Hydrops fetalis

# Overview
Hydrops Fetalis indicates an excessive accumulation of interstitial fluid in extravascular compartments and body cavities which is characterized by generalized skin edema, ascites, pleural, or pericardial effusion, and placental enlargement. It may be classified into two groups based on the presence or absence of rhesus iso-immunization. Although Rh disease is the major cause of immune-mediated hydrops fetalis, with the decreased prevalence of Rh disease, non-immune causes (eg, cardiovascular diseases, chromosomal abnormalities, lymphatic anomalies, hematologic diseases, etc.) are responsible in the majority of cases. Screening for Rh(D) incompatibility by Rh(D) blood typing and antibody testing are strongly recommended for all pregnant women during their first visit for pregnancy-related care. Also repeated Rh(D) antibody testing for all unsensitized Rh(D)-negative women at 24 to 28 weeks gestation is recommended unless the biological father is known to be Rh(D) negative. Prognosis is generally poor, and the mortality rate of patients with non-immune hydrops fetalis (NIHF) is approximately 43.2% at 1 year of age, and the presence of either large birth weight, polyhydramnios, or prematurity are associated with a particularly poor prognosis among patients. Ultrasound may be helpful in the diagnosis of hydrops fetalis. Findings on ultrasound suggestive of hydrops fetalis include increased skin thickness (indicative of generalized skin edema), increased placental thickness (indicative of placental edema), polyhydramnios, ascites, pleural effusion, and pericardial effusion. Detailed evaluation and resuscitation are recommended among all neonates with hydrops fetalis. Treatment is usually based on the underlying etiology.

# Historical Perspective
Hydrops fetalis was first discovered by Dr. John William Ballantyne, a Scottish physician and obstetrician, in 1892.

# Classification
Hydrops Fetalis may be classified into two groups based on the presence or absence of rhesus iso-immunization:
- Immune Hydrops Fetalis
- Non-Immune Hydrops Fetalis (NIHF)

# Pathophysiology
It is thought that hydrops fetalis is caused by conditions with either increased rate of fluid transudation from the vascular compartment or decreased lymphatic return to the circulation.
- This is shown to be originated from developmental defects in microcirculation and lymphatic system, respectively.
- The potential causes may be immune or non-immune, and they often result in anemia and further hypoxia.
- The sympathetic system becomes activated due to hypoxia, and it causes blood redistribution with decreased blood flow to the liver and kidneys.
- Decreased blood flow to the liver and kidneys, results in decreased albumin, increased ADH, and increased activity of RAAS.
- Following these changes, the central venous pressure increases, which further results in decreased lymphatic return.
- As a result, hydrops fetalis (the accumulation of fluid, or edema, in at least two fetal compartments) occurs.
- The pathophysiology of non-immune causes also depend on the underlying conditions, include:
Decreased ventricular filling during diastole (i.e. tachyarrhythmias)
Increased central venous pressure due to the increased right heart pressure (i.e. cardiac tumors and subendocardial fibroelastosis)
Obstruction of lymphatic drainage due to a mass (i.e. cystic hygroma)
- Decreased ventricular filling during diastole (i.e. tachyarrhythmias)
- Increased central venous pressure due to the increased right heart pressure (i.e. cardiac tumors and subendocardial fibroelastosis)
- Obstruction of lymphatic drainage due to a mass (i.e. cystic hygroma)

