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Infertility and Pregnancy Management in Women of Advanced Age

Infertility and Pregnancy Management in Women of Advanced Age

A woman's fertility declines steadily after reaching peak levels between ages 18 and 25. From then to age 35 the average woman's fertility drops by about one half and thereafter declines more rapidly.

By age 40 the average fertility rate is 15% of that found at age 25. The down slope continues until it reaches very low levels (1% or less per month chance of pregnancy) at age 44 and beyond.

The results of many studies cluster around a 35% per month chance of pregnancy as the maximum of human fertility, seen in women between 18 and 25 years of age. By age 40 the chance of fertility declines to about 5% per month.

In vitro fertilization (IVF) therapy provides  opportunity to look at the female age effect.

Successful IVF programs, have found that their success rates in couples remain quite high, 40-45% per attempt, through the thirties until age 35. Then the rates begin to drop fairly precipitously. Success rates at age 41 are generally half that of the below age 35 group and by age 45 they are essentially nil.

Thus it appears that the IVF process, by harvesting multiple eggs and then transferring multiple embryos, can overcome the normal fertility decline observed in the thirties, up to a point. That point, which has been verified over and over again by IVF programs worldwide, is age 35. Something clearly happens at that time that even IVF, our most powerful infertility treatment, can not completely compensate for.

Egg Factor
For years there was considerable debate among infertility specialists as to why the fertility of women declines so rapidly as they approach 40. Is it due to solely to a gradual loss of eggs or to uterine factors or possibly to both? Several ovum donation studies done in the last 10 years have demonstrated no apparent decline in the chances of conceiving a successful pregnancy from ages 40 to 50 when eggs from a young donor were used. This clearly highlighted changes in the egg supply as the most likely cause of age related fertility loss.

The most rapid decline in female fertility begins at about age 30-31 which is, on average, 20 years before menopause. To date the only factors known to influence the rate of loss of eggs are: cigarette smoking, cancer chemotherapy drugs and radiation therapy.
There are differences in the rate of loss of eggs from one woman to the next. Thus we have seen 33 and 34 year old women who seemed to be at the very end of their egg supply and yet have also seen a few women 10 years older who seemed to have a great number of eggs left.

Uterine Effect

The ovum donation studies initially seemed to indicate that all of the age caused female fertility decline was due to the changes in egg number and quality. More recent data has shown that to not be completely correct. There actually is some loss of "uterine fertility" over time, caused most likely by a combination of reduced pelvic blood flow and a gradual loss of hormone receptors in the endometrium.

The natural decline in uterine receptivity, which is due to a gradual loss of hormone receptors inside the cells lining the uterine cavity, is relatively gradual until the mid fifties. Therefore, up to age 55 the observed decline in female fertility with age is 90-95% due to "egg effect" and 5-10% "uterine effect."

Measuring the Age Effect
Unfortunately there is no simple test that will tell us precisely where someone is on the fertility-age continuum. We have a few tests that can give us certain clues as to fertility.

FSH (Follicle Stimulating Hormone) Blood Test
FSH is produced by the pituitary gland at the base of the brain and when the ovaries are working well, only a small amount of FSH is needed to stimulate them. Thus under normal circumstances the FSH levels in blood are low, say 10 mIU/ml or less. This number, by the way, does vary a bit from one lab to the next, depending on which assay system is used. Also, the FSH Test has value only when the blood sample is obtained on menstrual cycle day 2 or 3.

When the ovaries run low on good quality eggs the circulating blood level of FSH rises. So when a particular woman's FSH level is high we know she has a big problem with her ovarian egg supply. Fertility rates are extremely low, even with IVF treatment, when a single FSH level is 20 or more. Values between 10 and 20 represent a situation of considerably reduced fertility. This part of the FSH Test, the bad news side, is very reliable. Where it is not so useful is at the other end, the supposed good news side. A low, or normal, FSH level on day 2 or 3 unfortunately does not guarantee that everything is fine with the egg supply.

Estradiol Blood Test
If a woman has a high level of estradiol (>80 pg/mL) in her blood at the beginning of the cycle (days 2-4), this may mean that she is experiencing accelerated follicular development and may be associated with reproductive aging.

Anti-Mullerian Hormone (AMH)
This hormon is produced by the granulosa cells of preantral and small antral follicles and inhibits the initiation of primordial follicle growth. The serum level of AMH in women with normal cycles declines with age and becomes undetectable by the time of menopause. As the ovarian primordial follicle count decreases, the serum AMH concentration also decreases, making this hormone an ideal candidate for the early detection of ovarian reserve depletion, a threshold value of 8.1 pmol/L,  predicts a poor ovarian response during a subsequent IVF cycle.

Antral Follicle Count
This is the visual measurement performed by transvaginal ultrasound early in the menstrual cycle (days 2-4) which determines how many immature eggs are available per month and reflects the underlying egg supply and future response to ovarian stimulation.

