Gabapentin in pregnancy and the risk of adverse neonatal and maternal outcomes: A population-based cohort study nested in the US Medicaid Analytic eXtract dataset

Background Despite the widespread use, only sparse information is available on the safety of gabapentin during pregnancy. We sought to evaluate the association between gabapentin exposure during pregnancy and risk of adverse neonatal and maternal outcomes. Methods and findings Using the United States Medicaid Analytic eXtract (MAX) dataset, we conducted a population-based study of 1,753,865 Medicaid-eligible pregnancies between January 2000 and December 2013. We examined the risk of major congenital malformations and cardiac defects associated with gabapentin exposure during the first trimester (T1), and the risk of preeclampsia (PE), preterm birth (PTB), small for gestational age (SGA), and neonatal intensive care unit admission (NICUa) associated with gabapentin exposure early, late, or both early and late in pregnancy. Gabapentin-unexposed pregnancies served as the reference. We estimated relative risks (RRs) and 95% confidence intervals (CIs) using fine stratification on the propensity score (PS) to control for over 70 confounders (e.g., maternal age, race/ethnicity, indications for gabapentin, other pain conditions, hypertension, diabetes, use of opioids, and specific morphine equivalents). We identified 4,642 pregnancies exposed in T1 (mean age = 28 years; 69% white), 3,745 exposed in early pregnancy only (28 years; 67% white), 556 exposed in late pregnancy only (27 years; 60% white), and 1,275 exposed in both early and late pregnancy (29 years; 75% white). The reference group consisted of 1,744,447 unexposed pregnancies (24 years; 40% white). The adjusted RR for major malformations was 1.07 (95% CI 0.94-1.21,p= 0.33) and for cardiac defects 1.12 (0.89-1.40,p= 0.35). Requiring >= 2 gabapentin dispensings moved the RR to 1.40 (1.03-1.90,p= 0.03) for cardiac defects. There was a higher risk of preterm birth among women exposed to gabapentin either late (RR, 1.28 [1.08-1.52],p< 0.01) or both early and late in pregnancy (RR, 1.22 [1.09-1.36],p< 0.001), SGA among women exposed to gabapentin early (1.17 [1.02-1.33],p= 0.02), late (1.39 [1.01-1.91],p= 0.05), or both early and late in pregnancy (RR, 1.32 [1.08-1.60],p< 0.01), and NICU admission among women exposed to gabapentin both early and late in pregnancy (RR, 1.35 [1.20-1.52],p< 0.001). There was no higher risk of preeclampsia among women exposed to gabapentin after adjustment. Study limitations include the potential for residual confounding and exposure misclassification. Conclusions In this large population-based study, we did not find evidence for an association between gabapentin exposure during early pregnancy and major malformations overall, although there was some evidence of a higher risk of cardiac malformations. Maternal use of gabapentin, particularly late in pregnancy, was associated with a higher risk of PTB, SGA, and NICUa. Author summaryWhy was this study done? In addition to being currently US Food and Drug Administration (FDA)-approved for the treatment of partial seizures and postherpetic neuralgia, gabapentin is extensively used off-label for many conditions, including neuropathic pain, fibromyalgia, anxiety, and tremor. Despite the increasing number of patients receiving gabapentin prescriptions, little information is available on the safety of this medication during pregnancy. We therefore evaluated the association between the use of gabapentin exposure during pregnancy and the risk of a range of neonatal and maternal outcomes. What did the researchers do and find? We conducted a large population-based cohort study and used several strategies to minimize potential confounding and misclassification of the exposure and the outcome. We did not find evidence of an association between gabapentin exposure during the first trimester (T1) of pregnancy and major malformations overall, although there was some evidence of a higher risk of cardiac malformations. There was a higher risk of preterm birth, small for gestational age (SGA), and neonatal intensive care unit admission (NICUa) among women exposed to gabapentin, particularly in late pregnancy. What do these findings mean? Pregnant women and their physicians should weigh the benefits of treatment with gabapentin with the risks of potential adverse pregnancy outcomes associated with its use.