In Utero Exposure to Selective Serotonin Reuptake Inhibitors and Risk for Autism Spectrum Disorder

Gidaya, Nicole B.; Lee, Brian K.; Burstyn, Igor; Yudell, Michael; Mortensen, Erik Lykke; Newschaffer, Craig J.

doi:10.1007/s10803-014-2128-4

Cited by 106 publications

(126 citation statements)

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“…Most of the included studies point to a linkage between SSRIs and ASD, with almost all published studies pointing to increases in risk even if in individual studies the increase is not significant [68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83].…”

Section: Resultsmentioning

confidence: 99%

Links between serotonin reuptake inhibition during pregnancy and neurodevelopmental delay/spectrum disorders: A systematic review of epidemiological and physiological evidence

Healy

Noury

Mangin

2016

JRS

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Abstract. OBJECTIVE:To investigate possible linkages between neurodevelopmental delay and neurodevelopmental spectrum disorders and exposure to medication with effects on serotonin reuptake inhibition during pregnancy. METHODS: We systematically reviewed the epidemiological literature for studies bearing on this relationship in children born with neurodevelopmental spectrum disorder and related conditions, as well as animal studies giving serotonin reuptake inhibitors to pregnant animals and in addition reviewed the literature for proposals as to possible mechanisms that might link effects on serotonin reuptake with cognitive changes post-partum.The epidemiological studies were analysed to produce Forest plots to illustrate possible relations. RESULTS: The odds ratio of Autistic Spectrum or related Disorders in children born to women taking serotonin reuptake inhibiting antidepressants during pregnancy in case control studies was 1.95 (95% C.I. 1.63, 2.34) and in prospective cohort studies was 1.96 (95% C.I. 1.33, 2.90).CONCLUSIONS: There appears to be a link between serotonin reuptake inhibition in pregnancy and developmental delay and spectrum disorders in infancy leading to cognitive difficulties in childhood. More work needs to be done to establish more precisely the nature of the difficulties and possible mechanisms through which this link might be mediated.Keywords: Autism spectrum disorder, neurodevelopmental delay, neurodevelopmental spectrum disorders, antidepressants, serotonin reuptake inhibitors, pregnancy BackgroundThe clinical syndrome later called autism was first reported in 1943 [1]. The first studies of the prevalence of autism or autistic disorder (AD) in the 1960s pointed to a rate of 4 per 10,000 [2,3]. Later studies indicated the existence of a spectrum of disorders, and brought the term autistic spectrum disorder (ASD) into being in the mid-1990s 126 D. Healy et al. / Link between SSRIs in pregnancy and autistic spectrum disordersand ASD also now includes other syndromes such as Pervasive Developmental Disorder and Aspergers Disorder so that it is difficult to know how closely current clinical usage of an ASD diagnosis maps onto AD and ASD as first conceived. Current estimates are that ASD in research studies occurs at a rate of more than 1 in 70 children [5,6].Kanner autism was recognized before the emergence of modern psychotropic drugs, and given its submergence in ASD, it may not now be possible to establish whether it is linked to commonly used psychotropic medications. A number of clinical pictures linked to psychotropic drug use, fetal anticonvulsant syndrome (FACS), fetal valproate syndrome (FVS), and fetal alcohol syndrome (FAS) and fetal alcohol spectrum disorder (FASD) have been described since 1970. Aside from the link to treatment, the clinical features of these disorders are consistent with a diagnosis of ASD but not Kanner autism. A growing number of epidemiological studies point to an increase in rates of ASD. This translates popularly into concerns about a change in the p...

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Section: Resultsmentioning

confidence: 99%

Links between serotonin reuptake inhibition during pregnancy and neurodevelopmental delay/spectrum disorders: A systematic review of epidemiological and physiological evidence

Healy

Noury

Mangin

2016

JRS

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“…10,11 Fourth, Shi and Li propose that an alternative approach would be to conduct sensitivity analyses wherein the chosen study is replaced with an excluded study. However, given that both Sørensen et al 5 and Gidaya et al 6 had incomplete control for confounding by indication, the results would be less robust. In fact, Hviid et al 4 was the only study, of 8 evaluated, that had adequate control for distorting influences.…”

