In South Africa the process of oocyte donation in peri- and post-menopausal women is not as common as in Europe and the USA, but the request for donor oocytes in couples where a younger male enters into a relationship with a peri- or postmenopausal female, with or without her own children, is becoming more common. Two very good articles published recently1,2 discuss some of the challenges in guiding these couples to make an informed and sound decision in these mostly unique circumstances.
Success Rates of Oocyte Donation in Older Women
While the success of donor oocyte IVF (D-IVF) in older pre- and perimenopausal women was firmly established by the early 1990s, there were some very strong concerns whether or not to offer D-IVF to women with natural menopause over the age of 50. Many clinicians were sceptical of the receptivity of the menopausal normal uterus, even when hormonally prepared, to implantation and development of a normal embryo.
Animal studies demonstrated lower implantation and pregnancy rates with increasing maternal age.3,4 However, this phenomenon seemed not evident in a subsequent report in 1992 of even older recipients, including postmenopausal women over 50 years of age.5 Endometrial biopsies of women of advanced reproductive age that were appropriately primed with hormones before transfer, had normal histological appearance and showed no difference from biopsies obtained from younger women.6
In a 10 year review of postmenopausal women at the University of Southern California with a mean age of 52.8 ± 2.9 years, 121 embryo transfers (89 fresh and 32 frozen) using D-IVF were performed and a pregnancy rate of 45.5% with a live birth rate of 37.2% was achieved. These results were no different than rates in younger recipients at the same institute.7
The reported success of oocyte donation in women in their 50s8,9 and early 60s10,11 suggests that pregnancy is still possible in almost all women with a normal uterus, regardless of ovarian status, and is determined by the age of the donor, and seemingly not influenced by the age of the recipient.
Maternal and Fetal Risks
While oocyte donation is successful in helping older women achieve pregnancy and have babies, it does carry risks. Women of advanced maternal age (AMA, defined as older than 35 years), have long been known to have an increased risk of pregnancy related complications. These include hypertensive disorders, gestational diabetes, abnormal placentation, preterm deliveries, stillbirths and caesarean deliveries.12-14 Studies have also shown that neonates born to AMA women have an increased risk of being small for gestational age, developing respiratory distress syndrome, being admitted to neonatal intensive care units and experiencing a greater overall mortality rate.14 It is thus not surprising that as maternal age increases above 50, factors contributing to maternal and neonatal morbidity and mortality also increase.
In the largest consecutive series of patients from a single treatment centre, published recently, comprising of 101 deliveries in patients 50 years and older, it was found that no major differences in obstetric and neonatal outcomes occurred compared with patients 42 years and younger, who also fell pregnant through D-IVF.15
Perhaps of greater concern are reports of maternal deaths in women undergoing D-IVF. Reports of a cardiac arrest8 and also a case of maternal death following worsening HELLP syndrome after delivering twins16 underline the reason for extensive medical screening to be performed prior to performing D-IVF in this population:
Screening recommendation for women over 50 years of age prior to attempting pregnancy
Medical and reproductive history including general physical examination and pelvic examination.
a. Laboratory Tests:
- Standard preconception testing and counseling
- Rubella and varicella titres
- Full blood count
- Complete metabolic screen
- Fasting lipid screen
- Coagulation studies
- Haemoglobin A1c or glucose tolerance test
- Pap smear, testing for N gonorrhea and C trachomatis
- Infectious disease screen (HIV, Hep B and C testing)
- Stool testing for occult blood
- ECG or Echo of heart (if stress test is abnormal or risk factors exist)
- Chest X ray
- Transvaginal ultrasound
- Assessment of uterine cavity (hysteroscopy)
- Skin cancer survey
c. Mental health and psychosocial assessment.
Advanced paternal age has also been associated with chromosomal abnormalities such as Down and Klinefelter syndromes,17,18 new dominant mutations resulting in congenital anomalies19 and an increased risk of autism20 and schizophrenia21 in the offspring. Clinical data have been difficult to evaluate because maternal age often increases with that of the male partner. When eggs from a young woman are donated, the impact on abnormalities in the offspring can be evaluated. Two small studies suggest that fertilisation, pregnancy, live birth rates and the risks of abnormalities of the offspring, when the male partner is over 50, are identical to those with younger male partners when donor eggs are provided.22,23Optimisation of health should occur preconceptually and involve specialists in internal medicine, fetal maternal medicine and also with the guidance from a psychologist with an interest in reproductive health.
Multiple Pregnancies and Increased Risks
Limiting the number of multiple pregnancies in older patients by careful selection of embryos for Single Embryo Transfer (SET) is essential in order to lessen complications. Given the potential for serious maternal and neonatal complications resulting from multiple gestation, the American Society for Reproductive Medicine (ASRM) guidelines,24 with regard to the number of embryos transferred to recipients of donor oocytes, gives very useful guidelines. Transfer of more than one embryo should be a decision taken only after careful discussion between parents to be and the clinician.
