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ABOUT HYDROPS FETALIS

FRANÇAIS



Our site is the result of one year spent looking for information about causes of non-immune hydrops and abnormalities-related in order to try to find out the truth. Unfortunately, almost all of the Web sites we could find on fetal hydrops were of little use to anyone outside the scientific community. Anyway, if you do not understand the reference list here below, you can show it to your physician who assured you that he had already done everything possible to help you in your quest...

This pathological condition which occurs rarely (about 1/3,000 pregnancies) is only the consequence of many heterogeneous disorders, some of them are well known such as cardiovascular malformations, chromosomal abnormalities and some congenital infections but most of them remain poorly understood or they are so rare that a physician do not even consider carrying out appropriate investigation. Multiple congenital anomalies can also be associated with hydrops, though the mechanism is obscure for everything except cardiac anomalies.

Until the advent of RhoGam vaccine, the most common cause of hydrops fetalis was blood group isoimmunization, usually involving the Rhesus blood group antigens. The success of isoimmunization prevention programs has been such that most cases of hydrops fetalis are now nonimmune or related to secondary blood-group antigens such as C, E & Kell Antigens.

Hydrops fetalis is caused by three main mechanisms : anemia, hypoproteinemia and cardiac failure. But in some complex cases, there may be more than one candidate as the cause of hydrops fetalis.

Most frequent causes of hydrops fetalis (60% of cases)

Cardiac causes :

  • Malformation (40 % of cases) such as left ventricular hypoplasia, atrioventricular canal, right ventricular hypoplasia, restricted foramen ovale, endocardial fibroelastosis
  • Arrhythmia (not always caused by identifiable anatomic lesions) such as tachyarrhythmias (25% of cases) and bradyarrhythmias (7 %) which may be caused by complete heart block or maternal connective tissue disease (lupus, polyarthritis)
  • High output cardiac failure (15 %) may result in placental chorioangiomas or sacrococcygeal teratoma
  • Cardiomyopathies and cardiac rhabdomyoma

Chromosomal causes :

  • Turner syndrome - 45X (42 % of cases)
  • Trisomies 21 (34 %) and 18 (9 %)
  • Triploidy (5 %) - Trisomy 13, 15, 16
  • Tetraploidy

Thoracic and pulmonary causes :

  • Congenital cystic adenomatoid malformation of lung
  • Pulmonary sequestration
  • Right-sided diaphragmatic hernia
  • Intrathoracic teratoma/neoplasm
  • Enterogenous, bronchogenic cysts
  • Dyschondroplasias
  • Laryngeal atresia with congenital pulmonary hyperinflation
  • Chylothorax / Hydrothorax (due to lymphatic obstruction) causes pulmonary hypoplasia and involve only isolated pleural effusions

Causes of fetal anemia :

  • Homozygous Alpha-thalassemia (55% of cases)
  • Hematologic diseases (hemoglobinopathies, dyserythropoiesis…)
  • Red blood cell enzymopathy
  • Glucose-6-phosphate dehydrogenase deficiency
  • Parvovirus B19
  • Fetomaternal transfusion
  • Isoimmunization (rare nowadays)
  • Intrafetal hemorrhage

Fetal infections :

Cytomegalovirus (30% of cases) & syphilis which cause ascites.

Monochorionic twinning or Twin transfusion syndrome (TTS) :

Often resulting in fetal death of one of the twins, the survivor develops right-sided pleural effusions and dies in the neonatal period.

Less common causes of hydrops fetalis

Maternal infections (difficult to interpret as the real cause of fetal hydrops) :

Toxoplasmosis, rubella, herpes, listeria, diabete

Genitourinary tract malformation / Hepatic or intestinal pathology :

  • Multicystic or polycystic kidneys (recessive disease)
  • Cloacal malformation (12 % of cases)
  • Urethral obstruction (35%)
  • Kaufman-McKusick syndrome

Fetal akinesia/hypomobility :

  • Myotonic dystrophy
  • Neu-Laxova syndrome
  • Multiple pterygium syndrome
  • Congenital muscular dystrophy

Component of hydrops fetalis

Causes of cystic hygroma/nuchal edema :

  • Chromosomal disorders (Turner, for instance)
  • Non chromosomal disorders such as Noonan syndrome, Multiple pterygium syndrome, Fryns syndrome, Achondrogenesis, Brachmann-de Lange syndrome, Fraser syndrome

Causes of ascites - effusion of fluid into the peritoneal cavity :

  • Urinary tract obstruction which causes pulmonary hypoplasia secondary to oligohydramnios
  • Hepatic disease
  • Intestinal perforation
  • Pancreatic disease
  • Congenital heart disease
  • Genetic metabolic disorders (with enzyme deficiency)

Although rare, the lysosomal storage diseases (1/5,000 live births) collectively are significant causes of nonimmune hydrops. Whenever the major causes of hydrops have been excluded, it is important to carry out the appropriate investigation in a problem-oriented manner. Diagnosis of these diseases is important for reproductive prognosis.

