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

doi:10.1371/journal.pmed.1003322

. 2020 Sep 1;17(9):e1003322. doi: 10.1371/journal.pmed.1003322

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 ^1,^*, Sonia Hernandez-Diaz ², Krista F Huybrechts ¹, Rishi J Desai ¹, Jacqueline M Cohen ², Helen Mogun ¹, Brian T Bateman ^1,³

Editor: Sarah J Stock⁴

¹Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America

²Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America

³Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, United States of America

⁴University of Edinburgh, UNITED KINGDOM

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.

^✉

* E-mail: epatorno@bwh.harvard.edu

Roles

Elisabetta Patorno: Conceptualization, Formal analysis, Investigation, Methodology, Project administration, Supervision, Writing – original draft, Writing – review & editing

Sonia Hernandez-Diaz: Conceptualization, Formal analysis, Funding acquisition, Investigation, Supervision, Writing – original draft, Writing – review & editing

Krista F Huybrechts: Conceptualization, Formal analysis, Funding acquisition, Investigation, Supervision, Writing – original draft, Writing – review & editing

Rishi J Desai: Formal analysis, Investigation, Writing – review & editing

Jacqueline M Cohen: Formal analysis, Investigation, Writing – review & editing

Helen Mogun: Formal analysis, Investigation, Writing – review & editing

Brian T Bateman: Conceptualization, Formal analysis, Investigation, Methodology, Project administration, Supervision, Writing – original draft, Writing – review & editing

Sarah J Stock: Academic Editor

PMCID: PMC7462308 PMID: 32870921

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.

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.

In a cohort study of pregnant women included in the US Medicaid Analytic eXtract (MAX) dataset, Elisabetta Patorno and colleagues investigate neonatal and maternal outcomes associated with gabapentin exposure during pregnancy.

Author summary

Why 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.

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.

Despite the large number of patients receiving gabapentin prescriptions, only sparse information is available on the safety of this medication during pregnancy. The available information on the occurrence of major malformations in the offspring of mothers exposed to gabapentin early in pregnancy appears to rule out large increases in risk, although available studies included small numbers of gabapentin-exposed pregnancies and therefore were not well powered to identify potential smaller teratogenic effects [4–11]. Even fewer data are available on the association between gabapentin and other neonatal or maternal outcomes. Preliminary signals of a potential increase in the risk of selected adverse outcomes, including preterm birth [4, 9, 11], small for gestational age (SGA) [9,11], and admission to the neonatal intensive care unit (NICUa) [9], have been documented, although studies were small and largely did not account for confounding.

Because of the increasing use of gabapentin in many settings of care and the limited information on its safety in pregnancy, there is a critical need for evidence to help pregnant women or women of childbearing age and their healthcare providers to balance the risks and benefits of gabapentin treatment with regard to pregnancy-related outcomes.

To provide evidence on the safety of gabapentin use in pregnancy, we conducted a large cohort study of pregnant women within the US Medicaid Analytic eXtract (MAX) [12] and assessed a range of neonatal and maternal outcomes.

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. The date of LMP was estimated based on the date of delivery combined with diagnostic codes for preterm delivery, using a validated algorithm [14]. Continuous Medicaid eligibility was also required among the linked infants for a minimum of three months after birth, unless they died, in which case a shorter eligibility period was allowed. Pregnancies with a documented chromosomal abnormality and pregnancies with exposure to acknowledged teratogenic agents during the first trimester (T1) were excluded (Fig 1). A description of our planned analyses is included in the supplemental material (S1 text). This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 STROBE Checklist).

Exposure definition

We created four different exposure groups to match the potentially etiologically relevant exposure windows for the outcomes of interest. T1 exposure was defined as pregnancies with at least one filled prescription for gabapentin during the first 90 days of pregnancy (starting from the date of LMP), independently of exposure to gabapentin later in pregnancy. Exposure early in pregnancy was defined as at least one gabapentin dispensing in the first 140 days of pregnancy and no dispensing between the 141st and 245th days. Exposure late in pregnancy was defined as at least one gabapentin dispensing between the 141st and 245th days of pregnancy and no dispensings in the first 140 days. Exposure both early and late in pregnancy was defined as at least one gabapentin dispensing in the first 140 days of pregnancy and at least one dispensing between the 141st and 245th days. For all exposure groups, the reference group consisted of pregnancies with no gabapentin dispensings from 3 months before the start of pregnancy, in order not to misclassify as unexposed women who still had medications from an earlier dispensing available at the start of pregnancy, through the date of delivery.

Outcomes

For T1 exposure to gabapentin, the primary outcome was the presence of a major congenital malformation in the infant, defined on the basis of inpatient or outpatient ICD-9 diagnostic and procedural codes in the maternal (first month after delivery) [15] or infant (first three months after birth) records. Secondary outcomes included cardiac malformations, the most common malformation type [16]. Other malformations were evaluated as exploratory outcomes (see S1 Table for detailed information on specific outcome definitions).

For gabapentin exposure in early, late, and both early and late pregnancy, we evaluated preeclampsia, preterm birth, SGA, and NICU admission (see S2 Table for specific definitions). For the definition of preeclampsia, preterm birth, and SGA, we used previously validated definitions [16,17].

Covariates

We considered a large number of potential confounders: maternal age at delivery, race/ethnicity, year of delivery, Medicaid eligibility group, multiple gestation, indications for gabapentin (e.g., epilepsy or seizure, neuropathic pain), other pain conditions, psychiatric disorders, other medical conditions, smoking and other lifestyle factors, concomitant use of medications (e.g., opioids and specific morphine equivalents, other anticonvulsant medications, angiotensin-converting enzyme [ACE] inhibitors), and indicators of disease burden, including the Obstetric Comorbidity Index [18] and measures of healthcare utilization [19] (see S3 Table for a complete list). Race or ethnicity was considered to represent a potentially important confounding factor and was categorized based on information submitted to the Centers for Medicare & Medicaid Services by individual states. For the primary analyses, we measured maternal comorbidities and concomitant medication use during the 3 months before pregnancy through the end of T1. Information deriving from T1 was included in the definition of these covariates, because information on existing medical conditions, which are not expected to be causal intermediates between gabapentin exposure and pregnancy complications, has more opportunity to be recorded during T1 due to the routine checks and examinations related to a new pregnancy. Measures of healthcare intensity (e.g., number of medical visits) were measured only during the 3-month period before pregnancy, in order for these not to be affected by early awareness of possible pregnancy complications.

Primary analysis

For each exposure group, we defined the prevalence of covariates by exposure group and used standardized differences to evaluate covariate balance between the exposed pregnancies and the reference group [20]. Absolute risks of outcomes and unadjusted risk ratios (RRs) with 95% confidence interval (CI) were calculated. Separately for each exposure group, we estimated propensity scores (PSs) in logistic regression models as the predicted probability of receiving gabapentin conditional upon the previously described covariates. We trimmed the population whose PS fell within the nonoverlapping areas of the PS distributions, and created 50 PS strata according to the distribution of the exposed pregnancies [21]. Due to the large overlap in the PS distribution of gabapentin exposed and unexposed women, all exposed women across the four exposure groups, except for one exposed to gabapentin late in pregnancy, were retained in the analysis after trimming (see S1, S2, S3 and S4 Figs). We calculated weights for the reference group of unexposed pregnancies on the basis of the distribution of the exposed in PS strata and estimated adjusted RR and 95% CI in generalized linear models. We tested the use of the robust variance estimator to account for correlations within women with multiple pregnancies and found it did not appreciably change Cis; thus, we did not include correlation structures in the analyses.

For all analyses presented, results were described as similar to or different from the reference group based on the magnitude of the point estimates, taking into account the precision of each estimate as reflected in the width of its 95% CI. We focused on estimating magnitude of effects in preference to dichotomizing the results as statistically significant or not [22]. Specifically, we judged estimates to be similar to or different from the reference group by three criteria: (1) the strength of the adjusted RR (regardless of whether the 95% CI includes the null), (2) the degree to which the upper bound of the 95% CI indicates low compatibility between the data and a strong adverse effect (i.e., the upper bound of the CI excludes a large increase in the risk of the adverse outcome of concern), and (3) the consistency of the effect estimates across the sensitivity analyses that we conducted. Interpretation of the effect estimates by clinicians and patients to help inform treatment decisions during pregnancy will vary, depending on perceived benefits of treatment, the severity of the adverse outcome, and what is known about the safety of therapeutic alternatives.

Sensitivity analyses

We conducted several sensitivity analyses to assess the robustness of our findings. First, in order to reduce the potential for exposure misclassification, we updated the exposure definition as filling ≥2 gabapentin prescriptions during each of the previously specified periods of interest, with the assumption that filling multiple prescriptions would increase the likelihood that gabapentin was actually taken or taken more consistently. Second, to ensure that maternal malformations were not being erroneously attributed to the offspring, and thus reduce the chances of outcome misclassification, we redefined the outcome of major malformations using infant claims only and extended infant follow-up to 1 year for infants continuously eligible for Medicaid for ≥1 year. Third, to reduce potential residual confounding due to channeling bias, (1) we used high-dimensional propensity score (hdPS), which enriched the original PS with 100 additional empirically identified covariates [23,24], and (2) we conducted analyses restricted to pregnancies among subgroups of women with either indication of epilepsy or seizures or indication of pain. Fourth, for exposure to gabapentin early, late, and both early and late in pregnancy, to ensure that potential confounders beyond the end of T1 were captured and accounted for, we updated the covariate assessment period by measuring maternal comorbidities, concomitant medication, and healthcare intensity from LMP through the first 140 days of pregnancy. Fifth, to assess the presence of a potential dose-response relationship for gabapentin, we examined the risk of outcomes according to tertiles of the first and the highest prescribed daily dose filled during the specific exposure period of interest. Sixth, for the malformation outcome, as we only included live births in our study cohort, we examined the potential impact of differences in the proportion of terminations among women exposed to gabapentin versus those unexposed on the primary PS-adjusted estimate [25]. Seventh, as maternal smoking has been identified as an important predictor of preterm birth [26], SGA [27], and preeclampsia [28] and is not completely captured in claims data, we quantified the potential impact of residual confounding by smoking on preterm birth, SGA, and preeclampsia in a bias analysis. This quantified the impact of varying the imbalance in the prevalence of maternal smoking between gabapentin-exposed and unexposed pregnancies [29].

Ethics statement

The research was approved by the Institutional Review Board of Brigham and Women’s Hospital. The Institutional Review Board granted a waiver of informed consent (IRB 2013P001741).

