Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Prenatal antidepressant exposure is associated with risk for attention-deficit hyperactivity disorder but not autism spectrum disorder in a large health system

Abstract

Previous studies suggested that risk for Autism Spectrum Disorder (ASD) may be increased in children exposed to antidepressants during the prenatal period. The disease specificity of this risk has not been addressed and the possibility of confounding has not been excluded. Children with ASD or attention-deficit hyperactivity disorder (ADHD) delivered in a large New England health-care system were identified from electronic health records (EHR), and each diagnostic group was matched 1:3 with children without ASD or ADHD. All children were linked with maternal health data using birth certificates and EHRs to determine prenatal medication exposures. Multiple logistic regression was used to examine association between prenatal antidepressant exposures and ASD or ADHD risk. A total of 1377 children diagnosed with ASD and 2243 with ADHD were matched with healthy controls. In models adjusted for sociodemographic features, antidepressant exposure prior to and during pregnancy was associated with ASD risk, but risk associated with exposure during pregnancy was no longer significant after controlling for maternal major depression (odds ratio (OR) 1.10 (0.70–1.70)). Conversely, antidepressant exposure during but not prior to pregnancy was associated with ADHD risk, even after adjustment for maternal depression (OR 1.81 (1.22–2.70)). These results suggest that the risk of autism observed with prenatal antidepressant exposure is likely confounded by severity of maternal illness, but further indicate that such exposure may still be associated with ADHD risk. This risk, modest in absolute terms, may still be a result of residual confounding and must be balanced against the substantial consequences of untreated maternal depression.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Investigators AaDDMNSYP Prevalence of Autism Spectrum Disorders — Autism and Developmental Disabilities Monitoring Network. MMWR Surveill Summ 2012; 61: 1–19.

    Google Scholar 

  2. Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 1995; 25: 63–77.

    Article  CAS  PubMed  Google Scholar 

  3. Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T et al. Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry 68: 1095–1102.

  4. Ansorge MS, Zhou M, Lira A, Hen R, Gingrich JA . Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice. Science 2004; 306: 879–881.

    Article  CAS  PubMed  Google Scholar 

  5. Croen LA, Grether JK, Yoshida CK, Odouli R, Hendrick V . Antidepressant use during pregnancy and childhood autism spectrum disorders. Arch Gen Psychiatry 2011; 68: 1104–1112.

    Article  PubMed  Google Scholar 

  6. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  7. 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.

    Article  CAS  PubMed  Google Scholar 

  8. Cohen LS, Altshuler LL, Harlow BL, Nonacs R, Newport DJ, Viguera AC et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA 2006; 295: 499–507.

    Article  CAS  PubMed  Google Scholar 

  9. Oberlander TF, Warburton W, Misri S, Aghajanian J, Hertzman C . Neonatal outcomes after prenatal exposure to selective serotonin reuptake inhibitor antidepressants and maternal depression using population-based linked health data. Arch Gen Psychiatry 2006; 63: 898–906.

    Article  PubMed  Google Scholar 

  10. Daniels JL, Forssen U, Hultman CM, Cnattingius S, Savitz DA, Feychting M et al. Parental psychiatric disorders associated with autism spectrum disorders in the offspring. Pediatrics 2008; 121: e1357–e1362.

    Article  PubMed  Google Scholar 

  11. Piven J, Palmer P . Psychiatric disorder and the broad autism phenotype: evidence from a family study of multiple-incidence autism families. Am J Psychiatry 1999; 156: 557–563.

    CAS  PubMed  Google Scholar 

  12. Figueroa R . Use of antidepressants during pregnancy and risk of attention-deficit/hyperactivity disorder in the offspring. J Dev Behav Pediatr 2010; 31: 641–648.

    Article  PubMed  Google Scholar 

  13. Laugesen K, Olsen MS, Telen Andersen AB, Froslev T, Sorensen HT . In utero exposure to antidepressant drugs and risk of attention deficit hyperactivity disorder: a nationwide Danish cohort study. BMJ Open 2013; 3: e003507.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Murphy SN, Mendis M, Hackett K, Kuttan R, Pan W, Phillips LC et al. Architecture of the open-source clinical research chart from Informatics for Integrating Biology and the Bedside. AMIA Annu Symp Proc 2007; 548–552.

  15. Murphy S, Churchill S, Bry L, Chueh H, Weiss S, Lazarus R et al. Instrumenting the health care enterprise for discovery research in the genomic era. Genome Res 2009; 19: 1675–1681.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Murphy SN, Weber G, Mendis M, Gainer V, Chueh HC, Churchill S et al. Serving the enterprise and beyond with informatics for integrating biology and the bedside (i2b2). J Am Med Inform Assoc 17: 124–130.

