Review
Exposure to selective serotonin reuptake inhibitors during pregnancy and risk of autism spectrum disorder in children: A systematic review and meta-analysis of observational studies

https://doi.org/10.1016/j.neubiorev.2014.11.020Get rights and content

Highlights

  • The use of SSRIs in pregnant women is a complex decision.

  • Recent studies investigated SSRIs in pregnancy and risk of ASD in children.

  • Our meta-analysis confirmed the association between SSRIs and ASD.

  • Causality remains to be confirmed.

Abstract

This study is a critical analysis of the association between selective serotonin reuptake inhibitors (SSRIs) exposure during pregnancy and autism spectrum disorder (ASD) risk in children. Electronic databases were searched for observational studies published from January 1946 to June 2014 related to the association between SSRI exposure during pregnancy and ASD in children. Studies relevant to the association between SSRI exposure during pregnancy and ASD in children were extracted and compiled for meta-analysis evaluation. Ninety-five citations were identified and seven observational studies were included. Four case–control studies were eligible for the meta-analysis and two cohort studies were narratively reviewed. The pooled crude and adjusted odds ratios of the case–control studies were 2.13 (95% CI 1.66–2.73) and 1.81 (95% CI 1.47–2.24) respectively. Low heterogeneity was observed between studies. The two population-based cohort studies, utilizing the same Denmark data set, have conflicting results. The findings of this meta-analysis and narrative review support an increased risk of ASD in children of mothers exposed to SSRIs during pregnancy; however, the causality remains to be confirmed.

Introduction

Untreated maternal depression has been associated with poor health outcomes for both mothers and children (Sontag-Padilla et al., 2013). Antidepressants are therefore indicated for pregnant women if the benefits outweigh the risk (National, 2007, Joint Formulary Committee, 2014). Selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed anti-depressant classes. Substantial placental transfer occurs with SSRIs (Rampono et al., 2009) and may cause unwanted effects to the unborn child. Currently, meta-analysis results demonstrate that SSRI exposure during pregnancy is associated with preterm birth and low birth rate (Huang et al., 2014), congenital malformation (Myles et al., 2013), and persistent pulmonary hypertension (Grigoriadis et al., 2014). The use of SSRIs in pregnant women is a complex decision that requires weighing the effectiveness of treating depressive symptoms while considering potential adverse events in mother and child.

Recent studies have indicated a possible association between the use of SSRIs in pregnancy and the risk of autism spectrum disorder (ASD) in children (Croen et al., 2011, Eriksson et al., 2012, Gidaya et al., 2014, Harrington et al., 2014, Hviid et al., 2013, Rai et al., 2013, Sorensen et al., 2013). SSRIs are able to cross not only the blood–brain barrier for intended pharmacological actions but also the placental barrier for possible unintended consequences (Kendall-Tackett and Hale, 2010). This is evidenced by the high SSRI cord/maternal distribution ratio, i.e., 0.70–0.86 (Rampono et al., 2009). Animal studies demonstrate that transient usage of fluoxetine during early development produces abnormal emotional behaviors in adult mice, suggesting the role of serotonin transporter modulation during development of brain systems involved in emotional and stress related responses (Ansorge et al., 2004). Pharmacokinetic and pharmacodynamic data, albeit weak and indirect in nature, suggest a plausible biological mechanism between in utero exposure of SSRIs and ASD in children. However, in the scientific literature, evidence of this association contradicted several epidemiological studies supporting a positive association (Croen et al., 2011, Eriksson et al., 2012, Gidaya et al., 2014, Sorensen et al., 2013) whilst others indicated no association (Harrington et al., 2014, Hviid et al., 2013, Rai et al., 2013). Given conflicting results from studies, it is difficult to reach a consensus as to whether there is a link between the use of SSRIs in pregnancy and ASD in children.

ASD affects 1 in 88 children in the United States (US) and prevalence is approximately 1–1.2% in the United Kingdom (UK) (Baird et al., 2006, Baron-Cohen et al., 2009). Due to ASD's early onset, their lifelong persistence and associated pervasive impairment (Simonoff et al., 2008), there is significant impact on social outcomes, education and health of patients and their families (Bolton et al., 1998, Buescher et al., 2014). In the US and UK, the cost of supporting an ASD individual with intellectual disability throughout their lifetime is estimated to be US$2.2–2.4 million and US$1.4 million for an ASD individual without intellectual disability (Buescher et al., 2014). Additionally, there is a high prevalence of mental health conditions in individuals with ASD, including attention deficit hyperactivity disorder, global and specific learning disabilities, emotional disorders, anxiety and depressive disorders, and chronic tic disorder (Bradley and Bolton, 2006, Green et al., 2005, Simonoff et al., 2008). Understanding the risk factors for the development of ASD is an important public health issue.

In view of the above issues, we undertook a systematic review and meta-analysis of published observational studies to evaluate whether SSRI exposure during pregnancy increases the risk of ASD in children.

Section snippets

Method

A systematic literature search was conducted using the search terms (SSRI OR Serotonin uptake inhibitor OR antidepressant) AND pregnancy AND (autism OR autistic OR pervasive developmental disorder OR Asperger syndrome OR Asperger's syndrome OR ASD). PubMed, EMBASE, PsycINFO and the Cochrane Review databases were searched up to 25 June 2014. English titles and abstracts were screened and full texts of relevant articles were retrieved for further review to identify relevant studies. A hand-search

Results

PubMed, EMBASE, PsycINFO and the Cochrane Review databases were searched; yielding 26, 53, 16 and 0 records respectively, with a total of 95 articles, from 1 January 1946 to 25 June 2014. Seventy-one records remained after the removal of duplicates. Titles and abstracts were screened and full texts of relevant articles were retrieved for further review with 64 studies meeting the exclusion criteria. Seven observational studies (Croen et al., 2011, Eriksson et al., 2012, Gidaya et al., 2014,

Discussion

To our knowledge, this is the first systematic review and meta-analysis of SSRI use in pregnancy and risk of ASD in children. Based on the results from the meta-analyses of the case control studies and review of cohort studies, SSRI exposure during pregnancy appears to be associated with the risk of ASD in children.

Three out of four published case–control studies reported significantly positive association between SSRI exposure during pregnancy and ASD in children (Croen et al., 2011, Gidaya et

Conclusion

The findings of this meta-analysis and narrative review of epidemiological studies support an increased risk of ASD in children exposed to SSRIs during pregnancy; however, causality remains to be confirmed. In view of the challenges and difficulties in evaluating this association, further replication studies in this area are recommended.

Conflict of interest

Prof. Wong and Prof. Simonoff receive grant from Innovative Medicines Initiative (IMI) for the European Autism Interventions (EU-AIMS) project. Prof. Simonoff also receives funding from National Institute for Health Research Program Grant for Applied Research: Improving outcomes for people with autism spectrum disorder by reducing mental health problems and from Autism Speaks (Why do people with autism fare so differently in adult life?) and the NIHR Biomedical Research Centre for Mental

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