ASD in Offspring After Prenatal Antidepressant Use Raises Questions

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The increased risk for ASDs in children exposed in utero could well be related to maternal depression or other psychiatric disorders.
The increased risk for ASDs in children exposed in utero could well be related to maternal depression or other psychiatric disorders.

A major review published in the Journal of Pediatrics found that preconception antidepressant use was more strongly associated with a higher risk of autism spectrum disorders (ASD) in babies than the mother's use of antidepressants during any of the 3 trimesters of pregnancy.1 The controversy about the use of antidepressants during pregnancy was not resolved by the meta-analysis of current literature by Mezzacappa, et al, but it did point to a shift of attention to preconception exposure. Furthermore, the reviewers found indications that ASD risk may be more closely tied to psychiatric illness in the mother than her use of antidepressants.

The investigative team from the Université Paris-Sud in Paris, France, conducted a literature search of 95 articles from PubMed to identify 10 relevant studies — the results of which were highly inconsistent.

Meta-analysis of 6 case-controlled studies2-7 covering 117,737 patient records indicated a positive correlation between antidepressant exposure during pregnancy (odds ratio (OR) 1.81; 95% CI1.49-2.20) and ASD, although in their review, the investigators found no strong correlation between prenatal antidepressant exposure and ASD in the offspring.1

The same 6 studies2-7 demonstrated significant relationships between exposure to antidepressants in each trimester and ASD. These were all weakened after adjusting for previous psychiatric history, but remained significant for the first 2 trimesters. For the third trimester, the association was no longer significant. When the data from 2 large cohort studies (772,331 patients)33,46 was pooled for analysis there was broad heterogeneity between the studies (I2 67%), and no association to ASD was found for the first trimester or for the whole pregnancy (hazard ratio [HR] 1.26; 95% CI, 0.91-1.74).

Four studies2,3,7,8 reported significant correspondence with antidepressant exposure in the preconception period (OR, 1.96; 95% CI, 1.65-2.32), which remained significant, even after controlling for past depression (OR, 1.77; 95%CI, 1.49-2.09), with no heterogeneity between studies (I2 0%).

The reviewers found they could neither refute nor support previous claims of a risk for ASD associated with prenatal use of antidepressants. They did point to the preconception stage as the period most significantly associated with ASD in infants, and further speculated that antidepressant use might only be a marker for the real risk factor for psychiatric depression in mothers. “The increased risk for ASDs in children exposed in utero could well be related to maternal depression or other psychiatric disorders rather than to antidepressant medications per se,” they wrote.

The analysis contained some significant biases, including the fact that 9 of the 10 studies evaluated were not standard case-controlled design, but used population registry data. Depression severity was not assessed, as the indication for antidepressant use was frequently not available. The reviewers also suggested that many of the patients were taking additional pharmacotherapies, including psychotropic agents, which might also have influenced the risk for ASD.

 

Nevertheless, this study has important implications for prenatal health, as discontinuation of necessary antidepressants could pose serious risks to mother and child, including the potential for self-harm or suicide. The investigators recommended continued evaluations of antidepressants at each stage of pregnancy.

References

  1. Mezzacappa A, Lasica PA, Gianfagna F, et al. Risk for autism spectrum disorders according to period of prenatal antidepressant exposure: a systematic review and meta-analysis [published online April 17, 2017]. JAMA Pediatr. doi:10.1001/jamapediatrics.2017.0124
  2. Castro VM, Kong SW, Clements CC, et al. Absence of evidence for increase in risk for autism or attention-deficit hyperactivity disorder following antidepressant exposure during pregnancy: a replication study. Transl Psychiatry. 2016;6:e708.
  3. Clements CC, Castro VM, Blumenthal SR, et al. Prenatal antidepressant exposure is associated with risk for attention-deficit hyperactivity disorder but not autism spectrum disorder in a large health system. Mol Psychiatry. 2015;20:727-734.
  4. Harrington RA, Lee LC, Crum RM, Zimmerman AW, Hertz-Picciotto I. Prenatal SSRI use andoffspring with autism spectrum disorder or developmental delay. Pediatrics. 2014;133:e1241-e1248.
  5. 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. 2013;346:f2059.
  6. Eriksson MA, Westerlund J, Anderlid BM, Gillberg C, Fernell E. First-degree relatives of young children with autism spectrum disorders: some gender aspects. Res Dev Disabil. 2012;33:1642-1648.
  7. Croen LA, Grether JK, Yoshida CK. Antidepressant use during pregnancy and childhood autism spectrum disorders. Arch Gen Psychiatry. 2011;68:1104-1112.
  8. Boukhris T, Sheehy O, Mottron L, Bérard A. Antidepressant use during pregnancy and the risk of autism spectrum disorder in children. JAMA Pediatr. 2016;170:117-124.
  9. Hviid A, Melbye M, Pasternak B. Use of selective serotonin reuptake inhibitors during pregnancy and risk of autism. N Engl J Med. 2013;369:2406-2415.
  10. Gidaya NB, Lee BK, Burstyn I. In utero exposure to selective serotonin reuptake inhibitors and risk for autism spectrum disorder. J Autism Dev Disord. 2014;44:2558-2567.
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