Nonimmune hydrops fetalis in the neonate: Causes, presentation, and overview of neonatal management

INTRODUCTION — Hydrops fetalis is a condition of excess fluid accumulation in the fetus. It may result in fetal demise and is associated with considerable risk of neonatal morbidity and mortality. (See 'Outcome' below.)

Hydrops fetalis can be immune-mediated or nonimmune:

●Immune-mediated hydrops fetalis is a result of severe fetal anemia in the setting of alloimmune hemolytic anemia due to Rh incompatibility between the mother and fetus. This is discussed separately. (See "Alloimmune hemolytic disease of the newborn: Postnatal diagnosis and management", section on 'Hydrops fetalis'.)

●Nonimmune hydrops fetalis (NHF) is associated with numerous disorders that include cardiac, pulmonary, infectious, and genetic etiologies (table 1). In the modern era, NHF accounts for almost 90 percent of hydropic cases in neonates.

This topic will discuss the causes and presentation of NHF and will provide an overview of the initial management of a newborn with NHF. Other related topics include:

●(See "Nonimmune hydrops fetalis".)

●(See "Alloimmune hemolytic disease of the newborn: Postnatal diagnosis and management".)

●(See "RhD alloimmunization in pregnancy: Overview".)

●(See "RhD alloimmunization in pregnancy: Management".)

●(See "RhD alloimmunization: Prevention in pregnant and postpartum patients".)

EPIDEMIOLOGY

●Nonimmune hydrops fetalis – Nonimmune hydrops fetalis (NHF) is uncommon, with an estimated prevalence of approximately 2 to 3 cases per 10,000 live births [1]. There is some variation depending on the prevalence of certain genetic conditions in the population (eg, increased incidence of alpha thalassemia in Southeast Asia) and whether late pregnancy terminations were included in the analysis. The epidemiology of NHF is discussed in greater detail separately. (See "Nonimmune hydrops fetalis", section on 'Prevalence'.)

●Immune-mediated hydrops fetalis – In high-resource countries, the incidence of immune-mediated hydrops fetalis has dramatically declined since the 1970s due to the implementation of antenatal Rh(D) immune globulin prophylaxis [2,3]. However, in some parts of the world, immune causes remain a significant cause of hydrops fetalis [4]. This is discussed separately. (See "RhD alloimmunization in pregnancy: Overview".)

CAUSES — Causes of nonimmune hydrops fetalis (NHF) are summarized in the table (table 1) [3,5-9].

In a systematic review that included >1300 neonates with NHF, the relative frequencies of various underlying causes were as follows [5]:

●Cardiovascular disease, including structural congenital heart disease and congenital arrythmias (20 percent)

●Lymphatic dysplasia (15 percent)

●Hematologic diseases (eg, alpha thalassemia) (9 percent)

●Chromosomal abnormalities (9 percent)

●Infections (7 percent)

●Syndromic causes without a known genetic defect (6 percent)

●Twin-to-twin transfusions and placental vascular abnormalities (4 percent)

●Thoracic malformations (2 percent)

●Inborn error of metabolism (1 percent)

●Congenital anomalies of the kidney and urinary tract (1 percent)

●Thoracic tumors (1 percent)

●Miscellaneous (4 percent)

●Idiopathic (20 percent)

A more detailed discussion of the etiologies of NHF is provided separately. (See "Nonimmune hydrops fetalis", section on 'Etiology and prenatal management of disorders associated with hydrops'.)

PATHOGENESIS — Understanding the basic mechanisms that underlie the development of hydrops fetalis is important in directing both antenatal and postnatal treatment of hydrops fetalis.

Normally, the formation of interstitial fluid from the vascular space is balanced by the return of interstitial fluid back to the central venous system through the lymphatic system. The process is governed by Starling's Law and is dependent upon the four following components:

●Capillary hydrostatic pressure

●Capillary oncotic pressure

●Interstitial hydrostatic pressure

●Interstitial osmotic pressure, which is dependent on lymphatic return

The fetus is particularly vulnerable to increased interstitial fluid accumulation because of its greater capillary permeability, compliant interstitial compartments, and increased susceptibility to impaired lymphatic flow.

In cases of hydrops fetalis, accumulation of interstitial fluid occurs because the production of interstitial fluid greatly exceeds the lymphatic return. Although the pathogenesis is not clearly understood, hydrops fetalis appears to be multifactorial due to mechanisms that produce elevated central venous pressure, impair lymphatic return, and increase capillary leakage.

Elevated venous pressure — Elevated central venous pressure (CVP) increases capillary hydrostatic pressure and impairs lymphatic return to the vascular space [10,11].

