The Harvard Medical School Family Health Guide
Infertility, Pregnancy, and Childbirth
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Infertility

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Fertility Changes with Age

Surprising news for both men and women: your biological clocks have been ticking for longer than you think. The results of recent research show fertility begins to decline in women as early as age 27 and in men around age 35. But the news isn't all bad; the fertile period (or open window for conception) during a woman's cycle remains the same length between ages 19 and 39.

The study, published in the May 2002 issue of the journal Human Reproduction, involved 782 European couples practicing the rhythm method of contraception. Women recorded their daily body temperatures, the days they had sex, and the days of their menstrual bleeding. Fertility was measured by the probability of becoming pregnant per menstrual cycle.

Analysis of the results showed women under the age of 27 had a greater than 50% chance of becoming pregnant during a menstrual cycle, assuming their partners were the same age and they had sex two days before ovulation, which is the best time for conception. This probability dropped off notably at the age of 27. Women ages 35–39 were nearly 50% less likely to become pregnant during a cycle than women under 27.

Scientists have speculated that the decrease in women's fertility with age was a result of a shortened fertile period during the menstrual cycle. Yet, the results of this study show this is not the case. For women ages 19–39, the fertile period (when chances of conception were greater then 5%) occurred during the 6 days prior to ovulation.

The researchers also found women age 35 with partners of the same age were 29% likely to become pregnant on their most fertile day, while women age 35 with partners five years older were only 18% likely to become pregnant. This indicates the fertility of men begins to drop sometime during their late 30s. The researchers indicate many reasons may be responsible for this decrease, including genetic defects in the sperm or structural changes in the testes and prostate.

Experts say that this study is not a cause for alarm. The results show an average decline in fertility as women and men age. At any age, however, fertility levels vary widely among individuals. In general, as women age, they should expect it to take longer to become pregnant than when they were younger.

June 2002 Update

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In-vitro fertilization may cause birth defects, low birth weight

It's been 24 years since the first baby was conceived with the help of in-vitro fertilization (IVF), bringing hope to thousands of childless couples. In 1999 alone, over 30,000 babies were born in America with the help of artificial reproductive technologies (ART), including IVF. Since then, an estimated 300,000 IVF babies have been born worldwide. But this revolutionary way to overcome infertility is not risk-free. Two new studies published in the March 7, 2002, issue of the New England Journal of Medicine suggest that ART babies are more likely to be born with birth defects and low birth weights than newborns conceived naturally.

In IVF the man's sperm and the women's egg are combined in a laboratory dish. After fertilization, the resulting embryo is then transferred to the women's uterus to develop naturally. A special IVF procedure called intracytoplasmic sperm injection (ICSI), where the sperm is injected directly into the egg, can also be used for severe male infertility.

ARTs, including IVF, increase the risk of multiple births because several embryos are usually transferred to the uterus at one time to increase the probability of a successful pregnancy. But this practice is controversial because multiple births are associated with low birth weight, which puts the newborn at an increased risk for short- and long-term disabilities and even death. However, in one of the new studies, researchers with the U.S. Centers for Disease Control found that even ART babies born alone were 2.6 times as likely to have a low birth weight than a naturally conceived single infant.

In the other study, Australian researchers found that about 9% of the 301 IVF babies studied had birth defects, such as heart trouble, stunted limbs, Down syndrome, and cleft palate, compared to only 4.2% of the 4,000 naturally conceived babies studied. The risk was still more than doubled when multiple births were not considered.

Neither these nor previous studies have been able to identify whether the reason for the excess risk of low birth weight and birth defects is related to the underlying infertility itself or to the procedures and drugs used to overcome it.

To many advocates of assisted reproduction, the results of these studies aren't necessarily frightening, but reassuring. They look at them and celebrate that more than 90% of IVF babies are born healthy. But regardless of the interpretation of the numbers, couples looking for help with fertility should consider these risks.

May 2002 Update

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Shapely Sperm and Fertility

The shape of a man's sperm is the best gauge of fertility, according to a recent study in The New England Journal of Medicine.

Researchers from the National Cooperative Reproductive Medicine Network have found the best sperm structure is an oval head and long straight tail. Unusually shaped sperm — those with very large or small heads, or tails with twists and coils — were not able to fertilize the egg. The World Health Organization (WHO) publishes standards of normal semen measurements, but the guidelines on the quantity of quality semen indicative of fertility have varied throughout the years and have not proved themselves in thorough testing.

The men in the study were more likely to be infertile if fewer than 9 percent of their sperm were well shaped, while they were most likely to be fertile if more than 12 percent of their sperm looked normal.

While there is no surefire way to diagnose fertility, these findings on well-shaped sperm could help standardize the WHO's criteria.
December 2001 Update

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Hormone Level Best Predictor of Drug Success in Treating Ectopic Pregnancy

The prevalence of ectopic pregnancies has risen sharply since the 1970s. Some women are at increased risk for an ectopic pregnancy — for example, women who smoke, or have had prior pelvic surgery, or have used an IUD in the past, and those with a history of infertility. An ectopic pregnancy occurs when an embryo starts to develop outside the uterus, usually in a fallopian tube. This quirk of nature is difficult. The embryos are rarely normal, and it is impossible for the pregnancy to continue. This situation also threatens a woman's health. If an ectopic pregnancy goes undetected, the fallopian tube could rupture and the woman could suffer severe internal bleeding. If it is not detected early enough, there can be damage to the woman's reproductive organs that can compromise her fertility. Symptoms of an ectopic pregnancy may include vaginal bleeding, sharp abdominal cramps, or pains on one side; however, ectopic pregnancy can be painless or associated with only mild cramps.

