Successful pregnancy and delivery of a healthy child gets more difficult as women become older. The reproductive aging process is complex and multi-faceted but the aspect which comes into play relatively early (in the mid-30s) pertains to decreasing viability of eggs and embryos (fertilized dividing eggs).
This decrease in viability reflects higher frequency of errors in chromosome number (aneuploidy). These errors arise during the development of immature eggs found in small ovarian follicles (fluid-filled sacs containing the eggs) into mature eggs found in the large follicles at ovulation. Chromosome number errors (i.e. too many or too few chromosomes) arise in each individual egg and are not inherited from either parent both of whom have the correct number of chromosomes.
The primary adverse effect of aneuploidy is on embryo development after 3 days and especially on implantation (attachment of the 5-7 day old embryo to the uterus). The earlier steps of ovulation and fertilization progress normally. Early division of the embryo is pre-programmed by the mother’s genes but subsequent development and implantation require activation of the embryo’s own genes at which point the errors manifest themselves. Needless to add, we do not currently have the ability to either prevent or repair such abnormalities albeit embryo biopsy permits their detection (Genetics and PGD).
Clinically, these chromosomal abnormalities lead to one or more of the following:
- sub-fertility with infrequent conception
- early miscarriages
- elective terminations prompted by finding an abnormality on amniocentesis or chorionic villus sampling (CVS)
The graph below portrays the decline in live births with advancing age in all women undergoing embryo transfers after IVF with their own eggs in the United States in year 2005 as reported by the CDC.
While the IVF data are best documented, the same decline occurs in spontaneous conceptions in fertile couples as well as with other infertility treatments. You may want to note that the steep declining slope begins as early as the age of 33 years.
Since there are no direct interventions to counteract the age factor, the available therapeutic approaches are indirect and limited. One such strategy is to increase the total number of eggs being ovulated within a given period of time, such as a cycle or a year, by using FSH hormone to induce ovarian stimulation with simultaneous release of multiple eggs (What Is Ovulation Induction?).
This strategy is central to IVF (IVF Primer) but it can also be used as a standalone approach in conjunction with intrauterine insemination (IUI) in couples where the woman’s tubes are open and the sperm is likely to fertilize the eggs in vivo. The success of this strategy is dependent upon the ability of the ovaries to respond to FSH by producing multiple follicles containing healthy eggs which is known as ovarian reserve (How Do We Test Ovarian Reserve?). Ovarian stimulation does not create new eggs or follicles within the ovaries but merely induces simultaneous growth of several follicles thus overcoming the body’s natural tendency to select a single dominant follicle containing just one egg.
Women who have infertility associated with both age factor and reduced ovarian reserve typically derive little benefit from ovarian stimulation because their ovaries have few follicles and FSH does not result in the maturation of multiple eggs. In addition women above the age of 43 have generally low live birth rates with IVF and ovarian stimulation even if their ovaries are capable of producing multiple eggs at the same time. Patients in these categories are much more likely to achieve live birth with donor eggs than with their own gametes as shown in the graph below adapted from the 2005 national CDC report.
The graph above also demonstrates that the primary effect of aging is upon the ovaries and eggs rather than the uterus which is capable of carrying pregnancy long after the ovaries cease to function. While there is a mild decline in outcome of donor eggs cycles due to uterine factors its magnitude is relatively small and it does not occur till about 48-50 years of age (Donor Egg Program).
Are men affected by age factor? While the effect of age on male fertility is slight by comparison to women, there is evidence of increased frequency of point mutations in chromosomes of men above the age of 45 years. By comparison with aneuploidy associated with advanced female age, such small mutations rarely cause a problem because most of time their effect is obscured by the presence of the other normal chromosome.