**1.2 Epidemiology**

The precise incidence of hydrops fetalis is difficult as some cases spontaneously resolve or diagnosis is not seen until fetal demise or miscarriage. The overall incidence of fetal hydrops reported in the literature is between 1 in 1500 and 1 in 3000 pregnancies [4].

### *Complications of Pregnancy*

With the advent of anti-D immunoglobulin, the incidence and mortality due to immune hydrops fetalis have reduced with an increase in nonimmune fetal hydrops in about 90% of cases [5–8].

The diagnosis of hydrops fetalis is usually made antenatally and is a challenging condition to counsel and is usually a preterminal manifestation of many different pathophysiological conditions.

A recent publication from a single centre in Australia showed that the overall survival from diagnosis was 27%. The perinatal mortality risk is high when infants are born with hydrops fetalis and is dependent on the underlying diagnosis.

## **2. Classification**

Hydrops fetalis is broadly classified into immune and nonimmune.

### **2.1 Immune fetal hydrops**

Immune hydrops fetalis is due to red cell antibodies. There are many red cell antibodies of which rhesus D, c, and E are the commonest. The incidence of Rh D antibodies is reducing secondary due to the widespread use of anti-D at least in the developed countries. There appears to be an increase in other red cell antibodies that are now commonly associated with immune hydrops fetalis that can cause hemolytic disease of the newborn. These are kell antibodies, Duffy, and other red cell antibodies. Lewis and p antibodies rarely cause hemolytic disease of the newborn. The mechanism of fetal hydrops is secondary to fetal anemia. Fetal anemia is due to direct red cell destruction by the red cell antibodies that cross the placenta, especially if the baby has a different blood group and type to the mother. Anemia causes high output cardiac failure and fetal hydrops.

 In the Caucasian population, about 85% are rhesus (Rh) positive, which leaves about 15% Rh negative. When the mother is Rh negative and has never been sensitized before (no previous pregnancy, miscarriage, termination of pregnancy, or ectopic pregnancy), the sensitization event happens with the first pregnancy if the partner is positive. A sensitization event can happen spontaneously during pregnancy (feto maternal hemorrhage) and in labour or during an event such as maternal trauma, abruption, invasive procedures, antepartum hemorrhage, and external cephalic version. During these events, anti-D must be administered in Rh-negative women with an Rh positive partner. When possible, partner testing for both phenotype and genotype of his blood group must be requested. Currently, the widespread use of free fetal DNA in the detection of fetal D gene is helpful in identifying the Rh status of the fetus from maternal blood sample performed after 10 weeks of gestation. Amniocentesis can be performed to assess the fetal Rh D status as well; this will again increase the sensitization during pregnancy.

 Hydrops fetalis that develop in the absence of red cell hemolysis is termed as nonimmune fetal hydrops (NIFH) and was first described by Dr. Potter in 1943. The reported incidence of nonimmune fetal hydrops (NIFH) is 1 in 2000–3000 pregnancies [4, 5]. These result in about 3% of perinatal mortality and 50% diagnosed in utero will result in fetal demise and 50% of live born will not survive the neonatal period.

### **2.2 Nonimmune fetal hydrops (NIFH)**

 There are many causes for nonimmune fetal hydrops. In the past, many were thought to be idiopathic. Recent literature review shows that a cause can be identified prenatally in 65% of cases and up to 85% postnatally [9]. They are broadly divided as maternal, fetal, placental, and idiopathic causes.

## *2.2.1 Maternal*

Hemoglobinopathies (both alpha and beta thalassemia) are caused especially when both parents are carriers. Alpha thalassemia can cause severe fetal hydrops early in pregnancy, especially Barts [10] hemoglobinopathy (4 gene deletion) hemolysis is the cause of fetal hydrops, fetomaternal hemorrhage (abruption), and maternal hemolytic anemia.

Infection—some maternal infections can cause fetal infection and affect neural development, e.g., cytomegalovirus, toxoplasmosis, parvovirus [11] (erythrogenic), syphilis, and Zika virus.

Maternal antibodies—anti-Ro and La antibodies can be positive in mothers with autoimmune disorders such as systemic lupus erythematosis, rheumatoid arthritis. These mothers are tested for other antibodies including antiphospholipid and extractable nuclear antibodies (Ro and La). These antibodies cross the placenta and in 6% of cases can cause congenital heart block in the fetus as they affect the purkinje fibers of the heart. With a very low heart rate, the fetus is at increased risk of developing hydrops [12, 13] (low cardiac output and heart failure).

Neonatal alloimmune thrombocytopenia and idiopathic thrombocytopenia—in neonatal alloimmune thrombocytopenia (NAIT), due to incompatible platelet antibodies (human platelet antibody A1A and 5A) between maternal and paternal platelets, there is production of antibodies against maternal platelets. The risk of neonatal thrombocytopenia is very high, 85–100%. These IgG antibodies cross the placenta and destroy fetal platelets causing anemia and fetal hydrops. Unlike rhesus alloimmunisation where the first pregnancy is less likely to be affected when there was no preceding sensitizing event, NAIT affects the first pregnancy (diagnosis is made after the affected pregnancy) and increases the risk for subsequent pregnancies.

