Original cartoon by Alex Martin
Source: Original cartoon by Alex Martin

The average age of first-time mothers in the USA increased by almost five years, from 21.4 to 26.3, between 1970 and 2014. This emerges when a recent report by T.J Mathews and Brady Hamilton from the U.S. National Center for Health Statistics covering the period 2000-2014 is combined with their earlier report for 1970-2000. A similar trend occurred in Europe. But women's peak fertility and maximum likelihood of successful pregnancy span a decade between ages 22 and 32. The shift from the lower to the upper end of that range over 45 years is alarming, especially because subsequent pregnancies are even later. But for many women the shift reflects the dilemma of balancing childbearing against a career, and often there is simply no suitable partner at the right time. Is there an effective solution?

An optimal time for pregnancy

Author’s adaptation of a figure in Doring 1969
Histogram showing estimated proportions of menstrual cycles at different ages with normal ovulation (red bars and blue numbers above), with a short phase after ovulation (pink) and with no ovulation at all (white).
Source: Author’s adaptation of a figure in Doring 1969

It is well known that menopause, the upper limit for female fertility at about 50 years of age, is preceded by a gradual decline from 35 onwards. Abundant evidence indicates that fertility is typically highest in the decade between the ages of 22 and 32. One early source is a 1969 paper by Gerd Döring reviewing over 3000 menstrual cycles of girls and women aged 12-50, inferring ovulation from basal body temperature. The proportion of normal cycles with clearly indicated ovulation gradually increased to over 80% by 35 years of age and then dropped to zero by 50. A 2010 paper by Hamish Wallace and Thomas Kelsey reviewing studies of human ovaries neatly complemented Döring’s report by modelling the numbers of starter follicles (egg precursors) present from embryonic life through to menopause. Women aged 30 have already lost 88% of the follicles present at birth, and that loss climbs to 97% by the time they are 40.

Author’s adaptation of a figure in Mencken et al. 1986
Marital fertility rates by 5-year age groups for 10 historical populations (arranged in descending order at age 20-24): Hutterites, 1921-1930; Geneva bourgeoisie, husbands born 1600-1649; Canada, 1700-1730; Normandy, 1760-90; Hutterites, pre-1921; Tunis Europeans, 1840-1858; Normandy, 1674-1742; Norway, 1874-1876; Iran villages, 1940-1950; Geneva bourgeoisie, husbands born pre-1600.
Source: Author’s adaptation of a figure in Mencken et al. 1986

Because most couples in developed countries today use contraception, studies of natural fertility rates are no longer possible. To overcome this obstacle, a 1986 paper by Jane Menken and colleagues reviewed data from 10 historical populations that lacked family limitation. Although fertility levels differed between populations, a remarkably consistent pattern emerged: Within the age range of 22-32 for women, fertility rates showed a mild decline which then became distinctly steeper after age 35. A separate analysis of Mormon genealogical data yielded matching evidence for men. Male fertility also declined over time, but did so more slowly: men aged 50-54 still showed three-quarters of the peak level evident in the early 20's.

Results of assisted reproduction also reveal declining female fertility after age 35, as in a 1982 study using data from the French Fédération CECOS, a group of institutions devoted to preserving and studying human semen. For over 2000 artificial inseminations by donor the highest success rate occurred with women aged 20-30, with a moderate reduction at ages 31-35 and a much steeper decline thereafter. Thanks to the Fertility Clinic Success Rate and Certification Act of 1992, over 440 clinics In the USA now submit annual reports to the Centers for Disease Control and Prevention summarizing success rates of techniques such as in vitro fertilization and embryo transfer. The most recent report, for 2013, tabulated information for almost 200,000 treatment cycles. The proportion of treatment cycles resulting in live births was around 40% for ages up to 35 but declined to half that for women aged 38-40 and fell below 2% for women older than 44.

Author’s adaptation of a figure in Federation CECOS et al. 1982
Graph showing success rate of artificial insemination by donor for women in different age groups.
Source: Author’s adaptation of a figure in Federation CECOS et al. 1982

Equally importantly, rates of maternal mortality, stillbirth and congenital defects climb with increasing maternal age, especially after age 35. Gestational diabetes, high blood pressure, wrongly positioned placenta (placenta praevia), intrauterine growth retardation, pre-term birth and operative delivery also increase markedly with maternal ages above 35. Although maternal death during childbirth is now very rare in developed countries, it nonetheless increases distinctly with maternal age. In 2004 Marleen Temmerman and colleagues reviewed maternal mortality in Belgium between 1991 and 2000. For women aged 20-29 maternal mortality averaged 2.9 pregnancy-related deaths per 100,000 live births, but the risk was seven times greater for women aged 35-39 and thirty times higher for women older than 40. This is worrying because by 2000 nearly half of all births were to women older than 30.