Ethical and psychological issues and infertility treatment: Should we have the ‘right to reproduce’? Are you ever too old to have a baby? Older parenthood raises a variety of important factual and ethical questions.25 We do not know much about the safety, economic, and psychosocial impact of these emerging practices on children or parents.25
Some more Questions Asked:
How do we describe older parenting and fertility treatment? Is it legal and ethical to offer fertility treatment and assisted reproduction to older and post-menopausal women? Should infertility programs discourage, tolerate, or encourage pregnancy in old age? Or, instead, should ethical programs try to discourage and constrain who it is that can bear a child in their later years? None of these questions have received sufficient attention despite the rapid expansion in the numbers of older parents.
Decision makers, medical practitioners, scientists, courts and the public in general are facing new quandaries that involve controversies among profoundly held values.26
Firstly, why do women of later reproductive age want to have children?
Their motivations vary.
New technology exists that permit the creation of children.
- “Forty may be the new thirty.”
- Egg donation makes it possible for older women to have children.
- Older couples will use techniques such as sperm, egg, or embryo donation but keep that fact a secret.
The fact that a certain procedure is technologically possible does not make it ethically right. There are some speed breakers where we should stop and analyse the deep social impact of the latest developed technology before embracing it with open arms.
Secondly, why is old age an ethical and psychosocial problem?
The important ethical question is: whether there is an age at which a women should be viewed as “too old” to have a child.
Arguments for age limits for treatment are health risks for older women, social factors and child wellbeing.
- Health risks Pregnancy and childbirth pose greater risks for older women (discussed earlier). In view of the lack of data about maternal and fetal safety, providing donor oocytes or embryos for transfer to any women over age 55 years, even when she has no underlying medical problems, should be discouraged.
Why pick on women only? Some see sexism when issues of older parenting are raised since most questions arise about older women. Men are not placed at any serious risk by the process of generating sperm. There is some evidence that older men are at risk of creating children with a higher incidence of genetics problems and diseases. The risk to children however is far greater in women than it is in men.
One important concern for the use of IVF in older women may be the age and associated comorbidity of the old mother which may restrict them from being an appropriate parent and this is often seen as an infringement of the resultant child’s rights. We do not know much about the development of children resulting from such services and how they fare with children with comparatively aged parents. From a psychosocial perspective we do know that a child, at least, needs parenting until the age of 15 – 16 years of age, when they reach the young adult stage of life. Thus putting a cap on maternal age of 50 – 55 years when undergoing infertility treatment is something to be considered.
- Social Factors and Child Wellbeing
Older and post-menopausal women, who conceive, face a shorter life expectancy. Statistically, those conceiving in their late sixties are more unlikely to see the child to adulthood. Children that lost their parents at a young age are more at risk for stress, depression and drug abuse. Parental loss is one of the most stressful life events for children or adolescents. Parenting imposes both physical and emotional demands, which older parents may have difficulty meeting. Socially, both parents and their children may experience isolation and stigma from having significantly older parents.
In the South African context it is also culturally appropriate for children to look after, care and support their ageing parent not only physically but also financially. Is it fair to expect a 25 year old to look after parents in their late seventies?
We clearly need more data to fully address these important issues related to safety of both mother and child, and family welfare. Physicians should carefully assess each prospective case, and decide on offering care based upon the merits of the patient’s profile.
A psychosocial evaluation of the women and couple is also important to perform during the precycle evaluation. Parenting is emotionally stressful and physically demanding and is reasonable to ensure. The focus should be on attempting to address the complex moral, ethical and psychological issues that confront these unique families.
The ASRM continues to publish both practice and ethical guidelines to responsibly conduct egg and embryo donation. It would serve us all well if everyone involved with assisted reproduction and gamete donation would read them and adhere to their recommendations.
These guidelines are to protect the best interest of children created by technology in new familial circumstances, internationally recognised and to enforce standards for fertility clinics and ethical committees to follow and ought to be enacted in making decisions about treating older parents seeking infertility services.
- Women considering oocyte or embryo donation because of advanced reproductive age should undergo a comprehensive medical evaluation.
- Medical and gestational risks of AMA should be discussed involving a physician familiar with these risks.
- In view of the lack of data about maternal and fetal safety in D-IVF in women over the age of 55 years of age, D-IVF or embryo donation in even older women should be discouraged (even if no underlying medical problems are present).
- SET should be the standard
- Prospective parents should be counseled by a psychologist, familiar with fertility, to consider short- and long term parenting and child-rearing issues specific to their age.
- Be honest with older pre- and perimenopausal women that still have regular cycles who might have the wish (and an unrealistic expectation) of having a baby through IVF using their own genetic material. They should be made fully aware of their very slim, if not impossible chance of taking a baby home.
- Grossman LC, Kort DH, Sauer MV. Managing assisted reproduction in women over the age of 50: a clinical update. Expert Rev. Obstet. Gynecol 2012; 7(6): 525 – 533.
