, Jerusalem, Israel. 2
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evidence showing that OD is an independent risk factor for pre-eclampsia, and we suggest recommendations for women approaching OD treatment in advanced age. Recent Evidence
Several recent studies have demonstrated an independent impact of OD treatment on the rate of perinatal complications. In an anonymous-questionnaire study, Keegan et al. evaluated 199 OD recipients and 488 infertile in vitro fertilization (IVF) women < 35 or > 40 years of age who had a live birth. These women were treated in one center during a period of 5 years. The OD recipients had significantly higher rates of pregnancy-induced hypertension than their IVF counterparts did. The OD recipients < 35 years had the highest rate (42%), followed by those > 40 years (26%), IVF women > 40 years (14%), and IVF patients < 35 years (12%).12 Similarly, in a matched-cohort single-center study, Klatsky et al. compared 77 OD recipients to 81 autologous IVF-treated women who had a live birth during a period of 8 years. Matching was performed for age and fetal plurality. The incidence of gestational hypertension and pre-eclampsia was significantly higher in OD recipients than in women undergoing autologous IVF (24.7% compared with 7.4%, p < 0.01, and 16.9% compared with 4.9%, p = 0.02, respectively). OD recipients were more likely than women undergoing autologous IVF to deliver prematurely (34% compared with 19%).13 Stoop et al., in a matched-pair cohort study in a single center over a period of 10 years, analyzed the results of 205 OD pregnancies in young recipients (mean age, 36.0) beyond 20 weeks gestation with 205 intracytoplasmic sperm injection (ICSI) pregnancies with autologous oocytes.14 After excluding all confounding factors, OD was associated with an increased risk of pregnancy-induced hypertension (matched odds ratio [OR] = 1.50, 95% confidence interval [CI]: 1.02–2.20) and first-trimester bleeding (matched OR = 1.49, 95% CI: 1.04–2.15). In a well-designed cohort study set in a single center during a period of 3 years, Le Ray et al. studied 380 women who gave birth after their 43rd birthday.15 The study included 236 (62.1%) women with naturally conceived pregnancies, 40 who had IVF without OD (10.5%), and 104 who had both IVF and OD (27.4%). Overall, there were 326 singleton and 54 multiple pregnancies. After adjustment for confounding factors, the risk of pre-eclampsia was significantly higher in women with OD than in pregnant women without IVF (adjusted OR = 3.3, 95% CI: 1.2–8.9). In addition, other independent, well-documented risk factors, such as advanced maternal age, nulliparity, and multiple pregnancies, were reconfirmed. In a recently published matched-cohort study, Sekhon et al. analyzed the results of 56 women with IVF twin pregnancies who had OD and 56 age-matched controls with IVF twin pregnancies who used autologous oocytes.16 Women aged > 50 years were excluded owing to lack of controls. A significantly increased incidence of gestational hypertension (32.1% vs. 13.0%) and pre-eclampsia (28.3% vs. 13.0%) was found in the group that underwent IVF with donor oocytes in comparison to controls. There were no differences in outcomes between the groups in regard to preterm birth, birth weight, or gestational diabetes. Accumulating evidence from cohort studies suggests that OD itself is an independent and unrelated factor for devel-
YOUNIS AND LAUFER
oping pregnancy-induced hypertension and pre-eclampsia. This finding has been shown in both young women and the advanced-age groups. This evidence should be employed to counsel infertile women considering OD treatment. Advanced maternal age and multifetal pregnancy—two previously well-known, accepted, and independent factors that may complicate these pregnancies—may have a more pronounced impact within the setting of OD. Evidence concerning perinatal complications in women over 50 years of age is limited in the OD setting, and data are scant regarding maternal and fetal safety for women over 55 years of age. This new evidence originating from the OD model19 revives the immunological theory of pre-eclampsia development. Significant histological and immunohistochemical differences have been demonstrated between the placentas of egg donor and autologous IVF pregnancies. Dense fibrinoid deposition in