# Systematic review of gabapentinoid use during pregnancy and its impact on pregnancy and childhood outcomes: A ConcePTION study

Anna-Belle Beau, Jingping Mo, Xavier Moisset, Justine Bénévent, Christine

Damase-Michel

<figure><img src="image_1.png" /></figure>

► To cite this version:

Anna-Belle Beau, Jingping Mo, Xavier Moisset, Justine Bénévent, Christine Damase-Michel. Systematic review of gabapentinoid use during pregnancy and its impact on pregnancy and childhood outcomes: A ConcePTION study. Therapies, 2025, 80 (4), pp.378-416. 10.1016/j.therap.2024.10.049. hal-04803603

HAL Id: hal-04803603

https://hal.science/hal-04803603v1

Submitted on 25 Sep 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_2.png" /></figure>
DRUGS AND PREGNANCY

# Systematic review of gabapentinoid use during pregnancy and its impact on pregnancy and childhood outcomes: A ConcePTION study

Anna-Belle Beau<sup>a,*</sup>, Jingping Mo<sup>b</sup>, Xavier Moisset<sup>c</sup>, Justine Bénévent<sup>a</sup>, Christine Damase-Michel<sup>a</sup>

Received 22 July 2024; accepted 11 October 2024

Available online 18 October 2024

KEYWORDS

Pregabalin ;
Gabapentin ;
Congenital anomaly ;
Childhood outcomes ;
Systematic review

Summary

**Objective.** — In the general population, there has been a noticeable rise in the dispensing of gabapentinoids in recent years. The aim of this study was to provide an overview of all available data on the use and safety of gabapentinoids during pregnancy.

**Methods.** — A systematic review was performed in PubMed and Reprotox using the search terms: "gabapentin", "pregabalin", "antiepileptic drugs" and terms associated with pregnancy. We included all studies in English that reported on the use and safety of gabapentin and pregabalin during pregnancy. We excluded abstracts, literature reviews, case reports and studies involving fewer than 5 exposures. Descriptive analyses and narrative syntheses were performed.

**Results.** — A total of 27 high-quality studies were described. The prevalence of gabapentinoid use during pregnancy remained very low, at less than 1%. Five studies reported significant findings with increased risks of overall congenital anomalies, specific anomalies (nervous system, eyes, oro-facial clefs, urinary and genital system), miscarriage, stillbirth and specific neurodevelopmental outcomes after exposure to pregabalin during pregnancy. Concerning exposure to gabapentin, increased risks of preterm birth, preeclampsia, small-for-gestational-age and NICU admission were reported in two studies.

<footnote><sup>a</sup> Toulouse University Hospital, CERPOP-SPHERE Team, Inserm UMR 1295, Toulouse University, 31000 Toulouse, France</footnote>

<footnote><sup>b</sup> Worldwide Medical and Safety, Pfizer Inc., New York, NY 10001-2192, USA</footnote>

<footnote><sup>c</sup> Université Clermont Auvergne, CHU de Clermont-Ferrand, Inserm, Neuro-Dol, 63000 Clermont-Ferrand, France</footnote>

<footnote>* Corresponding author. Toulouse University Hospital, CERPOP-SPHERE Team, Inserm UMR 1295, 37, allées Jules-Guesde Bat C, Floor 3, 31000 Toulouse, France.</footnote>

<footnote>E-mail address: anna-belle.beau@univ-tlse3.fr (A.-B. Beau).</footnote>
Conclusions. — Prenatal exposure to pregabalin is associated with an increased risk of congenital anomalies and long-term neurodevelopmental outcomes while gabapentin exposure was associated with an increased risk of preeclampsia, preterm birth and small-for-gestational age. Larger studies are needed to confirm these data and explore additional outcomes. The combined evidence from this systematic review and animal studies raises concerns about the safety of using gabapentinoids during pregnancy. Careful evaluation of the benefit–risk balance for both mother and fetus/infant is essential when these medications cannot be avoided during pregnancy.

© 2024 The Author(s). Published by Elsevier Masson SAS on behalf of Société française de pharmacologie et de thérapeutique. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

## Abbreviations

<table><tr><td>ADHD</td><td>attention deficit hyperactivity disorder</td></tr><tr><td>ASD</td><td>autism spectrum disorder</td></tr><tr><td>ASM-exposure</td><td>antiseizure medication exposure</td></tr><tr><td>HR</td><td>hazard ratio</td></tr><tr><td>ICD-10</td><td>International Statistical Classification of Diseases and Related Health Problems 10th Revision</td></tr><tr><td>IMI</td><td>innovative medicines initiative</td></tr><tr><td>NCIU</td><td>Neonatal Intensive Care Unit</td></tr><tr><td>NOS</td><td>Newcastle–Ottawa-Scale</td></tr><tr><td>OR</td><td>odd ratio</td></tr><tr><td>PR</td><td>prevalence ratio</td></tr><tr><td>PRISMA</td><td>Preferred Reporting Items for Systematic Reviews and Meta-analysis</td></tr><tr><td>RR</td><td>risk ratio</td></tr><tr><td>SGA</td><td>small-for-gestational-age</td></tr><tr><td>SmPC</td><td>summary of product characteristics</td></tr></table>

## Introduction

In Europe, pregabalin and gabapentin, initially approved for epilepsy, were subsequently approved to treat neuropathic pain and generalized anxiety disorder (pregabalin only). In addition, off-label use has been reported, such as in the treatment of non-neuropathic pain including migraine and fibromyalgia, restless leg syndrome, or bipolar disorders. Pregabalin and gabapentin cross the placenta barrier using active transport mechanisms [1,2], raising concerns about potential adverse effects on the fetus and infants when these medications are used during pregnancy.

In the general population, there has been an observed increase in the dispensing of gabapentinoids in recent years, possibly due in part to their various uses and abuse [3–6]. In pregnant women, a European study found that the prescribing of pregabalin and gabapentin during pregnancy has increased markedly in the United Kingdom from around 0.3 per 1000 in 2007 to 2.5–3.0 per 1000 in 2016, with about one-seventh of prescriptions likely intended for pain management [7]. A less pronounced increase was observed in

France (prevalence of pregabalin rose from 0.5 to 1.2 per 1000 over the same period). In Italy, prevalence rates have remained stable in recent years [7].

In animal studies, prenatal exposure to gabapentin has been associated with fetal growth retardation and increased incidence of hydroureter, hydronephrosis and fetal loss [8,9]. Pregabalin exposure has been linked to a higher incidence of skeletal anomalies [10]. These findings, although derived from animals, highlight potential risks that warrant further investigation in humans.

Despite the increased use of gabapentinoids during pregnancy, there are limited publications and contradictory results regarding their effects on the fetus and/or child. Nevertheless, in March 2022, the summary of product characteristics (SmPC) for Lyrica® (pregabalin) was updated to state ‘‘use in the first trimester of pregnancy may cause major birth defects in the unborn child’’ [11]. Following this update, a critical appraisal of controlled studies was published, indicating the data from published studies did not support the SmPC statement of an increased risk of congenital anomalies following in utero exposure to pregabalin [12]. In parallel, a meta-analysis of eight cohort studies assessed the relationship between exposure to gabapentinoids and the risk of congenital anomalies, small-for-gestational-age (SGA), preterm birth, spontaneous abortion and termination of pregnancy [13]. The results were reassuring regarding congenital anomalies, but highlighted an increased risk of preterm birth, spontaneous abortion and termination of pregnancy following exposure to gabapentinoids during pregnancy. Thus, the UK regulator advises against the use of gabapentinoids during pregnancy [14].

The present review described the use of gabapentinoids and their safety during pregnancy. We extended the outcomes of interest by examining the long-term effects on the newborn. Consequently, we have compiled all the available data on the use and safety of gabapentinoids during pregnancy into a single document.

This study was conducted as part of the innovative medicines initiative (IMI) Conception project, a large-scale collaboration between academic, regulatory and industry partners, to create an enhanced monitoring and communication system for the safe use of medications during pregnancy and lactation (http://www.imi-conception.eu/).
<table><caption>**Table 1** Selection criteria for eligibility.</caption><tr><td>Population</td><td>Pregnant women</td></tr><tr><td>Intervention</td><td>In utero exposure to gabapentin or pregabalin (monotherapy or combination therapy)</td></tr><tr><td>Controls/comparators</td><td>If present,<br/>- women not exposed to the medication of interest during pregnancy<br/>- women exposed to other antiepileptics during pregnancy<br/>- general population of pregnant women</td></tr><tr><td>Outcomes</td><td>Prevalence of gabapentinoid use during pregnancy<br/>Pregnancy outcomes, such as live birth, miscarriage, stillbirth, congenital anomaly, preterm birth, small for gestational age...<br/>Childhood outcomes, such as cognitive outcomes, signal of atypical neurodevelopment (autism spectrum disorder, attention-deficit/hyperactivity disorder)</td></tr><tr><td>Type of study</td><td>Observational studies (cohort, case-control...)<br/>Pregnancy registry studies</td></tr></table>

<figure><img src="image_3.png" /><figcaption>**Figure 1.** Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) 2020 flowchart.</figcaption></figure>
<table><caption>Table 2 Overview of the 27 high-quality studies included in the review.</caption><thead><tr><td>Author and year</td><td>Country, study period</td><td>Population-based</td><td>Study design, data source</td><td>Characteristics of study population, No.</td><td>Exposure ascertainment</td><td>Medications investigated</td><td>Outcomes investigated</td><td>Study quality</td></tr></thead><tbody><tr><td>Almgren et al., 2009 [46]</td><td>Sweden, 1995–2005</td><td>Yes</td><td>Cohort, National registers</td><td>Singleton, n = 900,739 children</td><td>Structured interview made by a midwife (Swedish Medical Birth Registry)</td><td>ASM including gabapentin</td><td>Head circumference</td><td>8</td></tr><tr><td>Bech et al., 2018 [52]</td><td>Denmark, 2005–2008</td><td>Yes</td><td>Case-cohort, Danish national registers</td><td>Singletons born from mother exposed to antiepileptic drugs before or during pregnancy, n = 1070 children</td><td>Danish national prescription register</td><td>ASM including gabapentin</td><td>Learning disabilities in the first year of compulsory education</td><td>9</td></tr><tr><td>Bjørk et al., 2022 [48]</td><td>Denmark (1997–2017), Finland (1996–2016), Iceland (2004–2017), Norway (2005–2017), and Sweden (2006–2017)</td><td>Yes</td><td>Cohort, National registers</td><td>Live birth singletons without chromosomal disorders, n = 4,494,926 children</td><td>Nordic national prescription registers</td><td>ASM including gabapentin and pregabalin</td><td>Intellectual disability, autism spectrum disorder and any neurodevelopmental disorder</td><td>9</td></tr><tr><td>Blotière et al., 2018 [33]</td><td>France, 2007–2015</td><td>Yes</td><td>Cohort, National French healthcare databases</td><td>Pregnant women identified, n = 9,647,843 pregnancies</td><td>Prescription/ dispensing database</td><td>ASM including gabapentin and pregabalin</td><td>Prevalence of ASM use during pregnancy</td><td>7</td></tr><tr><td>Blotière et al., 2019 [40]</td><td>France, 2011–2015</td><td>Yes</td><td>Cohort, National French healthcare databases</td><td>Pregnancies with at least 20 weeks of gestation, n = 1,886,825 pregnancies</td><td>Prescription/ dispensing database</td><td>ASM including gabapentin and pregabalin</td><td>23 major congenital malformations</td><td>8</td></tr><tr><td>Blotière et al., 2020 [49]</td><td>France, 2011–2014 (follow-up until end 2016)</td><td>Yes</td><td>Cohort, National French healthcare databases</td><td>Live births prenatally exposed to ASM monotherapy, n = 9034 children</td><td>Prescription/ dispensing database</td><td>ASM including gabapentin and pregabalin</td><td>Various neurodevelopmental outcomes</td><td>8</td></tr></tbody></table>
<table><caption>Table 2 (Continued)</caption><thead><tr><td>Author and year</td><td>Country, study period</td><td>Population-based</td><td>Study design, data source</td><td>Characteristics of study population, No.</td><td>Exposure ascertainment</td><td>Medications investigated</td><td>Outcomes investigated</td><td>Study quality</td></tr></thead><tbody><tr><td>Bobo et al., 2012 [53]</td><td>US, 2001–2007</td><td>Yes</td><td>Cohort</td><td>Live births, n = 585, 615 deliveries</td><td>Prescription/ dispensing database</td><td>ASM including gabapentin and pregabalin</td><td>Use of ASM among pregnant women</td><td>7</td></tr><tr><td>Christensen et al., 2024 [47]</td><td>Denmark (1997–2017), Finland (1996–2016), Iceland (2004–2017), Norway (2005–2017), and Sweden (2006–2017)</td><td>Yes</td><td>Cohort, National registers</td><td>Live birth singletons without chromosomal disorders, n = 4,494,918 children</td><td>Nordic national prescription registers</td><td>ASM including gabapentin and pregabalin</td><td>Fetal growth indicators (birth weight and head circumference)</td><td>9</td></tr><tr><td>Coste et al., 2020 [50]</td><td>France, 2011–2014 (follow-up until end 2016)</td><td>Yes</td><td>Cohort, National French healthcare databases</td><td>Liveborn singleton, n = 1,721,990 children</td><td>Prescription/ dispensing database</td><td>ASM including gabapentin and pregabalin</td><td>Early neurodevelopmental disorders</td><td>8</td></tr><tr><td>Desrochers et al., 2024 [32]</td><td>Canada, 1995–2019</td><td>Yes</td><td>Cohort, Manitoba Health Database</td><td>Pregnant women, n = 289,227 pregnancies</td><td>Prescription database</td><td>Gabapentin</td><td>Major congenital anomalies, cardiac and oro-facial anomalies, and neonatal intensive care unit admission</td><td>9</td></tr><tr><td>Dreier et al., 2023 [51]</td><td>Denmark (1997–2017), Finland (1996–2016), Iceland (2004–2017), Norway (2005–2017), and Sweden (2006–2017)</td><td>Yes</td><td>Cohort, National registers</td><td>Singleton without chromosomal disorders born from mother with epilepsy, n = 38,661 children</td><td>Nordic national prescription registers</td><td>ASM including gabapentin and pregabalin</td><td>Child psychiatric disorders</td><td>8</td></tr></tbody></table>
<table><caption>Table 2 (Continued)</caption><thead><tr><td>Author and year</td><td>Country, study period</td><td>Population-based</td><td>Study design, data source</td><td>Characteristics of study population, No.</td><td>Exposure ascertainment</td><td>Medications investigated</td><td>Outcomes investigated</td><td>Study quality</td></tr></thead><tbody><tr><td>Dudukina et al., 2023 [39]</td><td>Denmark, Finland, and Norway (2005–2015), Sweden (2006–2016) (follow-up until end 31 December 2017 in Sweden and Norway; 31 December 2016 in Denmark and Finland)</td><td>Yes</td><td>Cohort, National registers</td><td>Births (live births and stillbirths) from fetus without prenatal exposure to medications known as potentially teratogenic during the first pregnancy trimester and without chromosomal abnormality diagnosis, n = 3,118,680 pregnancies</td><td>Nordic national prescription registers</td><td>Pregabalin</td><td>Major congenital anomalies, 12 specific sub-group of major congenital anomalies, adverse birth outcomes (stillbirth, low birth weight, preterm birth, being small for gestational age, low Apgar score at 5 min, microcephaly), and postnatal neurodevelop- mental outcomes (attention deficit/ hyperactivity disorder, autism spectrum disorder, intellectual disability)</td><td>9</td></tr><tr><td>Forbes et al., 2024 [45]</td><td>United Kingdom, 1995–2018</td><td>Yes</td><td>Cohort, Clinical Practice Research Datalink (CPRD) Pregnancy Register</td><td>Single pregnancies with a known outcome identified in the CPRD Pregnancies Register using data from primary care, n = 1,023,787 pregnancies</td><td>Prescription from general practice</td><td>ASM including gabapentin and pregabalin</td><td>Miscarriage</td><td>9</td></tr></tbody></table>
<table><caption>Table 2 (Continued)</caption><thead><tr><td>Author and year</td><td>Country, study period</td><td>Population-based</td><td>Study design, data source</td><td>Characteristics of study population, No.</td><td>Exposure ascertainment</td><td>Medications investigated</td><td>Outcomes investigated</td><td>Study quality</td></tr></thead><tbody><tr><td>Hurault-Delarue et al., 2019 [7]</td><td>United Kingdom, France, and Italy, 2007–2016</td><td>Yes</td><td>Cohort, health care databases</td><td>All pregnancies with a known pregnancy outcome, n = 66, 681 pregnancies in France, 294,151 in Tuscany (Italy), 355,767 in Emilia-Romagna (Italy), and 380,499 in the UK</td><td>Issue (UK) or dispensing (France and Italy) of a prescription</td><td>ASM including gabapentin and pregabalin</td><td>Patterns of antiepileptic medications</td><td>7</td></tr><tr><td>Källén et al., 2013 [36]</td><td>Sweden, 1996–2011</td><td>Yes</td><td>Cohort, Swedish Medical Birth Register</td><td>All infants born during the study period, n = 1,575,847 children</td><td>Standardized forms from the medical birth registry</td><td>ASM including gabapentin and pregabalin</td><td>Congenital anomalies</td><td>7</td></tr><tr><td>Kilic et al., 2014 [43]</td><td>Denmark, 1997–2008</td><td>Yes</td><td>Cohort, National registers</td><td>Singleton liveborn children, n = 679,762 children</td><td>Danish national prescription register</td><td>ASM including gabapentin and pregabalin</td><td>Adverse birth outcomes: birth weight, gestational age, head circumference, preterm birth, SGA</td><td>9</td></tr><tr><td>Margulis et al., 2019 [44]</td><td>Sweden, 1996–2013</td><td>Yes</td><td>Cohort, National registers</td><td>Liveborn children, n = 6720 children</td><td>Swedish national prescription register, Standardized forms from the medical birth registry</td><td>ASM including pregabalin</td><td>Pregnancy duration and birth weight, length, and head circumference</td><td>9</td></tr><tr><td>Mølgaard-Nielsen et al., 2011 [54]</td><td>Denmark, 1996–2008</td><td>Yes</td><td>Cohort, National registers</td><td>All live births during the study period, n = 837, 795 live births</td><td>Danish national prescription register</td><td>ASM including gabapentin</td><td>Major congenital anomalies</td><td>8</td></tr></tbody></table>
<table><caption>Table 2 (Continued)</caption><thead><tr><td>Author and year</td><td>Country, study period</td><td>Population-based</td><td>Study design, data source</td><td>Characteristics of study population, No.</td><td>Exposure ascertainment</td><td>Medications investigated</td><td>Outcomes investigated</td><td>Study quality</td></tr></thead><tbody><tr><td>Morrow et al., 2006 [42]</td><td>UK, 1996–2005</td><td>No, enrolment</td><td>UK epilepsy and pregnancy register</td><td>Pregnant women with epilepsy, n = 3607 pregnancies with full outcome data</td><td>Retrospectively reported by healthcare professionals</td><td>ASM including gabapentin</td><td>Major congenital anomalies</td><td>7</td></tr><tr><td>Mostacci et al., 2018 [55]</td><td>Italy, 2009–2011</td><td>Yes</td><td>Cohort, administrative data bases</td><td>Women who had a delivery or underwent an abortion, n = 145,243 pregnancies</td><td>Prescription/ dispensing database</td><td>ASM including gabapentin and pregabalin</td><td>Prevalence of ASM use during pregnancy, congenital anomalies, SGA, APGAR scores</td><td>9</td></tr><tr><td>Patorno et al., 2017 [38]</td><td>US, 2000–2010</td><td>Yes</td><td>Cohort, US Medicaid Analytic extract (MAX) and the Truven Health marketscan Commercial Claims and Encounters Database (marketscan)</td><td>MAX data: Pregnancies resulting in live births, n = 1,323,432 pregnancies Marketscan data: Pregnancies resulting in live births, n not reported</td><td>Prescription/ dispensing database</td><td>Pregabalin</td><td>Major congenital anomalies</td><td>8</td></tr><tr><td>Patorno et al., 2020 [30]</td><td>US, 2000–2013</td><td>Yes</td><td>Cohort, administrative data bases</td><td>Pregnancies resulting in live births, n = 1,753,865 pregnancies</td><td>Prescription/ dispensing database</td><td>ASM including gabapentin</td><td>Major congenital anomalies, preeclampsia, preterm birth, SGA, NICU admission</td><td>9</td></tr><tr><td>Richards et al., 2018 [35]</td><td>New-Zealand, 2009–2014</td><td>Yes</td><td>Cohort, administrative data bases</td><td>Women who had a delivery or underwent an abortion, n = 472,544 pregnancies</td><td>Prescription/ dispensing database</td><td>ASM including gabapentin</td><td>Rates of ASM use, pregnancy terminations, abortions</td><td>8</td></tr></tbody></table>
<table><caption>Table 2 (Continued)</caption><thead><tr><td>Author and year</td><td>Country, study period</td><td>Population-based</td><td>Study design, data source</td><td>Characteristics of study population, No.</td><td>Exposure ascertainment</td><td>Medications investigated</td><td>Outcomes investigated</td><td>Study quality</td></tr></thead><tbody><tr><td>Shouman et al., 2022 [31]</td><td>Canada, 1997–2018</td><td>Yes</td><td>Cohort, administrative data bases</td><td>Pregnant women, n = 273,492 pregnancies</td><td>Prescription/ dispensing database</td><td>ASM including gabapentin</td><td>ASM use</td><td>7</td></tr><tr><td>Spoendlin et al., 2021 [34]</td><td>Switzerland, 2014–2018</td><td>Yes</td><td>Cohort, administrative data bases</td><td>Pregnant women who had a delivery (live birth or stillbirth), n = 387,418 pregnancies</td><td>Prescription/ dispensing database</td><td>ASM including pregabalin</td><td>Valproate and other antiseizure drugs use</td><td>7</td></tr><tr><td>Veiby et al., 2014 [37]</td><td>Norway, 1999–2011</td><td>Yes</td><td>Cohort, National registers</td><td>Deliveries and termination of pregnancy for fetal anomaly at 12 or more weeks of gestation, n = 779,362 outcomes of pregnancy</td><td>Standardized forms from the medical birth registry</td><td>ASM including gabapentin and pregabalin</td><td>Major congenital anomalies, fetal growth restriction</td><td>7</td></tr><tr><td>Wide et al., 2004 [56]</td><td>Sweden, 1995–2001</td><td>Yes</td><td>Cohort, National registers</td><td>Live births, n = 582,656 children</td><td>Standardized forms from the medical birth registry</td><td>ASM including gabapentin</td><td>Congenital anomalies</td><td>7</td></tr></tbody></table>

