Skip to main content

Prenatal exposure to selective serotonin reuptake inhibitors and social responsiveness symptoms of autism: population-based study of young children


Selective serotonin reuptake inhibitors (SSRIs) are considered safe and are frequently used during pregnancy. However, two case–control studies suggested an association between prenatal SSRI exposure with childhood autism.


To prospectively determine whether intra-uterine SSSRI exposure is associated with childhood autistic symptoms in a population-based study.


A total of 376 children prenatally exposed to maternal depressive symptoms (no SSRI exposure), 69 children prenatally exposed to SSRIs and 5531 unexposed children were included. Child pervasive developmental and affective problems were assessed by parental report with the Child Behavior Checklist at ages 1.5, 3 and 6. At age 6, we assessed autistic traits using the Social Responsiveness Scale (n = 4264).


Prenatal exposure to maternal depressive symptoms without SSRIs was related to both pervasive developmental (odds ratio (OR) = 1.44, 95% CI 1.07–1.93) and affective problems (OR = 1.44, 95% CI 1.15–1.81). Compared with unexposed children, those prenatally exposed to SSRIs also were at higher risk for developing pervasive developmental problems (OR = 1.91, 95% CI 1.13–3.47), but not for affective problems. Children prenatally exposed to SSRIs also had more autistic traits (B = 0.15, 95% CI 0.08–0.22) compared with those exposed to depressive symptoms only.


Our results suggest an association between prenatal SSRI exposure and autistic traits in children. Prenatal depressive symptoms without SSRI use were also associated with autistic traits, albeit this was weaker and less specific. Long-term drug safety trials are needed before evidence-based recommendations are possible.

Corresponding author
Henning Tiemeier, Department of Child and Adolescent Psychiatry, Erasmus Medical Centre, Sophia Children's Hospital, Rotterdam, 3000 CB, The Netherlands. Email:
Hide All

See invited commentaries, pp. 103–106, this issue.

The Sophia Children's Hospital Fund (SSWO-616) supported this work financially. The first phase of the Generation R Study was made possible by financial support from the Erasmus Medical Centre and The Netherlands Organization for Health Research and Development (Zon MW Geestkracht Program 10.000.1003 & ZonMw TOP 40-00812-98-11021, NWO Brain & Cognition Program Grant 433-09-311 and VIDI Grant 017.106.370).

Declaration of interest

F.C.V. is head of the Department of Child and Adolescent Psychiatry at Erasmus Medical Centre, which publishes the Achenbach System of Empirically Based Assessment (ASEBA) and from which the department receives remuneration.

