The Article
Cooper et al. "Major Congenital Malformations after First-Trimester Exposure to ACE Inhibitors."
N Engl J Med, 354 (2006): 2443-51.
Background
Angiotensin-converting-enzyme (ACE) inhibitors are very important drugs in the treatment of high blood pressure, diabetes, kidney disease, coronary artery disease and heart failure. They were first developed in the 1970’s and are now one of the most widely prescribed class of drugs. It is well known that ACE inhibitors cause birth defects when taken in the second and third trimester but until recently, it was thought that they were safe during the first trimester.
Type of Study
This was an observational and retrospective study to look for an associated between ACE inhibitors and major congenital malformations. Although it relied on the review of several databases, the investigators assessing for birth defects were blinded to the infant's exposure to ACE inhibitors. This type of study can assess for an association between ACE inhibitors and congenital malformations but cannot conclusively prove it.
Defining the Outcome
The study was looking for major congenital malformations or birth defects that were not caused by a chromosomal problem or a clinical genetic syndrome. The authors defined major congenital malformation based on the criteria used by the CDC’s Metropolitan Atlanta Congenital Defects Program.
Sources of Data
The study was based on 1985 to 2000 Medicaid data from the state of Tennessee. There appears to have been good documentation of the mother’s medical records and filled prescriptions as well as the infant’s vital records and medical records. Because it involves Medicaid data, the data may not be representative of the population as a whole. However, based on the data provided, it appears to be a good and reliable source of information.
Exclusion Criteria
There were 33,810 infants who were identified from another study looking for an association between congenital malformations and antibiotic exposure. Infants of mothers with diabetes were excluded because diabetes is known to birth defects and ACE inhibitors are routinely used in diabetes. Of the remaining 32,749 infants, another 3,242 were excluded because they were exposed either to other cancer causing drugs or blood pressure medications beyond the first trimester (including ACE inhibiors and angiotensin-receptor blockers). This left 29,507 infants without obvious risk factors for birth defects.
Statistical Analysis
The infants were placed into three groups according to mother’s use of blood pressure medications during the first trimester.
- Group 1: ACE inhibitors
- Group 2: Other blood pressure medications
- Group 3: No medications for blood pressure during entire pregnancy
The researchers then looked for the outcome (birth defects) in each group and tried to determine if there was an increased risk. The relative risk was determine with respect to infants with no exposure to blood pressure medications.
Results
- There were 411 infants (1.4%) who had exposure to either ACE inhibitors or other blood pressure medications during the first semester (Group 1 and Group 2). They were roughly equal between the two groups. This meant that 98.6% of the infants had mothers not taking blood pressure medications.
- The mothers of the infants in Group 1 and Group 2 were on the average 3-5 years older, had previous pregnancies, and had a higher number of chronic illnesses when compared to Group 3. The mothers of the infants exposed to ACE inhibitors (Group 1) were on the average 3 years old, better educated and with less asthma than those on other blood pressure medications (Group 2).
- There were 856 infants (2.9%) born with at least one major birth defect and 203 (0.7%) had multiple defects. Most defects involve principally five body systems: cardiovascular (35.6%), musculoskeletal (22.8%), genitourinary (20.2%), gastrointestinal (13.9%) and central nervous system (9.7%)
- The results showed that those infants exposed to ACE inhibitors had a higher rate of birth defects (7.1% vs 2.6%) and their relative risk was 2.7 times as great.
Conclusions
The authors concluded exposure to ACE inhibitors during the first trimester is potentially dangerous and cannot be considered safe. They felt that the association between ACE inhibitor exposure and major birth defects were unlikely due to confounding factors associated with the use of ACE inhibitors.
