http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, 2014; 27(16): 1703–1709 ! 2014 UK. DOI: 10.3109/14767058.2013.871702
REVIEW ARTICLE
The risks and outcome of pregnancy in an advanced maternal age in oocyte donation cycles
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Yoel Shufaro and Joseph G. Schenker Department of Obstetrics and Gynecology, Hadassah University Hospital, Jerusalem, Israel
Abstract
Keywords
The maternal age at the first and repeated deliveries constantly rises in developed countries due to current social trends that favor values of personal achievements upon procreation. Assisted reproduction technologies and especially the availability of oocyte donation programs extend the age of fecundity to the fifth and sixth decades of life. The ability to conceive and deliver at such age raises serious medical, moral, social and legal concerns regarding the health and welfare of the mother and child will be presented and discussed here.
Advanced maternal age, assisted reproduction, oocyte donation, pregnancy outcome
Introduction Women over 50 can conceive and deliver following the transfer of embryos originating from oocytes donated by young women for reproductive purposes. When taken to the extreme, cases of successful pregnancies in women over 60 have been reported in the medical literature and popular media [1–4]. Improvements and standardization in the human embryological biotechnology, and the possibility to safely stimulate and collect oocytes from young donors, have enabled the transfer and successful implantation of embryos into the uterus of women much beyond their reproductive years [5,6]. As a consequence, women even beyond the assisted reproduction extended fecundity period, up to the sixth decade of life, are now able to conceive, carry pregnancies and deliver. In affluent societies, there is a growing trend to delay childbearing in favor of the fulfillment of personal inspirations. As a consequence, the number of women contemplating and achieving pregnancies in the fifth and sixth decades of life is constantly rising. Despite apparently good general well-being and health, pregnancies at such an advanced maternal age, beyond the natural human limits, are associated with increased maternal and fetal morbidities [7,8]. Contrary to ovarian age, it appears that embryo implantation is less affected by the endometrial age, therefore oocyte donation cycles in elderly women are as successful as assisted reproduction in the donors’ age group [9]. The uterus retains its receptivity to embryo implantation for a substantial period of time after the ovarian germ cell Address for correspondence: Dr. Yoel Shufaro, MD, PhD, Department of Obstetrics and Gynecology, Hadassah University Hospital, POB 12000, Jerusalem 91120, Israel. E-mail: [email protected]
History Received 21 October 2013 Accepted 30 November 2013 Published online 8 January 2014
reserve diminishes, as long as adequate endogenous or exogenous hormonal support exists or is provided. The implantation rate of embryos from donated oocytes is almost unaffected by the recipients’ age [7], but the chance for a successful final outcome is significantly affected by the occurrence of complications associated with advanced maternal age. Purposefully planned and induced pregnancies at an advanced maternal age (contrary to the rare ones occurring spontaneously) raise major medical and ethical concerns regarding the maternal, fetal and neonatal well-being. Therefore, it is important to openly discuss these issues in order to facilitate a public discussion towards determining the society’s position on expediting women of advanced age to reproduce beyond their natural limits. Each society should discuss in accordance to its values and available resources if such choices are acceptable, and at which financial, social, and personal risk costs. The objective of this review was to raise the medical and ethical concerns and to try to answer some of them from our perspective which represents our specific social and medical set-up.
Maternal considerations Several considerations should be taken into account when planning reproductive treatments in women of advanced age. Fertility at advanced age Fertility and fecundity decrease as a women’s age advances [10]. The leading cause for the age-related decrease in fecundity is the declining quality of the human oocyte that parallels aging. The endometrial receptivity and the chance of implantation also decrease with aging [11], but to a much
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lesser extent and in most cases endometrial receptivity is preserved by hormonal replacement or additive therapy [5]. Other factors contributing to infertility such as sperm anomalies, and pelvic pathologies (endometriosis adhesions and hydrosalpinges) may also co-exist. The fecundity and cumulative pregnancy rates, spontaneous and via assisted reproduction, decrease from age 35 onwards. In addition, the miscarriage rate increases in parallel to maternal aging, reaching as much as 20–40% at age 45, mainly due to an increase in chromosomal aberrations [12]. When oocytes from young donors are used instead of those originating from the aging patients, after adequate endometrial preparation with exogenous estrogens and progesterone, the pregnancy and miscarriage rate correspond to those obtained with assisted reproduction in the donor’s age group [9]. Advanced age and pregnancy-induced changes Even for young women the hemodynamic, respiratory, renal, and endocrinologic changes induced by pregnancy cause a considerable stress. The cardiac output gradually increases during pregnancy reaching 140% by the beginning of the third trimester. During labor, there are transient increases above this level. The ability of the cardiovascular system to adapt to these changes over 40 is not obvious. The respiratory volumes and effort and the glomelular filtration rate are also significantly increased [13]. The prevalence of hypertension, heart diseases, diabetes, chronic lung diseases, renal diseases, essential hypertension (and resulting placental complications) are directly associated with the maternal age [14,15], as well as the mortality associated with neoplasms and heart diseases [2]. At the fifth and sixth decades, such diseases might exist at a subclinical level and be unveiled by pregnancy, and might severely jeopardize the mother and fetus. In addition, gestational trophoblastic diseases, myomatous uteri, and urinary tract infections are also more prevalent at advanced age and might also complicate pregnancies in these patients [16–18]. Thus, it is well established that pregnancy in the older population potentially constitutes a major maternal health risk. The dilemma is to what extent and how to screen the candidates in order to avoid serious maternal morbidity on one hand, but allow pregnancy to those who can go through the gestation in relative safety on the other. Dynamic tests designed to unmask occult diseases like ergometry, Thallium scans, spirometry or even maximal oxygen consumption are of short duration and do not reliably mimic the changes known to occur in advanced pregnancy. No diagnostic test actually and faithfully simulates these conditions other than the actual pregnancy. For example, it is unclear if a pregestational normal heart function at echocardiography and a negative Thallium scan actually predict a pregnancy free from cardiac complications. Therefore, the negative predictive value of normal functional heart, lung or renal tests performed before pregnancy is uncertain.
Obstetrical considerations Advanced maternal age is prominent risk factor of chronic hypertension, pregnancy induced or exacerbated hypertension and preeclampsia [14]. The prevalence of impaired glucose tolerance and diabetes are also increased at advanced age.
