Nonimmune Hydrops Fetalis

Etiology

Hydrops fetalis is associated with a broad spectrum of disorders, which are classified into 2 main categories—immune and NIHF.

Immune Hydrops Fetalis

Immune hydrops fetalis is primarily caused by red blood cell alloimmunization due to Rh or ABO incompatibility. In Rh incompatibility, the fetal blood carries paternal Rh-positive antigens, which are recognized as foreign by the immune system of an Rh-negative mother, leading to the production of maternal anti-D antibodies. In subsequent pregnancies with Rh-positive fetuses, these antibodies can be produced in larger quantities as the maternal immune system retains a memory of the antigen. A similar mechanism occurs in ABO incompatibility, where maternal antibodies target fetal red blood cells carrying A or B antigens not present in the maternal blood. This immune response can lead to severe fetal or neonatal complications, including anemia, jaundice, hydrops fetalis, or kernicterus. However, with the introduction of anti-D immune globulin, immune hydrops fetalis has become rare.[9][10] Please see StatPearls' companion resource, "Hemolytic Disease of the Fetus and Newborn," for more information.

Nonimmune Hydrops Fetalis

Currently, etiologies other than red blood cell alloimmunization account for approximately 85% to 95% of all cases of fetal hydrops.[3][4] The most common underlying causes of NIHF are cardiovascular, chromosomal, and hematologic disorders.[6] However, NIHF can be a clinical feature of a wide range of conditions that disrupt the fetal body's ability to regulate interstitial fluid. The below-mentioned etiologies are associated with NIHF.

Cardiac disorders: In approximately 20% of patients, an underlying cardiac condition is the cause of NIHF, typically due to a structural defect that leads to increased central venous pressure or diastolic ventricular dysfunction. Common conditions associated with this include paroxysmal supraventricular tachycardia, hypoplastic left heart syndrome, endocardial cushion defects, and congenital pulmonary airway malformation.[6] Please see StatPearls' companion resources, "Paroxysmal Supraventricular Tachycardia," "Hypoplastic Left Heart Syndrome," "Atrioventricular Canal Defects," and "Congenital Pulmonary Airway Malformation," for more information on these conditions.

Chromosomal anomalies: Genetic abnormalities are a common cause of NIHF. Although chromosomal disorders are often associated with cardiac or lymphatic defects, NIHF can also occur in syndromes without any associated structural abnormalities. Chromosomal anomalies frequently leading to NIHF include Turner, Down, and Edward syndromes, as well as other aneuploidies.[6] Please see StatPearls' companion resources, "Turner Syndrome," "Down Syndrome," and "Edward Syndrome," for more information.

Lymphatic abnormalities: Conditions that cause lymphatic dysfunction often present as NIHF, including congenital lymphatic dysplasia, lymphedema distichiasis syndrome, and Milroy disease.[5] Please see StatPearls' companion resource, "Lymphangiomas," for more information.

Infections: Infections such as parvovirus B19, cytomegalovirus, and syphilis in pregnant women are linked to anemia, anoxia, endothelial cell damage, and increased capillary permeability, all of which can lead to NIHF. Among these, parvovirus B19 is the most common infectious cause of NIHF.[6] Please see StatPearls' companion resources, "Parvoviruses," "Cytomegalovirus," and "Syphilis," for more information.

Metabolic diseases: Inborn metabolic disorders that lead to decreased red blood cell production, anemia, and reduced serum proteins, such as Niemann-Pick disease type C, Gaucher disease type 2, and β-glucuronidase enzyme deficiency, are associated with NIHF.[5][6]

Fetal tumors: Fetal tumors such as sacrococcygeal teratoma, hepatic tumors, and neuroblastomas can cause NIHF due to increased cardiac demand or occupied space.[4] Please see StatPearls' companion resources, "Myelomeningocele," "Congenital Hemangioma," and "Neuroblastoma," for more information.

