Pediatric Drugs

, Volume 17, Issue 6, pp 443–448 | Cite as

Prenatal Antidepressant Exposure and Childhood Autism Spectrum Disorders: Cause for Concern?

  • Lars Henning Pedersen
Leading Article


There is empirical evidence for a role for serotonin in autism . In experimental animals, early life exposure to serotonergic antidepressants or maternal stress affects brain development, with subsequent changes in serotonin tone in adult animals. Recently, antidepressant exposure during pregnancy has been associated with autism in epidemiological studies. At least part of the association is potentially explained by maternal depression or factors associated with depression. Importantly, even if there is no causal relation between prenatal antidepressant exposure and autism, use of antidepressants during pregnancy is a marker of potential problems later in life across five independent study populations, and exposed children may need special attention regardless of the underlying mechanism. Future studies need to disentangle the effects of maternal depression and antidepressant use during pregnancy while adjusting for the postnatal environment. One promising strategy is to use results from basic science to guide the inclusion of potential biological intermediates in advanced epidemiological studies.


Autism Spectrum Disorder Selective Serotonin Reuptake Inhibitor Childhood Autism Maternal Depression Asperger Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The author has no conflicts of interest. No specific funding was used to assist in the preparation of the review.


  1. 1.
    Andrade S, Raebel M, Brown J, Lane K, Livingston J, Boudreau D, et al. Use of antidepressant medications during pregnancy: a multisite study. Am J Obstet Gynecol. 2008;198(2):194.e1–e5.Google Scholar
  2. 2.
    Bjorn AM, Norgaard M, Hundborg HH, Nohr EA, Ehrenstein V. Use of prescribed drugs among primiparous women: an 11-year population-based study in Denmark. Clin Epidemiol. 2011;3:149–56.PubMedCentralCrossRefPubMedGoogle Scholar
  3. 3.
    Jimenez-Solem E, Andersen JT, Petersen M, Broedbaek K, Andersen NL, Torp-Pedersen C, et al. Prevalence of antidepressant use during pregnancy in Denmark, a Nation-Wide Cohort Study. PLoS One. 2013;8(4):e63034.PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Knight M Kenyon S, Brocklehurst P, Neilson J, Shakespeare J, Kurinczuk JJ, editors. On behalf of MBRRACE—UK. Saving lives, improving mothers’ care—lessons learned to inform future maternity care from the UK and Ireland confidential enquiries into maternal deaths and morbidity 2009–12. Oxford: National Perinatal Epidemiology Unit, University of Oxford; 2014.Google Scholar
  5. 5.
    Alwan S, Reefhuis J, Rasmussen SA, Olney RS, Friedman JM. Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med. 2007;356(26):2684–92.CrossRefPubMedGoogle Scholar
  6. 6.
    Grzeskowiak LE, Gilbert AL, Morrison JL. Investigating outcomes following the use of selective serotonin reuptake inhibitors for treating depression in pregnancy: a focus on methodological issues. Drug Saf. 2011;34(11):1027–48.CrossRefPubMedGoogle Scholar
  7. 7.
    Pedersen LH, Henriksen TB, Vestergaard M, Olsen J, Bech BH. Selective serotonin reuptake inhibitors in pregnancy and congenital malformations: population based cohort study. BMJ. 2009;339:b3569.PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Malm H, Artama M, Gissler M, Ritvanen A. Selective serotonin reuptake inhibitors and risk for major congenital anomalies. Obstet Gynecol. 2011;118(1):111–20.CrossRefPubMedGoogle Scholar
  9. 9.
    Louik C, Lin AE, Werler MM, Hernandez-Diaz S, Mitchell AA. First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. N Engl J Med. 2007;356(26):2675–83.CrossRefPubMedGoogle Scholar
  10. 10.
    Pedersen LH, Henriksen TB, Olsen J. Fetal exposure to antidepressants and normal milestone development at 6 and 19 months of age. Pediatrics. 2010;125(3):e600–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Pedersen LH, Henriksen TB, Bech BH, Licht RW, Kjaer D, Olsen J. Prenatal antidepressant exposure and behavioral problems in early childhood—a cohort study. Acta Psychiatr Scand. 2013;127(2):126–35.CrossRefPubMedGoogle Scholar
