Aging, Reproduction, and Infertility

Randy S. Morris M.D.

636 Raymond, Suite 303, Naperville, IL 60563, (312) 440-5055

The largest number of births ever in the United States occurred in the post World War II "baby boom" between 1947 and 1965. Women born during this time period have reached the age of 35 starting in 1982 and will continue until the end of the century. During this time period, there is an unprecedented number of women in their late child bearing years.

In addition, many women have decided for various reasons to delay childbearing. This is a significant change from the patterns of our parents' generation, and means that more couples will be seeking pregnancy after the age of 35. Furthermore, these couples also have a desire to complete their families in a shorter period of time.

Increase in Infertility with Age

Although there is still some disagreement over the issue, most fertility experts now agree that fertility decreases with age. There are several pieces of evidence that point to this fact. Some of the most interesting studies involve a religious group known as the Hutterites. The Hutterites migrated to the U.S. from Switzerland in the 1870s and now live in the Dakotas, Montana, and parts of Canada. They are believers in large families and condemn the use of any form of contraception. They also marry only within their own group and since they live in a set geographic area, are relatively easy to investigate. For these reasons, they make ideal candidates to study the effects of aging on reproduction. It was thus found that the fertility rate (the number of women achieving a pregnancy per 100 women) is much higher in younger women (twenties) than in older women (forties). After a pregnancy is delivered, it is the Hutterites' practice to immediately attempt to achieve pregnancy again. However, it was noted that the time between pregnancies became increasingly longer with increasing age of the women studied. The average age at the time of the last pregnancy was 40.9.

Other data also supports the notion that fertility decreases with age. Compared with younger women, women over the age of 35 seek evaluation for infertility twice as often. Some investigators have suggested that this decline is due to a decreased frequency of intercourse in "older couples". For this reason, investigators in France studied the fertility rate amongst women who were attempting to become pregnant in a donor insemination program because their own partners had no sperm. In this way, the frequency of intercourse did not interfere with calculations of fertility. As expected, the fertility rate dropped significantly after the age of 30 and again after the age of 35. Another similar study suggested that the probability of having a baby decreased 3.5% per year after the age of 30.

Increased Risk of Miscarriage with Age

In addition to the lower chance of becoming pregnant, as women age they also have a higher chance of losing the pregnancy (miscarriage). What are the reasons for this? To explain, it is necessary to discuss some aspects of genetics.

We basically all start out when our father's sperm fertilizes our mother's egg. We therefore have the characteristics of both our parents. These characteristics are coded in a special way and are found in the structures known as chromosomes. In fact, the information found on these chromosomes contains all the information about every part of us.

The sperm and egg each contain 1/2 of the chromosomes necessary to make a complete human being. In fact, to describe it in lay terms, the process of making sperm and eggs is nothing more than the packaging of different combinations of chromosomes so that they can be "mixed" together with another egg or sperm to make different varieties of humans.
Women are born with all the eggs that they will ever have in their lives (with the chromosomes inside). Men, on the other hand, make fresh sperm continuously throughout their whole lives. It takes approximately 90 days for a sperm to be made and to reach maturity. This is an extremely important difference between the sexes because, for example, if a 35 year old man and a 35 year old women attempt to achieve a pregnancy, they are basically trying to combine a 35 year old egg with a 3 month old sperm.

The longer an egg sits around in the ovary, however, the more likely it is to develop abnormalities in its chromosomes. If an egg with abnormal chromosomes is fertilized, then the chances are greater that the resulting pregnancy will end in miscarriage. In fact, chromosomal abnormality is the single most common cause of miscarriage. From many studies, we know that at least 1/2 of all miscarriages are due to abnormal chromosomes. A young women (in her 20s), therefore, has only a 12-15% chance of having a miscarriage each time she becomes pregnant. A women in her 40s has, however, a 50% risk of miscarriage.

Down's Syndrome and other Chromosomal problems

Not every pregnancy in which the embryo has abnormal chromosomes will end in a miscarriage. Some will continue to develop and even result in the birth of a live baby. These babies, however, can have varying problems, including birth defects and mental retardation. Down's syndrome is the most common problem of this type but there are others. There is a progressive increase in the risk as age increases. This is all as a result of aging of the eggs.

Why does Fertility Decrease? The Debate Between the Eggs and the Uterus.

Up until recently, it was not known why fertility decreases with age. One thing was known for sure and that was that the age of the male partner didn't seem to matter much. Even men in their 70s still seemed to be able to produce pregnancies. The Bible carries stories of men in their 90s fathering children. In women however, the likelihood a pregnancy after age 45 is an extremely rare event.

