Non-immune hydropsDr Anita Srinivasan

2nd year DM resident

Dept. of Neonatology,

Seth GSMC & KEMGH,Parel,mumbai

Hydrops fetalisHydrops fetalis is a condition in the fetus characterized by an abnormal collection of fluid with at least two of the following:

Edema(fluid beneath the skin, more than 5 mm).

Ascites

Pleural effusion

Pericardial effusion

In addition, hydrops fetalis is frequently associated with polyhydramnios and a thickened placenta (>6 cm).

Broadly divided into 2 categories:

Immune Hydrops &

Non-immune hydops

incidenceAccurate estimates of incidence are difficult to obtain because many cases are not detected before intrauterine death, and some cases may spontaneously resolve antenatally.

Reported incidences of NIHF vary depending on the region studied because of differences in etiology, ethnicity of population, and availability of sophisticated investigations.

CausesHydrops fetalis is found in about 1 per 2,000 births and is categorized as immune or nonimmune hydrops.

Immune hydrops (accounts for 10-20%of cases)

Antigen incompatibility between the mother and fetus---maternal sensitization---fetal hemolysis and anaemia---cardiac failure and decreased colloid osmotic pressure---fetal Hydrops.

Well defined cause

Established diagnostic and therapeutic approach

Good prognosis

Decreased incidence since the widespread use of anti-D

B BB Nonimmune hydrops (accounts for 80 -90% of cases)

Any other cause besides immune.

No identifiable circulating antibody to any red cell antigen.

In general nonimmune hydrops (NIH) is caused by a failure of the interstitial fluid (the liquid between the cells of the body) to return into the venous system .

It is an end result of an array of disorders of the fetus, umbilical cord and placenta that leads to deranged fluid homeostasis.

A wide range of fetal organs are involved - No common mechanism is responsible for the signs of hydrops.

PathogenesisThis may due to:

Cardiac failure(High output failure from anemia, sacrococcygeal teratoma, fetal adrenal neuroblastoma, etc.)

Impaired venous return(Metabolic disorders)

Obstruction to normal lymphatic flow (Thoracic malformations)

Increased capillary permeability

Decreased colloidal osmotic pressure (Congential nephrosis)

More than 100 causes or associations of NIHF have been found. About 10 to 20% of cases are idiopathic depending on the thoroughness of investigations. However, when cases of prenatally diagnosed NIHF and intrauterine fetal deaths are included, the success rate in finding an underlying cause for NIHF may be as low as 40%4. Most reports on NIHF are derived from case reports, small case series, and reviews of these.

It has been found that, in addition to idiopathic causes, the majority of cases are due to seven major categories: cardiovascular pathologies (35 %), chromosomal anomalies (20%), anemias (15%), malformation syndromes (15%), infections (10%), liver diseases (5%), and miscellaneous causes (5%

Normal return of of interstitial fluid to veins though lymphatic system

(high pressure to low pressure)

Blood capillaries

Interstitial Fluid

Lymph capillaries and veins

Large

Veins

Mechanisms that may cause increased interstitial fluid

Increased

capillary

permeability

OR

Decreased colloidal osmotic pressure

Lymph capillaries and veins

Large Veins

Blood capillaries

Obstruction to lymph

flow

Large Veins

Blood capillaries

Lymph capillaries and veins

Impaired venous return

OR

Cardiac failure

Non-immune Hydrops Fetalis

Normal four

Chamber Cardiac

View

Pericardial Effusion

Heart

Body wall

edema in a

hydropic fetus

www.thefetus.net Fetal Ascites

Hydrocele can

be an early

manifestation

in hydrops

Soft Tissue

shadow and

pleural

effusion in

hydropic

neonate

Conditions Associated with NIH(This list is not exhaustive)

Cardiac Cardiomyopathy, Ebstein's anomaly, pulmonary atresia, coarctation of the aorta, hypoplastic left heart, complete AV canal, left sided obstructive lesions, premature closure of the foramen ovaleIntracardiac tumors (tuberous sclerosis) Cardiac arrhythmia

SVT, flutter, heart block, WPW syndrome

Chromosomal /Genetic SyndromesT13, T18, T21, XO (Turners syndrome) , Noonan syndrome , multiple pterygium syndrome, Pena-Shokeir, arthrogryposis

Fetal AnemiaAlpha (α) thalassemia, parvovirus, fetal hemorrhage, G-6-PD deficiency

Infection Parvovirus, CMV, syphilis, coxsackie virus, rubella, toxoplasmosis, herpes,varicella, adenovirus, enterovirus, influenza, listeria

Thoracic AbnormalitiesCongenital cystic adenomatoid malformation (CCAM) , chylothorax, diaphragmatic hernia, mediastinal tumor, skeletal dysplasias

TwinnningTwin to twin transfusion Severe anemia in the donor twin or high-output failure in the recipient

TumorsFetal sacrococcygeal teratoma, hemangiomas (Hepatic, Klippel-Trenaunay syndrome), fetal adrenal neuroblastoma, placental tumors(chorioangioma)

Miscellaneous Cystic hygromas, inheritable disorders of metabolism (lysosomal storage diseases) ,maternal thyroid disease, congenital nephroticsyndrome.