Results

Study cohort and patient characteristics

Overall, 1,753,865 pregnancies met the inclusion criteria. Among these, 4,642 (0.26%) were exposed to gabapentin during T1, 3,745 (0.21%) were exposed to gabapentin early in pregnancy only (during the first 140 days), 556 (0.03%) were exposed late in pregnancy but not early, and 1,275 (0.07%) were exposed in both early and late pregnancy (Fig 1).

Across all exposure groups, women exposed to gabapentin were older, more frequently white, and had more frequently recorded diagnoses of neuropathic and non-neuropathic pain conditions, epilepsy or seizures, and psychiatric disorders, compared with unexposed pregnancies. They had a higher prevalence of hypertension and diabetes and were more likely smokers. They were more frequently users of other anticonvulsant medications, opioids and other pain agents, and psychotropic medications and were characterized by a more pronounced overall burden of disease (Tables 1 and S3). Across all exposure groups, characteristics were well balanced between pregnancies exposed and unexposed to gabapentin after PS adjustment, as evaluated by absolute standardized differences <0.1 [20] (Tables 1 and S4).

Table 1. Selected baseline characteristics of gabapentin-exposed and unexposed women before PS adjustment, with standardized differences before and after PS adjustment.

Baseline characteristics	Reference: Unexposed (N = 1,744,447)	Exposed during T1 (N = 4,642)	St. Diff. before PS adjustment	St. Diff after PS adjustment	Exposed early in pregnancy (N = 3,745)	St. Diff. before PS adjustment	St. Diff after PS adjustment	Exposed late in pregnancy (N = 556)	St. Diff. before PS adjustment	St. Diff after PS adjustment	Exposed early and late in pregnancy (N = 1,275)	St. Diff. before PS adjustment	St. Diff after PS adjustment
Age at delivery, mean (SD)	24.3 (5.8)	28.4 (6.0)	0.69	0.00	28.1 (6.1)	0.64	0.00	27.2 (5.8)	0.50	0.00	28.9 (5.8)	0.79	0.01
Race/ethnicity, N (%)
White	698,670 (40.1)	3,210 (69.2)	0.61	−0.05	2,492 (66.5)	0.55	−0.04	334 (60.1)	0.41	−0.02	961 (75.4)	0.77	−0.05
Black	569,089 (32.6)	615 (13.3)	−0.47	0.03	561 (15.0)	−0.42	0.03	116 (20.9)	−0.27	0.01	125 (9.8)	−0.58	0.04
Hispanic	250,779 (14.4)	317 (6.8)	−0.25	0.02	294 (7.9)	−0.21	0.02	55 (9.9)	−0.14	0.01	53 (4.2)	−0.36	0.03
Other¹	225,909 (13.0)	500 (10.8)	−0.07	0.01	398 (10.6)	−0.07	0.01	51 (9.2)	−0.12	0.01	136 (10.7)	−0.07	0.02
Multiple gestation, N (%)	59,636 (3.4)	219 (4.7)	0.07	0.00	177 (4.7)	0.07	0.00	34 (6.1)	0.13	−0.01	59 (4.6)	0.06	0.00
Labeled indications, N (%)
Epilepsy or seizures	11,861 (0.7)	347 (7.5)	0.35	0.02	193 (5.2)	0.27	0.02	36 (6.5)	0.32	0.06	179 (14.0)	0.53	0.06
Neuropathic pain	21,701 (1.2)	1,116 (24.0)	0.73	0.08	918 (24.5)	0.74	0.08	65 (11.7)	0.43	0.04	264 (20.7)	0.65	0.05
Restless legs syndrome	345 (0.0)	37 (0.8)	0.12	0.03	24 (0.6)	0.11	0.02	<11	0.05	0.01	15 (1.2)	0.15	0.04
Pain conditions, N (%)
Fibromyalgia	14,545 (0.8)	397 (8.6)	0.37	0.04	332 (8.9)	0.38	0.04	35 (6.3)	0.30	0.03	91 (7.1)	0.33	0.02
Arthritis, arthropathies, and musculoskeletal pain	146,564 (8.4)	1,862 (40.1)	0.80	0.01	1,518 (40.5)	0.81	0.01	169 (30.4)	0.58	0.00	482 (37.8)	0.74	0.00
Back and neck pain	135,116 (7.8)	2,099 (45.2)	0.94	0.00	1,681 (44.9)	0.93	0.00	162 (29.1)	0.57	0.00	567 (44.5)	0.92	−0.01
Migraine or headache	124,860 (7.2)	1,194 (25.7)	0.52	−0.01	975 (26.0)	0.52	−0.01	111 (20.0)	0.38	0.00	313 (24.6)	0.49	0.00
Psychiatric conditions, N (%)
Depression	106,658 (6.1)	1,261 (27.2)	0.59	−0.02	1,013 (27.1)	0.59	−0.02	98 (17.6)	0.36	0.00	336 (26.4)	0.57	−0.02
Bipolar disorder	21,146 (1.2)	573 (12.3)	0.45	0.02	434 (11.6)	0.43	0.02	42 (7.6)	0.31	0.03	174 (13.7)	0.49	0.03
Anxiety	64,514 (3.7)	1,047 (22.6)	0.58	0.00	798 (21.3)	0.55	0.00	87 (15.7)	0.41	0.02	332 (26.0)	0.66	0.00
Other maternal conditions, N (%)
Hypertension	39,100 (2.2)	419 (9.0)	0.30	0.01	318 (8.5)	0.28	0.00	40 (7.2)	0.24	0.00	132 (10.4)	0.34	0.02
Diabetes	27,469 (1.6)	370 (8.0)	0.30	0.00	295 (7.9)	0.30	0.00	28 (5.0)	0.19	0.00	104 (8.2)	0.31	0.01
Concomitant use of medications, N (%)
Opioids and opioid-related treatment in T1
Codeine	54,340 (3.1)	418 (9.0)	0.25	−0.02	351 (9.4)	0.26	−0.02	44 (7.9)	0.21	−0.03	100 (7.8)	0.21	−0.02
Hydrocodone	99,899 (5.7)	1,505 (32.4)	0.72	−0.01	1,195 (31.9)	0.71	−0.01	159 (28.6)	0.64	−0.03	442 (34.7)	0.77	−0.02
Oxycodone	20,474 (1.2)	642 (13.8)	0.49	0.04	503 (13.4)	0.48	0.04	59 (10.6)	0.41	0.02	202 (15.8)	0.54	0.03
Morphine equivalents, mg, mean (SD)	50.6 (544.4)	1,064.4 (2,662.4)	0.53	0.06	978.3 (2,532.6)	0.51	0.06	732.2 (2,228.5)	0.42	0.03	1,395.5 (3,128.5)	0.60	0.05
Anticonvulsants in T1
Carbamazepine	1,671 (0.1)	74 (1.6)	0.16	0.01	29 (0.8)	0.10	0.00	<11	0.06	0.01	51 (4.0)	0.28	0.04
Phenytoin	1,484 (0.1)	55 (1.2)	0.14	0.01	31 (0.8)	0.11	0.01	<11	0.12	0.02	26 (2.0)	0.19	0.02
Topiramate	3,342 (0.2)	158 (3.4)	0.24	0.03	122 (3.3)	0.24	0.03	<11	0.08	0.00	47 (3.7)	0.26	0.02
Valproate	3,007 (0.2)	87 (1.9)	0.17	0.00	53 (1.4)	0.14	0.00	<11	0.13	0.02	39 (3.1)	0.23	0.01
Other anticonvulsants	8,030 (0.5)	288 (6.2)	0.32	0.02	205 (5.5)	0.30	0.03	20 (3.6)	0.22	0.03	104 (8.2)	0.39	0.03
Markers of burden of disease
Obstetric Comorbidity Index², mean (SD)	0.8 (1.4)	1.7 (2.0)	0.52	0.01	1.6 (1.9)	0.48	0.01	1.6 (1.8)	0.45	−0.01	1.9 (2.1)	0.60	0.02
Number of distinct filled prescriptions, mean (SD)	1.7 (2.4)	6.1 (4.4)	1.23	−0.02	5.9 (4.3)	1.20	−0.03	4.5 (4.1)	0.82	−0.02	6.3 (4.5)	1.26	0.00
Number of outpatient physician visits, mean (SD)	2.1 (3.5)	6.2 (7.4)	0.70	0.04	6.1 (7.5)	0.69	0.04	4.7 (6.9)	0.47	0.05	6.0 (6.7)	0.72	0.01
Patients hospitalized, N (%)	62,587 (3.6)	305 (6.6)	0.14	0.02	235 (6.3)	0.12	0.02	33 (5.9)	0.11	0.02	91 (7.1)	0.16	0.02
Number of emergency room visits, mean (SD)	0.3 (0.9)	0.9 (1.7)	0.45	−0.02	0.9 (1.7)	0.45	−0.02	0.8 (1.5)	0.38	−0.02	0.9 (1.6)	0.46	−0.02

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Maternal comorbidities and concomitant medication use were measured during the 3 months before pregnancy through the end of T1. Measures of healthcare intensity (e.g., number of medical visits) were measured only during the 3-month period before pregnancy, in order for these not to be affected by early awareness of possible pregnancy complications.

¹Other race includes Asian, Native American, Other, and Unknown.

²The Obstetric Comorbidity Index predicts severe maternal morbidity. The range for the maternal comorbidity index is 0 to 45, with lower values associated with lower burden of maternal illness and higher values associated with higher burden of maternal illness [18].

In accordance with the data use agreement, we do not report information for frequency cells with less than 11 cases. These are noted as <11.

Abbreviations: PS, propensity score; SD, standard deviation; St. Diff., standardized differences, i.e., the difference in means or proportions divided by the pooled standard deviation [20]; T1, first trimester

Absolute and relative risks of neonatal and maternal outcomes

The prevalence of overall major congenital and cardiac malformations was 5.0 and 1.9 per 100 live births, respectively, among pregnancies exposed to gabapentin during T1, and 3.3 and 1.1 per 100 among unexposed pregnancies (Table 2). In unadjusted analyses, gabapentin was associated with a higher risk of both overall and cardiac malformations (RR, 1.49 [95% CI 1.31–1.69, p < 0.001]; RR, 1.77 [1.43–2.18], p < 0.001, respectively) compared to unexposed pregnancies. After PS adjustment, the RR were 1.07 (0.94–1.21, p = 0.33), and 1.12 (0.89–1.40, p = 0.35), respectively.

