Challenges for the mother
Generally, the risk of early pregnancy loss is very high in quadruplet pregnancies (16.7%) [5]. Up to the limits of viability, this quadruplet pregnancy was surprisingly uneventful despite the advanced reproductive age. The patient declined questions on attempts to become pregnant after her pregnancy 10 years ago. Her unique situation may explain why consequences of prenatal counselling were refused, including fetal reduction. Earlier administration of antenatal corticosteroids for fetal (lung) maturation was also declined by the mother– one of few interventions with evidence for reducing mortality and morbidity of extremely immature infants [6].
Pregnancy in advanced age is a cardiovascular burden that can worsen any preexisting cardiac disorder resulting in life threatening complications, particularly in multi-fetal or twin pregnancy [7-9]. High incidences of preeclampsia and diabetes warrant early screening [10-12].
When asked about her motivation to become pregnant at this age and to take tremendous risks for herself and for likely very preterm infants into account, the mother insistently referred to the wish of her youngest daughter to have one or more younger siblings. Since oxytocin release has been described as a “love and bonding” hormone, influencing neuroadaptation, sexual arousal and social bonding, it may play a role in the desire to become pregnant [13-15]. Thus, the question on the desire for oxytocin may deserve attention in the psychoneuroendocrinology research of postmenopausal pregnancy. The underlying hypothesis of addiction to oxytocin release is even more interesting if the semen donor is not the partner, and the pregnant postmenopausal woman acts as surrogate mother.
Challenges for the infants
The individual risk for death or profound impairment of the infants appears to be higher due to advanced reproductive age, if one considers that mean carriage of quadruplets reaches approximately 28 weeks of gestation. But such associations cannot be confirmed in this report. According to the extremely preterm birth outcome data of the NICHD Neonatal Research Network, the expected survival rate individually calculated for each quadruplet ranged between 60% and 82% [16]. More recent data from Germany indicate a slightly higher survival rate for ELBW infants born at 25 completed weeks of gestation (84.2 % in triplets and 79.5% in higher order multifetal pregnancies) [17]. All four infants survived; however, poor neurodevelopmental outcome remains the major concern.
The calculated individual survival rate, without moderate to severe neurodevelopmental impairment,* ranged only between 13% and 22% [16]. If multifetal pregnancy is not considered as additional risk factor, higher survival rates without moderate to severe impairment (mean 44.5%) or without severe impairment (mean 61.4%), at 18-22 months of corrected age have been reported in ELBW infants born at 25 completed weeks of gestation [18]. More reliable are long-term outcome measures obtained at 5-6 years [19]. To date, at least the quadruplet baby with IVH suffers from long-term sequelae of extreme prematurity. We are not aware of valid data on the question how the very advanced reproductive age (>65 years) might affect later requirements for individualized, neuro-developmental care and normal assessment in all four children.
Because this quadruplet pregnancy resulted from egg and semen donations, the risk of chromosomal abnormalities and structural anomalies may not be higher as in other cases of IVF and embryo transfer. However, the impact of epigenetic changes due to advanced reproductive age with higher risk of gestational complications such as hypertension, diabetes and hormone insufficiency is entirely unclear in humans and may deserve evaluation.
Challenges for society
Early on in pregnancy, the case generated a debate on ethical, psycho-social and medical questions in our interdisciplinary team. This debate, however, focused on responsibility of the patient and responsibility of the doctors who initiated this pregnancy.
Notably, in Germany quadruplet pregnancy at the age of 65 years would not have been possible without cross-border reproduction medicine for several reasons; a) IVF with donor eggs (but not donor semen) is prohibited in Germany, b) eligibility for IVF is restricted to medical indications, couples and heterosexuals. However, IVF does not underlay legislative restriction regarding maternal age, while cost coverage by non-private health insurances for IVF is strictly age-limited (< 40 years in females, and < 50 years in males), and c) according to national guidelines and as documented in the registry of the European Society of Human Reproduction and Embryology (ESHRE), transfer of four or more embryos is normally not practiced [20]. Prohibition of IVF with egg donation and restriction of eligibility for IVF, are controversially discussed in the German society and legislative politics. Both issues result in cross-border reproductive care to Eastern (e.g. Ukraine, Czech Republic) or Southern (e.g. Spain) European countries [3, 21, 22].
While the mother argued on her fundamental human right in decision making on her reproductive activity independent of her age, there were questions raised on the implications for society with increasing late maternity in postmenopausal women and the financial burden in a system of public health coverage. Physicians also need to consider the aspects of beneficence, that is provision of benefit to the patient and nonmaleficence, the principle of doing no harm, when planning assisted reproduction in advanced menopausal women, especially in the light of the risks to the mother and children [23]. The protection of additional parties, including egg and semen donors, and importantly the children born with the highest risk for severe life-long disabilities were rather eclipsed into the background of the debate.
As treating physicians, we should not personally judge about moral, ethical, justice or beneficial issues relevant for this case. However, in our opinion, the human rights of the children need to be moved into the foreground of ongoing debates and considerations about medically assisted reproduction in our societies. Our report on the extreme case of quadruplets at maternal age 65 years, with anonymous egg and semen donations in cross-border reproduction medicine, confirms that the individual wish for having a child (across the natural limits of fecundity, in singles, lesbian and gay couples, transsexual people and any other alternate family arrangement) cannot be regulated by national (or even international) law or medical guidelines. Therefore, international bodies such as the United Nations, urgently need to discuss intensively the social, legal and medical implications of the current and future practice in reproductive medicine and – most importantly – to finally strengthen the rights of children, such as information on their biological identity, born after anonymous egg and/or semen donation.