**3. Pathophysiology**

 There have been many hypotheses for fetal hydrops. Distribution of body water is between the intracellular (blood and tissues) and extracellular (plasma, interstitial space, and transcellular) space.

The basic mechanism is an abnormal fluid movement between plasma and tissues and the imbalance between the interstitial production and lymphatic return [21].

Four main theories have been postulated:


**Figure 1.** 

*Flow chart of possible pathophysiology in NIFH [6].* 

Fluid accumulation may be due to congestive cardiac failure, obstruction to the lymphatic flow, or reduced oncotic pressure. The fetus has greater capillary permeability and an interstitial compartment that can accommodate extra fluid.

When there is fetal hypoxia, there is redistribution to the vital organs such as brain, heart, and adrenals. There is reduced blood flow to fetal kidneys and gut. The reduced renal blood flow activates the renin angiotensin system (RAS) to enhance cardiac output. This also increases the venous pressure and thereby increases in interstitial fluid accumulation.

Due to reduced hepatic blood flow and increase in extramedullary hematopoiesis, there is reduction in albumin production causing hypoalbuminemia, thereby reducing the oncotic pressure and causing fluid shift. Many animal models have been studied in order to understand hydrops. The largest systematic review by Bellini et al. [6] also illustrated the possible pathophysiological causes of NIFH (**Figure 1**).

With fetal hydrops, there is a risk of maternal mirror syndrome (Ballantyne's syndrome) in some patients, where the mother develops edema similar to the hydropic fetus.

Mirror syndrome represents a form of preeclampsia characterized by edema (90%), high blood pressure (60%), and proteinuria (40%) of cases [22–25]. The incidence is unclear and may not be reported. Review of literature shows a maternal mortality of about 20% secondary to pulmonary edema. With treatment for fetal hydrops, maternal symptoms have noted to resolve.

The imbalance between the angiogenic and antiangiogenic factors that are implicated in severe preeclampsia is also thought to be the underlying pathogenesis of this condition. When the underlying NIFH cannot be treated and when there are ongoing symptoms of maternal mirror syndrome, delivery is indicated.

## **4. Investigations**

Maternal blood tests—the first line of investigation would be to rule out immune hydrops fetalis.

### **Figure 2.**

*Ultrasound findings fetal hydrops [1]. (A) Pericardial effusions, (B) pleural effusions; note: midline heart anterior to small lungs with bilateral effusions, (C) placental thickening, with placenta measuring >4 mm in thickness, (D) skin thickening at level of fetal skull, (E) ascites, sagittal, with free-floating loops of bowel surrounded by ascites, and (F) ascites in upper abdomen, at level of fetal liver and stomach [1].* 

Maternal rhesus status, antibodies, full blood count, Kleihauer-Betke test, and indirect Coombs test are requested.

The other blood tests are for nonimmune hydrops fetalis.

Hemoglobin electrophoresis is requested to rule out thalassemia, both alpha and beta. This screen is especially important in Mediterranean, Indian, and Asian ethnic groups.

TORCHS+P serology (toxoplasma, rubella, cytomegalovirus, herpes, syphilis, and parvovirus).

If fetal heart rate is lower than 100 bpm, anti-Ro and La antibodies to be requested.

Maternal serum electrolytes and liver function tests, including urinary PCR, are recommended to rule out maternal mirror syndrome. When fetal hydrops is associated with abnormal placenta, triploidy or partial molar pregnancy cannot be ruled out; hence, serum beta-HCG and thyroid function tests are performed in this situation.

### **Figure 3.**

*Transverse section of fetal head showing middle cerebral artery—Google images.* 

A detailed tertiary ultrasound of the fetus/fetuses is recommended including amniotic fluid volume and Doppler studies looking for fetal anemia.

Fetal tertiary ultrasound is the key to diagnose most of the above-mentioned fetal structural abnormalities. A thorough assessment including fetal weight, morphology, amniotic fluid volume, and placental morphology are recommended.

Fetal heart rate documentation is vital to rule out both tachy and brady arrhythmias.

Fetal dopplers including umbilical artery, vein, ductus venosus, tricuspid regurgitation, and middle cerebral artery peak systolic velocity (MCA PSV) measurements are very helpful in the investigation of hydrops fetalis.

 The middle cerebral artery Doppler known as MCA peak systolic velocity is a good noninvasive measure of fetal anemia. With fetal anemia and possible hypoxia, velocity of blood flow to the fetal brain increases. When the MCA PSV is above 1.5 multiples of the median (MoM), there is a high risk of fetal anemia. The falsepositive rate of this measurement is around 10% and increases after 35 weeks of gestation (**Figures 2** and **3**).

Invasive testing such as amniocentesis and amniodrainage [26] is discussed and performed under ultrasound guidance. Maternal rhesus status is checked so that the patient is given anti-D when not sensitized.

The amniotic fluid is sent for chromosome tests—fluorescent in situ hybridization (FISH), chromosomal microarray, rasopathy, or hydrops panel including Noonan's syndrome, lysosomal storage disease and in some centres whole exome sequencing. Polymerase chain reaction (PCR) from the amniotic fluid is sent for fetal infection such as TORCHS+parvovirus' DNA for specific conditions if known.

When there is evidence of fetal pleural effusion, either a pleural tap or insertion of a pleuroamniotic shunt is inserted to drain the pleural effusion/effusions [27]. The sample is also sent for lymphocytes apart from infection and karyotype.

The presence of fetal sacrococcygeal teratoma is confirmed, and fetal magnetic resonance imaging (MRI) may be required to identify the intrapelvic extension.