Hide All
1 Barbey, JT, Roose, SP. SSRI safety in overdose. J Clin Psychiatry 1998; 59 (suppl 15): 42–8.
2 Hirschfeld, RMA. Clinical importance of long-term antidepressant treatment. Br J Psychiatry 2001; 179 (suppl 42): s48.
3 Bakker, MK, Kolling, P, van den Berg, PB, de Walle, HE, de Jong van den Berg, LT. Increase in use of selective serotonin reuptake inhibitors in pregnancy during the last decade, a population-based cohort study from The Netherlands. Br J Clin Pharmacol 2008; 65: 600–6.
4 Sanz, EJ, De-las-Cuevas, C, Kiuru, A, Bate, A, Edwards, R. Selective serotonin reuptake inhibitors in pregnant women and neonatal withdrawal syndrome: a database analysis. Lancet 2005; 365: 482–7.
5 Levinson-Castiel, R, Merlob, P, Linder, N, Sirota, L, Klinger, G. Neonatal abstinence syndrome after in utero exposure to selective serotonin reuptake inhibitors in term infants. Arch Pediatr Adolesc Med 2006; 160: 173–6.
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.
7 Croen, LA, Grether, JK, Yoshida, CK, Odouli, R, Hendrick, V. Antidepressant use during pregnancy and childhood autism spectrum disorders. Arch Gen Psychiatry 2011; 68: 1104–12.
8 Nulman, I, Rovet, J, Stewart, DE, Wolpin, J, Pace-Asciak, P, Shuhaiber, S, et al. Child development following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: a prospective, controlled study. Am J Psychiatry 2002; 159: 1889–95.
9 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: 1026–32.
10 Casper, RC, Fleisher, BE, Lee-Ancajas, JC, Gilles, A, Gaylor, E, DeBattista, A, et al. Follow-up of children of depressed mothers exposed or not exposed to antidepressant drugs during pregnancy. J Pediatr 2003; 142: 402–8.
11 Pedersen, LH, Henriksen, TB, Olsen, J. Fetal exposure to antidepressants and normal milestone development at 6 and 19 months of age. Pediatrics 2010; 125: e6008.
12 El Marroun, H, Jaddoe, VW, Hudziak, JJ, Roza, SJ, Steegers, EA, Hofman, A, et al. Maternal use of selective serotonin reuptake inhibitors, fetal growth, and risk of adverse birth outcomes. Arch Gen Psychiatry 2012; 69: 706–14.
13 Rayburn, WF, Gonzalez, CL, Christensen, HD, Kupiec, TC, Jacobsen, JA, Stewart, JD. Effect of antenatal exposure to paroxetine (Paxil) on growth and physical maturation of mice offspring. J Matern Fetal Med 2000; 9: 136–41.
14 Chambers, CD, Johnson, KA, Dick, LM, Felix, RJ, Jones, KL. Birth outcomes in pregnant women taking fluoxetine. N Engl J Med 1996; 335: 1010–5.
15 Lund, N, Pedersen, LH, Henriksen, TB. Selective serotonin reuptake inhibitor exposure in utero and pregnancy outcomes. Arch Pediatr Adolesc Med 2009; 163: 949–54.
16 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: 898906.
17 Simon, GE, Cunningham, ML, Davis, RL. Outcomes of prenatal antidepressant exposure. Am J Psychiatry 2002; 159: 2055–61.
18 Jaddoe, VW, van Duijn, CM, van der Heijden, AJ, Mackenbach, JP, Moll, HA, Steegers, EA, et al. The Generation R Study: design and cohort update 2010. Eur J Epidemiol 2010; 25: 823–41.
19 Talge, NM, Neal, C, Glover, V. Antenatal maternal stress and long-term effects on child neurodevelopment: how and why? J Child Psychol Psychiatry 2007; 48: 245–61.
20 Walter, SD. Hoehler's adjusted kappa is equivalent to Yule's Y. J Clin Epidemiol 2001; 54: 1072–3.
21 Derogatis, LR, Melisaratos, N. The Brief Symptom Inventory: an introductory report. Psychol Med 1983; 13: 595605.
22 de Beurs, E. Brief Symptom Inventory Handleiding (Brief Symptom Inventory Manual). PITS, 2004.
23 Andrews, G, Peters, L. The psychometric properties of the Composite International Diagnostic Interview. Soc Psychiatry Psychiatr Epidemiol 1998; 33: 80–8.
24 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (4th edn) (DSM-IV). APA, 1994.
25 Cox, JL, Holden, JM, Sagovsky, R. Detection of postnatal depression. Development of the 10-item Edinburgh Postnatal Depression Scale. Br J Psychiatry 1987; 150: 782–6.
26 Pop, VJ, Komproe, IH, van Son, MJ. Characteristics of the Edinburgh Post Natal Depression Scale in The Netherlands. J Affect Disord 1992; 26: 105–10.
27 Verburg, BO, Steegers, EA, De Ridder, M, Snijders, RJ, Smith, E, Hofman, A, et al. New charts for ultrasound dating of pregnancy and assessment of fetal growth: longitudinal data from a population-based cohort study. Ultrasound Obstet Gynecol 2008; 31: 388–96.
28 Achenbach, TM, Rescorla, LA. Manual for ASEBA Preschool Forms & Profiles. University of Vermont, Research Center for Children, Youth and Families, 2000.
29 Constantino, JN, Gruber, CP. Social Responsiveness Scale (SRS): Manual. Western Psychological Services, 2005.
30 Constantino, JN, Przybeck, T, Friesen, D, Todd, RD. Reciprocal social behavior in children with and without pervasive developmental disorders. J Dev Behav Pediatr 2000; 21: 211.
31 Tick, NT, van der Ende, J, Koot, HM, Verhulst, FC. 14-year changes in emotional and behavioral problems of very young Dutch children. J Am Acad Child Adolesc Psychiatry 2007; 46: 1333–40.
