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:

Infant serotonin transporter (SLC6A4) promoter genotype is associated with adverse neonatal outcomes after prenatal exposure to serotonin reuptake inhibitor medications

Molecular Psychiatry volume 13, pages 65–73 (2008)Cite this article

Abstract

Reduced Apgar scores and birth weight, increased risk of respiratory distress, jitteriness and increased tone have been reported in up to 30% of neonates with prenatal exposure to serotonin reuptake inhibitor (SRI) antidepressant medications. In adults, effects of these medications may be related to the genotype for the serotonin transporter (SLC6A4) promoter. In this study we investigated whether SLC6A4 genotype influences the risk for adverse outcomes in neonates with prenatal SRI exposure. Neonatal outcomes including Apgar scores, birth weight, gestational age at birth, symptoms of poor neonatal adaptation and genotype for SLC6A4 were determined in 37 prenatally SRI exposed neonates and compared with 47 non-exposed neonates. Reduced 5 min Apgar scores were observed in exposed neonates and this was moderated by the ss genotype (P<0.001). Birth weight was lower in exposed ls neonates (P=0.008). Risk for respiratory symptoms (respiratory distress and rapid breathing) was higher in exposed neonates with the ll genotype compared to non-exposed neonates (P<0.05) and risk for neuromotor symptoms increased in exposed ss neonates (P<0.026). These relationships remained when controlling for maternal mood during pregnancy, length of gestational medication exposure and gestational age at birth and cesarean section rate. Prenatal SRI exposure was associated with adverse neonatal outcomes and these effects were moderated by infant SLC6A4 genotype. Relationships between polymorphisms and specific outcomes varied during the neonatal period, suggesting that beyond apparent gene-medication interactions, multiple mechanisms contribute to adverse neonatal outcomes following prenatal SRI exposure.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Moses-Kolko EL, Bogen D, Perel J, Bregar A, Uhl K, Levin B et al. Neonatal signs after late in utero exposure to serotonin reuptake inhibitors: literature review and implications for clinical applications. JAMA 2005; 18, 293 2372–2383.

    Article  Google Scholar 

  2. 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: 402–408.

    Article  CAS  PubMed  Google Scholar 

  3. Chambers CD, Johnson KA, Dick LM, Felix RJ, Jones KL . Birth outcomes in pregnant women taking fluoxetine. N Engl J Med 1996; 335: 1010–1015.

    Article  CAS  PubMed  Google Scholar 

  4. Costei AM, Ho T, Kozer E, Ito S, Koren G . Perinatal outcome following third trimester exposure to paroxetine. Pediatric Research 2002; 51: 66A.

    Google Scholar 

  5. Malm H, Klaukka T, Neuvonen PJ . Risks associated with selective serotonin reuptake inhibitors in pregnancy. Obstet Gynecol 2005; 106: 1289–1296.

    Article  CAS  PubMed  Google Scholar 

  6. US Food Drug Administration. FDA Medwatch Drug Alert on Effexor (venlafaxine HCI) and Effexor XR (venlafaxine HCI). 2004 Jun 3. www.fda.gov/medwatch/safety/2004/safety04.htm#effexor (Accessed 26 January 2007).

  7. Health Canada. Health Canada advises of potential adverse effects of SSRIs and other anti-depressants on newborns. 2004 Jul 9. http://www.hc-sc.gc.ca/english/protection/warnings/2004/2004_44.htm (Accessed 26 January 2007).

  8. Bonari L, Pinto N, Ahn E, Einarson A, Steiner M, Koren G . Perinatal risks of untreated depression during pregnancy. Can J Psychiatry 2004; 49: 726–735.

    Article  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. Laine K, Heikkinen T, Ekblad U, Kero P . Effects of exposure to selective serotonin reuptake inhibitors during pregnancy on serotonergic symptoms in newborns and cord blood monoamine and prolactin concentrations. Arch Gen Psychiatry 2003; 60: 720–726.

    Article  CAS  PubMed  Google Scholar 

  11. Oberlander TF, Misri S, Fitzgerald CE, Kostaras X, Rurak D, Riggs W . Pharmacologic factors associated with transient neonatal symptoms following prenatal psychotropic medication exposure. J Clin Psychiatry 2004; 65: 230–237.

    Article  CAS  PubMed  Google Scholar 

  12. 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: 47–57.

