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

Elisabetta Patorno , Sonia Hernandez-Diaz, Krista F. Huybrechts, Rishi J. Desai, Jacqueline M. Cohen, Helen Mogun, Brian T. Bateman

Abstract

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.

Introduction

Gabapentin is a gamma-aminobutyric acid (GABA) analog with GABA agonist activity. In addition to being currently US Food and Drug Administration (FDA)-approved for the treatment of partial seizures and postherpetic neuralgia [1,2] and—in its prodrug version—restless legs syndrome [3], gabapentin is extensively used off-label for many pain conditions, including diabetic neuropathy and other neuropathic pain, fibromyalgia, postoperative pain, anxiety disorders, hot flushes, alcohol withdrawal, and tremor.

Methods

Source of data and study population

Using the MAX dataset, we collected data for 46 US states and the District of Columbia during the period January 2000 through December 2013. Montana and Connecticut were excluded because of difficulty in linking data for mothers and infants, Michigan was excluded because of incomplete data, and data from Arizona were not available. The details of the strategy used to build the study cohort have been previously reported [13]. The study population included all pregnancies resulting in live births among Medicaid-enrolled women 12 to 55 years old, who had continuous eligibility in Medicaid starting from three months prior to the estimated last menstrual period (LMP) to one month after delivery.

Discussion

In a large population-based study, we evaluated neonatal and maternal outcomes in over 4,000 women exposed to gabapentin early in pregnancy and approximately 2,000 women exposed in late pregnancy. We did not find evidence for an association between gabapentin exposure during early pregnancy and major malformations overall, though there was some evidence of a higher risk of cardiac malformations. Sensitivity analyses restricted to women that may use gabapentin more consistently suggested there may be an increased risk of cardiac malformations, and a subsequent post hoc analysis, which evaluated individual cardiac malformations, revealed a potential increase in the risk of conotruncal defects specifically. Despite the large attenuations from crude to adjusted results, maternal use of gabapentin late in pregnancy, regardless of its use early in pregnancy, remained associated with an approximately 20% to 30% increased risk of preterm birth and a 30% to 40% increased risk of SGA. We also observed a 35% increased risk in NICU admission among the offspring of women exposed to gabapentin throughout pregnancy.

Conclusions

Results from this large cohort study suggest that gabapentin exposure during early pregnancy does not appear to be associated with teratogenic effects, although a moderately higher risk of cardiac malformations—in particular, conotruncal defects—cannot be excluded. Maternal use of gabapentin, particularly late in pregnancy, was associated with a higher risk of preterm birth, SGA, and NICU admission; an association that was only partially explained by confounders. Clinicians should weigh these potential risks with the clinical benefits of using gabapentin to treat painful and disabling conditions.

Citation: Patorno E, Hernandez-Diaz S, Huybrechts KF, Desai RJ, Cohen JM, Mogun H, et al. (2020) 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. PLoS Med 17(9): e1003322. https://doi.org/10.1371/journal.pmed.1003322

Academic Editor: Sarah J. Stock, University of Edinburgh, UNITED KINGDOM

Received: September 9, 2019; Accepted: July 30, 2020; Published: September 1, 2020

Copyright: © 2020 Patorno et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: Because of the data use agreement in place, the research team cannot share the database used for the current paper, which was based on Medicaid, a joint federal and state program that helps provide healthcare coverage for people with low incomes and limited resources in the United States. Other researchers may request to gain access to the Medicaid database through the Research Data Assistance Center (ResDAC) (https://www.resdac.org/).

Funding: This study was supported by an R01 grant (R01 MH100216) from the National Institute of Mental Health. EP is supported by a career development grant K08AG055670 from the National Institute on Aging. BTB was supported by a career development grant K08HD075831 from the National Institute Of Child Health & Human Development of the National Institutes of Health. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

Competing interests: We have read the journal's policy and the authors of this manuscript have the following competing interests: EP is investigator of an investigator-initiated grant to the Brigham and Women’s Hospital from Boehringer Ingelheim, not related to the topic of the submitted work. SH-D has consulted for Boehringer-Ingelheim and UCB for unrelated topics and has worked with the AED pregnancy registry, which is funded by multiple companies. KFH, BTB, and SH-D have been investigators on grants to the Brigham and Women’s Hospital from Lilly, GSK, and Pfizer and BTB on grants from Baxalta and Pacira, unrelated to the topic of this manuscript. BTB consults for Aetion for unrelated projects and was a consultant on a postpartum hemorrhage quality improvement project sponsored by a grant from Merck for Mothers. RJD reports grants from Merck, outside the submitted work.

Abbreviations: ACE, angiotensin-converting enzyme; ARR, apparent relative risk; CI, confidence interval; FDA, United States Food and Drug Administration; GABA, gamma-aminobutyric acid; hdPS, high-dimensional propensity score; LMP, last menstrual period; MAX, United States Medicaid Analytic eXtract; NICUa, neonatal intensive care unit admission; PS, propensity score; RR, relative risk; SGA, small for gestational age; STROBE, Strengthening the Reporting of Observational Studies in Epidemiology; T1, first trimester