Data for the study were obtained from the Tennessee Medicaid database for the years between 1985 and 2000, which allowed for the examination of the prenatal record as well as infant outcomes.
Pharmacy records were also reviewed and the fetus was considered to have an exposure to an ACE inhibitor if the mother filled a prescription for the drug during the first trimester of pregnancy. Mothers with evidence of diabetes were excluded from the study, and infants exposed to antihypertensive medications after the first trimester or to other teratogenic agents during gestation were also excluded.
To reach the outcome, the study's authors compared infants exposed to ACE inhibitors with a cohort of children whose mothers received other antihypertensive drugs and a group of infants not exposed to any antihypertensive drugs. Most of the infants in the ACE group had been exposed to at least 2 months of the drug.
The study employed the definitions of the Centers for Disease Control and Prevention for major malformations. The cardiovascular malformations observed were mainly atrial and ventricular septal defects and patent ductus arteriosus. The CNS malformations included spina bifida and significant eye defects. 2 cases of renal dysplasia and some intestinal malformations were also present.
One-third of the birth defects involved the heart, one-quarter the limbs or the face, and one-tenth involved the brain or spinal cord. Some defects, such as the heart problems, might be curable with surgery or other treatment, but others resulted in retardation or permanent disability.
The study's findings were corroborated by blinded investigators reviewing the medical records, and the comparison of the 3 groups was adjusted for other risk factors for malformation.
Based on these findings, taking ACE inhibitors during early pregnancy "cannot be considered safe and should be avoided," according to Dr William Cooper, a pediatrician at Vanderbilt Children's Hospital in Nashville, and leader of the study.
Critics say the fact that such serious findings are only first recorded 25 years after the ACE inhibitors came on the market demonstrates the inability to collect safety data on the ill-effects of drugs used during pregnancy.
Prior to FDA approval, new drugs are tested on pregnant animals to see whether they cause birth defects because it is considered unethical to include pregnant women in clinical trials unless the drug is intended to treat a pregnancy-related condition.
Studies of large databases such as Medicaid records that show pregnant women already taking a medication are about the only means available to measure risks to the fetus from a particular drug.
In an editorial accompanying the study in the NEJM, Dr J M Friedman, MD, PhD, a medical geneticist at the University of British Columbia, said the ACE study highlights the larger problem about the lack of safety data. "Birth defects caused by teratogenic treatments are preventable," he wrote, "and babies and their mothers are being harmed unnecessarily because we do not know enough about which treatments to use and which to avoid."
"Further study is needed," he said, "to determine the precise risk and its relationship to individual drugs but the increase appears to be great enough to require discussion with all women of reproductive age who are prescribed ACE inhibitors."
"A woman who learns she is pregnant while taking an ACE inhibitor," Dr Friedman warns, "should immediately be switched to another antihypertensive agent to minimize the risk of fetopathy."
"Detailed fetal ultrasonography and echocardiography at about 18 weeks of gestation," he said in the NEJM, "should be offered to women who have taken such drugs in the first trimester of pregnancy." ACE inhibitors include:
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