# Causes
Hydrops Fetalis is caused by either immune or non-immune conditions.
- Immune hydrops fetalis
Antibodies may occur due to the exposure to non-self RBC antigens during the previous pregnancy or transfusion.
In the next pregnancy, these antibodies may attack the fetal erythrocytes if the fetus has that antigen.
Following the red blood cell destruction, hemolytic disease of the fetus and newborn (HDFN) may occur with a wide range of clinical outcome from only mild anemia to high output heart failure and hydrops fetalis.
Rh disease is the major cause of immune-mediated hydrops fetalis; however, owing to preventative methods developed in the 1970s, the incidence of Rh disease has markedly declined.
Rh disease can be prevented by the administration of anti-D IgG (Rho (D) Immune Globulin) injections to RhD-negative mothers during pregnancy and/or within 72 hours of the delivery.
ABO incompatibility usually occurs asymptomatic without any clinically significant outcomes. However, it may rarely cause hemolytic disease of the fetus and newborn (HDFN) which may further results in hydrops fetalis.
- Antibodies may occur due to the exposure to non-self RBC antigens during the previous pregnancy or transfusion.
- In the next pregnancy, these antibodies may attack the fetal erythrocytes if the fetus has that antigen.
- Following the red blood cell destruction, hemolytic disease of the fetus and newborn (HDFN) may occur with a wide range of clinical outcome from only mild anemia to high output heart failure and hydrops fetalis.
Rh disease is the major cause of immune-mediated hydrops fetalis; however, owing to preventative methods developed in the 1970s, the incidence of Rh disease has markedly declined.
Rh disease can be prevented by the administration of anti-D IgG (Rho (D) Immune Globulin) injections to RhD-negative mothers during pregnancy and/or within 72 hours of the delivery.
ABO incompatibility usually occurs asymptomatic without any clinically significant outcomes. However, it may rarely cause hemolytic disease of the fetus and newborn (HDFN) which may further results in hydrops fetalis.
- Rh disease is the major cause of immune-mediated hydrops fetalis; however, owing to preventative methods developed in the 1970s, the incidence of Rh disease has markedly declined.
- Rh disease can be prevented by the administration of anti-D IgG (Rho (D) Immune Globulin) injections to RhD-negative mothers during pregnancy and/or within 72 hours of the delivery.
- ABO incompatibility usually occurs asymptomatic without any clinically significant outcomes. However, it may rarely cause hemolytic disease of the fetus and newborn (HDFN) which may further results in hydrops fetalis.
- Non-immune hydrops fetalis (NIHF)
Currently, with the decreased prevalence of Rh disease, non-immune causes are responsible in the majority of cases.
The most common causes of non-immune hydrops fetalis are cardiovascular diseases, chromosomal abnormalities, lymphatic anomalies, and hematologic diseases. Causes of NIHF include:
Structural cardiac malformations (especially hypoplastic left heart, endocardial cushion defect)
Arrhythmias
Congenital lymphatic dysplasia
Chromosomal abnormalities (Turner Syndrome, trisomy 13, trisomy 18, trisomy 21)
Alpha-thalassemia
Fetomaternal transfusion
Infections (Parvovirus-B19, CMV, Adenovirus, Enterovirus)
Twin to twin transfusion syndrome (both donor and recipient fetus)
Congenital cystic adenomatoid malformation
Diaphragmatic hernia
Extrapulmonary sequestration
Hydrothorax
Chylothorax
Noonan Syndrome
Urethral Obstruction
Prune belly syndrome
Lysosomal storage diseases
Vascular tumors
Teratoma
Leukemia
Hepatic tumors
Neuroblastoma
Meconium peritonitis
Gastrointestinal obstructions
Approximately 20% of the NIHF cases are idiopathic.
- Currently, with the decreased prevalence of Rh disease, non-immune causes are responsible in the majority of cases.
- The most common causes of non-immune hydrops fetalis are cardiovascular diseases, chromosomal abnormalities, lymphatic anomalies, and hematologic diseases. Causes of NIHF include:
Structural cardiac malformations (especially hypoplastic left heart, endocardial cushion defect)
Arrhythmias
Congenital lymphatic dysplasia
Chromosomal abnormalities (Turner Syndrome, trisomy 13, trisomy 18, trisomy 21)
Alpha-thalassemia
Fetomaternal transfusion
Infections (Parvovirus-B19, CMV, Adenovirus, Enterovirus)
Twin to twin transfusion syndrome (both donor and recipient fetus)
Congenital cystic adenomatoid malformation
Diaphragmatic hernia
Extrapulmonary sequestration
Hydrothorax
Chylothorax
Noonan Syndrome
Urethral Obstruction
Prune belly syndrome
Lysosomal storage diseases
Vascular tumors
Teratoma
Leukemia
Hepatic tumors
Neuroblastoma
Meconium peritonitis
Gastrointestinal obstructions
- Structural cardiac malformations (especially hypoplastic left heart, endocardial cushion defect)
- Arrhythmias
- Congenital lymphatic dysplasia
- Chromosomal abnormalities (Turner Syndrome, trisomy 13, trisomy 18, trisomy 21)
- Alpha-thalassemia
- Fetomaternal transfusion
- Infections (Parvovirus-B19, CMV, Adenovirus, Enterovirus)
- Twin to twin transfusion syndrome (both donor and recipient fetus)
- Congenital cystic adenomatoid malformation
- Diaphragmatic hernia
- Extrapulmonary sequestration
- Hydrothorax
- Chylothorax
- Noonan Syndrome
- Urethral Obstruction
- Prune belly syndrome
- Lysosomal storage diseases
- Vascular tumors
- Teratoma
- Leukemia
- Hepatic tumors
- Neuroblastoma
- Meconium peritonitis
- Gastrointestinal obstructions
- Approximately 20% of the NIHF cases are idiopathic.

