Over 400,000 pregnant women and their fetuses experience Major Depressive Disorder (MDD) every year in the United States. It is the third leading cause of disease burden in developed countries and is associated with shorter gestation, child sleep problems (shortened sleep cycles, frequent awakening), and child psychopathology. Remission of maternal depression in the infant and child years is associated with fewer problems in adolescence, highlighting the need for effective treatment. Serotonin/Norepinephrine Reuptake Inhibitors (SRIs), antidepressant medications remain the most commonly chosen treatment for MDD during pregnancy;8% of all pregnant women are prescribed SRI medication. SRIs alter neurotransmitter signaling, particularly for serotonin, which plays a role in motor control, sleep and circadian rhythms, and emotion. Newborns whose mothers took SRIs in pregnancy are more likely to experience acute adverse events in the first month after delivery. Although these symptoms appear to be transient, recent evidence suggests there are continued problems with sensory-motor development. There is a lack of long-term data on outcomes following prenatal SRI exposure. Despite strong preclinical evidence of both positive and negative latent effects on motor, sleep, and behavioral outcomes from early SRI exposure, to our knowledge, there is no long-term data on the effects of prenatal SRI exposure on these key areas of development. Lack of information on the risks of prenatal SRI exposure versus exposure to untreated MDD, with respect to later development, greatly hinders informed risk-benefit decision making for MDD treatment during pregnancy. Obtaining this information is also critical to advancing the field's understanding of the mechanisms of developmental psychopathology in children exposed to maternal MDD and to MDD plus SRIs. The objective of this application is twofold: (1) to determine how prenatal SRI exposure and associated changes in fetal serotonin affect outcomes in preschool children;and (2) to identify potential biomarkers associated with these effects. The central hypothesis is that children who were exposed to prenatal maternal MDD without SRI treatment will have a different developmental trajectory and a different profile of neurobehavioral outcomes through age five, compared to children who were exposed to prenatal MDD with SRI treatment. The study will follow at least 193 of the infants currently enrolled in the prenatal prospective, longitudinal stuy through age 5 to examine the long-term effects from prenatal MDD+SRI or MDD-only exposure on motor development, sleep-state organization, circadian rhythms, and psychiatric outcomes. The critical serotonin-related processes of sleep and circadian rhythms have not been examined in children at risk for developmental psychopathology due to MDD and SRI exposure. The expected outcomes will have a positive impact because they will lead to informed risk-benefit decision-making for pregnant women with MDD and provide new preventive and therapeutic targets for psychopathology in children, resulting in a decrease in the prevalence of childhood and later psychiatric conditions. This will further translate into enormous reductions in overall costs due to the social and functional disability that may result from such conditions.

Public Health Relevance

Data from the parent study of this renewal agrees with published data showing that prenatal SRI exposure is associated with acute adverse effects in newborns and extends those findings into both fetal and toddler development. Preclinical evidence strongly suggests both positive and negative latent effects on motor, sleep, and behavioral outcomes from early SRI exposure, however, to our knowledge, there is no long-term data on the effects of prenatal SRI exposure on these key serotonin-related developmental processes in humans. This renewal study will continue to study the effects of prenatal antidepressant exposure and untreated maternal depression on sleep, neurobiological rhythms, and socio-emotional development through age 5 with the goals of identifying guidelines for the treatment of depression during pregnancy and biomarkers for developmental psychopathology.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Study Section
Child Psychopathology and Developmental Disabilities Study Section (CPDD)
Program Officer
Zehr, Julia L
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Women and Infants Hospital-Rhode Island
United States
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Salisbury, Amy L; O'Grady, Kevin E; Battle, Cynthia L et al. (2016) The Roles of Maternal Depression, Serotonin Reuptake Inhibitor Treatment, and Concomitant Benzodiazepine Use on Infant Neurobehavioral Functioning Over the First Postnatal Month. Am J Psychiatry 173:147-57
Partridge, Marie-Claire A E; Salisbury, Amy L; LaGasse, Linda L (2016) Fine Motor Differences and Prenatal Serotonin Reuptake Inhibitors Exposure. J Pediatr 175:144-149.e1
Battle, Cynthia L; Salisbury, Amy L; Schofield, Casey A et al. (2013) Perinatal antidepressant use: understanding women's preferences and concerns. J Psychiatr Pract 19:443-53
Ponder, Kathryn L; Salisbury, Amy; McGonnigal, Bethany et al. (2011) Maternal depression and anxiety are associated with altered gene expression in the human placenta without modification by antidepressant use: implications for fetal programming. Dev Psychobiol 53:711-23
McFarland, Julie; Salisbury, Amy L; Battle, Cynthia L et al. (2011) Major depressive disorder during pregnancy and emotional attachment to the fetus. Arch Womens Ment Health 14:425-34
Salisbury, Amy L; Wisner, Katherine L; Pearlstein, Teri et al. (2011) Newborn neurobehavioral patterns are differentially related to prenatal maternal major depressive disorder and serotonin reuptake inhibitor treatment. Depress Anxiety 28:1008-19
Lester, Barry M; Miller, Robin J; Hawes, Katheleen et al. (2011) Infant neurobehavioral development. Semin Perinatol 35:8-19
Battle, Cynthia L; Salisbury, Amy L (2010) Treatment of antenatal depression. J Midwifery Womens Health 55:479; author reply 479-80
Stroud, Laura R; Paster, Rachel L; Papandonatos, George D et al. (2009) Maternal smoking during pregnancy and newborn neurobehavior: effects at 10 to 27 days. J Pediatr 154:10-6
Pearlstein, Teri; Howard, Margaret; Salisbury, Amy et al. (2009) Postpartum depression. Am J Obstet Gynecol 200:357-64

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