Skip to main content
Log in

Safety of Selective Serotonin Reuptake Inhibitors in Pregnancy: A Review of Current Evidence

  • Review Article
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressant medications worldwide. However, over the past decade, their use during pregnancy, a period of extreme vulnerability to the onset of depression, has become highly concerning to patients and their healthcare providers in terms of safety to the developing fetus. Exposure to SSRIs in pregnancy has been associated with miscarriage, premature delivery, neonatal complications, birth defects—specifically cardiac defects—and, more recently, neurodevelopmental disorders in childhood, specifically autism spectrum disorders. Studies addressing the effect of individual SSRIs indicate a small but higher risk for birth defects with maternal fluoxetine and paroxetine use. Though the excess in absolute risk is small, it may still be of concern to some patients. Meanwhile, antenatal depression itself is associated with adverse perinatal outcomes, and discontinuing antidepressant treatment during pregnancy is associated with a high risk of relapse of depression. Whether the observed adverse fetal effects are related to the mother’s medication use or her underlying maternal illness remains difficult to determine. It is important that every pregnant woman being treated with an SSRI (or considering such treatment) carefully weighs the risks of treatment against the risk of untreated depression for both herself and her child. The importance of recognizing a higher risk for the development of adverse outcomes lies in the potential for surveillance and possibly a timely intervention. Therefore, we recommend that pregnant women exposed to any SSRI in early pregnancy be offered options for prenatal diagnosis through ultrasound examinations and fetal echocardiography to detect the presence of birth defects. Tapering off or switching to other therapy in early pregnancy, if appropriate for the individual, may also be considered on a case-by-case basis.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Alwan S, Reefhuis J, Rasmussen SA, Friedman JM. Patterns of antidepressant medication use among pregnant women in a United States population. J Clin Pharmacol. 2011;51(2):264–70.

    Article  PubMed  Google Scholar 

  2. Andrade SE, Raebel MA, 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 e1–1945.

    Article  PubMed  CAS  Google Scholar 

  3. Mann JJ. The medical management of depression. N Engl J Med. 2005;353:1819–34.

    Article  CAS  PubMed  Google Scholar 

  4. Meunier MR, Bennett IM, Coco AS. Use of antidepressant medication in the United States during pregnancy, 2002–2010. Psychiatr Serv. 2013;64(11):1157–60.

    Article  PubMed  Google Scholar 

  5. Mitchell AA, Gilboa SM, Werler MM, Kelley KE, Louik C, Hernandez-Diaz S. Medication use during pregnancy, with particular focus on prescription drugs: 1976–2008. Am J Obst Gynecol. 2011;205(1):51 e1–518.

    Article  Google Scholar 

  6. Källén BA, Otterblad Olausson P. Maternal use of selective serotonin re-uptake inhibitors in early pregnancy and infant congenital malformations. Birth Defects Res A Clin Mol Teratol. 2007;79(4):301–8.

    Article  PubMed  CAS  Google Scholar 

  7. Cole JA, Ephross SA, Cosmatos IS, Walker AM. Paroxetine in the first trimester and the prevalence of congenital malformations. Pharmacoepidemiol Drug Saf. 2007;16(10):1075–85.

    Article  PubMed  Google Scholar 

  8. Buznikov GA, Lambert HW, Lauder JM. Serotonin and serotonin-like substances as regulators or early embryogenesis and morphogenesis. Cell Tissue Res. 2001;305:177–86.

    Article  CAS  PubMed  Google Scholar 

  9. Moiseiwitsch JR, Lauder JM. Serotonin regulates mouse cranial neural crest migration. Proc Natl Acad Sci. 1995;92(16):7182–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yavarone MS, Shuey DL, Tamir H, Sadler TW, Lauder JM. Serotonin and cardiac morphogenesis in the mouse embryo. Teratology. 1993;47:573–84.

    Article  CAS  PubMed  Google Scholar 

  11. Shuey DL, Sadler TW, Tamir H, Lauder JM. Serotonin and morphogenesis. Transient expression of serotonin uptake and binding protein during craniofacial morphogenesis in the mouse. Anat Embryol (Berl). 1993;187:75–85.

