Developmental Disorders of the Lymphatics

An information blog for disorders of the lymphatics. For all articles, please click on "Archives" - Due to spammers, I will no longer allow comments, sorry.

Saturday, June 17, 2006

Hydrops Fetalis


Hydrops fetalis is Latin for edema of the fetus. Ballantyne first described hydrops fetalis in 1892, although it had been recognized for almost 200 years.

The hallmark of the disease is the abnormal accumulation of fluid in body cavities (pleural, pericardial, peritoneal) and soft tissues with a wall thickness of greater than 5 mm. In addition, hydrops fetalis is associated with polyhydramnios and a thickened placenta (>6 cm) in as many as 30-75% of patients. Many affected fetuses also have hepatosplenomegaly.


The basic problem is an imbalance in fluid homoeostasis, with more fluid accumulating than can be resorbed. This imbalance can result from 2 broad categories of pathologies, namely, those of an immune origin and those of a nonimmune origin.

Immune-related hydrops fetalis (IHF) results from alloimmune hemolytic disease or Rh isoimmunization.

The mother is sensitized and has antibodies against fetal blood cells, causing hemolysis in the fetus when circulated maternal antibodies (immunoglobulin G [IgG]) cross the placenta to reach fetal circulation. Most cases occur because of antibodies to D-positive Rh antigen, although some cases can occur because of antibodies to C-positive and E-positive Rh antigens. Rare blood group antibodies, such as the Kell (K) system and the Duffy (Fy) system, also can cause hydrops.

Nonimmune-related hydrops fetalis (NIHF) can result from primary myocardial failure, high-output cardiac failure, decreased colloid oncotic plasma pressure, increased capillary permeability, and obstruction of venous or lymphatic flow. Fetal cardiac anomalies are the most common cause of nonimmune-related hydrops fetalis. Chromosomal anomalies are the second most common cause.

In addition to the causes of IHF, several conditions can cause NIHF. The most common cause of NIHF is cardiovascular abnormality, followed by chromosomal abnormalities; however, the number of nonimmune-related causes that can and have resulted in hydrops fetalis is extensive and includes the following partial list:
Fetal structural abnormalities

Cranial - Cerebral tumor, intracranial hemorrhage, and vein of Galen aneurysm

o Cardiovascular - Arrhythmias (tachyarrhythmias, bradyarrhythmias), cardiac tumors (rhabdomyoma, hemangioma, hamartoma), cardiomyopathy, Ebstein anomaly, endocardial fibroelastosis, high-output failure (fetal angiomas, sacrococcygeal teratomas, vein of Galen aneurysm, twin-twin transfusion syndrome, twin-reversed arterial perfusion [TRAP] syndrome), myocardial infarction, myocarditis, premature closure of the foramen ovale, right or left heart hypoplasia, and single ventricle

o Neck or thoracic masses - Congenital cystic adenomatoid malformation, cystic hygromas, diaphragmatic hernia, hydrothorax/chylothorax, mediastinal teratoma, pulmonary sequestration, and thoracic tumors

o Gastrointestinal-tract abnormalities - Bowel atresias and volvulus, cirrhosis, hemochromatosis, hepatic tumors (hemangioendotheliomas), hepatitis, hepatoblastoma, lymphangiomas, and meconium peritonitis

o Urinary-tract abnormalities - Congenital nephritic syndrome, polycystic kidneys, prune belly syndrome, renal vein thrombosis, and urinary tract obstructions (lower or upper)

o Chromosomal anomalies - Trisomy 21, trisomy 18, trisomy 13 triploidy, and XO syndrome (Turner syndrome)

· Anemias -
Thalassemia, congenital leukemia, fetomaternal hemorrhage, glucose-6-phosphate dehydrogenase (G-6-PD) deficiency, human parvovirus B19 (B19V) infection, twin-twin transfusion syndrome (donor), and fetal closed-space hemorrhage

· Infection - Coxsackie virus, cytomegalovirus (CMV), hepatitis A virus, leptospirosis, listerosis, B19V, rubella virus, syphilis, toxoplasmosis, and varicella virus

