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Does Pregabalin Raise the Risk of Birth Defects?

June 14, 2016
A new study reports evidence that women taking pregabalin during their first trimester of pregnancy are at increased risk of major birth defects.

Interview with Ursula Winterfeld, PhD, and comments by Steven Danehy, a media relation representative for Pfizer

The therapeutic benefits of pregabalin (Lyrica, other) are numerous for a variety of patient conditions.1 An antiepileptic commonly used to treat neuropathic pain, fibromyalgia, seizures, and anxiety disorders, pregabalin has also been used in the treatment of restless leg syndrome and some psychiatric conditions.2

Before pregnancy, women should discuss the risks versus benefits of taking pregabalin. Result of new study raises concerns about an increased risk of birth defects with the use of the agent.

However, little research has explored the safety of pregabalin for pregnant women, and now, new data suggests doctors should consider careful fetal monitoring of pregnant patients taking the drug, as there may be a possible increased risk of birth defects.3

In the new study, a group of researchers collected data from 164 pregnancies in which patients were exposed to pregabalin during their first trimester. Compared to the 656 controls, women exposed to pregabalin during pregnancy showed a higher major birth defect (MBD) rate and a lower rate of live births, primarily due to elective and medically-indicated pregnancy terminations.3

“To our knowledge, this prospective observational study reporting on pregnancy outcomes after in utero exposure to pregabalin is the largest report published yet,” the authors noted. Because of the results of the research, it may raise a cautionary signal about the possible dangers of women ingesting pregabalin during the course of a pregnancy.

While there are some important caveats to consider about the results of this new study, the possibility of pregabalin being toxic to the reproductive process is not an entirely novel notion. Some notable past animal studies have found evidence suggesting pregabalin to be toxic to in utero development.4-7 Studies have documented birth defects, including:

  • Skeletal malformations
  • Neural tube defects
  • Growth retardation
  • Behavioral anomalies
  • Increased rates of spontaneous abortions

However, data in humans has been scant. A recent database study of 30 pregabalin exposures documented a major malformation observed in 1 infant.8 Such findings are limited by the small sample size. But similar concerns have been expressed over gabapentin, another anticonvulsant agent that has been associated with an increased risk of low birth weight and preterm births in women exposed during pregnancy.9

Ursula Winterfeld, PhD, lead author the new study, noticed a scarcity of research into pregabalin while researching the drug as part of the European Network of Teratology Information Services (ENTIS), a resource for patients and doctors providing information on drug-drug interactions and drug safety. Typically, ENTIS research aims to provide reassuring evidence of a drug’s known safety. “This why we did not necessarily expect these study results, even though other antiepileptic drugs have been shown to be teratogenic,” Dr. Winterfeld told Practical Pain Management.

Pregabalin Found Associated with Birth Malformations

In new multicenter study, researchers culled patient data using ENTIS from patients based mostly in Northern and Western European countries, including the United Kingdom, France, Italy, Finland, Switzerland, the Netherlands, and Turkey. The researchers assessed the patient’s maternal characteristics, such as history of tobacco and alcohol use, medical and obstetrical records, and previous and current medication exposure.

Certain patient cases of note were excluded from the study, including any exposure during pregnancy to some kind of major teratogen or fetotoxicant or treatment for malignancy. The researchers also refrained from calculating minor or total birth defect rates, given the fact that minor birth defects are oftentimes underreported.

Researchers found that of the 164 women exposed to pregabalin during pregnancy, 98% were being treated for pain, mostly neuropathic pain (n=115), with a median daily pregabalin dose of 150 mg (range: 75-300). Seventy-seven percent of the patients had been taking pregabalin before pregnancy and subsequently discontinued use at a median gestational age of 6 weeks (range: 5-11).

“Altogether, MBD were reported more frequently in pregnancies exposed to pregabalin than in the control group," noted the researchers. This persisted even when the researchers excluded chromosomal aberration syndromes, and cases of exposure during the first trimester were analyzed separately (7/116 [6.0%] vs. 12/580 [2.1%]; P=0.03).

“The rate of live births was lower in the pregabalin group, primarily due to a higher rate of both elective and medical pregnancy terminations. The crude spontaneous abortion rate was also higher in the pregabalin group.” In a Cox model, exposure to pregabalin appeared to significantly increase the risk for pregnancy termination (HR 2.81, 95% CI 1.60-4.93, P< 0.001), the authors reported.

Limitations of the Study

Given the results of the study, the researchers concluded that “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," including a detailed morphological ultrasound examination. “In patients of childbearing age, effective contraception should be advised when prescribing pregabalin, and its indication must be carefully re-examined in cases of desired or established unexpected pregnancy,” Dr. Winterfeld told Practical Pain Management.

While the possible genetic causes behind these birth complications have not been explored, it is possible pregabalin, a centrally acting agent, could be signaling teratogenic effects in humans. And although it is difficult to establish a phenotype to help characterize possible pregabalin-induced central nervous system (CNS) changes, the cerebral ventricle enlargement found in all 4 cases of CNS malformations reported could be a “fortuitous association,” the authors noted.

However, there are still significant caveats to consider about the study. For instance, MBD risk was higher in pregabalin-treated patients who reported smoking during pregnancy, compared to those who did not smoke. According to Steven Danehy, a media relations representative for Pfizer, a manufacturer of Lyrica, such limitations like smoking and medication use should be considered.

“As the authors agree, the study has significant limitations and cannot be used to draw definitive conclusions. The study was small, did not account for other medical conditions or medications, and the women taking Lyrica had higher rates of smoking and diabetes, all of which can negatively affect pregnancy outcomes,” Mr. Danehy said.

However, the odds ratios of birth defects between smoking and nonsmoking pregabalin patients did not actually reach statistical significance. Also, despite the fact that 13% of pregabalin patients were taking a concomitant antiepileptic drug, only 1 infant in this context presented with an MBD. There was also no difference in the daily pregabalin doses of mothers of fetuses with structural anomalies compared to mothers of healthy children (113 mg compared with 150 mg, P=0.9), seemingly ruling out a possible dose-dependent effect.

Indeed, the study authors concluded that while the data raises an important cautionary signal about the possible dangers of pregabalin use in pregnant patients, there is now a need for independent studies with competent sample sizes to further explore this notion. “In general, the results of studies should be included in regularly updated drug labeling. Even though we’re still not certain, the possibility of a teratogenic action of pregabalin in humans needs to be taken seriously right now,” Dr. Winterfeld said.

Considering many pregnancies are unplanned, and given the widespread use of pregabalin for various conditions, patients can be at risk of inadvertent exposure to the drug during the early stages of pregnancy. So while the study may raise more questions than it answers, it may open the door to the discussion of the safety of anticonvulsant mono- and polytherapy for women, especially during early pregnancy.

There was no targeted funding reported for this study. The authors of the study reported no relevant conflicts of interest to the study manuscript. For full disclosure information, go to neurology.org.

Last updated on: June 28, 2016
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