Skip to main content
SpringerLink
Log in

Association between maternal antidepressant use during pregnancy and the risk of autism spectrum disorder and attention deficit hyperactivity disorder in offspring

  • Original Contribution
  • Published:
European Child & Adolescent Psychiatry Aims and scope Submit manuscript

Abstract

Prenatal antidepressant exposure has been reported to be associated with adverse neurodevelopmental outcomes, yet studies considering confounding factors in Asian populations are lacking. This study utilized a nationwide data base in Taiwan, enrolling all liveborn children registered in the National Health Insurance system between 2004 and 2016. Subjects were divided into two groups: antidepressant-exposed (n = 55,707)) and antidepressant-unexposed group (n = 2,245,689). The effect of antidepressant exposure during different trimesters on autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) was examined. Sibling controls and parallel comparisons by paternal exposure status were treated as negative controls. Additional sensitivity analyses were conducted to examine the effects of antidepressant exposure before and after pregnancy. Prenatal antidepressant exposure was associated with increased risks of ASD and ADHD in population-wide and adjusted analysis. However when comparing antidepressant-exposed children with their unexposed siblings, no differences were found for ASD (Hazard ratio [HR]: 1.04, 95% confidence interval [CI] 0.76–1.42 in first trimester; HR: 0.96, 95% CI 0.62–1.50 in second trimester; HR: 0.69, 95% CI 0.32–1.48 in third trimester) and ADHD (HR: 0.98, 95%CI 0.84–1.15 in first trimester; HR: 0.91, 95% CI 0.73–1.14 in second trimester; HR: 0.79, 95% CI 0.54–1.16 in third trimester). Increased risks for ASD and ADHD were also noted in paternal control, before and after pregnancy analyses. These results imply that the association between prenatal antidepressant exposure and ASD and ADHD is not contributed to by an intrauterine medication effect but more likely to be accounted for by maternal depression, genetic, and potential environmental factors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data availability

The data is with the corresponding author and will be made available at a reasonable request.

References

  1. Woody CA et al (2017) A systematic review and meta-regression of the prevalence and incidence of perinatal depression. J Affect Disord 219:86–92. https://doi.org/10.1016/j.jad.2017.05.003

    Article  CAS  PubMed  Google Scholar 

  2. Patkar AA, Bilal L, Masand PS (2004) Pharmacotherapy of depression in pregnancy. Ann Clin Psych 16(2):87–100. https://doi.org/10.1080/10401230490453662

    Article  Google Scholar 

  3. Cohen LS et al (2006) Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA 295(5):499–507. https://doi.org/10.1001/jama.295.5.499

    Article  CAS  PubMed  Google Scholar 

  4. Gelaye B, Rondon MB, Araya R, Williams MA (2016) Epidemiology of maternal depression, risk factors, and child outcomes in low-income and middle-income countries. Lancet Psychiatry 3(10):973–982. https://doi.org/10.1016/s2215-0366(16)30284-x

    Article  PubMed  PubMed Central  Google Scholar 

  5. Gentile S (2017) Untreated depression during pregnancy: Short- and long-term effects in offspring. A systematic review. Neuroscience 342:154–166. https://doi.org/10.1016/j.neuroscience.2015.09.001

    Article  CAS  PubMed  Google Scholar 

  6. Becker M, Weinberger T, Chandy A, Schmukler S (2016) Depression during pregnancy and postpartum. Curr Psychiatry Rep 18(3):32. https://doi.org/10.1007/s11920-016-0664-7

    Article  PubMed  Google Scholar 

  7. Luppino FS et al (2010) Overweight, obesity, and depression: a systematic review and meta-analysis of longitudinal studies. Arch Gen Psychiatry 67(3):220–229. https://doi.org/10.1001/archgenpsychiatry.2010.2

    Article  PubMed  Google Scholar 

  8. MacQueen GM et al (2016) Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 6. Special Populations: Youth, Women, and the Elderly. Canadian J Psychiatr Revue canadienne de psychiatrie 61(9):588–603. https://doi.org/10.1177/0706743716659276

  9. McAllister-Williams RH et al (2017) British Association for Psychopharmacology consensus guidance on the use of psychotropic medication preconception, in pregnancy and postpartum 2017. J Psychopharmacol (Oxford, England) 31(5):519–552. https://doi.org/10.1177/0269881117699361

    Article  Google Scholar 

  10. Nonacs R, Cohen LS (2003) Assessment and treatment of depression during pregnancy: an update. Psychiatr Clin North Am 26(3):547–562. https://doi.org/10.1016/s0193-953x(03)00046-7