  17. Castro VM, Gallagher PJ, Clements CC, Murphy SN, Gainer VS, Fava M et al. Incident user cohort study of risk for gastrointestinal bleed and stroke in individuals with major depressive disorder treated with antidepressants. BMJ Open 2012; 2: e000544.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Owens MJ, Morgan WN, Plott SJ, Nemeroff CB . Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites. J Pharmacol Exp Ther 1997; 283: 1305–1322.

    CAS  PubMed  Google Scholar 

  19. Schieve LA, Tian LH, Baio J, Rankin K, Rosenberg D, Wiggins L et al. Population attributable fractions for three perinatal risk factors for autism spectrum disorders, 2002 and 2008 autism and developmental disabilities monitoring network. Ann Epidemiol 2014; 24: 260–266.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Lash TL Fox MP Fink AK . A Guide to Implementing Quantitative Bias Analysis. In Gail M, Krickeberg K, Samet J, Tsiatis A, Wong W (eds). Applying Quantitative Bias Analysis to Epidemiologic Data, 1st edn, Springer: New York, NY, 2009. pp 215–220.

    Chapter  Google Scholar 

Download references

Acknowledgements

This work was supported through funding from the National Institute of Mental Health (5R01MH100286–02). Dr Perlis is supported by NIMH R01MH086026 and by the Stanley Center for Psychiatric Research. The i2b2 platform (PI: Kohane) is supported by award number 2U54LM008748 from the NIH/National Library of Medicine. We express our gratitude to the staff at the Massachusetts Registry of Vital Records and Statistics including Kevin Foster and Dean DiMartino.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to R H Perlis.

Ethics declarations

Competing interests

Dr Perlis has received consulting fees or served on scientific advisory boards for Genomind, Healthrageous, Pamlab, Perfect Health, Pfizer, Proteus Biomedical, Psybrain and RIDventures, and received patent fees/royalties from Concordant Rater Systems (now UBC/Medco).

Dr Smoller is a member of the Scientific Advisory Board of Psybrain, Inc.

Dr Fava reports the following: Research Support: Abbott Laboratories, Alkermes, Aspect Medical Systems, Astra-Zeneca, Bristol-Myers Squibb Company, Cephalon, Eli Lilly & Company, Forest Pharmaceuticals Inc., GlaxoSmithkline, J & J Pharmaceuticals, Lichtwer Pharma GmbH, Lorex Pharmaceuticals, Novartis, Organon Inc., PamLab, LLC, Pfizer Inc, Pharmavite, Roche, Sanofi/Synthelabo, Solvay Pharmaceuticals, Inc., Wyeth-Ayerst Laboratories. Advisory/Consulting: Aspect Medical Systems, Astra-Zeneca, Bayer AG, Biovail Pharmaceuticals, Inc., BrainCells, Inc. Bristol-Myers Squibb Company, Cephalon, Compellis, Cypress Pharmaceuticals, Dov Pharmaceuticals, Eli Lilly & Company, EPIX Pharmaceuticals, Fabre-Kramer Pharmaceuticals, Inc., Forest Pharmaceuticals Inc., GlaxoSmithkline, Grunenthal GmBH, Janssen Pharmaceutica, Jazz Pharmaceuticals, J & J Pharmaceuticals, Knoll Pharmaceutical Company, Lundbeck, MedAvante, Inc., Neuronetics, Novartis, Nutrition 21, Organon Inc., PamLab, LLC, Pfizer Inc, PharmaStar, Pharmavite, Roche, Sanofi/Synthelabo, Sepracor, Solvay Pharmaceuticals, Inc., Somaxon, Somerset Pharmaceuticals, Wyeth-Ayerst Laboratories. Speaking: Astra-Zeneca, Boehringer-Ingelheim, Bristol-Myers Squibb Company, Cephalon, Eli Lilly & Company, Forest Pharmaceuticals Inc., GlaxoSmithkline, Novartis, Organon Inc., Pfizer Inc, PharmaStar, Wyeth-Ayerst Laboratories. Equity Holdings: Compellis, MedAvante. Royalty/patent, other income: none.

The remaining authors declare no conflict of interests.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Clements, C., Castro, V., Blumenthal, S. 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 20, 727–734 (2015). https://doi.org/10.1038/mp.2014.90

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2014.90

This article is cited by

Search

Quick links