Table 2. Absolute and relative risk of neonatal and maternal outcomes associated with exposure to gabapentin compared with unexposed pregnancies.

Exposure group	Unexposed	Exposed during T1	Exposed early in pregnancy	Exposed late in pregnancy	Exposed early and late in pregnancy
Total	1,744,447	4,642	3,745	556	1,275
Outcomes
Major congenital malformations
Events	58,086	230	.	.	.
Risk/100 births	3.3	5.0	.	.	.
Unadjusted RR (95% CI), p-value	Ref.	1.49 (1.31–1.69), <0.001	.	.	.
PS-adjusted RR (95% CI), p-value	Ref.	1.07 (0.94–1.21), 0.33	.	.	.
Cardiac malformations
Events	18,514	87	.	.	.
Risk/100 births	1.1	1.9	.	.	.
Unadjusted RR (95% CI), p-value	Ref.	1.77 (1.43–2.18), <0.001	.	.	.
PS-adjusted RR (95% CI), p-value	Ref.	1.12 (0.89–1.40), 0.35	.	.	.
Preeclampsia
Events	72,197	.	182	33	80
Risk/100 births	4.1	.	4.9	5.9	6.3
Unadjusted RR (95% CI), p-value	Ref.	.	1.17 (1.01–1.35), 0.03	1.43 (1.03–2.00), 0.03	1.52 (1.23–1.87), <0.001
PS-adjusted RR (95% CI), p-value	Ref.	.	0.87 (0.75–1.00), 0.05	0.96 (0.69–1.33), 0.80	0.92 (0.74–1.13), 0.42
Preterm delivery
Events	182,445	.	571	107	258
Risk/100 births	10.5	.	15.2	19.2	20.2
Unadjusted RR (95% CI), p-value	Ref.	.	1.46 (1.35–1.57), <0.001	1.84 (1.55–2.18), <0.001	1.93 (1.73–2.16), <0.001
PS-adjusted RR (95% CI), p-value	Ref.	.	1.00 (0.93–1.08), 0.89	1.28 (1.08–1.52), <0.01	1.22 (1.09–1.36), <0.001
SGA
Events	55,803	.	205	35	92
Risk/100 births	3.2	.	5.5	6.3	7.2
Unadjusted RR (95% CI), p-value	Ref.	.	1.71 (1.50–1.96), <0.001	1.97 (1.43–2.71), <0.001	2.26 (1.85–2.75), <0.001
PS-adjusted RR (95% CI), p-value	Ref.	.	1.17 (1.02–1.33), 0.02	1.39 (1.01–1.91), 0.05	1.32 (1.08–1.60), <0.01
NICU admission
Events	101,202	.	411	68	224
Risk/100 births	5.8	.	11.0	12.2	17.6
Unadjusted RR (95% CI), p-value	Ref.	.	1.89 (1.73–2.07), <0.001	2.11 (1.69–2.63), <0.001	3.03 (2.69–3.41), <0.001
PS-adjusted RR (95% CI), p-value	Ref.	.	1.01 (0.93–1.11), 0.77	1.21 (0.97–1.51), 0.09	1.35 (1.20–1.52), <0.001

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Abbreviations: CI, confidence interval; NICU, neonatal intensive care unit; PS, propensity score; Ref., reference; RR, risk ratio; SGA, small for gestational age; T1, first trimester

Among pregnancies exposed to gabapentin in early, late, and both early and late pregnancy, the prevalence of the other outcomes was 4.9, 5.9, and 6.3 per 100 live births, respectively, for preeclampsia (compared to 4.1 per 100 among unexposed pregnancies), 15.2, 19.2, and 20.2 per 100 live births for preterm birth (compared to 10.5 per 100 among unexposed), 6.1, 6.8, and 7.6 per 100 live births for SGA (compared to 4.9 per 100 among unexposed), and 11.0, 12.2, and 17.6 per 100 live births for NICU admission (compared to 5.8 per 100 among unexposed). Before PS adjustment, gabapentin was associated with an higher risk of preeclampsia (RR, 1.17 [1.01–1.35], p = 0.03 for early exposure; RR, 1.43 [1.03–2.00], p = 0.03 for late exposure; RR, 1.52 [1.23–1.87], p < 0.001 for early and late exposure), preterm birth (RR, 1.46 [1.35–1.57], p < 0.001 for early exposure; RR, 1.84 [1.55–2.18], p < 0.001 for late exposure; RR, 1.93 [1.73–2.16], p < 0.001 for early and late exposure), SGA (RR, 1.71 [1.50–1.96], p < 0.001 for early exposure; RR, 1.97 [1.43–2.71], p < 0.001 for late exposure; RR, 2.26 [1.85–2.75], p < 0.001 for early and late exposure), and NICU admission (RR, 1.89 [1.73–2.07], p < 0.001 for early exposure; RR, 2.11 [1.69–2.63], p < 0.001 for late exposure; RR, 3.03 [2.69–3.41], p < 0.001 for early and late exposure). In PS-adjusted analyses, there was no increase in risk of preeclampsia, regardless of the timing of the gabapentin exposure during pregnancy (RR, 0.87 [0.75–1.00], p = 0.05 for early exposure; RR, 0.96 [0.69–1.33], p = 0.80 for late exposure; RR, 0.92 [0.74–1.13], p = 0.42 for early and late exposure). Conversely, the risks remained elevated for 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], for SGA among women exposed to gabapentin early (RR, 1.17 [1.02–1.33], p = 0.02), late (RR, 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 for NICU admission among women exposed to gabapentin both early and late in pregnancy (RR, 1.35 [1.20–1.52], p<0.001).

Sensitivity, secondary, and post hoc analyses

Sensitivity and subgroup analyses were largely consistent with the main findings before and after PS adjustment (Tables 3 and S5). After PS adjustment, there was a consistent increase in the risk of preterm birth, SGA, and NICUa associated with gabapentin exposure either late or both early and late in pregnancy, and no increase in risk of overall major malformations or preeclampsia (Table 3). In a few instances, point estimates, although consistent in magnitude and direction of the association, had less precise CIs due to the smaller sample size in analyses restricted to subsets of the gabapentin-exposed population, particularly for women with late exposure only. Of note, the risk of cardiac malformations in pregnancies exposed to gabapentin during T1 was increased when we redefined the exposure based on ≥2 filled prescriptions (RR, 1.40 [1.03–1.90], p = 0.03) and in a post hoc analysis with hdPS adjustment (RR, 1.40 [1.03–1.90], p = 0.03), and remained apparently elevated, with a wider CI, in a subgroup analysis that was restricted to patients with a recorded diagnosis of epilepsy or seizures (RR, 1.40 [0.73–2.71], p = 0.31). An additional post hoc analysis, which evaluated specific types of cardiac malformations, revealed an increased risk for conotruncal defects (RR, 1.99 [1.03–3.82], p = 0.04] (S6 Table), which persisted in analyses that were restricted to pregnant women that filled ≥2 prescriptions, redefined the outcome using infant claims only, and with hdPS adjustment. Elevated but imprecisely estimated risks were also observed for left-sided defects and other cardiac defects. Elevated point estimates were observed for central nervous system defects, ear anomalies, and noncardiac vascular defects, albeit with wide CIs (S7 Table). Analyses based on tertiles of the first or the highest gabapentin prescribed daily dose filled during the specific exposure period of interest did not reveal dose-response relations for any of the examined outcomes (S8 Table). After accounting for potential differences in the probability of termination of malformed fetuses among exposed and unexposed women, the range of plausible RRs for major overall malformations estimated for pregnancies exposed to gabapentin during T1 was 1.09 to 1.17 (S5 Fig). Finally, quantification of the bias associated with potential residual imbalances in maternal smoking between exposed and unexposed pregnancies revealed that adjusted RRs of preterm birth, SGA, and preeclampsia for gabapentin exposure either late in pregnancy or both early and late in pregnancy were fairly robust even under extreme scenarios that assumed maternal smoking prevalence to be up to 2.5-fold higher among gabapentin-exposed compared with unexposed pregnancies (Fig 2).

Table 3. Sensitivity and secondary analyses for the RRs of neonatal and maternal outcomes associated with exposure to gabapentin compared with unexposed pregnancies after PS adjustment.