    Article  PubMed  Google Scholar 

  11. Vigod SN et al (2019) A patient decision aid for antidepressant use in pregnancy: pilot randomized controlled trial. J Affect Disord 251:91–99. https://doi.org/10.1016/j.jad.2019.01.051

    Article  PubMed  Google Scholar 

  12. Mitchell AA et al (2011) Medication use during pregnancy, with particular focus on prescription drugs: 1976–2008. Am J Obstet Gynecol 205(1):51.e51-58. https://doi.org/10.1016/j.ajog.2011.02.029

    Article  Google Scholar 

  13. Andrade SE et al (2008) Use of antidepressant medications during pregnancy: a multisite study. Am J Obstet Gynecol 198(2):194.e191-195. https://doi.org/10.1016/j.ajog.2007.07.036

    Article  CAS  Google Scholar 

  14. Thompson BL, Levitt P, Stanwood GD (2009) Prenatal exposure to drugs: effects on brain development and implications for policy and education. Nat Rev Neurosci 10(4):303–312. https://doi.org/10.1038/nrn2598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lauder JM, Wallace JA, Krebs H (1981) Roles for serotonin in neuroembryogenesis. Adv Exp Med Biol 133:477–506. https://doi.org/10.1007/978-1-4684-3860-4_28

    Article  CAS  PubMed  Google Scholar 

  16. Andrade C, Rao NS (2010) How antidepressant drugs act: a primer on neuroplasticity as the eventual mediator of antidepressant efficacy. Indian J Psychiatry 52(4):378–386. https://doi.org/10.4103/0019-5545.74318

    Article  PubMed  PubMed Central  Google Scholar 

  17. Miceli S et al (2013) High serotonin levels during brain development alter the structural input-output connectivity of neural networks in the rat somatosensory layer IV. Front Cell Neurosci 7:88. https://doi.org/10.3389/fncel.2013.00088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lee LJ, Lee LJ (2012) Neonatal fluoxetine exposure alters motor performances of adolescent rats. Dev Neurobiol 72(8):1122–1132. https://doi.org/10.1002/dneu.20942

    Article  CAS  PubMed  Google Scholar 

  19. Yan W, Wilson CC, Haring JH (1997) 5-HT1a receptors mediate the neurotrophic effect of serotonin on developing dentate granule cells. Brain Res Dev Brain Res 98(2):185–190. https://doi.org/10.1016/s0165-3806(96)00175-7

    Article  CAS  PubMed  Google Scholar 

  20. Gaspar P, Cases O, Maroteaux L (2003) The developmental role of serotonin: news from mouse molecular genetics. Nat Rev Neurosci 4(12):1002–1012. https://doi.org/10.1038/nrn1256

    Article  CAS  PubMed  Google Scholar 

  21. Ansorge MS et al (2004) Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice. Science (New York, NY) 306(5697):879–881. https://doi.org/10.1126/science.1101678

    Article  CAS  Google Scholar 

  22. Simpson KL et al (2011) Perinatal antidepressant exposure alters cortical network function in rodents. Proc Natl Acad Sci USA 108(45):18465–18470. https://doi.org/10.1073/pnas.1109353108

    Article  PubMed  PubMed Central  Google Scholar 

  23. Carvajal-Oliveros A, Campusano JM (2020) Studying the contribution of serotonin to neurodevelopmental disorders. Can This Fly? Front Behav Neurosci 14:601449. https://doi.org/10.3389/fnbeh.2020.601449

    Article  CAS  PubMed  Google Scholar 

  24. Rotem-Kohavi N, Oberlander TF (2017) Variations in neurodevelopmental outcomes in children with prenatal SSRI antidepressant exposure. Birth Defects Res 109(12):909–923. https://doi.org/10.1002/bdr2.1076

    Article  CAS  PubMed  Google Scholar 

  25. Man KKC et al (2017) Prenatal antidepressant use and risk of attention-deficit/hyperactivity disorder in offspring: population based cohort study. BMJ (Clin Res ed) 357:j2350. https://doi.org/10.1136/bmj.j2350

    Article  Google Scholar 

  26. Boukhris T, Sheehy O, Mottron L, Bérard A (2016) Antidepressant use during pregnancy and the risk of autism spectrum disorder in children. JAMA Pediatr 170(2):117–124. https://doi.org/10.1001/jamapediatrics.2015.3356

    Article  PubMed  Google Scholar 

  27. Rai D et al (2017) Antidepressants during pregnancy and autism in offspring: population based cohort study. BMJ (Clin Res ed) 358:j2811. https://doi.org/10.1136/bmj.j2811