Both low (eg, cardiac arrhythmia, congenital structural heart disease, and myocarditis) and high-output cardiac failure (eg, severe anemia, arterial-venous malformations, and twin-twin transfusion syndrome) cause elevated CVP that may result in hydrops fetalis [3,12-20]. Elevation of CVP appears to be a critical component in the pathogenesis of hydrops fetalis because animal studies have demonstrated that severe anemia alone does not cause hydrops fetalis, but rather only causes hydrops fetalis in the presence of increased CVP [21,22].

CVP elevation may also be caused by obstruction of either the superior and/or inferior vena cavas as demonstrated in cases of congenital cystic adenomatoid malformation, omphalocele, cervical or mediastinal teratoma, or congenital high airway obstruction syndrome [23-27]. Compression of the vascular system impedes lymphatic return and results in edema formation.

Impaired lymphatic drainage — Lymph return to the central venous system is reduced either by structural abnormality or, as previously discussed, by functional impairment due to increased CVP.

Anomalous development results in structural dysgenesis of the lymphatic network and is seen in the following conditions: chylothorax, cervical hygroma, congenital lymphedema, and cystic lymphangiectasia [3,28-31]. These structural anomalies are often associated with chromosomal abnormalities, such as Turner syndrome [32]. (See "Enlarged nuchal translucency and cystic hygroma".)

Capillary oncotic pressure — In theory, reduced capillary oncotic pressure should contribute to hydrops fetalis. However, data from animal studies demonstrated that hypoproteinemia does not result in nonimmune hydrops fetalis (NHF) [33].

Hypoxia — Animal studies have shown that severe fetal hypoxia causes hydrops fetalis. In these studies, there is sustained activation of the renin-angiotensin system with elevation of renin in the absence of renal injury or elevation of CVP [34,35]. In addition, hypoxia results in endothelial injury and interferes with nitric oxide and cyclic guanosine monophosphate production [36,37], which may increase capillary leakage, resulting in greater movement of fluid from the vascular to the interstitial space.

PRESENTATION

●Prenatal diagnosis and evaluation – Most cases of nonimmune hydrops fetalis (NHF) are diagnosed prenatally with ultrasonography. Prenatal detection of NHF and the subsequent evaluation are discussed separately. (See "Nonimmune hydrops fetalis", section on 'Diagnosis' and "Nonimmune hydrops fetalis", section on 'Postdiagnostic evaluation'.)

●Postnatal findings – Findings at birth in the newborn may include:

•Skin edema

•Pleural effusion

•Pericardial effusion

•Ascites

•Respiratory distress

•Circulatory collapse or shock

OVERVIEW OF INITIAL NEONATAL MANAGEMENT

Delivery room care — Delivery room care requires close collaboration between the obstetric and neonatal teams. Whenever possible, delivery should occur at a center with a level III neonatal intensive care unit where the required resources are available (neonatal resuscitation team, mechanical ventilatory support, exchange transfusion, pediatric surgery).

Resuscitation in the delivery room should proceed according to standard guidelines, as summarized in the figure (algorithm 1) and discussed in detail separately. (See "Neonatal resuscitation in the delivery room".)

The neonatal team should anticipate any special needs of the newborn based upon the prenatal evaluation. For example:

●Preparation should anticipate the possible need to drain fluid if there are symptomatic pleural effusions. (See "Approach to the neonate with pleural effusions", section on 'Thoracocentesis'.)

●If severe anemia is anticipated, unmatched type O, RhD-negative packed red blood cells should be available. (See "Red blood cell (RBC) transfusions in the neonate", section on 'Use of O-negative blood'.)

Subsequent care

General supportive measures — General supportive care for the hydropic infant includes:

●Providing respiratory support as needed. Many affected infants require intubation and mechanical ventilation. (See "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn" and "Overview of mechanical ventilation in neonates".)

●Red blood cell transfusion if the neonate has severe anemia. This can usually be accomplished with a simple transfusion administered cautiously. However, neonates with long-standing in-utero anemia (eg, twin-twin transfusion, chronic fetomaternal hemorrhage) may have elevated circulating blood volume and evidence of high-output heart failure. Such patients may tolerate partial exchange transfusion better than simple transfusion. (See "Red blood cell (RBC) transfusions in the neonate".)

●Hemodynamic support if the neonate has signs of shock. (See "Neonatal shock: Management".)

●Drainage of significant symptomatic fluid collections (eg, pleural effusion, ascites). (See "Approach to the neonate with pleural effusions", section on 'Thoracocentesis'.)