Exposure group	Unexposed	Exposed during T1		Exposed early in pregnancy		Exposed late in pregnancy		Exposed early and late in pregnancy
Outcomes		PS-adjusted RR (95% CI)	p-Value	PS-adjusted RR (95% CI)	p-Value	PS-adjusted RR (95% CI)	p-Value	PS-adjusted RR (95% CI)	p-Value
Major congenital malformations
Main PS-adjusted analysis	Ref.	1.07 (0.94–1.21)	0.33	.		.		.
≥2 Rx	Ref.	1.15 (0.95–1.39)	0.15	.		.		.
Infant claims	Ref.	1.05 (0.92–1.20)	0.48	.		.		.
1-year follow-up¹	Ref.	1.05 (0.94–1.18)	0.37
hdPS-adjusted	Ref.	1.06 (0.93–1.20)	0.40	.		.		.
≥1 epilepsy or seizure dx	Ref.	1.01 (0.66–1.56)	0.96	.		.		.
No epilepsy or seizure dx	Ref.	1.07 (0.93–1.22)	0.35	.		.		.
≥1 pain dx²	Ref.	1.06 (0.91–1.22)	0.48	.		.		.
No pain dx	Ref.	1.14 (0.87–1.49)	0.33	.		.		.
Cardiac malformations
Main PS-adjusted analysis	Ref.	1.12 (0.89–1.40)	0.35	.		.		.
≥2 Rx	Ref.	1.40 (1.03–1.90)	0.03	.		.		.
Infant claims	Ref.	1.13 (0.89–1.44)	0.33	.		.		.
1-year follow-up¹	Ref.	1.10 (0.92–1.53)	0.41
hdPS-adjusted	Ref.	1.11 (0.88–1.40)	0.37	.		.		.
hdPS-adjusted, ≥2 Rx³	Ref.	1.40 (1.03–1.90)	0.03	.		.		.
≥1 epilepsy or seizure dx	Ref.	1.40 (0.73–2.71)	0.31	.		.		.
No epilepsy or seizure dx	Ref.	1.08 (0.84–1.38)	0.56	.		.		.
≥1 pain dx²	Ref.	1.07 (0.82–1.40)	0.61	.		.		.
No pain dx	Ref.	1.32 (0.84–2.06)	0.23	.		.		.
Preeclampsia
Main PS-adjusted analysis	Ref.	.		0.87 (0.75–1.00)	0.05	0.96 (0.69–1.33)	0.80	0.92 (0.74–1.13)	0.42
≥2 Rx	Ref.	.		0.98 (0.78–1.23)	0.88	1.17 (0.64–2.14)	0.60	0.87 (0.67–1.14)	0.32
hdPS-adjusted	Ref.	.		0.86 (0.75–1.00)	0.05	0.96 (0.69–1.33)	0.78	1.00 (0.80–1.25)	0.99
Updated CAP⁴	Ref.			0.88 (0.76–1.02)	0.08	0.98 (0.70–1.36)	0.89	0.93 (0.75–1.15)	0.51
≥1 epilepsy or seizure dx	Ref.	.		0.74 (0.39–1.41)	0.37	1.43 (0.37–5.46)	0.60	0.82 (0.46–1.46)	0.49
No epilepsy or seizure dx	Ref.	.		0.88 (0.76–1.01)	0.08	0.96 (0.68–1.35)	0.82	0.96 (0.76–1.20)	0.71
≥1 pain dx²	Ref.	.		0.91 (0.77–1.06)	0.23	0.83 (0.52–1.31)	0.42	0.94 (0.74–1.19)	0.61
No pain dx	Ref.	.		0.74 (0.54–1.02)	0.06	1.18 (0.74–1.89)	0.49	0.84 (0.51–1.38)	0.49
Preterm delivery
Main PS-adjusted analysis	Ref.	.		1.00 (0.93–1.08)	0.89	1.28 (1.08–1.52)	<0.01	1.22 (1.09–1.36)	<0.001
≥2 Rx	Ref.	.		0.98 (0.86–1.12)	0.81	1.27 (0.93–1.74)	0.14	1.28 (1.12–1.46)	<0.001
hdPS-adjusted	Ref.	.		1.01 (0.93–1.08)	0.89	1.25 (1.06–1.49)	<0.01	1.22 (1.08–1.37)	<0.01
Updated CAP⁴	Ref.			0.99 (0.92–1.06)	0.74	1.24 (1.04–1.47)	0.01	1.20 (1.08–1.34)	<0.01
≥1 epilepsy or seizure dx	Ref.	.		1.07 (0.81–1.42)	0.62	1.14 (0.51–2.51)	0.75	1.47 (1.13–1.91)	<0.01
No epilepsy or seizure dx	Ref.	.		1.00 (0.93–1.08)	0.94	1.30 (1.09–1.55)	<0.01	1.20 (1.06–1.35)	<0.01
≥1 pain dx²	Ref.	.		0.96 (0.88–1.04)	0.32	1.24 (1.00–1.54)	0.05	1.22 (1.08–1.38)	<0.01
No pain dx	Ref.	.		1.15 (0.99–1.34)	0.07	1.33 (1.01–1.75)	0.05	1.19 (0.92–1.54)	0.17
SGA
Main PS-adjusted analysis	Ref.	.		1.17 (1.02–1.33)	0.02	1.39 (1.01–1.91)	0.05	1.32 (1.08–1.60)	<0.01
≥2 Rx	Ref.	.		1.15 (0.92–1.45)	0.22	1.35 (0.74–2.46)	0.33	1.28 (1.00–1.63)	0.05
hdPS-adjusted	Ref.	.		1.17 (1.02–1.33)	0.02	1.36 (0.99–1.88)	0.06	1.39 (1.12–1.72)	<0.01
Updated CAP⁴	Ref.	.		1.15 (1.01–1.32)	0.04	1.36 (0.99–1.88)	0.06	1.31 (1.08–1.60)	<0.01
≥1 epilepsy or seizure dx	Ref.	.		1.35 (0.83–2.20)	0.23	1.03 (0.15–7.10)	0.98	1.46 (0.89–2.38)	0.13
No epilepsy or seizure dx	Ref.	.		1.17 (1.01–1.34)	0.03	1.46 (1.05–2.02)	0.02	1.30 (1.05–1.62)	0.02
≥1 pain dx²	Ref.	.		1.16 (1.00–1.35)	0.05	1.33 (0.88–2.01)	0.18	1.29 (1.04–1.61)	0.02
No pain dx	Ref.	.		1.14 (0.85–1.51)	0.39	1.44 (0.86–2.39)	0.16	1.32 (0.84–2.07)	0.22
NICU admission
Main PS-adjusted analysis	Ref.	.		1.01 (0.93–1.11)	0.77	1.21 (0.97–1.51)	0.09	1.35 (1.20–1.52)	<0.001
≥2 Rx	Ref.	.		1.08 (0.93–1.25)	0.31	1.00 (0.64–1.57)	0.99	1.43 (1.24–1.65)	<0.001
hdPS-adjusted	Ref.	.		1.01 (0.92–1.11)	0.80	1.19 (0.95–1.49)	0.12	1.31 (1.15–1.50)	<0.001
Updated CAP⁴	Ref.	.		1.00 (0.91–1.09)	0.95	1.16 (0.93–1.45)	0.18	1.33 (1.18–1.50)	<0.001
≥1 epilepsy or seizure dx	Ref.	.		0.68 (0.42–1.11)	0.16	0.31 (0.05–2.15)	0.24	1.18 (0.83–1.68)	0.35
No epilepsy or seizure dx	Ref.	.		1.04 (0.95–1.14)	0.43	1.29 (1.03–1.61)	0.03	1.38 (1.22–1.56)	<0.001
≥1 pain dx²	Ref.	.		0.95 (0.86–1.06)	0.38	1.13 (0.85–1.50)	0.41	1.30 (1.13–1.48)	<0.001
No pain dx	Ref.	.		1.18 (0.99–1.42)	0.07	1.33 (0.94–1.90)	0.11	1.56 (1.21–2.01)	<0.001

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¹Restricted to infants continuously eligible for ≥1 year.

²Includes neuropathic pain, fibromyalgia, arthritis, arthropathies and musculoskeletal pain, back and neck pain, migraine or headache, osteoarthritis, rheumatoid arthritis, or other pain.

³Post hoc analysis.

⁴CAP measured from the LMP through the first 140 days of pregnancy.

Abbreviations: CAP, covariate assessment period; CI, confidence interval; dx, diagnosis; hdPS, high-dimensional propensity score; LMP, last menstrual period; NICU, neonatal intensive care unit; PS, propensity score; Ref., reference; RR, risk ratio; Rx, filled prescription; SGA, small for gestational age; T1, first trimester

Fig 2 — Bias analysis quantifying the impact on point estimates of increasing residual differences in the prevalence of maternal smoking between unexposed and gabapentin-exposed women either late (A, C, E) or both early and late in pregnancy (B, D, F). ARR, apparent relative risk; P_C1, prevalence of maternal smoking among exposed women; RR, relative risk; SGA, small for gestational age

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.

Our results confirm the findings from previous studies, which excluded large increases in the risk of major malformations associated with maternal use of gabapentin [4,5,7–10]. However, these studies assessed the risk of major malformations in small populations, which included between 31 and 223 gabapentin-exposed pregnancies, mostly among women with epilepsy, and reported rather imprecise RR estimates (ranging from 0.3 to 1.8 for the use of gabapentin) [5,7–10]. Our study population, which included 4,642 pregnancies exposed to gabapentin during T1 and was not limited to women with epilepsy, allowed us to rule out meaningful increases in the risk of overall major malformations among pregnancies exposed to gabapentin during T1 with higher precision, while permitting to identify a potential moderate increase in the risk of cardiac malformations among women that may use gabapentin more consistently. The specific association observed between gabapentin and conotruncal defects has not been previously reported and should be confirmed or refuted in future investigations.

Our results are also consistent with the limited prior research on the association of gabapentin with other pregnancy-related outcomes. The European Gabapentin Registry study found that among 39 women exposed to gabapentin during pregnancy, the frequency of maternal complications, including eclampsia and SGA, were similar to those observed in the general population, although the frequency of preterm birth was elevated (22.7% versus 11.8%) [4]. A cohort study comparing 223 gabapentin-exposed pregnancies with 223 pregnancies exposed to a nonteratogenic substance described a higher frequency of preterm births (10.5% versus 3.9%), low birth weight (10.5% versus 4.4%), and NICU admission (38% versus 2.9%), but not SGA [9]. Finally, a small population-based study in Italy comparing 11 newborns exposed to gabapentin during pregnancy to unexposed pregnancies found that gabapentin exposure was associated with increased risk of preterm birth (OR = 7.37, 95% CI 1.87–30.54) and SGA (OR = 5.14, 95% CI 1.10–20.23) [11]. The careful adjustment for over 70 potential confounders that was implemented in our study, including detailed accounting for maternal use, timing, and dose of opioids, may explain the reduced magnitude of the associations compared to previous studies, and the large attenuation from our crude to PS-adjusted results, in particular for NICU admission.

This study has limitations. First, certain important patient characteristics (e.g., lifestyle factors and severity of comorbidities) may not be fully captured in claims databases, and this could cause residual confounding that may explain the increased risk for preterm birth, SGA, and NICU admission observed for gabapentin, particularly when used late in pregnancy. However, (1) additional analyses aimed at mitigating possible residual confounding, i.e., hdPS-adjustment, the restriction to women with either epilepsy/seizures or pain indications, and the extension of the covariate assessment period through the first 140 days of pregnancy, produced results consistent with the main analyses; and (2) an analysis that quantified the potential bias associated with a strong risk factor for preterm birth, SGA, and preeclampsia (protective), revealed that adjusted results were fairly robust even under extreme scenarios of imbalance of maternal smoking prevalence between exposed and unexposed pregnancies. Second, although claims databases include detailed data on filled medications, they do not include information on their actual use by patients, which could lead to drug exposure misclassification. To limit this possibility, in sensitivity analyses we updated the definition of exposure as filling ≥2 gabapentin prescriptions during each of the previously specified periods of interest; these analyses largely confirmed the main findings. Third, the identification of outcomes in claims databases may be affected by outcome misclassification. To reduce this possibility, we used either validated or highly specific definitions of the outcomes [16,17]. We also redefined the malformation outcomes using infant claims only and extended follow-up to 1 year for infants continuously eligible for ≥1 year, which confirmed the primary results. Fourth, because we restricted our study population to live births, spontaneous abortions or therapeutic terminations due to congenital malformations diagnosed early in pregnancy remain unobserved. It has been previously documented that planned terminations may be approximately 10% higher among gabapentin users [9]. A bias analysis, which quantified the potential impact of such missed terminations, suggested that a corrected RR estimate for overall malformations would range between 1.09 and 1.17 depending on the selection probability among the unexposed. Fifth, in the context of multiple analyses, the possibility of a chance finding should be taken into consideration. Finally, our study population included only women who had continuous eligibility in Medicaid starting from three months prior to the estimated LMP to one month after delivery. This may have resulted in the selection of a more disadvantaged subpopulation within Medicaid, mostly composed of low-income adults, multiparae, and women with disabilities, as previously shown [30]. The characteristics of this population of pregnant women, i.e., young, racially diverse, with a high burden of disabilities, are not expected to affect the biological relations evaluated in this study. Therefore, our findings should generalize to other populations.