    Article  CAS  PubMed  Google Scholar 

  12. Sari Y, Zhou FC. Serotonin and its transporter on proliferation of fetal heart cells. Int J Dev Neurosci. 2003;21:417–24.

    Article  CAS  PubMed  Google Scholar 

  13. Hansson SR, Mezey E, Hoffman BJ. Serotonin transporter messenger RNA expression in eural crest-derived structures and sensory pathways of teh developing rat embryo. Neuroscience. 1999;89(1):243–65.

    Article  CAS  PubMed  Google Scholar 

  14. Davies TS, Kluwe WM. Preclinical toxicological evaluation of sertraline hydrochloride. Drug Chem Toxicol. 1998;21:521–37.

    Article  CAS  PubMed  Google Scholar 

  15. Singh Y, Jaiswal AK, Singh M, Bhattacharya SK. Effect of prenatal diazepam, phenobarbital, haloperidol and fluoxetine exposure on foot shock induced aggression in rats. Indian J Exp Biol. 1998;36(10):1023–4.

    CAS  PubMed  Google Scholar 

  16. Crowley JM, Dopheide M, Countryman RA, et al. Early developmental exposure to fluoxetine (Prozac): enduring effects on learning, memory, and agression. Neurotoxicol Teratol. 2001;23(3):289.

    Google Scholar 

  17. 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.

    Article  CAS  PubMed  Google Scholar 

  18. Kulin NA, Pastuszak A, Sage SR, Schick-Boschetto B, Spivey G, Feldkamp M, Ormond K, Matsui D, Stein-Schechman AK, Cook L, Brochu J, Rieder M, Koren G. Pregnancy outcome following maternal use of the new selective serotonin reuptake inhibitors: a prospective controlled multicenter study. JAMA. 1998;279:609–10.

    Article  CAS  PubMed  Google Scholar 

  19. Diav-Citrin O, Shechtman S, Weinbaum D. Pregnancy outcome after gestational exposure to paroxetine: a prospective controlled study cohort. Teratology. 2002;65(6):298.

    Google Scholar 

  20. Reis M, Kallen B. Delivery outcome after maternal use of antidepressant drugs in pregnancy: an update using Swedish data. Psychol Med. 2010;40(10):1723–33.

    Article  CAS  PubMed  Google Scholar 

  21. Kallen B, Borg N, Reis M. The use of central nervous system active drugs during pregnancy. Pharmaceuticals (Basel). 2013;6(10):1221–86.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Nordeng H, van Gelder MM, Spigset O, Koren G, Einarson A, Eberhard-Gran M. Pregnancy outcome after exposure to antidepressants and the role of maternal depression: results from the Norwegian Mother and Child Cohort Study. J Clin Psychopharmacol. 2012;32(2):186–94.

    Article  CAS  PubMed  Google Scholar 

  23. Davis RL, Rubanowice D, McPhillips H, Raebel MA, Andrade SE, Smith D, Yood MU, Platt R, HMO Research Network Center for Education, Research in Therapeutics. Risks of congenital malformations and perinatal events among infants exposed to antidepressant medications during pregnancy. Pharmacoepidemiol Drug Saf. 2007;16(10):1086–94.

    Article  PubMed  Google Scholar 

  24. Oberlander TF, Warburton W, Misri S, Riggs W, Aghajanian J, Hertzman C. Major congenital malformations following prenatal exposure to serotonin reuptake inhibitors and benzodiazepines using population-based health data. Birth Defects Res B. 2008;83:68–76.

    Article  CAS  Google Scholar 

  25. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Colvin L, Slack-Smith L, Stanley FJ, Bower C. Dispensing patterns and pregnancy outcomes for women dispensed selective serotonin reuptake inhibitors in pregnancy. Birth Defects Res A Clin Mol Teratol. 2011;91(3):142–52.

