Effects of Prenatal Exposure to Second-Generation Antipsychotics on Development and Behavior Among Preschool-Aged Children: Preliminary Results From the National Pregnancy Registry for Psychiatric Medications

Carol Swetlik, MD; Lee S. Cohen, MD; Lauren A. Kobylski, MPH; Ellen T. Sojka, BA; Parker C. Killenberg, BS; Marlene P. Freeman, MD; Adele C. Viguera, MD

J Clin Psychiatry 2024;85(1):23m14965

ABSTRACT

Objective: Data are lacking on the neurodevelopmental outcomes of children prenatally exposed to second-generation antipsychotics (SGAs). The objective of this study is to examine neurodevelopmental outcomes of children exposed in utero to SGAs compared to those unexposed in a cohort of mothers with psychiatric morbidity.

Methods: We conducted a cross-sectional assessment of preschool-aged children whose mothers were enrolled in the National Pregnancy Registry for Psychiatric Medications. Two validated, parent-report developmental and behavioral screening assessments, the Ages and Stages Questionnaire, Third Edition (ASQ-3) and the Preschool Child Behavior Checklist for Ages 1½–5 (CBCL/1½–5), respectively, were delivered electronically to eligible participants. Outcomes of children exposed in utero to SGAs were compared to those unexposed to SGAs in a cohort of mothers with a history of psychiatric illness. Exposure to other psychotropic medications during pregnancy was not an exclusion criterion for either group.

Results: From January 2, 2018, to February 2, 2021, 520 children were eligible, and 352 responses were collected (67.7%), including 178 children in the SGA-exposed group (mean age = 2.6 years) and 174 children in the unexposed comparison group (mean age = 2.1 years). No significant differences between groups were detected (OR = 1.24, 95% CI, 0.74–2.09) with respect to developmental outcomes assessed by the ASQ-3. Similarly, for behavioral outcomes, adjusted analysis showed no significant differences in odds of an abnormal “clinical” score on the CBCL/1½–5 composite scales.

Conclusions: The current study is the first to examine neurobehavioral outcomes of preschool-aged children exposed prenatally to SGAs. No significant differences in overall development or behavior were detected in the exposed versus unexposed group. These preliminary findings are an important step in delineating neurodevelopmental effects of prenatal SGA exposure.

J Clin Psychiatry 2024;85(1):23m14965

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References (32)

