Non-Immune Hydrops

 

Reveiwed by Clinical Practice Group
February 2018
Clinical Guidelines Back Newborn Services Home Page

Immune hydrops fetalis is caused by red blood cell alloimmunisation haemolytic disease. All other causes are described as non-immune hydrops fetalis (NIHF). Hydrops is a symptom of a wide range of conditions which have resulted in an imbalance in fetal fluid between the vascular and interstitial space.1 Diagnostic criteria areF fluid in at least two body cavities (pleural space, pericardial space, peritoneal space, skin or placental enlargement). The prognosis depends on associated prematurity, the underlying cause, the severity of any associated pulmonary hypoplasia and the severity of the ongoing post-natal fluid accumulation (with problems of infection and malnutrition).2

Studies have found a perinatal mortality rate of up to 57%.3,4,5 Mortality and morbidity appears dependent on cause and gestational age at diagnosis. There is high risk for premature delivery.Neonatal motality remains high at 35% with an overall mortality of 43% at one year.There is one retrospective review reporting normal developmental outcome in half of 56 cases followed-up at one year and is more likely when NIHF is associated with tachyarrhythmia, congenital chylothorax, meconium peritonitis and parvovirus.4

Resuscitation

Any baby known to have NIHF should be delivered at a tertiary centre. Find out about the size of pleural effusions and severity of the hydrops from obstetric staff before delivery. It is important to prepare equipment before delivery. Resuscitation and stabilisation is often difficult. The level III specialist should be informed and may well need to attend the delivery. A senior neonatal nurse should also attend. It may be necessary to drain pleural effusions or ascites in the delivery room, at the same time as resuscitating the baby.

Associations with Non-Immune Hydrops

There is a long list of possible causes of NIHF see table below.

Half of the reported causes of NIHF comprise of cardiovascular anomalies/arrhythmias (21.4%), chromosomal abnormalities (12.5%) or are idiopathic - unexplained (18.2%).6
 

Click here to see images of hydropic infants.

Congenital Chylothorax

Lymphatic dysplasia, predominantly seen as chylothorax, contributes up to 15% of NIHF cases.6,7 The pleural fluid is serous until milk feeding begins and it turns chylous. Diagnosis is based on a high lymphocyte presence and protein concentration in the pleural fluid, in addition triglyceride and lipoproteins are present with feeding.

There is a risk of loss of anticoagulant factors and immunoglobulins along with malnutrition. Medium chain triglycerides are absorbed directly into the portal vein, bypassing lymphatic drainage. Enteral feeds are usually started with an MCT based formula while waiting for the chylous leakage to improve. The usual clinical course may take longer than 4 weeks to resolve. Note - MCT formulas do not contain essential fatty acids and may need supplementing if used for an extended period.

Evidence for the use of octreotide is based on collective case reports with a range of success.8 There is no standard treatment recommendation for the use of octreotide although it appears to be safe in neonates.9-12

Pathophysiological mechanism of NIHF

(Adapted from reference Bellini 2012)

Investigations

Many of these may have been done antenatally. Particular clinical findings may indicate other investigations for aetiology. Target investigations at clinical features. Collect cord blood EDTA and clotted samples.

Anaemia
  • Evidence of fetal anaemia.
  • Maternal blood group and antibodies.
  • Baby blood group and Coombs.
  • Early haemoglobin/PCV.
  • Maternal Kleihauer
Biochemistry
  • Liver function including albumin/protein
  • Renal function.
Cardiac rhythm in utero
  • Evidence from ultrasound scans and CTGs.
  • Post-natal ECG + monitoring.
Fluid examination
  • Protein and albumin
  • Cell cytology (commonly finding marked lymphocytosis).
  • Triglyceride levels after feeding started.
Placenta
  • Macroscopic examination, histology and Toxoplasma PCR.
Ultrasound
  • Head, heart, chest, abdomen.
X-rays
  • Chest, abdomen and long bones (skeletal abnormalities and congenital infection).
  • Further CT/MRI as indicated by clinical course and other results.
Genetics
  • SNP-Array if not performed antenatally +/- targeted gene testing (Discuss with Genetic services).
  • DNA sample sent for storage
  • Consider a skeletal survey
Hb electrophoresis  
Metabolic testing
  • If no other cause is found discuss with metabolic services regarding appropriate testing, for example consider lysosomal disorders.

Infective causes

Parvovirus
  • Fetal anaemia that may have recovered
  • PCR, IgG and IgM titres
  • Send baby/cord serum.
CMV
  • Urine culture/PCR.
  • Serum for CMV PCR.
Toxoplasma
  • Maternal and baby blood, placenta and amniotic fluid PCR
  • Baby/cord IgM.
Syphilis
  • Maternal serology (VDRL)
  • Baby/cord serology.
Congenital hepatitis
  • Maternal hepatitis B serology
  • Baby LFTs and liver US.
Rubella
  • Maternal serology before pregnancy
  • Urine ± CSF PCR.
  • WBC for rubella PCR
  • Serum IgM.
Herpes simplex
  • WBC PCR.
Varicella
  • Other features of congenital varicella.

Look for supportive evidence with long bone X-rays, cerebral US/CT and ophthalmic exam.