the basal plate with severe chronic deciduitis containing significantly increased numbers of T helper and natural killer cells were demonstrated in egg donor placentas, suggesting a host vs. graft rejection-like phenomenon.20,21 These clinical and histological conjoined results tend to support the notion of immunological maladaptation/intolerance as a cause of pre-eclampsia. That is, in pregnancies with OD, the fetus may be considered as a totally allogenic graft for the woman and no longer a semiallogenic graft. This may disrupt normal protective mechanisms to prevent rejection of the fetomaternal unit. As a result, poor early placentation may develop, leading to increased vascular resistance and contributing to the development of pre-eclampsia. The Impact of Multifetal Pregnancy
Multifetal pregnancy, including twins, increases maternal morbidity and both fetal and neonatal morbidity and mortality. Major maternal complications are pre-eclampsia, gestational diabetes, and preterm labor and delivery. The risks for fetal demise during the third trimester, perinatal mortality, preterm birth, and both low ( < 2,500 g) and very low ( < 1,500 g) birth weight increase with the number of fetuses in a multiple gestation. Fetal growth restriction and discordance contribute to the increased perinatal morbidity and mortality in multifetal pregnancies.22 The introduction of single-embryo transfer (SET) has substantially reduced the risks of multifetal pregnancy and consequently preterm birth and low birth weight in autologous IVF setting. In a meta-analysis of randomized trials comparing double-embryo transfer (DET) and SET strategies, the multiple-birth rate was shown to be reduced significantly: from 29% to 2% (OR = 0.04, 95% CI: 0.01–0.12).23 Although live-birth rate per transfer has been shown to be higher for DET than for SET,23,24 cumulative live-birth rate of SET was found to be similar to one fresh DET corresponding to 38% and 42%, respectively (OR = 0.85, 95% CI: 0.62–1.15).23 In most parts of the world, donors are required to be young, under age 35. Therefore, good-quality embryos are available, and a favorable clinical pregnancy rate is anticipated. It would be reasonable to recommend SET in an OD setting, especially in women with advanced age, to avoid multifetal pregnancy complications. In a single-center OD setting, SET and DET strategies were compared during a period of 9 years. In this cohort study, 1,139 OD-recipient fresh cycles with at least three
OOCYTE DONATION IN ADVANCED AGE
available embryos for transfer were evaluated: 1,073 from DET and 66 from SET. The clinical pregnancy rates were found to be similar after SET (45.5%) and DET (57.1%), whereas the multifetal pregnancy rate was 0% and 39.5% for SET and DET, respectively.25 Recommendations for Advanced-Age Women Considering OD
Based on recently accumulated observations, it may be practical to divide women of advanced age considering OD treatment into two groups: those > 45 years of age and those > 50 years of age (extreme advanced age). The suggested recommendations accord with the latest literature and European Society of Human Reproduction and Embryology (ESHRE) and American Society for Reproductive Medicine (ASRM) statements.26–28 A comprehensive medical history; physical, cardiovascular, and gynecological examination; and relevant complementary tests must be performed in all recipients. Special attention should be given to women in the extreme-advancedage group. Patients should be evaluated for chronic diseases identified as risk factors for obstetric complications, such as hypertension, diabetes mellitus, obesity, and others. If present, a detailed expert evaluation should be obtained and discussed. Risk-factor evaluation should include a complete blood count (CBC), prothrombin time (PT), partial thromboplastin time (PTT), fasting glucose, kidney and liver function tests, lipid profile, and thyroid-stimulating hormone (TSH) blood tests, as well as viral-disease screening for hepatitis B, C, and HIV. In addition, screening should be performed for breast, uterine cervix, and (for women above 50 years of age) colon malignancy. If a medical disease/risk factor is present, a multidisciplinary evaluation is mandatory, including reproductive and perinatal medicine specialists, as well as a relevant medical specialist. All women referred