Bromley RL, Bickle Graz M, Bluett-Duncan M, et al. Expert consensus on neurodevelopmental outcomes in pregnancy pharmacovigilance studies. Front Pharmacol. 2023;14:1094698. PubMed CrossRef
Gentile S. Neurodevelopmental effects of prenatal exposure to psychotropic medications. Depress Anxiety. 2010;27(7):675–686. PubMed CrossRef
Viguera AC, Freeman MP, Kobylski LA, et al. Risk of major malformations following first-trimester exposure to olanzapine: preliminary data from the Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications. J Clin Psychopharmacol. 2023;43(2):106–112. PubMed CrossRef
Poels EMP, Schrijver L, Kamperman AM, et al. Long-term neurodevelopmental consequences of intrauterine exposure to lithium and antipsychotics: a systematic review and meta-analysis. Eur Child Adolesc Psychiatry. 2018;27(9):1209–1230. PubMed CrossRef
Peng M, Gao K, Ding Y, et al. Effects of prenatal exposure to atypical antipsychotics on postnatal development and growth of infants: a case-controlled, prospective study. Psychopharmacology (Berl). 2013;228(4):577–584. PubMed CrossRef
Toh S, Li Q, Cheetham TC, Prevalence and trends in the use of antipsychotic medications during pregnancy in the US, 2001–2007: a population-based study of 585,615 deliveries. Arch Womens Ment Health. 2013;16(2):149–157. PubMed CrossRef
Cohen LS, Viguera AC, McInerney KA, et al. Reproductive safety of second-generation antipsychotics: current data from the Massachusetts General Hospital National Pregnancy Registry for Atypical Antipsychotics. Am J Psychiatry. 2016;173(3):263–270. PubMed CrossRef
Huybrechts KF, Hernández-Díaz S, Patorno E, et al. Antipsychotic use in pregnancy and the risk for congenital malformations. JAMA Psychiatry. 2016;73(9):938–946. PubMed CrossRef
Viguera AC, Freeman MP, Góez-Mogollón L, et al. Reproductive safety of second-generation antipsychotics: updated data from the Massachusetts General Hospital National Pregnancy Registry for atypical antipsychotics. J Clin Psychiatry. 2021;82(4):20m13745. PubMed CrossRef
Kulkarni J, Worsley R, Gilbert H, et al. A prospective cohort study of antipsychotic medications in pregnancy: the first 147 pregnancies and 100 one year old babies. PLoS One. 2014;9(5):e94788. PubMed CrossRef
Shao P, Ou J, Peng M, et al. Effects of clozapine and other atypical antipsychotics on infants development who were exposed to as fetus: a post-hoc analysis. PLoS One. 2015;10(4):e0123373. PubMed CrossRef
Johnson KC, LaPrairie JL, Brennan PA, et al. Prenatal antipsychotic exposure and neuromotor performance during infancy. Arch Gen Psychiatry. 2012;69(8):787–794. PubMed CrossRef
Schrijver L, Robakis TK, Kamperman AM, et al. Neurodevelopment in school-aged children after intrauterine exposure to antipsychotics. Acta Psychiatr Scand. 2023;147(1):43–53. PubMed CrossRef
Hálfdánarson Ó, Cohen JM, Karlstad Ø, et al. Antipsychotic use in pregnancy and risk of attention/deficit-hyperactivity disorder and autism spectrum disorder: a Nordic cohort study. Evid Based Ment Health. 2022;25(2):54–62. PubMed CrossRef
Wang Z, Chan AYL, Coghill D, et al. Association between prenatal exposure to antipsychotics and attention-deficit/hyperactivity disorder, autism spectrum disorder, preterm birth, and small for gestational age. JAMA Intern Med. 2021;181(10):1332–1340. PubMed CrossRef
Straub L, Hernández-Díaz S, Bateman BT, et al. Association of antipsychotic drug exposure in pregnancy with risk of neurodevelopmental disorders: a national birth cohort study. JAMA Intern Med. 2022;182(5):522–533. PubMed CrossRef
Squires J, Twombly E, Bricker D, et al. Psychometric Studies of ASQ. In: ASQ‐3 User’s Guide. 3rd ed. Brookes Publishing; 2009.
Achenbach TM, Ruffle TM. The Child Behavior Checklist and related forms for assessing behavioral/emotional problems and competencies. Pediatr Rev. 2000;21(8):265–271. PubMed
Cohen LS, Viguera AC, McInerney KA, et al. Establishment of the National Pregnancy Registry for atypical antipsychotics. J Clin Psychiatry. 2015;76(7):986–989. PubMed CrossRef
Harris PA, Taylor R, Minor BL, et al; REDCap Consortium. The REDCap consortium: building an international community of software platform partners. J Biomed Inform. 2019;95:103208. PubMed CrossRef
Harris PA, Taylor R, Thielke R, et al. Research electronic data capture (REDCap)–a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377–381. PubMed CrossRef
SAS Institute Inc. Basic Analysis 16. SAS Institute Inc.; 2020–2021.
Havron N, Ramus F, Heude B, et al. The effect of older siblings on language development as a function of age difference and sex. Psychol Sci. 2019;30(9):1333–1343. CrossRef
Hoff-Ginsberg E. The relation of birth order and socioeconomic status to children’s language experience and language development. Appl Psycholinguist. 1998;19(4):603–629. CrossRef
Meador KJ, Baker GA, Browning N, et al; NEAD Study Group. Effects of fetal antiepileptic drug exposure: outcomes at age 4.5 years. Neurology. 2012;78(16):1207–1214. PubMed CrossRef
Meador KJ, Baker GA, Browning N, et al; NEAD Study Group. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurol. 2013;12(3):244–252. PubMed CrossRef
Misri S, Reebye P, Kendrick K, et al. Internalizing behaviors in 4-year-old children exposed in utero to psychotropic medications. Am J Psychiatry. 2006;163(6):1026–1032. PubMed CrossRef
Suri R, Lin AS, Cohen LS, et al. Acute and long-term behavioral outcome of infants and children exposed in utero to either maternal depression or antidepressants: a review of the literature. J Clin Psychiatry. 2014;75(10):e1142–e1152. PubMed CrossRef
Brody BA, Kinney HC, Kloman AS, et al. Sequence of central nervous system myelination in human infancy, I: an autopsy study of myelination. J Neuropathol Exp Neurol. 1987;46(3):283–301. PubMed CrossRef
Cohen LS, Church TR, Freeman MP, et al. Reproductive safety of lurasidone and quetiapine: update from the National Pregnancy Registry for psychiatric medications. J Womens Health (Larchmt). 2023;32(4):452–462. PubMed CrossRef
Cohen LS, Góez-Mogollón L, Sosinsky AZ, et al. Risk of major malformations in infants following first-trimester exposure to quetiapine. Am J Psychiatry. 2018;175(12):1225–1231. PubMed CrossRef
Freeman MP, Viguera AC, Góez-Mogollón L, et al. Reproductive safety of aripiprazole: data from the Massachusetts General Hospital National Pregnancy Registry for atypical antipsychotics. Arch Womens Ment Health. 2021;24(4):659–667. PubMed CrossRef