The next question to answer was, why? Research has focused on two areas: aging of the uterus versus aging of the eggs. Until recently there was no way to separate these factors out. However, the technology of egg donation has enabled to look at these factors separately. Egg donation is the process whereby eggs from a young woman can be fertilized and placed into the uterus of an older woman. If fertility decreases because an older woman's uterus is less capable of carrying a pregnancy, then using younger eggs shouldn't produce very many pregnancies in older women.

What we found, of course, was exactly the opposite. If you use younger eggs, the rate of achieving pregnancies in older women is very high. In fact, egg donation gives the highest rate of pregnancy that is achievable with any type of fertility treatment! Women in their forties, fifties, and even sixties can all achieve very high pregnancy rates with egg donation. This is excellent proof that fertility decreases with age due to aging of the eggs and chromosomes. Studies that have removed eggs from the ovaries of older women have shown that a large percentage of them have abnormal chromosomes. So there is probably a continuum of possible outcomes in chromosomally abnormal eggs. Most probably won't fertilize, of those that due many will be lost to miscarriage, the few that remain will end up as a Down's Syndrome or a related problem.

But I had a friend who had a normal baby when she was 46 years old!

Every human being is different. Not all women will develop abnormalities in their eggs chromosomes at the same age. And if course, even if a women has a majority of her eggs that contain abnormal chromosomes, it only takes one to achieve that "normal pregnancy". The great majority of women will not be able to become pregnant at age 46. On the other hand, some younger women can have a more rapid decline in the ability of their eggs to produce a pregnancy.

Fertility tests and Fertility Treatments

The most important test we currently have to determine a woman's "ovarian reserve", that is, the capability of her eggs being able to produce a pregnancy, is a blood test called FSH. FSH stands for Follicle Stimulating Hormone. FSH is made in a gland near the brain gland called the pituitary. It is the KEY hormone responsible for the cyclic development of eggs every month. As a woman's eggs become less capable of producing a pregnancy, the levels of FSH begin to rise. Therefore, as you might expect, FSH generally increases in women as they get older. Women who have gone through menopause have very high levels of FSH (and are incapable of becoming pregnant with their own eggs). However, young women who have had an accelerated decline in the quality of their eggs can also have high FSH levels.

In order to determine a woman's FSH levels for the purpose of predicting fertility, the blood should be drawn on the third day of the menstrual cycle. At my laboratory, a normal level for FSH on day 3 is less than 10 IU. Women with levels between 10 and 15 are considered elevated but have been able to achieve pregnancies with us. Women with levels over 15, even sporadically, have an extremely poor chance for pregnancy.

Now to add little more complexity. Day 3 FSH levels can vary from month to month and can be affected by such things as estrogen levels. In other words, a high FSH level one month doesn't necessarily mean it will be elevated every month. There is evidence accumulating that, if a woman has levels of FSH that fluctuate greatly, she may have a better chance of achieving a pregnancy in a month when her FSH is lower than in a month when it is very high (though her chance will probably never be as good as in a woman who never has high FSH levels).

Unfortunately, there are no treatments available which can "turn back the clock" on a woman's ovaries. Many physicians use fertility medications to try to increase the chance of pregnancy. For this indication, the idea behind using fertility medications is to increase the number of eggs that develop in a given month, thus enhancing the chance that at least one of them might be able to be fertilized and develop into a viable pregnancy. This seems to result in some improvement in results, but the pregnancy rates are not as good as in younger women. Also, many women don't respond well to fertility medications as they get older.

Others have advocated in-vitro fertilization (IVF) as a means to achieve pregnancy in such cases. Unfortunately, the pregnancy rates with IVF in women over the age 40 are still very low. The most exciting innovation is the use of preimplantation genetic diagnosis (PGD) to discover embryos with an abnormal number of chromosomes so that normal embryos can by replaced during IVF. Some evidence indicates that if we are able to replace normal embryos in the uterus, that the chance for pregnancy may be doubled.

Currently, the only consistently successful method to improve pregnancy rates in women with age related infertility is egg donation. As compared to pregnancy rates of less than 10% per cycle for women over the age of forty, egg donation results in pregnancy rates of over 50% per cycle. In addition, the risks of miscarriage and Down's Syndrome are dramatically reduced. Thus the likelihood of "taking home a baby" are very much higher.

CONCLUSIONS

Fertility decreases with age. This decrease is most likely due to aging of the eggs and the chromosomes inside them. The risk of miscarriage and chromosomal abnormalities in babies also increase with age. The most successful method for achieving a pregnancy and taking home a baby at advanced female age is with the use of egg donation.

 

 

   

 

   


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