ASM: antiseizure medications; CPRD: clinical practice research dataling; NCIU: neonatal intensive care unit; SGA: small-for-gestational-age.
<table><caption>**Table 3** Prevalence of pregnancies exposed to pregabalin and gabapentin in 20 of the 27 high-quality studies included.</caption><thead><tr><th>Reference number</th><th>Author and year</th><th>Exposure/period</th><th>Results</th></tr></thead><tbody><tr><td>Pregabalin exposure [48]</td><td>Bjørk et al., 2022</td><td>Pregabalin monotherapy/from LMP date to end of pregnancy</td><td>1666 infants (0.04%)</td></tr><tr><td>[33]</td><td>Blotière et al., 2018</td><td>Pregabalin/from LMP date to end of pregnancy</td><td>2007–2014: 7250 (0.1%)<br>2007: 547 (0.06%)<br>2008: 652 (0.07%)<br>2009: 780 (0.08%)<br>2010: 901 (0.09%)<br>2011: 927 (0.10%)<br>2012: 1069 (0.11%)<br>2013: 1150 (0.12%)<br>2014: 1224 (0.13%)</td></tr><tr><td>[40]</td><td>Blotière et al., 2019</td><td>Pregabalin monotherapy/between 1 month before and 2 months after the beginning of pregnancy</td><td>2011–2015: 1671 (0.09%)</td></tr><tr><td>[53]</td><td>Bobo et al., 2012</td><td>Pregabalin/from the LMP date to the delivery date</td><td>73 pregnancies (0.01%)</td></tr><tr><td>[47]</td><td>Christensen et al., 2024</td><td>Pregabalin monotherapy/from 30 days before the first day of the last menstrual period to the date of birth</td><td>2214 children (0.05%)</td></tr><tr><td>[50]</td><td>Coste et al., 2020</td><td>Pregabalin monotherapy/the beginning of the month preceding onset of pregnancy and the end of pregnancy</td><td>1777 children (0.10%)</td></tr><tr><td>[39]</td><td>Dudukina et al., 2023</td><td>Pregabalin/from 90 days before LMP date to birth</td><td>Denmark: n = 325 pregnancies (0.05%)<br>Finland: n = 965 pregnancies (0.15%)<br>Norway: n = 307 pregnancies (0.05%)<br>Sweden: n = 1275 pregnancies (0.11%)</td></tr><tr><td>[45]</td><td>Forbes et al., 2024</td><td>Pregabalin/first trimester of pregnancy</td><td>882 pregnancies (0.09%)</td></tr><tr><td>[7]</td><td>Hurault-Delarue et al., 2019</td><td>Pregabalin/during pregnancy</td><td>Emilia-Romagna: 61 pregnancies (0.02%)<br>Tuscany: 149 pregnancies (0.05%)<br>France: 53 pregnancies (0.08%)<br>United Kingdom: 395 pregnancies (0.10%)</td></tr><tr><td>[36]</td><td>Källén et al., 2013</td><td>Pregabalin/during pregnancy</td><td>128 children (0.01%)</td></tr><tr><td>[43]</td><td>Kilic et al., 2014</td><td>Pregabalin/from 30 days before LMP date to birth</td><td>18 children (0.003%)</td></tr><tr><td></td><td>Kilic et al., 2014</td><td>Pregabalin monotherapy/from 30 days before LMP date to birth</td><td>13 children (0.002%)</td></tr><tr><td>[55]</td><td>Mostacci et al., 2018</td><td>Pregabalin/first trimester of pregnancy</td><td>14 newborns (0.01%)</td></tr></tbody></table>
<table><caption>**Table 3** (Continued)</caption><thead><tr><th>Reference number</th><th>Author and year</th><th>Exposure/period</th><th>Results</th></tr></thead><tbody><tr><td rowspan="2">[38]</td><td>Patorno et al., 2017</td><td>Pregabalin/first trimester of pregnancy</td><td>477 pregnancies (0.04%)</td></tr><tr><td>Patorno et al., 2017</td><td>Pregabalin monotherapy/first trimester of pregnancy</td><td>353 pregnancies (0.03%)</td></tr><tr><td rowspan="7">[34]</td><td rowspan="7">Spoendl et al., 2021</td><td rowspan="7">Pregabalin/during pregnancy</td><td>2014: 2.7 per 10,000 pregnancies</td></tr><tr><td>2015: 5.6 per 10,000 pregnancies</td></tr><tr><td>2016: 3.2 per 10,000 pregnancies</td></tr><tr><td>2017: 2.3 per 10,000 pregnancies</td></tr><tr><td>2018: 5.6 per 10,000 pregnancies</td></tr><tr><td>2014–2018: 3.8 per 10,000 pregnancies (weighted prevalence, weighting factors included calendar year, canton, age, and sex)</td></tr><tr><td>30 children (0.004%)</td></tr><tr><td rowspan="2">[37]</td><td rowspan="2">Veiby et al., 2014</td><td rowspan="2">Pregabalin monotherapy/during pregnancy</td><td rowspan="2">965 children (0.02%)</td></tr><tr><td>2007–2014: 2192 pregnancies (0.03%)</td></tr><tr><td rowspan="11">Gabapentin exposure [48]</td><td rowspan="5">Bjørk et al., 2022</td><td rowspan="5">Gabapentin monotherapy/from LMP date to end of pregnancy</td><td>2007: 331 pregnancies (0.04%)</td></tr><tr><td>2008: 248 pregnancies (0.03%)</td></tr><tr><td>2009: 252 pregnancies (0.03%)</td></tr><tr><td>2010: 231 pregnancies (0.02%)</td></tr><tr><td>2011: 230 pregnancies (0.02%)</td></tr><tr><td rowspan="4">Blotière et al., 2018</td><td rowspan="4">Gabapentin/from LMP date to end of pregnancy</td><td>2012: 290 pregnancies (0.03%)</td></tr><tr><td>2013: 283 pregnancies (0.03%)</td></tr><tr><td>2014: 327 pregnancies (0.04%)</td></tr><tr><td>2011–2015: 365 pregnancies (0.02%)</td></tr><tr><td>[40]</td><td>Blotière et al., 2019</td><td>Gabapentin monotherapy/between 1 month before and 2 months after the beginning of pregnancy</td><td>988 pregnancies (0.17%)</td></tr><tr><td>[53]</td><td>Bobo et al., 2012</td><td>Gabapentin/from the LMP date to the delivery date</td><td>1336 children (0.03%)</td></tr><tr><td>[47]</td><td>Christensen et al., 2024</td><td>Gabapentin monotherapy/from 30 days before the first day of the last menstrual period to the date of birth</td><td></td></tr></tbody></table>
<table><caption>**Table 3** (Continued)</caption><thead><tr><th>Reference number</th><th>Author and year</th><th>Exposure/period</th><th>Results</th></tr></thead><tbody><tr><td>[50]</td><td>Coste et al., 2020</td><td>Gabapentin monotherapy/the beginning of the month preceding onset of pregnancy and the end of pregnancy</td><td>467 children (0.03%)</td></tr><tr><td>[32]</td><td>Desrochers et al., 2024</td><td>Gabapentin/during pregnancy</td><td>870 pregnancies (0.30%)</td></tr><tr><td>[45]</td><td>Forbes et al., 2024</td><td>Gabapentin/first trimester of pregnancy</td><td>1224 pregnancies (0.12%)</td></tr><tr><td>[7]</td><td>Hurault-Delarue et al., 2019</td><td>Gabapentin/during pregnancy</td><td>Emilia-Romagna: 36 pregnancies (0.01%)<br>Tuscany: 102 pregnancies (0.03%)<br>France: 16 pregnancies (0.02%)<br>UK: 429 pregnancies (0.11%)</td></tr><tr><td>[36]</td><td>Källén et al., 2013</td><td>Gabapentin/during pregnancy</td><td>207 (0.01%) children (143 early exposures and 64 late exposures)</td></tr><tr><td>[43]</td><td>Kilic et al., 2014</td><td>Gabapentin/from 30 days before LMP date to birth</td><td>91 children (0.01%)</td></tr><tr><td></td><td>Kilic et al., 2014</td><td>Gabapentin monotherapy/from 30 days before LMP date to birth</td><td>72 children (0.01%)</td></tr><tr><td>[54]</td><td>Mølgaard-Nielsen et al., 2011</td><td>Gabapentin/first trimester of pregnancy</td><td>59 children (0.01%)</td></tr><tr><td>[55]</td><td>Mostacci et al., 2018</td><td>Gabapentin/first trimester of pregnancy</td><td>10 newborns (0.01%)</td></tr><tr><td>[30]</td><td>Patorno et al., 2020</td><td>Gabapentin/first trimester of pregnancy</td><td>4642 pregnancies (0.26%)</td></tr><tr><td></td><td>Patorno et al., 2020</td><td>Gabapentin/early in pregnancy (first 140 days of pregnancy and no gabapentin dispensing from the 141 and 245 days)</td><td>3745 pregnancies (0.21%)</td></tr><tr><td></td><td>Patorno et al., 2020</td><td>Gabapentin/late in pregnancy (at least one dispensing in the 141 and 245 days of pregnancy and no dispensing in the first 140 days)</td><td>556 pregnancies (0.03%)</td></tr><tr><td></td><td>Patorno et al., 2020</td><td>Gabapentin/early and late in pregnancy (at least one dispensing in the first 140 days and at least one in the 141 and 245 days of pregnancy)</td><td>1275 pregnancies (0.07%)</td></tr><tr><td>[35]</td><td>Richards et al., 2018</td><td>Gabapentin/during pregnancy</td><td>2009: 0.27 women per 1000 births<br>2014: 0.97 women per 1000 births</td></tr><tr><td>[31]</td><td>Shouman et al., 2022</td><td>Gabapentin/during pregnancy</td><td>785 pregnancies (0.29%)</td></tr><tr><td>[37]</td><td>Veiby et al., 2014</td><td>Gabapentin monotherapy/during pregnancy</td><td>39 children (0.005%)</td></tr></tbody></table>
<table><caption>**Table 3** (Continued)</caption><thead><tr><td>Reference number</td><td>Author and year</td><td>Exposure/period</td><td>Results</td></tr></thead><tbody><tr><td>[56]</td><td>Wide et al., 2004</td><td>Gabapentin monotherapy/in early pregnancy</td><td>18 children (0.003%)</td></tr></tbody></table>

LMP: last menstrual period.

