Neurodevelopment of Children Exposed in Utero to Antidepressant Drugs
Irena Nulman, M.D., Joanne Rovet, Ph.D., Donna E. Stewart, M.D., Jacob Wolpin, Ph.D., H. Allan Gardner, M.D., Jochen G.W. Theis, M.D., Nathalie Kulin, B.Sc., and Gideon Koren, M.D.
Background Many women of reproductive age have depression, necessitatingtherapy with either a tricyclic antidepressant drug or a drug,such as fluoxetine, that inhibits the reuptake of serotonin.Whether these drugs affect fetal neurodevelopment is not known.
Methods We studied the children of 80 mothers who had receiveda tricyclic antidepressant drug during pregnancy, 55 childrenwhose mothers had received fluoxetine during pregnancy, and84 children whose mothers had not been exposed during pregnancyto any agent known to affect the fetus adversely. The children'sglobal IQ and language development were assessed between 16and 86 months of postnatal age by age-appropriate Bayley Scalesof Infant Development or the McCarthy Scales of Children's Abilities(for IQ) and the Reynell Developmental Language Scales.
Results The mean (±SD) global IQ scores were 118±17in the children of mothers who received a tricyclic antidepressantdrug, 117±17 in those whose mothers received fluoxetine,and 115±14 in those in the control group. The languagescores were similar in all three groups. The results were similarin children exposed to a tricyclic antidepressant drug or fluoxetineduring the first trimester and those exposed throughout pregnancy.There were also no significant differences in temperament, mood,arousability, activity level, distractibility, or behavior problemsin the three groups of children.
Conclusions In utero exposure to either tricyclic antidepressantdrugs or fluoxetine does not affect global IQ, language development,or behavioral development in preschool children.
Source Information
From the Motherisk Program (I.N., J.W., J.G.W.T., N.K., G.K.), the Division of Clinical Pharmacology and Toxicology (I.N., J.G.W.T., N.K., G.K.), the Department of Pediatrics (I.N., J.R., J.G.W.T., G.K.), Research Institute (J.R., G.K.), and the Department of Psychology (J.R.), Hospital for Sick Children and University of Toronto, Toronto; Women's Health Program, Toronto Hospital and University of Toronto, Toronto (D.E.S.); and Oshawa General Hospital, Oshawa, Ont., Canada (H.A.G.).
Address reprint requests to Dr. Koren at the Division of Clinical Pharmacology, the Hospital for Sick Children, 555 University Ave., Toronto, ON M5G 1X8, Canada.
Suri, R., Altshuler, L., Hellemann, G., Burt, V. K., Aquino, A., Mintz, J.
(2007). Effects of Antenatal Depression and Antidepressant Treatment on Gestational Age at Birth and Risk of Preterm Birth. Am. J. Psychiatry
164: 1206-1213
[Abstract][Full Text]
Louik, C., Lin, A. E., Werler, M. M., Hernandez-Diaz, S., Mitchell, A. A.
(2007). First-Trimester Use of Selective Serotonin-Reuptake Inhibitors and the Risk of Birth Defects. NEJM
356: 2675-2683
[Abstract][Full Text]
Looper, K. J.
(2007). Potential Medical and Surgical Complications of Serotonergic Antidepressant Medications. Psychosomatics
48: 1-9
[Abstract][Full Text]
Oberlander, T. F., Reebye, P., Misri, S., Papsdorf, M., Kim, J., Grunau, R. E.
(2007). Externalizing and Attentional Behaviors in Children of Depressed Mothers Treated With a Selective Serotonin Reuptake Inhibitor Antidepressant During Pregnancy. Arch Pediatr Adolesc Med
161: 22-29
[Abstract][Full Text]
Misri, S., Reebye, P., Kendrick, K., Carter, D., Ryan, D., Grunau, R. E., Oberlander, T. F.
(2006). Internalizing Behaviors in 4-Year-Old Children Exposed in Utero to Psychotropic Medications. Am. J. Psychiatry
163: 1026-1032
[Abstract][Full Text]
Levinson-Castiel, R., Merlob, P., Linder, N., Sirota, L., Klinger, G.
(2006). Neonatal Abstinence Syndrome After In Utero Exposure to Selective Serotonin Reuptake Inhibitors in Term Infants. Arch Pediatr Adolesc Med
160: 173-176
[Abstract][Full Text]
Moses-Kolko, E. L., Bogen, D., Perel, J., Wisner, K. L., Bregar, A., Uhl, K., Levin, B.
