FDA Public Health Advisory: Birth Defects with High Blood Pressure-Lowering Drugs Containing Angiotensin-Converting Enzyme (ACE) Inhibitors

The FDA issued a public health advisory on June 8 concerning the possibility of a higher probability of birth defects in children born to mothers who took the widely prescribed family of blood pressure-lowering drugs, known as angiotensin-converting enzyme (ACE) inhibitors, during the first trimester of pregnancy.

The full text of the public health advisory is available on the FDA’s Web site at http://www.fda.gov/cder/drug/advisory/ACEI.htm.

Researchers studying the birth defects’ links to ACE inhibitors concluded that exposure to ACE inhibitors during the mother’s first trimester cannot be considered safe and should be avoided.

Half of the birth defects linked to the ACE inhibitors were various types of heart defects. Half also included some malformations of the central nervous system, the urinary system, or other systems.  

Problems with the possibility of birth defects when ACE inhibitors are used in the second and third trimesters are well-known. All marketed ACE inhibitors carry a black box warning in their professional product labels or package inserts, but this is the first study to raise concerns about use in the first trimester.

The FDA public health advisory was based on research published in the June 8 New England Journal of Medicine that found that infants who had been exposed to ACE inhibitors during the mother’s first trimester of pregnancy had a 2.71-fold increase in the occurrence of birth defects compared to children not exposed to blood pressure medication in utero.

The researchers were from the Vanderbilt University School of Medicine in Nashville, Tenn., and the Slone Epidemiology Center at Boston University. They were supported by grants from the FDA and the Agency for Healthcare Research and Quality, Centers for Education and Research on Therapeutics.

The researchers studied a group of 29,507 infants enrolled in the Tennessee Medicaid program who were born between 1985 and 2000. Researchers identified 209 newborns who were exposed only to ACE inhibitors during their mother’s first trimester and 202 babies with exposure to other blood pressure-lowering drugs during the first trimester. These groups of newborns were compared to 29,096 newborns whose mothers took no high blood pressure-lowering drugs during their pregnancies.

The mothers taking an ACE inhibitor were on average older and more likely to have other chronic health conditions than were the mothers not taking any blood pressure-lowering drugs.

Birth defects were identified from linked vital records and hospitalization claims during the first year of life and confirmed by review of medical records.

Other blood pressure-lowering drugs could also be linked to birth defects, according to researchers.

The table below lists products containing only an ACE inhibitor, an ACE inhibitor in combination with the diuretic (water pill) hydrochlorothiazide, and products containing an ACE inhibitor and a calcium channel blocker, another family of high blood pressure-lowering drugs.

Birth Defects with Angiotensin Receptor Blockers

The family of blood pressure-lowering drugs known as angiotensin receptor blockers (ARBs) has properties similar to the ACE inhibitors. Both families of drugs have an effect on a natural substance that raises blood pressure called angiotensin.

A senior FDA official was quoted as saying, “we have no data here on ARBs” with regard to the ARBs and birth defects; however, “ARBs seem to have similar liabilities” as ACE inhibitors.  

The professional product labels for all marketed ARBs also carry a black box warning concerning the use of these drugs in the second and third trimesters of pregnancy.

The table below lists drugs that contain an ARB alone and combination drugs with an ARB and thiazide diuretic.

Pregnancy and Hypertension: What Course is Best?

The Merck Manual, a respected source of medical information, recommends that women with pre-existing mildly elevated blood pressure (140/90 to 150/100 millimeters of mercury) discontinue antihypertensive drugs as soon as pregnancy is confirmed and monitor their blood pressure regularly. For expectant mothers with pre-existing moderate high blood pressure (150/100 to 180/110 millimeters of mercury), methyldopa (ALDOMET) is the best option. Women with severe high blood pressure (greater than or equal to 180/110 millimeters of mercury) represent a much more complicated medical condition in which less desirable drugs may be appropriate.

The National Institutes of Health (NIH) also recommends methyldopa in pregnancy in “The Seventh Report of the Joint National Committee (JNC 7) on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.” This reference is available on the Internet at www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf.

The Merck Manual and JNC 7 recommendations are based on long-term follow-up studies of methyldopa supporting the drug’s safety during pregnancy.

What You Can Do

You should contact your physician immediately if you are pregnant and are taking either an ACE or ARB inhibitor at any stage in pregnancy.

The drug of choice for pregnant patients with mild-to-moderate high blood pressure before they became pregnant is methyldopa (ALDOMET). Because blood pressure typically drops during the first trimester, some women with mild hypertension may be able to manage without any medication during that time.

DO NOT discontinue a blood pressure-lowering drug without first consulting the prescriber.