    Article  CAS  PubMed  Google Scholar 

  13. Weissman MM, Wickramaratne P, Nomura Y, Warner V, Pilowsky D, Verdeli H . Offspring of depressed parents: 20 years later. Am J Psychiatry 2006; 163: 1001–1008.

    Article  PubMed  Google Scholar 

  14. Pollock BG, Ferrell RE, Mulsant BH, Mazumdar S, Miller M, Sweet RA et al. Allelic variation, in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression. Neuropsychopharmacology 2000; 23: 587–590.

    Article  CAS  PubMed  Google Scholar 

  15. Kim DK, Lim SW, Lee S, Sohn SE, Kim S, Hahn CG et al. Serotonin transporter gene polymorphism and antidepressant response. Neuroreport 2001; 11: 215–219.

    Article  Google Scholar 

  16. Online mendelian inheritance in man (OMIM). http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=182138. 2006. Available at URL: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=182138 (Accessed 26 January 2007).

  17. Ramamoorthy S, Bauman AL, Moore KR, Han H, Yang-Feng T, Chang AS et al. Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization. Proc Natl Acad Sci USA 1993; 90: 2542–2546.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lesch KP, Wolozin BL, Estler HC, Murphy DL, Riederer P . Isolation of a cDNA-encoding the human brain-serotonin transporter. J Neural Transm-Gen Sect 1993; 91: 67–72.

    Article  CAS  PubMed  Google Scholar 

  19. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996; 274: 1527–1531.

    CAS  PubMed  Google Scholar 

  20. Heils A, Teufel A, Petri S, Stober G, Riederer P, Bengel D et al. Allelic variation of human serotonin transporter gene expression. J Neurochem 1996; 66: 2621–2624.

    Article  CAS  PubMed  Google Scholar 

  21. Lesch KP, Mossner R . Genetically driven variation in serotonin uptake: is there a link to affective spectrum, neurodevelopmental, and neurodegenerative disorders? Biol Psychiatry 1998; 44: 179–192.

    Article  CAS  PubMed  Google Scholar 

  22. Collier DA, Stober G, Li T, Heils A, Catalano M, Di Bella D et al. A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders. Mol Psychiatry 1996; 1: 453–460.

    CAS  PubMed  Google Scholar 

  23. Yu YW, Tsai SJ, Chen TJ, Lin CH, Hong CJ . Association study of the serotonin transporter promoter polymorphism and symptomatology and antidepressant response in major depressive disorders. Mol Psychiatry 2002; 7: 1115–1119.

    Article  CAS  PubMed  Google Scholar 

  24. Murphy Jr GM, Hollander SB, Rodrigues HE, Kremer C, Schatzberg AF . Effects of the serotonin transporter gene promoter polymorphism on mirtazapine and paroxetine efficacy and adverse events in geriatric major depression. Arch Gen Psychiatry 2004; 61: 1163–1169.

    Article  CAS  PubMed  Google Scholar 

  25. Rausch JL, Johnson ME, Fei YJ, Li JQ, Shendarkar N, Hobby HM et al. Initial conditions of serotonin transporter kinetics and genotype: influence on SSRI treatment trial outcome. Biol Psychiatry 2002; 51: 723–732.

    Article  CAS  PubMed  Google Scholar 

  26. Smeraldi E, Zanardi R, Benedetti F, Di BD, Perez J, Catalano M . Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Mol Psychiatry 1998; 3: 508–511.

    Article  CAS  PubMed  Google Scholar 

  27. Hamilton M . A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23: 56–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hamilton M . The assessment of anxiety states by rating. Br J Med Psychol 1959; 32: 50–55.

    Article  CAS  PubMed  Google Scholar 

  29. Cox JL, Holden JM, Sagovsky R . Detection of postnatal depression. Development of the 10-item Edinburgh Postnatal Depression Scale. Br J Psychiatry 1987; 150: 782–786.

    Article  CAS  PubMed  Google Scholar 

  30. Gentile S . SSRIs in pregnancy and lactation: emphasis on neurodevelopmental outcome. CNS Drugs 2005; 19: 623–633.

    Article  CAS  PubMed  Google Scholar 

  31. Kim J, Riggs KW, Misri S, Kent N, Oberlander TF, Grunau RE et al. Stereoselective disposition of fluoxetine and norfluoxetine during pregnancy and breast-feeding. Br J Clin Pharmacol 2006; 61: 155–163.

    Article  CAS  PubMed  Google Scholar 

  32. Lane R, Baldwin D . Selective serotonin reuptake inhibitor-induced serotonin syndrome: review. J Clin Psychopharmacol 1997; 17: 208–221.

