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To evaluate how the diagnosis of major fetal anomalies and resulting pregnancy outcomes affected the risk of postpartum depression, as assessed by the Edinburgh Postnatal Depression Scale (EPDS).Singleton pregnancies with prenatal diagnosis of major fetal anomalies were ascertained from prospectively-maintained databases that included perinatal outcomes and subsequent EPDS responses from 1/2010 to 5/2018. EPDS scores ≥13 were considered positive and prompted referral for mental health follow-up, which was verified by electronic chart review. Statistical analyses were performed using odds ratios and χ2 with P<.05 considered significant. IRB approval was obtained.912 women had a prenatal diagnosis of an anomalous fetus and postpartum EPDS screening, and 82 (9%) screened positive. Positive screening was more common with multiple fetal anomalies (15.3% vs 8.0%, P=.004) or aneuploidy (17.1% vs 8.6%, P=.02). Pregnancies complicated by fetal death (N=79, 8.6%), neonatal death (N=52, 5.7%), and termination for anomaly (N=69, 7.6%) were significantly more likely to screen positive than those with neonatal survival to discharge (all OR >2, P<.001). 34 (40%) screen-positive women attended their follow-up appointment with a mental health provider, and 18 (53%) were diagnosed with a depressive disorder.Women with prenatal diagnosis of major fetal anomalies and perinatal loss had a two-fold increased likelihood for positive depression screening using EPDS. More than half of screen positive women who seek mental health follow-up were diagnosed with a depressive disorder. Effective screening with intervention is warranted in this vulnerable population.