Pregnancy over Age 35 and Related Risks
There is a noticeable decline in the fertility rate starting at age 35 to a level of about 10% per month. A woman seeking pregnancy over 35 should consult a fertility specialist after only 6 months of actively attempting to become pregnant. The pregnancy risk over 35 is higher as well as evidenced an increase in the miscarriage rate and the incidence of genetic abnormality in pregnancy. At 35, the miscarriage rate is 25% and the risk of Down syndrome becomes about 1/350.

Pregnancy over 40 and Related Risks
There is a sharp decline in a woman’s ability to achieve pregnancy over age forty. The fertility rate per month is only about 5% and even with in Vitro Fertilization (IVF), the most successful infertility treatment available, the pregnancy rate is only about 10% per try. Therefore, women who desire a pregnancy over 40 should seek help after only 3 months of trying to become pregnant.
Estimates from embryo biopsy reveal that at least 90% of a woman’s eggs are genetically abnormal when a woman is over 40. This is explains the increased pregnancy risk over 40. The miscarriage rate is 33% at age 40. Genetically abnormal pregnancies are more common as well with an incidence of 1/38 at age 40. For this reason, there are many women over 40 who choose to use an egg donor to become pregnant.

Eggs from a woman in their early twenties are used along with their husbands sperm to create embryos that are much more likely to lead to successful pregnancy. Pregnancy rates of about 80% are common in most egg donation programs. This is the best way to increase the likelihood of pregnancy over 40.

 As women get older the risks of medical conditions complicating pregnancy increase. Complications of pregnancy that increase with age include elevated blood pressure, gestational diabetes, premature labor and bleeding disorders such as placental abruption.

Pregnancy over 45 and Related Risks
Women over 45 have less than a 1% chance of getting pregnant using their own eggs. This is because virtually all of their remaining eggs are genetically abnormal. Successful pregnancy over 45 is therefore nearly always the result of egg donation.

The pregnancy risk over 45 is also increased. In the unlikely event that a woman over 45 becomes pregnant with her own eggs, the pregnancy risk over 45 results in a miscarriage rate of at least 50% and the incidence of a genetically abnormal pregnancy of 1 in 12. There is also a significantly higher risk of maternal and fetal mortality with pregnancy over 45 compared to younger women. It is especially important to make sure that a woman’s body is able to tolerate the stresses that pregnancy places on it prior to becoming pregnant. This means that a woman should be checked for problems like high blood pressure, heart disease and diabetes before trying to become pregnant.

Treatment Options for Infertility Due to Advanced Age

In general, fertility therapy for normal older women is directed toward increasing the number of available oocytes through fertility medications and assisted reproductive technologies such as in vitro fertilization (IVF). However, due to the low implantation rates (in spite of increased egg production and normal fertilization), these treatments are associated with disappointing success rates beyond the age of 41. This age-related decline in IVF success is related to decreased ovarian responsiveness to gonadotropins and, more importantly, to a marked decline in embryo implantation rates Embryonic aneuploidy is likely the major reason for implantation failure in older women.
The preimplantation genetic diagnosis (PGD) may lower the spontaneous abortion rate in IVF cycles However, the technique is expensive and  its role in the treatment of age-related infertility has yet to be defined.

Egg Donation
Eggs from a younger woman are likely to result in pregnancy and less likely to end in miscarriage even when carried by a older woman.

Egg freezing
Egg freezing provides a way for women to be their own donors. Women can have their eggs retrieved at a younger age and preserve them using cryopreservation technology. When a woman is ready to get pregnant, she has her younger eggs available to increase her chances of success.

Embryo Donation
if the male partner also has a sperm problem embryo donation is the right option.

 A surrogate is a woman who agrees to become pregnant for a couple using the male partners sperm and her own egg [traditional surrogate] or using the male partners sperm and the female partners egg [gestational surrogate].

Dealing With Advanced – Age and Pregnancy
Although many women who conceive at an advanced age are at a higher risk, that certainly does not mean that she won’t have a healthy pregnancy and delivery. It just means that she should take a few more precautions and her doctor should monitor her and the baby a little more closely.

Women who are considered to be of advanced age when becoming pregnant have higher risk of multiple births, down syndrome and pregnancy related complications such as high blood pressure, diabetes and cardiovascular disease.

Due to increased risk of abnormalities, genetic testing is available to any woman 35 or older that is attempting to conceive. The standard tests offered are chorionic villus sampling (CVS) and amniocentesis. CVS testing can be performed as early as nine weeks, with results within a few days, yet amniocentesis has been around longer and used much more extensively, mostly performed until the 14 - 16 week, with results available within a week or two.

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Prepared by: Basel Jallad

Source :

Williams Gynecology 2008
Berek & Novak's Gynecology, 14th Edition 2007
Fertility and Sterility Vol. 86, Suppl 4, November 2006

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