Author’s adaptation of a figure in Kassebaum et al. 2014
Graph depicting global change in maternal mortality for women at different ages for the years 1990 and 2013.
Source: Author’s adaptation of a figure in Kassebaum et al. 2014

A potential solution

Over the past decade, awareness of risks of postponing pregnancies until later in life encouraged increasing use of a procedure called elective fertility preservation (EFP): Eggs are collected, preferably during a woman’s prime reproductive years of 22-32, and kept deep-frozen until used. Fertility preservation was originally developed to enable female cancer patients to have children after treatment and recovery, but now it is also increasingly used to offset the hazards of delayed childbirth. Eggs collected from a 25-year-old and preserved until use after age 35 retain their youthful character.

In a well-researched 2014 commentary Emma Rosenblum reported that each cycle of egg collection and freezing costs about $10,000. Drugs and storage fees trigger extra payments and several cycles are often needed to obtain enough eggs, so the total cost may be $50,000  —  described by one 35-year-old interviewee as “more than a car but less than a house”. Egg collection is straightforward but nonetheless challenging. Following hormonal stimulation for over a week, eggs are extracted from the ovaries with a needle inserted through the vagina wall. They are then rapidly frozen through vitrification  —  a process widely adopted only five years ago  —  and stored in liquid nitrogen. When a woman decides to use her eggs, they are thawed, fertilized (usually by injecting a single sperm) and transferred to her womb. According to a woman’s age, about 10 eggs are needed for each successful pregnancy.

Author’s adaptation of a figure in Cobo et al. 2016
Histogram showing age distribution of women undergoing egg retrieval and storage for elective fertility preservation.
Source: Author’s adaptation of a figure in Cobo et al. 2016

EFP is such a recent development that few surveys have been conducted as yet. One exception is a 2016 report by Ana Cobo and colleagues, based on information on almost 1,500 patients from 13 fertility centers in Spain. 120 women who had chosen EFP returned to use their eggs, and about a third of them had a live birth. The average age of women at egg collection and freezing was a little over 37 years, and the mean storage time before use a shade more than two years. For women younger than 35 the live birth rate (50%) was twice as high as for older women (22.9%). A questionnaire survey by Brooke Hodes-Werz and colleagues, published in 2013, yields additional insight. 183 women who underwent egg retrieval and freezing between 2005 and 2011 responded. In fact, confirming other reports, the main reason for postponing pregnancy indicated by nine tenths of them was lack of a partner. But one in five reported that workplace inflexibility also contributed to their decision. By the time of the survey, only 7% of women had returned to use their frozen eggs, and just three reported successful conception.

A cautionary note

Although EFP offers a possible solution for women seeking a ‘‘time-out’’ before childbearing, it is not yet working effectively. Collection and freezing of eggs should ideally be scheduled at about age 25. Instead, the average age of women who choose to have eggs collected and frozen is currently about 37. As noted by Cobo and colleagues, women should be advised to sign up at younger ages if they wish to employ this procedure. So the recent Pentagon proposal to provide EFP for female US military personnel is questionable. It would surely be better to find ways to reconcile timing and demands of childbirth with a suitably adjusted pattern of military service, rather than encouraging women to postpone pregnancies until later in life, when risks are so much greater. Effects of ageing are not the only hazards involved, and the age-related decline in female fertility is not just a medical question; it is first and foremost a social issue. As Temmerman and colleagues sagely concluded: “These data call for further research and action to facilitate career and reproduction, and for special care for older pregnant women.”

References

Cobo, A., Garcia-Velasco, J.A., Coello, A., Domingo, J., Pellicer, A. & Remohí, J. (2016) Oocyte vitrification as an efficient option for elective fertility preservation. Fertility & Sterility 105:755-764.

Döring, G.K. (1969) The incidence of anovular cycles in women. Journal of Reproduction & Fertility, Supplement 6:77-81.

Fédération CECOS, Schwartz, D. & Mayaux, M.J. (1982) Female fecundity as a function of age: results of artificial insemination in 2193 nulliparous women with azoospermic husbands. New England Journal of Medicine 306:404-406.

Kassebaum, N.J. et al. (2014) Global, regional, and national levels and causes of maternal mortality during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 384:980-1004.

Mathews, T.J. & Hamilton, B.E. (2002) Mean age of mother, 1970-2000. National Vital Statistics Reports 51(1):1-13.

Mathews, T.J. & Hamilton, B.E. (2016) Mean age of mothers is on the rise: United States, 2000-2014. NCHS Data Brief No. 232:1-6.

Menken, J., Trussell, J. & Larsen, U. (1986) Age and infertility. Science 233:1389-1394.

Richards, S.E. (2013) Motherhood, Rescheduled: The New Frontier of Egg Freezing and the Women Who Tried It. New York: Simon Spotlight Entertainment.

Rosenblum, E. (2014): http://www.bloomberg.com/bw/articles/2014-04-17/new-egg-freezing-technol...

Stoop, D. (2016) Oocyte vitrification for elective fertility preservation: lessons for patient counseling. Fertility & Sterility 105:603-604.

Temmerman, M., Verstraelen, H., Martens, G. & Bekaert, A. (2004) Delayed childbirthing and maternal mortality. European Journal of Obstetrics & Gynecology & Reproductive Biology 114:19-22.

Wallace, W.H.B. & Kelsey, T.W. (2010) Human ovarian reserve from conception to the menopause. PLoS One 5(1),e8772:1-9.

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