    Article  CAS  PubMed  Google Scholar 

  27. Malm H, Artama M, Gissler M, Ritvanen A. Selective serotonin reuptake inhibitors and risk for major congenital anomalies. Obst Gynecol. 2011;118(1):111–20.

    Article  Google Scholar 

  28. Jimenez-Solem E, Andersen JT, Petersen M, Broedbaek K, Jensen JK, Afzal S, et al. Exposure to selective serotonin reuptake inhibitors and the risk of congenital malformations: a nationwide cohort study. BMJ Open. 2012;2(3):e001148.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Ban L, Gibson JE, West J, Fiaschi L, Sokal R, Smeeth L, et al. Maternal depression, antidepressant prescriptions, and congenital anomaly risk in offspring: a population-based cohort study. BJOG. 2014;121(12):1471–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Berard A, Zhao JP, Sheehy O. Sertraline use during pregnancy and the risk of major malformations. Am J Obstet Gynecol. 2015;212(6):795.e1–795.e12.

    Article  CAS  Google Scholar 

  31. 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.

    Article  CAS  PubMed  Google Scholar 

  32. 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.

    Article  CAS  PubMed  Google Scholar 

  33. Berard A, Ramos E, Rey E, Blais L, St.-Andre M, Oraichi D. First trimester exposure to paroxetine and risk of cardiac malformations in infants: the importance of dosage. Birth Defects Res B Dev Reprod Toxicol. 2007;80(1):18–27.

    Article  CAS  PubMed  Google Scholar 

  34. Bakker MK, Kerstjens-Frederikse WS, Buys CH, de Walle HE, Jong-van den Berg LT. First-trimester use of paroxetine and congenital heart defects: a population-based case-control study. Birth Defects Res A Clin Mol Teratol. 2010;88(2):94–100.

    CAS  PubMed  Google Scholar 

  35. Yazdy MM, Mitchell AA, Louik C, Werler MM. Use of selective serotonin-reuptake inhibitors during pregnancy and the risk of clubfoot. Epidemiology. 2014;25(6):859–65.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Theophile H, Laporte JR, Moore N, Martin KL, Begaud B. The case-population study design: an analysis of its application in pharmacovigilance. Drug Saf. 2011;34(10):861–8.

    Article  PubMed  Google Scholar 

  37. de Jonge L, Zetstra-van der Woude PA, Bos HJ, de Jong-van den Berg LT, Bakker MK. Identifying associations between maternal medication use and birth defects using a case-population approach: an exploratory study on signal detection. Drug Saf. 2013;36(11):1069–78.

    Article  PubMed  Google Scholar 

  38. Einarson A, Choi J, Einarson TR, Koren G. Incidence of major malformations in infants following antidepressant exposure in pregnancy: results of a large prospective cohort study. Can J Psychiatry. 2009;54(4):242–6.

    PubMed  Google Scholar 

  39. Klieger-Grossmann C, Weitzner B, Panchaud A, Pistelli A, Einarson T, Koren G, et al. Pregnancy outcomes following use of escitalopram: a prospective comparative cohort study. J Clin Pharmacol. 2012;52(5):766–70.

    Article  CAS  PubMed  Google Scholar 

  40. Malm H, Klaukka T, Neuvonen PJ. Risks associated with selective serotonin reuptake inhibitors in pregnancy. Obstet Gynecol. 2005;106:1289–96.

    Article  CAS  PubMed  Google Scholar 

  41. Kjaersgaard MI, Parner ET, Vestergaard M, Sorensen MJ, Olsen J, Christensen J, et al. Prenatal antidepressant exposure and risk of spontaneous abortion: a population-based study. PLoS One. 2013;8(8):e72095.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Andersen JT, Andersen NL, Horwitz H, Poulsen HE, Jimenez-Solem E. Exposure to selective serotonin reuptake inhibitors in early pregnancy and the risk of miscarriage. Obstet Gynecol. 2014;124(4):655–61.

