Risk for Autism Spectrum Disorders According to Period of Prenatal Antidepressant Exposure: A Systematic Review and Meta-analysis | Autism Spectrum Disorders | JAMA Pediatrics | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
Yonkers  KA, Wisner  KL, Stewart  DE,  et al.  The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists.  Obstet Gynecol. 2009;114(3):703-713.PubMedGoogle ScholarCrossref
Melville  JL, Gavin  A, Guo  Y, Fan  MY, Katon  WJ.  Depressive disorders during pregnancy: prevalence and risk factors in a large urban sample.  Obstet Gynecol. 2010;116(5):1064-1070.PubMedGoogle ScholarCrossref
Gentile  S.  Untreated depression during pregnancy: short- and long-term effects in offspring: a systematic review.  Neuroscience. 2017;342:154-166.PubMedGoogle ScholarCrossref
Grote  NK, Bridge  JA, Gavin  AR, Melville  JL, Iyengar  S, Katon  WJ.  A meta-analysis of depression during pregnancy and the risk of preterm birth, low birth weight, and intrauterine growth restriction.  Arch Gen Psychiatry. 2010;67(10):1012-1024.PubMedGoogle ScholarCrossref
Robertson  E, Grace  S, Wallington  T, Stewart  DE.  Antenatal risk factors for postpartum depression: a synthesis of recent literature.  Gen Hosp Psychiatry. 2004;26(4):289-295.PubMedGoogle ScholarCrossref
Leigh  B, Milgrom  J.  Risk factors for antenatal depression, postnatal depression and parenting stress.  BMC Psychiatry. 2008;8:24.PubMedGoogle ScholarCrossref
Dubber  S, Reck  C, Müller  M, Gawlik  S.  Postpartum bonding: the role of perinatal depression, anxiety and maternal-fetal bonding during pregnancy.  Arch Womens Ment Health. 2015;18(2):187-195.PubMedGoogle ScholarCrossref
McLearn  KT, Minkovitz  CS, Strobino  DM, Marks  E, Hou  W.  The timing of maternal depressive symptoms and mothers’ parenting practices with young children: implications for pediatric practice.  Pediatrics. 2006;118(1):e174-e182.PubMedGoogle ScholarCrossref
Paulson  JF, Dauber  S, Leiferman  JA.  Individual and combined effects of postpartum depression in mothers and fathers on parenting behavior.  Pediatrics. 2006;118(2):659-668.PubMedGoogle ScholarCrossref
Biederman  J, Faraone  SV, Hirshfeld-Becker  DR, Friedman  D, Robin  JA, Rosenbaum  JF.  Patterns of psychopathology and dysfunction in high-risk children of parents with panic disorder and major depression.  Am J Psychiatry. 2001;158(1):49-57.PubMedGoogle ScholarCrossref
Fihrer  I, McMahon  CA, Taylor  AJ.  The impact of postnatal and concurrent maternal depression on child behaviour during the early school years.  J Affect Disord. 2009;119(1-3):116-123.PubMedGoogle ScholarCrossref
Feldman  R, Granat  A, Pariente  C, Kanety  H, Kuint  J, Gilboa-Schechtman  E.  Maternal depression and anxiety across the postpartum year and infant social engagement, fear regulation, and stress reactivity.  J Am Acad Child Adolesc Psychiatry. 2009;48(9):919-927.PubMedGoogle ScholarCrossref
American Psychiatric Association.  Practice Guideline for the Treatment of Patients With Major Depressive Disorder. Arlington, VA: American Psychiatric Association; 2010.
National Institute for Health and Care Excellence.  Depression in Adults: Recognition and Management. London, England: National Institute for Health and Care Excellence; 2009.
Andrade  SE, Reichman  ME, Mott  K,  et al.  Use of selective serotonin reuptake inhibitors (SSRIs) in women delivering liveborn infants and other women of child-bearing age within the US Food and Drug Administration’s Mini-Sentinel program.  Arch Womens Ment Health. 2016;19(6):969-977.PubMedGoogle ScholarCrossref
Jimenez-Solem  E, Andersen  JT, Petersen  M,  et al.  Prevalence of antidepressant use during pregnancy in Denmark, a nation-wide cohort study.  PLoS One. 2013;8(4):e63034.PubMedGoogle ScholarCrossref