It is difficult to find a plausible explanation for the development of hydrops in many cases listed in the previous slide (such as malformations, hepatic causes or metabolic diseases) which may represent chance associations. However, as a general rule, NIHF presenting before 24 weeks is usually due to chromosomal aberrations, while hydropspresenting after this is usually due to structural anomalies (such as cardiac and pulmonary)

Cardiac structural and functional anomalies are a common cause of NIHF. Structural defects are commonly associated with karyotypic abnormalities, for example, coarctation of aorta with Turner syndrome and arterioventricular canal and septal defects with Down syndrom.

. Fetal supraventricular tachyarrhythmias (SVT) are an important cause of hydropswhich are rarely associated with any other structural anomalies, can be detected by fetal echocardiography, and is amenable to therapy. Hence, apart from SVT, most cardiac lesions lead to in-utero or early neonatal death

Congenital heart block (CHB) may also lead to hydrops and occurs in over 60% of pregnancies complicated by maternal collagen disease (especially lupus). Maternal IgG antinuclear antibodies cross the placenta and attack fetal collagen in the conduction bundle5. However, not all fetuses with CHB develop hydrops which suggests that no single pathogenic mechanism can explain all cases of NIHF

Chromosomal abnormalities are a frequent cause of NIHF. Genetic syndromes, apart from inherited hemoglobinopathies (see below), and inborn errors of metabolism are rare.

The commonest chromosomal anomaly is Turner syndrome typified by ultrasound finding of cystic hygromas which are vascular tumours associated with defects of lymphatic drainage commonly found in the neck but can also be found in the abdomen or thoracic regions.

Many other chromosomal anomalies and genetic syndromes are associated with non –immune hydrops. Prognosis is poor in the majority of cases due to associated structural, functional, and / or metabolic defects.

Severe fetal anemia leading to hypoxia and high output cardiac failure account for a significant proportion of cases of NIHF in SEA as a result of homozygous a-thalassemia (Hb Barts). In one report from South East Asia, 86 % (25/29) of hydrops were due to Hb Bart’s.

Fetal anemias which lead to hydrops can also result from fetal hemorrhage (such as intracranial bleeding from arterio-venous malformation or sacrococcygeal teratoma),

fetal-maternal hemorrhage (such as from abruptio or from placental tumours such as chorioangioma),

hemolysis (such as congenital spherocytosis, glucose-6-phosphate dehydrogenase or pyruvate deficiency), or

failure to form erythrocytes (such as marrow dysfunction due to parvovirus B19, leukemia, or pure red cell aplasia). It is postulated that fetal anemia is the underlying mechanism of hydrops seen in monozygous twin to twin transfusion, although uteroplacental insufficiency of the donor twin leading to preferential shunting of blood away to the recipient twin has been suggested as another reason.

Malformation syndromes can involve any of the major system including pulmonary, renal-urologic, gastrointestinal, neurologic and skeletal. Congenital cystic adenomatoid malformation of the lung (CCAM) is the most common thoracic lesion associated with hydrops. In CCAM abnormal capillary-alveolar development results in functionless cystic lung masses which act as a space occupying lesion in the chest5. This causes compression and underdevelopment of normal lung tissue (resulting in hypoplastic lung which is invariably lethal), shifting of mediastinum and heart, and obstruction of cardiac venous return causing central venous hypertension which ultimately leads to hydrops in severe cases. Other pulmonary causes of hydropsprobably share the same pathogenesis.

An important gastrointestinal cause is congenital diaphragmatic hernia (CDH) whereby bowel or liver herniates through a defect in the malformed diaphragm leading to an intrathoracic mass effect similar to CCAM.

Other gastrointestinal causes include esophageal atresia, midgut volvulus, meconium peritonitis, duodenal diverticulum, intestinal duplication, malrotation, and imperforate anus.