Our results add to the current understanding of the safety of gabapentin prenatal use and provide pregnant women with pain conditions and epilepsy and their providers with important information, which can guide clinical decisions during pregnancy. Our findings also suggest that pregnant women using gabapentin during pregnancy may be considered for targeted interventions to monitor for and promptly respond to the potential adverse outcomes associated with the use of this agent.

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.

Supporting information

S1 Table. Definitions for congenital malformations.

(DOCX)

Click here for additional data file.^{(40.6KB, docx)}

S2 Table. Definitions for preeclampsia, preterm birth, SGA, and NICUa.

NICUa, neonatal intensive care unit admission; SGA, small for gestational age.

(DOCX)

Click here for additional data file.^{(37.2KB, docx)}

S3 Table. Baseline characteristics of gabapentin-exposed and unexposed women, before PS adjustment.

PS, propensity score.

(DOCX)

Click here for additional data file.^{(72.6KB, docx)}

S4 Table. Baseline characteristics of gabapentin-exposed and unexposed women, after PS adjustment.

PS, propensity score.

(DOCX)

Click here for additional data file.^{(81.7KB, docx)}

S5 Table. Sensitivity and secondary analyses for the RR of neonatal and maternal outcomes associated with exposure to gabapentin compared with unexposed pregnancies before and after PS adjustment.

PS, propensity score; RR, relative risk.

(DOCX)

Click here for additional data file.^{(68.2KB, docx)}

S6 Table. Post hoc analyses for the RR of specific types of cardiac malformations associated with exposure to gabapentin during T1 compared with unexposed pregnancies.

RR, relative risk; T1, first trimester.

(DOCX)

Click here for additional data file.^{(43.9KB, docx)}

S7 Table. Sensitivity and secondary analyses for the RR of individual noncardiac major malformation groups associated with exposure to gabapentin compared with unexposed pregnancies.

RR, relative risk.

(DOCX)

Click here for additional data file.^{(43.9KB, docx)}

S8 Table. RR of cardiac malformations comparing gabapentin-exposed to unexposed women, stratified by dose tertiles of the first and the highest prescription filled during each exposure period of interest.

RR, relative risk.

(DOCX)

Click here for additional data file.^{(50.3KB, docx)}

S1 Fig. PS distributions of gabapentin-exposed and unexposed women during the T1, after PS trimming and weighting.

PS, propensity score; T1, first trimester.

(TIF)

Click here for additional data file.^{(262.3KB, tif)}

S2 Fig. PS distributions of gabapentin-exposed and unexposed women early in pregnancy, after PS trimming and weighting.

PS, propensity score.

(TIF)

Click here for additional data file.^{(128.9KB, tif)}

S3 Fig. PS distributions of gabapentin-exposed and unexposed women late in pregnancy, after PS trimming and weighting.

PS, propensity score.

(TIF)

Click here for additional data file.^{(105.3KB, tif)}

S4 Fig. PS distributions of gabapentin-exposed and unexposed women early and late in pregnancy, after PS trimming and weighting.

PS, propensity score.

(TIF)

Click here for additional data file.^{(119.4KB, tif)}

S5 Fig. Corrected RR for the association between gabapentin exposure during the T1 and major malformations.

RR, relative risk; T1, first trimester.

(TIF)

Click here for additional data file.^{(97.6KB, tif)}

S1 Text. Planned analyses.

(DOCX)

Click here for additional data file.^{(43.8KB, docx)}

S1 STROBE Checklist. STROBE, Strengthening the Reporting of Observational Studies in Epidemiology.

(DOCX)

Click here for additional data file.^{(45.9KB, docx)}

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

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 Statement

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.

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PLoS Med. doi: 10.1371/journal.pmed.1003322.r001

Decision Letter 0

Caitlin Moyer

30 Jan 2020

Dear Dr. Patorno,

Thank you very much for submitting your manuscript "Gabapentin in Pregnancy and the Risk of Neonatal and Maternal Outcomes" (PMEDICINE-D-19-03278) for consideration at PLOS Medicine.

Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

In addition, we request that you upload any figures associated with your paper as individual TIF or EPS files with 300dpi resolution at resubmission; please read our figure guidelines for more information on our requirements: http://journals.plos.org/plosmedicine/s/figures. While revising your submission, please upload your figure files to the PACE digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at PLOSMedicine@plos.org.

We expect to receive your revised manuscript by Feb 13 2020 11:59PM. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

We ask every co-author listed on the manuscript to fill in a contributing author statement, making sure to declare all competing interests. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. If new competing interests are declared later in the revision process, this may also hold up the submission. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. You can see our competing interests policy here: http://journals.plos.org/plosmedicine/s/competing-interests.

Please use the following link to submit the revised manuscript:

https://www.editorialmanager.com/pmedicine/

Your article can be found in the "Submissions Needing Revision" folder.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see http://journals.plos.org/plosmedicine/s/submission-guidelines#loc-methods.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

We look forward to receiving your revised manuscript.

Sincerely,

Adya Misra

Senior Editor

PLOS Medicine

On behalf of

Caitlin Moyer, Ph.D.

Associate Editor

PLOS Medicine

plosmedicine.org

-----------------------------------------------------------

Requests from the editors:

1.Data Availability Statement: Thank you for your willingness to include all relevant data within the manuscript and supporting information files. As noted by reviewer 3, the data are not present in their entirety. Please modify your statement for the data used in your study:

a) If the data are freely or publicly available, note this and state the location of the data: within the paper, in Supporting Information files, or in a public repository (include the DOI or accession number).

b) If the data are owned by a third party but freely available upon request, please note this and state the owner of the data set and contact information for data requests (web or email address). Note that a study author cannot be the contact person for the data.

c) If the data are not freely available, please describe briefly the ethical, legal, or contractual restriction that prevents you from sharing it. Please also include an appropriate contact (web or email address) for inquiries (again, this cannot be a study author).

2. Prospective Analysis Plan: Did your study have a prospective protocol or analysis plan? Please state this (either way) early in the Methods section.

a) If a prospective analysis plan (from your funding proposal, IRB or other ethics committee submission, study protocol, or other planning document written before analyzing the data) was used in designing the study, please include the relevant prospectively written document with your revised manuscript as a Supporting Information file to be published alongside your study, and cite it in the Methods section. A legend for this file should be included at the end of your manuscript.

b) If no such document exists, please make sure that the Methods section transparently describes when analyses were planned, and when/why any data-driven changes to analyses took place.

c) In either case, changes in the analysis—including those made in response to peer review comments—should be identified as such in the Methods section of the paper, with rationale

3. Title: Please revise your title according to PLOS Medicine's style. Your title must be nondeclarative and not a question. It should begin with main concept if possible. "Effect of" should be used only if causality can be inferred, i.e., for an RCT. Please place the study design ("A randomized controlled trial," "A retrospective study," "A modelling study," etc.) in the subtitle (ie, after a colon).

4. Abstract: Please structure your abstract using the PLOS Medicine headings (Background, Methods and Findings, Conclusions).

5. Abstract: Please include the study design, population and setting, years during which the study took place,and length of follow up.

6. Abstract: Methods and Findings: Please list some examples of the 70 confounders most critical to the study.

7. Abstract: Methods and Findings: Of the 1,753,865: please also clarify numbers for the unexposed (reference) group.

8. Abstract: Methods and Findings: For all results quantified regarding risk associated with exposure, please present both the 95% CIs and p values.

9. Abstract: Methods and Findings: Please clarify if results presented are for those exposed both early and late in pregnancy, or if these are combined effects of early and late gabapentin exposure on PTB, SGA, and NICUa, and if so, please present separate results for early vs. late exposure (with 95% CIs and p values).

10. Abstract: Methods and Findings: In the last sentence of the Abstract Methods and Findings section, please describe the main limitation(s) of the study's methodology.

11. Abstract: Conclusions: Please address the study implications without overreaching what can be concluded from the data; the phrase "In this study, we observed ..." may be useful.

12. Author Summary: At this stage, we ask that you include a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract. Please see our author guidelines for more information: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary

13. Methods: Thank you for your note (1st paragraph under “Source of Data and Study Population”) that the details of building the study cohort were previously published. Please however provide some relevant details, in particular which US states were not represented, and the fact that LMP was estimated (and how) as it seems like this could potentially impact interpretations regarding pregnancy timepoints.

14. Methods: How was race/ethnicity defined and by whom? Why was race/ethnicity considered important in this study and what it is believed to represent?

15. Methods: Sensitivity analyses: In the first scenario, you restrict analyses to greater or equal to two gabapentin prescriptions filled during each period to reduce the potential for exposure misclassification. Can you please clarify what is meant by exposure misclassification more explicitly? In the discussion, the interpretation is that such individuals may use gabapentin more consistently.

16. Results: Please note the comment from Reviewer 3 regarding the presentation of the unadjusted results in the text. If presenting both, please consistently describe the adjusted or unadjusted in the text for all outcomes. In the tables, please present both the unadjusted and PS-adjusted results for all measures.

17. Results: As also alluded to by a reviewer, please revise the final sentence of the first paragraph under “Absolute and relative risks of neonatal and maternal outcomes” to: “The relative risks were no longer statistically significant after PS adjustment…”

18. Results: For relative risks associated with all congenital and cardiac malformations, please provide both the 95% CIs and p values associated.

19. Results: In the second paragraph under “Absolute and relative risks of neonatal and maternal outcomes”: please revise to “In PS-adjusted analyses, there was no statistically significant increase in risk of preeclampsia regardless…” Please also present the risk with 95% CIs and p values associated. For associations with preterm birth, small for gestational age, and NICU admissions, please also present the p values for the PS-adjusted findings.

20. Results: Under “Sensitivity, secondary and post-hoc analyses”, please remove the word meaningful and revise the sentence to read: “No significant associations between gabapentin exposure and individual non-cardiac malformations were identified, and elevated point estimates observed for central nervous system defects, ear anomalies, and non-cardiac vascular defects were not statistically significant (eTable6).”

