Hydrops Fetalis

Etiology

Hydrops are associated with a broad spectrum of disorders. There are 2 main categories of hydrops fetalis:

Immune Hydrops Fetalis

Isoimmunization, such as Rh isoimmunization and ABO incompatibility, anti-c, C, e, E, Duffy antibodies, and Kell alloimmunization are the causes of immune hydrops fetalis. A detailed discussion of the immune hydrops is beyond the scope of this activity.  

Nonimmune hydrops 

Nonimmune hydrops (NIHF) accounts for approximately 80% to 90% of all cases of the condition. It occurs when an underlying disease, genetic disorder, or birth defect interferes with the fetal body's ability to manage fluid. NIHF can result from many various underlying conditions, such as:

• Cardiac causes: Paroxysmal supraventricular tachycardia, hypoplastic left heart, endocardial cushion defects, and congenital pulmonary airway malformation
• Chromosomal anomalies: Turner syndrome, Down syndrome, and Edward syndrome
• Lymphatic causes: Congenital lymphatic dysplasia
• Infections: Parvovirus B19 (fifth disease), cytomegalovirus, and syphilis infections in pregnant women
• Metabolic diseases: Niemann-Pick disease type-C (NPC), Gaucher disease type 2, and beta-glucuronidase enzyme deficiency
• Tumors: Teratoma (sacrococcygeal teratoma), hepatic tumors, and neuroblastoma
• Maternal diseases: Diabetes mellitus and hyperthyroidism
• Urinary causes: Congenital nephrosis and prune belly syndrome
• Digestive causes: Volvulus and meconium peritonitis  
• Hematologic causes: Alpha-thalassemia, twin-to-twin transfusion syndrome (TTTS) in monochorionic twin pregnancies, and leukemias
• Disorders of red blood cell (RBC) metabolism: Glucose phosphate isomerase deficiency, pyruvate kinase deficiency, and glucose-6-phosphate dehydrogenase (G6PD) deficiency
• Disorders of RBC production: Congenital dyserythropoietic anemia, Diamond-Blackfan syndrome, and Fanconi anemia 
• Disorders of RBC membrane: Hereditary spherocytosis, hereditary elliptocytosis, hereditary pyropoikilocytosis, and hereditary stomatocytosis syndromes[4]

Epidemiology

NIHF prevalence ranges from 1 in 1500 to 1 in 4000 births. There is a wide variation in the reported prevalence due to differences in definitions, populations, thoroughness of evaluation, and whether late pregnancy terminations were included. The widespread use of anti-D immunoglobulin dramatically decreased the prevalence of RhD alloimmunization and associated hydrops after 1968, when the drug became available. As a result, NIHF now accounts for almost 90% of hydrops fetalis cases.[5]

Pathophysiology

Hydrops fetalis is mainly found in any condition that increases the rate of fluid transudation from the vascular compartment or delays lymphatic return to circulation. This is mainly due to the developmental defects in the microcirculation and lymphatic system. Hypoxia is another consequence of both immune and nonimmune hydrops fetalis. Hypoxia increases catecholamines and decreases hepatic and renal blood flow because of the redistribution of blood to the brain, heart, adrenals, and ductus venosus. This causes the renin-angiotensin system's activation, an increase in the anti-diuretic hormone, and a decrease in albumin. These mechanisms elevate central venous pressure and lead to a decreased return of lymphatic flow into the systemic circulation, further complicating the loss of intravascular volume and resulting in severe and progressive edema in the fetuses.[6]

Although the pathophysiology of nonimmune hydrops fetalis is not completely understood, it often results from various mechanisms depending on the underlying cause. Decreased ventricular filling during diastole is the most common mechanism of NIHF in tachyarrhythmias. In contrast, increased central venous pressure resulting from increased right heart pressure is mainly seen in cardiac tumors and subendocardial fibroelastosis. Obstructed lymphatic drainage in thoracic and abdominal cavities results from masses like cystic hygroma, increased capillary permeability, and decreased osmotic pressure in congenital infections and nephrosis. Hence, management should focus mainly on reversing the underlying diseases.[7][8]

History and Physical

Hydrops fetalis presents with an abnormal fluid collection in 2 or more cavities or compartments, mainly pleural effusion, ascites, pericardial effusion, and skin edema. The number of fluid collection sites is directly correlated to the neonatal prognosis. The diagnosis is mainly based on prenatal ultrasound or the postnatal evaluation of the fetus. Other features include anemia, placentomegaly, polyhydramnios, and hepatosplenomegaly. Pleural effusion can be unilateral or bilateral. Mild effusions can cause respiratory distress, and severe effusions result in lung hypoplasia and respiratory or circulatory diseases associated with poor prognosis after birth.[9] Patients can also present with pneumothorax or chylothorax. These are rare and serious clinical conditions with high mortality.[10][11]