An ectopic pregnancy is generally treated with surgery, which is invasive and carries certain risks. Another approach is the use of a drug called methotrexate. Methotrexate is traditionally used as part of cancer therapy because it obstructs the metabolism of rapidly growing cells. In the case of an ectopic pregnancy, the drug prevents embryonic cells from multiplying. While there are clear advantages to medical treatment of an ectopic pregnancy (no surgical risks, faster recovery time, and possibly better preservation of fertility), it isn't always effective and sometimes surgery is required.

Researchers from the University of Tennessee, Memphis, recently did a study to determine what factors might help predict whether methotrexate treatment will be successful. They monitored 350 women with ectopic pregnancies who were given the drug; 320 of the women were treated successfully. After comparing various factors, such as the size of the embryo and the presence of fluid in the abdominal cavity, the researchers determined that the level of a hormone produced during pregnancy was the single most important factor in determining whether drug treatment would be successful. The hormone, called human chorionic gonadotropin (HCG), is produced by the placenta and helps ensure the production of progesterone, thus preserving the pregnancy. (It is the hormone measured in home pregnancy tests.) High levels of the hormone suggest an embryo that is still developing and growing. Methotrexate treatment was more successful in women whose HCG levels were 15,000 or less. It is important to keep in mind that the women in this study had very early ectopic pregnancies and no signs of internal bleeding.

Ectopic pregnancy can be a painful experience both emotionally and physically. Medical treatment with methotrexate, rather than surgery, can be a somewhat less traumatic way to handle this problem.

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New Fertility Drug Ovidrel (R) Expected to Hit Market in 2001

Ovidrel (R) — the first fertility drug to contain recombinant human chorionic gonadotropin — has been approved for subcutaneous injection. If all goes according to plan, Ovidrel (R) will be available for patient use sometime in 2001.

For the past 40 years, human chorionic gonadotropin, collected from the urine of pregnant women, has been the only hormonal preparation commercially available to help trigger ovulation in women with infertility due to anovulation. For the past 20 years, the urine-derived human chorionic gonadotropin (uHCG) has also been used to promote final maturation of eggs in the ovaries of women undergoing assisted reproductive technologies such as in-vitro fertilization. Commercial preparations of uHCG have suffered from batch-to-batch inconsistency, which can lead to variations in response — not only from patient to patient but also within one patient from cycle to cycle. In contrast, Ovidrel has a high level of purity, which means that its strength and accuracy can be measured precisely, and that it can be produced uniformly. According to a recent study, Ovidrel is just as efficient as uHCG in terms of number of eggs produced in women. But, in producing mature eggs, Ovidrel (R) was found to be more efficient.

One clear advantage to using Ovidrel is the fact that the women in the study had a much better tolerance locally to its injection. The uHCG injections must be administered intramuscularly (a deep shot, requiring a long needle), rather than just under the skin, as Ovidrel requires (using a needle similar to that used for insulin injections). For women in the study, administration of uHCG was four times as likely to cause adverse events, such as pain, inflammation, and bruising at the injection site when compared with the subcutaneous injection of Ovidrel. Even women who had suffered an adverse local reaction to uHCG were able to tolerate the injection of Ovidrel much better. Women's improved tolerance of Ovidrel is clearly a plus in terms of comfort and ease of use, in addition to its clinical benefits.
October 2000 Update

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The Benefits of Bed Rest after Intrauterine Insemination

A randomized study conducted in Quebec, Canada, is the first to demonstrate that bed rest after intrauterine insemination (IUI) increases the rate of successful conception. Out of 116 couples chosen to participate in the study, 95 completed it (all of whom were diagnosed with "unexplained infertility"). The women were all younger than 38 years old, had their ovulation confirmed, and had open fallopian tubes. The men all had a normal semen analysis. The couples had experienced infertility for between one and three years and were randomly assigned to two groups.

Patients in each group received the same treatments, screenings, and drugs in the same doses at the same time in their cycles, for a maximum of three treatment cycles. Patients in group I were allowed to get up immediately after IUI, while patients in group II were asked to remain lying on their backs for 10 minutes after the procedure. Group I was made up of 40 couples; four of the women in this group became pregnant. Group II was made up of 55 couples; 16 of the women in this group became pregnant.

Researchers are not exactly sure why 10 minutes of bed rest made such a difference in the rate of pregnancy between the two groups. One reason they offer is that standing and moving around after IUI might cause most of the sperms to be expelled from the uterus and vagina. Study investigators could not say just how much bed rest is "best" but believe that 10 minutes seems to be enough. They also suggest that 10 minutes of bed rest after sexual intercourse might also increase the chance of conception. In light of these findings, these researchers recommend that 10 minutes of bed rest after IUI become standard practice.

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