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Therefore, it is not surprising that diabetes diagnosed during pregnancy, is more prevalent at advanced maternal age [14]. These two complications were reported to be of high prevalence in the advanced age group in almost all the published reports on this issue. Moreover, the prevalence of these complications was shown to be in direct correlation with advanced age [19]. When compared to women age 40–49, in women over 50 the occurrence rates of cardiac diseases, hypertension, diabetes, and preeclampsia were all elevated in the older age group [15]. These observations were confirmed by other studies [7,8,19]. The risk for any complication requiring hospitalization was substantially higher over 50 than under 50 and reached 63%. In a historical cohort study conducted between the years 1995 and 2012 in Jerusalem that included 349 singleton live births of women 45 and older the risk of preeclampsia was compared between natural conceptions and assisted reproduction conceptions with donor eggs. The absolute risk of preeclampsia in oocyte donation recipients over 45 was 12.6% compared to 0.9% in natural conceptions. Contrary to natural conceptions, the preeclampsia risk in oocyte donation recipients over 45 was constant and was unaffected by parity or increasing age (unpublished data, Dr. Uri Dior, Hadassah University Hospital). Age was found to independently correlate with the occurrence of placental abruption and placenta previa, even when confounding factors such as smoking or hypertension were corrected [17]. After stratification, the prevalence of both these complications was found to be in direct correlation with maternal age, even within the oocyte donation recipient group. The risk of placenta previa, placental abruption or both increases with advanced age [19]. Changes in the uterine microvasculature occurring with aging [20] might be an explanation. In the case of multi-fetal gestations, a common result of assisted reproduction, such hypertensive and placental complications are markedly increased [7]. Therefore, women of advanced age are more likely to experience preterm labor or complications necessitating premature delivery [2,7,8,15,19,21,22]. As a consequence, the prevalence of low birth weight and preterm deliveries is significantly increased over 50 for multiple and even singleton gestations [7]. The occurrence of various patterns of labor and instrumental deliveries in older primiparas varies between reports even after correction for confounding factors [23,24]. Infertility and especially oocyte donation pregnancies were strongly associated with delivery by cesarean section [21]. Cesarean section rate has been shown to be directly associated with maternal age [25]. It is safe to state that currently most of primiparas over 50 are delivered by cesarean section, even in the absence of complications. The obstetrical implications of this are mainly short termed, since these women are unlikely to have multiple repeated operations in most cases. Although longer hospitalization periods and increased febrile morbidity are associated with cesarean section (compared to vaginal deliveries), the utilization of intensive care unit hospitalizations and blood transfusion were not significantly increased in older patient group [19]. Since most of the partuitants of advanced age conceiving by assisted reproduction will not deliver again, more serious long-term sequel
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such as placenta previa or uterine rupture are unlikely. Although the maternal morbidity is definitely increased parallel to aging, the overall neonatal outcome did not appear to be affected [21,24].
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Maternal mortality The reported maternal mortality (direct and indirect) rises in correlation with age. The etiology is mainly pre-existing conditions exacerbated by the pregnancy itself, or the occurrence of pregnancy associated complications such as preeclampsia, placental abruption, postpartum hemorrhage, and thromboembolic phenomena [26]. The common performance of cesarean sections for delivering women of advanced age does not appear to contribute to the maternal mortality [2]. Sporadic maternal deaths following ovum donation in advanced age have been published [26], but it can be assumed that sub-reporting of such cases in the literature exists in order to avoid legal complications. However, the prevalence of maternal mortality, even at advanced age, is very low in countries with an up-to-date prenatal care system. Even if the relative risk of maternal mortality at advanced age is increased in comparison to the general population, the absolute mortality risk with adequate antenatal care is still very low. The neonate The prevalence of low birth weight, and stillbirths is increased in neonates born to mothers of advanced age [2,9,15,21,27,28]. These result from the increased risk of pre-term labor, complications necessitating pre-term delivery, and abnormal placental function in this group. On the other hand, the rate of low Apgar scores, asphyxia and metabolic complications (in live births) is not increased in women of advanced age [19,21]. The prevalence of chromosomal and congenital anomalies is increased in the offspring of older premenopausal women conceiving from their own oocytes, attributed mainly to the older egg factor. When oocytes from young donors are used, the prevalence of fetal and neonatal anomalies does not differ from the general population [9]. The long-term psychological and social impact of being the child of an elderly mother or parents varies greatly between countries, populations and societies. Oocyte donation programs Donor oocytes are currently used in timely and premature ovarian failure, low ovarian response to exogenous gonadotropins, and replace autologous oocytes in the cases of carriership of disorders inherited through the mitochondrial DNA, or other maternally inherited conditions in which pregestational diagnosis is not feasible. The oocytes are obtained either from in vitro fertilization (IVF) patients donating surplus oocytes, or from financially compensated volunteers. If fresh embryo transfer is contemplated, then the uterus must be prepared and synchronized. Alternatively oocytes or embryos can be frozen or vitrified and transferred to the recipient in another occasion [29]. In menopausal recipients, artificial endometrial preparation is achieved using estrogens followed by the supplementation with progesterone agents [5]. After pregnancy is confirmed, the endometrial support
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administration continues until placental steroid hormone production autonomy occurs. In the case that regularly ovulating recipients, embryos can be transferred based on the endogenous ovarian steroid secretion without artificial endometrial preparation. The reported global ongoing pregnancy and delivery rate is currently approximately 50% per transfer [30]. The increasing effectiveness of embryo and oocyte cryopreservation and its central role in current IVF practice has decreased patient willingness to donate oocytes, since most will prefer to cryopreserve their eggs or surplus embryos for their own use [31]. Therefore in most cases, oocytes for the recipients were aspirated from paid volunteers who are ‘‘compensated’’ for their ‘‘donation’’. Candidates must be under 35, in good current and past health, free of diseases transmitted through body fluids and hereditary disorders. Bilateral permanent anonymity is crucial for all parties involved, donor, recipient and the offspring. The volunteers to donate oocytes undergo moderate ovarian stimulation and oocyte recruitment under uItrasonographic guidance. Excessive ovarian stimulation is hazardous to the donor and is also unbeneficial to the quality of the obtained oocytes. A treatment protocol using a GnRH antagonist for protection against spontaneous LH surge and a GnRH analog instead of hCG for triggering oocyte maturation [32] protects the donor from ovarian hyper-stimulation syndrome without reducing the chance of implantation in the endometrium of the separately prepared recipient. In countries in which oocyte donation from compensated volunteers is performed, relevant legislation or directives exist, usually as a part of the human reproduction regulations. In most cases such regulation is set to protect the health, rights and anonymity of the donor [33]. Presently the entire stimulation and pick-up procedure bear little risk for the donors allowing oocyte donation to peri and post-menopausal women to be performed in many centers worldwide. Women of advanced age with low or absent ovarian reserve are the major patient group in need of oocyte donations, surpassing young low responders and genetic cases by far. However, on the recipients’ side it is surprising that there is an international paucity of regulations, despite the significant hazards that pregnancy might impose on them. A large share of oocyte donations treatments is performed across borders, with no actual supervision on age and health status of the recipients.