Cardiovascular
  • SVT
  • Heart block
  • Truncus arteriosus
  • Coxsackie myocarditis
  • Hypoplastic Left Heart Syndrome
  • Endocardial fibroelastosis
  • VSD/AV canal
  • Premature closure of foramen ovale
  • Premature closure of PDA
  • Tumours (rhabdomyomas)
  • Arterial calcification
  • Cardiomyopathy (e.g. carnitine deficiency)
  • AV malformations
  • Any cause of heart failure
Chromosomal
  • Trisomy 21
  • Triploidy
  • 45XO (Turner's)
  • Many others reported
Dysmorphic Syndromes
 
Neurological
  • Encephalocoele
  • Agenesis of the corpus callosum
  • Tuberous sclerosis
  • Vein of Galen aneurysm
  • Arthrogryposis
Gastrointestinal
  • Jejunal atresia
  • Midgut volvolus
  • Meconium peritonitis
  • Hepatitic fibrosis
  • Hepatic vascular malformations
  • Familial cirrhosis and portal hypertension
Genitourinary
  • Congenital nephrotic syndrome
  • Urethral obstruction and renal dysplasia
  • Polycystic kidneys
  • Renal vein obstruction
  • Vaginal and uterine abnormalities
Haematological
  • Twin-twin transfusion
  • Rhesus isoimmunisation
  • Feto-maternal haemorrhage
  • α-thalassaemia (homozygous)
  • Fetal anaemia or blood loss
  • G6PD deficiency
  • Pyruvate kinase deficiency
Lymphatic
  • Chylothorax
  • Congenital lymphangectasia
  • Cystic hygroma of neck
  • Noonan's Syndrome
Infective
  • Parvovirus
  • CMV
  • Toxoplasma
  • Syphilis
  • Leptospirosis
  • Chagas Disease
  • Congenital hepatitis
  • Rubella
  • Herpes simplex
  • Varicella
Respiratory
  • Diaphragmatic hernia
  • Cystic adenomatoid malformation
  • Hamartoma
  • Tracheo-oesophageal fistula
  • Atresia of right main bronchus
  • Sequestration
  • Pulmonary lymphangiectasia
  • Mediastinal teratoma
Other
  • Retroperitoneal fibrosis
Skeletal
  • Osteogenesis imperfecta
  • Asphyxiating thoracic dystrophy
  • Thanatophoric dwarfism
  • Achondrogenesis
  • Hyperphosphatasia
  • Saldino-Noonan dwarfism

Tumours

  • Teratoma
  • Neuroblastoma
  • Haemangioma
Placental/Umbilical
  • True knot
  • UV thrombosis
  • Placental chorioangioma
  • UA aneurysm
Maternal
  • Diabetes
  • Preeclampsia
  • Drugs (i.e. indomethacin)
Metabolic
  • Gaucher's Disease
  • GM1 gangliosidosis
  • Hurler's Syndrome (MP 1H)
  • Morquio (MP IVb)
  • MP type VII
  • Mucolipidosis type I and II
  • Sialic acid storage disease
  • Galactosialidosis

This list is not comprehensive! Also it does not give an idea of how common conditions may be.

References

1 Bellini C and Hennekam CM. Non-immune hydrops fetalis: A short review of etiology and pathophysiology. Am J Med Genet Part A. 2012;158A:597-605.
2 Steurer MA, Peyvandi S, Baer RJ et al. Epidemiology of live born infants with nonimmune hydrops fetalis Insights from a population-based dataset. J Pediatr 2017;187:182-8.
3 Ota S, Sahara J, Mabuchi A, Yamamoto R, Ishii K, and Mitsuda N. Perinatal and one-year outcomes of non-immune hydrops fetalis by etiology and age at diagnosis. J Obstet Gynaecol Res. 2016;42(4):385-91.
4 Fukushima K, Morokuma S, Fujita Y, et al. Short-term and long-term outcomes of 214 cases of non-immune hydrops fetalis. Early Human Development 2011;87:571-75.
5 Sohan K, Carroll SG, De La Fuente S, Soothill P and Kyle P. Analysis of outcome in hydrops fetalis in relation to gestational age at diagnosis, cause and treatment. Acta Obstet Gynecol Scand 2001;80:726-30.
6 Bellini C, Donarini G, Paladini D et al. Etiology of Non-immune hydrops fetalis: An update. Am J Med Genet Part A. 2015;167A:1082-88.
7 Abrams ME, Meredith KS, Kinnard P and Clark RH. Hydrops Fetalis: A retrospective review of cases reported to a large national database and identification of risk factors associated with death. Pediatrics 2007;120:84-89.
8 Shah D., Sinn JK. Octreotide as therapeutic option for congenital idiopathic chylothorax: a case series. Acta Paediatricia. 2012;101(4):e151-5.
9 Das A, Shah PS. Octreotide for the treatment of chylothorax in neonates. (Review). Cochrane Database of Systematic Reviews 2010, issue 9; No: CD006388.
10 Bellini C, Ergaz Z, Radicioni M et al. Congenital fetal and neonatal visceral chylous effusions: neonatal chylothorax and chylous ascities revisited. A multicentre retrospective study. Lymphology. 2012;45(3):91-102
11 Testoni D, Hornik CP, Neely ML et l. Safety of octreotide in hospitalized infants. Early Human Development. 2015;91(7):387-92
12 Bialkowski A, Poets CF, Franz AR; Erhebungseinheit fur padiatrische Erkrankungen in Deutschland Study Group. Congenital chylothorax: a prospective nationwide epidemiological study in Germany. Archives Dis Child Fetal & Neonatal Ed. 2015;100(2):F169-72.