The study objective was to summarize published data on the use of gabapentinoids in pregnancy and its association with adverse pregnancy/childhood outcomes.

## Methods

A narrative systematic review method was used to synthesize current research on all available literature regarding gabapentinoid exposure during pregnancy and childhood outcomes.

## Protocol and registration

This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) group guidelines [15].

## Eligibility criteria

Only observational studies (cohort, case-control, registry studies) were eligible, as no randomised clinical trials exists to assess safety of medication use among the pregnant population. Abstracts, literature reviews, case reports, case series, and spontaneous reports were excluded.

Eligible studies included those that evaluated the prevalence of gabapentin and/or pregabalin use during pregnancy, regardless of indication. Studies evaluating associations between the use of gabapentinoids during pregnancy and childhood outcomes were also eligible. Outcomes included major congenital malformations, birth and prenatal outcomes (such as miscarriage, stillbirth, preterm birth, small for gestational age); as well as long-term childhood outcomes (such as cognitive developmental delay, autism/dyspraxia, developmental delay and social impairment).

## Information sources and search strategy

The studies were identified on January 24, 2022, by a search of the Medline (PubMed) and Reprotox databases. The last updated search, carried out on July 2, 2024, added 7 new studies. The search was limited to papers published in English from January 2000 onwards. The search strategy included terms associated with the medications of interest: gabapentin, pregabalin and antiepileptic drugs; as well as terms associated with pregnancy. The results were limited to humans. The search terms are available in the Appendix (Supplementary method).

## Study selection

The list of studies generated after the database search was compiled in Rayyan, a platform for data management in systematic review projects, and duplicates were removed [16]. The screening and selection of relevant studies was performed in two stages. In the first round, the titles and abstracts of all citations retrieved from electronic databases were reviewed by one researcher (ABB). In the second round, the full-texts of the articles selected in the first round were independently evaluated on the basis of the predefined inclusion criteria (Table 1) by two researchers (ABB and JM). In case of disagreement, a consensus was reached on inclusion or exclusion by discussion and, if necessary, a third researcher (CDM) was consulted. Studies involving fewer than 5 exposures were excluded.

## Data extraction and data elements

A data extraction form based on the Cochrane model for non-RCTs was used. Data collection was performed by two researchers (ABB and JM).

For each eligible study, the following information was extracted: (1) study characteristics, including country and study period; (2) design and methodology, including type of study, sample size, medication, comparator if present, pregnancy/childhood outcomes and (3) results, including prevalence and measures of association [such as odd ratio (OR), risk ratio (RR), hazard ratio (HR) and prevalence ratio (PR)].

## Assessment of risk of study bias

We assessed the risk of bias in included studies using the Newcastle-Ottawa-Scale (NOS) for case-control or cohort studies. Two researchers (ABB, JM) applied the tool to each included study and recorded information and justifications for risk of bias judgements for each domain. The NOS ranged from a minimum of zero and a maximum of nine points. As there is no harmonized criterion for defining high quality, studies with an NOS score above six points were considered to be of high quality. Any discrepancies in the assessment of risk of bias or in the justification of assessments were resolved by discussion between the two researchers in order to reach a consensus, with a third author (CDM) acting as referee if necessary.

## Synthesis of results

The results of the included studies were described narratively and combined in tables to describe (1) the
characteristics of the different studies, (2) the results reported for each study and (3) the quality of the data. Results were presented separately for pregabalin and gabapentin. We reported the results of studies considered to be of high quality (NOS score greater than six) in the main text.

# Results

## Search results

Our literature search identified 1253 records, which, after the screening process, yielded 248 potentially relevant articles for inclusion (Fig. 1). After full-text review, 40 studies met the eligibility criteria, including the 7 additional studies following the updated search.

## Characteristics of the included studies

Thirty-one (31) studies were observational (all cohort studies) and 9 were studies based on pregnancy registries. The studies used 22 distinct data sources from 14 different countries [Australia, Canada, Denmark, Finland, France, Iceland, Israel, Italy, New-Zealand, Norway, Sweden, Switzerland, United Kingdom (UK), and United States (US)] (Table 2).

## Methodological quality results

Overall, 27 studies (68%) had a NOS score greater than six and were thus considered to be of high-quality (Table 2). The 27 high-quality studies were described and discussed in the following sections, whereas results of the remaining 13 studies [17–29] ranked as studies of lower quality are reported in the Appendix Tables S1–S4. This ranking is explained by the lack of comparator or control group in the analysis [29], self-reported outcome or exposure assessment [18,21–23,25,27,29], non-exposed cohort drawn from a different source [19,23], selected group of users [18,19,21–23,25–29], and no description of ascertainment of the outcome or the exposure [20].

## Prevalence of gabapentinoid use in pregnancy

Table 3 shows the 15 studies that estimated the prevalence of pregabalin use during pregnancy. Seven studies assessed exposure to monotherapy while the others did not mention the regimen of use. The prevalence of pregabalin use was less than 0.15%. The prevalence of gabapentin use during pregnancy was assessed in 18 studies: seven studies assessing exposure to monotherapy while the others did not mention the regimen of use. Prevalence has been estimated to range from 0.01% and to over 0.2–0.3% in the US [30] and Canada [31,32].

Only three studies reported the prevalence over time, and showed an increase in use in the recent years [33–35].

## Overall and specific congenital anomalies

Of the five studies assessing the risk of congenital anomalies after pregabalin exposure [36–40], three reported significant results [38–40]. The first study found an increased

risk of overall congenital anomalies after first trimester pregabalin monotherapy exposure (crude RR = 1.31 [95% CI: 1.26–2.58], 15 exposed cases) [38]. However, the increase in risk was no longer significant after controlling for founders, with a PS-adjusted RR = 0.87 (95% CI: 0.53–1.42) [38]. The second study reported significant associations when compared with exposure to lamotrigine and/or duloxetine (adjusted PR between 1.27 and 1.42 > 150 exposed cases) [39]. However, no increased risk was reported when compared with no exposure to antiepileptic [39]. In addition, after taking confounding factors into account, an increased risk of congenital anomalies of the nervous system, eyes, oro-facial clefs, and genital system was identified following pregabalin exposure [39]. The third study found an increased risk of coarctation of aorta following pregabalin monotherapy exposure [crude OR = 5.8 (95% CI: 1.6–14.9), 4 exposed cases] [40].

Of the six studies assessing the risk of congenital anomalies after gabapentin exposure [30,32,36,40–42], one study reported an increase of overall risk (crude RR = 1.49 [95% CI: 1.31–1.69], 230 exposed cases), as well as risk of major cardiac anomalies (crude RR = 1.77 [95% CI: 1.43–2.18], 87 exposed cases), however the increased risks were no longer observed after controlling for confounding factors (adjusted RR = 1.07 [95% CI: 0.94–1.21] for any major anomalies and adjusted RR = 1.12 [95% CI: 0.89–1.40] for major cardiac anomalies) [30] (Table 4).

## Pregnancy outcomes

Pregnancy outcomes were examined in five studies and included miscarriage, stillbirth, preterm birth, and preeclampsia [30,39,43–45].

Comparing pregabalin to lamotrigine exposure, an increased risk of miscarriage was identified, specifically among women with epilepsy (adjusted HR = 2.18 [95% CI: 1.38–3.44], 13 exposed cases), but not among women with psychiatric or somatic conditions [45]. Additionally, an increased risk of stillbirth was reported when comparing pregabalin exposure to no ASM-exposure (antiseizure medication exposure), to lamotrigine, and to lamotrigine and/or duloxetine exposure, with adjusted PRs ranging from 1.25 to 2.71, although some 95% CIs for adjusted PR included 1 [39]. No increased risk of preterm birth was observed after exposure to pregabalin, after controlling for confounding factors. A study also reported an increased risk of preeclampsia (adjusted RR = 1.43 [95% CI: 1.03–2.00], 33 exposed cases) and preterm birth (adjusted RR = 1.28 [95% CI: 1.08–1.52], 107 exposed cases) following gabapentin exposure in late pregnancy [30]. No increased risk was observed in the remaining studies [43,44] (Table 5).

