Age and Ovarian Reserve: Their Effect on IVF Outcome
An ever increasing number of women are deferring having babies until they have fulfilled career aspirations. Advancing age beyond 35 years is associated with a progressive decline in egg quality. This is due to a progressive increase in the number of chromosomally abnormal (aneuploid) eggs, which equates to decline in egg “competency” (i.e., the ability to propagate embryos that can produce babies). In addition, as women age, they also get closer to the menopause. About 6-8 years before the menopause, there occurs a steady diminution in ovarian reserve (DOR) and with this, fewer eggs are available for harvesting through IVF. These two factors (age-related decline in egg competency and DOR) which together determine the “time” remaining on the “Biological Clock” are associated with a progressive decline in reproductive performance which manifests as reduced fertility, increased risk of miscarriage, and a higher incidence of birth defects such as Down syndrome. It is therefore not surprising that the mean age of women seeking IVF services is also on the rise.
It is indeed unfortunate that older women only come to realize their predicament when they are confronted with the ravages of the biological clock. At that point they face two opposing issues. First, as they get closer to the menopause, DOR will inevitably lead to a reduction in the availability of their eggs at the time of egg retrieval (ER). Second, the quality of their eggs will decline due to an increasing incidence of aneuploidy, such that at a certain point, time will run out on the “biological clock” and the option of using their own eggs will no longer be available to them. That is when the woman will have to choose between remaining childless or seeking the services of an egg donor.
It is grappling with the choice of whether to continue on (the often hopeless path of) trying to use own eggs or whether to seek the services of an egg donor, that usually creates the greatest amount of internal conflict and torment. It becomes the responsibility of the treating physician to help navigate this journey.This often requires the assistance of a qualified counselor, psychologist and in some cases, even a psychiatrist.
Obviously, most women far prefer to have a baby using their own eggs than to use an egg donor. In fact, in my experience, even those women who in addition to age related egg quality issues, also have DOR (and accordingly a much reduced chance of achieving a pregnancy through IVF with their own eggs), will usually push to at least have one attempt with their own eggs before going to egg donation. They feel a need to reach “closure” before moving on. It is however incumbent upon the treating physician to explain the predicament to them, whereupon it is the patient’s right to make the final decision.
The woman’s age, largely through the effect on her eggs, will determine both her natural fertility potential as well as her ability to achieve success following in vitro fertilization. However, age can also impact both the ability to successfully complete a pregnancy as well as the health of the newborn baby(ies) . Older women (especially those over the age of 39 years) are far more likely to have underlying medical conditions such as diabetes, hypertension, coronary and cerebral vascular disease, as well as an increased potential to develop thromboembolism. For this reason it is advisable that such women routinely undergo detailed screening before embarking on a journey to achieve a pregnancy. A full physical examination as well as pap smears, pelvic ultrasound and tests such as EKG, chest X-ray, blood urea/ electrolytes/creatinine/lipid profile/thrombophilia panel/liver enzymes as well as a glucose tolerance test should be done.Those who pass such testing will be far less likely to develop pregnancy-induced complications such as preeclampsia, placental abruption, gestational diabetes, and pre-term delivery. Their babies are also less likely to be low birth weight and/or to suffer complications related to intrauterine growth retardation or to be autistic.
Needless to say, egg donation is the only recourse for women with totally depleted ovarian reserve (regardless of their age) and should be regarded as the treatment of choice for those over the age of 43 years who otherwise would have less than a 10% chance of a baby per IVF cycle of treatment (using own eggs). Any such woman who insists on using her own eggs should be informed of this, but, if in spite of being fully informed, she still chooses to go ahead and is physically and mentally equipped to do so, she should be afforded the opportunity to try.
I will never forget a patient who came to me at the age of 47 years demanding to do IVF with her own eggs. In spite of my protestations, she ultimately prevailed and we embarked upon what I then considered to be an exercise in “futility” rather than “fertility”. It took several attempts, but at age 48, she did conceive and subsequently gave birth to a healthy little boy, of whom I am the proud godfather.
I’m often told by older women that a baby born through the use of donated eggs would not be their own biological child. My answer in such cases is that the woman, by giving birth, is by definition the biological parent. Since a man cannot bear a child, he is a genetic contributor…not a “biological parent”. With conception using “own eggs” a woman is both a genetic contributor and a biological parent, while by using donated eggs, she forgoes the genetic contribution, but retains the biological contribution.
