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Meta-Analysis
. 2020 Dec;65(12):821-834.
doi: 10.1177/0706743720904860. Epub 2020 Mar 9.

Pregnancy and Delivery Outcomes Following Benzodiazepine Exposure: A Systematic Review and Meta-analysis

Sophie Grigoriadis  1   2   3   4 , Lisa Graves  5 , Miki Peer  2 , Lana Mamisashvili  2 , Myuri Ruthirakuhan  6 , Parco Chan  6 , Mirna Hennawy  3 , Supriya Parikh  3 , Simone Natalie Vigod  4   7 , Cindy-Lee Dennis  8 , Meir Steiner  9 , Cara Brown  4 , Amy Cheung  1   3   4 , Hiltrud Dawson  10 , Neil Rector  1   3   4 , Melanie Guenette  2   11 , Margaret Richter  1   3   4
Affiliations
Free PMC article
Meta-Analysis

Pregnancy and Delivery Outcomes Following Benzodiazepine Exposure: A Systematic Review and Meta-analysis

Sophie Grigoriadis et al. Can J Psychiatry. 2020 Dec.
Free PMC article

Abstract
in English, French

Objective: Understanding the effects of benzodiazepines (BZDs) on maternal/fetal health remains incomplete despite their frequent use. This article quantifies the effects of antenatal BZD exposure on delivery outcomes.

Data sources: Medline, PsycINFO, CINAHL, Embase, and the Cochrane Library were searched till June 30, 2018.

Study selection: English-language cohort studies comparing antenatal BZD exposure to an unexposed group on any delivery outcome were eligible. In all, 23,909 records were screened, 56 studies were assessed, and 14 studies were included.

Data extraction: Two reviewers independently assessed quality and extracted data. Estimates were pooled using random effects meta-analysis. Sub-analyses examined several potential moderators including timing of exposure.

Results: There were 9 outcomes with sufficient data for meta-analysis. Antenatal BZD exposure was significantly associated with increased risk of 6 outcomes initially: spontaneous abortion (pooled odds ratio = 1.86; 95% confidence interval [CI], 1.43 to 2.42), preterm birth (1.96; 95% CI, 1.25 to 3.08), low birth weight (2.24; 95% CI, 1.41 to 3.88), low Apgar score (2.19; 95% CI, 1.94 to 2.47), Neonatal Intensive Care Unit (NICU) admission (2.61; 95% CI, 1.64 to 4.14), and induced abortion (2.04; 95% CI, 1.23 to 3.40). There was significant heterogeneity between studies for most outcomes without consistent moderators. Birth weight (mean difference [MD]: -151.35 g; 95% CI, -329.73 to 27.03), gestational age (-0.49 weeks; 95% CI, -1.18 to 0.19), and small for gestational age (SGA; 1.42; 95% CI, 1.00 to 2.01) did not show significant associations although after adjusting for publication bias, gestational age, and SGA became significant, totaling 8 significant outcomes.

Conclusions: Antenatal BZD exposure appears to be statistically associated with increased risk of several adverse perinatal outcomes. Although confounds cannot be ruled out, NICU admission does appear clinically relevant and consistent with the antidepressant literature.

Objectif :: Comprendre les effets des benzodiazépines sur la santé de la mère et du fœtus demeure incomplet malgré l’usage fréquent de ces médicaments. Le présent article quantifie les effets de l’exposition prénatale aux benzodiazépines sur les résultats de l’accouchement.

Sources de données :: Une recherche a été menée dans Medline, PsycINFO, CINAHL, Embase, et la Cochrane Library jusqu’au 30 juin 2018.

Sélection des études :: Les études de cohortes en anglais comparant l’exposition prénatale aux benzodiazépines avec un groupe non exposé selon le résultat de l’accouchement étaient admissibles. La recherche a repéré 23 909 études, 56 ont été évaluées, et 14 études ont été incluses.

Extraction des données :: Deux réviseurs ont évalué indépendamment la qualité et les données extraites. Les estimations ont été regroupées à l’aide d’une méta-analyse à effets aléatoires. Des sous-analyses ont examiné plusieurs modérateurs potentiels, notamment la durée d’exposition.

Résultats :: Il y avait 9 résultats dont les données suffisaient pour la méta-analyse. L’exposition prénatale aux benzodiazépines était significativement associée à un risque accru de six résultats initialement: avortement spontané (rapport de cotes regroupées = 1.86; intervalle de confiance à 95% CI, 1.43 à 2.42), naissance prématurée (1.96; 1.25 à 3.08), faible poids à la naissance (2.24; 1.41 à 3.88), faible indice d’Agpar (2.19; 1.94 à 2.47), hospitalisation à l’unité de soins intensifs néonatals (USIN; 2.61; 1.64 à 4.14), et avortement provoqué (2.04; 1.23 à 3.40). Il y avait une hétérogénéité significative entre les études pour la majorité des résultats sans modérateur constant. Le poids à la naissance (différence moyenne (DM): −151.35 g; −329.73 à 27.03), l’âge gestationnel (DM = −0.49 semaines; −1.18 à 0.19), et nourrisson petit pour l’âge gestationnel (1.42; 1.00 à 2.01) n’indiquaient pas d’associations significatives bien qu’après ajustement pour biais de publication, l’âge gestationnel et nourrisson petit pour l’âge gestationnel devenaient significatifs, totalisant 8 résultats significatifs.

Conclusions :: L’exposition prénatale aux benzodiazépines semble être statistiquement associée à un risque accru de plusieurs résultats périnatals indésirables. Bien que des facteurs de confusion ne puissent être exclus, l’hospitalisation à l’USIN semble cliniquement pertinente et compatible avec la littérature sur les antidépresseurs.

Keywords: benzodiazepines; delivery; fetus/neonatal; maternal; outcomes; pregnancy.

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Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Sophie Grigoriadis has received personal fees from UpToDate, Eli Lilly, Actavis/Allergan, Pfizer, Psychotherapy to go, Compendium of pharmaceuticals, outside the submitted work; Simone Natalie Vigod has received personal fees from UpToDate. Lisa Graves, Miki Peer, Lana Mamisashvili, Myuri Ruthirakuhan, Parco Chan, Mirna Hennawy, Supriya Parikh, Cindy-Lee Dennis, Meir Steiner, Cara Brown, Amy Cheung, Hiltrud Dawson, Neil Rector, Melanie Guenette, and Margaret Richter report no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years, and no other relationships or activities that could appear to have influenced the submitted work.

Figures

Figure 1.
Figure 1.
Flow diagram of study identification, selection, and reasons for exclusion in systematic review.
Figure 2.
Figure 2.
(A) (B), (C), (D) and (E). Significant adverse delivery outcomes following antenatal exposure to benzodiazepines. Pooled odds ratio for (A) spontaneous abortion, (B) preterm birth, (C) low birth weight, (D) low Apgar scores at 5 min, and (E) Neonatal Intensive Care Unit admission.
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