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Are All Antihypertensive Agents Safe and Effective? More Evidence, For and Against: ACE Inhibitors Should Be Avoided Completely During Pregnancy


ACE Inhibitors Should Be Avoided Completely During Pregnancy

Exposure to angiotensin-converting enzyme (ACE) inhibitors during the first trimester of pregnancy cannot be considered safe and should be avoided, according to the results of a new study in the June 8 issue of The New England Journal of Medicine.[7] If this recommendation is followed, however, physicians and their patients may find that there are few alternative antihypertensive therapies that have been shown to be safe throughout pregnancy, an accompanying commentary warns.[8]

In a study funded jointly by the US Food and Drug Administration (FDA) and the Agency for Healthcare Research and Quality (AHRQ), Centers for Education and Research on Therapeutics, researchers led by William O. Cooper, MD, MPH, (Vanderbilt University School of Medicine, Nashville, Tennessee), examined data gathered from the Tennessee Medicaid program. They studied 29,507 infants born between 1985 and 2000, of whom 209 were identified as having been exposed to ACE inhibitors during the first trimester. A further 202 infants had comparable exposure to other antihypertensive medications, and 29,096 had no maternal use of antihypertensive drugs at any time during gestation. Major congenital malformations were identified from linked vital records and hospitalization claims during the first year of life and confirmed by review of medical records.

The researchers found that major congenital malformations were diagnosed in 856 (2.9%) of infants, of whom 203 infants had more than 1 malformation. Among infants exposed to ACE inhibitors in the first trimester, the proportion born with major congenital malformations was 7.1%, compared with 1.7% among infants exposed to other antihypertensive medications. The rate of major congenital malformations in the general population is about 3%.

The chances of a major congenital malformation among infants exposed to ACE inhibitors during the first trimester were 2.71 times higher than in infants whose mothers did not use any hypertension medications. The increased overall risk seen with ACE inhibitors was due primarily to higher risks for cardiovascular and central nervous system malformations, including atrial septal defects, patent ductus arteriosus, hydrocephalus, and spina bifida. The infants had a 3.72- and 4.39-fold increase in risk for malformations of the cardiovascular system and the central nervous system, respectively. The risk for all other types of malformations, including those of the musculoskeletal, gastrointestinal, and genital systems, was not significantly increased by first-trimester exposure to ACE inhibitors, the researchers found.

"This study raises the important issue of a woman and her physician being aware of potential risks of medications that she might be taking before she becomes pregnant," Dr. Cooper said. "While we believe the increased risk that we found in our study represents a true increase, further studies are needed to confirm these findings and to assess the risks of specific drugs and durations of exposure."

This study is the first to find an adverse impact of ACE inhibitors on a fetus when taken only during the first trimester of pregnancy. ACE inhibitors already carry an FDA "black box" warning stating that they can cause injury and even death to the developing fetus when used during the second and third trimesters of pregnancy. The warning states that use of ACE inhibitors should be discontinued as soon as possible when pregnancy is detected.

The AHRQ is sponsoring follow-up studies on the effects of drug exposures during pregnancy. Research on other related classes of medications, including angiotensin receptor blockers, will be conducted with the FDA.

In an editorial published alongside the Tennessee study,[8] Jan M Friedman, MD, PhD (University of British Columbia, Vancouver, Canada), concurs that a woman who learns that she is pregnant while taking an ACE inhibitor should immediately be switched to another antihypertensive agent to minimize the risk of fetopathy. However, there are few alternatives, Prof. Friedman points out, since little is known about the teratogenic risks of other antihypertensive drugs, including 39 of the 47 other oral antihypertensive drugs listed in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7).[9]

Therapeutic doses of 8 drugs (chlorothiazide, chlorthalidone, hydrochlorothiazide, atenolol, acebutolol, pindolol, nifedipine, and reserpine) are considered unlikely to pose a substantial teratogenic risk, although the available data for these drugs are "no better than fair," Prof. Friedman says, and "each drug raises concerns of other kinds." "Because of our ignorance, some pregnant women may not receive treatments that would benefit their own health and that of the fetus," he cautions. "Birth defects caused by teratogenic treatments are preventable, and babies and their mothers are being harmed unnecessarily because we do not know enough about which treatments to use and which to avoid," he concludes.

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