Ethical considerations The success rate of oocyte donation remains high even at advanced ages [30]. Any reasonably healthy woman with a uterus is a treatment candidate. This raises the issue of age limitation in reproductive technology. When taking into account the welfare of the patient, offspring, family and society, limitations the reproductive choice should be seriously considered against the right personal freedom in making reproductive choices. The attitude towards enabling elderly women to conceive using advanced technology and donor oocytes should be decided by each society individually. In addition, in places where the financial and egg donation resources are limited, a priority system for their
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allocation should also be established, reflecting the local values and laws.
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The issue of choice The will to reproduce is evolutionarily strong in most human societies. Starting about half a century ago, modern liberal societies cherish and value individual privacy and rights for autonomous reproductive choices. Assisted reproduction has opened new reproductive options not existent before [5]. Oocyte donation to an older woman is such a reproductive choice [34]. In an era of prolonged life expectancy and improving quality of life, a woman may not feel unsuitable to deliver and raise a child even if she in timely menopause. In developed countries with a good health system, a woman who has reached 50 in good health has an average additional life expectancy of at least another 25 years [35], long enough to raise a child to adulthood. Many women decide to postpone childbearing to the age she has achieved her career and financial goals. Others postpone also their marriage (or other type of life partnership arrangement) from the same reasons. The age that a woman or couple decides to conceive might easily be advanced and finally parallel menopause. Young couples who encounter a problem of infertility divert a tremendous amount of personal energy and resources in order to conceive. Childbearing in younger women with lifethreatening medical conditions or with inherited disorders is not prohibited in open societies. In some societies, these efforts are even encouraged and substantially are supported by the public health system. Only in the most extreme conditions, in which the risk of maternal mortality is high, a young woman would be prohibited from conceiving and fertility treatments (if needed) denied. Refusing the presently feasible option of oocyte donation to women of advanced age, for this reason solely without any other actual risk, is a denial of a basic right for reproductive choice, and even genderbased discrimination [36]. When it comes to age and reproduction, men and women are not equally viewed; while older women are considered unable to conceive naturally, older men are considered suitable for parenting with younger female partners. In the natural fecundity set-up, this cannot be regarded as discriminatory, since women bear children, deliver them, nurse them and bear the medical risks of pregnancy. But when the (safe) age of biological motherhood is extended, it is only fair to modestly correct this long standing gender-based difference in parenting opportunities [36]. It can be argued against this, that enabling pregnancy at an age in which it is naturally impossible might be a hazardous action against our biological limitations [34]. Adversely, this argument can be extended to other ‘‘unnatural’’ situations resolved by assisted reproduction such as severe male factor and mechanical infertility. Currently, it seems totally unacceptable to deny childbearing from young couples with severe oligoteratoasthenospermia, blocked fallopian tubes, premature ovarian failure, or anovulation on the grounds that assisted reproduction is ‘‘unnatural’’. It is obvious to all that assisted reproductive technologies should be made available exactly in these very cases. Then why should women be denied conception on the grounds of age alone?
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The current trends in liberal societies emphasize women’s right for career achievements, equal contribution and opportunities. Many women decide to postpone childbearing as a consequence of these changes, but this is not always the case when a woman or couple seek oocyte donation [37]. Some women find themselves in fifth and sixth decades in a new marriage and desire a child with their new partner. Others loose their grown-up children to disease, accidents or violence, and would like to deliver again as rehabilitation from their tragedy. In other situations, repeated artificial reproduction attempts fail and time passes [37]. Denying access to oocyte donation in such circumstances, on the grounds of age alone, is obviously unfair and even cruel. The welfare of the child Opponents to pregnancies in woman of advanced age may base their opposition on the interest and welfare of the future offspring, thus implying that older individuals are less capable of coping with parenthood, physically and mentally [38]. Having parents of advanced age may cause children to endure a greater generation gap, grow up without grandparents, cope with geriatric diseases and finally become orphans at a young age [34]. On the other hand, older parents, singles or couples, are in general more mature and experienced than younger ones. In average older people have more time, emotional and material resources to nurture their children and cope with their raising. In cases of prolonged infertility, the long-lasting desire for a child might be more beneficial to the child than detrimental [37]. Taking all these into consideration, it is reasonable to assume that the welfare of children born to mothers or parents of more advanced age is not negatively affected by this factor. Nevertheless, creating a supporting family and social backup system in case of parental impairment or death is a wise step. A crucial additional factor to the psychological well-being of the offspring is maintaining donor anonymity, though secrecy and disclosure policies after adulthood should be considered and publically discussed. Coping with the medical risks ‘‘Primum non nocere’’ is a universal medical concept. It is also axiomatic that a woman’s health and well-being is prior to any reproductive choice or plan. The higher occurrence of medical and obstetrical complications in this age group is mainly caused by a higher incidence of chronic diseases among women of advanced age. Most of the published data are retrospective and does not represent the true incidence rate of these complications among meticulously screened patients determined to be healthy. It is not unsound to assume that a publication bias exists towards reporting more complications in such retrospective series. Mortality, in a carefully monitored pregnancy, is an extremely rare event. The almost universal tendency towards delivery by (mostly elective) cesarean section in women of advanced age mildly contributes to short-term morbidity, but does not significantly contribute to long term morbidity or to mortality. In a well-screened population specifically determined to be healthy and free of chronic diseases, the maternal morbidity and mortality is low enough to permit the undertaking of oocyte donation and
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pregnancy despite the age factor [39]. When careful obstetrical management is provided, the maternal and neonatal outcomes are reasonably good. The basic strategy should be caution and active expectation for complications. Pregnancies at advanced age should be regarded as ones with a high maternal and neonatal risk, even if the mother is found healthy at the pre-gestational screen and there is no apparent problem during pregnancy. If the preceding health screen and the prenatal care are meticulous, even if complications do occur, the outcome will be generally favorable. As applies for any age, only medical conditions which might be seriously exacerbated during the gestation and endanger the life of the mother or fetus, are the only contraindications to pregnancy. In addition to the routine tests performed in the general IVF patient population, most centers providing oocyte donation for women over 45 perform the following the following workup; a complete medical history and physical exam; a cardiac workup consisting an ECG; glucose tolerance testing, a complete hematological, hepatic, renal, and lipid profile, and imaging studies to rule out occult breast cancer. A major weakness of the screening system is that the physiological changes of pregnancy cannot be faithfully mimicked, therefore the negative