· Genetic disorders

Metabolic disorders - Gaucher disease, Hurler disease, hypothyroidism, hyperthyroidism, mucolipidosis, and mucopolysaccharidosis

o Skeletal dysplasias - Achondrogenesis, achondroplasia, asphyxiating thoracic dystrophy, lethal osteoporosis, Noonan syndrome, short rib–polydactyly syndrome, and thanatophoric dysplasia
o Fetal hypokinesis - Arthrogryposis, congenital myotonic dystrophy, Neu-Laxova syndrome, and Pena Shokeir syndrome

· Idiopathic disorders - Recurrent isolated hydrops

· Maternal disorders - Graves disease, severe anemia, severe diabetes mellitus, and severe hypoproteinemia

· Placental disorders - Chorioangioma, chorionic vein thrombosis, cord torsion (knot or tumor), umbilical artery aneurysm, and venous thrombosis


Hydrops fetalis is more common in undeveloped countries than in developed countries. Figures from Thailand suggest an estimated incidence of 1 case per 500-1500 pregnancies because of an association with homozygous athalassemia. The incidence of IHF has decreased with the development of better prophylaxis, and it is not considered a major problem in developed countries. However, in undeveloped countries, IHF still occurs in a small and declining number of cases.


Mortality and mortality figures vary, but in general, the mortality rate is high.

Treatment is reported to be successful in 10-40% of patients, depending on the cause of the disease and the sophistication of available diagnostic and therapeutic options.

Many cases of NIHF occur as a result of complex chromosomal or anatomic anomalies that worsen the prognosis.

Other causes of poor prognosis include pulmonary hypoplasia caused by pleural and peritoneal fluid accumulation and an early onset of labor because of distention of the uterus caused by polyhydramnios and/or fetal body enlargement secondary to edema.

Race: Certain racial predilections exist for pathologic conditions that can lead to hydrops fetalis.
Predisposing factors include the severity of hemolysis in African populations and the variations in the a-chain structure in Asian and Mediterranean populations.

In the Far East, a thalassemia is a major cause of nonimmune-related hydrops fetalis. The condition is uniformly fatal and associated with a significant risk of maternal morbidity. The a thalassemia gene is found in 20-30% of the population in Southeast Asia.


X-linked chromosomal abnormalities are found in many fetuses with hydrops fetalis.


Hydrops fetalis is often diagnosed by using routine sonograms when the typical features are depicted. In other fetuses, a clinical suspicion of hydrops fetalis may exist because of a previous family history of a similarly affected baby or because ultrasonography is performed to evaluate polyhydramnios.

Clinical Details:

The conditions causing hydrops fetalis are diverse; however, common mechanisms that cause the fluid imbalance can be identified. These causes include the following:

(1) cardiac failure resulting from myocardial disease, arrhythmia, complex anatomic cardiac defects, or abnormal intracardiac or extracardiac shunts (high-output failure);
(2) abnormal blood composition with severe anemia or abnormal red cell physiology or counts;
(3) aberrations of lymphatic drainage; and
(4) masses in the abdomen or chest that hamper venous return.

Sonograms depict anasarca (edema) and fluid collection in serous cavities, such as the pleural, pericardial, and peritoneal spaces. Polyhydramnios and an edematous thick placenta are often present.

Ascites may be small and be just enough to form a film over the abdominal contents, or ascites may be extensive with the contents of the abdomen, liver, and gut floating in the fluid. The ascites may extend into the scrotum to form a hydrocele.

Pleural effusions can be unilateral or bilateral. Unilateral effusions indicate the presence of a process such as chylothorax. Large effusions can compress the mediastinal vessels, cause upper body edema, and interfere with esophageal functioning to cause secondary polyhydramnios.

Edema may be localized to one part of the body, or it may be generalized. Edema is seen most easily over the skull, over which a halo is formed. Edema may be seen in other parts of the body as well.

Placental thickening is a late occurrence, and when affected, the placenta is thicker than 4-5 cm over its entire extent.

The distribution and size of fluid accumulations may indicate the pathology. In IHF, ascites appears first, with edema and pleural collections appearing late.

The findings of specific organ pathology, for example, skeletal abnormalities or cardiac tumors, may indicate a specific cause in hydrops fetalis.