# Differential Diagnosis
- Hydrops Fetalis must be differentiated from other diseases that cause generalized skin edema, ascites, pleural, or pericardial effusion, placental enlargement, such as Mirror (Ballantyne) syndrome.
- However, Mirror (Ballantyne) syndrome is also characterized by maternal edema (the mother mirrors the edema present in the fetus), proteinuria, and hypertension.
- Hydrops fetalis must also be differentiated from other conditions that cause ascites such as portal hypertension. In hydrops fetalis, the serum ascites albumin gradient (SAAG) ratio should be less than 11 g/L (indicates that the etiology is not related to portal hypertension).

# Epidemiology and Demographics
- In developed countries, the incidence of non-immune hydrops fetalis (NIHF) is 25-79 per 100.000 live born infants worldwide.
- The median gestational age (GA) at diagnosis of NIHF is 23 weeks.

# Risk Factors
Maternal risk factors in the development of non-immune hydrops fetalis (NIHF) include:
- Multiple gestation
- Preexisting maternal diabetes
- Mental illness
- Illicit drug use
- Preeclampsia

# Screening
- According to the U.S. Preventive Services Task Force (USPSTF), screening for Rh(D) incompatibility by Rh(D) blood typing and antibody testing are strongly recommended for all pregnant women during their first visit for pregnancy-related care.
- The USPSTF recommends repeated Rh(D) antibody testing for all unsensitized Rh(D)-negative women at 24 to 28 weeks gestation, unless the biological father is known to be Rh(D) negative.

# Natural History, Complications, and Prognosis
- Without treatment or termination of pregnancy, the patient will develop conditions of neonatal asphyxia, skin edema, pleural effusion, ascites, polyhydramnios, or multiple malformations, which may eventually lead to intrauterine fetal death or neonatal death.
- Patients rarely survive after the neonatal period, and some of those patients who survive, die at 1 year of age.
- Approximately 68% of patients who survive after 1 year of age, have normal development. However, rest of those patients have developmental delay, mental retardation, and psychomotor retardation with marked growth failure in long-term follow-up.
- Prognosis is generally poor, and the mortality rate of patients with non-immune hydrops fetalis (NIHF) is approximately 43.2% at 1 year of age.
Deaths usually occur in the neonatal period.
The cause of deaths after the neonatal period are usually underlying disease rather than hydrops fetalis itself.
Gestational age is predictive of mortality, as preterm infants with this condition are more likely to die.
The presence of either large birth weight, polyhydramnios, or prematurity are associated with a particularly poor prognosis among patients.
- Deaths usually occur in the neonatal period.
- The cause of deaths after the neonatal period are usually underlying disease rather than hydrops fetalis itself.
- Gestational age is predictive of mortality, as preterm infants with this condition are more likely to die.
- The presence of either large birth weight, polyhydramnios, or prematurity are associated with a particularly poor prognosis among patients.