predictive value the tests performed is unknown. Pregnancy complications may arise despite a comprehensive negative pregestational evaluation, and the health care professional providing antenatal care for these women should anticipate them. Law and religion Oocyte donation is not entirely arranged by law in many countries. Legislation is important to guarantee the rights of the donors, regulate the relationship between the oocyte donor and the recipient, guard the rights of the offspring, and the method of performance and documentation. Gamete donation, sperm and oocytes, is prohibited because of religious reasons in several Catholic European countries, in South America and in Sunni Islamic countries. According to the Judaism, oocyte donation is allowed only from unmarried donors. The Roman Catholic, the Eastern Orthodox, and the Protestant faiths prohibit oocyte donation. In Sunni Islam, oocyte donation parallels adultery is therefore impermissible. Hinduism and Buddhism do not address the issue of oocyte donation [40]. Oocytes for donation are available in limited numbers, and the issue of their allocation is an ethical dilemma. Unfortunately, allocation is most often based on the free market (i.e. the ability to pay) rather than the recipients’ urgency and strength of need. Though often theoretical, an ideal society should aspire that women and couples that have been deprived of children as a result of a medical condition are given first priority before those who purposely delayed childbearing. It might seem ethically acceptable to give priority to young women with premature ovarian failure or ovarian dysgenesis, rather than to menopausal woman with or without children. Ideally oocyte donation should be voluntary and altruistic, but this is a naive expectation in in our day and time. Currently, donor payments are provided as financial ‘‘compensation’’ for time and effort. However other
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forms of donor compensation, like free oocyte vitrification for the donors’ future personal use, should be considered and encouraged instead of direct payment. Any restrictions on providing fertility treatments to women of advanced age must be based on sound objective medical, psychological or social grounds, not on fears and personal beliefs. Reproduction is a basic right in our society, and withholding donor oocytes or other treatments from those who need them essentially negates this right. However, life is not endless and an age limit to assisted reproduction should exist and be determined by society and the medical community in an open lucid discussion. Some suggest that this limit should be set to 60, based on the average life expectation, minus 20 years - the approximate age of adulthood. In the popular media those who provide oocyte donation to this age group are depicted as greedy, ruthless, acting irresponsibly, or playing God. On the other hand, the opponents are portrayed as paternalistic and deniers of human rights. The public opinion in most western countries where late motherhood using donor oocytes is feasible is often split. The questions of where and how to draw the line and who should decide are the issue of ongoing public debate. Our opinion is that when setting an age limit to recipients of oocyte donation, not only medical considerations must be taken into account, but also social and ethical positions. Therefore, any age limit to maternal age in assisted reproduction should be set in accordance to local medical circumstances and social values, by doctors, experts in bioethics, sociologists, prominent public figures and politicians. Local life expectancy, public health conditions, the quality, level and availability of medical services, the access to adequate fertility treatments, and the value of childbearing in the local culture should all be considered when an age limit is set. In Israel a law arranging all aspects of oocyte donation treatments was passed in 2010. The maximal age of the recipients of embryos originating from donated oocytes was set to 54 years. This limit was established after years of public debates on oocyte donation from designated compensated volunteers. This recipients’ age limit set up by this law reflects the life expectancy in Israel, the high level and good availability of the public health system, and the significance of biological parenthood the Israeli society. Although this age limit was narrowly set to be the upper limit for Israeli recipients of eggs donated by Israeli women, it was quickly adopted by the fertility providers in Israel as an upper age limit to other treatment types and set-ups (frozen-thawed embryo transfers and off-shore oocyte donations). This decision-making process can result in a different age limit elsewhere.
Summary and conclusions Presently, it is more common and socially acceptable for peri and postmenopausal women to conceive and deliver children. Advances in assisted reproduction and the availability of donor oocytes have made pregnancies beyond the biological barrier of the human ovary possible. The impact of advanced age on the maternal well-being and the outcome of the pregnancy remains controversial. Apparently pregnancy at advanced age might be hazardous to the mother
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and fetus. On the other hand, with appropriate preconception screening and meticulous prenatal and intra partum care, a reasonably successful pregnancy outcome can be achieved in most cases, despite the reported higher prevalence of various complications. Patients should undergo a meticulous medical and psychological preparation before contemplating pregnancy at an advanced age in order to exclude those who will not be able to cope physically or psychologically. The implantation and pregnancy rates obtained from the transfer of embryos originating from donor oocytes is almost unaffected by age, and any woman with an intact uterus is a potential candidate. However, the global pregnancy complications’ rate is significantly raised in this age group. This concern raises a debate whether or not to limit the age of the recipients, and on what ground. Categorically denying older women a biologically available option to reproduce contradicts their rights and personal freedom. On the other hand, it is our duty to protect these women from harm via sound and transparent guidelines which will assure that pregnancy will be achieved safely and result in a good outcome. Even when all screening tests turn out to be negative, we believe that an absolute line should eventually be drawn. The precise position of this line should be in accordance to specific social and medical factors such as culture, religion, life expectancy, quality of medical care and antenatal management. Such an age limitation should be periodically revised and updated in accordance to life expectancy, the level of the available medical support and social trends. Just as the currently feasible pregnancy at age 50 would have been considered extremely risky 20 years ago, we foresee that if (and where) the life expectancy and life quality parameters continue to rise, the currently accepted age limit will become obsolete and a new one will be established in accordance to timely circumstances.
Key issues
Pregnancies can be achieved beyond the natural age of fecundity using assisted reproduction and even more by using donor oocytes. The predictive value of conventional cardiovascular and other screening tests performed prior to such pregnancies is undetermined. Pregnancies at advanced age are associated with an increased prevalence of maternal and fetal complications, but most of them result in a reasonably favorable outcome if meticulously prepared and monitored. Parenthood at advanced age raises a conflict between the right to autonomy in reproductive choices and the potential harm associated with maternal fetal and neonatal complications. Setting an age limit to assisted reproduction by regulation is warranted and should take into consideration local and timely social and medical individual and public factors that should be periodically re-evaluated.
Declaration of interest Yoel Shufaro is an assisted reproduction specialist working in a public tertiary hospital, providing (among many other
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services) assisted reproduction and prenatal care to women of advanced age in accordance to Israeli law and regulations. Joseph Schenker has participated in regulatory committees and other public policy making national and international bodies handling various topics in OB GYN and fertility medicine. The authors declare no conflicts of interests. The authors alone are responsible for the content and writing of this article.