There have been several important developments in the field of advanced assisted reproduction that provide attractive options for women who anticipate, or find themselves already in a situation where they seek to have a child at a later age. These include the following:
- Customizing protocols for ovarian stimulation
As women get older, so do their ovaries. In the process, they respond differently to standard, “recipe” type protocols of ovarian stimulation. What works in the younger woman might not necessarily work in an older woman or in a woman with DOR. In such cases, protocols of stimulation need to be customized to meet individual needs. To the developing follicle and egg in such women, the biggest enemy is overexposure to LH-induced male hormones (androgens), mainly testosterone, which can compromise egg development and increases the risk of egg aneuploidy. In such women, it is important to avoid protocols that either deliver too much LH (fertility drugs such as Menopur have too much hCG/LH-like activity) or cause too much LH to be released by the pituitary gland, as occurs with “flare” (short) protocols or with the administration of Clomiphene and Letrozole). In such women, LH concentrations should be kept low prior to and during the stimulation. My preference is to prescribe what we call agonist/antagonist conversion protocol (A/ACP) which in certain cases includes estrogen priming. Having said this, it is important to note that no ovarian stimulation protocol can offset the inevitable increase in egg aneuploidy that occurs with advancing age. All it can do is avoid compromising the ovarian environment during ovarian stimulation and thereby avoid further prejudicing egg quality.
- Blastocyst transfers
A blastocyst is an advanced embryo that contains more than 100 cells. It takes 5-6 days for healthy embryos to reach this stage. Those that do not make it are almost always aneuploid and not worthy of transfer. Those that do make it are more likely to be (but certainly not always) chromosomally normal. Thus in my opinion, other than convenience, there is little reason to transfer earlier cleaved (day 2-3) embryos. Furthermore, by taking embryos to the blastocyst stage it is possible to improve the “efficiency” of the IVF process. With few exceptions, I recommend this to my patients.
- Ultrarapid embryo freezing (Vitrification)
Conventional (slow) freezing causes ice crystals to form in the cells and so damages them. That is why in the past, IVF success rates wee dismal following frozen embryo transfers (FET). With Vitrification, the rate of freezing is >600 times faster, thus avoiding ice crystal formation. As a result, eggs and embryos so frozen are virtually as viable as are their fresh (unfrozen) counterparts. In addition, following vitrification, more than 95% of embryos and eggs will survive the thaw.
- Comparative Genomic Hybridization (CGH) for identifying chromosomally normal embryos
Proudly, we innovated the use of CGH in IVFto select those embryos that are most likely to propagate a viable pregnancy. This now allows us to selectively transfer only embryos that are chromosomally normal. When we transfer such CGH-normal embryos, the baby rate per embryo is dramatically improved (>60%) and when we vitrify the leftover normal blastocysts, they are just as likely to propagate a baby as are fresh ones.
- Embryo Banking
Since older women often produce few eggs/embryos per cycle and a small percentage of these are likely to be “competent” there is often an advantage in performing several egg retrieval procedures sequentially (over several months) in order to stockpile as many CGH-normal embryos as possible. In this way, the woman can prolong her own reproductive potential by subsequently transferring 1 or more embryos to her uterus at a time. CGH may well turn out to be a “game changer” in the case of the older women seeking embryo banking by making it possible to provide such women with more confidence that their vitrified, banked embryos will have a high potential to propagate viable babies regardless of their age.
CGH embryo testing can obviously not, in and of itself improve embryo quality. Rather, it selects the most “competent” embryos – those which upon being transferred to the uterus are most likely to propagate a live birth. No IVF laboratory, regardless of skill or technology, can convert an aneuploid egg to a chromosomally normal (euploid) egg. It is largely the chromosomal integrity of the egg that will ultimately, upon fertilization, determine embryo competency. It is genetic factors (influenced by age) that determine the number (and percentage) of a woman’s eggs that will have the potential, upon hormone-induced development, of being euploid, and thus capable of propagating “competent” embryos. It follows that since laboratory procedures such as assisted hatching (AH) and embryo co-culturing cannot alter the chromosomal makeup of an embryo, such “fancy footwork” is in reality of no value. The only way that we as fertility specialists can influence egg/ embryo quality is by protecting egg development during ovarian stimulation through individualized protocols used for ovarian stimulation. This is especially the case with older women and those with DOR since they are most at risk of having eggs that otherwise might have developed normally, but end up being aneuploid and propagating “incompetent” embryos.