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Ibuprofen may ‘raise miscarriage risk’

“Women who take even a small dose of painkillers such as ibuprofen early in their pregnancy more than double their risk of suffering a miscarriage,” The Guardian has reported.

This news story covered a study that looked at women who had miscarried in early pregnancy and compared their use of non-steroidal anti-inflammatory drugs (NSAIDs, such as ibuprofen, diclofenac and naproxen) with that of pregnant women who had not miscarried. The researchers found the risk of miscarriage to be 2.4 times greater in women taking any type of NSAID, compared with women not taking these drugs.

The findings of this large well-conducted study are likely to be reliable. NSAIDs are already known to carry potential risk in pregnancy, and the British National Formulary states that they should be avoided during pregnancy, unless the potential benefit is expected to outweigh the risks. Other potential risks that have been associated with NSAID use include delayed onset of labour and failed closure of the ductus arteriosus, which forms part of the foetal heart circulation.

Paracetamol is regarded as safe to take during pregnancy, when pain relief is needed. Pregnant women who are in need of regular pain relief, or who are finding paracetamol insufficient, are advised to consult their doctor, as the cause of pain and the most appropriate course of management require proper medical assessment.

Where did the story come from?

The study was carried out by researchers from the University of Montreal, Quebec, Canada, and the Ecole Nationale de la Statistique et de l’Analyse de l’Information, Rennes, France. It was funded by two Canadian organisations, Fonds de la recherché en santé du Quebec and the Reseau Quebecois de recherché sur l’usage des medicaments. The study was published in the peer-reviewed Canadian Medical Association Journal.

The study was widely reported in the UK media, which tended to concentrate on the risk of miscarriage from ibuprofen, a well-known over-the-counter painkiller of the NSAID class. It was generally covered well, with many papers including comments and advice to pregnant women from independent experts.

What kind of research was this?

The researchers point out that although NSAIDs are one of the most commonly used medications during pregnancy, there have been concerns about their potential risks. However, studies investigating this have had inconsistent results and there is a lack of data on the scale of the risk from different types and dosages of NSAIDs.

This was a nested case-control study that looked at the possible risk of miscarriage associated with specific types and dosages of NSAIDs (excluding aspirin, which is also technically classed as an NSAID but the researchers say is now more commonly used as an anti-blood-clotting drug) in a cohort of pregnant women. In this type of study, cases (in this study, women who experienced miscarriage) are identified from a defined population group and each case is matched to a specified number of matched controls from the same group who have not experienced this outcome.

The alternative, and slightly more statistically reliable approach, would have been a prospective cohort study that followed a group of pregnant women, some who used NSAIDs and some who didn’t, and observed them to see whether they experienced the study outcome. Case controls are often used instead as they are easier to carry out and require smaller study populations. This is particularly the case when the study outcome is quite rare as, in a cohort, you would need a large population sample in order for a reasonable number of those included to experience the outcome of interest. Arguably, as miscarriage is a relatively common pregnancy outcome, a cohort design could also have been used.

What did the research involve?

The researchers used data from the Quebec Pregnancy Registry to identify 4,705 women, aged between 15 and 45, who experienced miscarriage (medically confirmed) prior to 20 weeks of pregnancy, during their first pregnancy. For each case of miscarriage, they randomly selected 10 controls from the remaining women in the registry who had not miscarried. The controls were matched so that they were the same number of weeks pregnant as the ‘case’ had been when they miscarried.

The use of non-aspirin NSAIDs was then compared between women who had miscarried and those who had not. Exposure to non-aspirin NSAIDs was identified as the women having filled in at least one prescription for any type of this drug during the first 20 weeks of pregnancy or in the two weeks before the start of the pregnancy. (In Quebec ibuprofen is available over the counter, but this group of pregnant women were insured to get it on prescription).

