Photo Credit: Elena Pimukova

The following is a summary of “Genetic diseases underlying a spectrum of fetal effusions,” published in the May 2025 issue of American Journal of Obstetrics & Gynecology by Gulrajani et al. 

Non-immune hydrops fetalis (NIHF) was recognized as a heterogeneous condition often caused by genetic diseases, while less was known about the prevalence and features of genetic conditions underlying isolated fetal effusions, creating uncertainty in clinical management.  

Researchers conducted a retrospective study to specify the diagnostic yield of exome sequencing (ES) by type of fetal effusion and presence of structural abnormalities and to identify distinct presenting features of underlying genetic diseases.  

They enrolled pregnancies with NIHF and other fetal effusions from across the United States. Inclusion required non-diagnostic chromosomal microarray and/or karyotype results and at least 1 fetal effusion, including NT ≥3.5 mm, cystic hygroma, pleural effusion, pericardial effusion, ascites, and/or skin edema and ES was performed in a CLIA-approved institutional laboratory, and results were returned to participants and providers. Fetal phenotypic data were collected from imaging (ultrasound, MRI, echocardiogram), pathology, and lab reports to aid variant interpretation. Cases with pathogenic or likely pathogenic variants were classified as diagnostic or positive. The primary outcome was the diagnostic yield of ES by effusion type, with or without structural abnormalities. Secondary outcomes included the types of fetal effusions by genetic disease category.  

The results showed that 118 pregnancies with NIHF and other fetal effusions underwent ES, with 23% (27/118) yielding positive (diagnostic) findings. Among pregnancies with NIHF, diagnostic yields were 21% (9/42) with concurrent structural abnormalities and 40% (6/15) without (P=0.15). For isolated pleural effusions, diagnostic yields were 23% (6/26) with and 17% (1/6) without structural abnormalities (P=0.61). Pregnancies with increased NT or cystic hygroma showed higher diagnostic yield when structural abnormalities were present (42%, 5/12) compared to when absent (0%, 0/17) (P<0.01). Genetic conditions such as RASopathies and musculoskeletal disorders were linked to all types of effusions, while disorders associated with postnatal neurodevelopmental delays were seen with all effusions except NIHF.  

Investigators concluded that ES demonstrated high diagnostic utility for various fetal effusions, except isolated increased nuchal translucency or cystic hygroma, revealing diverse in utero presentations of genetic diseases. 

Source: ajog.org/article/S0002-9378(25)00304-7/abstract