MEDIA STATEMENT


30th August 2006

Ofori B et al. Risk of congenital anomalies in pregnant users of non-steroidal anti-inflammatory drugs: a nested case-control study. Birth Defects Research Part B: Development and Reproductive Toxicology 2006; published online 23 August 2006. doi 10.1002/bdrb.20085

This observational study investigated the risk of birth defects in infants exposed to an NSAID during the first trimester of pregnancy. It found that women who were prescribed an NSAID shortly before or during the first trimester were more likely to have a baby with a birth defect, and with a heart defect in particular. The study did not investigate the short-term use of low-dose over-the-counter (OTC) analgesics.

How was the study carried out?
This analysis of medical records was carried out on a database of 36,387 pregnant women in Canada. Of these, 1,056 had filled a prescription for an NSAID (excluding aspirin, indomethacin and diclofenac/misoprostol) during or shortly before the first trimester. The authors believed that they were unlikely to have paid for OTC analgesics because their medical insurance covered them for medicines. These women gave birth to 93 infants (8.8%) with one or more birth defects.

These outcomes were compared with a group of women who had not taken an NSAID and who were matched for risk factors such as age and area of residence. This group of 35,331 controls gave birth to 2,478 infants with one or more birth defects (7.0%).

Five NSAIDs (naproxen, ibuprofen, rofecoxib, diclofenac and celecoxib) accounted for 95% of the NSAIDs included in the study.

What did the analysis find?
After adjusting for risk factors that could affect the results, first trimester exposure to an NSAID increased the odds of any birth defect approximately 2-fold (odds ratio, OR, 2.21; CI95% 1.72 - 2.85).1 Looking only at heart abnormalities known as cardiac septal defects,2 the odds ratio was 3.34 (CI95% 1.87 - 5.98). Defects involving the respiratory system were also associated with NSAID exposure (odds ratio 9.55, CI95% 3.08 - 29.63); however, 83% of these defects were not recorded as a specific diagnosis and, when these were excluded, this association was no longer statistically significant.

Further analysis showed that, of the NSAIDs studied, ibuprofen was the only one for which the association with birth defects overall was statistically significant; however, the associations with cardiac septal closure and respiratory system abnormalities alone were not statistically significant.

Interpretation
The authors conclude that their study 'suggests that women who fill prescriptions for NSAIDs in the first trimester of pregnancy may be at greater risk of having children with congenital anomalies than those who do not'. Their findings agree with most of the relevant epidemiological studies conducted in Europe.

When trying to understand what this study means, it is important to note that it refers to prescribed NSAIDs, not OTC NSAIDs which are typically used at low doses for short periods of time. It is also important to remember that an observational study such as this cannot prove a cause and effect relationship. This is because this type of study cannot exclude important sources of potential bias that may affect the results.

The authors were careful to control for many of the problems that could affect their analysis (such as the lower socioeconomic status and greater use of health resources by the women who were prescribed NSAIDs) but some residual effect may have remained. They acknowledge that some conditions for which an NSAID is prescribed may have contributed to the observed effects. For example, they say, a viral infection may cause congenital anomalies of the heart and is one indication for an NSAID. In this context, they note that women who were prescribed an NSAID were also more likely to have taken paracetamol (which may be used to treat fever associated with a viral infection). Nevertheless, the authors generally felt confident about their conclusions.

This study confirms what is already known about the effects of prescribed NSAIDs taken early in pregnancy. It does not provide information about OTC NSAIDs. It emphasises the importance of not taking any medication during pregnancy, or when contemplating pregnancy, except under medical supervision. Women who are, might be or are planning to become pregnant should always consult their doctor before considering self-treatment with any medication.


Notes

1. The odds ratio is a measure of the likelihood that an event will occur. It is calculated by dividing the odds of the event in the study group by the odds of the event in the control group. If the odds ratio is 1, there is no difference between the groups. If the odds ratio is 2, the event is twice as likely to occur in the study group.

CI95% denotes the 95% confidence intervals of the odds ratio. This is a statistical tool which means that if the study was repeated 100 times, the results would lie within the range quoted 95 times. Confidence intervals that include 1.0 are taken to mean there is no evidence of an effect.

2. A cardiac septal defect is sometimes referred to as a 'hole in the heart'. In this condition, the walls between the atria (the upper chambers) or the ventricles (the lower chambers) of the heart do not form completely. This means that blood flow to the lungs is increased and the heart has to do more work. Some ventricular septal defects close spontaneously but in most cases surgery is necessary. These abnormalities accounted for 92% of the cardiac defects found in this study.

According to the British Heart Foundation, a congenital heart defect occurs in about 8 in every 1,000 births in the UK; of these, half are minor and need no treatment. More information about congenital heart defects is available from the British Heart Foundation web site (www.bhf.org.uk).

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