- 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(2): 337 – 340.
- Harman SM, Talbert GB. The effect of maternal age on ovulation, corpora lutea of pregnancy and implantation failure in mice. J. Reprod. Fertil 1970; 23(1): 33 – 39.
- Holinka CF, Tseng YC, Finch CE. Reproductive aging in C57BL/6J mice: plasma progesterone, viable embryos and resorption frequency throughout pregnancy. Biol. Reprod 1979; 20(5):1201 – 1211.
- Sauer MV, Paulson RJ, Lobo RA. Reversing the natural decline in human fertility: an extended clinical trial of oocyte donation to women of advanced reproductive age. J. Am. Med. Assoc 1992; 268: 1270 – 1275.
- Sauer MV, Miles RA, Dahmoush L et al. Evaluating the effect of age on endometrial responsiveness to hormone replacement therapy: a histological, ultrasonography and tissue receptor analysis. J. Assist. Reprod. Genet 1993; 10: 47 – 52.
- 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 (18): 2320 – 2323
- Sauer MV, Paulson RJ, Lobo RA. Pregnancy after 50: application of oocyte donation to women after natural menopause. Lancet 1993; 341: 321 – 323.
- Kort DH, Gosselin J, Choi JM et al. Pregnancy after age 50: defining risks for mother and child. Am J Perinatal 2012; 29: 245 – 250.
- Paulson RJ, Thornton MH, Frances MM et al. Successful pregnancy in a 63 year old woman .Fertil. Steril 1997; 67: 949 – 951.
- Antinori S, Gholami GH, Versaci C et al. Obstetric and prenatal outcome in menopausal women: a 12 year clinical study. Reprod Biomed Online 2003; 6: 257 – 261.
- Kirz DS, Dorchester W, Freeman RK. Advanced maternal age: the mature gravida. Am. J. Obstet. Gynecol 1985; 152 (1): 7-12.
- Berkowitz GS, Skovron ML, Lapinski et al. Delayed childbearing and the outcome of pregnancy. N. Engl. J. Med 1990; 322 (10): 659 – 664.
- Shrim A, Levin I, Mallozzi A et al. Does very advanced maternal age, with or without egg donation, really increase obstetric risk in a large tertiary centre? J. Perinat. Med 2010; 38 (6):645 – 650.
- Kort DH, Gosselin J, Choi JM et al. Pregnancy after age 50: defining risks for mother and child. Am. J. Perinatol 2012; 29(4): 245 -250.
- Schutte JM, Schuitemaker NW, Steegers EA et al. Dutch maternal Mortality Committee. Maternal death after oocyte donation at high maternal age: case report. Reprod. Health 2008; 5:12.
- Fish H, Hyun G, Golden R et al. The influence of paternal age on Down syndrome. J Urol 2003; 169:2275 – 2278.
- Lowe X, Eskenazi B, Nelson D Oetal. Frequency of XY sperm increases with age in fathers of boys with Klinefelter syndrome. AM J Hum Genet 2001;69: 1046 – 1054.
- McIntosh GC, Olshan AF, Baird PA. Paternal age and the risk of birth defects in offspring. Epidemiology1995; 6: 282 – 288.
- Reichenberg A, Gross R, Weiser M et al. Advanced paternal age and autism. Arch Gen Psychiatry 2006; 63: 1026 – 1032.
- Sipos A, Rasmussen F, Harrison Getal. Paternal age and schizophrenia: a population based cohort study. BMJ 2004; 329: 1070.
- Gallardo E, Simon C, Levy M et al. Effect of age on sperm fertility potential: oocyte donation as a model. Fertil. Steril 1996; 66: 260 – 264.
- Paulson RJ, Milligan RC, Sokol RZ. The lack of influence of age on male fertility. Am J Obstet Gynecol 2001; 184: 818 – 822.
- Practice Committee of the American Society for Reproductive Medicine. Guidelines on number of embryos transferred. Fertil.Steril 2009; 92(5): 1518 – 1519.
- Caplan A L and Patrizio P. Are you ever too old to have a baby? The ethical challenges of older women using infertility services. Seminars in Reproductive Medicine 2010; 28(4): 281-286.
- Banerjee A. An insight into the ethical issues related to in vitro fertilisation. The Internet Journal of Health 2006; 6(1): 1-11.
- Cohen C Bed. New ways of making babies: The Case of Egg Donation. Indianapolis, IN: Indiana University Press 1996.
- Saletan W. Is it OK to impregnate 60-year-old women? 2009. Available at: https://www.slate.com/id223900/.
- Sloter E, Nath J, Eskenazi Betal. Effects of male age on frequencies of germinal and heritable chromosomal abnormalities in humans and rodents. Fertil Steril 2004;81(4):925-943.
- Froman D. Assisted reproduction and age: Is there any limit? 2012. Available at: https://www.theafa.org/article/assisted-reproduction- and-ageis-there-any-limit/.