32 Ivanova, MY, Achenbach, TM, Rescorla, LA, Harder, VS, Ang, RP, Bilenberg, N, et al. Preschool psychopathology reported by parents in 23 societies: testing the seven-syndrome model of the child behavior checklist for ages 1.5–5. J Am Acad Child Adolesc Psychiatry 2010; 49: 1215–24.
33 Sikora, DM, Hall, TA, Hartley, SL, Gerrard-Morris, AE, Cagle, S. Does parent report of behavior differ across ADOS-G classifications: analysis of scores from the CBCL and GARS. J Autism Dev Disord 2008; 38: 440–8.
34 Muratori, F, Narzisi, A, Tancredi, R, Cosenza, A, Calugi, S, Saviozzi, I, et al. The CBCL 1.5-5 and the identification of preschoolers with autism in Italy. Epidemiol Psychiatr Sci 2011; 20: 329–38.
35 Achenbach, TM, McConaughy, SH, Howell, CT. Child/adolescent behavioral and emotional problems: implications of cross-informant correlations for situational specificity. Psychol Bull 1987; 101: 213–32.
36 Schetter, CD. Psychological science on pregnancy: stress processes, biopsychosocial models, and emerging research issues. Annu Rev Psychol 2011; 62: 531–58.
37 Statistics Netherlands. Allochtonen in Nederland 2004 (Migrants in The Netherlands 2004). Voorburg/Heerlen, 2004 (
38 Statistics Netherlands. Standaard Onderwijsindeling 2003 (Standard Classification of Education 2003). Voorburg/Heerlen, 2004 (
39 Bakker, R, Kruithof, C, Steegers, EA, Tiemeier, H, Mackenbach, JP, Hofman, A, et al. Assessment of maternal smoking status during pregnancy and the associations with neonatal outcomes. Nicotine Tob Res 2011; 13: 1250–6.
40 Jaddoe, VW, Verburg, BO, de Ridder, MA, Hofman, A, Mackenbach, JP, Moll, HA, et al. Maternal smoking and fetal growth characteristics in different periods of pregnancy: the generation R study. Am J Epidemiol 2007; 165: 1207–15.
41 Rothman, KJ. No adjustments are needed for multiple comparisons. Epidemiology 1990; 1: 43–6.
42 Matthews, JN, Altman, DG. Interaction 3: how to examine heterogeneity. BMJ 1996; 313: 862.
43 Matthews, JN, Altman, DG. Statistics notes. Interaction 2: compare effect sizes not P values. BMJ 1996; 313: 808.
44 Mickey, RM, Greenland, S. The impact of confounder selection criteria on effect estimation. Am J Epidemiol 1989; 129: 125–37.
45 Rothman, KJ, Greenland, S, Lash, TL. Modern Epidemiology (3rd edn). Lippincott Williams & Wilkins, 2008.
46 Greenland, S, Finkle, WD. A critical look at methods for handling missing covariates in epidemiologic regression analyses. Am J Epidemiol 1995; 142: 1255–64.
47 Nakamura, BJ, Ebesutani, C, Bernstein, A, Chorpita, BF. A psychometric analysis of the Child Behavior Checklist DSM-Oriented Scales. J Psychopathol Behav Assess 2009; 31: 178–89.
48 Gaspar, P, Cases, O, Maroteaux, L. The developmental role of serotonin: news from mouse molecular genetics. Nat Rev Neurosci 2003; 4: 1002–12.
49 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: 199207.
50 Maciag, D, Simpson, KL, Coppinger, D, Lu, Y, Wang, Y, Lin, RC, et al. Neonatal antidepressant exposure has lasting effects on behavior and serotonin circuitry. Neuropsychopharmacology 2006; 31: 4757.
51 Pardo, CA, Eberhart, CG. The neurobiology of autism. Brain Pathol 2007; 17: 434–47.
52 Simpson, KL, Weaver, KJ, de Villers-Sidani, E, Lu, JY, Cai, Z, Pang, Y, et al. Perinatal antidepressant exposure alters cortical network function in rodents. Proc Natl Acad Sci U S A 2011; 108: 18465–70.
53 Mulder, EJ, Ververs, FF, de Heus, R, Visser, GH. Selective serotonin reuptake inhibitors affect neurobehavioral development in the human fetus. Neuropsychopharmacology 2011; 36: 1961–71.
54 Courchesne, E, Campbell, K, Solso, S. Brain growth across the life span in autism: age-specific changes in anatomical pathology. Brain Res 2011; 1380: 138–45.
55 Courchesne, E, Pierce, K, Schumann, CM, Redcay, E, Buckwalter, JA, Kennedy, DP, et al. Mapping early brain development in autism. Neuron 2007; 56: 399413.
56 Austin, MP. To treat or not to treat: maternal depression, SSRI use in pregnancy and adverse neonatal effects. Psychol Med 2006; 36: 1663–70.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

The British Journal of Psychiatry
  • ISSN: 0007-1250
  • EISSN: 1472-1465
  • URL: /core/journals/the-british-journal-of-psychiatry
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
Type Description Title
Supplementary materials

Marroun et al. supplementary material
Supplementary Tables S1-S2

 PDF (55 KB)
55 KB
Supplementary materials

Marroun et al. supplementary material
Supplementary Tables S1-S2

 PDF (55 KB)
55 KB
Supplementary materials

Marroun et al. supplementary material
Supplementary Tables S1-S2

 PDF (55 KB)
55 KB


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 21 *
Loading metrics...

Abstract views

Total abstract views: 81 *
Loading metrics...

* Views captured on Cambridge Core between 2nd January 2018 - 20th March 2018. This data will be updated every 24 hours.

Prenatal exposure to selective serotonin reuptake inhibitors and social responsiveness symptoms of autism: population-based study of young children

Submit a response


No eLetters have been published for this article.


Reply to: Submit a response

Your details

Conflicting interests

Do you have any conflicting interests? *