Pregabalin Linked to Major Birth Defects

Liam Davenport

May 24, 2016

An epilepsy medication commonly used to treat pain and psychiatric disorders may be associated with an increased risk for major birth defects, results of a multinational study suggest.

Ursula Winterfeld, PhD, from the Swiss Teratogen Information Service and Lausanne University Hospital in Switzerland, and colleagues found that pregabalin exposure during pregnancy was associated with a three-fold increase in the risk for major birth defects, with the risk even higher for central nervous system malformations.

While acknowledging that further studies are required to confirm they findings, the team concludes: "Pregabalin should only be prescribed in women of childbearing age on a valid indication and after thorough risk-benefit analysis. In patients exposed to pregabalin during pregnancy, enhanced fetal monitoring may be warranted."

The drug (Lyrica, Pfizer) is approved by the US Food and Drug Administration for epilepsy, fibromyalgia, and neuropathic pain and is used off-label for psychiatric disorders, including generalized anxiety disorder.

The research was published online on May 18 in  Neurology.

However, in an accompanying editorial, Page B. Pennell, MD, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts, and Kimford J. Meador, MD, Stanford University School of Medicine, Palo Alto, California, note that the study had several limitations.

Alongside the relatively small sample size, they say that "not only did the primary indicated neuropsychiatric diagnosis differ between the pregabalin-treated and untreated groups, as expected, but other important factors also differed, including other medical conditions, concurrent medications, gestational age at contact (earlier in the pregabalin group), and tobacco use (higher in the pregabalin group)."

Dr Pennell told Medscape Medical News that the "bottom line is that a signal of concern" over pregabalin does not necessarily mean there is a conclusive association of cause and effect between the drug and an elevated risk for birth defects.

Still, she believes that it is unlikely that the study required to demonstrate a conclusive association will ever be carried out "because the prescribing practices for pregabalin in the United States, as well as obviously the other countries that contributed to this study, is that it is prescribed in a variety of disorders, of which epilepsy is a very, very small minority."

Dr Pennell said that, as highlighted in the current study, the drug is commonly given for pain and psychiatric disorders, which are far more prevalent than epilepsy. Therefore, "women who receive pregabalin are often going to be on other medications or are often going to have other medical illnesses, and they have higher rates of smoking."

She said that these pregabalin prescribing patterns mean that the current findings are "probably the best information we're going to get" on the potential association with birth defects.

Dr Pennell noted that when physicians and health practitioners other than neurologists prescribe epilepsy medications, they may not be thinking about the risk for birth defects and the "pros and cons of a woman staying on it to treat her disease during pregnancy."

The higher rates of elective terminations seen in patients receiving pregabalin vs controls, coupled with the early medication discontinuation, "suggest that many of the pregnancies in the pregabalin group were not planned," Dr Pennell and Dr Meador note in their editorial.

Dr Pennell said that the "more important point" from the current research is therefore to let prescribers know that, just like other epilepsy medications that have a potential elevated risk of birth defects, they "need to constantly be counseling women about the need for planned pregnancies, effective birth control and then, when a pregnancy occurs, to make sure they have close follow-up, as a team with the obstetrician."

Reproductive Toxicity

Because animal studies have suggested that pregabalin has reproductive toxicity but there are few data on its use during human pregnancy, the researchers conducted a multicenter, observational prospective cohort study that collected data from Teratology Information Services in France, the United Kingdom, Italy, Finland, Switzerland, the Netherlands, and Turkey.

Information on 164 pregnancies exposed to pregabalin and 656 control pregnancies was collated. This showed that pregabalin-exposed women were significantly more likely to report tobacco use, at 44.2% vs 18.2% (P < .001) for control women, and had slightly but significantly earlier gestational age at initial contact (P = .03).

Women with pregnancies exposed to pregabalin were also slightly but significantly more likely to have undergone a previous spontaneous abortion than control women (P = .03) and were significantly more likely to have medical conditions (P < .001).

The indication for pregabalin treatment was reported in 160 women and included pain in 115 cases, psychiatric disorders in 39 cases, and epilepsy in 5 cases. Pregabalin was prescribed for restless legs syndrome in 1 case.

The median daily pregabalin dose was 150 mg. The drug was started before pregnancy in 77% of cases and was discontinued at a mean gestational age of 6 weeks. Pregabalin was continued beyond week 6 in 61% of women, and beyond week 7 in 33%. First trimester exposure to the drug occurred in 96% of women.

Major birth defects were significantly more common in pregabalin-exposed than in control pregnancies, even after exclusion of cases of chromosomal aberration syndromes, at 7 of 116 (6.0%) vs 12 of 580 (2.1%) or an odds ratio of 3.0 (P = .03). The odds ratio was unaffected by controlling for concomitant treatment with antiepileptics, benzodiazepines, and antidepressants; alcohol consumption; or twin pregnancy.

The rate of central nervous system malformations was substantially higher in pregabalin-exposed than in control pregnancies, at 4 of 125 (3.2%) vs 3 of 570 (0.55%) or an odds ratio of 6.2. Other affected organ systems included the skeletal, cardiac, and skin or vascular systems.

The risk for major birth defects was higher in pregabalin-exposed women who reported smoking than in those who did not, at odds ratios of 9.5 and 1.3, respectively. However, the difference did not reach significance (P = .08).

The team found that the rate of live births was lower in pregabalin-exposed than control pregnancies, at 71.9% vs 85.2% (P < .001). This was largely due to a higher rate of elective and medically indicated terminations, at 9.8% vs 5.0% (P = .02) and 5.5% vs 1.8% (P = .008), respectively.

Pregabalin exposure was not associated with a significantly higher risk for spontaneous abortion on Cox proportional cause-specific analysis, at a hazard ratio of 1.60 (P = .08). However, the risk for pregnancy termination remained significant, at a hazard ratio of 2.18 (P < .001).

"Although our study raises a signal for a possible increase in the risk of major birth defects after pregabalin treatment during pregnancy, these results call for further confirmation through independent studies since the sample size is insufficient and differences across groups in maternal conditions and concomitant medication exposure do not allow definitive conclusions to be drawn," the researchers conclude.

No targeted funding reported. The authors have disclosed no relevant financial relationships. Dr Pennell is funded by the National Institutes of Health (NIH; National Institute of Neurological Disorders and Stroke and National Institute of Child Health and Human Development [NICHD]) grants and has received research support from the Epilepsy Foundation and Harvard Catalyst. She has received travel support and/or honoraria from the American Epilepsy Society, American Academy of Neurology, Tbilisi State Medical University, Indian Academy of Neurology, University of Maryland, University of California–San Francisco, University of Texas Southwestern, International Association of Therapeutic Drug Monitoring and Clinical Toxicology, and the NIH. Dr Pennell serves as associate clinical editor for Epilepsy Currents. Dr Meador has received research support from the NIH (National Institute of Neurological Disorders and Stroke and NICHD) grants, the Patient-Centered Outcomes Research Institute, and UCB Pharma and travel support from UCB Pharma. The Epilepsy Study Consortium pays Dr. Meador's university for his research consultant time related to Eisai, GW Pharmaceuticals, NeuroPace, Novartis, Supernus, Upsher-Smith Laboratories, UCB Pharma, and Vivus Pharmaceuticals.

Neurology Published online May 18, 2016. Abstract Editorial

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