Reproductive Aging in Women; What it means for Fertility in our Society by Phyllis Leppert, MD, PhD

Worldwide fertility rates are declining. In the United States the fertility rate, which was 70.9 births per 1000 women in 1990 was 56.1 per 1000 women in 2022. The age at first birth was 27 in 1990 but 30 in 2019 according to the 2019 Census data. Why is this happening? There are many reasons: young women are putting off having children as they pursue higher education and income, or they make a definite decision not to have many children for economic reasons or because they do not want to bring a child into a world that seems to them to be chaotic with no future for humans. Some young women have no understanding that as they age, and approach their late 30s and early 40s they will have difficulty becoming pregnant due to decreased ovarian function (1). As a woman ages pregnancies become more complicated and miscarriage and stillbirths are more common. Having children at ages over 35 is less optimal that at earlier years.

The Campion Fund’s mission is to ensure that all children now and in generations to come are born healthy and capable of a long life. Declining fertility is not a satisfactory place to be. Let’s review what science tells us about reproductive aging in women. It is complicated in detail but actually simple to appreciate. Simply put: All females develop oocytes (eggs) while they are themselves developing in their mother’s womb. Here is how it happens. At 7 weeks of gestation the female embryo has developed what is called primordial germ cells which migrate from the yolk sac endoderm to the gonadal ridge. During this migration these germ cells begin the process of mitosis (cell division). At 11- 12 weeks of gestation these primordial germ cells enter meiosis and develop into primary oocytes and are stored in the primordial follicles. (2). As part of the development of the ovaries these primary oocytes become surrounded by pre-granulosa cells and form primordial follicles at about 20 weeks gestation. At this time there are about 6-7 million primary follicles. Unfortunately, they do not all survive and at birth the number of primary follicles is reduced to 2 million. These primordial follicles which contain the primary oocytes stop developing and are “arrested” in meiosis 1 prophase 1 until puberty (2). This means that the oocytes have aged over a decade on average before the menstrual cycle begins. At puberty the hypothalamus- pituitary- axis begins to be established. This is the intricate biological system where the hypothalamus releases Gonadotropin Releasing Hormone (GnRH) in pulses that stimulates the pituitary gland to secrete Follicle Simulating Hormone in to the blood stream that travels to the ovary to the development of Follicular Cells that surround the oocyte leading to the secretion of estrogens. At about the 14th day of a menstrual cycle another hormone, Luteinizing Hormone (LH) is secreted leading to ovulation. This system is complex with positive and negative feedback loops on the pituitary and the hypothalamus to fine-tune the process (1-4). There are many other molecules involved in this system such as Kisspeptin, Inhibin A and B, anti-Mullerian Hormone to name a few which all have definite roles in the menstrual cycle (3,4). The cycle is such that only one follicle develops usually during each cycle allowing one oocyte to be released in ovulation. This complex system can function less optimally due to disease, malnutrition, stress, environmental factors (1-4). The complexity of the menstrual cycle is too complex to describe in depth in a blog but more detail is to be found in the suggested reading list.

As a woman grows older the oocyte quality diminishes. Chromosome abnormalities, DNA damage, telomeres become shorter, ovarian metabolism decreases and due to follicular and oocyte loss overtime the number of oocytes in the aging ovary decreased. The number of oocytes remaining is known as the ovarian reserve. The aging process varies of course in individuals and thus the age of menopause among women varies. At some point the loss is so great that pregnancy is possible only with In vitro fertilization. Menopause defined as the loss of menstruation for 12 consecutive months and an increase in FSH ends reproduction capability in women. The average age of menopause US women is 51-52 years of age. The range of normal age of menopause Is 40-60 years. Newspapers report on women in the 50s and 60s and rare situation of even older women giving birth. These pregnancies are the result of donor eggs and invitro fertilization and do not negate the decreased fertility of women as they age, starting at age 35-40. This is misleading to many younger women. For women, the most opportune time to conceive is age 20-25, yet our society currently does not make this a positive time for women to conceive. Education is now lengthy; our economy makes independence difficult to achieve at in the 20s. Marriage is delayed for many reasons, one being that many women have not found an appropriate partner.

As a society what strategies do we have to overcome the low fertility rates. Just telling women to have more children is not a solution. One strategy has been to enhance fertility treatments based on science. Young women freeze oocytes for future use. Reproductive science provides new methods to enhance invitro fertilization. This strategy will work only for women and couples who have the financial resources to accomplish their goal of preserving fertility. Plus, it is not optimal for all and is very expensive in the long run. Economics plays a very large part in the solutions. Most developed countries for years, have provided paid maternity leave as well as paternity leave. In Europe this has been the case for decades. France has provided paid leave since 1946. The rules and regulations regarding maternity and paternity leave a varied among European Union countries but all provide such leave (5, 6). All countries provide 14 weeks of paid maternal and paternal leave that includes pregnancy leave prior to childbirth and leave postpartum. Each country has different time periods for leave. In Bulgaria, for instance 58 weeks of paid leave is allowed, while in Poland and Luxembourg 20 weeks of maternal leave is allowed. Many countries allow more leave if twins or triplets and higher order births occur. This leave is also available to adoption parents as well, indicating that these countries understand that the parent infant bonding experience is vitally important to the ultimate emotional wellbeing of children. The websites listed at the end of this blog give detailed information. Contrast this with the US. We passed legislation giving 12 weeks of unpaid leave. There are 13 states (CA, CO, CT, DE, ME, MA, MD, MN, NJ, NY, RI WA and DC) that provide paid. The pay is a percentage of the mother’s work pay (7). It is work looking at the websites to see the variation. The bottom line, however, is that countries and states offering paid maternal and paternal leave are invested in making sure that the health of childbearing woman and their partners are themselves healthy and able to provide the essential care of their new infants to ensure their physical and emotional wellbeing. The other important aspect of these policies is the endorsement of the concept that women are going to contribute to the good of their societies by working in professions, business, farms and factories and that they are capable of doing so. There are many years outside of a woman’s life where she is able to contribute in very meaningful ways to the economy. Those years should not be wasted. It is not necessary for an individual woman to have dozens of children and therefore her life time offers many years of working in an environment that is not related to child rearing. Paid maternity leave allows a woman to conceive at the optimal physiologic time of 20-25 years.

Having stated that fact there is one more aspect to the solution that we have not addressed as a nation. The complexities of the workplace in 2025 which rewards higher education, prolongs the time needed for such education and many have not completed requirements for work until well past age 20-25. This has made it difficult for women. My field of medicine is grappling with this fact (8-9). Other professions have also not found the solution. This problem is to be found in the trades as well (10). Unions advocate for paid maternity-paternity leave. An important Corollary to this problem is that society needs to find ways to provide childcare to assist that mother and father in their roles. In that past this was usually accomplished by extended family members. In our mobile society this option rarely exists. All trades and professions face the issues of how to create a positive environment for a woman to conceive and birth at the optimum biological time period. This is our challenge.