Transplacental infections such as cytomegalovirus, Zika virus, toxoplasmosis, and rubella, especially if acquired in the perinatal period, are well-known causes of congenital anomalies. However, their phenotypic overlap with certain genetic syndromes can pose significant diagnostic challenges during fetal autopsy and prenatal counseling. With an objective to review and highlight the clinical and pathological similarities between congenital infections and genetic syndromes, and emphasizing diagnostic pitfalls in fetal autopsy and the importance of integrated approaches, a comprehensive literature review was performed of articles that discussed congenital infections, fetal autopsy findings, and differential diagnosis with genetic syndromes. We found that several transplacental infections mimic the phenotype of genetic syndromes through features such as microcephaly, intracranial calcifications, cardiac anomalies, and hydrops fetalis. Placental pathology, maternal serology, and targeted molecular testing are essential to delineate the cause. An awareness of overlapping features between congenital infections and genetic syndromes is crucial to avoid misdiagnosis. A multidisciplinary approach combining clinical, histopathological, and molecular insights is necessary to reach an accurate diagnosis, guide recurrence risk counseling, and inform management in future pregnancies.
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