to OD treatment should be counseled about the increased risk of perinatal complications, especially pre-eclampsia. In women above the age of 50, it is important to explain that data are limited. Social and/or psychological evaluation should be suggested to women above 45 years and recommended to women above 50 years of age. Short- and long-term parenting and child-rearing issues should be discussed, as well as the health of the partner. In the extreme-maternal-age group, OD treatment should be discouraged whenever there is an underlying medical problem that may jeopardize maternal or neonatal safety. Since data are scant in women > 55 years of age, OD treatment should be discouraged in this group of patients even if an individual woman has no underlying medical problem. As multifetal pregnancy further increases the risks of perinatal complications, SET should be strongly considered in all women above the age of 45. Conclusions
Maternal age at first pregnancy and age-related infertility are steadily increasing. ART results with autologous oocytes are poor in this group, leading to an increasing demand for OD treatment. Recent data suggest that OD treatment is an independent risk factor for perinatal complications, especially pre-eclampsia. This observation revives the hypothesis of immunological maladaptation and consequently defective
129
placentation as the basis for pre-eclampsia development. Moreover, since maternal age and multifetal pregnancy are other independent factors that may affect maternal and neonatal safety, clear recommendations ought to be adopted for women seeking OD treatment in advanced age, taking into account recent published evidence, reproductive-society recommendations, scarce data in some subgroups, and relevant ethical considerations. Author Disclosure Statement
No competing financial interests exist. References
1. Matthews TJ, Hamilton BE. Delayed childbearing: More women are having their first child later in life. NCHS Data Brief 2009;21:1–8. 2. Leridon H, Slama R. The impact of a decline in fecundity and of pregnancy postponement on final number of children and demand for assisted reproduction technology. Hum Reprod 2008;23:1312–1319. 3. Ferraretti AP, Goossens V, Kupka M, et al. Assisted reproductive technology in Europe, 2009: Results generated from European registers by ESHRE. Hum Reprod 2013;28: 2318–2331. 4. CDC. Assisted reproductive technology (ART) 2011 report. Section 5: ART cycles using donor eggs. Available at: http://www.cdc.gov/art/ART2011/section5.htm (Fig. 47; accessed on August 13, 2013). 5. Luke B, Brown MB, Wantman E, et al. Cumulative birth rates with linked assisted reproductive technology cycles. N Engl J Med 2012;366:2483–2491. 6. Kawwass JF, Monsour M, Crawford S, et al. Trends and outcomes for donor oocyte cycles in the United States, 2000–2010. JAMA 2013;310:2426–2434. 7. Weissman A, Leong M, Sauer MV, Shoham Z. Characterizing the practice of oocyte donation: A web-based international survey. Reprod Biomed Online 2014;28:443–450. 8. So¨derstro¨m-Anttila V. Pregnancy and child outcome after oocyte donation. Hum Reprod Update 2001;7:28–32. 9. Paulson RJ, Boostanfar R, Saadat P, et al. Pregnancy in the sixth decade of life: Obstetric outcomes in women of advanced reproductive age. JAMA 2002;288:2320–2323. 10. Porreco RP, Harden L, Gambotto M, Shapiro H. Expectation of pregnancy outcome among mature women. Am J Obstet Gynecol 2005;192:38–41. 11. Krieg SA, Henne MB, Westphal LM. Obstetric outcomes in donor oocyte pregnancies compared with advanced maternal age in in vitro fertilization pregnancies. Fertil Steril 2008;90:65–70. 12. Keegan DA, Krey LC, Chang HC, Noyes N. Increased risk of pregnancy-induced hypertension in young recipients of donated oocytes. Fertil Steril 2007;87:776–781. 13. Klatsky PC, Delaney SS, Caughey AB, Tran ND, Schattman GL, Rosenwaks Z. The role of embryonic origin in preeclampsia: A comparison of autologous in vitro fertilization and ovum donor pregnancies. Obstet Gynecol 2010;116: 1387–1392. 14. Stoop D, Baumgarten M, Haentjens P, et al. Obstetric outcome in donor oocyte pregnancies: A matched-pair analysis. Reprod Biol Endocrinol 2012;10:42. 15. Le Ray C, Scherier S, Anselem O, et al. Association between oocyte donation and maternal and perinatal outcomes in women aged 43 years or older. Hum Reprod 2012;27:896–901.