Preferred Examination:

Immune-related hydrops fetalis

A history of a previously affected fetus in the family is of critical importance. Once IHF is suspected, maternal blood typing and antibody screening against Rh and a determination of minor blood types (eg, Kell, Duffy, MNSs) should be performed. In mothers in whom immunoglobulin M (IgM) is detected, no further workup is needed, but if IgG is detected, titers of Rh-positive antibodies in the maternal blood need to be determined. A titer of greater than 1:16 is significant. If titer results are significant, amniocentesis should be performed to assess the severity of fetal hemolysis and anemia.

Fetal anemia can be monitored either by direct sampling of fetal blood by means of cordocentesis or by determining the delta optical density (OD) by using a wavelength of 450 mm in the amniotic fluid. This measurement gives an estimate of bilirubin levels during the third trimester. Delta OD results are plotted on the Liley 3-zone chart. The closer the results are to the third zone, the greater is the risk of IHF. A fetal hematocrit determination is the final test to be performed, and fetal transfusion should be considered in fetuses with a hematocrit level of less than 40%.

Nonimmune-related hydrops fetalis

NIHF can result from a large number of causes, including chromosomal abnormalities, cardiac failure, tumors, and twin-twin transfusion syndrome. Extensive clinical workup is required to attempt to identify the specific etiology. In patients in whom NIHF is suspected, the search for a cause starts with a maternal evaluation. Initial clinical history taking should be directed toward the presence of hereditary or metabolic diseases, diabetes, infections, anemias, and use of all medications. Initial investigations include an indirect Coombs test to exclude immune causes, followed by the determination of routine blood counts and indices to exclude thalassemias; maternal blood chemistry testing for G-6-PD deficiency; Betke-Kleihauer testing for fetal-maternal transfusion; and screening for toxoplasmosis, other infections, rubella, CMV, and herpes simplex (TORCH) infection during intrauterine pregnancy.

Amniocentesis is needed to perform fetal karyotyping, amniotic fluid culturing, testing for CMV infections, assessment of a-fetoprotein (AFP) levels, testing for thalassemia, and determination of the lecithin-sphingomyelin (L/S) ratio. Karyotyping can also be performed with tissue obtained by chorionic villous sampling (CVS) or with fluid obtained from one of the fetal cavities. A chromosome count and karyotype can be obtained rapidly by using fluorescent in situ hybridization (FISH) technique. The FISH technique can also help in the detection of specific deletions and chromosomal rearrangements, and the results are often available within 24-48 hours.

Fetal blood tests should include hemoglobin chain analysis for thalassemia and fetal serum albumin levels.
Initially, sonographic findings suggest hydrops fetalis in most cases, and ultrasonography can also be used for follow-up imaging to observe the progress of the condition if the pregnancy is continued.
Limitations of Techniques: Ultrasonographic findings are often reliably helpful in the diagnosis of the disease causing fetal hydrops, especially in fetuses in whom a chest mass or cardiac disease is present. However, in many fetuses, an exact etiology is not forthcoming after an ultrasonographic examination.

Blood tests performed in the mother can provide information regarding Rh and other immune causes of hydrops fetalis and evidence of infection and metabolic diseases. However, invasive fetal testing must eventually be performed by means of amniocentesis or cordocentesis. Both methods pose a risk of fetal death.

Differential Diagnosis

Cystic Hygroma Encephalocele Polyhydramnios

Other Problems to be Considered:

Urinary ascites
Meconium ascites
Isolated pericardial effusionIsolated ascites
Idiopathic polyhydramnios
Fetal cystic hygromas
Caput succedaneum
Crocodile skin



Antenatal radiography has no place in the diagnosis of fetal hydrops because it is essentially a disease of soft tissue and because of the reservations of using radiographs in pregnant women.

CAT Scan


CT scans may offer better anatomic resolution, but CT scans are difficult to obtain in the presence of an active fetus, and radiation exposure in pregnant women is a concern.



Exquisite anatomic detail can be depicted on MRIs, especially on those obtained with newer algorithms that allow fast acquisitions and that minimize the effect of fetal movement. However, MRI has not become a standard modality because of the limited availability of state-of-the-art equipment for fast imaging and because of the expense involved. In addition, ultrasonography is widely available and can adequately provide most of the required information. These factors have hindered a wider use of MRI in fetal imaging.



