NSAIDs During First Trimester Linked to Congenital Defects

MONTREAL, Aug. 24 -- Women who take NSAIDs during the first trimester have a greater risk of having babies with congenital anomalies, particularly cardiac septal defects, researchers here reported.

According to a population-based, nested case-control study of 36,387 pregnant women in Quebec province, women who filled NSAID prescriptions early in pregnancy had more than twice the risk for any congenital defect, reported Anick Berard, Ph.D., of Sainte-Justine Hospital, and colleagues, in the September issue of Birth Defects Research Part B.

Women who took first-trimester NSAIDs also and more than three times the risk of anomalies related to cardiac septal closure, mainly ventricular and atrial septal defects, the investigators found.

The effect of NSAID exposure on the fetus toward the end of pregnancy, causing premature closure of the ductus arteriosus and patent ductus arteriosus, are well documented, but the risks related to NSAID use in early pregnancy are less well defined, they said.

Of 1,056 women who filled prescriptions for NSAIDS during the first trimester of pregnancy, 8.8% had infants with congenital abnormalities, compared with 7% of 35,331 women who did not use NSAIDs, the investigators said.

Cases included infants with any congenital anomaly diagnosed in the first year of life, while up to 10 controls, infants with no detected congenital defects, were selected for each case.

To find the independent effect of NSAIDS on congenital anomalies, the researchers adjusted for health status, presence of rheumatoid arthritis, hypertension, hypothyroidism, use of other potentially teratogenic medications, and socioeconomic status.

The adjusted odds ratio (OR) for any congenital anomaly with NSAID use was 2.21 (95% CI 1.72-2.85), while the adjusted OR for anomalies related to cardiac septal closure was 3.34 (CI 1.87-5.98).

There were no significant associations with anomalies of other major organ systems, the researchers reported. Although at first there appeared to be an association with respiratory system defects, the association disappeared when further analysis in which anomalies defined as "unspecified" were excluded, the researchers said.

The percentage of cleft lip and palate was similar among those who used NSAIDS and those who did not, nor were there associations with musculoskeletal and neural-tube defects between the two groups, they added.

The five most commonly filled prescriptions were 35% for Aleve (naproxen), 26% for Advil (ibuprofen ), 15% for Vioxx (rofecoxib), 9% for Celebrex (celecoxib), and 9% for Cataflam or Arthrotec (diclofenac), representing 95% of all NSAID prescriptions.

It is conceivable, Dr. Berard said, that NSAID-mediated teratogenicity may be a result of vascular disruptions, given the relationship between Cox inhibitors, prostaglandins, and their vascular and endothelial effects.

One proposal for the pathogenic mechanisms of congenital cardiovascular anomalies is that forces generated within the developing heart tube with the initiation of cardiac contractions, combined with the secondary hemodynamic forces produced by blood flowing through cardiovascular structures, influence cell behavior, vessel and chamber size, and myocardial mass.

"It is conceivable, the researchers wrote, "that disruptions in the normal resistance of intracardiac blood flow by inhibitors of prostaglandin synthesis could result in congenital anomalies such as ventricular septal defects."

On important limitation of the study, the researchers wrote, was the assumption that those who filled prescriptions actually took enough of the medication to induce the effect. Some doses would certainly have been taken. But these agents are known to exhibit threshold phenomena. It was not possible, however, to establish whether the amount taken was above the critical threshold.

The potential risks of taking NSAIDS during pregnancy are not well publicized, the researchers said. "The hazards reported in this study are in accordance with previous findings but need to be replicated in other study populations," they concluded.