    Article  CAS  PubMed  Google Scholar 

  43. Nakhai-Pour HR, Broy P, Berard A. Use of antidepressants during pregnancy and the risk of spontaneous abortion. CMAJ. 2010;182(10):1031–7.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Morrison JL, Riggs KW, Rurak DW. Fluoxetine during pregnancy: impact on fetal development. Reprod Fertil Dev. 2005;17(6):641–50.

    Article  CAS  PubMed  Google Scholar 

  45. Reefhuis J, Devine O, Friedman JM, Louik C, Honein MA. Specific SSRIs and birth defects: bayesian analysis to interpret new data in the context of previous reports. BMJ. 2015;351:h3190.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Diav-Citrin O, Shechtman S, Weinbaum D, Wajnberg R, Avgil M, Di Gianantonio E, Clementi M, Weber-Schoendorfer CSC, Ornoy A. Paroxetine and fluoxetine in pregnancy: a prospective, multicenter, controlled, observational study. Br J Clin Pharmacol. 2008;66(5):695–705.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Merlob P, Birk E, Sirota L, Linder N, Berant M, Stahl B, Klinger G. Are selective serotonin reuptake inhibitors cardiac teratogens? Echocardiographic screening of newborns with persistent heart murmur. Birth Defects Res A Clin Mol Teratol. 2009;85(10):837–41.

    Article  CAS  PubMed  Google Scholar 

  48. Huybrechts KF, Palmsten K, Avorn J, Cohen LS, Holmes LB, Franklin JM, et al. Antidepressant use in pregnancy and the risk of cardiac defects. N Engl J Med. 2014;370(25):2397–407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Pastuszak A, Schick-Boschetto B, Zuber C, Feldkamp M, Pinelli M, Sihn S, Donnenfeld A, McCormack M, Leen-Mitchell M, Woodland C, et al. Pregnancy outcome following first-trimester exposure to fluoxetine (Prozac). JAMA. 1993;269:2246–8.

    Article  CAS  PubMed  Google Scholar 

  50. Broy P, Berard A. Gestational exposure to antidepressants and the risk of spontaneous abortion: a review. Curr Drug Deliv. 2010;7(1):76–92.

    Article  CAS  PubMed  Google Scholar 

  51. McElhatton PR, Garbis HM, Elefant E, Vial T, Bellemin B, Mastroiacovo P, Arnon J, Rodriguez-Pinilla E, Schaefer C, Pexieder T, Merlob P, Dal Verme S. The outcome of pregnancy in 689 women exposed to therapeutic doses of antidepressants. A collaborative study of the European Network of Teratology Information Services (ENTIS). Reprod Toxicol. 1996;10:285–94.

    Article  CAS  PubMed  Google Scholar 

  52. Margulis AV, Abou-Ali A, Strazzeri MM, Ding Y, Kuyateh F, Frimpong EY, et al. Use of selective serotonin reuptake inhibitors in pregnancy and cardiac malformations: a propensity-score matched cohort in CPRD. Pharmacoepidemiol Drug Saf. 2013;22(9):942–51.

    PubMed  Google Scholar 

  53. Zoega H, Kieler H, Norgaard M, Furu K, Valdimarsdottir U, Brandt L, et al. Use of SSRI and SNRI antidepressants during pregnancy: a population-based study from Denmark, Iceland, Norway and Sweden. PLoS One. 2015;10(12):e0144474.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Myles N, Newall H, Ward H, Large M. Systematic meta-analysis of individual selective serotonin reuptake inhibitor medications and congenital malformations. Aust N Z J Psychiatry. 2013;47(11):1002–12.

    Article  PubMed  Google Scholar 

  55. Cohen LS, Altshuler LL, Harlow BL, Nonacs R, Newport DJ, Viguera AC, Suri R, Burt VK, Hendrick V, Reminick AM, Loughead A, Vitonis AF, Stowe ZN. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA. 2006;295(5):499–507.