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33. Schenker JG. Sperm, oocyte, and pre-embryo donation. J Assist Reprod Genet 1995;12:499–508. 34. Ethics Committee of the American Society for Reproductive M. Oocyte donation to postmenopausal women. Fertil Steril 2004;82: S254–5. 35. WHO. 2011 Global Health Observatory. Available from: http:// www.who.int/gho/mortality_burden_disease/life_tables/life_tables/ en/index.html; http://www.who.int/gho/mortality_burden_disease/ life_tables/life_tables/en/index.html%3E [last accessed 10 Oct 2013]. 36. Pennings G. Postmenopausal women and the right of access to oocyte donation. J Appl Philos 2001;18:171–81. 37. Kortman M, Macklon NS. Oocyte donation in postmenopausal women: medical and ethical considerations. Obstetr Gynaecol Reprod Med 2008;18:168–9. 38. Goold I. Should older and postmenopausal women have access to assisted reproductive technology? Monash Bioeth Rev 2005;24: 27–46. 39. Edwards RG. Pregnancies are acceptable in post-menopausal women. Hum Reprod 1993;8:1542–4. 40. Eisenberg VH, Schenker JG. Pregnancy in the older woman: scientific and ethical aspects. Int J Gynaecol Obstet 1997;56:163–9.
REVIEW ARTICLE
The risks and outcome of pregnancy in an advanced maternal age in oocyte donation cycles
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Yoel Shufaro and Joseph G. Schenker Department of Obstetrics and Gynecology, Hadassah University Hospital, Jerusalem, Israel
Abstract
Keywords
The maternal age at the first and repeated deliveries constantly rises in developed countries due to current social trends that favor values of personal achievements upon procreation. Assisted reproduction technologies and especially the availability of oocyte donation programs extend the age of fecundity to the fifth and sixth decades of life. The ability to conceive and deliver at such age raises serious medical, moral, social and legal concerns regarding the health and welfare of the mother and child will be presented and discussed here.
Advanced maternal age, assisted reproduction, oocyte donation, pregnancy outcome
Introduction Women over 50 can conceive and deliver following the transfer of embryos originating from oocytes donated by young women for reproductive purposes. When taken to the extreme, cases of successful pregnancies in women over 60 have been reported in the medical literature and popular media [1–4]. Improvements and standardization in the human embryological biotechnology, and the possibility to safely stimulate and collect oocytes from young donors, have enabled the transfer and successful implantation of embryos into the uterus of women much beyond their reproductive years [5,6]. As a consequence, women even beyond the assisted reproduction extended fecundity period, up to the sixth decade of life, are now able to conceive, carry pregnancies and deliver. In affluent societies, there is a growing trend to delay childbearing in favor of the fulfillment of personal inspirations. As a consequence, the number of women contemplating and achieving pregnancies in the fifth and sixth decades of life is constantly rising. Despite apparently good general well-being and health, pregnancies at such an advanced maternal age, beyond the natural human limits, are associated with increased maternal and fetal morbidities [7,8]. Contrary to ovarian age, it appears that embryo implantation is less affected by the endometrial age, therefore oocyte donation cycles in elderly women are as successful as assisted reproduction in the donors’ age group [9]. The uterus retains its receptivity to embryo implantation for a substantial period of time after the ovarian germ cell Address for correspondence: Dr. Yoel Shufaro, MD, PhD, Department of Obstetrics and Gynecology, Hadassah University Hospital, POB 12000, Jerusalem 91120, Israel. E-mail: [email protected]
History Received 21 October 2013 Accepted 30 November 2013 Published online 8 January 2014
reserve diminishes, as long as adequate endogenous or exogenous hormonal support exists or is provided. The implantation rate of embryos from donated oocytes is almost unaffected by the recipients’ age [7], but the chance for a successful final outcome is significantly affected by the occurrence of complications associated with advanced maternal age. Purposefully planned and induced pregnancies at an advanced maternal age (contrary to the rare ones occurring spontaneously) raise major medical and ethical concerns regarding the maternal, fetal and neonatal well-being. Therefore, it is important to openly discuss these issues in order to facilitate a public discussion towards determining the society’s position on expediting women of advanced age to reproduce beyond their natural limits. Each society should discuss in accordance to its values and available resources if such choices are acceptable, and at which financial, social, and personal risk costs. The objective of this review was to raise the medical and ethical concerns and to try to answer some of them from our perspective which represents our specific social and medical set-up.
Maternal considerations Several considerations should be taken into account when planning reproductive treatments in women of advanced age. Fertility at advanced age Fertility and fecundity decrease as a women’s age advances [10]. The leading cause for the age-related decrease in fecundity is the declining quality of the human oocyte that parallels aging. The endometrial receptivity and the chance of implantation also decrease with aging [11], but to a much
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lesser extent and in most cases endometrial receptivity is preserved by hormonal replacement or additive therapy [5]. Other factors contributing to infertility such as sperm anomalies, and pelvic pathologies (endometriosis adhesions and hydrosalpinges) may also co-exist. The fecundity and cumulative pregnancy rates, spontaneous and via assisted reproduction, decrease from age 35 onwards. In addition, the miscarriage rate increases in parallel to maternal aging, reaching as much as 20–40% at age 45, mainly due to an increase in chromosomal aberrations [12]. When oocytes from young donors are used instead of those originating from the aging patients, after adequate endometrial preparation with exogenous estrogens and progesterone, the pregnancy and miscarriage rate correspond to those obtained with assisted reproduction in the donor’s age group [9]. Advanced age and pregnancy-induced changes Even for young women the hemodynamic, respiratory, renal, and endocrinologic changes induced by pregnancy cause a considerable stress. The cardiac output gradually increases during pregnancy reaching 140% by the beginning of the third trimester. During labor, there are transient increases above this level. The ability of the cardiovascular system to adapt to these changes over 40 is not obvious. The respiratory volumes and effort and the glomelular filtration rate are also significantly increased [13]. The prevalence of hypertension, heart diseases, diabetes, chronic lung diseases, renal diseases, essential hypertension (and resulting placental complications) are directly associated with the maternal age [14,15], as well as the mortality associated with neoplasms and heart diseases [2]. At the fifth and sixth decades, such diseases might exist at a subclinical level and be unveiled by pregnancy, and might severely jeopardize the mother and fetus. In addition, gestational trophoblastic diseases, myomatous uteri, and urinary tract infections are also more prevalent at advanced age and might also complicate pregnancies in these patients [16–18]. Thus, it is well established that pregnancy in the older population potentially constitutes a major maternal health risk. The dilemma is to what extent and how to screen the candidates in order to avoid serious maternal morbidity on one hand, but allow pregnancy to those who can go through the gestation in relative safety on the other. Dynamic tests designed to unmask occult diseases like ergometry, Thallium scans, spirometry or even maximal oxygen consumption are of short duration and do not reliably mimic the changes known to occur in advanced pregnancy. No diagnostic test actually and faithfully simulates these conditions other than the actual pregnancy. For example, it is unclear if a pregestational normal heart function at echocardiography and a negative Thallium scan actually predict a pregnancy free from cardiac complications. Therefore, the negative predictive value of normal functional heart, lung or renal tests performed before pregnancy is uncertain.