  12. 12.
    Nulman I, Rovet J, Stewart DE, Wolpin J, Gardner HA, Theis JG, et al. Neurodevelopment of children exposed in utero to antidepressant drugs. N Engl J Med. 1997;336(4):258–62.CrossRefPubMedGoogle Scholar
  13. 13.
    Casper RC, Gilles AA, Fleisher BE, Baran J, Enns G, Lazzeroni LC. Length of prenatal exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants: effects on neonatal adaptation and psychomotor development. Psychopharmacology. 2011;217(2):211–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Misri S, Reebye P, Kendrick K, Carter D, Ryan D, Grunau RE, et al. Internalizing behaviors in 4-year-old children exposed in utero to psychotropic medications. Am J Psychiatry. 2006;163(6):1026–32.CrossRefPubMedGoogle Scholar
  15. 15.
    Oberlander TF, Reebye P, Misri S, Papsdorf M, Kim J, Grunau RE. Externalizing and attentional behaviors in children of depressed mothers treated with a selective serotonin reuptake inhibitor antidepressant during pregnancy. Arch Pediatr Adolesc Med. 2007;161(1):22–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Croen LA, Grether JK, Yoshida CK, Odouli R, Hendrick V. Antidepressant use during pregnancy and childhood autism spectrum disorders. Arch Gen Psychiatry. 2011;68(11):1104–12.CrossRefPubMedGoogle Scholar
  17. 17.
    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.PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Sorensen MJ, Gronborg TK, Christensen J, Parner ET, Vestergaard M, Schendel D, et al. Antidepressant exposure in pregnancy and risk of autism spectrum disorders. Clin Epidemiol. 2013;5:449–59.PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Hviid A, Melbye M, Pasternak B. Use of selective serotonin reuptake inhibitors during pregnancy and risk of autism. N Engl J Med. 2013;369(25):2406–15.CrossRefPubMedGoogle Scholar
  20. 20.
    El Marroun H, White TJ, van der Knaap NJ, Homberg JR, Fernandez G, Schoemaker NK, et al. Prenatal exposure to selective serotonin reuptake inhibitors and social responsiveness symptoms of autism: population-based study of young children. Br J Psychiatry. 2014;205(2):95–102.CrossRefPubMedGoogle Scholar
  21. 21.
    Harrington RA, Lee LC, Crum RM, Zimmerman AW, Hertz-Picciotto I. Prenatal SSRI use and offspring with autism spectrum disorder or developmental delay. Pediatrics. 2014;133(5):e1241–8.PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Petersen I, Evans S, Nazareth I. Prenatal exposure to selective serotonin reuptake inhibitors and autistic symptoms in young children: another red herring? Br J Psychiatry. 2014;205(2):105–6.CrossRefPubMedGoogle Scholar
  23. 23.
    Clements CC, Castro VM, Blumenthal SR, Rosenfield HR, Murphy SN, Fava M, 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. 2014 26.Google Scholar
  24. 24.
    Fombonne E. Epidemiology of pervasive developmental disorders. Pediatr Res. 2009;65(6):591–8.CrossRefPubMedGoogle Scholar
  25. 25.
    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. 2011;68(11):1095–102.PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Colvert E, Tick B, McEwen F, Stewart C, Curran SR, Woodhouse E, et al. Heritability of autism spectrum disorder in a UK population-based twin sample. JAMA Psychiatry. 2015;72(5):415–23.CrossRefPubMedGoogle Scholar
  27. 27.
    Christensen J, Gronborg TK, Sorensen MJ, Schendel D, Parner ET, Pedersen LH, et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA. 2013;309(16):1696–703.PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Smith GD. Epidemiology, epigenetics and the ‘Gloomy Prospect’: embracing randomness in population health research and practice. Int J Epidemiol. 2011;40(3):537–62.CrossRefPubMedGoogle Scholar
  29. 29.
    Oberlander TF, Weinberg J, Papsdorf M, Grunau R, Misri S, Devlin AM. Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics. 2008;3(2):97–106.Google Scholar
  30. 30.
