We found no significant association between take up of prescriptions for non-steroidal anti-inflammatory drugs during pregnancy and risk of congenital abnormality, low birth weight, or preterm birth. There was, however, a significant association with miscarriage.
The full and independent registration of prescriptions and birth outcome prevented selection bias and some types of information bias. In the cohort study potential misclassification in the registration of congenital abnormalities would be unlikely to be related to the prescribing of non-steroidal anti-inflammatory drugs. The case-control study was based on routinely recorded data and was independent of diagnosis, thus there was no risk of recall bias, which can invalidate case-control studies that rely on interviews.15
Previous studies have shown high validity of data in both the prescription database and the birth registry.16,17
In a recent, as yet unpublished study that was based on a review of hospital records in the period 1 January 1991 to 31 December 1995, we found that more than 80% of patients coded as having a congenital abnormality in the regional hospital discharge registry were correctly coded. Data on the major confounding factors of maternal age, smoking status, and birth order were available in the cohort study; the case-control study, however, lacked data on smoking status.
We had no specific information on compliance. That the prescriptions for non-steroidal anti-inflammatory drugs were taken up at the pharmacy and paid for in part by the patient may improve compliance. Furthermore, a relevant indication for the use of non-steroidal anti-inflammatory drugs was documented in general practitioners' records in a high proportion of pregnancies. These drugs, however, are often used as short term analgesics and may be purchased over the counter, which may increase the likelihood of misclassification of women with respect to drug use and bias the risk estimates towards one.
Teratogens do not uniformly increase the risk of all congenital abnormalities, but rather of specific abnormalities.15
We did not find any specific trend in the distribution of congenital abnormalities, and we did not find evidence for a dose-response relation between mothers' use of non-steroidal anti-inflammatory drugs and adverse birth outcome. Like other researchers we did not find an increased risk of reduced fetal growth.8,9
Use of non-steroidal anti-inflammatory drugs in pregnancy is clearly associated with increased risk of miscarriage. We had no information about the gestational age at time of miscarriage. A critical factor in the case-control study, therefore, is the time period that was selected for the controls, as general practitioners may change their prescribing practice when they know that a woman is pregnant. Such a bias would probably be independent of any particular drug among drugs that have the same estimated risk profile; we therefore repeated the analyses for penicillin V instead of non-steroidal anti-inflammatory drugs and found an odds ratio of 1. This result, as well as the decreasing odds ratio with increasing time interval between time of prescribing of non-steroidal anti-inflammatory drugs and miscarriage, indicates that such bias was minimal but does not exclude the possibility of confounding by indication (for example, the prescribing of a drug to treat pain that may be a precursor of miscarriage). However, we cannot determine from our non-experimental data whether this association is causal or due to undetected confounding. Thus, in the case-control study we were not able to adjust for smoking status, as we did in the cohort study.
Apart from an unpublished study of use of ibuprofen in a cohort of 3178 pregnant women from the Michigan Medicaid surveillance study,18
we have not been able to identify any systematic studies of non-steroidal anti-inflammatory drug use in pregnant women. We have not found any studies of the association between non-steroidal anti-inflammatory drugs and miscarriage in humans. Because of the necessarily limited nature of studies of drug safety during pregnancy, it is important that all available data are combined to obtain the highest possible precision in the calculation of risk estimates. Our observation of an increased risk of miscarriage in women exposed to non-steroidal anti-inflammatory drug is new and needs to be confirmed.
What is already known on this topic
Current knowledge on the safety of taking non-steroidal anti-inflammatory drugs during pregnancy is based on studies with small sample sizes
What this study adds
Risk of adverse outcome at birth (congenital abnormality, low birth weight, or preterm birth) was not associated with the taking up of prescriptions for non-steroidal anti-inflammatory drugs during pregnancy
The taking up of such prescriptions was, however, associated with miscarriage