The use of ACE inhibitors in the first trimester has been linked to an array of congenital malformations of the fetal cardiovascular system, CNS, and renal system, and therefore can no longer be considered safe, according to an observational study involving more than 29,000 pregnancies conducted by Dr. William O. Cooper of Vanderbilt University, Nashville, Tenn., and his associates.
In light of these data, the Food and Drug Administration has issued a public health advisory to educate clinicians and consumers about these study findings and to remind them to consider other treatment options for hypertension in pregnancy, agency officials said at a press teleconference.
However, the agency considers the study findings “preliminary” and will not change the black box warning, or the designation of ACE inhibitors as pregnancy category D drugs, “until we've examined the findings and sought additional evaluation from other information sources,” said Dr. Sandra L. Kweder, deputy director of the Office of New Drugs at the FDA's Center for Drug Evaluation and Research.
ACE inhibitors have been contraindicated in the second and third trimesters for at least a decade because they were known to be associated with conditions including oligohydramnios, intrauterine growth retardation, hypocalvaria, renal dysplasia, anuria, renal failure, and fetal death.
The drugs' effects were thought to result directly from impairment of fetal renal function, which doesn't develop until later in pregnancy.
Their use in the first trimester has never been linked to adverse outcomes, but until now it has been assessed only in animal studies and “small, uncontrolled series and unpublished reports,” according to Dr. Cooper and his associates.
The researchers used a large Medicaid database to assess birth outcomes in 29,507 infants born in Tennessee between 1985 and 2000. They identified 209 infants who were exposed to ACE inhibitors in the first trimester, and 202 who were exposed to other antihypertensive drugs in the first trimester.
The risk of a major congenital malformation was 2.7 times higher in the infants exposed to ACE inhibitors than it was in those not exposed to any antihypertensive drugs and those exposed to other antihypertensive drugs, the investigators reported (N. Engl. J. Med. 2006;354:2443–51).
Infants exposed to ACE inhibitors showed an excess of cardiovascular malformations, including atrial septal defects and patent ductus arteriosus, as well as an excess of CNS malformations, including microcephaly and spina bifida. A post hoc analysis also showed an excess of renal malformations in the group exposed to ACE inhibitors.
A total of 18 infants exposed to ACE inhibitors (8.6%) developed major congenital malformations, and 7 of these infants had multiple malformations. In contrast, 4 of 202 infants (1.9%) exposed to other antihypertensive drugs and 834 of the 29,096 infants (2.8%) not exposed to antihypertensive medications developed such malformations.
Dr. Cooper and his associates noted that their findings “are based on small numbers … and should be confirmed in other studies that address possible mechanisms for teratogenicity of ACE inhibitors as well as the effects of specific drugs, doses, and durations.”
In an editorial accompanying the study, Dr. J. M. Friedman of the University of British Columbia, Vancouver, said, “Clearly, more research on the teratogenic potential of ACE inhibitors in early pregnancy is needed. This is not the last word on the subject, but it is shocking to realize that it is almost the first,” given the widespread use of these agents over the last 25 years.
The risks appear to be great enough “to require discussion with all women of reproductive age who are prescribed ACE inhibitors,” he said, adding that women who discover they are pregnant while taking them should immediately be switched to another antihypertensive agent (N. Engl. J. Med. 2006;354:2498–500).
The problem with switching medications is that data on teratogenic risk “are no better than fair” for any other antihypertensive agent, either, Dr. Friedman noted.
The FDA's Dr. Kweder pointed out that ACE inhibitors already carry a black box warning against their use in the second and third trimesters, and the warning also states that ACE inhibitors should be discontinued as soon as pregnancy is detected.
Dr. Robert Temple, associate director for medical policy at the FDA Center for Drug Evaluation and Research, said, “We all want to see more data on this, but the findings are important enough and impressive enough to tell people about them now.”
Both he and Dr. Kweder stressed that the congenital abnormalities reported in Dr. Cooper's study are rare even in exposed fetuses, with only 18 cases in 209 infants.
“These are not in the same league with thalidomide or isotretinoin,” Dr. Kweder said. Moreover, these abnormalities do not follow a specific pattern, which is atypical of teratogenic drug effects. “There's one spina bifida, one microcephaly, a couple of renal dysplasias, a hypospadias. Even the cardiovascular malformations, which are the most common defects cited, are of different types,” Dr. Temple said.
Dr. Kweder added that even the designation “major congenital malformations” is unusual in this study. “Most teratologists would not consider some of these things to be major birth defects,” she noted.
When asked how many pregnancies might be affected by the study findings, Dr. Kweder said that cannot yet be determined. “These drugs are very effective for hypertension and well-tolerated, and they're commonly used, particularly among women of childbearing age.
“The fact that there were this many [209] exposures in this study suggests that more attention needs to be paid to the message that women should carefully review their medications with their health care providers before becoming pregnant or as soon as they become pregnant.”
As Dr. Friedman noted in his editorial, the recommendation that such women should switch to a different antihypertensive agent is undercut by the lack of safety data on any of these drugs. “It's an unfortunate situation to be in—we're recommending that they switch to drugs about which there is very little information. And hypertension is very, very common in women of reproductive age,” Dr. Kweder said.
Dr. Temple added that the current consensus is that diuretics are safe. Alpha-methyldopa (Aldomet) also “is reasonably good for pregnancy,” although its safety might be questionable because it hasn't been widely used.
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