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16. Sekhon LH, Gerber RS, Rebarber A, et al. Effect of oocyte donation on pregnancy outcomes in in vitro fertilization twin gestations. Fertil Steril 2014;101:1326–1330. 17. Kort DH, Gosselin J, Choi JM, Thornton MH, ClearyGoldman J, Sauer MV. Pregnancy after age 50: Defining risks for mother and child. Am J Perinatol 2012;29:245–250. 18. Yogev Y, Melamed N, Bardin R, Tenenbaum-Gavish K, BenShitrit G, Ben-Haroush A. Pregnancy outcome at extremely advanced maternal age. Am J Obstet Gynecol 2010;203: 558.e1–7. 19. Younis JS, Simon A, Laufer N. Endometrial preparation: Lessons from oocyte donation. Fertil Steril 1996;66:873– 884. 20. Perni SC, Predanic M, Cho JE, Baergen RN. Placental pathology and pregnancy outcomes in donor and non-donor oocyte in vitro fertilization pregnancies. J Perinat Med 2005;33:27–32. 21. Gundogan F, Bianchi DW, Scherjon SA, Roberts DJ. Placental pathology in egg donor pregnancies. Fertil Steril 2010;93:397–404. 22. Practice Committee of American Society for Reproductive Medicine. Multiple gestation associated with infertility therapy: An American Society for Reproductive Medicine Practice Committee opinion. Fertil Steril 2012;97:825–834. 23. McLernon DJ, Harrild K, Bergh C, et al. Clinical effectiveness of elective single versus double embryo transfer: Meta-analysis of individual patient data from randomised trials. BMJ 2010;341:c6945.
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24. Baruffi RL, Mauri AL, Petersen CG, et al. Single-embryo transfer reduces clinical pregnancy rates and live births in fresh IVF and intracytoplasmic sperm injection (ICSI) cycles: A meta-analysis. Reprod Biol Endocrinol 2009;7:36. 25. Clua E, Tur R, Coroleu B, et al. Elective single-embryo transfer in oocyte donation programmes: Should it be the rule? Reprod Biomed Online 2012;25:642–648. 26. ESHRE Task Force on Ethics and Law. Gamete and embryo donation. Hum Reprod 2002;17:1407–1408. 27. Ethics Committee of the American Society for Reproductive Medicine. Oocyte or embryo donation to women of advanced age: A committee opinion. Fertil Steril 2013;100:337–340. 28. Practice Committee of American Society for Reproductive Medicine; Practice Committee of Society for Assisted Reproductive Technology. Recommendations for gamete and embryo donation: A committee opinion. Fertil Steril 2013; 99:47–62.
Address correspondence to: Johnny S. Younis, MD Reproductive Medicine Unit Department of Obstetrics and Gynecology Poriya Medical Center Tiberias 15208 Israel E-mail: [email protected]
Oocyte Donation Is an Independent Risk Factor for Pregnancy Complications: The Implications for Women of Advanced Age Johnny S. Younis, MD,1,2 and Neri Laufer, MD 3,4
Abstract
Maternal age at first pregnancy and age-related infertility are steadily increasing, and the demand for assisted reproductive technologies (ART) to treat age-related infertility is also on the rise. The latest registry findings from Europe and the United States show that the meager results of ART in women above 43 years of age have not improved much over the past 10 years. The latest evidence shows that the demand for oocyte donation (OD) is steadily increasing. Contrary to previous belief—attributing increased perinatal complications in OD recipients to advanced maternal age and multifetal pregnancy—accumulating evidence from the past few years suggests that OD itself is a significant and independent risk factor for pregnancy complications, mostly for preeclampsia. The increased rate of chronic maternal disease and medical complications in pregnancy observed in advanced maternal age, coupled with the growing demand for OD, with its independent association with preeclampsia, create an urgent need to adopt a clear policy taking these risks into account. We present recent evidence showing that OD is an independent risk factor for pre-eclampsia and suggest recommendations for women approaching OD treatment in advanced age.
