The relationship between ageing and assisted conception is complex and multifaceted. On one hand, advances in assisted reproductive technology (ART) have made it possible for many couples to conceive later in life. On the other hand, age remains one of the most significant factors determining the likelihood of being able to conceive, either naturally or with the help of ART.
Reproductive ageing refers to the decline in fertility that occurs with increasing age in both men and women, and which is more pronounced in women. In women, reproductive ageing is characterised by a decline in ovarian reserve, in terms of both the quantity and the quality of oocytes. Advancing female age is linked with a decline in fertility and an increased risk of miscarriage.
In this overview, we will focus on some of the aspects pertaining to female reproductive ageing and its impact on natural conception as well as ART outcomes.
FEMALE REPRODUCTIVE AGEING
Ovarian development begins from week 5 of gestation, and the total pool of primordial follicles is formed by the 20th week of fetal life. From this point onwards, there is a progressive depletion of primordial follicles until reproductive senescence, i.e. the menopause.1
Although it is thought that approximately 6–7 million primordial follicles are formed initially, only 300,000–400,000 are retained at menarche, and between 400 and 500 follicles reach the ovulatory phase during the reproductive lifespan of healthy women.2
'The lower success rates seen in older women undergoing IVF with their own eggs is attributed mainly to the poor quality of the embryos, as well as the increased embryo aneuploidy rate encountered with increasing female age.'
As women get older, their chances of getting pregnant naturally decline. Studies that have attempted to model the rate of this decline across populations have shown that, compared with the level observed in women aged 20–24 years, fertility is reduced by 6% for women aged 25–29 years, by 14% for those aged 30–34 years and by 31% for those aged 35–39 years, with a much greater decline thereafter.3
OVARIAN RESERVE
Although ovarian reserve has been shown to correlate inversely with age, there can be significant variations in ovarian reserve between women of the same chronologic age.4
Ovarian reserve testing refers to the means by which the primordial follicular pool can be determined. Biochemical hormone profiles, including early follicular phase follicle-stimulating hormone and inhibin B levels, can reflect ovarian reserve. However, they are subject to substantial inter-cycle variation. Serum concentrations of anti-Müllerian hormone (AMH), which is produced by early antral follicles, are more stable and potentially reflect the primordial follicular pool size more accurately.5
An antral follicle count, which is a ultrasonographic measure of ovarian reserve performed during the early follicular phase, has been shown to be equivalent to AMH in multiple studies.6
OOCYTE QUALITY AND EMBRYO EUPLOIDY
Ageing has been shown to result in a decline in oocyte quality as well as in number. This can be demonstrated by the restoration of pregnancy rates seen when older women opt to use egg donation with in vitro fertilisation (IVF) treatment, in comparison to pregnancy rates achieved when using their own eggs.
The lower success rates seen in older women undergoing IVF with their own eggs is attributed mainly to the poor quality of the embryos, as well as the increased embryo aneuploidy rate encountered with increasing female age. Aneuploid embryos are embryos with the wrong number of chromosomes, whereas euploid embryos are those with the correct number of chromosomes. According to some studies, the embryo aneuploidy rate is reported to be ~30% in women aged ≤30 years and as high as 85% in women aged >42 years.7 Embryo aneuploidy is also the main reason for the higher miscarriage rate among older women.
IMPACT ON ART OUTCOMES
The impact of ageing on fertility treatment outcomes is quite evident from ART registries. When examining Human Fertilisation and Embryology Authority data for 2019 birth rates for all women undergoing IVF in the UK, one can observe a clear trend. Comparing fresh IVF cycles only, the birth rate was 32% in the under-35 age group per embryo transfer, 25% for those aged 35–37, 19% for the 38–39 age group and below 5% for women aged 43 and above.8 Data from the Society for Assisted Reproductive Technology in the USA showed that, in 2019, the percentage of singleton live births per cycle started was 51% for under 35s, dropping to 38.3% in the 35–37 age group, 25.1% in those aged 38–40, and as low as 12.7% for women aged 41–42.5.9
FERTILITY PRESERVATION
In terms of therapeutic approaches to mitigate for the decline in female fertility with age, women may opt to undergo fertility preservation via oocyte vitrification.
The use of oocyte vitrification, primarily for social reasons, has seen improvements in the techniques, resulting in improved post-thaw viability, fertilisation and clinical pregnancy rates. The process is still limited, however, by age-dependent oocyte quality and capacity of the ovaries to respond to ovarian stimulation.10
CONCLUSION
Reproductive ageing results in a gradual decrease in both oocyte number and oocyte quality. This is evident when one examines the relative success rates of couples undergoing IVF with their own eggs, as there is a clear downward trend in live births associated with increasing female age. The fact that ART may, therefore, not be able to overcome or compensate for reproductive aging, following an infertility diagnosis, is an important message to communicate to all couples who are contemplating their reproductive wishes.
KUGAJEEVAN VIGNESWARAN, IPPOKRATIS SARRIS AND SESH K SUNKARA
King’s College London and King’s Fertility, London
REFERENCES
1. Nelson SM et al. 2013 Human Reproduction Update 19 67–83.
2. Wu J et al. 2022 Frontiers in Endocrinology 13 952471.
3. Menken J et al. 1986 Science 233 1389–1394.
4. Broer SL et al. 2013 Fertility & Sterility 100 420–429.
5. Broer SL et al. 2013 Human Reproduction Update 19 26–36.
6. La Marca A & Sunkara SK 2014 Human Reproduction Update 20 124–140.
7. Franasiak JM et al. 2014 Fertility & Sterility 101 656–663. e1.
8. HFEA 2021 Fertility Treatment 2019: Trends and Figures.
9. CDC 2021 2019 Assisted Reproductive Technology Fertility Clinic and National Summary Report.
10. Cobo A et al. 2021 Fertility & Sterility 115 1091–1101.
