Nonimmune hydrops fetalis (NIHF) is a serious fetal condition in which abnormal fluid accumulates in at least two different fetal compartments, and in which circulating antibodies against red cell antigens are absent in the mother. Hydrops fetalis is associated with a pathologic increase in interstitial and total fetal body water, usually appearing in fetal soft tissues and serous cavities. It may be either immunologic or nonimmunologic, depending on the presence or absence of maternal antibodies against fetal red cell antigens. While it was previously thought that the majority of cases of hydrops fetalis were secondary to maternal–fetal blood group incompatibilities, it is now estimated that over 90% of cases are nonimmunologic (Santolaya et al., 1992).

NIHF is a heterogeneous disorder, caused by a large number of underlying pathologic processes. The majority of cases appear to be idiopathic, although some investigators have stated that with thorough investigation an underlying cause can be identified in as many as 84% of cases (Holzgreve et al., 1984;Norton, 1994; Wilkins, 1999). When prenatally diagnosed cases of NIHF and cases of intrauterine fetal death are included, the success rate in discovering an underling cause for NIHF may be as low as 40% (Norton, 1994). The literature on NIHF consists almost entirely of case reports or small case series, together with reviews of these case series. A review of these reports suggests that the most common recognizable cause of NIHF is cardiovascular pathology (accounting for 17% to 35% of cases), followed by chromosomal abnormalities (accounting for 14% to 16% of cases), and hematologic disorders (accounting for 4% to 12% of cases) (Norton, 1994). The remainder of causes of NIHF are rare conditions, many of which are difficult to diagnose prenatally. The range of possible underlying causes for NIHF is summarized in Table 128-1, listed in order of expected incidence.

Other than idiopathic cases, cardiac malformations account for the majority of cases of NIHF (Knilans, 1995). There is no particular form of cardiac abnormality that always results in hydrops, although the more severe the malformation the greater the likelihood of hydrops developing. The common mechanism of NIHF in cases of cardiac malformation or arrhythmia is the development of congestive heart failure, with increasing generalized fluid overload. The prognosis for fetuses with structural cardiac malformations and hydrops is extremely poor, with a mortality rate approaching 100% in some series (Crawford et al., 1988).

Chromosomal causes of NIHF are common; the most frequent is Turner syndrome, with its typical sonographic finding of cystic hygroma. A wide range of other genetic syndromes is also associated with NIHF, such as arthrogryposis, tuberous sclerosis, Pena–Shokeir syndrome, and Noonan syndrome (Jauniaux et al., 1990).

The underlying mechanism for the association of NIHF with hematologic abnormalities is most likely severe fetal anemia leading to high-output cardiac failure (Arcasoy and Gallagher, 1995). Fetal anemia can result from failure to manufacture normal hemoglobin (such as α-thalassemia), fetal hemorrhage (such as intracranial bleeding), hemolysis, (such as glucose-6-phosphate dehydrogenase deficiency), or failure to form erythrocytes because of marrow destruction (such as parvovirus B19 infection).

Congenital cystic adenomatoid malformation (CCAM) is the most common thoracic lesion associated with hydrops. Other thoracic causes of hydrops include bronchopulmonary sequestration, thoracic masses, and diaphragmatic hernia. The underlying mechanism for the association of hydrops with these thoracic conditions is most likely obstruction to venous return because of increased intrathoracic pressure.

Congenital infection with a wide variety of organisms is a well-recognized cause of hydrops (Barron and Pass, 1995). Causative organisms include syphilis, cytomegalovirus, parvovirus B19, toxoplasmosis, herpes simplex, rubella, and coxsackievirus. Possible mechanisms for the association of congenital infection with hydrops include fetal anemia from suppression of erythrocyte production, fetal myocardIt is, or fetal hepatIt is. In some cases of congenital infection, such as syphilis, the presence of hydrops is associated with a very poor prognosis. In other cases, hydrops from congenital infection may be self-limited and may resolve spontaneously. Fetal parvovirus B19 infection results in an aplastic crisis, which leads to profound anemia, and hydrops, the outcome of which may be either fetal death or spontaneous resolution without long-term morbidity (Morey et al., 1991; Levy et al., 1997).

A wide variety of structural fetal malformations has been associated with the development of NIHF. These include skeletal dysplasias, which may be associated with thoracic compression, impairment of venous return, and subsequent hydrops. The association of other structural malformations with NIHF, such as gastrointestinal, genitourinary, and neurologic abnormalities, may represent chance occurrences, as it is difficult to elucidate a plausible underlying mechanism for hydrops in many cases.

Some fetal conditions, such as Finnish nephrosis and hepatic fibrosis, result in profound hypoproteinemia or cirrhosis, which may subsequently lead to hydrops. The mechanism for the association between metabolic disorders and NIHF is unclear, but may be related to soft-tissue swelling and obstruction of venous return to the heart. Certain non-cardiac fetal abnormalities may result in hydrops by causing high-output cardiac failure. Examples include sacrococcygeal teratoma, neuroblastoma, placental chorioangioma, and umbilical cord masses.

NIHF may very rarely occur in association with significant maternal medical illnesses, such as severe anemia, hypoproteinemia, or diabetes mellitus. The “mirror” syndrome, also known as Ballantyne syndrome, is the combination of fetal hydrops with generalized fluid overload and a preeclampsia-like state in the mother (Carbillon et al., 1997). In general, the maternal clinical features resolve only with delivery of the fetus and placenta.

The precise incidence of NIHF is difficult to elucidate, as many cases are not detected prior to intrauterine fetal death, and some cases may resolve spontaneously in utero. The generally reported incidence of NIHF is 1 in 1500 to 1 in 4000 deliveries (Romero et al., 1988; Wilkins, 1999).

The diagnosis of hydrops is made following the detection of abnormal or increased fluid accumulation in at least two distinct fetal body cavities. Examples include pericardial effusion, pleural effusion, ascites, subcutaneous edema, cystic hygroma, polyhydramnios, and placental thickening (Figures 128-1 and 128-2). In general, skin thickness of at least 5 mm is required to diagnose subcutaneous edema, and a placental thickness of at least 6 cm is required to diagnose placentomegaly (Romero et al., 1988). These features do not necessarily indicate hydrops; it should be noted that skin thickening of at least 5 mm may be commonly seen in macrosomic fetuses. If abnormal fluid accumulation is confined to only one site, then the diagnosis of hydrops should not be used, and the case should be described simply in terms of the involved site, such as isolated ascites or isolated pleural effusion.

NIHF may initially present with an isolated fluid accumulation in one site, such as pleural effusion with congenital cystic adenomatoid malformation, but as intrathoracic pressure increases and venous return decreases, generalized hydrops may present.

Fetal ascites is diagnosed sonographically by the visualization of an echolucent rim encompassing the entire fetal abdomen in a transverse view (see Figure 128-1). Loops of bowel and the outline of the fetal liver, spleen, bladder, and diaphragm are generally more easily seen in the presence of ascites. Pericardial effusion is diagnosed by the appearance of an echolucent rim of at least 1 to 3 mm thickness around both cardiac ventricles. Pleural effusion, which may be unilateral or bilateral, also presents as an echolucent space outlining the diaphragm.