Introduction
P
arallel to the steadily increasing average age of mothers at first birth in Western societies,1 the demand for assisted reproductive technologies (ART) to treat age-related infertility is also on the rise.2 Reproductive potential declines as female age advances, and current technology using autologous oocytes remains limited by the ovarian ‘‘biological clock.’’ According to the most recent registry statistics from Europe and the United States, ART results in women older than 43 years have not improved much over the past 10 years.3,4 The cumulative live-birth rate following ART has also been shown to be poor in women ‡ 43 years of age treated with autologous oocytes. By the third cycle, the conservative and optimal estimates of live-birth rates decline, from 63.3% and 74.6%, respectively, for women younger than 31 years of age, to 6.6% and 11.3% for those 43 years of age or older.5 Oocyte donation (OD), originally developed to treat premature ovarian failure in young women, is currently more commonly applied to treat age-related low ovarian reserve
infertility. High-quality evidence shows that the demand for OD is steadily increasing.6 It is now estimated that about 100,000 cycles of OD are performed annually worldwide,7 the majority for age-related infertility. Until recently, the prevailing notion was that increased perinatal complications in donated-oocyte recipients could be attributed to advanced maternal age and multifetal pregnancy.8–11 However, accumulating evidence from the past few years suggests that OD itself is a significant and independent risk factor for pregnancy complications, mostly for pre-eclampsia.12–17 The increased rate of chronic maternal disease (chronic hypertension and pregestational diabetes mellitus), medical complications in pregnancy (especially pre-eclampsia and gestational diabetes mellitus), higher Cesarean-section rate, postpartum maternal complications, and neonatal morbidity observed in advanced maternal age,18 coupled with the growing demand for OD,6 with its independent association with pre-eclampsia, create an urgent need to adopt a clear policy addressing these risks. This article presents recent
1
Reproductive Medicine Unit, Department of Obstetrics and Gynecology, Poriya Medical Center, Tiberias, Israel. Faculty of Medicine in Galilee, Bar-Ilan University, Safed, Israel. 3 Reproductive Medicine Unit, Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Ein-Karem, Jerusalem, Israel. 4 Hadassah Medical School, Hebrew University, Jerusalem, Israel. 2
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evidence showing that OD is an independent risk factor for pre-eclampsia, and we suggest recommendations for women approaching OD treatment in advanced age. Recent Evidence
Several recent studies have demonstrated an independent impact of OD treatment on the rate of perinatal complications. In an anonymous-questionnaire study, Keegan et al. evaluated 199 OD recipients and 488 infertile in vitro fertilization (IVF) women < 35 or > 40 years of age who had a live birth. These women were treated in one center during a period of 5 years. The OD recipients had significantly higher rates of pregnancy-induced hypertension than their IVF counterparts did. The OD recipients < 35 years had the highest rate (42%), followed by those > 40 years (26%), IVF women > 40 years (14%), and IVF patients < 35 years (12%).12 Similarly, in a matched-cohort single-center study, Klatsky et al. compared 77 OD recipients to 81 autologous IVF-treated women who had a live birth during a period of 8 years. Matching was performed for age and fetal plurality. The incidence of gestational hypertension and pre-eclampsia was significantly higher in OD recipients than in women undergoing autologous IVF (24.7% compared with 7.4%, p < 0.01, and 16.9% compared with 4.9%, p = 0.02, respectively). OD recipients were more likely than women undergoing autologous IVF to deliver prematurely (34% compared with 19%).13 Stoop et al., in a matched-pair cohort study in a single center over a period of 10 years, analyzed the results of 205 OD pregnancies in young recipients (mean age, 36.0) beyond 20 weeks gestation with 205 intracytoplasmic sperm injection (ICSI) pregnancies with autologous oocytes.14 After excluding all confounding factors, OD was associated with an increased risk of pregnancy-induced hypertension (matched odds ratio [OR] = 1.50, 95% confidence interval [CI]: 