The researchers also looked at the women’s use of combinations of NSAIDs and at possible associations between different types and dosages of NSAIDs. They classified women according to the overall proportion of the maximum daily dose of NSAIDs that they took between the start of the pregnancy and the date of the miscarriage and subdivided the doses into four categories. Women who did not fill in a prescription for an NSAID during this time were considered not to have taken these drugs.

The researchers used validated statistical methods to look at any association between use of NSAIDs and the risk of miscarriage. They adjusted their results for other confounders that might affect the risk of miscarriage including social and economic class, various medical conditions, use of other medications, and history of miscarriage or planned termination of pregnancy.

What were the basic results?

Overall, 7.5% of women who had had a miscarriage had filled in one or more prescriptions for non-aspirin NSAIDs during pregnancy compared with 2.6% of women who did not miscarry.

The main findings:

Overall, the use of NSAIDs during pregnancy was associated with an increased risk of miscarriage, and this increase was statistically significant (adjusted odds ratio [OR] 2.43, 95% CI 2.12 to 2.79).

The highest risk of miscarriage was associated with use of diclofenac (OR 3.09, 95% CI 1.96 to 4.87).

The risk with use of other NSAIDs varied: naproxen OR 2.64, 95% CI 2.13 to 3.28, celecoxib OR 2.21, 95% CI 1.42 to 3.45, ibuprofen OR 2.19, 95% CI 1.61 to 2.96, and rofecoxib (now no longer licensed for use in the UK) OR 1.83, 95% CI 1.24 to 2.70.

Using a combination of NSAIDs more than doubled the risk (OR 2.64, 95% CI 1.59 to 4.39).

There was no association between dosage and risk of miscarriage.

How did the researchers interpret the results?

The researchers say the results suggest a “class effect” for NSAIDs. This means that, according to these results, taking any type of NSAID during pregnancy may increase the risk of miscarriage and they urge that these drugs should be used with caution in pregnancy.

They have a theory that may explain the association. They say that it is possible that NSAIDs affect levels of natural compounds called prostaglandins that are usually suppressed during pregnancy. If the mechanism by which prostaglandin production is blocked during pregnancy fails, this may bring on a miscarriage.

Conclusion

This is a large, well-conducted study, the findings of which have been replicated in other studies and its conclusions are likely to be reliable. To explore whether women had taken NSAIDs during pregnancy, the researchers used accurate information from prescriptions rather than asking women to recall what drugs they might have used. Formal medical diagnosis of miscarriage was also used in the analysis rather than relying on patients’ recall. The researchers also adjusted their results for a large number of confounders that might affect the risk of miscarriage.

However, as the authors note, the study also had some limitations. It is possible (although probably unlikely), that some women used over-the-counter NSAIDs rather than prescription drugs and these women would not have been included in the data. It is also possible that women did not take the NSAIDs that had been prescribed for them.

A further limitation is that, though the researchers aimed to adjust their results for a wide range of medical conditions that could have affected the observed relationship between NSAID use and miscarriage, they did not have information on the specific conditions for which women were using NSAIDs. It is possible that these medical complaints could still have confounded the association between the drugs and miscarriage. For example, important confounders that were not assessed, and that have been associated with increased risk of miscarriage, are various viral and bacterial infections, including sexually transmitted infections such as chlamydia. Other possible confounders that were not assessed include lifestyle factors, such as smoking, alcohol consumption and body mass index.

This was a complex study, which included many different comparisons. As the researchers say, there is a possibility that 5% of the associations occurred by chance.

The British National Formulary currently states that NSAIDs should be avoided during pregnancy, unless the potential benefit is expected to outweigh the risks. Other potential risks that have been associated with NSAIDs include delayed onset of labour and failed closure of the ductus arteriosus, which forms part of the foetal heart circulation. Aspirin should also be avoided due to the same risks, and because of its effects on platelet function, which increase bleeding risk.

Paracetamol is regarded as safe to take during pregnancy, when pain relief is needed. Pregnant women who are in need of regular pain relief, or who are finding paracetamol insufficient, are advised to consult their doctor, as the cause of pain and the most appropriate course of management require proper medical assessment.

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