    Article  CAS  PubMed  Google Scholar 

  56. Puthiyachirakkal M, Mhanna MJ. Pathophysiology, management, and outcome of persistent pulmonary hypertension of the newborn: a clinical review. Front Pediatr. 2013;1:23.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Chambers CD, Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Jones KL, Mitchell AA. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med. 2006;354:579–87.

    Article  CAS  PubMed  Google Scholar 

  58. US Food and Drug Administration. Public health advisory: treatment challenges of depression in pregnancy and the possibility of persistent pulmonary hypertension in newborns. http://www.fdagov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124348htm Accessed 27 Nov 2015.

  59. Huybrechts KF, Bateman BT, Hernandez-Diaz S. Maternal antidepressant use and persistent pulmonary hypertension of the newborn: reply. JAMA. 2015;314(12):1294.

    Article  PubMed  Google Scholar 

  60. Kieler H, Artama M, Engeland A, Ericsson O, Furu K, Gissler M, et al. Selective serotonin reuptake inhibitors during pregnancy and risk of persistent pulmonary hypertension in the newborn: population based cohort study from the five Nordic countries. BMJ. 2012;344:d8012.

    Article  PubMed  CAS  Google Scholar 

  61. Wichman CL, Moore KM, Lang TR, St Sauver JL, Heise RH Jr, Watson WJ. Congenital heart disease associated with selective serotonin reuptake inhibitor use during pregnancy. Mayo Clin Proc. 2009;84(1):23–7.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Andrade SE, McPhillips H, Loren D, Raebel MA, Lane K, Livingston J, et al. Antidepressant medication use and risk of persistent pulmonary hypertension of the newborn. Pharmacoepidemiol Drug Saf. 2009;18(3):246–52.

    Article  PubMed  Google Scholar 

  63. Wilson KL, Zelig CM, Harvey JP, Cunningham BS, Dolinsky BM, Napolitano PG. Persistent pulmonary hypertension of the newborn is associated with mode of delivery and not with maternal use of selective serotonin reuptake inhibitors. Am J Perinatol. 2011;28(1):19–24.

    Article  PubMed  Google Scholar 

  64. Andrade C, Kumar CB, Surya S. Cardiovascular mechanisms of SSRI drugs and their benefits and risks in ischemic heart disease and heart failure. Int Clin Psychopharmacol. 2013;28(3):145–55.

    Article  PubMed  Google Scholar 

  65. Paraskevaidis I, Parissis JT, Fountoulaki K, Filippatos G, Kremastinos D. Selective serotonin re-uptake inhibitors for the treatment of depression in coronary artery disease and chronic heart failure: evidence for pleiotropic effects. Cardiovasc Hematol Agents Med Chem. 2006;4(4):361–7.

    CAS  PubMed  Google Scholar 

  66. Costei AM, Kozer E, Ho T, Ito S, Koren G. Perinatal outcome following third trimester exposure to paroxetine. Arch Pediatr Adolesc Med. 2002;156(11):1129–32.

    Article  PubMed  Google Scholar 

  67. 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(8):898–906.

    Article  PubMed  Google Scholar 

  68. Kallen B. Neonate characteristics after maternal use of antidepressants in late pregnancy. Arch Pediatr Adolesc Med. 2004;158:307–8.

    Article  Google Scholar 

  69. Casper RC, Fleisher BE, Lee-Ancajas JC, Gilles A, Gaylor E, DeBattista A, Hoyme HE. Follow-up of children of depressed mothers exposed or not exposed to antidepressant drugs during pregnancy. J Pediatr. 2003;142(4):402–8.

    Article  CAS  PubMed  Google Scholar 

  70. Cohen LS, Heller VL, Bailey JW, Grush L, Ablon JS, Bouffard SM. Birth outcomes following prenatal exposure to fluoxetine. Biol Psychiatry. 2000;48(10):996–1000.

    Article  CAS  PubMed  Google Scholar 

  71. Laine K, Heikkinin 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(7):720–6.

    Article  CAS  PubMed  Google Scholar 

  72. 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(2):173–6.