1.02–2.20) and first-trimester bleeding (matched OR = 1.49, 95% CI: 1.04–2.15). In a well-designed cohort study set in a single center during a period of 3 years, Le Ray et al. studied 380 women who gave birth after their 43rd birthday.15 The study included 236 (62.1%) women with naturally conceived pregnancies, 40 who had IVF without OD (10.5%), and 104 who had both IVF and OD (27.4%). Overall, there were 326 singleton and 54 multiple pregnancies. After adjustment for confounding factors, the risk of pre-eclampsia was significantly higher in women with OD than in pregnant women without IVF (adjusted OR = 3.3, 95% CI: 1.2–8.9). In addition, other independent, well-documented risk factors, such as advanced maternal age, nulliparity, and multiple pregnancies, were reconfirmed. In a recently published matched-cohort study, Sekhon et al. analyzed the results of 56 women with IVF twin pregnancies who had OD and 56 age-matched controls with IVF twin pregnancies who used autologous oocytes.16 Women aged > 50 years were excluded owing to lack of controls. A significantly increased incidence of gestational hypertension (32.1% vs. 13.0%) and pre-eclampsia (28.3% vs. 13.0%) was found in the group that underwent IVF with donor oocytes in comparison to controls. There were no differences in outcomes between the groups in regard to preterm birth, birth weight, or gestational diabetes. Accumulating evidence from cohort studies suggests that OD itself is an independent and unrelated factor for devel-
YOUNIS AND LAUFER
oping pregnancy-induced hypertension and pre-eclampsia. This finding has been shown in both young women and the advanced-age groups. This evidence should be employed to counsel infertile women considering OD treatment. Advanced maternal age and multifetal pregnancy—two previously well-known, accepted, and independent factors that may complicate these pregnancies—may have a more pronounced impact within the setting of OD. Evidence concerning perinatal complications in women over 50 years of age is limited in the OD setting, and data are scant regarding maternal and fetal safety for women over 55 years of age. This new evidence originating from the OD model19 revives the immunological theory of pre-eclampsia development. Significant histological and immunohistochemical differences have been demonstrated between the placentas of egg donor and autologous IVF pregnancies. Dense fibrinoid deposition in the basal plate with severe chronic deciduitis containing significantly increased numbers of T helper and natural killer cells were demonstrated in egg donor placentas, suggesting a host vs. graft rejection-like phenomenon.20,21 These clinical and histological conjoined results tend to support the notion of immunological maladaptation/intolerance as a cause of pre-eclampsia. That is, in pregnancies with OD, the fetus may be considered as a totally allogenic graft for the woman and no longer a semiallogenic graft. This may disrupt normal protective mechanisms to prevent rejection of the fetomaternal unit. As a result, poor early placentation may develop, leading to increased vascular resistance and contributing to the development of pre-eclampsia. The Impact of Multifetal Pregnancy
Multifetal pregnancy, including twins, increases maternal morbidity and both fetal and neonatal morbidity and mortality. Major maternal complications are pre-eclampsia, gestational diabetes, and preterm labor and delivery. The risks for fetal demise during the third trimester, perinatal mortality, preterm birth, and both low ( < 2,500 g) and very low ( < 1,500 g) birth weight increase with the number of fetuses in a multiple gestation. Fetal growth restriction and discordance contribute to the increased perinatal morbidity and mortality in multifetal pregnancies.22 The introduction of single-embryo transfer (SET) has substantially reduced the risks of multifetal pregnancy and consequently preterm birth and low birth weight in autologous IVF setting. In a meta-analysis of randomized trials comparing double-embryo transfer (DET) and SET strategies, the multiple-birth rate was shown to be reduced significantly: from 29% to 2% (OR = 0.04, 95% CI: 0.01–0.12).23 Although live-birth rate per transfer has been shown to be higher for DET than for SET,23,24 cumulative live-birth rate of SET was found to be similar to one fresh DET corresponding to 38% and 42%, respectively (OR = 0.85, 95% CI: 0.62–1.15).23 In most parts of the world, donors are required to be young, under age 35. Therefore, good-quality embryos are available, and a favorable clinical pregnancy rate is anticipated. It would be reasonable to recommend SET in an OD setting, especially in women with advanced age, to avoid multifetal pregnancy complications. In a single-center OD setting, SET and DET strategies were compared during a period of 9 years. In this cohort study, 1,139 OD-recipient fresh cycles with at least three
