Prenatal SSRI exposure and autistic traits

A quote to start today's post: "Our results suggest an association between prenatal SSRI exposure and autistic traits in children". That was a primary finding reported by Hanan El Marroun and colleagues [1] who looked at whether maternal depressive symptoms or a class of quite commonly used pharmaceutics - the selective serotonin reuptake inhibitors (SSRIs) - used to manage depressive symptoms, during pregnancy might impact on offspring development.

"Everything the light touches is our kingdom" 

Before progressing through some of the details around this area, I'm going to also direct your attention to a couple of important accompanying commentaries on the Marroun findings from Jones & McDonald [2] and Petersen and colleagues [3] (open-access). Both caution about reading too much too soon into the reported association between SSRIs and offspring outcomes, and the very real outcomes that can come about if psychiatric issues such as depression are not properly managed. Something I think most people might have heard about recently.

A few details about the Marroun paper might be useful:

• Following some previous discussions correlating maternal SSRI use during pregnancy and offspring outcome with autism in mind (see here) including the quite recent papers by Harrington and colleagues [4] and Rai and colleagues [5], the authors looked to "prospectively determine whether intra-uterine SSRI exposure is associated with childhood autistic symptoms in a population-based study". 
• "A total of 376 children prenatally exposed to maternal depressive symptoms (no SSRI exposure), 69 children prenatally exposed to SSRIs and 5531 unexposed children were included" for study. The commentary from Petersen et al notes how small a group were actually exposed to SSRIs and how "these numbers rapidly dwindled when it came to the measurement of the outcome".
• The Child Behavior Checklist and Social Responsiveness Scale (SRS) were used to assess "pervasive developmental and affective problems" and "autistic traits" respectively. 
• Results: aside from an association between prenatal selective serotonin reuptake inhibitor (SSRI) exposure and autistic traits in children, researchers also reported that: "Prenatal exposure to maternal depressive symptoms without SSRIs was related to both pervasive developmental (odds ratio (OR) = 1.44, 95% CI 1.07-1.93) and affective problems (OR = 1.44, 95% CI 1.15-1.81)". The suggested link between maternal depressive symptoms and autistic traits was to some degree weaker than the SSRI exposure correlation.
• The authors conclude that: "Long-term drug safety trials are needed before evidence-based recommendations are possible" as once again I'll direct you to the Jones and Petersen commentaries.

In the same way that the emerging data on prenatal valproate exposure *might* link into offspring outcome including the presence of autism (see here), so the Marroun paper potentially adds another medicine to the list. I would perhaps temper that last sentence by adding that the valproate story is perhaps a little further along in terms of rodent models of prenatal valproate exposure mimicking some features of autism (see here) and the data providing something like mechanisms to be looked at with further investigations in mind [6]. Still, the CDC Treating for Two initiative might be once again relevant.

The added complication with the SSRI-autism correlation is the discussion about maternal depressive symptoms also potentially mediating any link with offspring autism or autistic traits. The paper by Sørensen and colleagues [7] (open-access here) kinda hinted that this and other important confounding factors might impact on any studies of association, including details like: "paternal antidepressant use during the time of pregnancy was not associated with an increased risk of autism spectrum disorders, except for a 30% increase when the fathers took SSRI". Even more recently Clements and colleagues [8] talked about how maternal "major depression" confounded any medication relationship with offspring presentation. They also talked about a link with ADHD which brings me back to yesterday's post on comorbidity (see here)...

One would do well not to discount such confounding factors at this stage. Indeed, if one assumes that depression might have a physiological link to something like inflammation for example [9] we then start to arrive at the increasingly important research looking at maternal inflammation as being a risk factor for offspring autism (see here). And before you ask, yes, C-reactive protein (CRP) has been linked to depressive symptoms as per the meta-analysis by Valkanova and colleagues [10].

The Marroun results are interesting and add something to an increasing bank of peer-reviewed literature [11] suggestive of a possible link between SSRI use during pregnancy and offspring outcomes. On the basis of the current existing literature and with my blogging caveat of no medical advice given or intended, I would be minded to conclude that there is quite a bit more experimental investigation to be done on this category of medicines. But I don't yet think there is enough clear evidence to conclusively put an elevated risk of offspring autism on the list of potential side-effects of these medicines.

Music then. Scissor Sisters and Laura.

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[1] Marroun HE. et al. Prenatal exposure to selective serotonin reuptake inhibitors and social responsiveness symptoms of autism: population-based study of young children. The British Journal of Psychiatry. 2014; 205: 95-102.

[2] Jones I. & McDonald L. Living with uncertainty: antidepressants and pregnancy. The British Journal of Psychiatry. 2014; 205: 103-104.

[3] Petersen I. et al. Prenatal exposure to selective serotonin reuptake inhibitors and autistic symptoms in young children: another red herring? The British Journal of Psychiatry. 2014; 205: 105-106.

[4] Harrington RA. et al. Prenatal SSRI Use and Offspring With Autism Spectrum Disorder or Developmental Delay. Pediatrics. 2014 Apr 14.

[5] Rai D. et al. Parental depression, maternal antidepressant use during pregnancy, and risk of autism spectrum disorders: population based case-control study. BMJ. 2013 Apr 19;346:f2059.

[6] Bambini-Junior V. et al. Prenatal Exposure to Valproate in Animals and Autism. Comprehensive Guide to Autism. 2014: 1779-1793.

[7] Sørensen MJ. et al. Antidepressant exposure in pregnancy and risk of autism spectrum disorders. Clin Epidemiol. 2013 Nov 15;5:449-59.

[8] Clements CC. et al. Prenatal antidepressant exposure is associated with risk for attention-deficit hyperactivity disorder but not autism spectrum disorder in a large health system. Molecular Psychiatry. 2014. August 26.

[9] Berk M. et al. So depression is an inflammatory disease, but where does the inflammation come from? BMC Med. 2013 Sep 12;11:200.

[10] Valkanova V. et al. CRP, IL-6 and depression: a systematic review and meta-analysis of longitudinal studies. J Affect Disord. 2013 Sep 25;150(3):736-44.

[11] Rais TB. & Rais A. Association Between Antidepressants Use During Pregnancy and Autistic Spectrum Disorders: A Meta-analysis. Innov Clin Neurosci. 2014 May;11(5-6):18-22.

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Marroun, H., White, T., van der Knaap, N., Homberg, J., Fernandez, G., Schoemaker, N., Jaddoe, V., Hofman, A., Verhulst, F., Hudziak, J., Stricker, B., & Tiemeier, H. (2014). Prenatal exposure to selective serotonin reuptake inhibitors and social responsiveness symptoms of autism: population-based study of young children The British Journal of Psychiatry, 205 (2), 95-102 DOI: 10.1192/bjp.bp.113.127746