ARTICLE IN BRIEF
Investigators reported a significant increase in the risk of major birth defects after first trimester exposure to pregabalin.
Pregnant women who took pregabalin in one multicenter, prospective study had infants with a higher rate of major birth defects than a group of matched control subjects not taking an antiepileptic medication, according to a study published in the May 18 online edition of Neurology.
Most of the women — 96 percent — were exposed to pregabalin during their first trimester of pregnancy, and were taking it for relief of pain (73 percent for migraine and neuropathic pain), psychiatric disorders (45.1 percent, with some overlap with pain disorders), and epilepsy (3 percent).
While animal studies have suggested reproductive toxicity for pregabalin with skeletal malformations, neural tube defects, and other abnormalities, data on pregabalin use during human pregnancy are scarce, the study authors noted.
But based on the current findings, the study authors recommended avoiding any unnecessary exposure of pregabalin during pregnancy.
“Our findings raise a signal for a significant increase in the risk of major birth defects after first trimester exposure to pregabalin, which will have to be replicated in other studies,” said the lead study author Ursula Winterfeld, PhD, a clinical pharmacologist in the department of clinical pharmacology at the Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland. “In the meanwhile, we recommend thoroughly reconsidering the indications to expose potentially childbearing women to this medication.”
Researchers from eight participating Teratology Information Services in France, the United Kingdom, Italy, Finland, Switzerland, the Netherlands, and Turkey gathered data on maternal characteristics and medication exposure as well as birth outcomes on 164 women who took pregabalin during pregnancy and 656 women who did not take any antiepileptic drug between 2004 and 2014.
The median daily pregabalin dose taken by patients was 150 mg. Seventy-seven percent of the patients started pregabalin before pregnancy and discontinued the medication at a median gestational age of six weeks, and 33 percent stopped the medication after the seven-week mark.
In the pregabalin group, 22 (13 percent) patients were also treated with another antiepileptic drug.
Examining medication exposure during the first trimester of pregnancy separately and excluding chromosomal aberration syndromes, researchers found a significantly higher rate of major birth defects in women taking pregabalin during pregnancy than those in the control group — seven out of 116 or 6 percent compared with 12 out of 580 or 2.1 percent; OR 3.0, 95 percent CI (1.2-7.9, p=0.03).
When researchers limited analysis to 19 patients who took pregabalin monotherapy during the first trimester of pregnancy and compared them to the control group, the association with major birth defects remained significant — three out of 19 or 15.8 percent compared with 16 of 573 or 2.8 percent; OR 6.5, 95 percent CI 1.7-24.7, p=0.02 — but became non-significant after exclusion of chromosomal or genetic anomalies.
The birth defects in the pregabalin group included one infant also exposed to another antiepileptic medication who developed with multiple cardiac defects. The study authors noted that in this case, pregabalin exposure occurred beyond the critical period for cardiac birth defects, however. Other major birth defects in the pregabalin-exposed group included four chromosomal and eight structural anomalies distributed in the central nervous system (n=4), skeletal system (n=2), heart (n=2), and skin or vascular system (n=1).
When compared to controls, the risk for major birth defects was higher in pregabalin-treated patients who reported smoking during pregnancy (OR 9.5, 95 percent CI 1.9-46.9) than in patients who did not smoke (OR 1.3, 95 percent CI 0.3-6.0).
Among other findings, the rate of live births was lower in the pregabalin group, mostly due to a higher rate of both elective and medical pregnancy terminations — 71.9 percent versus 85.2 percent, p<0.001), mostly due to a higher rate of both elective (9.8 percent versus 5 percent, p=0.02) and medically-indicated pregnancy terminations (5.5 percent versus 1.8 percent, p=0.008). Pregabalin exposure significantly increased the risk for pregnancy termination (HR 2.81, 95 percent CI 1.60-4.93, p=0.001). The rate of CNS malformations in the pregabalin group was higher than in the control group (3.2 percent compared with 0.5 percent, OR 6.2, 95 percent CI 1.4-28.3, p=0.02).
“However, given that pregabalin is a centrally acting agent, the possibility that these findings may signal a teratogenic effect in humans needs to be considered,” the study authors wrote. “Our data are too scarce to establish whether a distinct phenotype might characterize pregabalin-induced CNS changes, and the cerebral ventricle enlargement reported in all four cases can still represent a fortuitous association.”
The study authors pointed out that in the four cases of malformations (in the pregabalin-exposed group), the infants had also been exposed to additional medications that resulted in more complicated medical conditions, and genetic causes for the malformations have not been formally investigated.
For instance, one infant exposed to pregabalin in utero was also exposed to paroxetine and citalopram, and was diagnosed with an atrial septal defect.
Study authors acknowledged some limitations of the study design. Among them, they cited the absence of a control group treated for similar conditions, a disease-matched control group, small sample size, and limited data on folate use and on prior pregnancy complications, among other factors.
They concluded, however, that “pregabalin should only be prescribed in women of childbearing age on a valid indication and after [a] thorough risk-benefit analysis. In patients exposed to pregabalin during pregnancy, enhanced fetal monitoring may be warranted.”
In an accompanying editorial, Page B. Pennell, MD, professor of neurology at Harvard Medical School and director of research in the division of epilepsy and women's health at Brigham and Women's Hospital, and Kimford J. Meador, MD, FAAN, professor of neurology and neurosciences at Stanford University, and clinical director of the Stanford Comprehensive Epilepsy Center, noted that it is not always possible to “clearly distinguish the effects of one medication from concomitant medications, maternal disease, or associated behaviors.”
In an interview with Neurology Today, Dr. Pennell pointed to important differences between the pregabalin-treated and untreated controls, including primary indicated neuropsychiatric diagnoses, other medical conditions, and concurrent medications. For instance, while 45 percent of the women taking pregabalin reported a psychiatric condition, just 18.6 percent of the control group did. The small sample size further limits study inferences, she said. The small sample size further limits study inferences, she noted.
However, the study reflects the typical, real-world prescribing pattern for pregabalin, Dr. Pennell said. “This is the reality of how this type of medication is prescribed, the diagnoses of the patients to which it's prescribed, disease comorbidity, risk factors that go along with the disease, and what types of concurrent medications these patients are taking.”
Dr. Pennell pointed out that such complex factors do not make for easy attribution of direct cause and effect when it comes to pregabalin and major birth defects.
“What we can take away from this study is that we need to not only think about birth control and planned pregnancy for our patients, but also when we have patients who present to us pregnant on these medications, we need to have them monitored early by an obstetrician,” she noted. In cases where there may be a malformation identified early, doctors can work with the pregnant patient to offer therapeutic options, including obtaining a neonatal treatment plan for the fetus-at-risk, Dr. Pennell added.
In the meanwhile, both the study authors and the authors of the editorial agreed that more and better-designed studies need to explore the finding of a significant signal for major birth defects in pregnant women taking pregabalin.