Renal and urologic causes include Finnish nephrosis leading to severe hypoproteinemia, hypoplastic kidney(s), polycystic kidneys, renal vein thrombosis, bladder outlet obstruction, and dysplastic kidneys. Neurologic malformations are a rare cause of hydrops which includes encephalocele, porencephaly with absent corpus callosum, fetal intracranial hemorrhage, and vein of Galen aneurysm.

Skeletal dysplasias such as achondroplasia, achondrogenesis, osteogenesisimperfecta, osteochondrodystrophy, thanatophoric dwarfism, asphyxiating thoracic dysplasia, chrondrodystrophy and chrondrodysplasia may all be associated with thoracic compression, impairment of venous return resulting in hydrops.

Intrauterine infection of the susceptible fetus with a wide variety of viral and bacterial organisms is another important cause of hydrops. Microbes implicated include toxoplasmosis, rubella, cytomegalovirus, herpes simplex, syphilis (collectively known as “TORCHS”), coxsackie virus, and parvovirus B194. Possible mechanisms for the development of hydrops from these infections include fetal anemia from hemolysis, suppressed erythropoesis and myelopoiesis, fetal myocarditis, of fetal hepatitis4,5. In some cases, such as with syphilis, hydrops is associated with a very poor prognosis whereas in other cases, such as with parvovirus B19, infection may be self limited and may resolve spontaneously.

Recent studies have found that parvovirus B19 may be the cause of as much as one third of all cases of NIHF. The virus attacks bone marrow erythropoietic stem cells leading to severe anemia from the red cell aplastic crisis. The outcome of fetusesinfected with this virus is surprisingly good with spontaneous recovery in a third of cases with NIHF without long term morbidity; approximately 85% of fetuses treated by in-utero transfusion survive.

NIHF may rarely occur in association with severe maternal medical conditions such as severe anemia, diabetes mellitus, or hypoproteinemia.

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 the use of all medications.

Presentation

Hydrops fetalis is typically diagnosed during ultrasound evaluation for other complaints such as :

Polyhydramnios

Size greater than dates

Fetal tachycardia

Decreased fetal movement

Abnormal serum screening

Antenatal hemorrhage

May be diagnosed on routine sonographic screening or may be diagnosed after fetal death.

Maternal complications

The mother may develop edema , hypertension, and proteinuria during conservative management of hydrops a condition known as Mirror syndrome (also known as pseudotoxemia or Ballantyne syndrome) . Symptoms may persist after delivery. The maternal condition can quickly deteriorate into fulminant pre-eclampsia, and eventually, eclampsia.

The collorary of this is that if the above situations are encountered, for example early onset severe pre-eclampsia or polyhydramnios beginning at 28 weeks, hydrops should be excluded by sonography.

In an attempt to compensate for the fetal hypoxia, placenta increases in size and sometimes also penetrate deeper into the myometrium. Thus causes the morbid adherence of placenta and can cause the problems for third stage of labor necessitating the manual removal of Placenta

INVESTIGATIONSInitial 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.

Detailed Ultrasound Scan

Fetal Echocardiography

Doppler Blood Flow Studies

Liquor Volume Assessment (AFI)

Placental Thickness & Echogenicity

Amniocentesis is needed to perform fetal karyotyping,

amniotic fluid culturing,

testing for CMV infections,

assessment of α-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 the 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 fetalserum albumin levels.

Initially, ultrasonographic findings suggest hydrops fetalis in most cases, and this modality can also be used for follow-up imaging to observe the progress of the condition if the pregnancy is continued.

Fetal echocardiogramConsider fetal heart rate monitoring for 12 to 24 hours if fetalarrhythmia is suspected.

Amniocentesis for fetal karyotype and PCR (polymerase chain reaction) for infections OR fetal percutaneous blood sampling for same and in addition fetal liver function; and metabolic testing if indicated. In the presence of a family history of an inheritable metabolic disorder or recurrent nonimmune hydrops test for :

Storage disorders such as Gaucher’s, gangliosidosis, sialidosis, beta-glucuronidase deficiency, and mucopolysaccharidosis

Enzyme analysis and carrier testing in parents and/or analysis of fetal or neonatal blood or urine.

Histological examination of fetal tissues.

MANAGEMENTCounseling

Long term prognosis depends on underlying cause and severity of the heart failure.

If the cause of NIH cannot be determined, the perinatal mortality is approximately 50%

Prognosis is much poorer if diagnosed at less than 24 weeks , pleural effusion is present, or structural abnormalities are present .

Pulmonary hypoplasia is a common cause of death in neonates with plerual effusions. Fetal hydrops associated with a structural heart defect is associated with an almost 100% mortality rate.