(2005). Neonatal Signs After In Utero Exposure to Selective Serotonin Reuptake Inhibitors--Reply. JAMA
294: 2300-2301
[Full Text]
Niebyl, J. R.
(2005). Antidepressant Drug Use in Pregnancy. Reproductive Sciences
12: 297-297
Hemels, M. E., Einarson, A., Koren, G., Lanctot, K. L, Einarson, T. R
(2005). Antidepressant Use During Pregnancy and the Rates of Spontaneous Abortions: A Meta-Analysis. The Annals of Pharmacotherapy
39: 803-809
[Abstract][Full Text]
Oberlander, T. F., Grunau, R. E., Fitzgerald, C., Papsdorf, M., Rurak, D., Riggs, W.
(2005). Pain Reactivity in 2-Month-Old Infants After Prenatal and Postnatal Selective Serotonin Reuptake Inhibitor Medication Exposure. Pediatrics
115: 411-425
[Abstract][Full Text]
Ansorge, M. S., Zhou, M., Lira, A., Hen, R., Gingrich, J. A.
(2004). Early-Life Blockade of the 5-HT Transporter Alters Emotional Behavior in Adult Mice. Science
306: 879-881
[Abstract][Full Text]
Weissman, A. M., Levy, B. T., Hartz, A. J., Bentler, S., Donohue, M., Ellingrod, V. L., Wisner, K. L.
(2004). Pooled Analysis of Antidepressant Levels in Lactating Mothers, Breast Milk, and Nursing Infants. Am. J. Psychiatry
161: 1066-1078
[Abstract][Full Text]
Koren, G.
(2004). Discontinuation Syndrome Following Late Pregnancy Exposure to Antidepressants. Arch Pediatr Adolesc Med
158: 307-308
[Full Text]
Kallen, B.
(2004). Neonate Characteristics After Maternal Use of Antidepressants in Late Pregnancy. Arch Pediatr Adolesc Med
158: 312-316
[Abstract][Full Text]
Costa, L. G., Steardo, L., Cuomo, V.
(2004). Structural Effects and Neurofunctional Sequelae of Developmental Exposure to Psychotherapeutic Drugs: Experimental and Clinical Aspects. Pharmacol. Rev.
56: 103-147
[Abstract][Full Text]
Kim, J., Riggs, K. W., Rurak, D. W.
(2004). STEREOSELECTIVE PHARMACOKINETICS OF FLUOXETINE AND NORFLUOXETINE ENANTIOMERS IN PREGNANT SHEEP. Drug Metab. Dispos.
32: 212-221
[Abstract][Full Text]
Zeskind, P. S., Stephens, L. E.
(2004). Maternal Selective Serotonin Reuptake Inhibitor Use During Pregnancy and Newborn Neurobehavior. Pediatrics
113: 368-375
[Abstract][Full Text]
Kohen, D.
(2004). Psychotropic medication in pregnancy. Adv. Psychiatr. Treat.
10: 59-66
[Abstract][Full Text]
Laine, K., Heikkinen, T., Ekblad, U., Kero, P.
(2003). 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
60: 720-726
[Abstract][Full Text]
Pryse-Phillips, W., Yuen, D. E., Pham, B.
(2003). Perinatal Outcome Following Third-Trimester Exposure to Paroxetine: An Alternative Interpretation. Arch Pediatr Adolesc Med
157: 601-601
[Full Text]
Simon, G. E., Cunningham, M. L., Davis, R. L.
(2002). Outcomes of Prenatal Antidepressant Exposure. Am. J. Psychiatry
159: 2055-2061
[Abstract][Full Text]
Nulman, I., Rovet, J., Stewart, D. E., Wolpin, J., Pace-Asciak, P., Shuhaiber, S., Koren, G.
(2002). Child Development Following Exposure to Tricyclic Antidepressants or Fluoxetine Throughout Fetal Life: A Prospective, Controlled Study. Am. J. Psychiatry
159: 1889-1895
[Abstract][Full Text]
Hendrick, V., Altshuler, L.
(2002). Management of Major Depression During Pregnancy. Am. J. Psychiatry
159: 1667-1673
[Full Text]
Epperson, N., Czarkowski, K. A., Ward-O'Brien, D., Weiss, E., Gueorguieva, R., Jatlow, P., Anderson, G. M.