    Devlin AM, Brain U, Austin J, Oberlander TF. Prenatal Exposure to Maternal Depressed Mood and the MTHFRC677T Variant Affect SLC6A4 Methylation in Infants at Birth. PLoS One. 2010;5(8):e12201.PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Levy SE, Mandell DS, Schultz RT. Autism. Lancet. 2009;374(9701):1627–38.PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    Oberlander TF, Gingrich JA, Ansorge MS. Sustained neurobehavioral effects of exposure to SSRI antidepressants during development: molecular to clinical evidence. Clin Pharmacol Ther. 2009;86(6):672–7.PubMedCentralCrossRefPubMedGoogle Scholar
  33. 33.
    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(5697):879–81.CrossRefPubMedGoogle Scholar
  34. 34.
    Maciag D, Simpson KL, Coppinger D, Lu Y, Wang Y, Lin RCS, et al. Neonatal antidepressant exposure has lasting effects on behavior and serotonin circuitry. Neuropsychopharmacology. 2006;31(1):47–57.PubMedCentralPubMedGoogle Scholar
  35. 35.
    Ansorge MS, Morelli E, Gingrich JA. Inhibition of serotonin but not norepinephrine transport during development produces delayed, persistent perturbations of emotional behaviors in mice. J Neurosci. 2008;28(1):199–207.CrossRefPubMedGoogle Scholar
  36. 36.
    Peters DA. Maternal stress increases fetal brain and neonatal cerebral cortex 5-hydroxytryptamine synthesis in rats: a possible mechanism by which stress influences brain development. Pharmacol Biochem Behav. 1990;35(4):943–7.CrossRefPubMedGoogle Scholar
  37. 37.
    Hayashi A, Nagaoka M, Yamada K, Ichitani Y, Miake Y, Okado N. Maternal stress induces synaptic loss and developmental disabilities of offspring. Int J Dev Neurosci. 1998;16(3–4):209–16.Google Scholar
  38. 38.
    Gidaya NB, Lee BK, Burstyn I, Yudell M, Mortensen EL, Newschaffer CJ. In utero exposure to selective serotonin reuptake inhibitors and risk for autism spectrum disorder. J Autism Dev Disord. 2014;44(10):2558–67.CrossRefPubMedGoogle Scholar
  39. 39.
    Grzeskowiak LE, Gilbert AL, Sorensen TI, Olsen J, Sorensen HT, Pedersen LH, et al. Prenatal exposure to selective serotonin reuptake inhibitors and childhood overweight at 7 years of age. Ann Epidemiol. 2013;23(11):681–7.CrossRefPubMedGoogle Scholar
  40. 40.
    Bourgeois JA, Coffey SM, Rivera SM, Hessl D, Gane LW, Tassone F, et al. A review of fragile X premutation disorders: expanding the psychiatric perspective. J Clin Psychiatry. 2009;70(6):852–62.PubMedCentralCrossRefPubMedGoogle Scholar
  41. 41.
    Hernan MA, Hernandez-Diaz S, Werler MM, Mitchell AA. Causal knowledge as a prerequisite for confounding evaluation: an application to birth defects epidemiology. AmJ Epidemiol. 2002;155(2):176–84.CrossRefGoogle Scholar
  42. 42.
    Dulac C, O’Connell LA, Wu Z. Neural control of maternal and paternal behaviors. Science. 2014;345(6198):765–70.PubMedCentralCrossRefPubMedGoogle Scholar
  43. 43.
    Vanderweele TJ, Mukherjee B, Chen J. Sensitivity analysis for interactions under unmeasured confounding. Stat Med. 2012;31(22):2552–64.PubMedCentralCrossRefPubMedGoogle Scholar
  44. 44.
    Tchetgen Tchetgen EJ. Vanderweele TJ. Identification of natural direct effects when a confounder of the mediator is directly affected by exposure. Epidemiology. 2014;25(2):282–91.CrossRefPubMedGoogle Scholar
  45. 45.
    Levitt P. Serotonin and the autisms: a red flag or a red herring? Arch Gen Psychiatry. 2011;68(11):1093–4.CrossRefPubMedGoogle Scholar
  46. 46.
    Pasternak B, Hviid A. Use of acyclovir, valacyclovir, and famciclovir in the first trimester of pregnancy and the risk of birth defects. JAMA. 2010;304(8):859–66.CrossRefPubMedGoogle Scholar
  47. 47.
    Mill J, Heijmans BT. From promises to practical strategies in epigenetic epidemiology. Nat Rev Genet. 2013;14(8):585–94.CrossRefPubMedGoogle Scholar
  48. 48.
    Chen Y, Pedersen LH, Chu WW, Olsen J. Drug exposure side effects from mining pregnancy data. ACM SIGKDD Explorations Newsletter. 2007;9(1):22–9.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Department of Clinical Medicine, Obstetrics and GynecologyAarhus UniversityAarhusDenmark

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