21. Discussion: Please clarify or remove the word “meaningful” from the following sentence (second paragraph, on page 12): “...allowed us to rule out meaningful increases in the risk of overall major malformations among pregnancies exposed to gabapentin during the first trimester with higher precision…”

22. Discussion: Please present and organize the Discussion as follows: a short, clear summary of the article's findings; what the study adds to existing research and where and why the results may differ from previous research; strengths and limitations of the study; implications and next steps for research, clinical practice, and/or public policy; one-paragraph conclusion. Specifically, a discussion of implications and next steps relevant for clinical practice is missing.

23. Conclusions: Please revise the first sentence of the conclusion to temper the implications that can be drawn, we suggest: “Results from this study suggest that gabapentin exposure during early pregnancy does not appear to be associated with teratogenic effects.” or similar.

24. Tables: Tables should be numbered 1-3 rather than 1, 3, and 4.

25. Table 1: Please define the abbreviation for “SD” in the legend.

26. Table 3: Please define abbreviation for T1. Please provide p values in addition to 95% CIs for all outcomes.

27. Table 4: Please define abbreviations for T1, Rx, dx. Please provide p values in addition to 95% CIs for all outcomes. Please also provide the unadjusted results.

28. Figure 2: Please define Pc0.

29. eTable3, eTable4: Please define abbreviation for SD.

30. eTable5: Please define “2 Rx” in the legend. Please provide p values in addition to 95% CIs.

31.eTable6: Please define “2 Rx” and T1 in the legend. Please provide p values in addition to 95% CIs.

32. eTable 7: Please define “T1” in the legend. Please provide p values in addition to 95% CIs. Please also provide the results of the unadjusted analyses.

33. eFigure1: Please define the abbreviation for “RR” in the legend.

34. References: Please use square brackets for in-text citations, like this: [1]. Please use the "Vancouver" style for reference list formatting, and see our website for other reference guidelines: https://journals.plos.org/plosmedicine/s/submission-guidelines#loc-references

35. Checklist: Please ensure that the study is reported according to the STROBE guideline, and include the completed STROBE checklist as Supporting Information. When completing the checklist, please use section and paragraph numbers, rather than page numbers. Please add the following statement, or similar, to the Methods: "This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 Checklist)."

Comments from the reviewers:

Reviewer #1: Thank you very much for allowing me to review this article on the use of Gabapentin in Pregnancy and the Risk of Neonatal and Maternal Outcomes. This is an important topic where safety information is lacking to support clinical management and policy decision making. The article is well written and the approach well reported thereby aiding transparency that is commendable. Please find my comments below for consideration that mainly relate to the methods and results section.

1) "Continuous Medicaid eligibility was also required among the linked infants for a minimum of three months after birth".

Could the authors describe why 3 months following birth was chosen to ascertain outcomes in neonates. Because there is an increased risk of pre-term birth with gabapentin-exposed patients meaning the period for outcome detection in infants born at term will be 40 weeks +12 weeks compared to e.g. pre-term 36 weeks +12 weeks, what is the possibility of differential outcome ascertainment of congenital anomalies in offspring? Is there an increased likelihood for example of detecting a cardiac defect if offspring are more likely to be admitted to the NICU etc.?

2) "Pregnancies with exposure to acknowledged teratogenic agents during the first trimester were excluded"

A minor point but there is a risk in misunderstanding this sentence as meaning the exclusion of all teratogenic agents. I suggest clarifying that certain teratogens were still included but handled differently (i.e. some anticonvulsants).

3) The first trimester is defined as the first 90 days of pregnancy. Exposure early in pregnancy is defined as the first 140 days of pregnancy. By definition all exposed individuals in the first trimester should appear in the exposure early in pregnancy cohort (the latter of which is likely to be the larger of the two). The results however, report the number of exposed patients in the first trimester as 4,642 and the number of patients exposed early in pregnancy as 3,745, which seems implausible if I have correctly understood the proposed definition. Please could the authors clarify.

4) A minor point but for clarity in the covariates section of the methods I would add in brackets what indications for gabapentin are included.

5) It is quite common that some lifestyle information is missing in electronic databases. Was there any missing data on smoking and lifestyle information? If so, how was this handled?

6) "For the primary analyses, we measured maternal comorbidities and concomitant medication use during the 3 months before pregnancy through the end of the first trimester."

Data on maternal comorbidities and concomitant medication were used to estimate the propensity for treatment with gabapentin. However, the propensity score is a subject's probability of treatment, conditional on observed baseline covariates. Including covariate information up to the end of the first trimester means post-baseline data can be used to estimate the propensity score. In many instances gabapentin may have been prescribed before or early in pregnancy it is possible that this population may have more baseline covariate information. What proportion of covariate information included in estimating the propensity score was present at the start of pregnancy between the groups and how might this affect the propensity score distributions? Could the authors discuss potential bias implications in using this approach?

7) "We trimmed the population whose PS fell within the non-overlapping areas of the PS distributions, and created 50 PS-strata according to the distribution of the exposed pregnancies."

Could a figure demonstrating the degree of overlap in the PS distributions be reported to help better understand how generalizable the findings may be?

8) The article reports some statistically significant associations between the use of gabapentin and cardiac malformations. The study also evaluates the risk of maternal outcomes using a cohort consisting of exposed late in pregnancy. Given this cohort of exposed late in pregnancy has already been established could the authors consider using it to test for potential residual confounding in the association with cardiac malformations if gabapentin exposure late in pregnancy may act as a negative control?

9) It may be interesting to examine whether the association with preterm delivery is consistent or varies by the main indications (i.e. epilepsy vs. chronic pain) in case the associated problems with chronic pain and its management influence the timing of delivery.

Reviewer #2: This paper tackles an extremely important issue, as the use of gabapentin during pregnancy has increased dramatically over recent years.

This is an excellent paper examining if gabapentin exposure during pregnancy increases the risk of neonatal maternal outcomes. The methodology is well thought out, with many additional sensitivy analyses included to confirm their results and is very carefully described in the paper. I really enjoyed reading this paper and can think of no imporvemens to it. It is an exceptional piece of work.

Reviewer #3: This study of the risks associated with gabapentin use during pregnancy is based on a retrospective analysis of a large claims database and on propensity score stratification to control for confounders when comparing women exposed vs not exposed to gabapentin. I found the methods appropriate and well described including a range of sensible sensitivity analyses. I also found the discussion and conclusion well written and reflecting the uncertainty due to potential residual confounding and multiplicity. I only have minor comments, mostly aimed at clarifying the presentation, listed below:

* Please indicate the design of the study in the title. For example: "Gabapentin in Pregnancy and the Risk of Neonatal and Maternal Outcomes: A Propensity-Matched retrospective Cohort Study"

* The data statement suggests that all data necessary to replicate the analysis is available without restriction; however, this does not seem to be the case. Only aggregate results are available in the supplement but not raw data. Given the nature of the data (US Claims data), I suspect that the authors would not have the authority to make the raw data available. This needs to be clarified.

* First trimester (T1) exposure (90 days) and early pregnancy exposure (first 140 days) appear very similar and I wonder whether we need them both. Is it mainly because early pregnancy exposure excludes exposures after day 140 while T1 exposure does not exclude exposure after Day 90. Please confirm and clarify the rationale.

* Please also clarify why exposure is limited to Day 245 and not later. In general, I would like to better understand the rationale for the different cutoffs chosen to define the exposure periods.

* Given how closely the exposure periods overlap, please clarify for selecting different outcomes for T1 exposure vs early pregnancy exposure.

* For the baseline characteristics listed in Table 1, eTable 3 and eTable 4, please clarify the corresponding measuring period when not clear i.e. in particular, please indicate whether the characteristic is measured before the pregnancy and, if so, the length of the "recall" period (e.g. in the 3 months preceding pregnancy) or during pregnancy or both. I note that this is quite well defined in the methods; however, adding details to the tables themselves might help.

* In the results, I would suggest not reporting the unadjusted results as we know that before PS adjustments, the groups are very different and the comparisons potentially misleading. I am not sure I would include unadjusted results in the tables unless the goal is to demonstrate the importance of adjusting.

* Results section, absolute and relative risks of neonatal and maternal outcomes: In the sentence "The relative risks were no longer meaningfully elevated after PS adjustment [RR, 1.07 (0.94-1.21); RR, 1.12 (0.89-1.40)]." I would suggest changing the wording to "statistically significant" instead of "meaningfully elevated" and clarify what PS "adjustment" mean by using more specific terminology e.g. "PS stratification and weighting".

* Table 4 includes many numbers, which makes it difficult to identify patterns (e.g. significant or inconsistent results). I would suggest using a forest plot instead of a table. This applies to some of the tables in the supplement too.

* Please consider including plots showing the propensity score distribution before adjustment in the supplement.

* When looking at the effect of gabapentin according to dose tertiles, please clarify whether each tertile has been separately adjusted using a new propensity score. To allow each tertile to be compared to the unexposed group, I would expect that a separate propensity score be calculated for each tertile as the propensity is likely to change as the dose increase. Please confirm that this is the approach used. An potential alternative to study a dose-response relationship is to perform an analysis according to tertiles of the propensity score itself.

* Is it possible to add confidence bands to Figure 2 and eFigure 1?

* Please include the STROBE checklist as well as the statistical analysis plan in the supplement.

-Laurent Billot

Reviewer #4: General comments

The authors present a large register-based study on the use of gabapentin in pregnancy and risk of congenital malformations and other important pregnancy and neonatal outcomes.

This author group has strong and well-documented credentials with the field as witnessed by this manuscript. The study is compelling in its scope, execution and reporting. This manuscript substantially advances knowledge on the use of gabapentin in pregnancy and provide much needed decision support to physicians and pregnant women.

That being said, there are some minor issues that I believe should be clarified, justified and discussed prior to publication.

Specific comments

Introduction

Short sharp and to the point. The sentence "As gabapentin actively crosses…" is trivial (all but very few drugs cross placenta, and I am not sure if the term "actively" is accurate) could be omitted with no loss of information.

