June 7, 2006 -- The FDA is encouraging women who are taking a class of drugs called ACE inhibitors, which lower blood pressure, to reconsider the use of those drugs before or during pregnancypregnancy.
That advice comes in the wake of a study published in The New England Journal of Medicine showing a higher rate of birth defects in babies born to women who filled prescriptions for ACE inhibitors in the first trimester of pregnancy.
ACE inhibitors are known to raise the risk of birth defects when taken later in pregnancy. The new study suggests that those risks may start earlier in pregnancy.
Examples of ACE inhibitors include Zestril, Prinivil, Accupril, Monopril, and Lotensin. The new study looks at ACE inhibitors in general, without mentioning specific drugs.
FDA: Reconsider Meds, but Don't Panic
"This isn't something to panic about. These are preliminary data," the FDA's Sandra Kweder, MD, told reporters in a teleconference. "But nonetheless, women should seek to change their medicine as soon as they become pregnant," she says.
Kweder is the deputy director of the FDA's Office of New Drugs at the Center for Drug Evaluation and Research.
"I think what's most important about the study is that it just brings to light the importance of women carefully reviewing medication information with their health care providers before becoming pregnant or as soon as they become pregnant, and being aware of the potential risks of certain medicines," Kweder says.
'Black Box' Warning
ACE inhibitors already carry a "black box" warning about birth defects when the drugs are taken during the second and third trimester of pregnancypregnancy. A black box warning is the FDA's strongest warning.
"The reason for that is that we've known for at least a decade, if not longer, that these drugs, when exposure occurs in the second half of pregnancy, are associated with abnormal kidney functions in infants, as well as sometimes abnormalities of the kidney anatomy itself," says Kweder.
The warning doesn't specifically mention the first trimester, but it states "that use of ACE inhibitors should be stopped or discontinued as soon as possible when pregnancy is detected," Kweder says.
The FDA will issue a public health advisory and fact sheets reinforcing that message, says Kweder. Until the FDA reviews the issue, Kweder says there are no plans to change the drugs' warnings.
About the Study
The study was conducted by William Cooper, MD, MPH, and colleagues. Cooper works in the pediatrics department of Vanderbilt University's medical school.
Cooper's team studied data on 29,507 babies born between 1985 and 2000 who were enrolled in Tennessee's Medicaid system.
The researchers checked the mothers' records for prescriptions filled during the first trimester of pregnancy for ACE inhibitors or other high blood pressurehigh blood pressure drugs (antihypertensive medications). They also checked the babies' records for major birth defects not linked to genetics.
Most babies weren't exposed to any high blood pressure drugs during the first trimester.
However, 411 babies were exposed to high blood pressure drugs during the first trimester alone. Of those babies, 209 were only exposed to ACE inhibitors during pregnancy's first trimester. The other 202 babies had been exposed to other high blood pressure drugs during the first trimester.
Measuring Risk
A total of 856 babies were born with birth defects. That's nearly 3% of the overall group.
Eighteen babies with first-trimester exposure to ACE inhibitors -- about 7% of all babies in that group -- were born with birth defects, the study shows. That's more than twice the rate of babies unexposed to any high blood pressurehigh blood pressure drugs.
Babies exposed in the first trimester to high blood pressure drugs that weren't ACE inhibitors weren't at higher risk of major birth defects than those with no exposure to any blood pressure drugs, according to the study.
"We found that fetal exposure to ACE inhibitors restricted to the first trimester of pregnancypregnancy, an exposure that was previously considered to be safe, was associated with a risk of a major congenital malformation that was 2.7 times as great as the risk with no fetal exposure to ACE inhibitors or other antihypertensive medications," write Cooper and colleagues.
The study was observational, so the results don't prove that ACE inhibitors caused birth defects.
It's possible that some women filled their prescriptions without taking the drugs, the researchers note. Because diabetesdiabetes can raise the risk of birth defects, none of the mothers included in the study had diabetes.
Three of the researchers (but not Cooper) report having received grants, served on advisory or drug safety monitoring boards, or consulted for drug companies, the journal notes.
Birth Defects, ACE Inhibitors
Here are details on birth defects seen in babies born with first-trimester exposure to ACE inhibitors:
- 7 babies had more than one malformation.
- Cardiovascular malformations were the most common type of major birth defect, affecting 9 babies.
- Malformations of the central nervous system were the second most common type of major birth defect, affecting 3 babies.
- The babies' moms ranged in age from 17-41 years.
- The babies were born at 32-41 weeks of gestational age.
"Many of these defects ... are potentially treatable. ... Some are much worse," the FDA's Robert Temple, MD, told reporters in the teleconference.
Temple is the associate director for medical policy at the FDA's Center for Drug Evaluation and Research.
He says Cooper's study doesn't show a "single pattern that at least is more typical" for birth defects in babies exposed to ACE inhibitors in the first trimester. There were very few cases of certain birth defects in Cooper's study, making it hard to draw conclusions, notes Temple.
Questions Remain
"One of the things that these data don't tell you is how early in pregnancypregnancy the drugs cause problems. We just don't know that," says Temple.
He says that for women who are pregnant or might become pregnant, "the main thing is to reconsider their medication."
Birth defects are "common" and can happen without exposure to ACE inhibitors, Kweder notes. She calls ACE inhibitors "very effective drugs" that are "generally well tolerated."
"We all believe that we want to see more data here but this is important enough and impressive enough to tell people about," Temple says.
Second Opinion
The New England Journal of Medicine also includes an editorial about Cooper's study. The editorial was written by J.M. Friedman, MD, PhD of Canada.
Friedman -- who wasn't involved in Cooper's study -- works in Vancouver, at the University of British Columbia's medical genetics department.
"Clearly, more research on the teratogenic potential of ACE inhibitors in early pregnancy is needed," Friedman writes. Teratogens are substances that can cause birth defects.
"This is not the last word on the subject, but it is shocking to realize that it is almost the first," Friedman adds, noting that many other drugs haven't been studied in pregnant women.
Drugs typically aren't tested on pregnant women.
Women's Options
Cooper's study doesn't make recommendations about other options for pregnant women needing treatment for high blood pressurehigh blood pressure.
"I think it's fair to say that not a lot is known about any of the options for women and their use in pregnancy," Kweder says. "There have not been very many studies on antihypertensives and pregnancy. There are a few minor exceptions but even those studies are not large."
"Trying to be able to provide better, more scientifically robust information about safety in medicines in pregnancy is an important priority for FDA," Kweder says.