Nonsteroidal anti-inflammatory drugs are among the most commonly used medications in pregnancy, with 23% of women in the United States recalling the use of one of these products in her first trimester, according to the National Birth Defects Prevention Study (Am. J. Obstet. Gynecol. 2012;206:228e1-8).
Although NSAIDs are typically contraindicated late in pregnancy, first trimester use has not consistently been associated with increased risks for congenital anomalies in human studies. Animal studies have suggested, in particular, that nonselective NSAIDs such as aspirin, ibuprofen, and naproxen – which inhibit both cyclooxegenase-1 and -2 – might be associated with increased risks for midline defects, diaphragmatic hernia, and ventricular septal defects. These animal studies have suggested a stronger association with aspirin and weaker effects with nonaspirin NSAIDs (Birth Defects Res. B Dev. Reprod. Toxicol. 2003;68:5-26).
A recent report from the National Birth Defects Prevention Study – an ongoing, large, U.S. multisite, case-control study of major congenital anomalies and maternal exposures – has suggested that specific NSAIDs might be associated with small to moderate increases in risk for several specific congenital anomalies. Using retrospective maternal interview data collected from 14,915 case and 5,546 control mothers who had due dates between 1997 and 2004, researchers found that 3,173 women (15.5%) reported exposure to NSAIDs and recalled specific frequency of use of the medication in the first trimester. An additional 1,452 women (7.1%) reported using an NSAID "as needed" in the first trimester. Among all women who recalled taking an NSAID, more than 98% reported using one of three NSAID types – aspirin, ibuprofen, or naproxen (Am. J. Obstet. Gynecol. 2012;206:228e1-8).
The results of this study suggested that NSAIDs are not a major cause of birth defects; however, the study did find several small to moderate statistically significant increases in nine specific defects among women who reported a known frequency of NSAID use in the first trimester (adjusted odds ratio range, 1.3-3.5). The defects that occurred with increased frequency included neural tube defects, eye defects, oral clefts, limb reduction defects, amniotic bands/limb body wall defects, and pulmonary valve stenosis. Specific associations varied by type of drug. Estimates of the odds ratios were said to be similar among women who reported "as needed" use of NSAIDs in the first trimester.
The association with oral clefts in this study could be consistent with previous animal studies and one human study from the Swedish Medical Birth Register (Reprod. Toxicol. 2001;15:371-5). However, most human studies have either shown no increased risks for these specific defects (PLoS One 2011;6:e22174), or have suggested a possible increased risk for heart defects, primarily cardiac septal defects (Reprod. Toxicol. 2003;17:255-61; Birth Defects Res. B Dev. Reprod. Toxicol. 2006;77:268-79).
The current study found no association with cardiac defects other than pulmonary valve stenosis.
The strengths of this recent case-control study are the large sample size, including sufficient numbers of specific defects to detect low to moderate risks for certain associations, and large enough numbers to examine risk with exposure to specific NSAID products; maternal interview data regarding actual use of the medications rather than just prescription dispensing; and information on important confounders such as alcohol, tobacco, and folic acid supplement use.
On the other hand, the interview data collection process involved maternal recall up to 24 months after delivery; thus, recollection of mothers – particularly for medications that might be taken sporadically and are available for purchase over the counter – might have been inaccurate. There are also concerns in any retrospective study that recall might be influenced by the mother’s knowledge of the status of her infant regarding birth defects. It is also unknown to what extent the underlying maternal conditions being treated by NSAIDs could have contributed to some of the increased risks that were found in this study.
In addition to these caveats, some or all of the findings in this study could be due to chance, and more studies are needed to follow-up on these concerns. For clinicians, it is important to recognize that the suggested increased risks are for relatively rare congenital anomalies. Thus, even if some of the reported associations are causal, mild to moderate increased risks for these specific defects translate to low absolute risks for the individual patient. For example, if the risk for cleft lip with or without cleft palate is 1 in 1,000 live births in the general population, this study would suggest that for every 1,000 women who take ibuprofen in the first trimester, an additional 0.6 infants would be born with cleft lip.