    Article  Google Scholar 

  28. Suarez EA et al (2022) Association of antidepressant use during pregnancy with risk of neurodevelopmental disorders in children. JAMA Intern Med 182(11):1149–1160. https://doi.org/10.1001/jamainternmed.2022.4268

    Article  PubMed  PubMed Central  Google Scholar 

  29. Sujan AC et al (2017) Associations of maternal antidepressant use during the first trimester of pregnancy with preterm birth, small for gestational age, autism spectrum disorder, and attention-deficit/hyperactivity disorder in offspring. JAMA 317(15):1553–1562. https://doi.org/10.1001/jama.2017.3413

    Article  PubMed  PubMed Central  Google Scholar 

  30. Lo C et al (2020) Pharmacogenomics in Asian subpopulations and impacts on commonly prescribed medications. Clin Transl Sci 13(5):861–870. https://doi.org/10.1111/cts.12771

    Article  PubMed  PubMed Central  Google Scholar 

  31. Hicks JK et al (2015) Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors. Clin Pharmacol Ther 98(2):127–134. https://doi.org/10.1002/cpt.147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Li CY et al (2016) Set-up and future applications of the Taiwan Maternal and Child Health Database (TMCHD). Taiwan J Public Health 35(2):209–220. https://doi.org/10.6288/TJPH201635104053

    Article  CAS  Google Scholar 

  33. van Hulzen KJE et al (2017) Genetic overlap between attention-deficit/hyperactivity disorder and bipolar disorder: evidence from genome-wide association study meta-analysis. Biol Psychiatry 82(9):634–641. https://doi.org/10.1016/j.biopsych.2016.08.040

    Article  PubMed  Google Scholar 

  34. Carroll LS, Owen MJ (2009) Genetic overlap between autism, schizophrenia and bipolar disorder. Genome Med 1(10):102. https://doi.org/10.1186/gm102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Allison PD (1999) Comparing logit and probit coefficients across groups. Sociol Methods Res 28(2):186–208. https://doi.org/10.1177/0049124199028002003

    Article  Google Scholar 

  36. Brew BK et al (2017) Using fathers as a negative control exposure to test the Developmental Origins of Health and Disease Hypothesis A case study on maternal distress and offspring asthma using Swedish register data. Scand J Public Health Supplement 17:36–40

    Article  Google Scholar 

  37. von Ehrenstein OS et al (2021) Maternal prenatal smoking and autism spectrum disorder in offspring: a california statewide cohort and sibling study. Am J Epidemiol 190(5):728–737. https://doi.org/10.1093/aje/kwaa182

    Article  Google Scholar 

  38. Frisell T, Öberg S, Kuja-Halkola R, Sjölander A (2012) Sibling comparison designs: bias from non-shared confounders and measurement error. Epidemiology 23(5):713–720. https://doi.org/10.1097/EDE.0b013e31825fa230

    Article  PubMed  Google Scholar 

  39. Dubovicky M, Belovicova K, Csatlosova K, Bogi E (2017) Risks of using SSRI / SNRI antidepressants during pregnancy and lactation. Interdiscip Toxicol 10(1):30–34. https://doi.org/10.1515/intox-2017-0004

    Article  PubMed  Google Scholar 

  40. Yang F et al (2017) Risk of autism spectrum disorder in offspring following paternal use of selective serotonin reuptake inhibitors before conception: a population-based cohort study. BMJ Open 7(12):e016368. https://doi.org/10.1136/bmjopen-2017-016368

    Article  PubMed  PubMed Central  Google Scholar 

  41. Tanrikut C et al (2010) Adverse effect of paroxetine on sperm. Fertil Steril 94(3):1021–1026. https://doi.org/10.1016/j.fertnstert.2009.04.039

    Article  CAS  PubMed  Google Scholar 

  42. Safarinejad MR (2008) Sperm DNA damage and semen quality impairment after treatment with selective serotonin reuptake inhibitors detected using semen analysis and sperm chromatin structure assay. J Urol 180(5):2124–2128. https://doi.org/10.1016/j.juro.2008.07.034

    Article  PubMed  Google Scholar 

  43. Lewis SE, Aitken RJ (2005) DNA damage to spermatozoa has impacts on fertilization and pregnancy. Cell Tissue Res 322(1):33–41. https://doi.org/10.1007/s00441-005-1097-5

