To investigate the genetic causes and pregnancy outcome of nonimmune hydrops fetalis (NIHF).

We retrospectively recruited 116 cases of hydrops fetalis diagnosed by ultrasound in our hospital from January 2014 to July 2020. All the cases were undergone prenatal diagnosis by at least one of the following tests: 1) karyotyping, 2) chromosomal microarray analysis (CMA) or 3) whole exome sequencing (WES). The medical records of pregnancy outcome was retrieved and analyzed.

Among 103 singleton pregnancies with NIHF, 45 cases (43.69%, 45/103) were reported to have clinically significant results including 30 cases with numerical disorders, 9 cases with pathogenic or likely pathogenic copy number variants (CNVs) and 6 cases with point mutations. Among 13 twin and multiple pregnancies with NIHF, 5 cases were diagnosed as aneuploidies. For the pregnancy outcome, 81singleton pregnancies were ended with termination of pregnancy. 19 singleton pregnancies chose to continue the pregnancy, except 8 cases died in utero. The remaining 11 cases were all live births, among which 6 cases were born premature and 5 cases were full-term. 4 cases (3 cases were premature, 1 case was in term deliveries) received post-birth surgical intervention, of which 3 cases were successful and 1 case died after operation. Among 6 cases without surgical intervention, 1 case had growth retardation and the other 5 cases manifested normal growth and development.

Numerical disorders, CNV disorders and point mutations are the main genetic causes of NIHF. The detection rate of CMA in NIHF is higher than chromosome karyotype analysis, so CMA should be used as a first-line method for genetic investigation of NIHF. WES is a valuable tool for the diagnosis of NIHF due to the ability to detect rare single-gene disorders.