Pregnancy and Drug

by Food and Drug Administration (FDA)

Jennifer, 25, of Baltimore wishes she only had to deal with the basics of pre-pregnancy planning, like going for a routine checkup and taking prenatal vitamins. "I get discouraged when I think of how much more I have to consider before trying to conceive," says Jennifer, who has taken the antidepressant Zoloft (sertraline) for three years.

She and her husband plan to try for a baby soon, but the questions feel overwhelming. Should Jennifer stop taking the antidepressant? Before conceiving or only after? For the first trimester or the whole pregnancy? What if she stops taking the medication and can't cope? Why aren't there definitive answers about the medicine's effect on babies, especially long-term? And what about breast-feeding? The couple has set up appointments with Jennifer's psychiatrist and an obstetrician in hopes of finding answers.

Unfortunately, there are times when such questions not only rattle the nerves of patients, but also of doctors. For example, there are no definitive answers about the long-term effects of Zoloft and many other medications on babies. Experts say that while they have certainly learned some useful information for successful drug treatment in pregnancy, their knowledge is limited for the most part. That goes for information in the literature and on the labels doctors use to make clinical decisions, says Beth Conover, a genetic counselor who coordinates the Teratogen Information Service at the University of Nebraska Medical Center. "Teratogen" is a term that refers to any substance with the potential to cause birth defects.

Conover says advising patients and doctors about medication use in pregnancy is like working in shades of gray. "Parents want someone to assure them their babies will be OK, and of course that's what we want to do," she says. "But it's very hard to prove absolute safety. We would need extensive, long-term studies to do that, and we don't have them in many cases."

The reality, of course, is that pregnant women get sick, whether it's with pneumonia or cancer. Or like Jennifer, they come to pregnancy with chronic conditions that require treatment. So despite some areas of uncertainty, health professionals must look to the resources they do have to make clinical decisions.

Dianne Kennedy, a regulatory health project manager with the Food and Drug Administration's Center for Drug Evaluation and Research (CDER), says withholding all medication during pregnancy is not the answer. Too many conditions pose more of a health risk if left untreated, she adds (see "The Danger of Untreated Disease"). In fact, medication use in pregnancy is common, and the number of prescriptions tends to rise with the mother's age. "We use the safest, best drugs we can so women can receive the treatment they need," Conover says.

The FDA has taken several steps to improve doctors' ability to give pregnant women safe and effective drug treatments. For example, the FDA regularly trains its reviewers in translating reproductive studies in animals into health risks for humans. The agency has also drafted a guidance document for industry on establishing pregnancy registries. Sponsored mostly by pharmaceutical companies, these studies identify women using certain drugs and then observe pregnancy outcomes.

In addition to general questions about safety, almost no information is available to help doctors know what the best dose of a particular medicine is for pregnant women. Changes in the body's physiology during pregnancy have the potential to require that doses be increased or decreased. In December 2000, the FDA and the National Institute of Child Health and Human Development held a meeting in Washington, D.C., on clinical pharmacology in pregnancy. Experts discussed the need for more and better data to assess the rational dosing of drugs that are often used to treat pregnant women, ethical issues in research, and ways to share data more effectively with health professionals through labeling and other education.

Challenges in Clinical Research

For Jennifer and her husband, the answers they'll find about Zoloft's effects in pregnancy will be "relatively reassuring," says Conover. Data from animal studies and small studies in humans suggest that use of Zoloft during pregnancy does not pose a high risk of birth defects, she explains, but the data are insufficient to state that there is no risk.

Zoloft's product labeling indicates that there are no well-controlled studies on the drug in pregnant women, that the effect of Zoloft on labor and delivery in humans is unknown, and that it also isn't known whether, or in what amount, the drug is excreted in human milk.

Unless research focuses on a pregnancy-related condition such as labor induction, drugs typically aren't studied in pregnant women because of the fear of exposing the woman to an experimental drug and harming the fetus. Catherine Stika, M.D., assistant professor of obstetrics and gynecology at Northwestern University School of Medicine, says the research approach for pregnant women has to be different than that for non-pregnant people who consent to participate in clinical trials.

Drugs are first studied in animals to make sure they are sufficiently safe to test in non-pregnant people. Human safety is evaluated from results of clinical trials, in which patients are observed for adverse events. To be well-controlled, a study needs to involve an adequate number of patients and have a control group — patients who are similar to the group being studied but who are receiving a different treatment regimen. Sometimes, the different treatment is another drug already approved to treat the disease; other times, it may be an inactive pill (placebo).

The limitations that go with conducting research on pregnant women don't mean we shouldn't do any research, Stika says. "We have to improve education for researchers about other ways to do clinical studies in pregnancy."

According to Maria Palmisano, M.D., director of clinical pharmacology-experimental medicine at Bristol-Myers Squibb Co., the natural population to recruit for research is pregnant women already needing to take a drug. But we need to first know a drug is safe in the general population and that it works before heading in that direction, she says.

Drugs enter the market based on clinical trials of several thousand people, and sometimes adverse events aren't revealed until later, after the drug is used in greater numbers in the general population. So the difficult part is determining when it is safe enough, Palmisano says. "There are some crucial mileposts in determining when a drug should be tested in pregnant women," she says. "Chief among them are establishing a drug's safety and effectiveness in the general population and knowing when a disease occurs in childbearing years."

Yvonne Maddox, deputy director of the National Institute of Child Health and Human Development, says she is putting together a consortium of experts to focus on advancing clinical research in pregnant women. "We want to try to find at least a couple of drug companies willing to take on what many have said is too risky," she says. "Academicians are asking why research in pregnant women should be any more risky than other high risk/high payoff research areas. But this type of research makes pharmaceutical companies worry more about financial loss from lawsuits."

About the Author

www.fda.gov
FDA is A United States government body that oversees medical devices, including contact lenses, intraocular lenses, excimer lasers and eyedrops. In the US, these products must be approved by the FDA before they can be marketed.