Methods

Well described. I would like clarification/justification/discussion of the following points:

a) Exposure window. The authors have chosen to eliminate the 30-day window prior to conception. This is fine, but I suggest they discuss the possible consequences thereof and elaborate on the typical prescription coverage of gabapentin (1 month? Three months?)

b) Exclusion criteria. The authors exclude some known teratogenic drugs. However, some quite notable drugs are omitted, especially ACE-inhibiting drugs and antiepileptics with documented increased risk of major congenital malformations: valproic acid, carbamazepine and phenytoin (I am aware that these latter exposures are included in the PS model). The authors should discuss.

c) Exposure definition. Please state the definition of the start of pregnancy explicitly (LMP?).

d) Outcome assessment. Please discuss the possible consequences of a short follow-up (3 months). Some - especially cardiac - malformations are detected later in the first year after birth.

e) Covariates. While I am confident that the following has been elaborately published elsewhere, I believe that this information is quite important for the reader to have at hand as these covariates are important:

Alcohol, overweight and smoking: Please briefly describe how these were assessed and stratified and list the % of missing data on these covariates in the original MAX dataset.

f) Inferential analysis for risk of preterm birth. I believe the authors should discuss the possibility of immortal time bias in this context.

g) Bias analysis (smoking). I acknowledge the reference to the assumed Pc0 prevalence of 30% maternal smoking, but such seem extremely high to me still. Please elaborate.

Results

Clearly presented if a somewhat long narrative section.

Discussion

Clear and well substantiated in the actual findings. Some adjustments may be warrented pending the response to the issues above.

Any attachments provided with reviews can be seen via the following link:

[LINK]

PLoS Med. 2020 Sep 1;17(9):e1003322. doi: 10.1371/journal.pmed.1003322.r002

Author response to Decision Letter 0

6 Mar 2020

Attachment

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PLoS Med. doi: 10.1371/journal.pmed.1003322.r003

Decision Letter 1

Caitlin Moyer

3 Apr 2020

Dear Dr. Patorno,

Thank you very much for submitting your revised manuscript "Gabapentin in Pregnancy and the Risk of Adverse Neonatal and Maternal Outcomes: A Population-based Cohort Study" (PMEDICINE-D-19-03278R1) for consideration at PLOS Medicine.

Your paper was re-evaluated by a senior editor and discussed among all the editors here. It was also re-reviewed by three reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of the remaining comments from Reviewer #3, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments, particularly the points raised by Reviewer #3 regarding the propensity score distributions. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

We expect to receive your revised manuscript by Apr 10 2020 11:59PM. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

Please use the following link to submit the revised manuscript:

https://www.editorialmanager.com/pmedicine/

Your article can be found in the "Submissions Needing Revision" folder.

We look forward to receiving your revised manuscript.

Sincerely,

Caitlin Moyer, Ph.D.

Associate Editor

PLOS Medicine

plosmedicine.org

-----------------------------------------------------------

Requests from the editors:

1. Abstract (and throughout): Thank you for your responses to this query in the previous round of revision, and we appreciate your willingness to consider the inclusion of p values for your results. Please provide p values in addition to 95% CIs.

2. Author summary: Thank you for including an author summary. Please also include the section: “What Do These Findings Mean?” (In this section, authors should reflect on the new knowledge generated by the research and the implications for practice, research, policy, or public health. Authors should also consider how the interpretation of the study’s findings may be affected by the study limitations.) Please see our author guidelines for more information on formatting this section: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary

3. Methods: “Source of Data and Study Population”: Please provide a reference for the US Medicaid Analytic eXtract (MAX) database used.

4. Methods: “Source of Data and Study Population”: Thank you for including the STROBE checklist. Please revise the last sentence to read: This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 Checklist)." or similar.

5. Results section, throughout: We thank you for your responses on this subject, but please do report p values to accompany the 95% CIs presented for all results. In instances where you report “significant” associations, please indicate whether the intended meaning is “statistical significance”.

6. Results: “Absolute and relative risks of neonatal and maternal outcomes”: Please provide p values along with 95% CIs for all presented analyses, unadjusted and adjusted, throughout this section. We suggest you change “the relative risks moved” to “the relative risks attenuated” or similar in the sentence “After PS adjustment, the relative risks moved to RR, 1.07 (0.94-1.21) and RR, 1.12 (0.89-1.40), respectively.” to enhance clarity.

7. Results “Sensitivity, secondary and post-hoc analyses”: Please provide p values along with 95% CIs for all presented analyses.

8. Results: (and response to editor comment #16): Thank you for your response to this, please do report (in the table) the unadjusted results for the secondary analyses.

9. Figure 2: In the title, please include panels E and F (...unexposed and gabapentin exposed women in either late (A, C, E) or both early and late in pregnancy (B, D, F)), or remove the panel IDs from the title as this information is found in the legend.

10. eFigure 1: Please use a consistent number of decimal places for the x axes across panels. In the legend, please provide a description of the comparison groups: Exp_Group: exposure group; Gaba_Group1-4: gabapentin exposed women in exposure groups 1 to 4 (presumably gaba = gabapentin, exposure groups 1-4 correspond to time periods of exposures). Please include a descriptive figure legend, if possible.

11. eTable 5: Please provide p values.

References: Please check the formatting for reference 3, removing the trademark symbol. Please double check that your references use the "Vancouver" style for reference formatting (it looks like you may need a period between the journal names and the publication year), and see our website for other reference guidelines https://journals.plos.org/plosmedicine/s/submission-guidelines#loc-references

12. Checklist: Thank you for providing your STROBE checklist. Please revise the checklist, using sections and paragraphs, rather than page numbers, to refer to locations throughout the manuscript.

Comments from the reviewers:

Reviewer #1: Thank you for asking me to review the revision. The responses are satisfactory. I am clearer that a patient's complete claim history prior to the pregnancy is not available. For this reason information accruing throughout the first trimester is the only way to identify the necessary information. Although it would normally be expected that key past medical history is recorded early on, I agree that more medical conditions could have chance to accumulate over time. The primary propensity score analysis was estimated only on the basis of chronic conditions or treatments that are not expected to be causal intermediates between gabapentin and pregnancy complications, which is valid and the variables are listed in etable 3. Assuming the high dimensional propensity score (HDPS) uses more covariates than simply those in etable 3, the HDPS could be more at risk from the appearance of conditions and treatments after gabapentin exposure has commenced. However, this is a secondary analysis and given the effect estimates are similar to those of the primary PS analysis it seems unlikely to be an issue here.

Reviewer #3: Looking at eFigure1 which shows the overlap in PS distribution, it looks as if 100% (or very close to 100%) of the unexposed group fell within the first bar of the histogram whereas, for the exposed groups, the proportion included in the first bar varied between approximately 65% and 92%. This indicates a substantial lack of overlap in the propensity score distributions between the exposed and non-exposed groups, yet the authors report retaining 100% (or 99.8%) of exposed cases.

Please clarify the rule used for trimming and the reason for having so few cases trimmed. This lack of PS overlap suggests that a number of exposed cases would have been matched (i.e. included in the same strata) as non-exposed cases who had a much lower propensity score. I wonder about the possible biases induced by including exposed cases with high (non-overlapping) propensity scores and whether a sensitivity analysis excluding exposed cases who have a "non-overlapping" propensity score might alleviate those concerns.

I note that the authors do not wish to report p-values. While p-values can indeed be misinterpreted, I feel that they help quantify the degree of consistency between the observed data and the hypotheses and are a useful complement to confidence intervals. In fact, the articles cited, e.g. the ASA statement, do not necessarily ask authors to avoid using p-values but rather warn against misinterpretation. For the sake of transparency and interpretation, I would encourage the reporting of p-values in addition to confidence intervals but will leave the decision with the editors.

Reviewer #4: The authors have satisfactorily addressed issues raised in my review and revised the manuscript accordingly.

Any attachments provided with reviews can be seen via the following link:

[LINK]

PLoS Med. 2020 Sep 1;17(9):e1003322. doi: 10.1371/journal.pmed.1003322.r004

Author response to Decision Letter 1

10 Apr 2020

Attachment

Submitted filename: Response_Gabapentin_PLOS_Med_Apr 10 2020_final.docx

Click here for additional data file.^{(356.6KB, docx)}

PLoS Med. doi: 10.1371/journal.pmed.1003322.r005

Decision Letter 2

Caitlin Moyer

6 May 2020

Dear Dr. Patorno,

Your paper was re-evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to a statistical reviewer for re-review. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of the outstanding editorial issues, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the editors' comments. In particular, please note that we cannot move forward with your manuscript without the inclusion of p-values. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response.

In revising the manuscript for further consideration, your revisions should address the specific points made by the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

We expect to receive your revised manuscript by May 13 2020 11:59PM. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

Please use the following link to submit the revised manuscript:

https://www.editorialmanager.com/pmedicine/

Your article can be found in the "Submissions Needing Revision" folder.

We look forward to receiving your revised manuscript.

Sincerely,

Caitlin Moyer, Ph.D.

Associate Editor

PLOS Medicine

plosmedicine.org

-----------------------------------------------------------

Requests from the editors:

1. Response to reviewers/editors: Thank you for the responses to the reviewer and editor comments.

- Response to Editorial Request #1:“We have asked on previous occasions for p values to be provided alongside 95% CIs. These are still not provided and I should advise you that we will be unwilling to continue with this paper unless you provide them. We understand the limitations of presenting and interpreting p-values that you have outlined in your response letter. However, our readers expect to see them, and thus PLOS Medicine requires both p-values and 95% CIs when presenting results. We will withdraw the paper from our files if these are not provided on the resubmission

- Response to Editorial Request #8: Please present the results from the unadjusted analyses in addition to the adjusted analyses as requested previously (in a separate table would be acceptable).

2. Title: Please include the population and setting (country)- we suggest “Gabapentin in pregnancy and the risk of adverse neonatal and maternal outcomes: A population-based cohort study of the US Medicaid Analytic eXtract (MAX) dataset”

3. Abstract: Methods and Findings: Please include some summary demographic information on the individuals included in the dataset and please include the months along with the years for the included pregnancies.

4. Abstract: Methods and Findings: Please provide p-values in addition to 95% CIs.

5. Abstract: Methods and Findings: Can you please clarify this sentence: “There was no association with preeclampsia after adjustment” to indicate which relationship you are describing?

6. Results: Last sentence of “Study cohort and patient characteristics”- does the superscript 19 indicate reference 19? If so please place the reference in square brackets: [19].

7. Results: “Absolute and relative risks of neonatal and maternal outcomes”: Please provide p-values associated with the risk ratios and 95% CIs here, and throughout the manuscript. In the methods, please specify the significance level used (eg, P<0.05, two-sided) and the statistical test used to derive a p-value.

