There is little doubt that age is a very important determinant of IVF outcome. This is mainly because a woman’s eggs undergo deterioration in quality as her age advances to and beyond her mid 30’s. Remember, eggs have been in the woman’s ovaries ever since she was incubating in her mother’s uterus. Thus, after a certain period of time….when she reaches her mid 30’s, a wear and tear effect increases the likelihood of chromosomal abnormalities that become unmasked with the maturation process. The latter occurs with the LH surge that precedes normal ovulation and the administration of hCG to induce ovulation. In this regard, it is important to recognize that it is predominantly the egg (and not the sperm) that determines the chromosomal integrity (karyotype) of the embryo and an embryo with an irregular number of chromosomes (aneuploid) is incapable of propagating a normal baby. In fact, aneuploid eggs often fail to fertilize, and those that do, either fail to divide normally or will implant defectively, resulting in an early pregnancy loss. Alas, in some cases the embryo might well attach and develop into a baby with a severe chromosomal abnormality that is often incompatible with survival but in some cases (such as with Down syndrome) might well survive through birth.
Here are a few general statistics that should help you understand the impact of age on embryo “competence” (ability to propagate a healthy pregnancy). Up until the early 30’s about 1:2 eggs and embryos are aneuploid. At 35-39 about 3 in 4 or 4 in 5 are aneuploid and by age 40, about 5 out of 6 eggs are chromosomally abnormal. By the mid 40’s about 9 out of 10 eggs/embryos are aneuploid. To make matters worse as the woman ages beyond 35 she gets ever closer to the menopause and the number of eggs that become available for harvesting in IVF declines progressively. Thus, with a greater percentage of embryos being aneuploid (“incompetent”) and fewer embryos available, it should come as no surprise that IVF success rates decline progressively with advancing age beyond the mid 30’s and then quite precipitously in the mid 40’s.
There is another point worth emphasizing and that is that an embryo that is numerically, chromosomally normal (euploid) has an excellent chance of propagating a viable pregnancy regardless of the age of the woman from whose ovary it was harvested. This means that the mechanism whereby advancing age progressively reduces the likelihood of a successful IVF pregnancy is the result of the declining potential in older woman to propagate euploid eggs rather than through progressive diminution in the overall quality of all her eggs.
Aside from the inevitable age-related decline in egg/embryo competency, there is also the fact that as women get older the amount of available eggs in their ovaries also diminishes. This diminution in ovarian reserve (DOR) is also associated with increased biological activity of pituitary LH which increased ovarian testosterone production to the point where it compromises egg development, further increasing the propensity for egg-embryo aneuploidy. Women who have DOR are also far more vulnerable to any ovarian stimulation protocol that fails to regulate LH-induced testosterone production.
So, what can be done to offset some of the above inevitabilities?
First: It is important to counsel older patients on the inevitable consequences of deliberately delaying treatment of infertility. I always counsel my older patients that the biological clock cannot be reset and that they should be both decisive and proactive when it comes to commencing IVF treatment.
Second: Since there is nothing anyone can do to reverse the effect of advancing age on egg/embryo aneuploidy, the only way we as physicians can attempt to influence the process is by trying to limit exposure to excess ovarian testosterone. In that my opinion this requires:
- Avoidance of ovarian stimulation protocols that increase pituitary LH release, e.g. short agonist “flare “protocols; administering drugs that promote additional LH release (clomiphene/Letrozole)
- Avoiding exogenous male hormone administration during ovarian stimulation (testosterone or DHEA)
- Avoiding exposure to additional exogenous LH or hCG (which acts like LH to cause increased ovarian testosterone production
Third: Seriously considering the option of “embryo banking”. Here we attempt to arrest the biological clock by banking the older woman’s embryos over a number of consecutive cycles in order to increase the number of available embryos for transfer. Such embryo banking can be further embellished by testing each embryo for its chromosomal integrity using Preimplantation Genetic Sampling (PGS) and then stockpiling the normal embryos for subsequent dispensation to the woman’s uterus. With this in mind, older women, as well as those who regardless of age have diminishing ovarian reserve, are in ever increasing numbers seeking access to embryo banking in the hope of so extending their reproductive potential.
Fourth: Finally, for those women for whom the biological clock has run out, there is always the option of egg donation. In my experience, this is an optimal option through which couples can still enjoy all the joy and happiness associated with family.