OOCYTE DONATION IN ADVANCED AGE
available embryos for transfer were evaluated: 1,073 from DET and 66 from SET. The clinical pregnancy rates were found to be similar after SET (45.5%) and DET (57.1%), whereas the multifetal pregnancy rate was 0% and 39.5% for SET and DET, respectively.25 Recommendations for Advanced-Age Women Considering OD
Based on recently accumulated observations, it may be practical to divide women of advanced age considering OD treatment into two groups: those > 45 years of age and those > 50 years of age (extreme advanced age). The suggested recommendations accord with the latest literature and European Society of Human Reproduction and Embryology (ESHRE) and American Society for Reproductive Medicine (ASRM) statements.26–28 A comprehensive medical history; physical, cardiovascular, and gynecological examination; and relevant complementary tests must be performed in all recipients. Special attention should be given to women in the extreme-advancedage group. Patients should be evaluated for chronic diseases identified as risk factors for obstetric complications, such as hypertension, diabetes mellitus, obesity, and others. If present, a detailed expert evaluation should be obtained and discussed. Risk-factor evaluation should include a complete blood count (CBC), prothrombin time (PT), partial thromboplastin time (PTT), fasting glucose, kidney and liver function tests, lipid profile, and thyroid-stimulating hormone (TSH) blood tests, as well as viral-disease screening for hepatitis B, C, and HIV. In addition, screening should be performed for breast, uterine cervix, and (for women above 50 years of age) colon malignancy. If a medical disease/risk factor is present, a multidisciplinary evaluation is mandatory, including reproductive and perinatal medicine specialists, as well as a relevant medical specialist. All women referred to OD treatment should be counseled about the increased risk of perinatal complications, especially pre-eclampsia. In women above the age of 50, it is important to explain that data are limited. Social and/or psychological evaluation should be suggested to women above 45 years and recommended to women above 50 years of age. Short- and long-term parenting and child-rearing issues should be discussed, as well as the health of the partner. In the extreme-maternal-age group, OD treatment should be discouraged whenever there is an underlying medical problem that may jeopardize maternal or neonatal safety. Since data are scant in women > 55 years of age, OD treatment should be discouraged in this group of patients even if an individual woman has no underlying medical problem. As multifetal pregnancy further increases the risks of perinatal complications, SET should be strongly considered in all women above the age of 45. Conclusions
Maternal age at first pregnancy and age-related infertility are steadily increasing. ART results with autologous oocytes are poor in this group, leading to an increasing demand for OD treatment. Recent data suggest that OD treatment is an independent risk factor for perinatal complications, especially pre-eclampsia. This observation revives the hypothesis of immunological maladaptation and consequently defective
129
placentation as the basis for pre-eclampsia development. Moreover, since maternal age and multifetal pregnancy are other independent factors that may affect maternal and neonatal safety, clear recommendations ought to be adopted for women seeking OD treatment in advanced age, taking into account recent published evidence, reproductive-society recommendations, scarce data in some subgroups, and relevant ethical considerations. Author Disclosure Statement
No competing financial interests exist. References
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Address correspondence to: Johnny S. Younis, MD Reproductive Medicine Unit Department of Obstetrics and Gynecology Poriya Medical Center Tiberias 15208 Israel E-mail: [email protected]