    Article  PubMed  Google Scholar 

  73. Austin MP. To treat or not to treat: maternal depression, SSRI use in pregnancy and adverse neonatal effects. Psychol Med. 2006;36(12):1663–70.

    Article  PubMed  Google Scholar 

  74. Simon GE, Cunningham ML, Davis RL. Outcomes of prenatal antidepressant exposure. Am J Psychiatry. 2002;159:2055–61.

    Article  PubMed  Google Scholar 

  75. Wen SW, Yang Q, Garner P, Fraser W, Olatunbosun O, Nimrod C, Walker M. Selective serotonin reuptake inhibitors and adverse pregnancy outcomes. Am J Obstet Gynecol. 2006;194(4):961–6.

    Article  CAS  PubMed  Google Scholar 

  76. Suri R, Altshuler L, Hellemann G, Burt VK, Aquino A, Mintz J. Effects of antenatal depression and antidepressant treatment on gestational age at birth and risk of preterm birth. Am J Psychiatry. 2007;164(8):1206–13.

    Article  PubMed  Google Scholar 

  77. Pearson KH, Nonacs RM, Viguera AC, Heller VL, Petrillo LF, Brandes M, Hennen J, Cohen LS. Birth outcomes following prenatal exposure to antidepressants. J Clin Psychiatry. 2007;68(8):1284–9.

    Article  CAS  PubMed  Google Scholar 

  78. Maschi S, Clavenna A, Campi R, Schiavetti B, Bernat M, Bonati M. Neonatal outcome following pregnancy exposure to antidepressants: a prospective controlled cohort study. BJOG. 2008;115(2):283–9.

    Article  CAS  PubMed  Google Scholar 

  79. Hendrick V, Stowe ZN, Altshuler LL, Hwang S, Lee E, Haynes D. Placental passage of antidepressant medications. Am J Psychiatry. 2003;160:993–6.

    Article  PubMed  Google Scholar 

  80. Stephansson O, Kieler H, Haglund B, Artama M, Engeland A, Furu K, et al. Selective serotonin reuptake inhibitors during pregnancy and risk of stillbirth and infant mortality. JAMA. 2013;309(1):48–54.

    Article  CAS  PubMed  Google Scholar 

  81. Moses-Kolko EL, Bogen D, Perel J, Bregar A, Uhl K, Levin B, Wisner KL. Neonatal signs after late in utero exposure to serotonin reuptake inhibitors: literature review and implications for clinical applications. JAMA. 2005;293(19):2372–83.

    Article  CAS  PubMed  Google Scholar 

  82. Oberlander TF, Grunau RE, Fitzgerald C, Papsdorf M, Rurak D, Riggs W. Pain reactivity in 2-month-old infants after prenatal and postnatal serotonin reuptake inhibitor medication exposure. Pediatrics. 2005;115:411–25.

    Article  PubMed  Google Scholar 

  83. Mulder EJ, Ververs FF, de Heus R, Visser GH. Selective serotonin reuptake inhibitors affect neurobehavioral development in the human fetus. Neuropsychopharmacology. 2011;36(10):1961–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Rurak D, Lim K, Sanders A, Brain U, Riggs W, Oberlander TF. Third trimester fetal heart rate and Doppler middle cerebral artery blood flow velocity characteristics during prenatal selective serotonin reuptake inhibitor exposure. Pediatr Res. 2011;70(1):96–101.

    Article  CAS  PubMed  Google Scholar 

  85. Salisbury AL, Ponder KL, Padbury JF, Lester BM. Fetal effects of psychoactive drugs. Clin Perinatol. 2009;36(3):595–619.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Knickmeyer RC, Meltzer-Brody S, Woolson S, Hamer RM, Smith JK, Lury K, et al. Rate of Chiari I malformation in children of mothers with depression with and without prenatal SSRI exposure. Neuropsychopharmacology. 2014;39(11):2611–21.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Anderson GM, Freedman DX, Cohen DJ, Volkmar FR, Hoder EL, McPhedran P, et al. Whole blood serotonin in autistic and normal subjects. J Child Psychol Psychiatry. 1987;28(6):885–900.