Renal and gastrointestinal conditions: Renal and gastrointestinal pathologies, such as congenital nephrotic syndrome, prune belly syndrome, volvulus, diaphragmatic hernia, and meconium peritonitis, can lead to decreased plasma oncotic pressure and are associated with NIHF.[11] Please see StatPearls' companion resources, "Congenital Nephrotic Syndrome," "Prune Belly Syndrome," "Volvulus," and "Diaphragmatic Hernia," for more information.

Hematologic causes: Conditions such as congenital dyserythropoietic anemia, Fanconi anemia, α-thalassemia, hereditary spherocytosis, glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, and leukemias can lead to NIHF due to high cardiac output or fetal anemia.[6][5] Please see StatPearls' companion resources, "Glucose-6-Phosphate Dehydrogenase Deficiency," "Hereditary Spherocytosis," "Fanconi Anemia," "Alpha Thalassemia," "Pyruvate Kinase Deficiency," for more information.[6]

Twin-twin transfusion syndrome: NIHF is often observed in monochorionic multiple gestations complicated by twin-twin transfusion syndrome, primarily due to high cardiac output failure in the affected fetuses.[12][6] Please see StatPearls' companion resource, "Twin-Twin Transfusion Syndrome," for more information.

Epidemiology

NIHF prevalence ranges from approximately 1 per 1700 to 3000 pregnancies overall; however, the incidence in live-born infants is about 1 in 4000 due to the high fetal mortality rate associated with some underlying etiologies and pregnancy terminations.[11] The widespread use of anti-D immunoglobulin, available since 1968, has markedly reduced the prevalence of RhD alloimmunization and associated immune fetal hydrops. Consequently, NIHF now accounts for nearly 90% of hydrops fetalis cases.[13]

Pathophysiology

Hydrops fetalis can occur in conditions that either increase fluid transudation from the vascular compartment or delay lymphatic return to circulation. These mechanisms include:

• Increased capillary hydrostatic pressure
• Reduced plasma oncotic pressure
• Obstructed lymphatic flow
• Damaged peripheral capillaries [11]

The exact pathophysiology of NIHF is not fully understood and largely depends on the specific fetal effects of the underlying etiology. For instance, decreased ventricular filling during diastole is a common mechanism in tachyarrhythmias, while increased central venous pressure, resulting from elevated right heart pressure, is typically observed in cardiac tumors and subendocardial fibroelastosis. Obstructed lymphatic drainage in the thoracic and abdominal cavities can occur due to masses such as cystic hygroma, as well as increased capillary permeability and decreased osmotic pressure associated with congenital infections and nephrosis. Consequently, management should primarily focus on addressing and reversing the underlying diseases.[14][6]

Hypoxia is another consequence of NIHF, leading to increased catecholamines and reduced hepatic and renal blood flow due to the redistribution of blood to the brain, heart, adrenals, and ductus venosus. This results in the activation of the renin-angiotensin system, increased antidiuretic hormone levels, and decreased albumin. These mechanisms elevate central venous pressure and impair lymphatic return to systemic circulation, exacerbating intravascular volume loss and resulting in severe and progressive edema in the fetus.[15]

History and Physical

Maternal Clinical Features

NIHF is primarily diagnosed through fetal clinical features observed on ultrasound imaging. Maternal presentation is often asymptomatic; however, in cases of polyhydramnios or mirror syndrome, clinical findings may include uterine enlargement, headache, visual disturbances, shortness of breath, and oliguria.[6]

Neonatal Clinical Features

Neonates with NIHF present with clinical findings similar to those observed on fetal ultrasound. However, intrauterine fetal demise and neonatal death are common. Surviving neonates may exhibit ascites, pleural effusion, and general edema.[16] Clinical features can vary based on the underlying etiology and may include cyanosis due to cardiac disease, hypotonia from congenital myopathy or hypothyroidism, hepatomegaly, cardiomyopathy, facial dysmorphism indicative of a metabolic storage disease, and dermatitis associated with TORCH infections (toxoplasmosis, rubella, cytomegalovirus, and herpes simplex).[17][18][19][20][21] Please see StatPearls' companion resource, "TORCH Complex," for more information.

