Continuing Education Activity

Hydrops fetalis, also known as fetal hydrops, is not a disease but rather a symptom of an underlying health problem that affects the fetus. If left untreated, the excess fluid can stress the fetal heart and other vital organs, putting the fetal life at risk. This activity outlines the evaluation and management of women carrying a fetus with hydrops fetalis and highlights the role of the interprofessional team in the care of pregnant women with this condition.

Objectives:

• Identify the pathophysiology of hydrops fetalis.

• Determine the important features for the diagnosis of hydrops fetalis.

• Identify the importance of ultrasound surveillance in decreasing the incidence of hydrops fetalis.

• Communicate the importance of improving care coordination among the interprofessional team members to improve healthcare outcomes for hydrops fetalis.

Introduction

Hydrops fetalis is a condition in the fetus characterized by the abnormal interstitial fluid collection in 2 or more compartments of the fetal body (peritoneal cavity, pleura, and pericardium). An alternative definition discusses liquid accumulation in 2 fetal anatomical areas or effusion in 1 site and anasarca.[1] 

Traditionally, the diagnosis was made after the delivery of a massively edematous neonate that was often stillborn. With sonography, hydrops fetalis has become a prenatal diagnosis. With condition progression, edema is invariably a component, often accompanied by placentomegaly and hydramnios. Hydrops fetalis may result from a wide range of conditions with varying pathophysiologies, each with the potential to affect the fetus severely. It is divided into 2 categories, namely immune and nonimmune. If found in association with red cell alloimmunization, it is termed immune hydrops fetalis. Otherwise, it is called nonimmune hydrops fetalis.

Immune hydrops or erythroblastosis fetalis results from antibodies in the maternal circulation that pass through the placenta and react with the fetal antigens, resulting in fetal hemolysis. Nonimmune hydrops result from causes other than antigen-antibody reactions.[2] Hydrops fetalis is not a consequence of heart failure but rather hypervolemia and the high vascular permeability of fetuses. In contrast, heart failure is a very late consequence of a long-standing overworked heart.[3]

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]

Deterrence and Patient Education

Hydrops fetalis carries a poor prognosis if fetuses develop pulmonary hypoplasia, have underlying heart diseases, or are diagnosed before 24 weeks of gestation. Termination of pregnancy is considered if hydrops is diagnosed in early gestation with no treatable cause. NIHF is associated with an overall perinatal mortality rate of 50% to 98%.[35] 

Prognosis depends upon the etiology, the gestational age at onset, the gestational age at delivery, and whether pleural effusions are present. In general, the earlier hydrops occur, the poorer the prognosis. In particular, pleural effusions and polyhydramnios before 20 weeks of gestation are poor prognostic signs because of increased risks of pulmonary hypoplasia and preterm prelabour rupture of membranes/preterm delivery, respectively. On the other hand, the absence of aneuploidy and major structural abnormalities confer a better prognosis.[36]

Recurrence in future pregnancies is uncommon unless it is associated with Rh incompatibility or chromosomal abnormalities. Repeated antenatal care with ultrasound surveillance is required every 1 to 2 weeks if the hydrops are resolving, and the mother is frequently evaluated for the signs of mirror syndrome. Patients treated for immune hydrops are delivered at 37 weeks of gestation or when the fetus's lung maturity is confirmed. There is no substantial evidence that a cesarean section has a superior outcome. Delivery is performed in a tertiary center with neonatal intensive care in the presence of an experienced neonatal team. Immediate resuscitation is done, and proper postnatal care is needed for newborn babies.

Enhancing Healthcare Team Outcomes

Carrying a baby with hydrops fetalis can be extremely stressful and challenging for the pregnant woman and her family. A close collaboration between the obstetric providers, maternal-fetal medicine specialists, radiologists, neonatologists, nursing staff, pharmacists, and social support workers is paramount to enhancing the outcome for the mother and her baby. The well-being of both the mother and the fetus(s) is always considered a priority. When hydrops fetalis is diagnosed in utero, the interprofessional team should be well prepared to detect the symptoms and signs of fetal hydrops.

Careful evaluation and monitoring are required to look for the development of complications for early detection and subsequent management to prevent perinatal morbidity and mortality. Additionally, pharmacists are vital in educating patients and monitoring their compliance with their prescribed medications. The nurse plays a vital role in educating the woman and her family and providing them with the necessary information. Pregnant women carrying a fetus with hydrops fetalis should be treated in a very respectful and sensitive manner. They should be given adequate time to express their views, wishes, and concerns. Their opinions and beliefs should be respected at all times.

Patient awareness helps in the early identification and timely reporting of symptoms. The nurse should ensure proper follow-up and notify the medical team about any untoward change or deterioration of the condition of the mother or the newborn. Social workers should also ensure that pregnant women are getting adequate emotional and financial support to deal with their condition. The interprofessional team members should collaborate and discuss with the woman and her family that the etiology of fetal hydrops can not always be determined; therefore, genetic consultation can be useful in estimating their risks and discussing their future pregnancy plans. Coordinated collaboration among interprofessional team members helps improve pregnant women's clinical outcomes. Still, it also helps to maximize the emotional, psychological, and mental well-being of women carrying fetuses with hydrops fetalis.