First-Trimester Use of ACE Inhibitors Linked to Major Birth Defects

NASHVILLE, Tenn. June 7 ? Infants whose mothers used ACE-inhibitors during the first trimester are 2.7 times more likely to have major congenital malformations of the cardiovascular and central nervous systems, according to researchers here.

Compared with infants who had no gestational exposure to ACE-inhibitors the risk of major congenital malformations in exposed infants was 2.71 (95 C.I. 1.72 to 4.72) William O. Cooper, M.D., M.P.H., of Vanderbilt, and colleagues, reported in the June 8 issue of the New England Journal of Medicine.

Dr. Cooper and epidemiology colleagues at Boston University studied 29,507 enrolled in the Tennessee Medicaid program. The infants were born between 1985 and 2000 and the cohort did not include children born to mothers with diabetes.

Two hundred and nine infants had first-trimester exposure to ACE inhibitors, and 202 were exposed to other antihypertensive medications including beta-blockers, diuretics and calcium channel blockers.

For cardiovascular malformations such as atrial and ventricular septal defects and patent ductus arteriosus the risk ratio was 3.72 (95% CI, 1.89-7.30) and for CNS malformations such as spina bifida and microcephaly the risk ratio associated with first-trimester ACE inhibitor exposure was 4.39 (95% CI 1.37-14.02), they wrote.

Eighteen of the 209 infants with first-trimester exposure to ACE-inhibitors had congenital malformations-nine with heart defects and three with CNS defects. Six more had a variety of other malformations including renal dysplasia, hypospadias, and diaphragmatic hernia.

Four of the 204 infants who had first-trimester exposure to other antihypertensive drugs had congenital malformations (RR 0.66, 95% C.I. 0.25-1.75) as did 834 of the 29,096 babies born to women who did not use any blood pressure medication (RR 1.0 reference).

The authors noted that ACE inhibitors, the most widely prescribed class of antihypertensive agents prescribed in the U.S., are already contraindicated during the second and third trimester because of ACE-inhibitor fetopathy, "a group of conditions that included oligohydramnios, intrauterine growth retardation, hypcalvaria, renal dysplasia, anuria, renal failure and death."

Data form the National Ambulatory Medical Survey indicate that use of ACE inhibitors by female patients aged 15 to 44 has increased by 83% from 1995 to 2002, although the drugs are still used by only a small minority of women in that age group (4.4% in 2002 up from 2.4% in 1995).

Nonetheless, Dr. Cooper and colleagues concluded that the increase in use is "likely to result in an increase in first-trimester fetal exposures. Our data suggest that such exposures cannot be considered safe and should be avoided."

In an accompanying editorial, J. M. Friedman, M.D., Ph.D., of the department of medical genetics at the University of British Columbia in Vancouver, pointed out that the study suggested the need to examine all antihypertensive drugs to determine whether others may have teratogenic effects, because "not knowing the teratogenic risks of these drugs really does matter."

He wrote that insufficient data are available to determine the teratogenic risk for 39 of the 47 other oral antihypertensive drugs listed in JNC-VII, the compendium of blood pressure therapies. "Therapeutic doses of eight drugs (chlorothiazide, chlorthalidone, hydrochlorothiazide, atenolol, acebutolol, pindolol, nifedipine, and reserpine) are considered unlikely to pose a substantial teratogenic risk, but each drug raises concerns of other kinds," he wrote. "Moreover, the data available on teratogenicity are no better than fair for any of these agents."

Dr. Friedman asserted that the study by Dr. Cooper and colleagues is unlikely to be the last word on ACE-inhibitors in early pregnancy "but it is shocking to realize that it is almost the first."

Dr. Cooper and colleagues determined mothers' use of antihypertensive medications from Medicaid pharmacy records that included the date the prescription was filled and the number of days for which the medication was supplied. First trimester was defined as the first day of the last menstrual period and the subsequent 90 days.

The authors noted that the study may be limited by the authors' definition of first-trimester exposure. "Some of the exposures may have occurred before conception," they wrote. "However, the findings were not substantially changed in a secondary analysis that used a definition that required the mother to have filled a prescription for ACE inhibitors at least 14 days after the last menstrual period."