Major Congenital Malformations after First-Trimester Exposure to ACE Inhibitors
Abstract & Commentary
By John C. Hobbins, MD, Professor and Chief of Obstetrics, University of Colorado Health Sciences Center, Denver, is Associate Editor for OB/GYN Clinical Alert.
Dr. Hobbins reports no financial relationship to this field of study.
Synopsis: Exposure to ACE inhibitors during the first trimester cannot be considered safe and should be avoided.
Source: Cooper WO, et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med. 2006;354:2443-2451.
A popular family of anti-hypertensive medications act by inhibiting angiotensin II converting enzyme. These ACE inhibitors have been implicated as adversely affecting fetal renal function but have generally been ignored as first trimester teratogens.
A report appeared in the June 8 issue of the New England Journal of Medicine in which the author searched a Tennessee Medicaid database for infants born between 1985 and 2000 who were exposed to antihypertensives during their mothers first trimesters. Through birth certificates, pharmacy records, etc, and after applying exclusion criteria such as diabetes and exposure to known teratogens, the authors came up with 411 infants who were exposed to antihypertensives in the first trimester and 29,096 infants who were not. In about half (209) the medication used was an ACE inhibitor and in the other half (202) other antihypertensive medications were used.
The results were fascinating. Those on antihypertensives tended to be older, showed up for care earlier, and, generally, had a higher level of education. The percentage of smokers was the same in all categories (29 to 30% which seemed high). Most importantly, there was a 7.1 % incidence of congenital anomalies in the ACE inhibitor group, compared with 1.73 % in the group of infants exposed to other antihypertensives. The incidence of anomalies in the unexposed 29,096 control infants, was 2.63 %.
The most common anomalies seen in association with the ACE inhibitors involved the heart and CNS, where the odd ratios (OR) were 3.7 (95 % CI = 1.89-7.30) and 4.4 (95% CI = 1.7-14.02), respectively.
Commentary
For some time it has been recommended that ACE inhibitors not be prescribed in pregnancy because of their potential for an adverse effect on the fetal renal system in the second and third trimester. However, little information has been available on their effect in the first trimester, and animal studies have generally yielded unexciting results with regard to teratogenicity.
ACE inhibitors are frequently employed in chronic hypertension because they are well tolerated and they work. Since about half of the pregnancies in the United States are unintended and even those with planned pregnancies may not get to see a provider until organogenesis is complete, a rather high percentage of women on ACE inhibitors will have fetuses that run a 7-fold greater risk of having a major congenital anomaly.
In looking at the data, it is clear, that once cardiac and CNS defects have been ruled out, the risk of other anomalies is no greater than that of the overall population of infants. Therefore, the diagnostic workup in those ACE inhibitors should start between 11 and 14 weeks with a nuchal translucency (NT) assessment (in those who seek care early enough to do this). Since about 50% of fetuses with cardiac anomalies will have an increased NT, these patients can be booked for an echocardiogram later. If early detection is essential for these patients, then a transvaginal fetal cardiac assessment can generally be accomplished prior to 16 weeks. Also, a combination of maternal serum alpha-fetoprotein (MSAFP) and a comprehensive second trimester sonogram should be able to rule out most CNS anomalies. Last, patients should be reassured that they will run about a 93% chance that their fetuses will not have a major abnormality despite being exposed to the ACE inhibitors, and if the above studies are reassuring, the risk drops to almost zero.
Additional Reading
- Cooper WO, et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med. 2006;354:2443-2451.
- Henshaw SK. Unintended pregnancy in the United States. Fam Plann Perspect. 1998;30:24-29, 46.
- Alwan S, et al. Angiotensin II receptor antagonist treatment during pregnancy. Birth Defects Res A Clin Mol Teratol. 2005;73:123-130.
- Chisholm CA, et al. Reversible oligohydramnios in a pregnancy with angiotensin-converting enzyme inhibitor exposure. Am J Perinatol. 1997;14:511-513.
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