## Short-term children outcomes

Seven studies examined low birth weight, small-for-gestational-age (SGA), microcephaly, low Apgar score and admission to neonatal intensive care unit (NICU) [30,32,39,43,44,46,47]. One study reported an increase risk of low birth weight (adjusted RR = 1.23 (95% CI: 1.03–1.47), 137 exposed cases) and SGA (adjusted RR = 1.16 [95% CI: 1.02–1.31], 318 exposed cases) when comparing pregabalin exposure to no ASM-exposure [47]. When the women were
<table><caption>Table 4 Overview of congenital anomalies risks described in the studies following exposure to gabapentinoids.</caption><thead><tr><th>Reference number</th><th>Author and year</th><th>Outcomes investigated</th><th>Exposure No events/No participants (%)</th><th>Comparison No events/No participants (%)</th><th>Results Measure of association (95% CI)</th></tr></thead><tbody><tr><td rowspan="4">Pregabalin exposure Overall congenital anomalies [39]</td><td>Dudukina et al., 2023</td><td>Major congenital anomalies detected up to 1 year after birth</td><td>First trimester exposure 162/2691 (6.02%)</td><td>ASM-unexposed 126,437/3,063,173 (4.13%)</td><td>Crude PR = 1.34 (1.15–1.57)<br>PS-adjusted PR = 1.14 (0.98–1.34)<br>MH-adjusted PR = 1.13 (0.98–1.32)</td></tr><tr><td>Dudukina et al., 2023</td><td>Major congenital anomalies detected up to 1 year after birth</td><td>First trimester exposure 157/2586 (6.07%)</td><td>First trimester lamotrigine exposure 362/7216 (5.02%)</td><td>Crude PR = 1.10 (0.91–1.34)<br>PS-adjusted PR = 1.31 (1.04–1.65)<br>MH-adjusted PR = 1.27 (1.04–1.55)</td></tr><tr><td>Dudukina et al., 2023</td><td>Major congenital anomalies detected up to 1 year after birth</td><td>First trimester exposure NR/2557</td><td>First trimester duloxetine exposure NR/2972</td><td>Crude PR = 1.09 (0.87–1.36)<br>PS-adjusted PR = 1.41 (1.09–1.81)<br>MH-adjusted PR = 1.42 (1.12–1.79)</td></tr><tr><td>Dudukina et al., 2023</td><td>Major congenital anomalies detected up to 1 year after birth</td><td>First trimester exposure 150/2463 (6.09%)</td><td>First trimester lamotrigine and duloxetine exposure 519/10,061 (5.16%)</td><td>Crude PR = 1.09 (0.90–1.31)<br>PS-adjusted PR = 1.28 (1.03–1.57)<br>MH-adjusted PR = 1.27 (1.05–1.53)</td></tr><tr><td>[36]</td><td>Källén et al., 2013</td><td>Relatively severe malformations</td><td>Monotherapy in early pregnancy 2/111 (1.80%)</td><td>Total population 49,499/1,575,847 (3.14%)</td><td>Not reported</td></tr><tr><td>[38]</td><td>Patorno et al., 2017</td><td>Non-chromosomal structural major congenital anomalies detected up to 90 days after birth</td><td>First trimester exposure MAX data: 28/477 (5.87%)<br>Marketscan data: not reported/174</td><td>Unexposed to any other anticonvulsant MAX data: 43,067/1,322,955 (3.26%)<br>Marketscan data: not reported/427,304</td><td>MAX data: Crude RR = 1.80 (0.80–2.14)<br>PS-adjusted RR = 1.16 (0.81–1.67)<br>Marketscan data: PS-adjusted RR = 1.03 (0.56–1.90)</td></tr></tbody></table>
<table><caption>Table 4 (Continued)</caption><thead><tr><th>Reference number</th><th>Author and year</th><th>Outcomes investigated</th><th>Exposure No events/No participants (%)</th><th>Comparison No events/No participants (%)</th><th>Results Measure of association (95% CI)</th></tr></thead><tbody><tr><td></td><td>Patorno et al., 2017</td><td>Non-chromosomal structural major congenital anomalies detected up to 90 days after birth</td><td>First trimester monotherapy exposure MAX data: 15/353 (4.25%) Marketscan data: not reported/118</td><td>Unexposed to any other anticonvulsant MAX data: 43,067/1,322,955 (3.26%) Marketscan data: not reported/427,304</td><td>MAX data: Crude RR = 1.31 (1.26–2.58) PS-adjusted RR = 0.87 (0.53–1.42) Marketscan data: PS-adjusted RR = 1.26 (0.64–2.49)</td></tr><tr><td>[37]</td><td>Veiby et al., 2014</td><td>Congenital anomaly detected up to 1 year after birth</td><td>Monotherapy any time during pregnancy 1/30 (3.33%)</td><td>No ASM in women with epilepsy 22,371/771,412 (2.90%)</td><td>Not reported</td></tr><tr><td>Specific congenital anomalies<sup>a</sup> [40]</td><td>Blotière et al., 2019</td><td>Spina bifida (detected up to 12 months after birth)</td><td>Monotherapy 1/1671 (0.06%)</td><td>Unexposed 616/1,875,733 (0.03%)</td><td>Crude OR = 1.8 (0.0–10.2)</td></tr><tr><td></td><td>Blotière et al., 2019</td><td>Ventricular septal defect (detected up to 12 months after birth)</td><td>Monotherapy 5/1671 (0.30%)</td><td>Unexposed 4643/1,875,733 (0.25%)</td><td>Crude OR = 1.1 (0.5–2.8)</td></tr><tr><td></td><td>Blotière et al., 2019</td><td>Atrial septal defect (detected up to 12 months after birth)</td><td>Monotherapy 6/1,671 (0.36%)</td><td>Unexposed 3268/1,875,733 (0.17%)</td><td>Crude OR = 1.9 (0.8–4.1)</td></tr><tr><td></td><td>Blotière et al., 2019</td><td>Hypoplastic left heart syndrome (detected up to 12 months after birth)</td><td>Monotherapy 1/1671 (0.06%)</td><td>Unexposed 216/1,875,733 (0.01%)</td><td>Crude OR = 5.2 (0.1–29.4)</td></tr><tr><td></td><td>Blotière et al., 2019</td><td>Coarctation of aorta (detected up to 12 months after birth)</td><td>Monotherapy 4/1671 (0.24%)</td><td>Unexposed 779/1,875,733 (0.04%)</td><td>Crude OR = 5.8 (1.6–14.9)</td></tr><tr><td></td><td>Blotière et al., 2019</td><td>Cleft lip with or without cleft palate (detected up to 12 months after birth)</td><td>Monotherapy 1/1671 (0.06%)</td><td>Unexposed 1637/1,875,733 (0.09%)</td><td>Crude OR = 0.7 (0.0–3.8)</td></tr></tbody></table>
<table><caption>Table 4 (Continued)</caption><thead><tr><th>Reference number</th><th>Author and year</th><th>Outcomes investigated</th><th>Exposure No events/No participants (%)</th><th>Comparison No events/No participants (%)</th><th>Results Measure of association (95% CI)</th></tr></thead><tbody><tr><td rowspan="12">[39]<sup>b</sup></td><td>Blotière et al., 2019</td><td>Cleft palate (detected up to 12 months after birth)</td><td>Monotherapy 2/1671 (0.12%)</td><td>Unexposed 1178/1,875,733 (0.06%)</td><td>Crude OR = 1.9 (0.2–6.9)</td></tr><tr><td>Blotière et al., 2019</td><td>Anorectal atresia (detected up to 12 months after birth)</td><td>Monotherapy 1/1671 (0.06%)</td><td>Unexposed 544/1,875,733 (0.03%)</td><td>Crude OR = 2.1 (0.1–11.6)</td></tr><tr><td>Blotière et al., 2019</td><td>Hypospadias (detected up to 24 months after birth)</td><td>Monotherapy 2/1671 (0.12%)</td><td>Unexposed 3371/1,875,733 (0.18%)</td><td>Crude OR = 0.7 (0.1–2.6)</td></tr><tr><td>Blotière et al., 2019</td><td>Craniosynostosis (detected up to 12 months after birth)</td><td>Monotherapy 3/1671 (0.18%)</td><td>Unexposed 766/1,875,733 (0.04%)</td><td>Crude OR = 4.4 (0.9–13.0)</td></tr><tr><td>Dudukina et al., 2023</td><td>Nervous system</td><td>First trimester exposure 6/2691 (0.22%)</td><td>ASM-unexposed 4134/3,063,173 (0.12%)</td><td>Crude PR = 2.50 (1.12–5.59)<br>PS-adjusted PR = 2.02 (0.88–4.63)<br>MH-adjusted PR = 1.15 (0.52–2.57)</td></tr><tr><td>Dudukina et al., 2023</td><td>Nervous system</td><td>First trimester exposure 6/2586 (0.23%)</td><td>Lamotrigine 10/7,216 (0.14%)</td><td>Crude PR = 2.05 (0.67–6.30)<br>PS-adjusted PR = 4.39 (1.36–14.13)<br>MH-adjusted PR = 3.20 (0.86–12.0)</td></tr><tr><td>Dudukina et al., 2023</td><td>Nervous system</td><td>First trimester exposure 6/2463 (0.24%)</td><td>Lamotrigine and duloxetine 18/10,061 (0.18%)</td><td>Crude PR = 1.98 (0.71–5.54)<br>PS-adjusted PR = 3.85 (1.21–12.25)<br>MH-adjusted PR = 1.70 (0.61–4.69)</td></tr><tr><td>Dudukina et al., 2023</td><td>Eye</td><td>First trimester exposure NR/2691</td><td>ASM-unexposed NR/3,063,173</td><td>Crude PR = 1.92 (1.03–3.57)<br>PS-adjusted PR = 2.09 (1.12–3.90)<br>MH-adjusted PR = 1.88 (1.01–3.49)</td></tr></tbody></table>
<table><caption>Table 4 (Continued)</caption><thead><tr><th>Reference number</th><th>Author and year</th><th>Outcomes investigated</th><th>Exposure No events/No participants (%)</th><th>Comparison No events/No participants (%)</th><th>Results Measure of association (95% CI)</th></tr></thead><tbody><tr><td></td><td>Dudukina et al., 2023</td><td>Congenital heart defects</td><td>First trimester exposure NR/2691</td><td>ASM-unexposed NR/3,063,173</td><td>Crude PR = 1.36 (1.06–1.74)<br>PS-adjusted PR = 1.08 (0.84–1.39)<br>MH-adjusted PR = 1.07 (0.84–1.37)</td></tr><tr><td></td><td>Dudukina et al., 2023</td><td>Oro-facial clefts</td><td>First trimester exposure 5/2691 (0.19%)</td><td>ASM-unexposed 5541/3,063,173 (0.18%)</td><td>Crude PR = 2.90 (1.21–6.98)<br>PS-adjusted PR = 2.90 (1.19–7.04)<br>MH-adjusted PR = 0.87 (0.36–2.10)</td></tr><tr><td></td><td>Dudukina et al., 2023</td><td>Oro-facial clefts</td><td>First trimester exposure 5/2586 (0.19%)</td><td>Lamotrigine 14/7,216 (0.19%)</td><td>Crude PR = 3.02 (0.88–10.34)<br>PS-adjusted PR = 4.21 (1.23–14.42)<br>MH-adjusted PR = 0.87 (0.37–2.04)</td></tr><tr><td></td><td>Dudukina et al., 2023</td><td>Oro-facial clefts</td><td>First trimester exposure 5/2557 (0.20%)</td><td>Duloxetine 5/2972 (0.17%)</td><td>Crude PR = 1.39 (0.27–7.20)<br>PS-adjusted PR = 3.30 (0.54–20.27)<br>MH-adjusted PR = 2.18 (0.51–9.36)</td></tr><tr><td></td><td>Dudukina et al., 2023</td><td>Oro-facial clefts</td><td>First trimester exposure NR/2463</td><td>Lamotrigine and duloxetine NR/10,061</td><td>Crude PR = 3.34 (1.06–10.54)<br>PS-adjusted PR = 4.97 (1.56–15.86)<br>MH-adjusted PR = 1.03 (0.43–2.44)</td></tr><tr><td></td><td>Dudukina et al., 2023</td><td>Digestive system</td><td>First trimester exposure 7/2691 (0.26%)</td><td>ASM-unexposed 6921/3,063,173 (0.23%)</td><td>Crude PR = 1.30 (0.62–2.73)<br>PS-adjusted PR = 1.02 (0.48–2.15)<br>MH-adjusted PR = 0.90 (0.43–1.90)</td></tr><tr><td></td><td>Dudukina et al., 2023</td><td>Digestive system</td><td>First trimester exposure 7/2586 (0.27%)</td><td>Lamotrigine 22/7,216 (0.30%)</td><td>Crude PR = 1.05 (0.44–2.51)<br>PS-adjusted PR = 1.54 (0.60–4.00)<br>MH-adjusted PR = 1.47 (0.60–3.60)</td></tr></tbody></table>
<table><caption>Table 4 (Continued)</caption><thead><tr><th>Reference number</th><th>Author and year</th><th>Outcomes investigated</th><th>Exposure No events/No participants (%)</th><th>Comparison No events/No participants (%)</th><th>Results Measure of association (95% CI)</th></tr></thead><tbody><tr><td></td><td>Dudukina et al., 2023</td><td>Digestive system</td><td>First trimester exposure 7/2463 (0.28%)</td><td>Lamotrigine and duloxetine 29/10,061 (0.29%)</td><td>Crude PR = 1.19 (0.51–2.76)<br>PS-adjusted PR = 1.34 (0.56–3.22)<br>MH-adjusted PR = 1.22 (0.53–2.78)</td></tr><tr><td></td><td>Dudukina et al., 2023</td><td>Urinary</td><td>First trimester exposure 15/2691 (0.56%)</td><td>ASM-unexposed 11,394/3,063,173 (0.37%)</td><td>Crude PR = 1.49 (0.90–2.48)<br>PS-adjusted PR = 1.41 (0.85–2.35)<br>MH-adjusted PR = 1.27 (0.77–2.11)</td></tr><tr><td></td><td>Dudukina et al., 2023</td><td>Urinary</td><td>First trimester exposure NR/2586</td><td>Lamotrigine NR/7216</td><td>Crude PR = 1.29 (0.67–2.51)<br>PS-adjusted PR = 3.02 (1.34–6.80)<br>MH-adjusted PR = 2.53 (1.09–5.86)</td></tr><tr><td></td><td>Dudukina et al., 2023</td><td>Urinary</td><td>First trimester exposure 12/2463 (0.49%)</td><td>Lamotrigine and duloxetine 45/10,061 (0.45%)</td><td>Crude PR = 1.14 (0.60–2.20)<br>PS-adjusted PR = 1.66 (0.80–3.45)<br>MH-adjusted PR = 1.37 (0.67–2.80)</td></tr><tr><td></td><td>Dudukina et al., 2023</td><td>Genital</td><td>First trimester exposure NR/2586</td><td>Lamotrigine NR/7216</td><td>Crude PR = 2.00 (0.99–4.03)<br>PS-adjusted PR = 2.13 (1.05–4.31)<br>MH-adjusted PR = 1.94 (0.97–3.89)</td></tr><tr><td></td><td>Dudukina et al., 2023</td><td>Genital</td><td>First trimester exposure NR/2557</td><td>Duloxetine NR/2972</td><td>Crude PR = 0.96 (0.49–1.90)<br>PS-adjusted PR = 2.64 (1.13–6.16)<br>MH-adjusted PR = 2.69 (1.09–6.65)</td></tr><tr><td></td><td>Dudukina et al., 2023</td><td>Genital</td><td>First trimester exposure NR/2463</td><td>Lamotrigine and duloxetine NR/10,061</td><td>Crude PR = 1.45 (0.79–2.68)<br>PS-adjusted PR = 2.26 (1.16–4.38)<br>MH-adjusted PR = 2.03 (1.06–3.87)</td></tr></tbody></table>
<table><caption>Table 4 (Continued)</caption><thead><tr><th>Reference number</th><th>Author and year</th><th>Outcomes investigated</th><th>Exposure No events/No participants (%)</th><th>Comparison No events/No participants (%)</th><th>Results Measure of association (95% CI)</th></tr></thead><tbody><tr><td rowspan="5">Gabapentin exposure Overall congenital anomalies [32]</td><td>Dudukina et al., 2023</td><td>Limb</td><td>First trimester exposure 29/2691 (1.08%)</td><td>ASM-unexposed 30,308/3,063,173 (0.99%)</td><td>Crude PR = 1.02 (0.71–1.47) PS-adjusted PR = 0.93 (0.64–1.34) MH-adjusted PR = 0.93 (0.65–1.33)</td></tr><tr><td>Dudukina et al., 2023</td><td>Limb</td><td>First trimester exposure 28/2586 (1.08%)</td><td>Lamotrigine 84/7216 (1.16%)</td><td>Crude PR = 0.86 (0.54–1.35) PS-adjusted PR = 1.61 (0.86–3.01) MH-adjusted PR = 1.12 (0.71–1.77)</td></tr><tr><td>Dudukina et al., 2023</td><td>Limb</td><td>First trimester exposure 27/2463 (1.10%)</td><td>Lamotrigine and duloxetine 111/10,061 (1.10%)</td><td>Crude PR = 0.90 (0.58–1.39) PS-adjusted PR = 1.11 (0.67–1.84) MH-adjusted PR = 1.05 (0.68–1.62)</td></tr><tr><td>Dudukina et al., 2023</td><td>Other</td><td>First trimester exposure 24/2691 (0.89%)</td><td>ASM-unexposed 14,534/3,063,173 (0.47%)</td><td>Crude PR = 1.82 (1.22–2.71) PS-adjusted PR = 1.42 (0.95–2.13) MH-adjusted PR = 1.32 (0.89–1.97)</td></tr><tr><td>Dudukina et al., 2023</td><td>Other</td><td>First trimester exposure NR/2586</td><td>Lamotrigine NR/7216</td><td>Crude PR = 1.37 (0.80–2.35) PS-adjusted PR = 2.33 (1.21–4.47) MH-adjusted PR = 2.10 (1.16–3.81)</td></tr><tr><td>[36]</td><td>Desrochers et al., 2024</td><td>Major congenital anomalies detected up to 1 year</td><td>First trimester exposure 41/870 (4.70%)</td><td>Unexposed 10,390/288,357 (3.60%)</td><td>Crude OR = 1.30 (0.94–1.81) Adjusted OR = 1.00 (0.72–1.38)</td></tr><tr><td>[36]</td><td>Källén et al., 2013</td><td>Relatively severe malformations</td><td>Monotherapy in early pregnancy 2/119 (1.68%)</td><td>Total population 49,499/1,575,847 (3.14%)</td><td>Not reported</td></tr><tr><td>[54]</td><td>Mølgaard-Nielsen et al., 2011</td><td>Major congenital anomalies detected up to 1 year</td><td>1/59 (1.70%)</td><td>Unexposed to any newer-generation antiepileptic drugs during pregnancy 19,911/83,6263 (2.40%)</td><td>Crude POR = 0.71 (0.10–5.10) Adjusted POR = 0.53 (0.07–3.85)</td></tr></tbody></table>
<table><caption>Table 4 (Continued)</caption><thead><tr><th>Reference number</th><th>Author and year</th><th>Outcomes investigated</th><th>Exposure No events/No participants (%)</th><th>Comparison No events/No participants (%)</th><th>Results Measure of association (95% CI)</th></tr></thead><tbody><tr><td>[42]</td><td>Morrow et al., 2006</td><td>Major congenital anomalies detected up to 6 weeks after birth</td><td>Monotherapy 1/31 (3.23%)</td><td>Carbamazepine monotherapy 20/900 (2.22%)</td><td>Crude OR = 1.33 (0.17–10.20)<br>Adjusted OR = 0.76 (0.22–14.49)</td></tr><tr><td>[30]</td><td>Patorno et al., 2020</td><td>Major congenital anomalies detected up to 3 months after birth</td><td>First trimester exposure 230/4642 (4.95%)</td><td>Unexposed 58,086/1,744,447 (3.33%)</td><td>Crude RR = 1.49 (1.31–1.69)<br>Adjusted RR = 1.07 (0.94–1.21)</td></tr><tr><td>Specific congenital anomalies<sup>a</sup></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>[40]</td><td>Blotière et al., 2019</td><td>Spina bifida (detected up to 12 months after birth)</td><td>Monotherapy 1/365 (0.27%)</td><td>Unexposed 616/1,875,733 (0.03%)</td><td>Crude OR = 8.4 (0.2–47.1)</td></tr><tr><td></td><td>Blotière et al., 2019</td><td>Ventricular septal defect (detected up to 12 months after birth)</td><td>Monotherapy 1/365 (0.27%)</td><td>Unexposed 4643/1,875,733 (0.25%)</td><td>Crude OR = 1.1 (0.0–6.3)</td></tr><tr><td></td><td>Blotière et al., 2019</td><td>Hypospadias (detected up to 24 months after birth)</td><td>Monotherapy 1/365 (0.27%)</td><td>Unexposed 3371/1,875,733 (0.18%)</td><td>Crude OR = 1.6 (0.0–8.9)</td></tr><tr><td>[32]</td><td>Desrochers et al., 2024</td><td>Cardiac anomalies detected up to 1 year</td><td>First trimester exposure 14/870 (1.61%)</td><td>Unexposed 2255/288,357 (0.78%)</td><td>Crude OR = 2.01 (1.12–3.62)<br>Adjusted OR = 1.29 (0.72–2.31)</td></tr><tr><td>[32]</td><td>Desrochers et al., 2024</td><td>Oro-facial anomalies</td><td>First trimester exposure ≤ 5/870</td><td>Unexposed 648/288,357 (0.22%)</td><td>Crude OR = 1.97 (0.69–5.60)<br>Adjusted OR = 1.37 (0.50–3.77)</td></tr><tr><td>[30]</td><td>Patorno et al., 2020</td><td>Major cardiac anomalies</td><td>First trimester exposure 87/4642 (1.87%)</td><td>Unexposed 18,514/1,744,447 (1.06%)</td><td>Crude RR = 1.77 (1.43–2.18)<br>Adjusted RR = 1.12 (0.89–1.40)</td></tr></tbody></table>

ASM: antiseizure medications; CI: confidence interval; MH: Mantel-Haenszel; NR: not reportable to keep masking of a low number of individuals (< 5) in other cells; OR: odds ratio; POR: proportion odds ratio; PR: prevalence ratio; PS: propensity score; RR: relative risk.

