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Biopanic, Advanced Maternal Age and Fertility Outcomes 1 Biopanic, advanced maternal age and fertility outcomes Larisa Corda, Amita Khanapure and Mahantesh Karoshi BIOPANIC 3.5% in those aged over 45, and a cumulative live birth rate of 14.4% after five IVF attempts Although obesity and smoking are the most in women over 40 in contrast to 45% for those obvious public health effects of the numerous under age 35. Diminished embryo implanta- social changes occurring in the late 20th and tion combined with the steep rise in the rate of early 21st centuries, a new epidemic is extend- miscarriage account for the substantial decline ing across the Western world and leading to in fertility noted after the age of 453–6. Accord- a considerable burden on health resources as ing to the UK Office of National Statistics (Fig- well as enormous personal suffering. This new ure 1), over the past several years the largest scourge is that of aging motherhood. In mod- increase in conception rates has occurred in ern society, the pressure of achieving financial, women aged 40 and over, and this trend has career and relationship fulfillments, whilst persisted with no sign of decline. However, ensuring a spontaneous conception, which has this change is juxtaposed against the biological least impact on the conceptus, optimum preg- irony of a significant reduction in fertility after nancy outcome and a capacity to withstand the age of 35, which clearly cannot change8. demands of the baby and child, has led to the The same picture holds true for the USA, coining of the term ‘biopanic’. which also has seen a remarkable shift in the 25–29 Importance of biopanic 300 30–34 250 35–39 Whereas less than 5% of women below the 40+ 200 age of 25 fail to conceive naturally, this rate 150 increases to 30% after the age of 351. More- over, the likelihood of a successful response to 100 ovarian stimulation resulting in egg retrieval Live births/1000 50 decreases as the woman ages and this, com- 0 pounded by the fact that older women have 1961 1971 1981 1991 2001 2004 a poor ovarian response, makes women aged Year 35 years or older less than ideal candidates for in vitro fertilization (IVF)2. For example, the Figure 1 Maternal age groups at childbirth embryo implantation rate is around 6% for in England and Wales, 1961–2004. (Office for women over 40, with a live birth rate around National Statistics, UK7) 3 PRECONCEPTIONAL MEDICINE demographics of childbearing. The number of pregnancy outcomes which creates a situation first births per 1000 women 35–39 years of of ‘biopanic’. age increased by 36% between 1991 and 2001, and the rate among women 40–44 years of age rose by a remarkable 70%9. The average ADVANCED MATERNAL AGE age of women seeking IVF treatment accord- ing to the Human Fertilisation and Embryol- Advanced maternal age (AMA) is defined as ogy Authority (HFEA) of the UK has risen in age 35 or more for the mother at the time of the 14 year interval between 1992 and 2005 delivery of her baby. from 33.8 years to 34.9 years, respectively, as Advanced maternal age predisposes to 10 is shown in Figure 2 . Down’s syndrome (trisomy 21). The risk of The age of menarche has decreased over having a Down’s syndrome baby rises with generations, and life span has increased, maternal age, essentially doubling from 1 in but the age of the menopause has remained 725 at maternal age 32 to 1 in 365 at maternal unchanged. The loss of female gametes with age 35. This risk continues to climb and is 1 in age is both quantitative and qualitative. The 32 at maternal age 45. sense of urgency to conceive in the time when the number of gametes available is likeliest to result in a successful spontaneous pregnancy with a low chance of chromosomal abnormali- Importance of advanced maternal age ties, and without encountering any obstetric or medical complications, is a pressure felt The effect of maternal age on the outcome of by a large number of women in modern day pregnancy may be best assessed by examin- society. At the same time as they are pursuing ing specific factors that can negatively affect their career, they desire to achieve successful the desired outcome of a pregnancy: declining fertility, miscarriage, chromosomal abnormali- ties, hypertensive complications, stillbirth and maternal mortality. 