Obstetrical considerations Advanced maternal age is prominent risk factor of chronic hypertension, pregnancy induced or exacerbated hypertension and preeclampsia [14]. The prevalence of impaired glucose tolerance and diabetes are also increased at advanced age.
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Therefore, it is not surprising that diabetes diagnosed during pregnancy, is more prevalent at advanced maternal age [14]. These two complications were reported to be of high prevalence in the advanced age group in almost all the published reports on this issue. Moreover, the prevalence of these complications was shown to be in direct correlation with advanced age [19]. When compared to women age 40–49, in women over 50 the occurrence rates of cardiac diseases, hypertension, diabetes, and preeclampsia were all elevated in the older age group [15]. These observations were confirmed by other studies [7,8,19]. The risk for any complication requiring hospitalization was substantially higher over 50 than under 50 and reached 63%. In a historical cohort study conducted between the years 1995 and 2012 in Jerusalem that included 349 singleton live births of women 45 and older the risk of preeclampsia was compared between natural conceptions and assisted reproduction conceptions with donor eggs. The absolute risk of preeclampsia in oocyte donation recipients over 45 was 12.6% compared to 0.9% in natural conceptions. Contrary to natural conceptions, the preeclampsia risk in oocyte donation recipients over 45 was constant and was unaffected by parity or increasing age (unpublished data, Dr. Uri Dior, Hadassah University Hospital). Age was found to independently correlate with the occurrence of placental abruption and placenta previa, even when confounding factors such as smoking or hypertension were corrected [17]. After stratification, the prevalence of both these complications was found to be in direct correlation with maternal age, even within the oocyte donation recipient group. The risk of placenta previa, placental abruption or both increases with advanced age [19]. Changes in the uterine microvasculature occurring with aging [20] might be an explanation. In the case of multi-fetal gestations, a common result of assisted reproduction, such hypertensive and placental complications are markedly increased [7]. Therefore, women of advanced age are more likely to experience preterm labor or complications necessitating premature delivery [2,7,8,15,19,21,22]. As a consequence, the prevalence of low birth weight and preterm deliveries is significantly increased over 50 for multiple and even singleton gestations [7]. The occurrence of various patterns of labor and instrumental deliveries in older primiparas varies between reports even after correction for confounding factors [23,24]. Infertility and especially oocyte donation pregnancies were strongly associated with delivery by cesarean section [21]. Cesarean section rate has been shown to be directly associated with maternal age [25]. It is safe to state that currently most of primiparas over 50 are delivered by cesarean section, even in the absence of complications. The obstetrical implications of this are mainly short termed, since these women are unlikely to have multiple repeated operations in most cases. Although longer hospitalization periods and increased febrile morbidity are associated with cesarean section (compared to vaginal deliveries), the utilization of intensive care unit hospitalizations and blood transfusion were not significantly increased in older patient group [19]. Since most of the partuitants of advanced age conceiving by assisted reproduction will not deliver again, more serious long-term sequel
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such as placenta previa or uterine rupture are unlikely. Although the maternal morbidity is definitely increased parallel to aging, the overall neonatal outcome did not appear to be affected [21,24].
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Maternal mortality The reported maternal mortality (direct and indirect) rises in correlation with age. The etiology is mainly pre-existing conditions exacerbated by the pregnancy itself, or the occurrence of pregnancy associated complications such as preeclampsia, placental abruption, postpartum hemorrhage, and thromboembolic phenomena [26]. The common performance of cesarean sections for delivering women of advanced age does not appear to contribute to the maternal mortality [2]. Sporadic maternal deaths following ovum donation in advanced age have been published [26], but it can be assumed that sub-reporting of such cases in the literature exists in order to avoid legal complications. However, the prevalence of maternal mortality, even at advanced age, is very low in countries with an up-to-date prenatal care system. Even if the relative risk of maternal mortality at advanced age is increased in comparison to the general population, the absolute mortality risk with adequate antenatal care is still very low. The neonate The prevalence of low birth weight, and stillbirths is increased in neonates born to mothers of advanced age [2,9,15,21,27,28]. These result from the increased risk of pre-term labor, complications necessitating pre-term delivery, and abnormal placental function in this group. On the other hand, the rate of low Apgar scores, asphyxia and metabolic complications (in live births) is not increased in women of advanced age [19,21]. The prevalence of chromosomal and congenital anomalies is increased in the offspring of older premenopausal women conceiving from their own oocytes, attributed mainly to the older egg factor. When oocytes from young donors are used, the prevalence of fetal and neonatal anomalies does not differ from the general population [9]. The long-term psychological and social impact of being the child of an elderly mother or parents varies greatly between countries, populations and societies. Oocyte donation programs Donor oocytes are currently used in timely and premature ovarian failure, low ovarian response to exogenous gonadotropins, and replace autologous oocytes in the cases of carriership of disorders inherited through the mitochondrial DNA, or other maternally inherited conditions in which pregestational diagnosis is not feasible. The oocytes are obtained either from in vitro fertilization (IVF) patients donating surplus oocytes, or from financially compensated volunteers. If fresh embryo transfer is contemplated, then the uterus must be prepared and synchronized. Alternatively oocytes or embryos can be frozen or vitrified and transferred to the recipient in another occasion [29]. In menopausal recipients, artificial endometrial preparation is achieved using estrogens followed by the supplementation with progesterone agents [5]. After pregnancy is confirmed, the endometrial support
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administration continues until placental steroid hormone production autonomy occurs. In the case that regularly ovulating recipients, embryos can be transferred based on the endogenous ovarian steroid secretion without artificial endometrial preparation. The reported global ongoing pregnancy and delivery rate is currently approximately 50% per transfer [30]. The increasing effectiveness of embryo and oocyte cryopreservation and its central role in current IVF practice has decreased patient willingness to donate oocytes, since most will prefer to cryopreserve their eggs or surplus embryos for their own use [31]. Therefore in most cases, oocytes for the recipients were aspirated from paid volunteers who are ‘‘compensated’’ for their ‘‘donation’’. Candidates must be under 35, in good current and past health, free of diseases transmitted through body fluids and hereditary disorders. Bilateral permanent anonymity is crucial for all parties involved, donor, recipient and the offspring. The volunteers to donate oocytes undergo moderate ovarian stimulation and oocyte recruitment under uItrasonographic guidance. Excessive ovarian stimulation is hazardous to the donor and is also unbeneficial to the quality of the obtained oocytes. A treatment protocol using a GnRH antagonist for protection against spontaneous LH surge and a GnRH analog instead of hCG for triggering oocyte maturation [32] protects the donor from ovarian hyper-stimulation syndrome without reducing the chance of implantation in the endometrium of the separately prepared recipient. In countries in which oocyte donation from compensated volunteers is performed, relevant legislation or directives exist, usually as a part of the human reproduction regulations. In most cases such regulation is set to protect the health, rights and anonymity of the donor [33]. Presently the entire stimulation and pick-up procedure bear little risk for the donors allowing oocyte donation to peri and post-menopausal women to be performed in many centers worldwide. Women of advanced age with low or absent ovarian reserve are the major patient group in need of oocyte donations, surpassing young low responders and genetic cases by far. However, on the recipients’ side it is surprising that there is an international paucity of regulations, despite the significant hazards that pregnancy might impose on them. A large share of oocyte donations treatments is performed across borders, with no actual supervision on age and health status of the recipients.