<footnote>a Only finding with at least one exposed case are reported.</footnote>

<footnote>b Only significant findings or findings with at least 5 exposed cases are reported, in bold significant results.</footnote>
<table><caption>Table 5 Overview of pregnancy and short-term children outcomes risks described in the studies following exposure to gabapentinoids.</caption><thead><tr><th>Reference number</th><th>Author and year</th><th>Outcomes investigated</th><th>Exposure No events/No participants (%)</th><th>Comparison No events/No participants (%)</th><th>Results Measure of association (95% CI)</th></tr></thead><tbody><tr><td rowspan="10">Pregnancy outcomes Pregabalin exposure [39]<sup>a</sup></td><td>Dudukina et al., 2023</td><td>Stillbirth</td><td>NR/2851</td><td>ASM-unexposed NR/3,061,487</td><td>Crude PR = 2.14 (1.27–3.60) PS-adjusted PR = 1.72 (1.02–2.91) MH-adjusted PR = 1.25 (0.74–2.11)</td></tr><tr><td>Dudukina et al., 2023</td><td>Stillbirth</td><td>NR/2740</td><td>Lamotrigine NR/7742</td><td>Crude PR = 2.24 (1.10–4.57) PS-adjusted PR = 1.87 (0.81–4.32) MH-adjusted PR = 1.30 (0.69–2.47)</td></tr><tr><td>Dudukina et al., 2023</td><td>Stillbirth</td><td>NR/2609</td><td>Lamotrigine and duloxetine NR/10,631</td><td>Crude PR = 2.09 (1.05–4.17) PS-adjusted PR = 2.71 (1.25–5.90) MH-adjusted PR = 1.93 (0.98–3.78)</td></tr><tr><td>Dudukina et al., 2023</td><td>Preterm birth</td><td>225/2812 (8.00%)</td><td>ASM-unexposed 151,114/3,009,386 (5.02%)</td><td>Crude PR = 1.78 (1.57–2.03) PS-adjusted PR = 1.13 (1.00–1.29) MH-adjusted PR = 1.12 (0.99–1.27)</td></tr><tr><td>Dudukina et al., 2023</td><td>Preterm birth</td><td>217/2704 (8.03%)</td><td>Lamotrigine 578/7580 (7.63%)</td><td>Crude PR = 1.28 (1.10–1.51) PS-adjusted PR = 0.98 (0.83–1.15) MH-adjusted PR = 0.99 (0.85–1.15)</td></tr><tr><td>Dudukina et al., 2023</td><td>Preterm birth</td><td>207/2674 (7.74%)</td><td>Duloxetine 248/2967 (8.36%)</td><td>Crude PR = 1.03 (0.85–1.24) PS-adjusted PR = 1.04 (0.86–1.27) MH-adjusted PR = 1.04 (0.87–1.24)</td></tr><tr><td>Dudukina et al., 2023</td><td>Preterm birth</td><td>201/2577 (7.80%)</td><td>Lamotrigine and/or duloxetine 810/10,418 (7.78%)</td><td>Crude PR = 1.21 (1.04–1.42) PS-adjusted PR = 1.05 (0.89–1.23) MH-adjusted PR = 1.06 (0.92–1.23)</td></tr></tbody></table>
<table><caption>Table 5 (Continued)</caption><thead><tr><th>Reference number</th><th>Author and year</th><th>Outcomes investigated</th><th>Exposure No events/No participants (%)</th><th>Comparison No events/No participants (%)</th><th>Results Measure of association (95% CI)</th></tr></thead><tbody><tr><td>[45]</td><td>Forbes et al., 2024</td><td>Miscarriage</td><td>165/882 (18.71%)</td><td>Lamotrigine 253/1916 (13.20%)</td><td>Fully-adjusted HR = 1.13 (0.89–1.44)</td></tr><tr><td>[45]</td><td>Forbes et al., 2024</td><td>Miscarriage</td><td>Among women with epilepsy 13/37 (35.14%)</td><td>Among women with epilepsy Lamotrigine 208/1656 (12.56%)</td><td>Fully-adjusted HR = 2.18 (1.38–3.44)</td></tr><tr><td>[45]</td><td>Forbes et al., 2024</td><td>Miscarriage</td><td>Among women with bipolar or other psychiatric conditions 153/831 (18.41%)</td><td>Among women with bipolar or other psychiatric conditions Lamotrigine 142/983 (14.45%)</td><td>Fully-adjusted HR = 1.12 (0.86–1.46)</td></tr><tr><td>[45]</td><td>Forbes et al., 2024</td><td>Miscarriage</td><td>Among women with other somatic conditions 88/434 (20.28%)</td><td>Among women with other somatic conditions 56/371 (15.09%)</td><td>Fully-adjusted HR = 0.98 (0.66–1.46)</td></tr><tr><td>[43]</td><td>Kilic et al., 2014</td><td>Preterm birth</td><td>Monotherapy 4/18 (22.22%)</td><td>No ASM 33,974/676,834 (5.02%)</td><td>Not reported</td></tr><tr><td>[44]</td><td>Margulis et al., 2019</td><td>Preterm birth</td><td>76/562 (13.52%)</td><td>Lamotrigine 180/2254 (7.99%)</td><td>Adjusted OR = 1.5 (1.0–2.4) Among mother with epilepsy: crude OR = 4.2 (1.6–11.4) Among first trimester user: crude OR = 1.9 (1.2–3.0)</td></tr><tr><td>Gabapentin exposure</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>[45]</td><td>Forbes et al., 2024</td><td>Miscarriage</td><td>201/1224 (16.42%)</td><td>Lamotrigine 253/1916 (13.20%)</td><td>Fully-adjusted HR = 1.00 (0.80–1.26)</td></tr><tr><td>[45]</td><td>Forbes et al., 2024</td><td>Miscarriage</td><td>Among women with epilepsy 11/75 (14.67%)</td><td>Among women with epilepsy Lamotrigine 208/1656 (12.56%)</td><td>Fully-adjusted HR = 1.13 (0.65–1.97)</td></tr><tr><td>[45]</td><td>Forbes et al., 2024</td><td>Miscarriage</td><td>Among women with bipolar or other psychiatric conditions 183/1105 (16.56%)</td><td>Among women with bipolar or other psychiatric conditions Lamotrigine 142/983 (14.45%)</td><td>Fully-adjusted HR = 1.02 (0.79–1.31)</td></tr></tbody></table>
<table><caption>Table 5 (Continued)</caption><thead><tr><th>Reference number</th><th>Author and year</th><th>Outcomes investigated</th><th>Exposure<br>No events/No participants (%)</th><th>Comparison<br>No events/No participants (%)</th><th>Results<br>Measure of association (95% CI)</th></tr></thead><tbody><tr><td>[45]</td><td>Forbes et al., 2024</td><td>Miscarriage</td><td>Among women with other somatic conditions<br>91/565 (16.11%)</td><td>Among women with other somatic conditions<br>56/371 (15.09%)</td><td>Fully-adjusted HR = 0.80 (0.54–1.17)</td></tr><tr><td>[43]</td><td>Kilic et al., 2014</td><td>Preterm birth</td><td>Monotherapy<br>11/91 (12.09%)</td><td>No ASM<br>33,974/676,834 (5.02%)</td><td>Crude RR = 2.41 (1.39–4.17)</td></tr><tr><td rowspan="7">[30]</td><td rowspan="2">Patorno et al., 2020</td><td rowspan="2">Preterm birth</td><td>Exposure early in pregnancy<br>571/3745 (15.25%)</td><td>Unexposed<br>182,445/1,744,447 (10.46%)</td><td>Crude RR = 1.46 (1.35–1.57)<br>Adjusted RR = 1.00 (0.93–1.08)</td></tr><tr><td>Exposure late in pregnancy<br>107/556 (19.24%)</td><td>Unexposed<br>182,445/1,744,447 (10.46%)</td><td>Crude RR = 1.84 (1.55–2.18)<br>Adjusted RR = 1.28 (1.08–1.52)</td></tr><tr><td>Patorno et al., 2020</td><td>Preterm birth</td><td>Exposure early and late in pregnancy<br>258/1275 (20.24%)</td><td>Unexposed<br>182,445/1,744,447 (10.46%)</td><td>Crude RR = 1.93 (1.73–2.16)<br>Adjusted RR = 1.22 (1.09–1.36)</td></tr><tr><td>Patorno et al., 2020</td><td>Preeclampsia</td><td>Exposure early in pregnancy<br>182/3745 (4.86%)</td><td>Unexposed<br>72,197/1,744,447 (4.14%)</td><td>Crude RR = 1.17 (1.01–1.35)<br>Adjusted RR = 0.87 (0.75–1.00)</td></tr><tr><td>Patorno et al., 2020</td><td>Preeclampsia</td><td>Exposure late in pregnancy<br>33/556 (5.94%)</td><td>Unexposed<br>72,197/1,744,447 (4.14%)</td><td>Crude RR = 1.43 (1.03–2.00)<br>Adjusted RR = 1.43 (1.03–2.00)</td></tr><tr><td>Patorno et al., 2020</td><td>Preeclampsia</td><td>Exposure early and late in pregnancy<br>80/1275 (6.27%)</td><td>Unexposed<br>72,197/1,744,447 (4.14%)</td><td>Crude RR = 1.52 (1.23–1.87)<br>Adjusted RR = 0.92 (0.74–1.13)</td></tr><tr><td>Short-term children outcomes<br>Pregabalin exposure<br>[47]</td><td>Christensen et al., 2024</td><td>Low birth weight</td><td>Monotherapy<br>136/2214 (6.14%)</td><td>ASM-unexposed<br>141,442/4,467,848 (3.17%)</td><td>Adjusted OR = 1.23 (1.03–1.47)<br>Among children with mother with epilepsy: Adjusted<br>OR = 0.92 (0.44–1.92)<br>Among children with mother without epilepsy: Adjusted<br>OR = 1.25 (1.04–1.51)</td></tr></tbody></table>
<table><caption>Table 5 (Continued)</caption><thead><tr><th>Reference number</th><th>Author and year</th><th>Outcomes investigated</th><th>Exposure No events/No participants (%)</th><th>Comparison No events/No participants (%)</th><th>Results Measure of association (95% CI)</th></tr></thead><tbody><tr><td>[47]</td><td>Christensen et al., 2024</td><td>Small for gestational age</td><td>Monotherapy 318/2214 (14.36%)</td><td>ASM-unexposed 446,267/4,467,848 (9.99%)</td><td>Adjusted OR = 1.16 (1.02–1.31)<br>Among children with mother with epilepsy: Adjusted OR= 1.01 (0.58–1.77)<br>Among children with mother without epilepsy: Adjusted OR = 1.17 (1.03–1.32)</td></tr><tr><td>[47]</td><td>Christensen et al., 2024</td><td>Microcephaly</td><td>Monotherapy 83/2214 (3.75%)</td><td>ASM-unexposed 134,023/4,467,848 (3.00%)</td><td>Adjusted OR = 1.01 (0.80–1.27)<br>Among children with mother with epilepsy: NA<br>Among children with mother without epilepsy: Adjusted OR = 1.02 (0.80–1.28)</td></tr><tr><td rowspan="5">[39]<sup>a</sup></td><td>Dudukina et al., 2023</td><td>Small for gestational age</td><td>NR/2776</td><td>ASM-unexposed NR/2,959,022</td><td>Crude PR = 1.55 (1.25–1.91)<br>PS-adjusted PR = 1.12 (0.91–1.39)<br>MH-adjusted PR = 1.10 (0.90–1.36)</td></tr><tr><td>Dudukina et al., 2023</td><td>Small for gestational age</td><td>NR/2669</td><td>Lamotrigine NR/7461</td><td>Crude PR = 1.56 (1.17–2.09)<br>PS-adjusted PR = 1.06 (0.79–1.42)<br>MH-adjusted PR = 1.09 (0.84–1.43)</td></tr><tr><td>Dudukina et al., 2023</td><td>Small for gestational age</td><td>NR/2543</td><td>Lamotrigine and/or duloxetine NR/10,280</td><td>Crude PR = 1.41 (1.08–1.83)<br>PS-adjusted PR = 0.99 (0.75–1.31)<br>MH-adjusted PR = 0.93 (0.73–1.19)</td></tr><tr><td>Dudukina et al., 2023</td><td>Low birth weight</td><td>178/2811 (6.33%)</td><td>ASM-unexposed 121,039/3,009,100 (4.02%)</td><td>Crude PR = 1.60 (1.38–1.85)<br>PS-adjusted PR = 1.04 (0.90–1.21)<br>MH-adjusted PR = 1.04 (0.90–1.20)</td></tr><tr><td>Dudukina et al., 2023</td><td>Low birth weight</td><td>172/2703 (6.36%)</td><td>Lamotrigine 394/7578 (5.20%)</td><td>Crude PR = 1.28 (1.06–1.55)<br>PS-adjusted PR = 0.91 (0.75–1.10)<br>MH-adjusted PR = 0.94 (0.79–1.11)</td></tr></tbody></table>
<table><caption>Table 5 (Continued)</caption><thead><tr><th>Reference number</th><th>Author and year</th><th>Outcomes investigated</th><th>Exposure No events/No participants (%)</th><th>Comparison No events/No participants (%)</th><th>Results Measure of association (95% CI)</th></tr></thead><tbody><tr><td></td><td>Dudukina et al., 2023</td><td>Low birth weight</td><td>166/2673 (6.21%)</td><td>Duloxetine 187/2966 (6.30%)</td><td>Crude PR = 0.97 (0.78–1.20)<br>PS-adjusted PR = 0.80 (0.64–1.00)<br>MH-adjusted PR = 0.78 (0.64–0.95)</td></tr><tr><td></td><td>Dudukina et al., 2023</td><td>Low birth weight</td><td>162/2576 (6.29%)</td><td>Lamotrigine and/or duloxetine 574/10,415 (5.51%)</td><td>Crude PR = 1.17 (0.97–1.40)<br>PS-adjusted PR = 0.87 (0.72–1.05)<br>MH-adjusted PR = 0.87 (0.74–1.03)</td></tr><tr><td></td><td>Dudukina et al., 2023</td><td>Low Apgar score</td><td>81/2812 (2.88%)</td><td>ASM-unexposed 39,807/3,009,480 (1.32%)</td><td>Crude PR = 2.05 (1.65–2.55)<br>PS-adjusted PR = 1.17 (0.94–1.46)<br>MH-adjusted PR = 1.16 (0.94–1.44)</td></tr><tr><td></td><td>Dudukina et al., 2023</td><td>Low Apgar score</td><td>76/2704 (2.81%)</td><td>Lamotrigine 165/7580 (2.18%)</td><td>Crude PR = 1.05 (0.79–1.39)<br>PS-adjusted PR = 0.93 (0.69–1.26)<br>MH-adjusted PR = 0.86 (0.66–1.12)</td></tr><tr><td></td><td>Dudukina et al., 2023</td><td>Low Apgar score</td><td>70/2577 (2.72%)</td><td>Lamotrigine and/or duloxetine 233/10,418 (2.24%)</td><td>Crude PR = 1.01 (0.77–1.33)<br>PS-adjusted PR = 0.86 (0.64–1.15)<br>MH-adjusted PR = 0.83 (0.64–1.08)</td></tr><tr><td></td><td>Dudukina et al., 2023</td><td>Microcephaly</td><td>69/2762 (2.50%)</td><td>ASM-unexposed 56,404/2,940,009 (1.92%)</td><td>Crude PR = 1.34 (1.06–1.69)<br>PS-adjusted PR = 1.10 (0.86–1.40)<br>MH-adjusted PR = 1.10 (0.87–1.38)</td></tr><tr><td></td><td>Dudukina et al., 2023</td><td>Microcephaly</td><td>64/2654 (2.41%)</td><td>Lamotrigine 156/7419 (2.10%)</td><td>Crude PR = 1.06 (0.77–1.44)<br>PS-adjusted PR = 1.01 (0.72–1.43)<br>MH-adjusted PR = 1.05 (0.77–1.44)</td></tr><tr><td></td><td>Dudukina et al., 2023</td><td>Microcephaly</td><td>66/2625 (2.51%)</td><td>Duloxetine 52/2936 (1.77%)</td><td>Crude PR = 1.27 (0.87–1.85)<br>PS-adjusted PR = 1.05 (0.70–1.58)<br>MH-adjusted PR = 1.06 (0.74–1.51)</td></tr></tbody></table>
<table><caption>Table 5 (Continued)</caption><thead><tr><th>Reference number</th><th>Author and year</th><th>Outcomes investigated</th><th>Exposure No events/No participants (%)</th><th>Comparison No events/No participants (%)</th><th>Results Measure of association (95% CI)</th></tr></thead><tbody><tr><td></td><td>Dudukina et al., 2023</td><td>Microcephaly</td><td>62/2528 (2.45%)</td><td>Lamotrigine and/or duloxetine 207/10,227 (2.02%)</td><td>Crude PR = 1.13 (0.84–1.52) PS-adjusted PR = 1.07 (0.77–1.48) MH-adjusted PR = 1.07 (0.80–1.44)</td></tr><tr><td>[43]</td><td>Kilic et al., 2014</td><td>Low birth weight</td><td>Monotherapy 3/18 (16.67%)</td><td>No ASM 23,503/673,844 (3.49%)</td><td>Not reported</td></tr><tr><td></td><td>Kilic et al., 2014</td><td>Small for gestational age</td><td>Monotherapy 5/18 (27.78%)</td><td>No ASM 65,118/673,844 (9.66%)</td><td>Not reported</td></tr><tr><td rowspan="5">[44]</td><td>Margulis et al., 2019</td><td>Birth weight z-score</td><td>Mean: -0.2 ± 1.1 n = 561</td><td>Lamotrigine Mean: 0.0 ± 1.1, n = 2248</td><td>Mean difference: -0.1 (-0.3 to 0.0)</td></tr><tr><td>Margulis et al., 2019</td><td>Birth length z-score</td><td>Mean: -0.3 ± 1.0 n = 553</td><td>Lamotrigine Mean: 0.0 ± 1.0, n = 2218</td><td>Mean difference: -0.1 (-0.2 to 0.0)</td></tr><tr><td>Margulis et al., 2019</td><td>Birth head circumference z-score</td><td>Mean: 0.1 ± 1.1 n = 549</td><td>Lamotrigine Mean: 0.2 ± 1.1, n = 2193</td><td>Mean difference: -0.0 (-0.1 to 0.1)</td></tr><tr><td>Margulis et al., 2019</td><td>Microcephaly</td><td>15/549 (2.73%)</td><td>Lamotrigine 48/2193 (2.19%)</td><td>Adjusted OR = 1.2 (0.5–2.9)</td></tr><tr><td>Margulis et al., 2019</td><td>Small for gestational age</td><td>22/547 (4.02%)</td><td>Lamotrigine 52/2184 (2.38%)</td><td>Adjusted OR = 1.3 (0.6–3.0)</td></tr><tr><td>Gabapentin exposure [46]</td><td>Almgren et al., 2009</td><td>Birth weight-adjusted mean head circumference (mean SDS from population control material)</td><td>Monotherapy n = 56 children</td><td>Population control n = 900,739 children</td><td>SDS, Mean ± SEM; P-value: -0.02 ± 0.13; 0.39</td></tr></tbody></table>
<table><caption>Table 5 (Continued)</caption><thead><tr><th>Reference number</th><th>Author and year</th><th>Outcomes investigated</th><th>Exposure No events/No participants (%)</th><th>Comparison No events/No participants (%)</th><th>Results Measure of association (95% CI)</th></tr></thead><tbody><tr><td>[47]</td><td>Christensen et al., 2024</td><td>Low birth weight</td><td>Monotherapy 76/1336 (5.69%)</td><td>No ASM 141,442/4,467,848 (3.17%)</td><td>Adjusted OR = 1.25 (0.98-1.59)<br>Among children with mother with epilepsy: Adjusted OR = 1.04 (0.50-2.14)<br>Among children with mother without epilepsy: Adjusted OR = 1.28 (1.00-1.66)</td></tr><tr><td>[47]</td><td>Christensen et al., 2024</td><td>Small for gestational age</td><td>Monotherapy 168/1336 (12.57%)</td><td>No ASM 446,267/4,467,848 (9.99%)</td><td>Adjusted OR = 1.13 (0.96-1.34)<br>Among children with mother with epilepsy: Adjusted OR = 0.91 (0.52-1.57)<br>Among children with mother without epilepsy: Adjusted OR = 1.16 (0.97-1.38)</td></tr><tr><td>[47]</td><td>Christensen et al., 2024</td><td>Microcephaly</td><td>Monotherapy 32/1336 (2.40%)</td><td>No ASM 134,023/4,467,848 (3.00%)</td><td>Adjusted OR = 0.67 (0.46-0.97)<br>Among children with mother with epilepsy: NA<br>Among children with mother without epilepsy: Adjusted OR = 0.69 (0.47-1.02)</td></tr><tr><td>[32]</td><td>Desrochers et al., 2024</td><td>NICU admission</td><td>78/870 (8.97%)</td><td>Unexposed 17,689/288,357 (6.13%)</td><td>Crude OR = 3.40 (2.85-4.05)<br>Adjusted OR = 2.18 (1.81-2.62)</td></tr><tr><td>[43]</td><td>Kilic et al., 2014</td><td>Low birth weight</td><td>Monotherapy 5/91 (5.49%)</td><td>No ASM 23,503/673,844 (3.49%)</td><td>Crude RR = 1.58 (0.67-3.70)</td></tr></tbody></table>
<table><caption>Table 5 (Continued)</caption><thead><tr><th>Reference number</th><th>Author and year</th><th>Outcomes investigated</th><th>Exposure<br>No events/No participants (%)</th><th>Comparison<br>No events/No participants (%)</th><th>Results<br>Measure of association (95% CI)</th></tr></thead><tbody><tr><td rowspan="7">[30]</td><td>Kilic et al.,<br>2014</td><td>Small for<br>gestational<br>age</td><td>Monotherapy<br>11/91 (12.09%)</td><td>No ASM<br>65,118/673,844<br>(9.66%)</td><td>Crude RR = 1.25 (0.72–2.18)</td></tr><tr><td>Patorno et al.,<br>2020</td><td>Small for<br>gestational<br>age</td><td>Exposure early in<br>pregnancy<br>205/3745 (5.47%)</td><td>Unexposed<br>55,803/1,744,447<br>(3.20%)</td><td>Crude RR = 1.71 (1.50–1.96)<br>Adjusted RR = 1.17 (1.02–1.33)</td></tr><tr><td>Patorno et al.,<br>2020</td><td>Small for<br>gestational<br>age</td><td>Exposure late in<br>pregnancy<br>35/556 (6.29%)</td><td>Unexposed<br>55,803/1,744,447<br>(3.20%)</td><td>Crude RR = 1.97 (1.43–2.71)<br>Adjusted RR = 1.39 (1.01–1.91)</td></tr><tr><td>Patorno et al.,<br>2020</td><td>Small for<br>gestational<br>age</td><td>Exposure early and<br>late in pregnancy<br>92/1275 (7.22%)</td><td>Unexposed<br>55,803/1,744,447<br>(3.20%)</td><td>Crude RR = 2.26 (1.85–2.75)<br>Adjusted RR = 1.32 (1.08–1.60)</td></tr><tr><td>Patorno et al.,<br>2020</td><td>NICU<br>admission</td><td>Exposure early in<br>pregnancy<br>411/3745 (10.97%)</td><td>Unexposed<br>101,202/1,744,447<br>(5.80%)</td><td>Crude RR = 1.89 (1.73–2.07)<br>Adjusted RR = 1.01 (0.93–1.11)</td></tr><tr><td>Patorno et al.,<br>2020</td><td>NICU<br>admission</td><td>Exposure late in<br>pregnancy<br>68/556 (12.23%)</td><td>Unexposed<br>101,202/1,744,447<br>(5.80%)</td><td>Crude RR = 2.11 (1.69–2.63)<br>Adjusted RR = 1.21 (0.97–1.51)</td></tr><tr><td>Patorno et al.,<br>2020</td><td>NICU<br>admission</td><td>Exposure early and<br>late in pregnancy<br>224/1275 (17.57%)</td><td>Unexposed<br>101,202/1,744,447<br>(5.80%)</td><td>Crude RR = 3.03 (2.69–3.41)<br>Adjusted RR = 1.35 (1.20–1.52)</td></tr></tbody></table>

