Introduction: Nonimmune hydrops fetalis (NIHF) is the most frequent etiology of hydrops fetalis (HF), accounting for around 95% of cases. It associates high perinatal mortality and morbidity rates. The aim of the study was, first, to investigate etiology, prenatal management, and perinatal outcome in a large single-center series of HF; second, to identify prenatal prognostic factors with impact on perinatal outcome. Materials and Methods: Observational retrospective study of 80 HF diagnosed or referred to a single tertiary center between 2012 and 2021. Clinical characteristics, etiology, prenatal management, and perinatal outcome were recorded. Adverse perinatal outcome was defined as intrauterine fetal death (IUFD), early neonatal death (first 7 days of life) and late neonatal death (between 7 and 28 days). Results: Seventy-six of the 80 cases (95%) were NIHF, main etiology being genetic disorders (28/76; 36.8%). A total of 26 women (32.5%) opted for termination of pregnancy, all of them in the NIHF group. IUFD occurred in 24 of 54 patients (44.4%) who decided to continue the pregnancy. Intrauterine treatment was performed in 29 cases (53.7%). There were 30 newborns (55.6%). Adverse perinatal outcome rate was 53.7% (29/54), significantly higher in those diagnosed <20 weeks of gestation (82.4% < 20 weeks vs. 40.5% ≥ 20 weeks; p = 0.004). Survival rate was higher when fetal therapy was performed compared to the expectantly managed group (58.6% vs. 32%; p = 0.05). Intrauterine blood transfusion and thoraco-amniotic shunt were the procedures that achieved the highest survival rates (88.9% and 100%, respectively, p = 0.003). Conclusion: NIHF represented 95% of HF with genetic disorders as the main etiology. Most of them were diagnosed before 20 weeks of gestation, with worse prognosis than cases detected later in gestation. Rates of TOP, IUFD, and early neonatal death were higher in NIHF. Intrauterine therapy, when indicated, improved the perinatal outcome.

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