Autism: Born out of SSRI?

22. February 2016
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The use of SSRIs during pregnancy is associated with an increased risk of autism in children – researchers recently made headlines with this result of a recent study. But what's really true in this story?

Following the publication of the study in JAMA Pediatrics [Paywall] in December 2015, coverage of the topic was dominated by horror stories – hardly surprising given the fact that even the official press release stokes fear by carrying the title “Taking antidepressants during pregnancy increases the risk of autism by 87%”.

The matter here actually relates to the existence of relative risk: researchers have found that autism spectrum disorder (ASD) was diagnosed for 31 out of 2,532 children (1.22%) whose mothers during the second or third trimester had taken antidepressants. For purpose of comparison: of the 140,732 children who were not exposed to in utero antidepressants, ASD was present at the rate of 1.008 (0.72%). This corresponds to an adjusted hazard ratio of 1.87 (95% confidence interval 1.15 to 3.04), which produces a good match with the results of a systematic review from the same year. Although in this one the time points of prenatal antidepressant exposure had not been studied, when looking over the entire pregnancy the study arrived at an adjusted odds ratio of 1.81 (95% confidence interval 1.47 to 2.24).

Interestingly enough, in the JAMA Pediatrics study only selective serotonin reuptake inhibitors (SSRIs) demonstrated an increased ASD-risk, whereas for the other classes of antidepressants such as SNRIs, MAO inhibitors and tricyclic antidepressants no statistically significant increased risk was found. “It is biologically plausible that antidepressants cause autism when they are used at the time of brain development in the womb, because serotonin is involved in numerous prenatal and postnatal development processes, including cell division, the migration of neurons, cell differentiation and synaptogenesis”, explains Dr. Anick Bérard, lead author of the study and professor at the Faculty of Pharmacy of the University of Montreal, Canada.

Large number of cases, but also methodological shortcomings

For the register-based cohort study, the group led by Prof. Bérard evaluated data from the Quebec Pregnancy/Children (QPC) Cohort. The analysis took in all full term single births which occurred between 1 January 1998 and 31 December of 2009. The 145,456 infants involved were observed over a period of 904,035.5 person-years. The large number of cases makes this analysis meaningful and represents one of the greatest strengths of the study.

Antidepressant exposure was defined by the researchers as provision of antidepressants during pregnancy – a weakness of the study, because it was not able to be determined from the data register whether the delivered drugs were actually taken by the expectant mother. In order to determine the adjusted hazard ratio, various variables such as socio-demographic data, psychiatric and chronic physical comorbidities of the mother and characteristics of the infant were taken into account in the data analysis.

Conflicting data situation

According to the study, however, antidepressant exposure one year before pregnancy as well as exposure in the first trimester was not associated with an increased risk of autism (adjusted hazard ratio 1.05 and 0.84, respectively) – as opposed to the intake of antidepressants during the second or third trimester. “During this time, the critical brain development of the child takes place”, says Bérard. This lends a ring of plausibility – but the evidence of a causal relationship between ASD and antidepressant was not able to be delivered by their study.

Other studies in addition led to entirely different results: as early as 2011 one population-based case-control study (though small in sample size) concluded that exposure during the first trimester carries the highest risk of ASD (adapted odds ratio 3.8; 95%, confidence interval 1.8 to 7.8). According to one study from 2013, not only was SSRI exposure in utero associated with an increased ASD-risk (adjusted odds ratio 1.65; 95% confidence interval 0.90 to 3.03), but taking tricyclic antidepressants was as well (adjusted odds ratio 2.69; 95% confidence interval 1, 04 to 6.96).

Still other studies conclude that prenatal exposure to antidepressants in general has no significant effect on ASD risk. This includes both a 2013-published large Danish cohort study as well as two US studies (published in 2015 [Paywall] and in 2016). With so many conflicting results uncertainty is the only certainty.

SSRI during pregnancy: hooey or phooey?

SSRIs are however not only discredited because of ASD suspicions – there are for instance also pieces of evidence of an association between prenatal SSRI exposure and an increased risk of congenital malformations [Paywall], prematurity, low birth weight, persistent pulmonary hypertension and behavioral disorders.

The decision to use antidepressant drugs during pregnancy therefore remains a difficult one. On the one hand it is important to consider the risks of the treatment for the unborn child, on the other hand the consequences of non-treatment need to be considered. Depression during a pregnancy occurs with a prevalence of approximately 6 to 17% [Paywall] and is associated with significant health risks for the mother and the unborn child. These include spontaneous abortion, prematurity and low birth weight. In addition, suicides are among the most common causes of death for a year postpartum and during pregnancy.

The reflexive reaction to discontinue the use of antidepressants based on the now published results is therefore not an advisable action. “The crucial step here involves educating women as to how big a particular risk actually is and how these risk factors are actually triggered. It is important to take away fear and the supposed guilt”, Dr. Antje Heck, specialist in clinical pharmacology and toxicology and director of special consultation process “drugs in pregnancy and lactation” at the Psychiatric Services Aargau AG (PDAG) in Switzerland, believes. “I think it is primarily important not to neglect the risks of mental illness for mother and child and to view them in relation to the potential side effects of the respective drugs. This assessment is an individual, time-consuming and sometimes very complex thing”.

Original publication:

Antidepressant Use During Pregnancy and the Risk of Autism Spectrum Disorder in Children [Paywall]
Takoua Boukhris et al.; JAMA Pediatr., doi: 10.1001/jamapediatrics.2015.3356; 2015

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