ASM: antiseizure medications; CI: confidence interval; MH: Mantel–Haenszel; NICU: neonatal intensive care unit; NR: not reportable to keep masking of a low number of individuals (< 5) in other cells; OR: odds ratio; PR: prevalence ratio; PS: propensity score; RR: relative risk; SGA: small-for-gestational-age.

<footnote>ª Only significant findings or findings with at least 5 exposed cases are reported, in bold significant results.</footnote>
stratified by conditions, the increased were only observed among children with mother without epilepsy [47]. When comparing gabapentin exposure to no exposure during pregnancy, one study reported an increased risk of SGA (adjusted RR = 1.39 [95% CI: 1.01–1.91], 35 exposed cases late in pregnancy) and an increased risk of NICU admission (adjusted RR = 1.35 [95% CI: 1.20–1.52], 224 exposed cases early and late in pregnancy) [30]. The increase risk of NICU admission was also observed in a second study (adjusted OR = 2.18 [95% CI: 1.81–2.62], 78 exposed cases) [32]. No increased risk was observed in the remaining studies [39,43,44,46] (Table 5).

## Long-term outcomes in children

Six studies examined overall neurodevelopmental disorders outcomes, as well as specific outcomes (such as autism spectrum disorder or mental retardation), learning disabilities and speech therapist visits [39,48–52]. One study reported an increased risk of hyperkinetic disorders following exposure to pregabalin when compared with no ASM-exposure (adjusted HR = 1.29 [95% CI: 1.03–1.63], 72 exposed cases), but the association was not present when compared with lamotrigine and/or duloxetine exposure [39]. Another one reported an increased risk of mental retardation (adjusted HR = 3.1 [95% CI: 1.2–8.3], 4 exposed cases) and utilization of orthoptics services (adjusted HR = 1.4 [95% CI: 1.1–1.6], 98 exposed cases) after monotherapy exposure to pregabalin when compared with no ASM-exposure in the absence of maternal mental illness [50]. No increased risk was observed after prenatal exposure to gabapentin [48–52] (Table 6).

## Discussion

### Main findings

The objective of this systematic review was to comprehensively analyze the existing literature on gabapentinoid use during pregnancy and its association with adverse pregnancy/childhood outcomes, as well as to identify research gaps in this area. The prevalence of gabapentinoid use during pregnancy remained very low, at less than 1%. Three studies reported an increased risk of overall congenital anomalies, certain specific anomalies (nervous system, eyes, oro-facial clefs, and genital system), miscarriage, stillbirth and specific neurodevelopmental outcomes after exposure to pregabalin during pregnancy [39,40,50]. Concerning exposure to gabapentin, increased risks of preterm birth, preeclampsia, small-for-gestational-age and NICU admission were reported in two studies [30,32].

### Interpretation

All studies reported a very low prevalence of gabapentinoid use during pregnancy, below 1% in the general population of pregnant women. However, the prevalence of use varied by country, with lower rates observed in Europe (below 0.05%) compared to the US or Canada. The prevalence of use of pregabalin were higher in France and UK (but still below 1%) compared to other European countries. Although limited data on gabapentinoid use over time were available, it seemed that an increase in use was observed in recent years.

Animal safety studies following prenatal exposure to gabapentinoids have shown some adverse effects on embryo development and viability. In mice, gabapentin exposure at doses ranging from 1 to 5 times the human equivalent was associated with fetal growth retardation [8], and increased incidence of hydroureter and hydronephrosis, conditions previously linked to developmental delay. Rabbits exposed during gestation to gabapentin at 0.3 to 8 times the human dose exhibited a higher rate of fetal loss [9]. Furthermore, an increased incidence of skeletal malformations was observed after prenatal exposure to pregabalin in mice [10]. While these findings from animals may not directly extrapolate to humans, they raise potential concerns that necessitate further investigation.

Regarding the risks associated with pregabalin, one recent large multicentric study with rigorous methodology reported an increase in risk of major congenital anomalies after first trimester exposure to pregabalin [39]. Sensitivity analyses showed similar results for monotherapy exposure [39]. The strengths of the study include a large sample size (including around 3 million pregnancies with more than 100 exposed cases), the use of national health registers in 4 countries (allowing accurate identification of the exposure and the outcomes), the use of several comparison groups (including active comparators) to strengthen the results, and the control for a large set of covariates. For specific congenital anomalies, no clear conclusions could be drawn from the limited number of studies investigating this aspect [39,40]. Significant signals were identified after exposure to pregabalin for anomalies from the nervous system, eyes, oro-facial clefs, urinary and genital system [39]. Although the results were not consistent across all the comparison groups, making it difficult to interpret the results, it is important to explore these signals further. In addition, an increased risk of coarctation of aorta was found after exposure to pregabalin monotherapy, however there were only 4 exposed cases and the study did not control for covariates [40]. Regarding pregnancy outcomes, one study pointed towards an increased risk of stillbirth after exposure to pregabalin [39]; however, this analysis was based on very few cases. Additionally, a recent study reported an increased risk of miscarriage among women with epilepsy [45], but this was not observed among women with psychiatric or somatic conditions, which are the primary conditions treated by gabapentinoids. Increased risk of low birth weight and SGA were reported in one study only, and especially among the children with mother without epilepsy [47].