Evaluation

Fetal Ultrasound Findings

The primary clinical criteria for diagnosing NIHF involve detecting 2 or more abnormal fetal fluid collections on fetal ultrasound. Common findings include pleural effusion, ascites, pericardial effusion, and generalized skin edema (eg, skin thickness >5 mm).[11] Additional features associated with NIHF may include:

• Placentomegaly
• Polyhydramnios (Please see StatPearls' companion resource, "Polyhydramnios," for more information.)
• Hepatosplenomegaly
• Pneumothorax
• Cystic hygroma (Please see StatPearls' companion resource, "Cystic Hygroma," for more information.)
• Chylothorax [44][45]

Polyhydramnios and placentomegaly, typically defined as placental thickness of 4 cm or more in the second trimester or 6 cm or more in the third trimester, are not part of the core ultrasound criteria for NIHF but are frequently observed.[22] These findings can occur alone or alongside other NIHF features. As many imaging characteristics of NIHF overlap with those of other conditions, it is crucial to consider differential diagnoses.[16][23] Furthermore, NIHF features may lead to secondary complications. For example, significant ascites can compress the bowel and lead to pulmonary hypoplasia.[24] Pleural effusion may be unilateral or bilateral, potentially leading to respiratory distress, lung hypoplasia, and associated respiratory or circulatory complications that can affect prognosis. Additionally, placentomegaly and polyhydramnios have been linked to an increased risk of preterm delivery in some studies.[25]

Additional Diagnostic Studies 

As NIHF is a symptom of various underlying conditions affecting the fetal body's fluid management, determining the etiology through diagnostic studies is essential. The underlying cause directly impacts symptom development and prognosis. When NIHF is identified incidentally on prenatal ultrasound, additional structural abnormalities should be investigated using ultrasound imaging and fetal echocardiogram, as these may indicate the underlying etiology, such as a fetal cardiac abnormality.[6] Fetal heart rate monitoring, umbilical artery pulsatility index, end-diastolic flow, and middle cerebral artery (MCA) Doppler assessment are also valuable for detecting underlying causes. An MCA Doppler peak systolic velocity greater than 1.5 is considered diagnostic of fetal anemia.[26]

Red blood cell alloimmunization should be ruled out initially by confirming the maternal blood type and Rh antigen status and performing an antibody screen, typically included in routine prenatal laboratory studies. Additional laboratory tests may be required to further investigate the etiology of NIHF, including a maternal complete blood count, Kleihauer-Betke stain, thyroid hormone levels, and tests for parvovirus B19 and TORCH titers.[22][6] Genetic etiologies should be considered if RBC alloimmunization is excluded and no structural cause is identified. This involves offering fetal karyotyping, fluorescence in situ hybridization studies, exome sequencing, and chromosomal microarray analysis, typically via amniocentesis or fetal blood sampling procedures.[5][22]

Treatment / Management

The primary management approach for NIHF is tailored according to the underlying etiology and the gestational age at which hydrops manifest. Careful evaluation and monitoring, along with effective resuscitation techniques, are crucial for improving the survival rates of affected neonates. For pregnancies with a lethal etiology, options include pregnancy termination or supportive care.[6][22](A1)

For underlying NIHF pathologies that are treatable, therapeutic strategies aim to address the specific etiology and may include:

• Intrauterine transfusions for fetal anemia.
• Antiarrhythmic agents for fetal cardiac arrhythmias.
• Drain or shunt placement for pleural effusion or chylothorax.
• Corticosteroids for congenital pulmonary airway malformations.
• Fetal therapy with sympathomimetics for atrioventricular block with ventricular rates less than 55 bpm.
• Laser coagulation of placental vessel anastomoses in twin-twin transfusion syndrome.[6][22]
(A1)