Yonkers  KA, Blackwell  KA, Glover  J, Forray  A.  Antidepressant use in pregnant and postpartum women.  Annu Rev Clin Psychol. 2014;10:369-392.PubMedGoogle ScholarCrossref
Robinson  GE.  Controversies about the use of antidepressants in pregnancy.  J Nerv Ment Dis. 2015;203(3):159-163.PubMedGoogle ScholarCrossref
Malm  H.  Prenatal exposure to selective serotonin reuptake inhibitors and infant outcome.  Ther Drug Monit. 2012;34(6):607-614.PubMedGoogle ScholarCrossref
Huybrechts  KF, Bateman  BT, Palmsten  K,  et al.  Antidepressant use late in pregnancy and risk of persistent pulmonary hypertension of the newborn.  JAMA. 2015;313(21):2142-2151.PubMedGoogle ScholarCrossref
Hadjikhani  N.  Serotonin, pregnancy and increased autism prevalence: is there a link?  Med Hypotheses. 2010;74(5):880-883.PubMedGoogle ScholarCrossref
Zimmerberg  B, Germeyan  SC.  Effects of neonatal fluoxetine exposure on behavior across development in rats selectively bred for an infantile affective trait.  Dev Psychobiol. 2015;57(2):141-152.PubMedGoogle ScholarCrossref
Kepser  LJ, Homberg  JR.  The neurodevelopmental effects of serotonin: a behavioural perspective.  Behav Brain Res. 2015;277:3-13.PubMedGoogle ScholarCrossref
Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal Investigators; Centers for Disease Control and Prevention (CDC).  Prevalence of autism spectrum disorder among children aged 8 years: autism and developmental disabilities monitoring network, 11 sites, United States, 2010.  MMWR Surveill Summ. 2014;63(2):1-21.PubMedGoogle Scholar
Park  HR, Lee  JM, Moon  HE,  et al.  A short review on the current understanding of autism spectrum disorders.  Exp Neurobiol. 2016;25(1):1-13.PubMedGoogle ScholarCrossref
Schaefer  GB.  Clinical genetic aspects of ASD spectrum disorders.  Int J Mol Sci. 2016;17(2):E180.PubMedGoogle ScholarCrossref
Mandy  W, Lai  MC.  Annual research review: the role of the environment in the developmental psychopathology of autism spectrum condition.  J Child Psychol Psychiatry. 2016;57(3):271-292.PubMedGoogle ScholarCrossref
Ruggeri  B, Sarkans  U, Schumann  G, Persico  AM.  Biomarkers in autism spectrum disorder: the old and the new.  Psychopharmacology (Berl). 2014;231(6):1201-1216.PubMedGoogle ScholarCrossref
McNamara  IM, Borella  AW, Bialowas  LA, Whitaker-Azmitia  PM.  Further studies in the developmental hyperserotonemia model (DHS) of autism: social, behavioral and peptide changes.  Brain Res. 2008;1189:203-214.PubMedGoogle ScholarCrossref
Yang  CJ, Tan  HP, Du  YJ.  The developmental disruptions of serotonin signaling may involved in autism during early brain development.  Neuroscience. 2014;267:1-10.PubMedGoogle ScholarCrossref
Rais  TB, Rais  A.  Association between antidepressants use during pregnancy and autistic spectrum disorders: a meta-analysis.  Innov Clin Neurosci. 2014;11(5-6):18-22.PubMedGoogle Scholar
Man  KK, Tong  HH, Wong  LY, Chan  EW, Simonoff  E, Wong  IC.  Exposure to selective serotonin reuptake inhibitors during pregnancy and risk of autism spectrum disorder in children: a systematic review and meta-analysis of observational studies.  Neurosci Biobehav Rev. 2015;49:82-89.PubMedGoogle ScholarCrossref
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(2):117-124.PubMedGoogle ScholarCrossref
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.PubMedGoogle ScholarCrossref
Vandenbroucke  JP, von Elm  E, Altman  DG,  et al; STROBE Initiative.  Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration.  Epidemiology. 2007;18(6):805-835.PubMedGoogle ScholarCrossref
El Marroun  H, White  T, Verhulst  FC, Tiemeier  H.  Maternal use of antidepressant or anxiolytic medication during pregnancy and childhood neurodevelopmental outcomes: a systematic review.  Eur Child Adolesc Psychiatry. 2014;23(10):973-992.PubMedGoogle ScholarCrossref