Management of the underlying cause — In many cases, the underlying cause of hydrops fetalis is identified prenatally and management is directed to the specific cause. Specific causes of hydrops fetalis are discussed in separate topic reviews:

●Structural heart disease (see "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Initial management')

●Fetal arrhythmia or congenital heart block (see "Fetal arrhythmias" and "Congenital third-degree (complete) atrioventricular block")

●Alloimmune hemolytic disease of the newborn (see "Alloimmune hemolytic disease of the newborn: Postnatal diagnosis and management", section on 'Postnatal management')

●Anemia due to nonimmune causes (eg, massive fetomaternal hemorrhage, alpha thalassemia) (see "Spontaneous massive fetomaternal hemorrhage" and "Alpha thalassemia major: Prenatal and postnatal management", section on 'Management (prenatal and neonatal)')

●In utero infections, examples include:

•Congenital cytomegalovirus (see "Congenital cytomegalovirus infection: Management and outcome")

•Congenital toxoplasmosis gondii (see "Congenital toxoplasmosis: Treatment, outcome, and prevention")

•Parvovirus B19 (see "Parvovirus B19 infection during pregnancy")

•Congenital syphilis (see "Congenital syphilis: Management and outcome")

●Congenital pulmonary and thoracic malformations, examples include:  

•Congenital diaphragmatic hernia (see "Congenital diaphragmatic hernia in the neonate")

•Bronchopulmonary sequestration (see "Bronchopulmonary sequestration")

•Congenital pulmonary airway malformation (see "Congenital pulmonary airway malformation")

●Aneuploidy or structural chromosomal abnormalities, examples include:

•Trisomy 21 (Down syndrome) (see "Down syndrome: Management")

•Trisomy 18 (Edward syndrome) (see "Congenital cytogenetic abnormalities", section on 'Trisomy 18 syndrome')

•Trisomy 13 (see "Congenital cytogenetic abnormalities", section on 'Trisomy 13 syndrome')

•45 X (Turner syndrome) (see "Management of Turner syndrome in children and adolescents")

●Metabolic disorders (eg, Gaucher’s disease, mucopolysaccharidoses) (see "Inborn errors of metabolism: Identifying the specific disorder" and "Gaucher disease: Treatment" and "Mucopolysaccharidoses: Treatment")

●Urologic disorders (eg, prune belly syndrome, posterior urethral valves) (see "Prune-belly syndrome" and "Management of posterior urethral valves")

POSTNATAL EVALUATION — In many cases, the underlying cause of hydrops fetalis is identified during the prenatal evaluation. The prenatal evaluation is discussed separately. (See "Nonimmune hydrops fetalis", section on 'Postdiagnostic evaluation'.)

Additional postnatal evaluation may be warranted to identify the underlying cause if it remains uncertain or to better characterize the prenatally diagnosed condition.

Postnatal evaluation generally includes:

●Pathologic examination of the placenta for evidence of congenital infection, chorioangioma, or other abnormalities [38,39]. (See "Gross examination of the placenta" and "The placental pathology report".)

●Detailed physical examination of the newborn to identify any dysmorphisms or clinical findings suggestive of congenital infection (table 2). (See "Congenital anomalies: Approach to evaluation", section on 'Physical examination' and "Overview of TORCH infections".)

●Laboratory tests (including complete blood count, serum electrolytes, kidney function tests, liver function tests, and blood gas) to identify infants with anemia, kidney disease, liver disease, or impaired gas exchange.

●Chest radiograph to evaluate for lung abnormalities and pleural effusions. Additional chest imaging may be warranted, depending on the prenatal findings.

●Cardiac evaluation, including pulse oximetry, electrocardiogram, and echocardiography, to identify an underlying rhythm disorder (arrhythmia, congenital heart block) or structural heart disease). (See "Identifying newborns with critical congenital heart disease".)

●Genetic evaluation if a genetic syndrome is suspected. This should be performed in consultation with a clinical geneticist. Chromosomal microarray analysis is typically the first-line test, if not performed prenatally [40]. (See "Congenital anomalies: Approach to evaluation", section on 'Laboratory studies'.)

●Infectious work-up if congenital infection is suspected. (See "Overview of TORCH infections", section on 'Approach to the infant with suspected intrauterine infection'.)

●Evaluation for inborn errors of metabolism if a metabolic disorder is suspected. (See "Inborn errors of metabolism: Identifying the specific disorder" and "Newborn screening for inborn errors of metabolism".)

OUTCOME

●Survival – Survival depends upon the underlying cause of hydrops fetalis [3]. Overall, the estimated survival (ie, surviving to hospital discharge) among live-born infants with hydrops fetalis is approximately 50 to 60 percent [3,41,42].