    Article  CAS  PubMed  Google Scholar 

  88. Cook EH Jr, Leventhal BL, Freedman DX. Free serotonin in plasma: autistic children and their first-degree relatives. Biol Psychiatry. 1988;24(4):488–91.

    Article  PubMed  Google Scholar 

  89. Vorhees CV, Acuff-Smith KD, Schilling MA, Fisher JE, Moran MS, Buelke-Sam J. A developmental neurotoxicity evaluation of the effects of prenatal exposure to fluoxetine in rats. Fundam Appl Toxicol. 1994;23(2):194–205.

    Article  CAS  PubMed  Google Scholar 

  90. Harrington RA, Lee LC, Crum RM, Zimmerman AW, Hertz-Picciotto I. Serotonin hypothesis of autism: implications for selective serotonin reuptake inhibitor use during pregnancy. Autism Res. 2013;6(3):149–68.

    Article  PubMed  Google Scholar 

  91. 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.

    Article  PubMed  Google Scholar 

  92. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  93. 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):1642–8.

    Article  PubMed  Google Scholar 

  94. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  95. 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.

    Article  CAS  PubMed  Google Scholar 

  96. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  97. 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.

    Article  PubMed  Google Scholar 

  98. 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.

    Article  PubMed  Google Scholar 

  99. 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. 2015;20(6):727–34.

    Article  CAS  PubMed  Google Scholar 

  100. 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;49:82–9.

    Article  CAS  PubMed  Google Scholar 

  101. Hanley GE, Brain U, Oberlander TF. Infant developmental outcomes following prenatal exposure to antidepressants, and maternal depressed mood and positive affect. Early Hum Dev. 2013;89(8):519–24.

    Article  CAS  PubMed  Google Scholar 

  102. Hanley GE, Brain U, Oberlander TF. Prenatal exposure to serotonin reuptake inhibitor antidepressants and childhood behavior. Pediatr Res. 2015;78(2):174–80.

    Article  CAS  PubMed  Google Scholar 

  103. Nulman I, Rovet J, Stewart DE, et al. Neurodevelopment of children exposed in utero to antidepressant drugs. N Engl J Med. 1997;4:258–62.

    Article  Google Scholar 

  104. Nulman I, Rovet J, Stewart DE, Wolpin J, Pace-Asciak P, Shuhaiber S, Koren G. Child development following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: a prospective, controlled study. Am J Psychiatry. 2002;159(11):1889–95.

    Article  PubMed  Google Scholar 

  105. Heikkinen T, Ekblad U, Kero P, Ekblad S, Laine K. Citalopram in pregnancy and lactation. Clin Pharmacol Ther. 2002;72(2):184–91.

    Article  PubMed  CAS  Google Scholar 

  106. Heikkinen T, Ekblad U, Palo P, Laine K. Pharmacokinetics of fluoxetine and norfluoxetine in pregnancy and lactation. Clin Pharmacol Ther. 2003;73(4):330–7.

    Article  CAS  PubMed  Google Scholar 

  107. 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.

    Article  PubMed  Google Scholar 

  108. 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.

    Article  PubMed  Google Scholar 

  109. Ryan D, Milis L, Misri N. Depression during pregnancy. Can Fam Physician. 2005;51:1087–93.

    PubMed  PubMed Central  Google Scholar 

  110. Berle JO, Mykletun A, Daltveit AK, Rasmussen S, Holsten F, Dahl AA. Neonatal outcomes in offspring of women with anxiety and depression during pregnancy. A linkage study from The Nord-Trondelag Health Study (HUNT) and Medical Birth Registry of Norway. Arch Womens Ment Health. 2005;8(3):181–9.

    Article  CAS  PubMed  Google Scholar 

  111. Larsson C, Sydsjo G, Josefsson A. Health, sociodemographic data, and pregnancy outcome in women with antepartum depressive symptoms. Obstet Gynecol. 2004;104(3):459–66.

