ACE inhibitors were not found more likely than other antihypertensive drugs to be associated with an increase in congenital heart defects when used in the first trimester only.
Rather, hypertension itself was suspected as the likeliest cause of increased risk.
The findings, from a large retrospective cohort study published online Oct. 18 in BMJ (BMJ 2011 Oct. 18 [doi: 10.1136/bmj.d5931]), challenge those of a smaller, 5-year-old study of similar design (N. Engl. J. Med. 2006;354:2443-51) that found first-trimester use of angiotensin converting enzyme (ACE) inhibitors associated with an increase in congenital heart and neural tube defects. (Other antihypertensives were not seen in that study as raising risk.)
ACE inhibitors have long been associated with birth defects when used in the second and third trimester, and are therefore contraindicated in pregnancy; however, it was not until the publication of the 2006 cohort study of about 30,000 infants that adverse outcomes were also linked to first-trimester use.
The question of teratogenicity in the first trimester is important, because many pregnancies are unplanned, and women may continue to use contraindicated drugs inadvertently after conceiving.
For their research, Dr. De-Kun Li of Kaiser Permanente in Oakland, Calif., and colleagues enrolled 465,754 mother-infant pairs representing all live births in Kaiser Permanente’s Northern California region between 1995 and 2008.
The researchers looked at incidence of heart and neural tube defects at birth, and the cohort included linked data on prescription history, maternal preexisting diabetes, pregnancy weight, age, ethnicity, and education, among other variables. Only 0.9 of every 1,000 women in the cohort used ACE inhibitors, and use of other antihypertensive medications was 2.4 per 1,000.
After adjustment for maternal age, ethnicity, parity, and obesity, use of ACE inhibitors was seen associated with congenital heart defects in 15 of 381 mother-infant pairs (3.9%), compared with 6,232 of 400,021 (1.6%) in infants born to normal controls, or women without hypertension and not taking take any antihypertensives during pregnancy (OR, 1.54; 95% CI 0.90-2.62).
Heart defects were seen in 28/1090 (2.6%) of infants whose mothers took other hypertensives in the first trimester only (OR, 1.52; 95% CI, 1.04-2.21).
Among hypertension controls – women diagnosed with hypertension but not taking antihypertensives – 708 of 29,735, (2.4%), of their infants had congenital heart defects.
Investigators found that, compared with hypertension controls, neither use of ACE inhibitors or other antihypertensives in the first trimester was associated with increased congenital heart defects risk (OR, 1.14 with a 95% CI of 0.65-1.98; OR, 1.12 with a 95% CI of 0.76-1.64).
Neural tube defects were not seen to differ significantly among the groups.
The findings, Dr. Li and colleagues wrote, "raise the question of whether the observed risk associated with antihypertensives in general was due to the effect of the drugs or the underlying hypertension."
In an editorial comment associated with Dr Li and colleagues’ study (BMJ 2011;343:d6667), Dr. Allen A. Mitchell of the Slone Epidemiology Center at Boston University, wrote that "[f]ew studies have been large and rigorous enough to provide useful information on the fetal safety of most antihypertensives." However, he praised the new findings as derived from a "larger and more diverse database" than were previous studies.
While Dr. Li and colleagues’ findings clashed with those of the 2006 study, which found an effect for ACE inhibitors in the first trimester (risk ratio 2.71; 95% CI, 1.72 to 4.27), Dr. Mitchell noted, two more recent studies found no increased risk when used in the first trimester only (Eur. J. Clin. Pharmacol. 2009;65:615-25 and Hypertension 2009;54:63-70).
"On the basis of all these findings, it is reasonable to conclude that exposure to ACE inhibitors during the first trimester poses no greater risk of birth defects than exposure to other antihypertensives," Dr. Mitchell wrote. "[I]t is possible that ACE inhibitors (and other antihypertensives) may be associated, if modestly, with one or another specific defect, but the greater concern is that the underlying hypertension itself places the fetus at risk."
The investigators conceded several weaknesses in their study, among which was that they had little information on the characteristics of women with treated and untreated hypertension. Therefore, they wrote, "we were not able to distinguish between the potential underlying differences in the risk of having a child with birth defects and treatment effect on the risk of birth defects."
Nevertheless, Dr. Li and colleagues continued, "untreated hypertension is likely to be less severe than treated hypertension, and the risk of having a child with birth defects was quite similar between women with treated hypertension (in the first trimester) and those with untreated hypertension."