Ultrasonography remains the cornerstone of fetal imaging in fetuses in whom hydrops fetalis is suspected. Sonograms demonstrate the cardinal signs of the disease, namely, fetal skin edema (>5 mm), fluid in a serous cavity, polyhydramnios, and a thickened placenta. These signs can be seen in different combinations and to differing extents in various diseases. Additional findings, depending on the specific etiology causing the hydrops, are occasionally seen as well.

The minimum diagnostic criteria include the following: fluid accumulation in at least 2 serous cavities (ascites, pleural effusion or pericardial effusion) or 1 serous effusion and generalized anasarca. A single site of fluid accumulation is generally not enough to diagnose hydrops unless a preexisting pathology that is strongly associated with hydrops (eg, chest mass) is also present.

False Positives/Negatives:

A few conditions mimic full-blown hydrops fetalis, but individual components of hydrops fetalis can be seen in other conditions, even as normal variants.

Normal fetal hair and a thick scalp can occasionally be seen, and this finding must be differentiated from skin edema. Similarly, cystic hygromas and loops of cord near the body wall can suggest skin thickening.

Occasionally, a thick layer of subcutaneous fat may cause confusion.

The thick, folded skin, occasionally termed crocodile skin, is a normal variant that can cause confusion with skin edema.

A congenital cystic adenomatoid malformation of the lung, a diaphragmatic hernia, and a bronchogenic cyst can suggest pleural effusions.

Pseudoascites, obstructed or mature bowel, fetal abdominal cysts, and an obstructed urinary system can mimic ascites. Pseudoascites refers to an artifactual hypoechoic rim that is sometimes seen in the fetal abdomen; this is due to hypoechoic deep abdominal wall muscles or the diaphragm. Pseudoascites usually disappears when scanning is performed from another direction. Other features that differentiate pseudoascites from ascites are as follows: (1) Pseudoascites is not seen past the anterior edge of the ribs. (2) Pseudoascites is confined to the upper abdomen, unlike ascites, which is diffuse. (3) With ascites, the hyperechoic outer margin of the umbilical vein can be seen, as can the falciform ligament.



The mainstay of treatment is interventional fetal therapy. In a few patients, drugs administered to the mother elicit a response and reach the fetus transplacentally. In fetuses with IHF, treatment essentially involves correcting fetal anemia. In all patients, fetal anemia associated with hydrops fetalis is an absolute indication for fetal blood sampling followed by in utero transfusion. Ultrasonographic guidance is essential for fetal blood transfusion. For this, intravascular transfusion (IVT) is preferred over the intraperitoneal route. Of the many methods available, the prognosis is better in fetuses receiving intravascular transfusions than in those receiving intraperitoneal transfusions because peritoneal absorption is often impaired in affected fetuses. With IVT, 70-85% of fetuses with hydrops and 85-95% of fetuses without hydrops can survive. The therapy associated with the highest incidence of consistent benefit to the fetus is correction of fetal anemia via fetal blood transfusions.

Treatment in patients with NIHF is more complex and must be directed at the cause. One way to classify treatments is to separate them into noninvasive and invasive categories.

Noninvasive treatment may include the following:

Antiarrhythmic drugs

o Antibiotics
o Correction of maternal diabetes and hyperthyroidism

· Invasive treatment: The aggressiveness with which the following treatments are performed depends on the resources, sophistication, and experience of the treating unit.

Some attempted procedures include the following:

Correction of fetal anemia in fetal hemorrhages, parvovirus infections, and, possibly, thalassemia

o Amnioreduction by means of serial amniocentesis
o Fetoscopic laser ablation of communicating vessels in twin-twin transfusion syndrome
o Cord occlusion in cardiac twins
o Thoracocentesis in chylothorax and large pleural collections
o Vesicoamniotic drainage in urinary tract obstructions
o Fetal surgery to correct diaphragmatic hernias and sacrococcygeal teratomas

Remember that the appearance of the features of hydrops fetalis usually signals an advanced stage in the progression of the disease, and the prognosis is poor in most fetuses. However, specialists in fetal medicine and intervention should be consulted in all cases to decide if therapy is appropriate and, if it is, to determine which therapy to use.

Indian Doctors