McDonagh  MS, Matthews  A, Phillipi  C,  et al.  Depression drug treatment outcomes in pregnancy and the postpartum period: a systematic review and meta-analysis.  Obstet Gynecol. 2014;124(3):526-534.PubMedGoogle ScholarCrossref
Gentile  S.  Prenatal antidepressant exposure and the risk of autism spectrum disorders in children: are we looking at the fall of Gods?  J Affect Disord. 2015;182:132-137.PubMedGoogle ScholarCrossref
Jones  I, McDonald  L.  Living with uncertainty: antidepressants and pregnancy.  Br J Psychiatry. 2014;205(2):103-104.PubMedGoogle ScholarCrossref
O’Dowd  A.  Antidepressants in pregnancy are linked to ADHD but not to autism, says study.  BMJ. 2014;349:g5315.PubMedGoogle ScholarCrossref
Pedersen  LH.  Prenatal antidepressant exposure and childhood autism spectrum disorders: cause for concern?  Paediatr Drugs. 2015;17(6):443-448.PubMedGoogle ScholarCrossref
King  BH.  Assessing risk of autism spectrum disorder in children after antidepressant use during pregnancy.  JAMA Pediatr. 2016;170(2):111-112.PubMedGoogle ScholarCrossref
Rosenberg  K.  A possible link between antidepressant use during pregnancy and autism spectrum disorder.  Am J Nurs. 2016;116(3):58-59. doi:10.1097/01.NAJ.0000481284.31967.9bGoogle Scholar
Andrade  C.  Antidepressant use in pregnancy and risk of autism spectrum disorders: a critical examination of the evidence.  J Clin Psychiatry. 2013;74(9):940-941.PubMedGoogle ScholarCrossref
El Marroun  H, White  TJ, van der Knaap  NJ,  et al.  Prenatal exposure to selective serotonin reuptake inhibitors and social responsiveness symptoms of autism: population-based study of young children.  Br J Psychiatry. 2014b;205(2):95-102.PubMedGoogle ScholarCrossref
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):2406-2415.PubMedGoogle ScholarCrossref
Sørensen  MJ, Grønborg  TK, Christensen  J,  et al.  Antidepressant exposure in pregnancy and risk of autism spectrum disorders.  Clin Epidemiol. 2013;5:449-459.PubMedGoogle ScholarCrossref
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(6):727-734.PubMedGoogle ScholarCrossref
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):2558-2567.PubMedGoogle ScholarCrossref
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-e1248.PubMedGoogle ScholarCrossref
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.PubMedGoogle ScholarCrossref
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(5):1642-1648.PubMedGoogle ScholarCrossref
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):1104-1112.PubMedGoogle ScholarCrossref
Kaplan  YC, Keskin-Arslan  E, Acar  S, Sozmen  K.  Prenatal selective serotonin reuptake inhibitor use and the risk of autism spectrum disorder in children: a systematic review and meta-analysis.  Reprod Toxicol. 2016;66:31-43.PubMedGoogle ScholarCrossref
Kobayashi  T, Matsuyama  T, Takeuchi  M, Ito  S.  Autism spectrum disorder and prenatal exposure to selective serotonin reuptake inhibitors: a systematic review and meta-analysis.  Reprod Toxicol. 2016;65:170-178.PubMedGoogle ScholarCrossref
Doherty  JL, Owen  MJ.  Genomic insights into the overlap between psychiatric disorders: implications for research and clinical practice.  Genome Med. 2014;6(4):29.PubMedGoogle ScholarCrossref
Daniels  JL, Forssen  U, Hultman  CM,  et al.  Parental psychiatric disorders associated with autism spectrum disorders in the offspring.  Pediatrics. 2008;121(5):e1357-e1362.PubMedGoogle ScholarCrossref
Larsson  HJ, Eaton  WW, Madsen  KM,  et al.  Risk factors for autism: perinatal factors, parental psychiatric history, and socioeconomic status.  Am J Epidemiol. 2005;161(10):916-925.PubMedGoogle ScholarCrossref
Petersen  I, Gilbert  RE, Evans  SJ, Man  SL, Nazareth  I.  Pregnancy as a major determinant for discontinuation of antidepressants: an analysis of data from The Health Improvement Network.  J Clin Psychiatry. 2011;72(7):979-985.PubMedGoogle ScholarCrossref
Original Investigation
June 2017

