Journal Club: Pregnancy outcome following maternal exposure to pregabalin may call for concern

INTERPRETATION

These findings strongly suggest that pregabalin should only be considered in women of childbearing age by balancing its potential risks to the child with the benefits to the mother. One major factor is that the debilitating consequences of the condition may necessitate the use of anticonvulsants (e.g., seizures in individuals with epilepsy or severe neuropathic pain).⁷ In addition to the pain-relieving effects of pregabalin, a recent study demonstrated a potential benefit of pregabalin on neurologic motor recovery among individuals with acute spinal cord injury.⁸

A study strength is that data were collected prospectively in multiple centers across Europe. The use of prospective data collection on drug exposures during pregnancy removes a major source of bias present in retrospective studies (recall bias). There are, however, some weaknesses to consider, including the following:

1. Relatively small sample size. While this was the largest human study to date exploring pregabalin use during pregnancy, only 164 individuals were exposed during pregnancy. Comparatively, other anticonvulsants have demonstrated negative effects on pregnancy in much larger patient cohorts.⁹

2. There were significant baseline differences in previous spontaneous abortions between the 2 study groups. From the data presented, it is unclear whether or not these women were on pregabalin at the time of spontaneous abortion.

3. In the pregabalin group, 13% were treated with another antiepileptic drug. There were also more complicated medical conditions in the exposed group. The authors adjusted for concomitant treatments with other antiepileptic drugs and some other medications such as antidepressants, but other unadjusted medications could be important confounders. By definition, confounders are associated with both the exposure and outcome, but not on the causal pathway between the exposure and outcome.

4. Accordingly, another potential confounder could be the indications for the anticonvulsant medications, including pain or epilepsy. Though there is mixed evidence, there are some data suggesting that epilepsy can increase the risk of adverse pregnancy outcomes, even in epileptic women not exposed to anticonvulsants.¹⁰ There is also some evidence to suggest that stress, which is highly correlated with pain, can increase the risk of birth defects.¹¹

5. Interaction effects of the drugs were not included in the analysis. From a pharmacologic point of view, drug–drug interactions are of great importance and thus should not be neglected. One exclusion criterion was maternal exposure to any known major teratogen or fetotoxicant. However, some of the reported concomitant drugs, such as topiramate and valproic acid, are known to be highly teratogenic (evidence for positive evidence of risk [Category D] or contraindicated in pregnancy [Category X]).¹² Taken together with the aforementioned concerns, it is difficult to completely discern the teratogenic effects of pregabalin from other drugs or interaction effects.

6. There was a mixture of methodology used to ascertain outcomes. Follow-up was obtained via a telephone interview or mailed questionnaire to the patient or health care professional. This issue would be particularly problematic if it differed by pregabalin use (i.e., nondifferential misclassification of outcome).

7. A dose response—one of the criteria for causality—was not observed, as with several other teratogens.¹³

8. Cases and controls were women who themselves or whose physician contacted one of the teratology centers. Thus, a selection bias in both groups cannot be ruled out.

Women of childbearing age contemplating a pregnancy and undergoing treatments for neuropathic pain, epilepsy, or psychiatric disorders represent a dilemma for treating physicians: is treatment with pregabalin or other anticonvulsants worth the risk of harm to the child? With their article, Winterfeld et al. provide evidence that antiepileptic drugs carry teratogenic potential. As this is the only current evidence on the matter, pregabalin should only be given to women of childbearing age after an informed decision, weighing the benefits and risks. Furthermore, all women requiring the use of antiepileptics of any kind should be stringently monitored during pregnancy.