    Article  CAS  PubMed  Google Scholar 

  33. Boyer EW, Shannon M . The serotonin syndrome. N Engl J Medi 2005; 352: 1112–1120.

    Article  CAS  Google Scholar 

  34. Haddad PM . Antidepressant discontinuation syndromes. Drug Saf 2001; 24: 183–197.

    Article  CAS  PubMed  Google Scholar 

  35. Lejoyeux M, Ades J . Antidepressant discontinuation: a review of the literature. J Clin Psychiatry 1997; 58 (Suppl 7): 11–15.

    CAS  PubMed  Google Scholar 

  36. Nordeng H, Lindemann R, Perminov KV, Reikvam A . Neonatal withdrawal syndrome after in utero exposure to selective serotonin reuptake inhibitors. Acta Paediatr 2001; 90: 288–291.

    Article  CAS  PubMed  Google Scholar 

  37. Isbister GK, Dawson A, Whyte IM, Prior FH, Clancy C, Smith AJ . Neonatal paroxetine withdrawal syndrome or actually serotonin syndrome? Arch Dis Child 2001; 85: F147–F148.

    Article  CAS  Google Scholar 

  38. Schatzberg AF, Haddad P, Kaplan EM, Lejoyeux M, Rosenbaum JF, Young AH et al. Possible biological mechanisms of the serotonin reuptake inhibitor discontinuation syndrome. Discontinuation consensus panel. J Clin Psychiatry 1997; 58 (Suppl 7): 23–27.

    CAS  PubMed  Google Scholar 

  39. Lesch KP, Balling U, Gross J, Strauss K, Wolozin BL, Murphy DL et al. Organization of the human serotonin transporter gene. J Neural Transm-Gen Sect 1994; 95: 157–162.

    Article  CAS  PubMed  Google Scholar 

  40. Grasmader K, Verwohlt PL, Rietschel M, Dragicevic A, Muller M, Hiemke C et al. Impact of polymorphisms of cytochrome-P450 isoenzymes 2C9, 2C19 and 2D6 on plasma concentrations and clinical effects of antidepressants in a naturalistic clinical setting. Eur J Clin Pharmacol 2004; 60: 329–336.

    PubMed  Google Scholar 

  41. Stahl SM . Mechanism of action of serotonin selective reuptake inhibitors. Serotonin receptors and pathways mediate therapeutic effects and side effects. J Affect Disord 1998; 51: 215–235.

    Article  CAS  PubMed  Google Scholar 

  42. Iversen L . Neurotransmitter transporters and their impact on the development of psychopharmacology. Br J Pharmacol 2006; 147 (Suppl 1): S82–S88.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 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 

Download references

Acknowledgements

This research was funded by March of Dimes Foundation (USA) (No. 12-FY01-30), the Canadian Institutes of Health Research (CIHR No. MOP 54490 and 57837) and HELP, UBC (Human Early Learning Partnership). TFO is supported by a HELP, Senior Career Award and has the R Howard Webster Professorship in Child Development (UBC, Faculty of Graduate Studies). CJDR is supported by CIHR and Michael Smith Foundation for Health Research Fellowships. This work was also supported by a grant from the CIHR and Canada Research Chair in Genetics and Behaviour to EMS. We are grateful to the mothers and their infants who participated and contributed to this work, as well as to Colleen Fitzgerald and Ursula Brain for their contributions organizing and facilitating this research program. We also gratefully acknowledge the thoughtful comments provided by Ursula Brain and Tracey Weir and the manuscript reviewers from Molecular Psychiatry.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Early Human Experience Unit, Centre for Community Child Health Research, University of British Columbia, Vancouver, BC, Canada

    T F Oberlander & M Papsdorf

  2. Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics and Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada

    R J Bonaguro, C J D Ross & E M Simpson

  3. Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada

    S Misri

Authors
  1. T F Oberlander
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R J Bonaguro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Misri
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Papsdorf
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C J D Ross
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E M Simpson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T F Oberlander.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Oberlander, T., Bonaguro, R., Misri, S. et al. Infant serotonin transporter (SLC6A4) promoter genotype is associated with adverse neonatal outcomes after prenatal exposure to serotonin reuptake inhibitor medications. Mol Psychiatry 13, 65–73 (2008). https://doi.org/10.1038/sj.mp.4002007

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4002007

Keywords

This article is cited by

Search

Advanced search

Quick links