Rai D, Lee BK, Dalman C, Golding J, Lewis G, Magnusson C. Parental depression, maternal antidepressant use during pregnancy, and risk of autism spectrum disorders: population based case-control study. BMJ 346: f2059

Centre for Mental Health, Addiction and Suicide Research, School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK.
BMJ (online) (Impact Factor: 17.45). 04/2013; 346(apr19 1):f2059. DOI: 10.1136/bmj.f2059
Source: PubMed


To study the association between parental depression and maternal antidepressant use during pregnancy with autism spectrum disorders in offspring.
Population based nested case-control study.
Stockholm County, Sweden, 2001-07.
4429 cases of autism spectrum disorder (1828 with and 2601 without intellectual disability) and 43 277 age and sex matched controls in the full sample (1679 cases of autism spectrum disorder and 16 845 controls with data on maternal antidepressant use nested within a cohort (n=589 114) of young people aged 0-17 years.
A diagnosis of autism spectrum disorder, with or without intellectual disability. EXPOSURES: Parental depression and other characteristics prospectively recorded in administrative registers before the birth of the child. Maternal antidepressant use, recorded at the first antenatal interview, was available for children born from 1995 onwards.
A history of maternal (adjusted odds ratio 1.49, 95% confidence interval 1.08 to 2.08) but not paternal depression was associated with an increased risk of autism spectrum disorders in offspring. In the subsample with available data on drugs, this association was confined to women reporting antidepressant use during pregnancy (3.34, 1.50 to 7.47, P=0.003), irrespective of whether selective serotonin reuptake inhibitors (SSRIs) or non-selective monoamine reuptake inhibitors were reported. All associations were higher in cases of autism without intellectual disability, there being no evidence of an increased risk of autism with intellectual disability. Assuming an unconfounded, causal association, antidepressant use during pregnancy explained 0.6% of the cases of autism spectrum disorder.
In utero exposure to both SSRIs and non-selective monoamine reuptake inhibitors (tricyclic antidepressants) was associated with an increased risk of autism spectrum disorders, particularly without intellectual disability. Whether this association is causal or reflects the risk of autism with severe depression during pregnancy requires further research. However, assuming causality, antidepressant use during pregnancy is unlikely to have contributed significantly towards the dramatic increase in observed prevalence of autism spectrum disorders as it explained less than 1% of cases.

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    • "There are several reports of a neonatal withdrawal syndrome (altered sleep, heart rate variability, jitteriness) in newborns exposed to different types of SSRIs in utero (Zeskind and Stephens, 2004; Alwan and Friedman, 2009; Gentile and Galbally, 2011; Hayes et al., 2012). Infants and young children exposed to SSRIs during early-life can also exhibit subtle psychomotor deficits (Casper et al., 2003), aberrant pain sensation (Oberlander et al., 2005), altered hypothalamic pituitary adrenal stress responses (Oberlander et al., 2008b), increased social avoidance and anxiety at age 3–4 (Oberlander et al., 2010; Klinger et al., 2011), and increased risk for autism (Croen et al., 2011; Harrington et al., 2013; Rai et al., 2013) (although there are conflicting reports on the risk for autism; see (Clements et al., 2014)). Human studies have not extended beyond childhood , so the long-term consequences of early-life SSRI exposure on human brain maturation and behavior remain unknown. "
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    • "Decreased seeking might protect a brain that is struggling to process an excess of stimulation . Good executive control (Johnson, 2012) and genetic and cognitive factors specific to girls (Robinson, Lichtenstein, Anckarsäter, Happé, & Ronald, 2013) have also been proposed as protective factors against a variety of developmental perturbations/disorders and a range of pre-natal or early post-natal risk factors (e.g., parental age; Gardener, Spiegelman, & Buka, 2009; maternal pre-natal medication use; Rai et al., 2013; pre-natal stress; Ronald, Pennell, & Whitehouse, 2011) and protective factors (e.g., amount of physical contact used by depressed mothers; Sharp et al., 2012) have been shown to modulate the effects of gene expression, accentuating or diminishing the severity of later manifested clinical symptoms. Much more work is required to understand how protective and risk factors interact. "
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