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Nonimmune hydrops fetalis

Diagnosis/definition: Non-immune hydrops is the presence of two or more abnormal fetal fluid collections in the absence of red cell alloimmunization. (Figure 1).Epidemiology/Incidence: Non-immune hydrops fetalis (NIHF) refers specifically to cases of hydrops not caused by red cell alloimmunization.  With the development and widespread use of Rh(D) immune globulin, the prevalence of Rh(D) alloimmunization and associated hydrops has dramatically decreased. As a result, NIHF now accounts for almost 90 percent of cases of hydrops4, with the prevalence in published series reported as 1 in 1700-3000 pregnancies.  However, many of these reports predate routine sonography and limited information is available on contemporary incidence of NIHF in a prenatal population.Risk factors/associations: NIHF can result from a large number of underlying conditions (Table 1). The most common etiologies include cardiovascular, chromosomal, and hematologic abnormalities, followed by structural fetal anomalies, complications of twinning, infection, and placental abnormalities.  The differential diagnosis is extensive, and the success in identifying a cause partially depends on the thoroughness of efforts to establish a diagnosis.  Although older studies considered many cases to be idiopathic, more recent, larger series and a systematic review report that a cause can be found in nearly 60 percent of cases prenatally and in 85% when postnatal detection is included.

Complications: Polyhydramnios and preterm birth occur frequently with NIHF, with reported incidences as high as 29%71 and 66%87, respectively.  Tocolytic agents are a consideration before 24 weeks if contractions occur secondary to a known inciting event, such as an invasive procedure performed for the diagnosis or management of NIHF.  Though in the past, preterm delivery has been advocated by some to potentially improve the outcome of NIHF, prematurity is likely to worsen the prognosis. For this reason, we recommend that preterm delivery be undertaken only for obstetric indications.
         Women with NIHF may develop mirror syndrome, an uncommon complication in which the mother develops edema that “mirrors” that of her hydropic fetus.  Mirror syndrome may represent a form of preeclampsia, and is characterized by edema in approximately 90 percent, hypertension in 60 percent, and proteinuria in 40 percent of cases.  As it is uncommon and likely under-diagnosed, the incidence is unclear.  Additional associated findings with the syndrome include headache, visual disturbances, oliguria, elevated uric acid, liver function tests, or creatinine levels, low platelets, anemia, and hemodilution.  Resolution occurs with either the treatment of the hydrops or with delivery. 

Screening and Work-Up:Evaluation of hydrops begins with an antibody screen (indirect Coombs test) to verify that it is non-immune, detailed sonography of the fetus(es) and placenta, including echocardiography and assessment for fetal arrhythmia, and middle cerebral artery Doppler evaluation for anemia, as well as fetal karyotype and/or chromosomal microarray analysis (CMA), regardless of whether a structural fetal anomaly is identified. (Figure 2)

Antepartum management and treatment:  Management is guided by the presence or absence of additional anomalies.  Sonographic evaluation should include a detailed survey for anomalies of the fetus, umbilical cord and placenta, and estimation of amniotic fluid volume.  A fetal echocardiogram should be included, as fetal cardiac anomalies are among the most common causes of NIHF. Recommended treatment depends on the underlying etiology and gestational age; preterm delivery is recommended only for obstetric indications including development of mirror syndrome. Candidates for corticosteroids and antepartum surveillance include those with an idiopathic etiology, an etiology amenable to prenatal or postnatal treatment, and those in whom intervention is planned if fetal deterioration occurs.  Antepartum surveillance is generally used in the setting of maternal or pregnancy complications associated with an increased risk for fetal demise, and when findings from surveillance will assist with delivery decisions.  For NIHF, antepartum testing has not been definitively shown to improve perinatal outcomes.

Delivery:  There are no management trials of delivery timing in the setting of NIHF upon which to base recommendations. Many hydropic fetuses succumb prior to viability. There is no evidence that elective preterm delivery will improve the outcome. In one retrospective series, preterm birth prior to 34 weeks was a poor prognostic factor. In the absence of clinical deterioration or other indication for earlier intervention, delivery by 37 to 38 weeks should be considered.  As discussed previously, we recommend delivery in most cases if mirror syndrome develops.  If the fetus is potentially treatable or considered viable, and if the decision to proceed with delivery is based on findings of antepartum surveillance or concern about deterioration of the fetal condition (e.g. based on sonographic findings), cesarean delivery may be indicated. Depending on the degree of associated effusions and anasarca, consideration should be given to the potential for dystocia at delivery. If a decision has been made not to intervene for fetal indications – to provide comfort care only, vaginal delivery is preferred unless otherwise contraindicated.   In general, fetuses with NIHF should be delivered at a facility with the capability to stabilize and treat critically ill newborns.  

Prognosis and Outcomes:  The prognosis depends on etiology, response to therapy if treatable, and on the gestational age at detection and delivery.  Aneuploidy confers a poor prognosis, and even in the absence of aneuploidy, neonatal survival is often less than 50%.  In one recent prenatal series, survival was approximately 50%, and only 25% survived without major morbidities. Among liveborn infants, neonatal mortality with NIHF is reported to be as high as 60%. With chylothorax as the underlying etiology, the mortality may be as low as 6%; however, when the infant has associated anomalies, almost two-thirds do not survive. Treatable causes of hydrops, such as fetal arrhythmia or infection with parvovirus B have a better prognosis.