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Original Investigation | Journal Club

Antidepressant Use During Pregnancy and the Risk of Autism Spectrum Disorder in Children

Takoua Boukhris, MSc1,2; Odile Sheehy, MSc2; Laurent Mottron, MD, PhD3,4,5,6; Anick Bérard, PhD1,2
[+] Author Affiliations
1Faculty of Pharmacy, University of Montréal, Montréal, Québec, Canada
2Research Unit on Medications and Pregnancy, Research Center, CHU Sainte-Justine, Montréal, Québec, Canada
3Centre d'excellence en Troubles Envahissants du Développement de l'Université de Montréal, Montréal, Québec, Canada
4Département de Psychiatrie, Hôpital Rivière-des-Prairies, Montréal, Québec, Canada
5Centre de Recherche de l'Institut Universitaire de Psychiatrie de l'Université de Montréal, Montréal, Québec, Canada
6Department of Pharmaceutical Sciences, University of Montréal, Montréal, Québec, Canada
JAMA Pediatr. 2016;170(2):117-124. doi:10.1001/jamapediatrics.2015.3356.
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Published online

Importance  The association between the use of antidepressants during gestation and the risk of autism spectrum disorder (ASD) in children is still controversial. The etiology of ASD remains unclear, although studies have implicated genetic predispositions, environmental risk factors, and maternal depression.

Objective  To examine the risk of ASD in children associated with antidepressant use during pregnancy according to trimester of exposure and taking into account maternal depression.

Design, Setting, and Participants  We conducted a register-based study of an ongoing population-based cohort, the Québec Pregnancy/Children Cohort, which includes data on all pregnancies and children in Québec from January 1, 1998, to December 31, 2009. A total of 145 456 singleton full-term infants born alive and whose mothers were covered by the Régie de l’assurance maladie du Québec drug plan for at least 12 months before and during pregnancy were included. Data analysis was conducted from October 1, 2014, to June 30, 2015.

Exposures  Antidepressant exposure during pregnancy was defined according to trimester and specific antidepressant classes.

Main Outcomes and Measures  Children with ASD were defined as those with at least 1 diagnosis of ASD between date of birth and last date of follow-up. Cox proportional hazards regression models were used to estimate crude and adjusted hazard ratios with 95% CIs.

Results  During 904 035.50 person-years of follow-up, 1054 children (0.7%) were diagnosed with ASD; boys with ASD outnumbered girls by a ratio of about 4:1. The mean (SD) age of children at the end of follow-up was 6.24 (3.19) years. Adjusting for potential confounders, use of antidepressants during the second and/or third trimester was associated with the risk of ASD (31 exposed infants; adjusted hazard ratio, 1.87; 95% CI, 1.15-3.04). Use of selective serotonin reuptake inhibitors during the second and/or third trimester was significantly associated with an increased risk of ASD (22 exposed infants; adjusted hazard ratio, 2.17; 95% CI, 1.20-3.93). The risk was persistent even after taking into account maternal history of depression (29 exposed infants; adjusted hazard ratio, 1.75; 95% CI, 1.03-2.97).

Conclusions and Relevance  Use of antidepressants, specifically selective serotonin reuptake inhibitors, during the second and/or third trimester increases the risk of ASD in children, even after considering maternal depression. Further research is needed to specifically assess the risk of ASD associated with antidepressant types and dosages during pregnancy.

Figures in this Article


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Figure 1.
Study Population

Flowchart of the cohort study. AD indicates antidepressant; ASD, autism spectrum disorder.

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Figure 2.
Adjusted Kaplan-Meier Survival Curves for the Time to Diagnosis of Autism Spectrum Disorder (ASD)

Survival curves are stratified by exposure to antidepressants (ADs) during the second and/or third trimester. The black line indicates exposure to ADs during the second and/or third trimester and the blue line indicates no exposure to ADs during the second and/or third trimester.

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Investigation failed to consider undiagnosed ASD in the mothers
Posted on December 15, 2015
Dr S Moore B.Eng.(Hons.) MSc. MBChB. MRCA
Conflict of Interest: Diagnosed with ASD at the age of 42 when my children were at primary school. Daughter awaiting assessment for ASD. Previously prescribed ADs prior to autism diagnosis (although did not take during pregnancy).
It is widely becoming recognised that there is a lost generation of women on the autism spectrum who were not diagnosed in childhood and either receive a diagnosis in adulthood or remain undiagnosed or misdiagnosed with other mental health conditions. Depression and anxiety feature heavily among these women and therefore the use of antidepressants.
Is it not possible that the reason that there may be an association between ASD and AD use in these mothers is that the mothers are undiagnosed autistics suffering from comorbid affective disorders, that often go hand in hand with autism, and that the link is genetic, rather than due to the ADs?
1. Identifying the lost generation of adults with autism spectrum conditions.
Lai MC, Baron-Cohen S.Lancet Psychiatry. 2015 Nov;2(11):1013-27
Failure to accurately represent study limitations will have harmful consequences
Posted on December 27, 2015
David Curtis MD, PhD, FRCPsych
UCL Genetics Institute, UCL, London
Conflict of Interest: None Declared
This report on the association between antidepressant use and ASD is concerning in a number of ways.

The first thing that needs emphasising is that none of the results reported would be statistically significant if the necessary corrections for multiple testing were made. Deep in the text, the authors admit that they \"cannot rule out chance\" but the abstract and \"At a Glance\" panel do not acknowledge this basic reservation. Moreover, the analysis restricted to only confirmed cases was not statistically significant but nevertheless the authors claim that an increased risk was \"observed\" . In their discussion, they claim that the findings of this analysis were \"consistent\", \"increasing the validity of our results\". In fact, simply put, the findings from the confirmed cases do not provide evidence for an increased risk. And, because of multiple testing issues, neither do any of the other results.

Aside from the statistical concerns, another major issue is the failure to adequately consider potential confounders. As already pointed out in the previous comment, one is that the mothers prescribed antidepressants (ADs) may be more like to have increased genetic susceptibility to ASD themselves . The fact that they were older is consistent with this. I would add that it is plausible that mothers prescribed ADs are more likely to be have a partner with ASD susceptibility. Also, there may well be very important effects around engagement with health services. The children studied were very young and hence a major determinant of whether they had a \"medical service claim\" for ASD would be whether their parents or health professionals working with them were concerned about them enough to arrange an assessment. Women who had been prescribed ADs could be assumed to be more likely to seek such an assessment . They would be more likely to be struggling to cope and through, having accepted a prescription, would be identified as being more open to receiving psychiatric input. One could also assume that health professionals would be working with them more closely in a way which would mean that any problems with the child would be more likely to be picked up sooner.

These kinds of flaws in statistical analysis and interpretation are commonplace and almost routine for this kind of epidemiological study. However this report is particularly problematic because of the predictable and serious consequences it will have. In spite of the caveats in the text, the abstract boldly concludes that the use of ADs increases the risk of ASD and the \"Antidepressants cause autism\" message will be taken up widely. Maternal depression is an important cause of avoidable mortality in mothers and, through infanticide, their babies. It is tragic that much morbidity and mortality associated with mental illness could be avoided if patients accepted treatments which are, by and large, safe and effective. Thus it is a matter for regret that this paper has been published in its present form in such a high profile journal.
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