Ethical considerations The success rate of oocyte donation remains high even at advanced ages [30]. Any reasonably healthy woman with a uterus is a treatment candidate. This raises the issue of age limitation in reproductive technology. When taking into account the welfare of the patient, offspring, family and society, limitations the reproductive choice should be seriously considered against the right personal freedom in making reproductive choices. The attitude towards enabling elderly women to conceive using advanced technology and donor oocytes should be decided by each society individually. In addition, in places where the financial and egg donation resources are limited, a priority system for their
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allocation should also be established, reflecting the local values and laws.
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The issue of choice The will to reproduce is evolutionarily strong in most human societies. Starting about half a century ago, modern liberal societies cherish and value individual privacy and rights for autonomous reproductive choices. Assisted reproduction has opened new reproductive options not existent before [5]. Oocyte donation to an older woman is such a reproductive choice [34]. In an era of prolonged life expectancy and improving quality of life, a woman may not feel unsuitable to deliver and raise a child even if she in timely menopause. In developed countries with a good health system, a woman who has reached 50 in good health has an average additional life expectancy of at least another 25 years [35], long enough to raise a child to adulthood. Many women decide to postpone childbearing to the age she has achieved her career and financial goals. Others postpone also their marriage (or other type of life partnership arrangement) from the same reasons. The age that a woman or couple decides to conceive might easily be advanced and finally parallel menopause. Young couples who encounter a problem of infertility divert a tremendous amount of personal energy and resources in order to conceive. Childbearing in younger women with lifethreatening medical conditions or with inherited disorders is not prohibited in open societies. In some societies, these efforts are even encouraged and substantially are supported by the public health system. Only in the most extreme conditions, in which the risk of maternal mortality is high, a young woman would be prohibited from conceiving and fertility treatments (if needed) denied. Refusing the presently feasible option of oocyte donation to women of advanced age, for this reason solely without any other actual risk, is a denial of a basic right for reproductive choice, and even genderbased discrimination [36]. When it comes to age and reproduction, men and women are not equally viewed; while older women are considered unable to conceive naturally, older men are considered suitable for parenting with younger female partners. In the natural fecundity set-up, this cannot be regarded as discriminatory, since women bear children, deliver them, nurse them and bear the medical risks of pregnancy. But when the (safe) age of biological motherhood is extended, it is only fair to modestly correct this long standing gender-based difference in parenting opportunities [36]. It can be argued against this, that enabling pregnancy at an age in which it is naturally impossible might be a hazardous action against our biological limitations [34]. Adversely, this argument can be extended to other ‘‘unnatural’’ situations resolved by assisted reproduction such as severe male factor and mechanical infertility. Currently, it seems totally unacceptable to deny childbearing from young couples with severe oligoteratoasthenospermia, blocked fallopian tubes, premature ovarian failure, or anovulation on the grounds that assisted reproduction is ‘‘unnatural’’. It is obvious to all that assisted reproductive technologies should be made available exactly in these very cases. Then why should women be denied conception on the grounds of age alone?
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The current trends in liberal societies emphasize women’s right for career achievements, equal contribution and opportunities. Many women decide to postpone childbearing as a consequence of these changes, but this is not always the case when a woman or couple seek oocyte donation [37]. Some women find themselves in fifth and sixth decades in a new marriage and desire a child with their new partner. Others loose their grown-up children to disease, accidents or violence, and would like to deliver again as rehabilitation from their tragedy. In other situations, repeated artificial reproduction attempts fail and time passes [37]. Denying access to oocyte donation in such circumstances, on the grounds of age alone, is obviously unfair and even cruel. The welfare of the child Opponents to pregnancies in woman of advanced age may base their opposition on the interest and welfare of the future offspring, thus implying that older individuals are less capable of coping with parenthood, physically and mentally [38]. Having parents of advanced age may cause children to endure a greater generation gap, grow up without grandparents, cope with geriatric diseases and finally become orphans at a young age [34]. On the other hand, older parents, singles or couples, are in general more mature and experienced than younger ones. In average older people have more time, emotional and material resources to nurture their children and cope with their raising. In cases of prolonged infertility, the long-lasting desire for a child might be more beneficial to the child than detrimental [37]. Taking all these into consideration, it is reasonable to assume that the welfare of children born to mothers or parents of more advanced age is not negatively affected by this factor. Nevertheless, creating a supporting family and social backup system in case of parental impairment or death is a wise step. A crucial additional factor to the psychological well-being of the offspring is maintaining donor anonymity, though secrecy and disclosure policies after adulthood should be considered and publically discussed. Coping with the medical risks ‘‘Primum non nocere’’ is a universal medical concept. It is also axiomatic that a woman’s health and well-being is prior to any reproductive choice or plan. The higher occurrence of medical and obstetrical complications in this age group is mainly caused by a higher incidence of chronic diseases among women of advanced age. Most of the published data are retrospective and does not represent the true incidence rate of these complications among meticulously screened patients determined to be healthy. It is not unsound to assume that a publication bias exists towards reporting more complications in such retrospective series. Mortality, in a carefully monitored pregnancy, is an extremely rare event. The almost universal tendency towards delivery by (mostly elective) cesarean section in women of advanced age mildly contributes to short-term morbidity, but does not significantly contribute to long term morbidity or to mortality. In a well-screened population specifically determined to be healthy and free of chronic diseases, the maternal morbidity and mortality is low enough to permit the undertaking of oocyte donation and
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pregnancy despite the age factor [39]. When careful obstetrical management is provided, the maternal and neonatal outcomes are reasonably good. The basic strategy should be caution and active expectation for complications. Pregnancies at advanced age should be regarded as ones with a high maternal and neonatal risk, even if the mother is found healthy at the pre-gestational screen and there is no apparent problem during pregnancy. If the preceding health screen and the prenatal care are meticulous, even if complications do occur, the outcome will be generally favorable. As applies for any age, only medical conditions which might be seriously exacerbated during the gestation and endanger the life of the mother or fetus, are the only contraindications to pregnancy. In addition to the routine tests performed in the general IVF patient population, most centers providing oocyte donation for women over 45 perform the following the following workup; a complete medical history and physical exam; a cardiac workup consisting an ECG; glucose tolerance testing, a complete hematological, hepatic, renal, and lipid profile, and imaging studies to rule out occult breast cancer. A major weakness of the screening system is that the physiological changes of pregnancy cannot be faithfully mimicked, therefore the negative predictive value the tests