I. DEFINITION. Hydrops fetalis has classically been defined as the presence of extracellular fluid in at least two fetal body compartments. These fluid collections include skin edema (>5-mm thickness), pericardial effusion, pleural effusions, and ascites; all are easily recognized on prenatal ultrasound (Figs. 5.1, 5.2, 5.3 and 5.4). Frequent additional findings included polyhydramnios (deepest vertical pocket of amniotic fluid of >8 cm or amniotic fluid index >24 cm) and placentomegaly (>4-cm thickness in the second trimester or >6-cm thickness in the third trimester).

II. INCIDENCE. The reported incidence of nonimmune hydrops fetalis (NIHF) varies between 1 in 1,700 and 3,700 pregnancies.

III. ETIOLOGY (Table 5.1). The advent of the widespread use of Rh immune globulin for the prevention of RhD alloimmunization has resulted in a shift in favor of nonimmune etiologies of fetal hydrops. In 1970, McAfee et al. reported that 82% of cases of fetal hydrops were related to red cell alloimmunization, whereas in one more recent series, 95% of cases of hydrops were classified as nonimmune. The etiology of NIHF is diverse. A systematic review of literature reports involving >10 cases was undertaken by Bellini et al. between 1997 and 2007. Fifty-one papers met the strict criteria of the authors and involved 5,437 patients. The authors found that cardiovascular malformations represented the most common etiology followed by idiopathic causes,
chromosomal abnormalities, and hematologic etiologies. A subsequent review by the same authors between 2007 and 2013 revealed an additional 24 papers involving 1,338 patients. A decreasing trend in chromosomal abnormalities, thoracic problems, urinary tract malformations, and twin-twin transfusion was noted between the two consecutive time periods while etiologies of lymphatic
dysplasia and gastrointestinal causes appear to have increased. The overall contributions of the various etiologies from the two series are noted in Table 5.1.

A recent systematic review addressed the issue of evaluation for lysosomal storage disease in cases of NIHF. In the 676 cases that were specifically evaluated for these conditions, the incidence was 5.2% of all cases tested and 17.5% of cases initially thought to be idiopathic. The three most common disorders were mucopolysaccharidosis type VII, Gaucher disease, and GM1 gangliosidosis.

IV. PATHOPHYSIOLOGY. Because the etiology of NIHF is so diverse, few studies have addressed the pathophysiology of this condition. Lymphatic return of interstitial fluid to the vascular space is either inadequate or compromised. Anatomical obstruction is present in cases of Turner syndrome or lymphatic dysplasia, whereas a functional obstruction can occur due to elevated right atrial pressures noted in cases of severe fetal anemia (parvovirus) or tachyarrhythmias.
Certain cardiac malformations (Ebstein anomaly) or intrathoracic tumors (cystic adenomatoid malformation) are associated with increased venous pressure and a resultant increase in the production of interstitial fluid. Alternatively, vasculitis from infection (cytomegalovirus) can result in intravascular protein loss and enhanced interstitial fluid production.

In a series of 20 fetuses with NIHF, umbilical venous pressure was elevated at the time of cordocentesis in 65% of the cases. Correction of some of the lesions resulted in normalization of the venous pressure on subsequent measurement which was accompanied by resolution of the hydrops. These authors concluded that an elevated umbilical venous pressure signaled inadequate cardiac output as the cause of the NIHF. Normalization of the venous pressure after correction of the fetal condition invariably resulted in perinatal survival.

V. EVALUATION (Table 5.2). The initial diagnosis of NIHF is often made at the time of a routine ultrasound examination (Fig. 5.5). At other times, the patient complains of a decrease in fetal movement or a rapid increase in weight gain or abdominal girth—signs of significant polyhydramnios.

A comprehensive ultrasound examination should be undertaken. Special emphasis should be placed on evaluation of cardiac structures and rhythm. If necessary, a fetal echocardiogram should be undertaken. The peak systolic velocity of the middle cerebral artery (MCA) should be measured as an elevated value of >1.5 multiples of the median corrected for gestational age has been associated with fetal anemia in cases of NIHF.