Ascites

Ascites can be an early manifestation of hydrops fetalis and are seen as early as 20 weeks of gestation. As isolated fetal ascites are seen in many other systemic diseases, it is essential to differentiate hydrops fetalis from other causes. Larger ascites can cause bowel compression and pulmonary hypoplasia. The serum ascites albumin gradient (SAAG) ratio of ascites with hydrops fetalis is less than 11 g/L, indicating nonportal hypertension's etiology. Spontaneous resolution with a good prognosis is seen in a few patients.[12] Pericardial effusion in the fetus is transient, which manifests as hydrops in Rh-sensitized females.[13] Skin edema is the subcutaneous tissue thickness on the scalp greater than 5mm. Sometimes, fluid accumulation behind the neck, known as nuchal translucency, and fat under the scalp is mistaken for skin edema.[14]

Anemia

Anemia in hydrops fetalis is caused mainly by red cell alloimmunization and parvovirus-B19 infection. Other causes include alpha thalassemia, Bart hemoglobin, and a mutation in the alpha-globin chain.[15]

Polyhydramnios

Polyhydramnios is the vertically measured amniotic fluid volume in the deepest pocket of more than 8 centimeters or an amniotic fluid index of more than 24 centimeters.[16] It is caused mainly due to impaired fetal swallowing, impaired renal function, and intestinal obstruction.[10]

Placentomegaly

Placentomegaly is an abnormally enlarged placenta that occurs due to disruption in the oncotic gradient. It is mainly seen in high cardiac output diseases like anemia and sacrococcygeal teratoma. Placentomegaly and polyhydramnios are considered predictors of survival.[17]

Hepatosplenomegaly

Hepatosplenomegaly is diagnosed in the second and third trimester of pregnancy. It is usually associated with myeloproliferative disease in trisomy 21.[18]

Neonates

Neonates with cyanosis and no response to oxygen supplements should raise suspicion of the presence of underlying cardiac diseases.[19] Neonates with hypotonia suggest the presence of congenital myopathy and congenital hypothyroidism.[20][21] In addition to hypotonia, the presence of hepatomegaly, cardiomyopathy, and facial dysmorphism suggest metabolic storage diseases.[22] Dermatitis, along with or without hepatosplenomegaly, suggests TORCH (toxoplasmosis, other infections such as rubella, cytomegalovirus, and herpes simplex) infections.[23]

Evaluation

Hydrops fetalis is mostly an incidental finding during routine prenatal workups. The underlying cause directly influences the development of symptoms and their prognosis. Hydrops due to chromosomal abnormalities are usually detected during early pregnancy, whereas cardiac causes are detected in the second or third trimester. Hence, a detailed prenatal workup should be done in suspected cases. The following are the various diagnostic modalities for the evaluation of hydrops fetalis. 

The first detailed ultrasound is done between 18 and 22 weeks of gestation. The most common findings detected during early pregnancy are ascites and skin edema (>5 mm thickness) in the fetal head, back of the neck, thorax, and abdomen. The cause of generalized skin edema is probably due to aneuploidy or associated anatomical defects. Polyhydramnios and placental edema are most commonly seen before 20 weeks, whereas pleural effusion and pericardial effusion in the fetus are rarely seen before 15 weeks of gestation.[24]

It is mandatory to look into the possibility of maternal TORCH and parvovirus B19. Parvovirus B19 infection is most commonly associated with fetal anemia and ascites; however, cytomegalovirus and toxoplasmosis present with congenital malformations like ventriculomegaly, microcephaly, and hyperechogenic bowel. Hence, the antibody screen for TORCH infections should always be considered.[24]

Fetal heart rate, umbilical artery pulsatility index, end-diastolic flow, and middle cerebral artery peak systolic velocity (MCA-PSV) are also helpful in detecting the underlying causes of hydrops. The mean fetal heart rate is increased in trisomy 21. Increased resistance to blood flow in the umbilical artery is seen in trisomy 18 and triploidy.[24] The measurement of MCA-PSV is very sensitive in determining fetal anemia. An MCA-PSV ratio of more than 1.5 is considered to be fetal anemia.[25] Cordocentesis helps find the cause of fetal anemia.[15]