    Article  CAS  PubMed  Google Scholar 

  44. Roberts AL, Lyall K, Weisskopf MG (2017) Maternal exposure to childhood abuse is associated with mate selection: implications for autism in offspring. J Autism Dev Disord 47(7):1998–2009. https://doi.org/10.1007/s10803-017-3115-3

    Article  PubMed  PubMed Central  Google Scholar 

  45. Viktorin A et al (2017) Autism risk following antidepressant medication during pregnancy. Psychol Med 47(16):2787–2796. https://doi.org/10.1017/s0033291717001301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Brown HK et al (2017) Association between serotonergic antidepressant use during pregnancy and autism spectrum disorder in children. JAMA 317(15):1544–1552. https://doi.org/10.1001/jama.2017.3415

    Article  CAS  PubMed  Google Scholar 

  47. Liu X et al (2017) Antidepressant use during pregnancy and psychiatric disorders in offspring: Danish nationwide register based cohort study. BMJ (Clinical research ed) 358:j3668. https://doi.org/10.1136/bmj.j3668

    Article  PubMed  Google Scholar 

  48. Avorn J et al (1998) Persistence of use of lipid-lowering medications: a cross-national study. JAMA 279(18):1458–1462. https://doi.org/10.1001/jama.279.18.1458

    Article  CAS  PubMed  Google Scholar 

  49. De Jong van den Berg LT, Feenstra N, Sorensen HT, Cornel MC (1999) Improvement of drug exposure data in a registration of congenital anomalies. Pilot-study: pharmacist and mother as sources for drug exposure data during pregnancy. EuroMAP Group. Eur Med Preg Group. Teratology 60 (1):33–36. https://doi.org/10.1002/(SICI)1096-9926(199907)60:1<33::AID-TERA9>3.0.CO;2-X

  50. Sjölander A, Zetterqvist J (2017) Confounders, mediators, or colliders: what types of shared covariates does a sibling comparison design control For? Epidemiology 28(4):540–547. https://doi.org/10.1097/ede.0000000000000649

    Article  PubMed  Google Scholar 

  51. Kalkbrenner AE et al (2020) Familial confounding of the association between maternal smoking in pregnancy and autism spectrum disorder in offspring. Autism Res 13(1):134–144. https://doi.org/10.1002/aur.2196

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This work was supported by grants from the Ministry of Science and Technology, Taiwan (MOST: 109-2314-B-468-001-MY2).

Author information

Author notes

  1. Min-Jing Lee and Yi-Lung Chen authors have equally contributed to the work.

Authors and Affiliations

  1. Department of Psychiatry, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

    Min-Jing Lee

  2. Department of Psychiatry, Chiayi Chang Gung Memorial Hospital, Chiayi County, Puzi City, Taiwan

    Min-Jing Lee & Vincent Chin-Hung Chen

  3. School of Medicine, Chang Gung University, Taoyuan, Taiwan

    Min-Jing Lee & Vincent Chin-Hung Chen

  4. Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung, Taiwan

    Yi-Lung Chen

  5. Department of Psychology, College of Medical and Health Science, Asia University, Taichung, Taiwan

    Yi-Lung Chen

  6. Department of Psychiatry, Mackay Memorial Hospital, Taipei, Taiwan

    Shu-I Wu

  7. Department of Medicine, Mackay Medical College, New Taipei City, Taiwan

    Shu-I Wu

  8. Division of Nephrology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

    Chien-Wei Huang

  9. School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Chien-Wei Huang

  10. Health Service and Population Research Department, King’s College London, London, UK

    Michael E. Dewey

Authors
  1. Min-Jing Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yi-Lung Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shu-I Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chien-Wei Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michael E. Dewey
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Vincent Chin-Hung Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

VC had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: VC and YLC; Acquisition, analysis, or interpretation of data: MJL and YLC; Drafting of the manuscript: MJL and CWH; Statistical analysis: YLC. All authors reviewed the results and approved the final version of the manuscript.

Corresponding author

Correspondence to Vincent Chin-Hung Chen.

Ethics declarations

Conflict of interest

The authors have no competing interests or financial support to disclose.

Ethical standards

This study was approved by the Research Ethics Committee of China Medical University and Hospital (approval number: CMUH108-REC1-142) and was executed as per the Declaration of Helsinki. The requirement for informed consent was waived.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 20 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee, MJ., Chen, YL., Wu, SI. et al. Association between maternal antidepressant use during pregnancy and the risk of autism spectrum disorder and attention deficit hyperactivity disorder in offspring. Eur Child Adolesc Psychiatry (2024). https://doi.org/10.1007/s00787-024-02460-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00787-024-02460-4

Keywords

Search

Navigation