performed is unknown. Pregnancy complications may arise despite a comprehensive negative pregestational evaluation, and the health care professional providing antenatal care for these women should anticipate them. Law and religion Oocyte donation is not entirely arranged by law in many countries. Legislation is important to guarantee the rights of the donors, regulate the relationship between the oocyte donor and the recipient, guard the rights of the offspring, and the method of performance and documentation. Gamete donation, sperm and oocytes, is prohibited because of religious reasons in several Catholic European countries, in South America and in Sunni Islamic countries. According to the Judaism, oocyte donation is allowed only from unmarried donors. The Roman Catholic, the Eastern Orthodox, and the Protestant faiths prohibit oocyte donation. In Sunni Islam, oocyte donation parallels adultery is therefore impermissible. Hinduism and Buddhism do not address the issue of oocyte donation [40]. Oocytes for donation are available in limited numbers, and the issue of their allocation is an ethical dilemma. Unfortunately, allocation is most often based on the free market (i.e. the ability to pay) rather than the recipients’ urgency and strength of need. Though often theoretical, an ideal society should aspire that women and couples that have been deprived of children as a result of a medical condition are given first priority before those who purposely delayed childbearing. It might seem ethically acceptable to give priority to young women with premature ovarian failure or ovarian dysgenesis, rather than to menopausal woman with or without children. Ideally oocyte donation should be voluntary and altruistic, but this is a naive expectation in in our day and time. Currently, donor payments are provided as financial ‘‘compensation’’ for time and effort. However other
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forms of donor compensation, like free oocyte vitrification for the donors’ future personal use, should be considered and encouraged instead of direct payment. Any restrictions on providing fertility treatments to women of advanced age must be based on sound objective medical, psychological or social grounds, not on fears and personal beliefs. Reproduction is a basic right in our society, and withholding donor oocytes or other treatments from those who need them essentially negates this right. However, life is not endless and an age limit to assisted reproduction should exist and be determined by society and the medical community in an open lucid discussion. Some suggest that this limit should be set to 60, based on the average life expectation, minus 20 years - the approximate age of adulthood. In the popular media those who provide oocyte donation to this age group are depicted as greedy, ruthless, acting irresponsibly, or playing God. On the other hand, the opponents are portrayed as paternalistic and deniers of human rights. The public opinion in most western countries where late motherhood using donor oocytes is feasible is often split. The questions of where and how to draw the line and who should decide are the issue of ongoing public debate. Our opinion is that when setting an age limit to recipients of oocyte donation, not only medical considerations must be taken into account, but also social and ethical positions. Therefore, any age limit to maternal age in assisted reproduction should be set in accordance to local medical circumstances and social values, by doctors, experts in bioethics, sociologists, prominent public figures and politicians. Local life expectancy, public health conditions, the quality, level and availability of medical services, the access to adequate fertility treatments, and the value of childbearing in the local culture should all be considered when an age limit is set. In Israel a law arranging all aspects of oocyte donation treatments was passed in 2010. The maximal age of the recipients of embryos originating from donated oocytes was set to 54 years. This limit was established after years of public debates on oocyte donation from designated compensated volunteers. This recipients’ age limit set up by this law reflects the life expectancy in Israel, the high level and good availability of the public health system, and the significance of biological parenthood the Israeli society. Although this age limit was narrowly set to be the upper limit for Israeli recipients of eggs donated by Israeli women, it was quickly adopted by the fertility providers in Israel as an upper age limit to other treatment types and set-ups (frozen-thawed embryo transfers and off-shore oocyte donations). This decision-making process can result in a different age limit elsewhere.
Summary and conclusions Presently, it is more common and socially acceptable for peri and postmenopausal women to conceive and deliver children. Advances in assisted reproduction and the availability of donor oocytes have made pregnancies beyond the biological barrier of the human ovary possible. The impact of advanced age on the maternal well-being and the outcome of the pregnancy remains controversial. Apparently pregnancy at advanced age might be hazardous to the mother
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and fetus. On the other hand, with appropriate preconception screening and meticulous prenatal and intra partum care, a reasonably successful pregnancy outcome can be achieved in most cases, despite the reported higher prevalence of various complications. Patients should undergo a meticulous medical and psychological preparation before contemplating pregnancy at an advanced age in order to exclude those who will not be able to cope physically or psychologically. The implantation and pregnancy rates obtained from the transfer of embryos originating from donor oocytes is almost unaffected by age, and any woman with an intact uterus is a potential candidate. However, the global pregnancy complications’ rate is significantly raised in this age group. This concern raises a debate whether or not to limit the age of the recipients, and on what ground. Categorically denying older women a biologically available option to reproduce contradicts their rights and personal freedom. On the other hand, it is our duty to protect these women from harm via sound and transparent guidelines which will assure that pregnancy will be achieved safely and result in a good outcome. Even when all screening tests turn out to be negative, we believe that an absolute line should eventually be drawn. The precise position of this line should be in accordance to specific social and medical factors such as culture, religion, life expectancy, quality of medical care and antenatal management. Such an age limitation should be periodically revised and updated in accordance to life expectancy, the level of the available medical support and social trends. Just as the currently feasible pregnancy at age 50 would have been considered extremely risky 20 years ago, we foresee that if (and where) the life expectancy and life quality parameters continue to rise, the currently accepted age limit will become obsolete and a new one will be established in accordance to timely circumstances.
Key issues
Pregnancies can be achieved beyond the natural age of fecundity using assisted reproduction and even more by using donor oocytes. The predictive value of conventional cardiovascular and other screening tests performed prior to such pregnancies is undetermined. Pregnancies at advanced age are associated with an increased prevalence of maternal and fetal complications, but most of them result in a reasonably favorable outcome if meticulously prepared and monitored. Parenthood at advanced age raises a conflict between the right to autonomy in reproductive choices and the potential harm associated with maternal fetal and neonatal complications. Setting an age limit to assisted reproduction by regulation is warranted and should take into consideration local and timely social and medical individual and public factors that should be periodically re-evaluated.
Declaration of interest Yoel Shufaro is an assisted reproduction specialist working in a public tertiary hospital, providing (among many other
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services) assisted reproduction and prenatal care to women of advanced age in accordance to Israeli law and regulations. Joseph Schenker has participated in regulatory committees and other public policy making national and international bodies handling various topics in OB GYN and fertility medicine. The authors declare no conflicts of interests. The authors alone are responsible for the content and writing of this article.
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