(2001). Maternal Sertraline Treatment and Serotonin Transport in Breast-Feeding Mother-Infant Pairs. Am. J. Psychiatry
158: 1631-1637
[Abstract][Full Text]
Szigethy, E. M., Ruiz, P.
(2001). Depression Among Pregnant Adolescents: An Integrated Treatment Approach. Am. J. Psychiatry
158: 22-27
[Full Text]
Wisner, K. L., Zarin, D. A., Holmboe, E. S., Appelbaum, P. S., Gelenberg, A. J., Leonard, H. L., Frank, E.
(2000). Risk-Benefit Decision Making for Treatment of Depression During Pregnancy. Am. J. Psychiatry
157: 1933-1940
[Abstract][Full Text]
Gijsman, H.
(2000). Review: fluoxetine use during the first trimester of pregnancy is not associated with an increased risk of major malformations. Evid. Based Ment. Health
3: 122-122
[Full Text]
Ito, S.
(2000). Drug Therapy for Breast-Feeding Women. NEJM
343: 118-126
[Full Text]
Committee on Drugs,
(2000). Use of Psychoactive Medication During Pregnancy and Possible Effects on the Fetus and Newborn. Pediatrics
105: 880-887
[Abstract][Full Text]
Wisner, K. L., Gelenberg, A. J., Leonard, H., Zarin, D., Frank, E.
(1999). Pharmacologic Treatment of Depression During Pregnancy. JAMA
282: 1264-1269
[Abstract][Full Text]
Spigset, O., Mårtensson, B.
(1999). Fortnightly review: Drug treatment of depression. BMJ
318: 1188-1191
[Full Text]
Wintz, C. J. B.
(1999). Difficult Decisions: Women of Childbearing Age, Mental Illness, and Psychopharmacologic Therapy. J Am Psychiatr Nurses Assoc
5: 5-14
[Abstract]
Cabrera-Vera, T. M., Battaglia, G.
(1998). Prenatal Exposure to Fluoxetine (Prozac) Produces Site-Specific and Age-Dependent Alterations in Brain Serotonin Transporters in Rat Progeny: Evidence from Autoradiographic Studies. J. Pharmacol. Exp. Ther.
286: 1474-1481
[Abstract][Full Text]
Grush, L. R., Witlin, A. G., Koren, G.
(1998). Risk of Fetal Anomalies With Exposure to Selective Serotonin Reuptake Inhibitors. JAMA
279: 1873-1873
[Full Text]
Bengel, D., Murphy, D. L., Andrews, A. M., Wichems, C. H., Feltner, D., Heils, A., Mössner, R., Westphal, H., Lesch, K.-P.
(1998). Altered Brain Serotonin Homeostasis and Locomotor Insensitivity to 3,4-Methylenedioxymethamphetamine ("Ecstasy") in Serotonin Transporter-Deficient Mice. Mol. Pharmacol.
53: 649-655
[Abstract][Full Text]
Kulin, N. A., Pastuszak, A., Sage, S. R., Schick-Boschetto, B., Spivey, G., Feldkamp, M., Ormond, K., Matsui, D., Stein-Schechman, A. K., Cook, L., Brochu, J., Rieder, M., Koren, G.
(1998). Pregnancy Outcome Following Maternal Use of the New Selective Serotonin Reuptake Inhibitors: A Prospective Controlled Multicenter Study. JAMA
279: 609-610
[Abstract][Full Text]
Goodwin, G. M
(1998). Antidepressant exposure before birth was not associated with language, physical, or behavioural development. Evid. Based Ment. Health
1: 30-30
[Full Text]
Mhanna, M. J., Bennet II, J. B., Izatt, S. D.
(1997). Potential Fluoxetine Chloride (Prozac) Toxicity in a Newborn. Pediatrics
100: 158-158
[Full Text]
(1997). Antidepressants in Pregnancy: Evidence for Their Safety. JWatch Women's Health
1997: 8-8
[Full Text]
(1997). Neurodevelopment after in Utero Exposure to Antidepressants. JWatch Psychiatry
1997: 19-19
[Full Text]
(1997). NEURODEVELOPMENT AFTER IN UTERO EXPOSURE TO ANTIDEPRESSANTS. JWatch General
1997: 4-4
[Full Text]