# Diagnosis

## Diagnostic Study of Choice
There are no established criteria for the diagnosis of hydrops fetalis.

## History and Symptoms
The hallmark of hydrops fetalis is an abnormal accumulation of fluid within the fetal body compartments. History and symptoms may differ among patients based on the etiology.
- A positive history of Rh(D) incompatibility is suggestive of immune hydrops fetalis.

## Physical Examination
The physical examination findings in the neonatal period may indicate the underlying diseases.
- The presence of cyanosis on physical examination and resistance to oxygen supplementation is highly suggestive of cardiac diseases.
- The presence of hypotonia on physical examination is highly suggestive of congenital myopathy and congenital hypothyroidism.
- Common physical examination findings of lysosomal storage diseases include hypotonia, facial dysmorphism, hepatomegaly, and cardiomyopathy.
- Common physical examination findings of TORCH infections include hepatomegaly, petechia/purpura, and chorioretinitis.

## Laboratory Findings
- Hydrops Fetalis may be caused by maternal TORCH infections, and parvovirus B19 infection, therefore, antibodies against these infections should be checked.
- Sjogren syndrome may cause hydrops fetalis with complete heart blocks and bradyarrhythmias, therefore, Anti-SS-A/SS-B antibodies should be considered in suspected cases.
- An elevated concentration of alpha-fetoprotein (AFP) may suggest fetomaternal hemorrhage, which may result in hydrops fetalis.
- Immune hydrops fetalis can be detected by direct and indirect coombs test.
- Thyroid hormone levels, complete blood count, and metabolic panel also should be checked in the neonatal period.

## Electrocardiogram
- A fetal ECG (fECG) may be helpful in the diagnosis of fetal arrythmias. Fetal ECG may show premature contractions, tachyarrhythmias, and bradyarrhythmias.
- Duration of tachycardia positively correlated with the presence of hydrops fetalis.

## Ultrasound
- Ultrasound may be helpful in the diagnosis of hydrops fetalis. Findings on ultrasound suggestive of hydrops fetalis include:
Increased skin thickness (indicative of generalized skin edema), most prominent in the fetal head and back of the neck. Also may be seen in the thorax and abdomen. It is usually the earliest finding.
Increased placental thickness (indicative of placental edema)
Polyhydramnios
Ascites
Pleural effusion
Pericardial effusion
Generalized skin edema, placental edema, polyhydramnios, and ascites are usually seen in early pregnancy.
Pleural effusion and pericardial effusion are findings seen later (rarely seen <15 weeks gestational age).
- Increased skin thickness (indicative of generalized skin edema), most prominent in the fetal head and back of the neck. Also may be seen in the thorax and abdomen. It is usually the earliest finding.
- Increased placental thickness (indicative of placental edema)
- Polyhydramnios
- Ascites
- Pleural effusion
- Pericardial effusion
Generalized skin edema, placental edema, polyhydramnios, and ascites are usually seen in early pregnancy.
Pleural effusion and pericardial effusion are findings seen later (rarely seen <15 weeks gestational age).
- Generalized skin edema, placental edema, polyhydramnios, and ascites are usually seen in early pregnancy.
- Pleural effusion and pericardial effusion are findings seen later (rarely seen <15 weeks gestational age).
- Ultrasonography may detect structural heart diseases, holoprosencephaly, or omphalocele. These associated findings may indicate the etiology of hydrops fetalis and may help in the differential diagnosis.

## Echocardiography
- Fetal echocardiography may be helpful in the diagnosis of structural heart diseases, cardiomyopathies, arrhythmias, heart failure, and other cardiac diseases. Thus, it may clarify the underlying etiology of non-immune hydrops fetalis (NIHF).