Chorionic villous sampling (CVS) is most frequently done for karyotyping if hydrops fetalis is diagnosed before 15 weeks of gestation.[24] CVS is also done to diagnose Bart hemoglobin (which has a high affinity for oxygen and thus is an ineffective oxygen carrier) in alpha thalassemia, which is an ultimately fatal condition between 10-12 weeks of gestation.[26]

Anti-SS-A/SS-B antibodies in maternal Sjögren syndrome can cause bradyarrhythmias and complete heart block in fetuses, resulting in hydrops' development. However, congenital heart block is the first manifestation to be seen on ultrasound during the first trimester. The prognosis for this is relatively poor.[27]

Elevated alpha-fetoprotein (AFP) during pregnancy indicates fetomaternal hemorrhage, which causes feal anemia and nonimmune hydrops. Hence, AFP levels are monitored closely.[28]

Direct and indirect Coomb tests detect immune hydrops fetalis, but they do not correlate with the disease severity.[2] Echocardiogram, thyroid hormone levels, complete blood count, and metabolic panel also detect other causes of NIHF after birth.[24]

Treatment / Management

Careful evaluation, monitoring, and effective resuscitation techniques are essential in improving the survival rate in affected neonates. Structural heart abnormalities and chromosomal disorders cannot be intervened with, and hence, the prognosis is very poor. Therefore, they are excluded first before performing any interventions. Intrauterine interventions like thoracocentesis and peritoneal-amniotic shunt can be performed if the ultrasound detects mediastinal shift, polyhydramnios, fetal edema, or rapid accumulation of fluid to confirm alveolar development and also helps in releasing the excessive amniotic fluid. In severe anemia and arrhythmias, intrauterine transfusion and antiarrhythmic drugs can be utilized, respectively. Intrauterine transfusions in patients with parvovirus-B19 infections can reverse hydrops, sometimes resulting in healthy live births. A few teratomas can be resected surgically in utero.[10]

Postnatal management includes initial resuscitation, identification, and treatment of the underlying cause. Most of the infants with hydrops fetalis require endotracheal intubation because of respiratory depression. Thoracentesis, paracentesis, and sometimes cardiocentesis are performed if the neonate presents with pleural effusion, ascites, and pericardial effusion. In cases of severe anemia, a blood transfusion is given.[10] Further, close monitoring is needed if tachyarrhythmias are transient or intermittent. They are corrected with cardioversion, antiarrhythmic drugs, and pacing if severe.[29]

Despite aggressive treatment, the survival rate is as low as 10%, with neurodevelopmental and cognitive defects in surviving infants. The recurrence rate is highest in mothers whose infants have chromosomal abnormalities or Rh incompatibility. Hence, autopsies, including histopathologic evaluation, placental examination, and molecular and genetic studies, are performed to determine the cause of hydrops.[30]

Differential Diagnosis

The differential diagnoses for hydrops fetalis include the following:

• Neonatal hemochromatosis
• Congestive cardiac failure
• TTTS
• Hepatitis B
• Hypercalcemia
• Hypernatremia
• Hypothrombinemia
• Maternal diabetes
• Fetal abdominal cysts
• Obstructed bowel
• Obstructed urinary system [31]

Prognosis

The prognosis of hydrops fetalis is dependent mainly on the underlying cause, gestational age at the time of the diagnosis, time of delivery, amount of fetal edema, and intrauterine interventions.[10] Neonates who present with thoracic causes and bronchopulmonary malformations have a good prognosis, while those with chromosomal abnormalities, structural abnormalities, and other genetic metabolic disorders are associated with poor prognosis.[32]

Survival in hydrops fetalis depends on the underlying disease, available fetal therapies to resolve hydrops, and the gestational age of delivery, not on the specific anatomic manifestations of hydrops. The cardiovascular profile score may be a useful prognostic indicator in fetuses with hydrops and high cardiothoracic ratios. Patients with hydrops who can have a fetal intervention for their underlying condition now benefits from improved survival, especially when hydrops can be resolved and there is no preterm delivery. While particular physiologic parameters such as the middle cerebral artery peak systolic velocity did not predict survival, the cardiovascular profile score is useful for predicting survival when the underlying cause results in a high cardiothoracic ratio. Furthermore, the fact that patients with such variable disease processes and cardiac manifestations can converge on the simple anatomic finding of fluid in 2 compartments suggests a basic fetal distress mechanism that is yet to be discovered.[17]

Complications

The complications that can manifest with hydrops fetalis are as follows:

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

Appendiceal rupture, cystic hygroma, intestinal obstruction, and severe neurodevelopment delay are seen in infants who survive with hydrops fetalis.[33][34]