The data on gabapentin exposure showed reassuring results regarding the risk of congenital anomalies, but the limited number of exposed cases in some studies limits the generalizability of these findings. The largest study including around 200 exposed cases (in mono or polytherapy), reported no significant association after adjustment for the covariates [30]. However, the authors presented in a subsequent post-hoc analyses a potential increase in the risk of conotruncal defects that should be investigated further [30]. The same study also reported an increased risk of preterm birth, preeclampsia, small-for-gestational-age and NICU admission after exposure to gabapentin [30]. The strengths of the study include a large sample size (including around 1.7 million pregnancies with around 4500 exposed women during the first trimester of pregnancy), the use of
<table><caption>**Table 6** Overview of long-term children outcomes risks described in the studies following exposure to gabapentinoids.</caption><thead><tr><th>Reference number</th><th>Author and year</th><th>Outcomes investigated</th><th>Exposure No events/No participants (%)</th><th>Comparison No events/No participants (%)</th><th>Results Measure of association</th><th>Other results</th></tr></thead><tbody><tr><td colspan="7"><strong>Pregabalin exposure Overall neurodevelopmental disorders</strong></td></tr><tr><td>[48]</td><td>Bjørk et al., 2022</td><td>Any neurodevelopmental disorder (ICD-10 codes: F70-F73, F79, F84.0, F84.1, F84.3, F84.4, F84.5, F84.8, F84.9)</td><td>Monotherapy 33/2064 (1.60%)</td><td>Women discontinuing pregabalin before pregnancy 51/3195 (1.60%)</td><td>Adjusted HR = 0.86 (0.54-1.38)</td><td></td></tr><tr><td>[49]</td><td>Blotière et al., 2020</td><td>Neurodevelopmental disorders (ICD-10 codes: F70-F98)</td><td>Monotherapy 28/not reported (5.0 per 1000 PY)</td><td>Lamotrigine monotherapy 51/not reported (4.9 per 1000 PY)</td><td>Adjusted HR = 0.6 (0.4-1.0)</td><td></td></tr><tr><td>[50]</td><td>Coste et al., 2020</td><td>Neurodevelopmental disorders (ICD-10 codes: F70-F98)</td><td>Monotherapy 28/not reported (5.0 per 1000 PY)</td><td>Unexposed 15,270/not reported (2.5 per 1000 PY)</td><td>Adjusted HR = 1.5 (1.0-2.1)</td><td>Among children born to a mother with no known mental illness Adjusted HR = 1.3 (0.6-2.7)</td></tr><tr><td>[51]</td><td>Dreier et al., 2023</td><td>Combined Psychiatric End Point (ICD-10 codes: F)</td><td>Monotherapy 8/120 (6.67%)</td><td>No ASM among women with epilepsy 1892/22,203 (8.52%)</td><td>Basic adjusted HR = 1.61 (0.80-3.26) Full adjusted HR = 1.06 (0.52-2.16)</td><td></td></tr><tr><td colspan="7"><strong>Specific neurodevelopmental disorders</strong></td></tr><tr><td>[48]</td><td>Bjørk et al., 2022</td><td>Intellectual disability (ICD-10 codes: F70-F73)</td><td>Monotherapy 5/1666 (0.60 [95% CI: 0.25-1.45] per 1000 PY)</td><td>General population 16,384/4,463,879 (0.42 [95% CI: 0.42-0.43] per 1,000 PY)</td><td>Adjusted HR = 1.31 (0.54-3.14)</td><td></td></tr><tr><td></td><td>Bjørk et al., 2022</td><td>Autism spectrum disorder (ICD-10 codes: F84.0, F84.1, F84.5)</td><td>Monotherapy 16/1666 (1.93 [95% CI: 1.18-3.15] per 1000 PY)</td><td>General population 38,437/4,463,879 (1.00 [95% CI: 0.99-1.01] per 1000 PY)</td><td>Adjusted HR = 1.55 (0.95-2.54)</td><td></td></tr></tbody></table>
<table><caption>Table 6 (Continued)</caption><thead><tr><th>Reference number</th><th>Author and year</th><th>Outcomes investigated</th><th>Exposure No events/No participants (%)</th><th>Comparison No events/No participants (%)</th><th>Results Measure of association</th><th>Other results</th></tr></thead><tbody><tr><td rowspan="3">[49]</td><td>Blotière et al., 2020</td><td>Pervasive developmental disorders (ICD-10 codes: F84)</td><td>Monotherapy 7/not reported (1.2 per 1000 PY)</td><td>Lamotrigine monotherapy 11/not reported (1.1 per 1000 PY)</td><td>Adjusted HR = 1.1 (0.4–3.0)</td><td></td></tr><tr><td>Blotière et al., 2020</td><td>Mental retardation (ICD-10 codes: F70–F79)</td><td>Monotherapy 7/not reported (1.2 per 1,000 PY)</td><td>Lamotrigine monotherapy 15/not reported (1.4 per 1000 PY)</td><td>Adjusted HR = 0.6 (0.2–1.8)</td><td></td></tr><tr><td>Blotière et al., 2020</td><td>Visits to a speech therapist</td><td>Monotherapy 61/not reported (11.0 per 1000 PY)</td><td>Lamotrigine monotherapy 157/not reported (15.2 per 1000 PY)</td><td>Adjusted HR = 0.7 (0.4–1.2)</td><td></td></tr><tr><td rowspan="4">[50]</td><td>Coste et al., 2020</td><td>Pervasive developmental disorders (ICD-10 codes: F84)</td><td>Monotherapy 7/not reported (1.2 per 1000 PY)</td><td>Unexposed 4280/not reported (0.7 per 1000 PY)</td><td>Adjusted HR = 1.4 (0.7–2.9)</td><td>Among children born to a mother with no known mental illness Adjusted HR = 0.7 (0.1–4.8)</td></tr><tr><td>Coste et al., 2020</td><td>Mental retardation (ICD-10 codes: F70–F79)</td><td>Monotherapy 7/not reported (1.2 per 1000 PY)</td><td>Unexposed 3398/not reported (0.6 per 1000 PY)</td><td>Adjusted HR = 1.7 (0.8–3.6)</td><td>Among children born to a mother with no known mental illness Adjusted HR = 3.1 (1.2–8.3)</td></tr><tr><td>Coste et al., 2020</td><td>Disorders of psychological development (ICD-10 codes: F80–F89)</td><td>Monotherapy 16/not reported (2.9 per 1000 PY)</td><td>Unexposed 10,010/not reported (1.6 per 1000 PY)</td><td>Adjusted HR = 1.3 (0.8–2.2)</td><td>Among children born to a mother with no known mental illness Adjusted HR = 1.1 (0.4–3.0)</td></tr><tr><td>Coste et al., 2020</td><td>Behavioural and emotional disorders with onset usually occurring in childhood and adolescence (ICD-10 codes: F90–F98)</td><td>Monotherapy 9/not reported (1.6 per 1000 PY)</td><td>Unexposed 4398/not reported (0.7 per 1000 PY)</td><td>Adjusted HR = 1.4 (0.8–2.8)</td><td>Among children born to a mother with no known mental illness Adjusted HR = 1.4 (0.3–5.5)</td></tr></tbody></table>
<table><caption>Table 6 (Continued)</caption><thead><tr><th>Reference number</th><th>Author and year</th><th>Outcomes investigated</th><th>Exposure No events/No participants (%)</th><th>Comparison No events/No participants (%)</th><th>Results Measure of association</th><th>Other results</th></tr></thead><tbody><tr><td rowspan="3">[50]</td><td>Coste et al., 2020</td><td>Health care utilization of speech therapy</td><td>Monotherapy 61/not reported (11.0 per 1000 PY)</td><td>Unexposed 72,012/not reported (1.6 per 1000 PY)</td><td>Adjusted HR = 0.9 (0.7–1.2)</td><td>Among children born to a mother with no known mental illness Adjusted HR = 1.0 (0.7–1.5)</td></tr><tr><td>Coste et al., 2020</td><td>Health care utilization of orthoptics</td><td>Monotherapy 225/not reported (43.3 per 1000 PY)</td><td>Unexposed 203,489/not reported (1.6 per 1000 PY)</td><td>Adjusted HR = 1.2 (1.1–1.4)</td><td>Among children born to a mother with no known mental illness Adjusted HR = 1.4 (1.1–1.6)</td></tr><tr><td>Coste et al., 2020</td><td>Health care utilization of psychiatry</td><td>Monotherapy 23/not reported (4.1 per 1000 PY)</td><td>Unexposed 22,365/not reported (1.6 per 1000 PY)</td><td>Adjusted HR = 0.9 (0.6–1.3)</td><td>Among children born to a mother with no known mental illness Adjusted HR = 1.0 (0.5–2.1)</td></tr><tr><td rowspan="3">[39]<sup>a</sup></td><td>Dudukina et al., 2023</td><td>Hyperkinetic disorders including ADHD</td><td>72/14,315 PY (5.0 per 1000 PY)</td><td>ASM-unexposed 38,693/17,874,961 PY (2.2 per 1000 PY)</td><td>Crude HR = 3.62 (2.87–4.55)<br>PS-adjusted HR = 1.29 (1.03–1.63)<br>MH-adjusted HR = 1.22 (0.97–1.54)</td><td></td></tr><tr><td>Dudukina et al., 2023</td><td>Hyperkinetic disorders including ADHD</td><td>67/13,634 PY (4.9 per 1000 PY)</td><td>Lamotrigine 139/39,148 PY (3.6 per 1000 PY)</td><td>Crude HR = 1.52 (1.12–2.06)<br>PS-adjusted HR = 1.04 (0.75–1.42)<br>MH-adjusted HR = 1.06 (0.80–1.42)</td><td></td></tr><tr><td>Dudukina et al., 2023</td><td>Hyperkinetic disorders including ADHD</td><td>69/13,058 PY (5.3 per 1000 PY)</td><td>Lamotrigine and/or duloxetine 227/55,645 PY (4.1 per 1000 PY)</td><td>Crude HR = 1.54 (1.17–2.04)<br>PS-adjusted HR = 1.20 (0.89–1.61)<br>MH-adjusted HR = 1.12 (0.86–1.47)</td><td></td></tr></tbody></table>
<table><caption>Table 6 (Continued)</caption><thead><tr><th>Reference number</th><th>Author and year</th><th>Outcomes investigated</th><th>Exposure No events/No participants (%)</th><th>Comparison No events/No participants (%)</th><th>Results Measure of association</th><th>Other results</th></tr></thead><tbody><tr><td rowspan="2"></td><td>Dudukina et al., 2023</td><td>Pervasive development disorders including ASD</td><td>NR/NR</td><td>ASM-unexposed 21,180/17,891,330 PY (1.2 per 1000 PY)</td><td>Crude HR = 1.99 (1.38–2.89) PS-adjusted HR = 0.98 (0.67–1.42) MH-adjusted HR = 0.95 (0.66–1.38)</td><td></td></tr><tr><td>Dudukina et al., 2023</td><td>Intellectual disability</td><td>NR/NR</td><td>ASM-unexposed 45,943/17,796,832 PY (2.6 per 1000 PY)</td><td>Crude HR = 1.58 (1.23–2.02) PS-adjusted HR = 1.00 (0.78–1.29) MH-adjusted HR = 0.98 (0.77–1.26)</td><td></td></tr><tr><td>Gabapentin exposure Overall neurodevelop- mental disorders [48]</td><td>Bjørk et al., 2022</td><td>Any neurodevelopmental disorder (ICD-10 codes: F70-F73, F79, F84.0, F84.1, F84.3, F84.4, F84.5, F84.8, F84.9)</td><td>Monotherapy 19/1658 (1.15%)</td><td>Women discontinuing gabapentin before pregnancy 57/3402 (1.68%)</td><td>Adjusted HR = 0.54 (0.30–0.98)</td><td></td></tr><tr><td>[49]</td><td>Blotière et al., 2020</td><td>Neurodevelopmental disorders (ICD-10 codes: F70–F98)</td><td>Monotherapy 4/not reported (3.1 per 1000 PY)</td><td>Lamotrigine monotherapy 51/not reported (4.9 per 1000 PY)</td><td>Adjusted HR = 0.4 (0.1–1.3)</td><td></td></tr><tr><td>[50]</td><td>Coste et al., 2020</td><td>Neurodevelopmental disorders (ICD-10 codes: F70–F98)</td><td>Monotherapy 4/not reported (3.1 per 1000 PY)</td><td>Unexposed 15,270/not reported (2.5 per 1000 PY)</td><td>Adjusted HR = 0.8 (0.3–2.1)</td><td>Among children born to a mother with no known mental illness Adjusted HR = 1.4 (0.4–5.7)</td></tr></tbody></table>
<table><caption>Table 6 (Continued)</caption><thead><tr><th>Reference number</th><th>Author and year</th><th>Outcomes investigated</th><th>Exposure No events/No participants (%)</th><th>Comparison No events/No participants (%)</th><th>Results Measure of association</th><th>Other results</th></tr></thead><tbody><tr><td>[51]</td><td>Dreier et al., 2023</td><td>Combined Psychiatric End Point (ICD-10 codes: F)</td><td>Monotherapy 16/138 (11.59%)</td><td>No ASM among women with epilepsy 1892/22,203 (8.52%)</td><td>Basic adjusted HR = 1.48 (0.90–2.42) Full adjusted HR = 1.30 (0.78–2.18)</td><td></td></tr><tr><td rowspan="2">Specific neurodevelop- mental disorders [52]</td><td>Bech et al., 2018</td><td>Learning disabilities in the first year of compulsory education</td><td>Monotherapy &lt; 4/29 (&lt; 13.8%)</td><td>No ASM 16/434 (3.69%)</td><td>Adjusted OR = 1.22 (0.14–10.52)</td><td></td></tr><tr><td>Bech et al., 2018</td><td>Learning disabilities in the first year of compulsory education</td><td>Monotherapy &lt; 4/29 (&lt; 13.8%)</td><td>Another ASM 37/527 (7.02%)</td><td>Adjusted OR = 0.31 (0.04–2.58)</td><td></td></tr><tr><td>[48]</td><td>Bjørk et al., 2022</td><td>Autism spectrum disorder (ICD-10 codes: F84.0, F84.1, F84.5)</td><td>Monotherapy 8/965 (1.73 [95% CI: 0.87–3.46] per 1000 PY)</td><td>General population 38,437/4,463,879 (1.00 [95% CI: 0.99–1.01] per 1000 PY)</td><td>Adjusted HR = 1.25 (0.63–2.51)</td><td></td></tr><tr><td rowspan="2">[49]</td><td>Blotière et al., 2020</td><td>Pervasive developmental disorders (ICD-10 codes: F84)</td><td>Monotherapy 3/not reported (2.3 per 1000 PY)</td><td>Lamotrigine monotherapy 11/not reported (1.1 per 1000 PY)</td><td>Adjusted HR = 1.8 (0.4–7.0)</td><td></td></tr><tr><td>Blotière et al., 2020</td><td>Visits to a speech therapist</td><td>Monotherapy 11/not reported (8.5 per 1000 PY)</td><td>Lamotrigine monotherapy 157/not reported (15.2 per 1000 PY)</td><td>Adjusted HR = 0.7 (0.5–1.0)</td><td></td></tr></tbody></table>
<table><caption>Table 6 (Continued)</caption><thead><tr><th>Reference number</th><th>Author and year</th><th>Outcomes investigated</th><th>Exposure No events/No participants (%)</th><th>Comparison No events/No participants (%)</th><th>Results Measure of association</th><th>Other results</th></tr></thead><tbody><tr><td rowspan="5">[50]</td><td>Coste et al., 2020</td><td>Pervasive developmental disorders (ICD-10 codes: F84)</td><td>Monotherapy 3/not reported (2.3 per 1000 PY)</td><td>Unexposed 4280/not reported (0.7 per 1000 PY)</td><td>Adjusted HR = 2.3 (0.8-7.3)</td><td>Among children born to a mother with no known mental illness Adjusted HR = 2.7 (0.4-19.2)</td></tr><tr><td>Coste et al., 2020</td><td>Disorders of psychological development (ICD-10 codes: F80-F89)</td><td>Monotherapy 4/not reported (3.1 per 1000 PY)</td><td>Unexposed 10,010/not reported (1.6 per 1000 PY)</td><td>Adjusted HR = 1.3 (0.5-3.3)</td><td>Among children born to a mother with no known mental illness Adjusted HR = 2.2 (0.5-8.6)</td></tr><tr><td>Coste et al., 2020</td><td>Health care utilization of speech therapy</td><td>Monotherapy 11/not reported (8.5 per 1000 PY)</td><td>Unexposed 72,012/not reported (11.9 per 1000 PY)</td><td>Adjusted HR = 0.6 (0.4-1.2)</td><td>Among children born to a mother with no known mental illness Adjusted HR = 0.9 (0.4-2.1)</td></tr><tr><td>Coste et al., 2020</td><td>Health care utilization of orthoptics</td><td>Monotherapy 42/not reported (35.1 per 1000 PY)</td><td>Unexposed 203,489/not reported (35.6 per 1000 PY)</td><td>Adjusted HR = 0.9 (0.7-1.2)</td><td>Among children born to a mother with no known mental illness Adjusted HR = 1.1 (0.7-1.7)</td></tr><tr><td>Coste et al., 2020</td><td>Health care utilization of psychiatry</td><td>Monotherapy 6/not reported (4.6 per 1000 PY)</td><td>Unexposed 22,365/not reported (3.7 per 1000 PY)</td><td>Adjusted HR = 0.9 (0.4-2.0)</td><td>Among children born to a mother with no known mental illness Adjusted HR = 1.7 (0.5-5.3)</td></tr></tbody></table>

ASM: antiseizure medications; CI: confidence interval; HR: hazard ratio; ICD-10: International Statistical Classification of Diseases and Related Health Problems 10th Revision; MH: Mantel-Haenszel; NR: not reportable to keep masking of a low number of individuals (<5) in other cells; OR: odds ratio; PS: propensity score; PY: person-year.

<footnote>a Only significant findings or findings with at least 5 exposed cases are reported, in bold significant result.</footnote>
a population-based cohort of Medicaid-enrolled women, the control for a large set of covariates (more than 70), and the conduct of several sensitivity and post-hoc analyses to assess the robustness of the results [30].

Regarding long-term childhood neurodevelopmental outcomes, data on overall neurodevelopmental outcomes reported reassuring findings [48–51]. Nevertheless, in two studies the mean follow-up was around 3.5 years, which limits the capacity to assess the occurrence of neurodevelopmental outcomes [49,50]. The reported associations between specific disorders such as mental retardation and hyperkinetic disorders including attention deficit hyperactivity disorder (ADHD), as well as utilization of orthoptics services and pregabalin exposure need further investigations [39,50]. In addition, the long-term outcomes investigated mainly focused on severe neurodevelopmental outcomes identified with International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10 codes), and more research is needed to explore potential effects on specific and less severe neurodevelopmental outcomes.

Data on the indication for gabapentinoid use were reported in 10 out of the 27 high-quality studies [30,31,38–40,44,45,47,48,50]. Pregabalin and gabapentin were mostly used for non-epilepsy indications, such as pain or psychiatric disorder, with epilepsy accounting for less than 10% of the exposed pregnancies. Only two recent studies have reported associations based on maternal diseases (one study distinguished between epilepsy, psychiatric and somatic conditions [45] while the other distinguished between epilepsy and no epilepsy) [47], limiting the ability to assess the impact of different conditions on outcomes. Nevertheless, the results indicated that maternal conditions influenced the outcomes, highlighting the importance of identifying underlying maternal diseases and stratifying analyses accordingly. The impact of different treatment indications should be explored further, as recent studies have provided valuable information on potential effects.