There are about 40 different diseases, each characterized by a specific lysosomial enzyme deficiency in a variety of tissues, i.e. carnitine deficiency, pyruvate kinase deficiency, etc… Enzymes are responsible for lysosomal degradation of intracellular waste but if one of them is defective, waste accumulate in the lysosomes which results in progressive destruction of the organs.

The reference list here below is not exhaustive :

  • Niemann-Pick disease
  • Gaucher disease type 2
  • Smith-Lemli-Opitz syndrome (defect in cholesterol metabolism)
  • Farber disease
  • Wolman disease
  • Hurler's syndrome
  • GM1 Gangliosidosis Type I
  • Haemochromatosis (iron overload)
  • Infantile free sialic acid storage disorder (ISSD)
  • Carbohydrate-deficient glycoprotein syndrome
  • Mucopolysaccharidosis IV, VI and VII (caused by beta-glucuronidase deficiency)
  • Galactosialidosis (caused by neuraminidase deficiency with beta-galactosidase deficiency)
  • Infantile sialidosis or mucolipidosis type I & II (caused by neuraminidase deficiency)
  • Glycogenosis II (Pompe disease), IIb (Danon disease) and IV (Andersen disease)

Investigations in case of hydrops

Maternal studies :

  • Blood type and group
  • Full blood count
  • Bacteriological studies
  • CMV, VDRL
  • TORCH & Parvovirus titers
  • Indirect Coombs to rule out immune etiologies
  • SMA20
  • Antiphospholipid, anticardiolipid and lupus anticoagulant antibodies
  • Antibody screen (AChR, anti RO & LA, etc.)
  • Kleihauer-Bethke test to eliminate the possibility of a fetomaternal hemorrhage
  • Red blood cell enzymopathies
  • G-6-PD
  • G.T.T / Glycosylated Hb
  • Hemoglobin electrophoresis
  • Alfa feto protein serum levels
  • HLA typing of the parents because lack of maternal blocking antibodies may predispose to this condition

Amniocentesis :

  • Karyotype analysis
  • Amniotic fluid analysis with cultures / PCR
  • Alfa feto protein of the amniotic fluid
  • Metabolic tests (Gaucher's, Tay-Sachs, GM1 Gangliosidosis)
  • Restriction endonuclease for Alpha thalassemia
  • Amniotic fluid supernatant analysis (glycosaminoglycans, oligosaccharides, free sialic acid and acid hydrolase activities)

Fetal and placental studies :

  • Fetal blood for investigation of :
    • Type and Group
    • Karyotype (also on chorionic villi)
    • Full blood count
    • Direct and indirect Coombs
    • Viral Screen / TORCH IgM, parvovirus
    • CBC
    • SMA20
    • Serum protein levels
    • Abnormal Hb studies
    • Red blood cell enzyme mutations
    • Viscosity studies
    • Arterial blood gases
    • Doppler Blood Flow Studies (umbilical artery, middle cerebral artery, aorta, umbilical artery pressure)
    • Molecular genetic studies (mitochondrial and metabolic disorders)
  • Complete and detailed fetal and placental ultrasound done by an experienced sonographist
  • Fetal echocardiography (see Blue Cross BlueShield of Tennessee Medical Policy Manual)
  • X-Rays (complete babaygram) with examination of the chest, abdomen, cranium, long-bones lengths, deformation and calcification
  • Clinical photographs of the fetus
  • Complete autopsy of the fetus
  • Analysis of fetal pericardial effusions (ascitic/pleural fluid) & cystic hygroma (if any) for protein levels, cell content and lymphocyte count
  • Biochemical, molecular, cytogenetic, virological, bacteriological studies of cultured amniotic fluid, fetal and placental tissue cells
  • Electron microscopy and enzyme assays (for instance, sialidase, B-Glucosidase, B-Galactosidase and Glucuronidase) in cultured fibroblasts
  • Electron microscopy to be used for myocardial mitochondria
  • Ultrastructural examination to be performed on myocardial fibers
  • Histologic examination of the placenta :
  • Liver or skeletal muscle biopsy due to the variable involvement of mitochondria in various tissues
  • Macroscopic and histologic examination of viscera
  • Special attention should be focused on the heart, parenchymal organs (liver, spleen, kidney), bone marrow and neuromuscular system (fetal hypomobility).
  • Fetal DNA should be stored for further investigation of syndromes (known and unknown) and confirmation of likely or actual genetic diseases that are diagnosed after the completion of the autopsy and during compilation of other test results.

Conclusion

Close attention at the sequential development of hydrops and the most affected areas may be the key to a diagnosis. The causal diagnosis of hydrops fetalis is often difficult to determine at autopsy especially if there has been prolonged fetal death. Moreover, only the strictly structural causes (and not functional ones) can be confirmed or ascertained at autopsy. But attempts should still be made to diagnose malformations and other genetic diseases. Therefore, thorough investigation of hydrops fetalis will be necessary for assessing the risk of recurrence. A diagnosis is often possible when obstetricians and pathologists carefully coordinate the management of prenatal and postnatal investigations and when new techniques such as molecular biology and DNA quantification are used.



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