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Reviewing the Literature: Teratogenicity Vivien Burt, PhD, MD The Women’s Life Center Resnick Neuropsychiatric Hospital at UCLA

Finnish Case-Control Study 600,000 + mother-child pairs Recorded first-time SSRI purchases Women who purchased SSRIs were: Less likely to be married More likely to: Smoke Have chronic diseases Use non-SSRI psychotropics Use nonpsychotropics Malm, H., Artama, M., Gissler, M., & Ritvanen, A. (2011). Selective serotonin reuptake inhibitors and risk for major congenital anomalies. Obstetrics & gynecology, 118(1), 111-120.

Study Results No significant increase in risk for overall major malformations Risk for ventricular septal defect (VSD) Fluoxetine X 2 SSRIs Risk for right ventricular outflow tract defects (RVOT) Risk for neural tract defects Paroxetine Citalopram X 5 X 2.5 Malm, H., Artama, M., Gissler, M., & Ritvanen, A. (2011). Selective serotonin reuptake inhibitors and risk for major congenital anomalies. Obstetrics & gynecology, 118(1), 111-120.

Risk of Fetal Alcohol Spectrum Disorders Underlying psychiatric conditions responsible for SSRI and alcohol use X 10 times in SSRI-exposed cases Confounding by indication Depression may predispose to adverse outcomes Malm, H., Artama, M., Gissler, M., & Ritvanen, A. (2011). Selective serotonin reuptake inhibitors and risk for major congenital anomalies. Obstetrics & gynecology, 118(1), 111-120.

Current study design Ideal study design SSRI-exposed Unexposed Placebo Vs Vs Depressed women Nondepressed women Depressed women Depressed women Unethical

A million members of a Medicaid population Study Results A million members of a Medicaid population Primary outcome Secondary outcome Major cardiac malformations (MCMs) Ventricular flow obstruction Ventricular septal defects Huybrechts, K. F., Palmsten, K., Avorn, J., Cohen, L. S., Holmes, L. B., Franklin, J. M., ... & Hernández-Díaz, S. (2014). Antidepressant use in pregnancy and the risk of cardiac defects. New England Journal of Medicine, 370(25), 2397-2407.

Population-Based Cohort Study Methodology Propensity matching Address the severity of maternal depression Using “proxies” Pain-related disorders Suggest severe depression Sleep disorders Smoking Chronic fatigue syndrome Exposure Pharmacy records of drugs supplied in the first trimester Recorded Cardiac malformations in maternal-infant records First 90 days postpartum Maternal depression diagnosis Huybrechts, K. F., Palmsten, K., Avorn, J., Cohen, L. S., Holmes, L. B., Franklin, J. M., ... & Hernández-Díaz, S. (2014). Antidepressant use in pregnancy and the risk of cardiac defects. New England Journal of Medicine, 370(25), 2397-2407.

Adjusted for depression and equivalent markers Conclusion Adjusted for depression and equivalent markers Unadjusted data Risk for overall cardiac defects with: No statistically significant risk of cardiac malformation with first trimester exposure to: Any antidepressant SSRIs SNRIs Bupropion SSRIs as a group Huybrechts, K. F., Palmsten, K., Avorn, J., Cohen, L. S., Holmes, L. B., Franklin, J. M., ... & Hernández-Díaz, S. (2014). Antidepressant use in pregnancy and the risk of cardiac defects. New England Journal of Medicine, 370(25), 2397-2407.

Conclusion No significant association between SSRIs as a group and overall cardiac defects No significant association between paroxetine and right ventricular outflow tract obstruction SSRIs No significant association between sertraline and ventricular septal defects Huybrechts, K. F., Palmsten, K., Avorn, J., Cohen, L. S., Holmes, L. B., Franklin, J. M., ... & Hernández-Díaz, S. (2014). Antidepressant use in pregnancy and the risk of cardiac defects. New England Journal of Medicine, 370(25), 2397-2407.

SSRI Antidepressants and Risk for Teratogenicity SSRIs are the most studied antidepressants in pregnancy. SSRI use is not associated with specific morphologic teratogenic risks. # 1 cardiac defects The background risk for major congenital malformations is 3%. 3% Most are self-correcting over the months of early infancy. VSD Alwan, S., Reefhuis, J., Rasmussen, S. A., Olney, R. S., & Friedman, J. M. (2007). Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. New England Journal of Medicine, 356(26), 2684-2692. Louik, C., Lin, A. E., Werler, M. M., Hernández-Díaz, S., & Mitchell, A. A. (2007). First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. New England Journal of Medicine, 356(26), 2675-2683. Greene, M. F. (2007). Teratogenicity of SSRIs—serious concern or much ado about little?. Wisner, K. L., Sit, D. K., Hanusa, B. H., Moses-Kolko, E. L., Bogen, D. L., Hunker, D. F., ... & Singer, L. T. (2009). Major depression and antidepressant treatment: impact on pregnancy and neonatal outcomes. Focus, 7(3), 374-384. Stewart, D. E. (2012). Clinical Practice: Depression During Pregnancy. Obstetric Anesthesia Digest, 32(4), 208-209.

Key Points Overall, SSRI use has not been associated with specific morphologic teratogenic risks. Maternal stress and depression during pregnancy are associated with serious maternal illness, poor health behaviors, and an increased risk for postpartum illness. Discontinuation of antidepressants in pregnancy is associated with a relapse of depression and incurs negative consequences for the mother, baby, and family.

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