    Article  PubMed  Google Scholar 

  112. Perkin MR, Bland JM, Peacock JL, Anderson HR. The effect of anxiety and depression during pregnancy on obstetric complications. Br J Obstet Gynaecol. 1993;100(7):629–34.

    Article  CAS  PubMed  Google Scholar 

  113. Hansen D, Lou HC, Olsen J. Serious life events and congenital malformations: a national study with complete follow-up. Lancet. 2000;356(9233):875–80.

    Article  CAS  PubMed  Google Scholar 

  114. Carmichael SL, Shaw GM. Maternal life event stress and congenital anomalies. Epidemiology. 2000;11(1):30–5.

    Article  CAS  PubMed  Google Scholar 

  115. Nimby GT, Lundberg L, Sveger T, McNeil TF. Maternal distress and congenital malformations: do mothers of malformed fetuses have more problems? J Psychiatr Res. 1999;33(4):291–301.

    Article  CAS  PubMed  Google Scholar 

  116. Field TDM, Hernandez-Reif M. Prenatal depression effects on the fetus and newborn: a review. Infant Behav Dev. 2006;29(3):445–55.

    Article  PubMed  Google Scholar 

  117. Orr ST, Miller CA. Maternal depressive symptoms and the risk of poor pregnancy outcome. Review of the literature and preliminary findings. Epidemiol Rev. 1995;17:165–71.

    CAS  PubMed  Google Scholar 

  118. Chung TK, Lau TK, Yip AS, Chiu HF, Lee DT. Antepartum depressive symptomatology is associated with adverse obstetric and neonatal outcomes. Psychosom Med. 2001;63(5):830–4.

    Article  CAS  PubMed  Google Scholar 

  119. 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):1012–24.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Hobel CJ, Goldstein A, Barrett ES. Psychosocial Stress and Pregnancy Outcome. Clin Obstet Gynecol. 2008;51(2):333–48.

    Article  PubMed  Google Scholar 

  121. Hanley GE, Oberlander TF. The effect of perinatal exposures on the infant: antidepressants and depression. Best Pract Res Clin Obstet Gynaecol. 2014;28(1):37–48.

    Article  PubMed  Google Scholar 

  122. Kozhimannil KB, Pereira MA, Harlow BL. Association between diabetes and perinatal depression among low-income mothers. JAMA. 2009;301(8):842–7.

    Article  CAS  PubMed  Google Scholar 

  123. Kurki T, Hiilesmaa V, Raitasalo R, Mattila H, Ylikorkala O. Depression and anxiety in early pregnancy and risk for preeclampsia. Obstet Gynecol. 2000;95(4):487–90.

    CAS  PubMed  Google Scholar 

  124. Ciesielski TH, Marsit CJ, Williams SM. Maternal psychiatric disease and epigenetic evidence suggest a common biology for poor fetal growth. BMC Pregnancy Childbirth. 2015;15:192.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Van-den-Bergh BR, Marcoen A. High antenatal maternal anxiety is related to ADHD symptoms, externalizing problems, and anxiety in 8- and 9-year-olds. Child Dev. 2004;75(4):1085–97.

    Article  PubMed  Google Scholar 

  126. Meltzer-Brody S. Treating perinatal depression: risks and stigma. Obstet Gynecol. 2014;124(4):653–4.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Food Drug Administration. Content and format of labeling for human prescription drug and biological products; requirements for pregnancy and lactation labeling. Final rule. Fed Regist. 2014;79(233):72063–103.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sura Alwan.

Ethics declarations

Funding

No sources of funding were used to assist in the preparation of this review.

Conflict of interest

Sura Alwan, Jan M. Friedman, and Christina Chambers have no conflicts of interest that are directly relevant to the content of this review.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Alwan, S., Friedman, J.M. & Chambers, C. Safety of Selective Serotonin Reuptake Inhibitors in Pregnancy: A Review of Current Evidence. CNS Drugs 30, 499–515 (2016). https://doi.org/10.1007/s40263-016-0338-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40263-016-0338-3

Keywords

Navigation