Data on the patterns of use during pregnancy were very rarely presented. Chronic or occasional use, as well as dosage, were barely not reported. Less than one third of the pregnancies were exposed during the first trimester of pregnancy and through the rest of the pregnancy [30,44,50,53].

## Strengths and limitations

This systematic review comprehensively analysed the existing literature on gabapentinoid use during pregnancy and its association with adverse pregnancy/childhood outcomes. It provides valuable information regarding the assessment of gabapentinoid risks during pregnancy and highlights gaps that need to be filled by further studies. This study provided guidance for future research aimed at assessing the safety of gabapentinoids during pregnancy. The recent IMI project ConcePTION, which the authors are part of, is addressing some of the research gaps by combining data from several large data sources across Europe. Future studies will aim to overcome limitations by including larger sample sizes, standardized outcome definitions, identification of treatment indications, and adjustment for confounding factors.

In this systematic review, we have not tried to realize a quantitative meta-analysis as the studies outcome mea-

surements and comparison groups were too heterogeneous. Some studies included in the review had relatively small sample sizes, leading to imprecise estimation of medication effect (with measures of associations with wide confidence intervals). Additionally, there was limit considerations for covariates control in some studies. The heterogeneity in defining comparison groups and ascertaining outcomes also posed challenges in interpreting the results. Concerning the comparison groups, some studies used a group of women not exposed to any ASM during pregnancy, other used active comparators for example with women exposed during pregnancy to lamotrigine. The use of active comparators is important to control for indication bias. As gabapentinoids has several indications, it might be relevant to use several active comparators for which the indications overlap with those of gabapentin and pregabalin, such as in the study by Dudukina et al. [39]. Concerning the ascertainment of the outcomes, some studies were based on medical files, other on women reports and others on validated diagnosis codes. However, even validated diagnosis codes do not allow for the identification of all cases, such as less severe cases. We could also note that there was a lack of data on the evolution of gabapentinoid use over time, on indication for treatment, on the patterns of use during pregnancy and on cases of misuse.

## Conclusion

Studies found an overall increased risk of congenital anomalies and long-term neurodevelopmental outcomes associated with prenatal exposure to pregabalin. Larger studies are needed to confirm the potential increased risks of specific congenital anomalies and stillbirth. Similarly, exposure to gabapentin was associated with an increased risk of preeclampsia, preterm birth and small-for-gestational age. More extensive studies are needed to evaluate the risk of congenital anomalies and fetal death associated with gabapentin. Collectively, the findings from this systematic review, combined with animal data, raise concerns about the safety of using gabapentinoids during pregnancy.

The benefit-risk balance for both mother and fetus/infant should be carefully evaluated if the use of these medications cannot be avoided during pregnancy.

## Author contributions

ABB, JM, CDM conceived the review. All authors contributed to the study design. ABB developed the search strategy. ABB and JM extracted data. All authors contributed to data analysis. ABB drafted the manuscript. All authors revised and approved the manuscript.

## Funding information

The ConcePTION project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 821520. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA.
## Acknowledgements

The research leading to these results was conducted as part of the ConcePTION consortium. This paper only reflects the personal views of the stated authors.

## Disclosure of interest

ABB, JB and CDM declare that they have no competing interest.

XM has received financial support from Allergan-Abbvie, Biogen, BMS, Grünenthal, Lilly, Lundbeck, Teva, Merck-Serono, Novartis, Pfizer, Roche, and Sanofi-Genzyme and non-financial support from SOS Oxygène not related to the submitted work.

JM is an employee of Pfizer Inc.

## Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.therap.2024.10.049.

## References

[1] Furugen A, Ishiguro Y, Kobayashi M, Narumi K, Nishimura A, Hirano T, et al. Involvement of l-type amino acid transporter 1 in the transport of gabapentin into human placental chorio-carcinoma cells. Reprod Toxicol 2017;67:48–55.

[2] Ohman I, Vitols S, Tomson T. Pharmacokinetics of gabapentin during delivery, in the neonatal period, and lactation: does a fetal accumulation occur during pregnancy? Epilepsia 2005;46:1621–4.

[3] Johansen ME. Gabapentinoid use in the United States 2002 through 2015. JAMA Intern Med 2018;178:292–4.

[4] Montastruc F, Loo SY, Renoux C. Trends in first gabapentin and pregabalin prescriptions in primary care in the United Kingdom, 1993–2017. JAMA 2018;320:2149–51.

[5] Goodman CW, Brett AS. Gabapentin and pregabalin for pain – Is increased prescribing a cause for concern? N Engl J Med 2017;377:411–4.

[6] Lawal OD, Meador KJ, Hume AL, Wen X. Utilization of antiseizure medications in women of childbearing age with epilepsy and nonepilepsy indications: a retrospective cohort study. Neurology 2023;101:e1083–96.

[7] Hurault-Delarue C, Morris JK, Charlton R, Gini R, Loane M, Pierini A, et al. Prescription of antiepileptic medicines including valproate in pregnant women: a study in three European countries. Pharmacoepidemiol Drug Saf 2019;28:1510–8.

[8] Prakash, Prabhu LV, Rai R, Pai MM, Yadav SK, Madhyastha S, et al. Teratogenic effects of the anticonvulsant gabapentin in mice. Singapore Med J 2008;49:47–53.

[9] European Medicines Agency. Summary of the European public assessment report: neurontin gabapentin. European Medicines Agency; 2006 [Accessed 11 October 2024] https://www.ema.europa.eu/en/medicines/human/referrals/neurontin.

[10] Etemad L, Mohammad A, Mohammadpour AH, Vahdati Mashhadi N, Moallem SA. Teratogenic effects of pregabalin in mice. Iran J Basic Med Sci 2013;16:1065–70.

[11] European Medicines Agency. Summary of the European public assessment report: lyrica pregabalin; 2022 [Accessed 11 October 2024] https://www.ema.europa.eu/en/medicines/human/EPAR/lyrica.

[12] Richardson JL, Damkier P, Diav-Citrin O, George N, Greenall AJ, Oliver AM, et al. A critical appraisal of controlled studies investigating malformation risks following pregabalin use in early pregnancy. Br J Clin Pharmacol 2023;89:630–40.

[13] Jin XL, Song BH, Zhao XD, Huang GB. Neonatal outcomes after gamma-aminobutyric acid analog use during pregnancy: a meta-analysis of cohort studies. Eur J Clin Pharmacol 2022;78:1739–47.

[14] Wise J. Avoid prescribing pregabalin during pregnancy if possible, says UK drug regulator. BMJ 2022;377:o1010.

[15] Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71.

[16] Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan-a web and mobile app for systematic reviews. Syst Rev 2016;5:210.

[17] Clavenna A, Campi R, Putignano D, Fortino I, Bonati M. Changes in antiepileptic drug prescriptions over a decade in childbearing women in Lombardy region, Italy. Br J Clin Pharmacol 2022;88:1152–8.

[18] Fujii H, Goel A, Bernard N, Pistelli A, Yates LM, Stephens S, et al. Pregnancy outcomes following gabapentin use: results of a prospective comparative cohort study. Neurology 2013;80:1565–70.

[19] Holmes LB, Hernandez-Diaz S. Newer anticonvulsants: lamotrigine, topiramate and gabapentin. Birth Defects Res A Clin Mol Teratol 2012;94:599–606.

[20] Shihman B, Goldstein L, Amiel N, Benninger F. Antiepileptic drug treatment during pregnancy and delivery in women with epilepsy – A retrospective single center study. Epilepsy Res 2019;149:66–9.

[21] Vajda FJ, Hitchcock A, Graham J, O'Brien T, Lander C, Eadie M. The Australian Register of Antiepileptic Drugs in Pregnancy: the first 1002 pregnancies. Aust N Z J Obstet Gynaecol 2007;47:468–74.

[22] Vajda FJE, Graham JE, Hitchcock AA, O'Brien TJ, Lander CM, Eadie MJ. Is lamotrigine a significant human teratogen? Observations from the Australian Pregnancy Register. Seizure 2010;19:558–61.

[23] Hernández-Diaz S, McElrath TF, Pennell PB, Hauser WA, Yerby M, Holmes LB. Fetal growth and premature delivery in pregnant women on antiepileptic drugs. Ann Neurol 2017;82:457–65.

[24] Mostacci B, Poluzzi E, D'Alessandro R, Cocchi G, Tinuper P. Adverse pregnancy outcomes in women exposed to gabapentin and pregabalin: data from a population-based study. J Neurol Neurosurg Psychiatry 2018;89:223–4.

[25] Vajda FJE, O'Brien TJ, Graham J, Lander CM, Eadie MJ. The Australian Register of Antiepileptic Drugs in Pregnancy: changes over time in the epileptic population. J Clin Neurosci 2014;21:1478–82.

[26] Vajda FJE, O'Brien TJ, Lander CM, Graham J, Eadie MJ. The teratogenicity of the newer antiepileptic drugs – an update. Acta Neurol Scand 2014;130:234–8.

[27] Vajda FJE, O'Brien TJ, Graham JE, Hitchcock AA, Lander CM, Eadie MJ. Antiepileptic drugs, foetal malformations and spontaneous abortions. Acta Neurol Scand 2017;135:360–5.

[28] Winterfeld U, Merlob P, Baud D, Rousson V, Panchaud A, Rothuizen LE, et al. Pregnancy outcome following maternal exposure to pregabalin may call for concern. Neurology 2016;86:2251–7.

[29] Montouris G. Gabapentin exposure in human pregnancy: results from the Gabapentin Pregnancy Registry. Epilepsy Behav 2003;4:310–7.

[30] Patorno E, Hernandez-Diaz S, Huybrechts KF, Desai RJ, Cohen JM, Mogun H, et al. Gabapentin in pregnancy and the risk
of adverse neonatal and maternal outcomes: a population-
based cohort study nested in the US Medicaid Analytic eXtract
dataset. PLoS Med 2020;17:e1003322.

[31] Shouman W, Delaney JA, Kowalec K, Ng M, Ruth C, Falk J, et al. Trends of utilization of antiseizure medications among pregnant women in Manitoba, Canada: a 20-year population-based study. Front Pharmacol 2022;13:871136.

[32] Desrochers B, Lavu A, Valencia E, Vaccaro C, Peymani P, Eltonsy S. Risks of congenital malformations and neonatal intensive care unit admissions with gabapentin use in pregnancy: a cohort study and scoping review with meta-analysis. Paediatr Perinat Epidemiol 2024;38:486-94.

[33] Blotière PO, Weill A, Dalichampt M, Billionnet C, Mezzarobba M, Raguideau F, et al. Development of an algorithm to identify pregnancy episodes and related outcomes in health care claims databases: an application to antiepileptic drug use in 4.9 million pregnant women in France. Pharmacoepidemiol Drug Saf 2018;27:763-70.

[34] Spoendlin J, Blozik E, Graber S, Rauch M, Marxer C, Rüegg S, et al. Use of valproate in pregnancy and in women of childbearing age between 2014 and 2018 in Switzerland: a retrospective analysis of Swiss healthcare claims data. Swiss Med Wkly 2021;151:w20386.

[35] Richards N, Reith D, Stitely M, Smith A. Antiepileptic drug exposure in pregnancy and pregnancy outcome from national drug usage data. BMC Pregnancy Childbirth 2018;18:84.

[36] Källén B, Borg N, Reis M. The use of central nervous system active drugs during pregnancy. Pharmaceuticals 2013;6:1221-86.

[37] Veiby G, Daltveit AK, Engelsen BA, Gilhus NE. Fetal growth restriction and birth defects with newer and older antiepileptic drugs during pregnancy. J Neurol 2014;261:579-88.

[38] Patorno E, Bateman BT, Huybrechts KF, MacDonald SC, Cohen JM, Desai RJ, et al. Pregabalin use early in pregnancy and the risk of major congenital malformations. Neurology 2017;88:2020-5.

[39] Dudukina E, Szépligeti SK, Karlsson P, Asomaning K, Daltveit AK, Hakkarainen K, et al. Prenatal exposure to pregabalin, birth outcomes and neurodevelopment – a population-based cohort study in four Nordic countries. Drug Saf 2023;46:661-75.

[40] Blotière PO, Raguideau F, Weill A, Elefant E, Perthus I, Goulet V, et al. Risks of 23 specific malformations associated with prenatal exposure to 10 antiepileptic drugs. Neurology 2019;93:e167-80.

[41] Mølgaard-Nielsen D, Hviid A. Newer-generation antiepileptic drugs and the risk of major birth defects. JAMA 2011;305:1996-2002.

[42] Morrow J, Russell A, Guthrie E, Parsons L, Robertson I, Waddell R, et al. Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psychiatry 2006;77:193-8.

[43] Kilic D, Pedersen H, Kjaersgaard MIS, Parner ET, Vestergaard M, Sørensen MJ, et al. Birth outcomes after prenatal exposure to antiepileptic drugs – a population-based study. Epilepsia 2014;55:1714-21.

[44] Margulis AV, Hernandez-Diaz S, McElrath T, Rothman KJ, Plana E, Almqvist C, et al. Relation of in-utero exposure to antiepileptic drugs to pregnancy duration and size at birth. PLoS One 2019;14:e0214180.

[45] Forbes H, Madley-Dowd P, Ahlqvist V, Campbell J, Davies NM. Liebling R, et al. First-trimester use of antiseizure medications and the risk of miscarriage: a population-based cohort study. J Neurol Neurosurg Psychiatry 2024;95:693-703.

[46] Almgren M, Källén B, Lavebratt C. Population-based study of antiepileptic drug exposure in utero – influence on head circumference in newborns. Seizure 2009;18:672-5.

[47] Christensen J, Zoega H, Leinonen MK, Gilhus NE, Gissler M, Igland J, et al. Prenatal exposure to antiseizure medications and fetal growth: a population-based cohort study from the Nordic countries. Lancet Reg Health Eur 2024;38:100849.

[48] Bjørk MH, Zoega H, Leinonen MK, Cohen JM, Dreier JW, Furu K, et al. Association of prenatal exposure to antiseizure medication with risk of autism and intellectual disability. JAMA Neurol 2022;79:672-81.

[49] Blotière PO, Miranda S, Weill A, Mikaeloff Y, Peyre H, Ramus F, et al. Risk of early neurodevelopmental outcomes associated with prenatal exposure to the antiepileptic drugs most commonly used during pregnancy: a French nationwide population-based cohort study. BMJ Open 2020;10:e034829.

[50] Coste J, Blotiere PO, Miranda S, Mikaeloff Y, Peyre H, Ramus F, et al. Risk of early neurodevelopmental disorders associated with in utero exposure to valproate and other antiepileptic drugs: a nationwide cohort study in France. Sci Rep 2020;10:17362.

[51] Dreier JW, Bjørk MH, Alvestad S, Gissler M, Igland J, Leinonen MK, et al. Prenatal exposure to antiseizure medication and incidence of childhood- and adolescence-onset psychiatric disorders. JAMA Neurol 2023;80:568-77.

[52] Bech LF, Polcwiartek C, Kragholm K, Andersen MP, Rohde C, Torp-Pedersen C, et al. In utero exposure to antiepileptic drugs is associated with learning disabilities among offspring. J Neurol Neurosurg Psychiatry 2018;89:1324-31.

[53] Bobo WV, Davis RL, Toh S, Li D-K, Andrade SE, Cheetham TC, et al. Trends in the use of antiepileptic drugs among pregnant women in the US, 2001-2007: a medication exposure in pregnancy risk evaluation program study. Paediatr Perinat Epidemiol 2012;26:578-88.

[54] Mølgaard-Nielsen D, Hviid A. Newer-generation antiepileptic drugs and the risk of major birth defects. JAMA 2011;305:1996-2002.

[55] Mostacci B, Bisulli F, Poluzzi E, Cocchi G, Piccinni C, Curti A, et al. Emilia-Romagna Study on Pregnancy and Exposure to Antiepileptic drugs (ESPEA): a population-based study on prescription patterns, pregnancy outcomes and fetal health. J Neurol Neurosurg Psychiatry 2018;89:983-8.

[56] Wide K, Winbladh B, Källén B. Major malformations in infants exposed to antiepileptic drugs in utero, with emphasis on carbamazepine and valproic acid: a nation-wide, population-based register study. Acta Paediatr 2004;93:174-6.