Assessing the Effects of Fertility Drugs : Health: While test-tube babies have received careful medical scrutiny, their mothers have been neglected. Now, that’s changing.

This year in the United States, close to 20,000 women will undergo in-vitro fertilization, the test-tube conception of embryos that was introduced here a decade ago.

In the process they take powerful hormone drugs to produce multiple eggs for every attempt. Yet infertility specialists are raising concerns that the long-term effects, if any, of these drugs are not known.

“The tradition has been to get details on the babies but not on the mothers,” said Florence Hazeltine, head of the National Institutes of Health’s office of population research. “It was clearly a gaping need.”

As the number of women seeking IVF grows with the aging of the baby boomers and postponed parenthood, officials are turning their attention to potential effects on what is suddenly a large population.

In an effort to see if the IVF hormone treatment plays any role in ovarian cancer, premature menopause, thyroid problems or other conditions, Hazeltine’s office is registering women undergoing IVF and other assisted reproduction techniques at nine fertility centers to follow their health.

The registry, which has catalogued 3,000 women in two years, is the only study worldwide tracking these women post-treatment. Although the project is funded for five years, researchers say they will need 15 years or more to follow the women through the hormonal changes of menopause, when any problems would be more likely to emerge.

To date, there is no reason to believe that the drugs are detrimental to most women. Indeed, for some couples the use of fertility drugs can enable the small miracle of a baby where there was no hope before.

The main infertility drugs, clomiphene citrate (brand names Serophene and Clomid), human menopausal gonadotropin (Pergonal) and follicle-stimulating hormone (Metrodin) have been marketed in the United States for more than 20 years. Although clomiphene citrate is a synthetic formulation, Pergonal and Metrodin are derived from the urine of post-menopausal women, who produce these hormones in such high concentration that they are excreted.

Traditionally, these fertility drugs were given as aids in natural conception to women of reproductive age who had ovulation problems.

But “there are really no long-term studies on the way we give things now,” said Maria Bustillo, an infertility specialist at Genetics and IVF Institute in Fairfax, Va.

In IVF and other variations of the technique called GIFT and ZIFT, the drugs are prescribed in greater amounts and different combinations in order to promote the development of multiple eggs. Women typically go through the procedure for three or four cycles before conceiving--or giving up. Some couples make more attempts. There are no regulations limiting the number.

Both women who donate eggs and those who receive them are also prescribed the drugs. “We don’t know what we can tell people now,” said Bustillo. “My biggest concern is that we get the data.”

The hormones are taken daily by injection according to a schedule that typically runs 28 days. Side effects can include hot flashes, mood swings, depression, nausea, breast tenderness, swelling or rash at the injection site, abdominal bloating and slight twinges of abdominal pain.

Robert Spirtas, chief of the contraceptive and reproductive evaluation branch of Hazeltine’s office, which is funding the registry, cautioned that women who attempt IVF are quite desperate for children:

“As long as they know what the risks are, and we can document them and know the likelihood of success, then they can make an informed choice.”

However, he added, “no one really knows that much about the side effects. How effective the treatment is is not well-documented either. They can’t make an informed choice.”

The NIH’s registry is formally called “Health Surveillance of Women Treated for Infertility by In-Vitro Fertilization.” Its title is misleading, for it is not limited to women attempting IVF but includes women subjected to ovulation-induction hormones for a number of procedures.

David Adamson, chairman of the research committee for the Society for Assisted Reproductive Technology, the national group of doctors performing these techniques, said the group feels it is “most important” that the NIH data continue to be collected.

For its part, since 1988, the society has been keeping a databank of every patient undergoing IVF and related techniques at registered infertility programs. Serono Laboratories Inc., which manufactures several fertility drugs, is planning a five- to 10-year study in consultation with the NIH, said company president Hisham Samra.

“I don’t think patients should be frightened or concerned that they’ve used these drugs,” said Adamson, director of the Fertility and Reproductive Health Institute of Northern California.

“Everything in life is a risk,” he said, “and the benefit of these drugs is obvious. You can increase pregnancy rates and allow many infertile couples to have families who otherwise would not have families. It’s difficult to see how a few cycles could result in enough change to cause significant clinical problems for individual women.

“However,” he added, “there may be some cause for concern for women who have undergone 15 or 20 cycles.” Adamson said he was aware of couples who had attempted IVF that many times. “We don’t take women that far at all,” he said of his institute. “Seven or eight cycles is the most we would do.”

Hazeltine has raised a major concern about another aspect of hormone drug use on the cutting edge of reproductive technology: the very new practice of egg donation. The women who donate eggs to infertile couples are not included in the NIH registry, although they too undergo the ovulation-stimulation regimen.

Inducing the ovaries of young fertile women to produce multiple eggs, said Hazeltine, is not the use for which these drugs were originally intended.

“There is no excuse for young girls to be getting these drugs to donate eggs,” she said. “These are young kids. There’s often a $2,000 to $3,000 inducement. We have no long-range data. How do you know their fertility won’t be impaired? We’re sticking their ovaries with needles (to aspirate out the eggs). Will they have early menopause?”

Sherry Sherman, director of the osteoporosis program at the National Institutes on Aging, said researchers do not yet understand what brings on menopause. She said only one factor--smoking--has been linked to the timing of its onset. Smokers begin menopause 1 1/2 to two years earlier than nonsmokers.

Mark Sauer, who directs the egg-donation program at USC--at five years one of the oldest and largest in the country--estimated that several hundred women have donated eggs across the United States and said the practice “is becoming more widespread,” he said.

“As the demand grows,” Sauer said, “we will see an increasing number of fertile women involved in ovulation-induction regimens that normally wouldn’t be exposed, and as a group they are a younger population.” He said his practice has seen no evidence of later impaired infertility or any psychological problems, such as remorse, in its donors, who have numbered about 100.

He said most of the infertile women in his program undergoing IVF and similar procedures are in their 30s. The donors tend to be in their late 20s. He said USC imposes a minimum age limit of 21 on donors and a maximum age limit of 35. Although donors are not required to already have children of their own, he said virtually all of them do.

USC’s donors typically go through five to 10 ovulation-inducing cycles over a two-year period. Sauer said two donors had done more than 12 cycles because they were called back to help in the conception of siblings for earlier babies conceived with their eggs.

The American Fertility Society has set no standards for how many times a woman may donate eggs--or undergo IVF, for that matter. Donation centers prefer younger women because their eggs are more viable.