When there is maternal idiopathic thrombocytopenia, the risk of fetal thrombocytopenia is low 1–2%, fetal monitoring is recommended both antenatally and intrapartum. The risk of fetal thrombocytopenia is high when maternal platelets fall below 20 × 106 .

### *2.2.2 Placental*

Placental chorioangiomas are tumors of the placenta and is usually a pathological diagnosis. When the size of the chorioangiomas is over 5 cms and the cord insertion is close to the chorioangioma, there is an increased vascular turbulence leading to microangiopathic anemia leading to fetal hydrops and polyhydramnios.

 Monochorionic twin pregnancies—especially in 15% of monochorionic diamniotic twin gestations, there is unbalanced vascular communication between the twins leading to unbalanced transfusion where one of the twins can be hydropic (recipient) or polycythemic, while the other can be anemic. Untreated twin-to-twin transfusion [14] leads to fetal hydrops in the recipient and fetal demise in one twin, which can in turn result in the death of the other twin as well.

### *2.2.3 Fetal*

There are many fetal conditions that can give rise to fetal hydrops, which can be broadly classified as:

1. chromosomal—trisomy and 45XO (Turner's syndrome) [15]

2. structural

	- toxoplasma, rubella, cytomegalovirus, herpes virus, syphilis, and parvovirus are the common fetal infections. Parvovirus is highly erythrogenic, and the resulting fetal anemia is due to failed erythropoiesis. There is an estimated 1–2% risk of seroconversion in pregnancy that increases to 10% during epidemics. There is still a fetal loss rate of 3–10% depending on gestational age of exposure

 Fetal tachyarrhythmia includes supraventricular tachycardia, fetal atrial fibrillation, or flutter. In total, 90% of fetal tachyarrhythmia is due to fetal supraventricular tachyarrhythmia. Atrial flutter (FHR > 300 bpm) and fibrillation are less common. When fetal heart rates are above 220 bpm, there is reduced diastolic filling with reduced ejection fraction and cardiac output. This in turn results in poor perfusion, reduced oxygenation, and elevated CVP and hepatic congestion. The risk of fetal hydrops is inversely related to gestational age, and this could be related to immaturity of fetal myocardium [17].

### *Hydrops Fetalis DOI: http://dx.doi.org/10.5772/intechopen.83443*

Fetal bradyarrhythmias are due to congenital heart block, and fetal hydrops is secondary to low cardiac output and inadequate oxygen perfusion and also to venous congestion. The risk is higher when FHR is less than 95 bpm and often when <65 bpm.

Congenital structural anomalies of the heart may predispose to high output failure and may be associated with other chromosomal or structural anomalies [18].

 Heritable hemoglobinopathies are usually autosomal recessive, and testing for this is done is either done pre or antenatally. Fetal anemia causes high output cardiac failure and increased central venous pressure, leading to fetal hydrops. Antiplatelet antibodies cross the placenta and destroy fetal platelets similar to rhesus alloimmunisation, resulting in fetal anemia and hydrops.

Fetal infection that crosses the placenta usually causes myocarditis, suppresses erythropoiesis, causes hemolysis, and hepatitis. Examples of fetal infection are toxoplasma, cytomegalovirus, rubella, herpes virus, syphilis, parvovirus and others include coxsackie virus, *Listeria monocytogenes*.

Hydrops fetalis is associated with more than 75 inborn errors of metabolism, genetic syndromes, and chromosomal abnormalities. The inheritance is usually autosomal recessive with some conditions that could be X linked.

Cystic hygromas are usually associated with aberration in lymphatic drainage. They are usually seen as cystic spaces in the fetal neck, but can also be seen in fetal thorax or abdomen. These findings can be associated with 45XO (Turner's syndrome) [6] and are usually seen in aborted fetuses. There are some cases of spontaneous resolution of cystic hygromas, but prognosis is usually poor (90–95% mortality) especially when associated with hydrops fetalis even with normal karyotype. The differential diagnoses include Noonan syndrome and multiple pterygium syndrome.

Thoracic and abdominal tumors, by way of their size and location, obstruct both venous and lymphatic return to the fetal heart, causing fetal hydrops.

In some tumors such as sacrococcygeal teratomas [19] or chorioangiomas, the resulting fetal hydrops is not only due to the size of the tumor but also due to the increased vascularity in them behaving like an arteriovenous malformation, leading to high output cardiac failure, and microangiopathic fetal anemia.

Isolated pleural effusion, unilateral or bilateral, is seen without progression to fetal hydrops, especially with abnormal lymphatic development [20].