## Genetic Testing
- Genetic tests for non-immune hydrops fetalis include karyotype analysis, which may demonstrate aneuploidy, and chromosomal microarray analysis (CMA) which may further demonstrate copy number variants (CNVs), submicroscopic deletions, and duplications (as small as 50  100 kb).
- Even after applying these genetic tests, half of the underlying etiology of NIHF remains unclear.
- A more detailed and broader genetic test, whole exam sequencing (WES), may be helpful in the diagnosis of NIHF.
Underlying etiologies of NIHF which can be detected by whole exam sequencing include RASopathies (disorders of RASMAPK cell-signaling pathway), inborn errors of metabolism, musculoskeletal, lymphatic, cardiovascular, neurologic, hematologic disorders, and others.
Approximately one-third of NIHF disorders with unclear etiology, whole exam sequencing (WES) is shown to detect a possible genetic cause.
- Underlying etiologies of NIHF which can be detected by whole exam sequencing include RASopathies (disorders of RASMAPK cell-signaling pathway), inborn errors of metabolism, musculoskeletal, lymphatic, cardiovascular, neurologic, hematologic disorders, and others.
- Approximately one-third of NIHF disorders with unclear etiology, whole exam sequencing (WES) is shown to detect a possible genetic cause.

## Other Diagnostic Studies
- Other diagnostic studies for hydrops fetalis include chorionic villus sampling (CVS), which may demonstrate chromosomal abnormalities or Hb Barts disease.

# Treatment
Detailed evaluation and resuscitation are recommended among all neonates with hydrops fetalis. Treatment is usually based on the underlying etiology.
- There is no treatment for some of the structural heart diseases and chromosomal abnormalities; the mainstay of therapy is supportive care.
- The mainstay of treatment for severe anemia in fetus and neonate are intrauterine transfusion and blood transfusion, respectively.
- Fetal interventional procedures such as shunt placement, and thoracentesis may be required among patients with the rapid accumulation of fluid, mediastinal shift, and polyhydramnios.
- Neonates with severe ascites, pleural effusions, and pericardial effusion may be treated with paracentesis,thoracentesis, and pericardiocentesis, respectively.
- Treatment with either antiaryythmics, defibrillation/cardioversion, pacemaker implantation, implantable cardiac defibrillator (ICD) or radiofrequency ablation may be warranted for the neonates presenting with arrhythmia.

# Prevention
- According to the U.S. Preventive Services Task Force (USPSTF):
Administration of a full (300g) dose of Rh (D) immunoglobulin is recommended for all unsensitized Rh (D)-negative women after repeated antibody testing at 2428 weeks gestation.
If an Rh (D)-positive or weakly Rh (D)-positive (eg, Du-positive) infant is delivered, a dose of Rh (D) immunoglobulin should be repeated postpartum, preferably within 72 hours after delivery. Administering Rh (D) immunoglobulin at other intervals after delivery has not been studied.
Unless the biological father is known to be Rh (D)-negative, a full dose of Rh (D) immunoglobulin is recommended for all unsensitized Rh (D)-negative women after amniocentesis and after induced or spontaneous abortion; however, if the pregnancy is less than 13 weeks, a 50 g dose is sufficient.
The benefit of routine administration of Rh (D) immunoglobulin after other obstetric procedures or complications such as chorionic villus sampling, ectopic pregnancy termination, cordocentesis, fetal surgery or manipulation (including external version), antepartum placental hemorrhage, abdominal trauma, antepartum fetal death, or stillbirth is uncertain due to inadequate evidence.
- Administration of a full (300g) dose of Rh (D) immunoglobulin is recommended for all unsensitized Rh (D)-negative women after repeated antibody testing at 2428 weeks gestation.
- If an Rh (D)-positive or weakly Rh (D)-positive (eg, Du-positive) infant is delivered, a dose of Rh (D) immunoglobulin should be repeated postpartum, preferably within 72 hours after delivery. Administering Rh (D) immunoglobulin at other intervals after delivery has not been studied.
- Unless the biological father is known to be Rh (D)-negative, a full dose of Rh (D) immunoglobulin is recommended for all unsensitized Rh (D)-negative women after amniocentesis and after induced or spontaneous abortion; however, if the pregnancy is less than 13 weeks, a 50 g dose is sufficient.
- The benefit of routine administration of Rh (D) immunoglobulin after other obstetric procedures or complications such as chorionic villus sampling, ectopic pregnancy termination, cordocentesis, fetal surgery or manipulation (including external version), antepartum placental hemorrhage, abdominal trauma, antepartum fetal death, or stillbirth is uncertain due to inadequate evidence.