In a report of 598 live-born infants with hydrops fetalis, survival was highest for infants with isolated congenital chylothorax (6 percent) and lowest for infants with multiple congenital anomalies (42 percent) [3]. Additional risk factors for mortality included lower gestational age, five-minute Apgar score ≤3, and need for intensive respiratory support (eg, high-frequency ventilation).

●Neurodevelopment outcome — Approximately 45 to 70 percent of surviving infants have neurodevelopmental impairments, including intellectual disability, learning disabilities, and motor disabilities (eg, cerebral palsy) [43,44]. The risk of disability depends on the underlying cause of hydrops fetalis and other comorbidities. All surviving infants warrant close neurodevelopmental surveillance. (See "Developmental-behavioral surveillance and screening in primary care".)

SUMMARY AND RECOMMENDATIONS

●Causes – Hydrops fetalis is a condition of excess fluid accumulation in the fetus. It can be immune-mediated or nonimmune:

•Immune-mediated hydrops fetalis results from severe anemia in the setting of alloimmune hemolytic anemia due to Rh incompatibility between the mother and fetus. This is discussed separately. (See "Alloimmune hemolytic disease of the newborn: Postnatal diagnosis and management", section on 'Hydrops fetalis'.)

•Nonimmune hydrops fetalis (NHF) is associated with numerous disorders that include cardiac, pulmonary, infectious, and genetic etiologies. The causes are summarized in the table (table 1) and discussed in detail separately. (See "Nonimmune hydrops fetalis", section on 'Etiology and prenatal management of disorders associated with hydrops'.)

●Presentation

•Prenatal diagnosis and evaluation – Most cases of NHF are diagnosed prenatally with ultrasonography. Prenatal detection of NHF and the subsequent evaluation are discussed separately. (See "Nonimmune hydrops fetalis", section on 'Diagnosis' and "Nonimmune hydrops fetalis", section on 'Postdiagnostic evaluation'.)

•Postnatal findings – Findings at birth in the newborn may include (see 'Presentation' above):

-Skin edema

-Pleural effusion

-Pericardial effusion

-Ascites

-Respiratory distress

-Circulatory collapse or shock

●Delivery room care – Resuscitation in the delivery room should proceed according to standard guidelines, as summarized in the figure (algorithm 1) and discussed in detail separately. (See "Neonatal resuscitation in the delivery room".)

The neonatal team should anticipate any special needs of the newborn based upon the prenatal evaluation. For example:

•Preparation should anticipate the possible need to drain fluid if there are symptomatic pleural effusions (see "Approach to the neonate with pleural effusions", section on 'Thoracocentesis')

•If severe anemia is anticipated, unmatched type O, RhD-negative packed red blood cells should be available (see "Red blood cell (RBC) transfusions in the neonate", section on 'Use of O-negative blood')

●General supportive measures – General supportive care for the hydropic infant includes (see 'General supportive measures' above):

•Providing respiratory support as needed (see "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn" and "Overview of mechanical ventilation in neonates")

•Red blood cell transfusion if the neonate has severe anemia (see "Red blood cell (RBC) transfusions in the neonate")

•Hemodynamic support if the neonate has signs of shock (see "Neonatal shock: Management")

•Drainage of significant symptomatic fluid collections (eg, pleural effusions) (see "Approach to the neonate with pleural effusions", section on 'Thoracocentesis')

●Management of the underlying cause – In many cases, the underlying cause of hydrops fetalis is identified prenatally and management is directed to the specific cause. (See 'Management of the underlying cause' above.)

●Postnatal evaluation – A postnatal evaluation is generally warranted to identify the underlying cause if it remains uncertain after the prenatal evaluation or to better characterize the prenatally diagnosed condition. The evaluation includes (see 'Postnatal evaluation' above):

•Examination of the placenta

•Detailed physical examination of the newborn to identify any dysmorphisms or clinical findings suggestive of congenital infection (table 2)

•Laboratory tests, including complete blood count, serum electrolytes, kidney function tests, liver function tests, and blood gas

•Chest radiograph

•Cardiac evaluation, including pulse oximetry, electrocardiogram, and echocardiography

•Genetic evaluation if a genetic syndrome is suspected

•Infectious work-up if congenital infection is suspected

•Evaluation for inborn errors of metabolism if a metabolic disorder is suspected

●Outcome – Outcomes for infants with NHF depend on the underlying etiology. In general, affected infants are at high risk of mortality and morbidity, including neurodevelopmental impairment. (See 'Outcome' above.)