Clinicians must also consider antenatal and intrapartum management of the pregnancy, including fetal monitoring for signs of deterioration with antenatal testing, determining delivery indications and mode, ensuring availability of an appropriate facility for delivery and neonatal resuscitation, and consulting specialists (such as neonatal cardiologists and cardiovascular surgeons).[11][6][22] Delivery considerations are influenced by several clinical factors. Generally, delivery is often reasonable for pregnancies with NIHF at 34 weeks or more gestational period, depending on the underlying etiology. In cases with NIHF and stable maternal-fetal conditions, delivery by 37 to 38 weeks may be considered if indications for earlier delivery or clinical worsening do not exist.[6](A1)

Postnatal management of NIHF involves several critical steps, including initial resuscitation to stabilize the neonate and identifying and treating the underlying cause. Most infants with hydrops fetalis require endotracheal intubation due to respiratory depression. Procedures such as thoracentesis, paracentesis, and occasionally cardiocentesis may be necessary to manage pleural effusion, ascites, and pericardial effusion. A blood transfusion may be required in cases of severe anemia.[6][22] Despite aggressive treatment, survival rates can be as low as 10%, with survivors at risk for neurodevelopmental and cognitive deficits. The recurrence rate is notably high in mothers whose infants have chromosomal abnormalities or Rh incompatibility. Therefore, autopsies, including histopathologic evaluation, placental examination, and molecular and genetic studies, may be performed to determine the cause of NIHF.[27](A1)

Differential Diagnosis

Any potential etiology of NIHF should be considered in the differential diagnoses, as mentioned below. (Please refer to "Nonimmune Hydrops Fetalis" in the Etiology section for more information.)

• Neonatal hemochromatosis
• Congestive cardiac failure
• Twin-twin transfusion syndrome
• Hepatitis B
• Hypercalcemia
• Hypernatremia
• Hypothrombinemia
• Maternal diabetes
• Fetal abdominal cysts
• Obstructed bowel
• Obstructed urinary system [28]

Prognosis

The prognosis of hydrops fetalis primarily depends on the underlying cause, gestational age at diagnosis, timing of delivery, extent of fetal edema, and intrauterine interventions.[29] Neonates with thoracic causes and bronchopulmonary malformations generally have a better prognosis, whereas those with chromosomal abnormalities, structural defects, or genetic metabolic disorders often face a poorer prognosis.[30]

Long-term survival in hydrops fetalis largely depends on the underlying disease, the effectiveness of fetal therapies to address hydrops, and the gestational age at delivery rather than the specific anatomical manifestations of hydrops. The cardiovascular profile score can be a useful prognostic indicator for fetuses with NIHF, particularly those with high cardiothoracic ratios. Patients with NIHF who receive fetal interventions for their underlying condition often experience improved survival, particularly when hydrops can be resolved without preterm delivery. Although specific physiological parameters, such as MCA peak systolic velocity, do not predict survival, the cardiovascular profile score is valuable for predicting outcomes, especially in cases with a high cardiothoracic ratio. Additionally, the observation that various disease processes and cardiac abnormalities can lead to the common finding of fluid in 2 compartments suggests an underlying fetal distress mechanism that remains to be fully understood.[4]

Complications

The complications associated with hydrops fetalis include:

• Spontaneous miscarriage
• Intrauterine fetal demise
• Preterm delivery
• Perinatal deaths
• Early neonatal deaths

Infants who survive hydrops fetalis may experience complications such as appendiceal rupture, cystic hygroma, intestinal obstruction, and severe neurodevelopmental delay. The most serious maternal complication is mirror syndrome, where the mother exhibits symptoms similar to those of her hydropic fetus. Clinical features of mirror syndrome often overlap with preeclampsia and may include pulmonary edema, peripheral edema, headache, visual disturbances, oliguria, elevated uric acid and liver function tests, low platelet count, and anemia.[31][32]