Section: Dr Brown and Colleagues Replymentioning

confidence: 92%

“…Third, Shi and Li question our exclusion of Gidaya et al, 6 since this study would have been included in pooled estimates for casecontrol studies, rather than cohort studies along with Hviid et al 4 We maintain that inclusion of both studies would have resulted in "duplication" of Danish study subjects 3 ; any bias in these data would have unduly influenced conclusions in a given analysis. We prioritized Hviid et al because of their superior control for confounding by indication; their mental illness variables included not just depression, anxiety, and schizophrenia but other potential indications as well, such as personality disorders and eating disorders.…”

Section: Dr Brown and Colleagues Replymentioning

confidence: 98%

“…3 Shi and Li comment on our decision to exclude, from the quantitative synthesis, 2 of 3 Danish studies with overlapping data sources and study periods. [4][5][6] We address their comments below.…”

Section: Dr Brown and Colleagues Replymentioning

confidence: 99%

“…Second, Shi and Li note that a previous meta-analysis 7 rated Hviid et al 5 and Sørensen et al 6 as having "high quality" using the Newcastle-Ottawa scale. 8 However, this scale does not explicitly address confounding by indication.…”

Section: Dr Brown and Colleagues Replymentioning

confidence: 99%

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Association Between Antenatal Exposure to Selective Serotonin Reuptake Inhibitors and Autism

Shi

Li²

2017

J. Clin. Psychiatry

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To the Editor: The recent systematic review and meta-analysis by Brown et al 1 that aimed to assess risk of autism spectrum disorder (ASD) in children whose mothers were exposed to selective serotonin reuptake inhibitors (SSRIs) during pregnancy was interesting. The authors reported an unclear association between antenatal exposure to SSRI and risk of ASD in offspring that warranted future studies. We applaud Dr Brown and colleagues' meaningful work. However, several important methodological issues regarding study selection should be noted.Of studies based on the same data sources and overlapping study periods and population, the authors retained the study with the highest rating score in quality assessment for metaanalysis. However, the authors failed to provide a clear theoretical background for that inclusion and exclusion. In the quality assessment section, a study by Hviid et al 2 was marked as moderate and was included for quantitative synthesis, but a study by Sørensen et al 3 was marked as low and was excluded because Hviid et al controlled for other psychotropic drugs. This reason for excluding the study by Sørensen et al is not adequate. First, no other included studies controlled for other psychotropic drugs and met the criteria for adequate consideration of distorting influences. Second, those 2 studies 2,3 were both rated as high quality using the NewcastleOttawa scale. 4 More importantly, the cohort study by Sørensen et al had an extra data source, the Danish National Hospital Register, and thus had a larger sample size with more ASD cases (91 cases in the SSRI-exposed group) than the study by Hviid et al (52 cases in the SSRI-exposed group), so the study by Sørensen et al might be more capable of assessing the causal association considering that autism cases are relatively rare. In this case, sensitivity analyses should be performed by excluding the study by Hviid et al and including the study by Sørensen et al.The rationale for excluding the case-control study by Gidaya et al 5 is also unclear. The authors stated that of the 2 studies that had the same final quality rating, the retrospective study by Hviid et al 2 was retained because of better control for distorting influences. That reason is not convincing, as the case-control study by Gidaya et al had a better exposure measure. Besides, data extracted from case-control studies and cohort studies were separately pooled in the quantitative analysis, so the interpretation of the results is based on the 2 pooled odds ratios. In consideration of the limited number of included studies, the results of a meta-analysis of case-control studies would be more robust with inclusion of the study by Gidaya et al.Overall, even though several studies used the same data sources, those studies were inconsistent in some methodological respects such as study design, sample size, or statistical analysis, which may potentially influence the association of interest. For studies with the same design, sensitivity analyses could be performed to assess the robustness of ...

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Association Between Serotonergic Antidepressant Use During Pregnancy and Autism Spectrum Disorder in Children

Brown

Ray

Wilton

et al. 2017

JAMA

121

117

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In Utero Exposure to Selective Serotonin Reuptake Inhibitors and Risk for Autism Spectrum Disorder

Cited by 106 publications

References 55 publications

Links between serotonin reuptake inhibition during pregnancy and neurodevelopmental delay/spectrum disorders: A systematic review of epidemiological and physiological evidence

Links between serotonin reuptake inhibition during pregnancy and neurodevelopmental delay/spectrum disorders: A systematic review of epidemiological and physiological evidence

Association Between Antenatal Exposure to Selective Serotonin Reuptake Inhibitors and Autism

Association Between Serotonergic Antidepressant Use During Pregnancy and Autism Spectrum Disorder in Children

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