35.0 Fertility rate and maternal age at 34.8 conception 34.6 34.9 34.4 Figure 3 shows the effect of maternal age 34.2 34.0 on the average rate of pregnancy, calculated 33.8 on the basis of ten different populations liv- 33.6 33.8 ing between the 17th and 20th centuries that 33.4 did not use contraceptives. Fertility remains erage age of patients (years) Av 33.2 relatively stable through to 30 years of age, at 1992 1994 1996 1998 2000 2002 2004 more than 400 pregnancies per 1000 exposed Year women per year, and then begins to decrease substantially. By 45 years of age, the fertility Figure 2 Trends in average age of patients rate is only 100 pregnancies per 1000 exposed requesting in vitro fertilization 1992–2005. (Repro- women11. Figure 49 and Table 112 depict the duced with permission from Human Fertilisation effect of age on the spontaneous miscarriage and Embryology Authority10) rate. 4 Biopanic, advanced maternal age and fertility outcomes Hutterites, marriages from 1921–30 Geneva bourgeoisie, husbands born in 1600–49 Canada, marriages 1700–30 Normandy marriages, 1760–90 Hutterites, marriages before 1921 Tunis, marriages of Europeans 1840–59 Normandy, marriages 1674–1742 Norway, marriages 1874–76 600 Iran, village marriages, 1940–50 Geneva bourgeoisie, husbands born before 1600 500 400 300 Rate per 1000 wives 200 100 0 20 25 30 35 40 45 50 Age of wife Figure 3 Fertility rates and advanced maternal age. (Reproduced from Menkel et al., 198611, with permis- sion from American Association for the Advancement of Science) Reproductive issues The implantation rates also decline dramati- cally as menopause approaches, dropping Fertility, defined as the natural ability of a from 20% at the age of 30 to less than 4% at woman to reproduce, declines gradually over the age of 40 years13. Accordingly, birth rates the woman’s life span13. Although this decline decrease significantly with advancing maternal seems to begin at about age 30, it is more age, presenting a drop of 95% at the age of 45, obvious between 35 and 40, and increases and of almost 100% around menopause2,13,14. dramatically thereafter. The possibility of a However, age 41 is generally considered to be spontaneous pregnancy occurring is less than the point when fertility stops and subfertility 2% around the age of 42 and almost 0% after starts. Therefore, menopause in reality occurs 45 years14–17. In actuality, fertility reaches its approximately 10 years after the substantial nadir after the age of 40. Thus, the overall loss of conception potential2,14 (Figure 5). contribution to the total number of births in There are 4–7 million primary oocytes in the a given population from 40-year-old women ovaries of a 20-week-old female fetus, but this is 1%, and from 47-year-old women 0.01%14. number is halved at birth. By puberty there are 5 PRECONCEPTIONAL MEDICINE only 400,000 oocytes available in the ovaries, contraceptives. The depleted oocytes undergo but only 400–500 eventually undergo ovula- atresia through apoptosis or necrosis18,19. tion13. From puberty onward, the loss of fol- Because the ovarian pool of follicles declines licles is continuous throughout the woman’s exponentially with advancing age, from the age reproductive life (Figure 6). The phenomenon of 35 there is an accelerated loss of follicles, so of oocyte depletion happens even under con- that at 38, a woman may have only 25,000 fol- ditions of ovarian suppression, as is the case licles available, at age 40, 15,000, at age 45, in pregnancy or with the use of combined oral her reserve may have declined to 5000, and in her early 50s, only a few hundred remain (Figure 6)20. Under these circumstances, IVF, 500 Fertility 100 a procedure selected by approximately 20% of 450 90 ) 600 400 80 500 350 70 y USA 400 Hutterites 300 60 300 250 50 Natural fertilit 200 200 40 100 150 30 Spontaneous Rate of spontaneous abortions (% Fertility rate (per 1000 married women) 0 100 abortions 20 20–24 25–29 30–34 35–39 40–44 45–49 50 10 Age (years) 0 0 Figure 5 Natural fertility according to age in dif- ≥ 45 ferent populations 20–24 25–29 30–34 35–39 40–44 Maternal age (years) 8,000,000 Figure 4 Fertility and miscarriage rates as a func- 7,000,000 tion of maternal age. (Reproduced from Heffner, s 6,000,000 20049, with permission from Massachusetts Medi- cal Society) 5,000,000 4,000,000 Table 1 Incidence of miscarriage by different Number of follicle 3,000,000 age groups. (Reproduced from Madankumar et al., 2,000,000 200312, with permission from Elsevier) 1,000,000 Maternal age (years) Miscarriage rates 0 <19 10.3% y Fetus Birth Pubert 20–29 9.7% 37 years 51 years (20 weeks) 30–34 11.5% 35–39 21.1% Figure 6 Number of follicles in the ovaries dur- 40+ 42.4% ing a woman’s life 6 Biopanic, advanced maternal age and fertility outcomes women between the ages of 35 and 44 wish- for older women, with trends being apparent ing to conceive, has a much less successful through the childbearing years as shown in outcome with advancing age, as the number the Confidential Enquiries into Maternal and of gametes available is much lower (Table 2).
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