Risk for Autism Spectrum Disorders According to Period of Prenatal Antidepressant Exposure: A Systematic Review and Meta-analysis

Author Affiliations
  • 1Department of Psychiatry, Assistance Publique–Hôpitaux de Paris, Bicêtre University Hospital, Le Kremlin Bicêtre, France
  • 2EPIMED Research Centre–Epidemiology and Preventive Medicine, Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy
  • 3Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli, Italy
  • 4Université Paris-Saclay, Univ Paris-Sud, UVSQ, CESP, INSERM U1178, Bicêtre University Hospital, Le Kremlin Bicêtre, France
  • 5Université Paris-Saclay, Univ Paris-Sud, UVSQ, CESP, INSERM U1178, Department of Biostatistics, Maison de Solenn, Paris, France
  • 6Research Center INSERM 1219, Bordeaux Population Health Bordeaux University, University Department of Adult Psychiatry, Charles-Perrens Hospital, Bordeaux, France
JAMA Pediatr. 2017;171(6):555-563. doi:10.1001/jamapediatrics.2017.0124
Key Points

Question  Does prenatal antidepressant exposure increase the risk for autism spectrum disorders?

Findings  This systematic review and meta-analysis suggests an association between increased autism spectrum disorder risk and maternal use of antidepressants during pregnancy; however, it appears to be more consistent during the preconception period than during each trimester. The association was weaker when controlled for past maternal mental illness.

Meaning  Maternal psychiatric disorders in treatment before pregnancy rather than antenatal exposure to antidepressants could have a major role in the risk for autism spectrum disorders.


Importance  Several studies have examined the links between prenatal exposure to antidepressants and autism spectrum disorders (ASDs) in children, with inconsistent results, especially regarding the impact of the trimester of exposure.

Objective  To perform a systematic review of the literature and a meta-analysis of published studies to assess the association between ASDs and fetal exposure to antidepressants during pregnancy for each trimester of pregnancy and preconception.

Data Sources  PubMed, EMBASE, and PsycINFO databases up to May 2016 were searched in June 2016 for observational studies. For the meta-analyses, data were analyzed on RevMan version 5.2 using a random-effect model. For the review, studies were included if they had been published and were cohort or case-control studies, and for the meta-analysis, studies were included if they were published studies and the data were not derived from the same cohorts.

Study Selection  We included all the studies that examined the association between ASDs and antenatal exposure to antidepressants.

Data Extraction and Synthesis  Three reviewers independently screened titles and abstracts, read full-text articles, and extracted data. The quality of the studies was also assessed.

Main Outcomes and Measures  Primary outcome was the association between antidepressants during pregnancy and ASDs. Secondary outcomes were the associations between antidepressants in each individual trimester or before pregnancy and ASDs.

Results  Our literature search identified 10 relevant studies with inconsistent results. For prenatal exposure, the meta-analysis on the 6 case-control studies (117 737 patients) evidenced a positive association between antidepressant exposure and ASDs (odds ratio [OR], 1.81; 95% CI, 1.49-2.20). The association was weaker when controlled for past maternal mental illness (OR, 1.52; 95% CI, 1.09-2.12). A similar pattern was found whatever the trimester of exposure considered (first trimester: OR, 2.09, 95% CI,1.66-2.64; second: OR, 2.00, 95% CI, 1.55-2.59; and third: OR, 1.90, 95% CI, 1.20-3.02. Controlled for past maternal mental illness: first trimester: OR, 1.79; 95% CI, 1.27-2.52, second: OR, 1.67, 95% CI, 1.14-2.45; and third: OR, 1.54, 95% CI, 0.82-2.90). No association was found when the 2 cohort studies were pooled (772 331 patients) for the whole pregnancy (hazard ratio, 1.26; 95% CI, 0.91-1.74) or for the first trimester. In addition, preconception exposure to antidepressants was significantly associated with an increased risk for ASDs (OR controlled for past maternal illness, 1.77; 95% CI, 1.49-2.09).

Conclusions and Relevance  There is a significant association between increased ASD risk and maternal use of antidepressants during pregnancy; however, it appears to be more consistent during the preconception period than during each trimester. Maternal psychiatric disorders in treatment before pregnancy rather than antenatal exposure to antidepressants could have a major role in the risk for ASDs. Future studies should address the problem of this potential confounder.