8. Results: “Sensitivity, secondary and post-hoc analyses”: For the following sentence, please clarify whether the risk was significantly increased for the subgroup of patients with an epilepsy/seizure diagnosis: “Of note, the risk of cardiac malformations in pregnancies exposed to gabapentin during T1 was significantly increased when we re-defined the exposure based on ≥2 filled prescriptions [RR, 1.40 (1.03-1.90)], and remained elevated in a post-hoc analysis with hdPS adjustment [RR, 1.40 (1.03-1.90)], and in a subgroup analysis that restricted to patients with a recorded diagnosis of epilepsy or seizures [RR, 1.40; 0.73-2.71)].”

9. Discussion: Last sentences of paragraph beginning “This study has limitations”: We suggest revising to: “Our results add to the current understanding of the safety of gabapentin prenatal use and provide pregnant women with pain conditions and epilepsy and their providers with important information, which can guide clinical decisions during pregnancy. Our findings also suggest that pregnant women using gabapentin during pregnancy may be considered for targeted interventions to monitor for and promptly respond to the potential adverse outcomes associated with the use of this agent.”

We also suggest that the discussion of the strengths and limitations of the study be a separate paragraph from the discussion of implications and next steps for research.

10. Conclusions: The caveat regarding the impact of multiple analyses on the cardiac finding would be more appropriately discussed in the paragraph describing the study’s limitations. “A moderate increase in the risk of cardiac malformations – in particular conotruncal defects – cannot be excluded, although in the context of multiple analyses the possibility of a chance finding should be taken into consideration.” In the last sentence, please change “clinicians need to” to “clinicians should” or similar.

11. Table 2 and Table 3, and eTable 5, 6, and 7: Please provide p values associated with these results.

Comments from the reviewers:

Reviewer #3: My previous query about the apparent lack of overlap in PS distribution has been adequately addressed. I have no further comment.

-Laurent Billot

Any attachments provided with reviews can be seen via the following link:

[LINK]

PLoS Med. 2020 Sep 1;17(9):e1003322. doi: 10.1371/journal.pmed.1003322.r006

Author response to Decision Letter 2

3 Jul 2020

Attachment

Submitted filename: Response_Gabapentin_PLOS_Med_July 1 2020_bb.docx

Click here for additional data file.^{(292.4KB, docx)}

PLoS Med. doi: 10.1371/journal.pmed.1003322.r007

Decision Letter 3

Caitlin Moyer

17 Jul 2020

Dear Dr. Patorno,

Thank you very much for re-submitting your manuscript "Gabapentin in Pregnancy and the Risk of Adverse Neonatal and Maternal Outcomes: A Population-based Cohort Study" (PMEDICINE-D-19-03278R3) for review by PLOS Medicine.

After discussing the paper with my colleagues, I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

Our publications team (plosmedicine@plos.org) will be in touch shortly about the production requirements for your paper, and the link and deadline for resubmission. DO NOT RESUBMIT BEFORE YOU'VE RECEIVED THE PRODUCTION REQUIREMENTS.

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

We expect to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.

We look forward to receiving the revised manuscript by Jul 24 2020 11:59PM.

Sincerely,

Caitlin Moyer, Ph.D.

Associate Editor

PLOS Medicine

plosmedicine.org

------------------------------------------------------------

Requests from Editors:

1.Title: Thank you for updating your title to: “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.” Please also make sure this title is updated on the manuscript submission form/system to ensure that the title is carried forward accurately.

2.Author summary: "Why was this study done?": Please remove the word “only” from the second bullet point.

3.Discussion: Conclusion paragraph: Please revise this sentence as follows, changing “increased” to “higher” to be consistent with wording elsewhere in the text: “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.”

4.Sections titled “Author contributions”, “Funding”, “Competing interests”, and “Data availability statement”: These can be removed from the manuscript body; please be sure the information is entered into the relevant place in the manuscript submission form and it will automatically be included with the manuscript.

5.Appendix: Please include each document/table as a separate supporting information file.

Any attachments provided with reviews can be seen via the following link:

[LINK]

PLoS Med. 2020 Sep 1;17(9):e1003322. doi: 10.1371/journal.pmed.1003322.r008

Author response to Decision Letter 3

29 Jul 2020

Attachment

Submitted filename: Response_Gabapentin_PLOS_Med_July 23 2020.docx

Click here for additional data file.^{(291.3KB, docx)}

PLoS Med. doi: 10.1371/journal.pmed.1003322.r009

Decision Letter 4

Caitlin Moyer

30 Jul 2020

Dear Dr Patorno,

On behalf of my colleagues and the academic editor, Dr. Sarah J Stock, I am delighted to inform you that your manuscript entitled "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" (PMEDICINE-D-19-03278R4) has been accepted for publication in PLOS Medicine.

PRODUCTION PROCESS

Before publication you will see the copyedited word document (in around 1-2 weeks from now) and a PDF galley proof shortly after that. The copyeditor will be in touch shortly before sending you the copyedited Word document. We will make some revisions at the copyediting stage to conform to our general style, and for clarification. When you receive this version you should check and revise it very carefully, including figures, tables, references, and supporting information, because corrections at the next stage (proofs) will be strictly limited to (1) errors in author names or affiliations, (2) errors of scientific fact that would cause misunderstandings to readers, and (3) printer's (introduced) errors.

If you are likely to be away when either this document or the proof is sent, please ensure we have contact information of a second person, as we will need you to respond quickly at each point.

PRESS

A selection of our articles each week are press released by the journal. You will be contacted nearer the time if we are press releasing your article in order to approve the content and check the contact information for journalists is correct. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact.

PROFILE INFORMATION

Now that your manuscript has been accepted, please log into EM and update your profile. Go to https://www.editorialmanager.com/pmedicine, log in, and click on the "Update My Information" link at the top of the page. Please update your user information to ensure an efficient production and billing process.

Thank you again for submitting the manuscript to PLOS Medicine. We look forward to publishing it.

Best wishes,

Caitlin Moyer, Ph.D.

Associate Editor

PLOS Medicine

plosmedicine.org

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Table. Definitions for congenital malformations.

(DOCX)

Click here for additional data file.^{(40.6KB, docx)}

S2 Table. Definitions for preeclampsia, preterm birth, SGA, and NICUa.

NICUa, neonatal intensive care unit admission; SGA, small for gestational age.

(DOCX)

Click here for additional data file.^{(37.2KB, docx)}

S3 Table. Baseline characteristics of gabapentin-exposed and unexposed women, before PS adjustment.

PS, propensity score.

(DOCX)

Click here for additional data file.^{(72.6KB, docx)}

S4 Table. Baseline characteristics of gabapentin-exposed and unexposed women, after PS adjustment.

PS, propensity score.

(DOCX)

Click here for additional data file.^{(81.7KB, docx)}

S5 Table. Sensitivity and secondary analyses for the RR of neonatal and maternal outcomes associated with exposure to gabapentin compared with unexposed pregnancies before and after PS adjustment.

PS, propensity score; RR, relative risk.

(DOCX)

Click here for additional data file.^{(68.2KB, docx)}

S6 Table. Post hoc analyses for the RR of specific types of cardiac malformations associated with exposure to gabapentin during T1 compared with unexposed pregnancies.

RR, relative risk; T1, first trimester.

(DOCX)

Click here for additional data file.^{(43.9KB, docx)}

S7 Table. Sensitivity and secondary analyses for the RR of individual noncardiac major malformation groups associated with exposure to gabapentin compared with unexposed pregnancies.

RR, relative risk.

(DOCX)

Click here for additional data file.^{(43.9KB, docx)}

RR, relative risk.

(DOCX)

Click here for additional data file.^{(50.3KB, docx)}

S1 Fig. PS distributions of gabapentin-exposed and unexposed women during the T1, after PS trimming and weighting.

PS, propensity score; T1, first trimester.

(TIF)

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S2 Fig. PS distributions of gabapentin-exposed and unexposed women early in pregnancy, after PS trimming and weighting.

PS, propensity score.

(TIF)

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S3 Fig. PS distributions of gabapentin-exposed and unexposed women late in pregnancy, after PS trimming and weighting.

PS, propensity score.

(TIF)

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S4 Fig. PS distributions of gabapentin-exposed and unexposed women early and late in pregnancy, after PS trimming and weighting.

PS, propensity score.

(TIF)

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S5 Fig. Corrected RR for the association between gabapentin exposure during the T1 and major malformations.

RR, relative risk; T1, first trimester.

(TIF)

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S1 Text. Planned analyses.

(DOCX)

Click here for additional data file.^{(43.8KB, docx)}

S1 STROBE Checklist. STROBE, Strengthening the Reporting of Observational Studies in Epidemiology.

(DOCX)

Click here for additional data file.^{(45.9KB, docx)}

Attachment

Submitted filename: Response_Gabapentin_PLOS_Med_Mar 6 2020.docx

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Attachment

Submitted filename: Response_Gabapentin_PLOS_Med_Apr 10 2020_final.docx

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Attachment

Submitted filename: Response_Gabapentin_PLOS_Med_July 1 2020_bb.docx

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Submitted filename: Response_Gabapentin_PLOS_Med_July 23 2020.docx

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Data Availability Statement

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PERMALINK

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

Roles

Abstract

Background

Methods and findings

Conclusions

Author summary

Why was this study done?

What did the researchers do and find?

What do these findings mean?

Introduction

Methods

Source of data and study population

Fig 1. Flowchart of the study cohort.

Exposure definition

Outcomes

Covariates

Primary analysis

Sensitivity analyses

Ethics statement

Results

Study cohort and patient characteristics

Table 1. Selected baseline characteristics of gabapentin-exposed and unexposed women before PS adjustment, with standardized differences before and after PS adjustment.

Absolute and relative risks of neonatal and maternal outcomes

Table 2. Absolute and relative risk of neonatal and maternal outcomes associated with exposure to gabapentin compared with unexposed pregnancies.

Sensitivity, secondary, and post hoc analyses

Table 3. Sensitivity and secondary analyses for the RRs of neonatal and maternal outcomes associated with exposure to gabapentin compared with unexposed pregnancies after PS adjustment.

Fig 2.

Discussion

Conclusions

Supporting information

Abbreviations

Data Availability

Funding Statement

References

Decision Letter 0

Caitlin Moyer

Roles

Author response to Decision Letter 0

Decision Letter 1

Caitlin Moyer

Roles

Author response to Decision Letter 1

Decision Letter 2

Caitlin Moyer

Roles

Author response to Decision Letter 2

Decision Letter 3

Caitlin Moyer

Roles

Author response to Decision Letter 3

Decision Letter 4

Caitlin Moyer

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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