Investigation of non-immune hydrops fetalis in singleton pregnancy: a practical guide for the perinatal pathologist

Hydrops fetalis is defined by abnormal fluid accumulation in at least two fetal compartments, resulting from a range of underlying pathological processes, and with a high mortality at the severe end of the spectrum. Identifying the specific cause is crucial for managing both current and future pregnancies. Despite comprehensive antenatal investigations, including obstetric imaging, serology and genetic testing, many cases of non-immune hydrops fetalis (NIHF) remain unexplained at delivery. Some diagnostic features may not be apparent on ultrasound, with perinatal autopsy providing additional valuable information, particularly when structural fetal anomalies are absent. In this review, a structured, phenotype-based approach to autopsy has been developed for cases of indeterminate aetiology, with categories including NIHF with bilateral cystic hygromas, the pale hydropic baby, NIHF associated with cardiovascular system abnormalities, NIHF with no obvious structural abnormality, and NIHF with prominent ascites. Both genetic and non-genetic causes are considered across all groups, with a particular focus on recently described entities and newly identified underlying aetiologies. Placental examination is also vital and may offer key diagnostic clues; though certain pitfalls must be avoided. Comprehensive evaluation by specialist perinatal pathologists can provide crucial diagnostic information in investigation of NIHF.