Nonimmune Hydrops Fetalis

Nonimmune hydrops fetalis is abnormal accumulation of fluid in two or more fetal compartments (ascites, pleural effusion, pericardial effusion, generalised skin oedema greater than 5 mm), or in one compartment together with polyhydramnios or placental thickening, in the absence of red cell alloimmunisation. It now accounts for more than 90 percent of hydrops cases. It is a final common pathway rather than a diagnosis.

Fluid accumulates when lymphatic return fails to keep pace with capillary filtration, through raised central venous pressure, reduced colloid oncotic pressure, increased capillary permeability, or primary lymphatic obstruction.

Causes, in approximate order of frequency in modern series:

• cardiovascular (structural defects, tachyarrhythmia, bradyarrhythmia from complete heart block)
• chromosomal (Turner syndrome, trisomies 21, 18, 13, triploidy)
• lymphatic dysplasia (cystic hygroma, generalised lymphatic dysplasia)
• thoracic lesions (congenital pulmonary airway malformation, diaphragmatic hernia, chylothorax)
• haematological (alpha thalassaemia major with Hb Bart, fetomaternal haemorrhage, red cell enzyme defects, parvovirus B19 aplasia)
• infection (parvovirus B19, cytomegalovirus, toxoplasmosis, syphilis, Zika)
• genetic syndromes (Noonan syndrome, RASopathies, inborn errors of metabolism including lysosomal storage disease)
• twin twin transfusion
• placental and cord tumours (chorioangioma, sacrococcygeal teratoma)
• idiopathic (about 15 to 25 percent)

Mortality overall is 50 to 60 percent and depends on cause and gestation at onset.

• Usually detected at routine ultrasound as fetal ascites, pleural or pericardial effusion, scalp or body wall oedema, or thickened placenta.
• Maternal presentation: uterus large for dates from polyhydramnios (present in about 30 to 75 percent), reduced fetal movements, and in some cases maternal mirror syndrome.
• Maternal mirror syndrome comprises maternal oedema, hypertension, proteinuria, haemodilution and raised urate resembling pre-eclampsia, with fetal hydrops, often with haemoglobin that is low rather than high.
• Maternal history relevant to cause: rash or fever or contact with children (parvovirus), travel (Zika), consanguinity, family history of thalassaemia or metabolic disease, maternal anti-Ro or anti-La antibodies (heart block), diabetes.
• Complications: pulmonary hypoplasia from prolonged thoracic compression, preterm labour from polyhydramnios, intrauterine death, and postpartum haemorrhage from placentomegaly and uterine overdistension.

• Detailed anatomical ultrasound including fetal echocardiography, to define which compartments are involved, exclude structural heart disease, and measure fetal rhythm by M-mode.
• Middle cerebral artery peak systolic velocity: above 1.5 multiples of the median indicates fetal anaemia and directs towards haematological, parvovirus or fetomaternal haemorrhage causes.
• Maternal blood: full blood count, group and antibody screen (to confirm non-alloimmune), Kleihauer-Betke or flow cytometry for fetal cells, haemoglobin electrophoresis, G6PD and pyruvate kinase where relevant, parvovirus B19 IgM and PCR, CMV, toxoplasma, syphilis serology, Zika where exposure, anti-Ro/La, glucose tolerance, and TORCH panel.
• Invasive testing: amniocentesis for chromosomal microarray, karyotype, PCR for CMV and toxoplasma, and exome sequencing in negative cases (diagnostic yield of exome sequencing in unexplained hydrops is about 30 percent). Fetal blood sampling when anaemia must be proven.
• Effusion sampling (pleural or ascitic) for lymphocyte percentage (chylothorax) and infection studies.
• Postnatal or post-mortem examination where the pregnancy ends: autopsy, placental histology, skeletal survey, skin biopsy and fibroblast culture, and metabolic testing.

Management is directed at the cause, the gestation, and the severity of fetal compromise, after counselling about the prognosis.

• Fetal anaemia (parvovirus B19, fetomaternal haemorrhage): intrauterine transfusion of O-negative, irradiated, CMV-safe, packed red cells by intravascular route, 10 to 20 mL/kg estimated fetal weight, targeting a post-transfusion haemoglobin of 14 to 16 g/dL (hydrops resolves over 4 to 8 weeks in most parvovirus cases).
• Fetal tachyarrhythmia: transplacental maternal digoxin loading 0.5 mg intravenously or 0.25 to 0.5 mg orally every 8 hours for 24 hours then 0.25 mg twice daily to a level of 1 to 2 ng/mL.
• Add flecainide 100 mg orally every 8 to 12 hours or sotalol 80 to 160 mg every 12 hours when response is inadequate (sotalol preferred for atrial flutter; monitor maternal QT and electrolytes).
• Complete heart block with anti-Ro: dexamethasone 4 mg daily has been used with variable benefit; beta agonist (salbutamol or terbutaline) for ventricular rates below 55.
• Large pleural effusion or chylothorax: thoracocentesis, or thoracoamniotic shunt (double pigtail) for recurrent reaccumulation, ideally before 32 weeks. Fetal pleural sclerosis with OK-432 is used in some centres.
• Congenital pulmonary airway malformation with hydrops: maternal betamethasone 12 mg intramuscularly in two doses 24 hours apart, or fetal resection or thoracoamniotic shunt in selected cases.
• Sacrococcygeal teratoma and chorioangioma with high output state: laser coagulation or radiofrequency ablation of feeding vessels in selected cases.
• Twin twin transfusion: fetoscopic laser coagulation of anastomoses.
• Alpha thalassaemia major: in utero transfusion programmes and postnatal stem cell transplantation are possible but are for specialist centres.
• Maternal care: serial ultrasound every 1 to 2 weeks for effusion size, MCA-PSV and amniotic fluid; maternal blood pressure and urine monitoring for mirror syndrome; amnioreduction for symptomatic polyhydramnios; antenatal corticosteroids if delivery before 34 weeks is anticipated.
• Delivery: at a tertiary centre with neonatal resuscitation expertise, with the paediatric surgery and cardiology teams informed. Caesarean section is for obstetric indications. Skin oedema and effusions can make ventilation difficult, so thoracocentesis and paracentesis may be needed immediately at birth. Postpartum haemorrhage prophylaxis is essential.
• Termination is an option within legal limits when a lethal cause such as trisomy 18 or 13 or alpha thalassaemia major is established.
• Recurrence counselling depends on the cause; autosomal recessive metabolic and haematological causes carry a 25 percent recurrence risk.