If early in pregnancy (less than 24 weeks) with no treatable cause the option of termination may be a consideration.

Recurrence is uncommon unless related to blood group incompatibility (isoimmunization) or inheritable disorder.

Antepartum

Follow up of the fetus will depend on the gestational age of the fetus, and the mother's wishes regarding intervention.

If treatment has been successful or hydrops is resolving spontaneously, the fetus may be followed with repeat sonograms every 1 to 2 weeks and antenatal testing.

Patients treated for immune hydrops are usually delivered at 37 weeks' or when fetal lung maturity has been confirmed.

Consultation with the neonatologist may help to decide when it is appropriate to proceed with preterm delivery for possible postnatal treatment .

The mother should be evaluated frequently for signs of "mirror" syndrome

Fetal therapy:

Only about 20 to 30% of fetuses with NIHF are suitable for fetal intervention even in the best equipped feto-maternal centers. Currently, only hydrops associated with these conditions may be amenable for antenatal treatment:

a) anemia,

b) arrhythmias,

c) pulmonary conditions,

d) twin-twin transfusion,

e) tumours, and

f) miscellaneous eg pleural effusion.

Decisions about whether to proceed with treatment are complicated by the fact that:

a) the natural history for many conditions are uncertain or unknown,

b) very few properly designed clinical trials are available regarding treatment efficacy and safety,

c) a good fetal outcome cannot be guaranteed despite significant fetal and maternal risks entailed in invasive fetal procedures, and

d) spontaneous remission of the hydropic process has been documented for cases such as cardiac arrhythmias, twin-twin transfusions, pulmonary sequestration, cystic adenomatoidmalformation of the lung, lysosomal storage diseases, cystic hygroma with or without Noonan syndrome, both parvovirus and CMV infections, placental chorangioma, and idiopathic ascites or pleural effusions, and

e) invasive interventions, such as fetal transfusion, may need to proceed before definitive tests results, such as karyotype, become available.

Fetal anemia is the pathology most amenable to prenatal therapy. A hematocrit of less than 30% is an indication for transfusion. Transfusion with irradiated Kell and Rhesus negative, type O, crossed matched blood compatible with maternal serum has led to an improved outcomes, not only for isoimmune hemolytic disease, but also for fetal anemia secondary to Parvovirus infection, fetomaternal hemorrhage, twin-twin transfusion, sacrococcygeal teratoma, and hemoglobinopathies

The majority of structural cardiac diseases leading to NIHF are lethal because they are usually severe lesions, many of which are associated with chromosomal aberrations, and few of which are amenable to neonatal surgical correction. Fetal arrhythmias with a structurally normal heart, on the contrary, can lead to resolution of hydrops in some cases. Treatment options for fetal arrhythmias include:

a) delivery at term and administering direct treatment to the neonate,

b) antenatal anti-arrhythmic drug treatment given directly to the fetus (via intraperitoneal, intramuscular, or intravenous routes during cordocentesis), or indirectly by maternal ingestion (whereby the drug reaches the fetus via the transplacental route).

Fetal surgery is not yet commonly available in India.

Interventions performed include:

Needle aspiration

Feto-amniotic shunting

repair of congenital diaphragmatic hernia, resection of cystadenomatoidmalformation of the lung, and excision of large sacrococcygeal teratomas.

Fetal endoscopic surgery for TRAP,PLUG for cases of CDH.

DELIVERYNeonatal Management:

Hydropic fetuses should be delivered as close to term as possible in a tertiary center with a multidisciplinary neonatal resuscitation team supported by a neonatal intensive care unit (NICU).

There are no evidence-based guidelines on the best time of delivery. In general, it is best to await fetal maturity until 37 weeks and avoid elective preterm delivery because premature delivery as a method of therapy usually fails and prematurity may worsen the already grim prognosis of hydrops. Early delivery, however, is indicated in the following situations in addition to usual obstetric indications:

a) if fetal testing becomes nonreassuring,

b) if pre-eclampsia complicates hydrops (which can be up to 50% of cases), or

c) if preterm labour is established (often precipitated by polyhydramnios, hence repeated amniocenteses may help prevent this and help relieve maternal discomfort).

Deliverya) ultrasound should be repeated early in labour to assess whether effusions in the lung, pericardium, or peritoneum may require aspiration before or at delivery (eg. thoracocentesis, paracentesis and chest tube drainage) to facilitate adequate postnatal ventilation and circulation.

Preparation of appropriate equipment for intubation

Umblical lines

Medications

Thoracocentesis and paracentesis

immediate neonatal endotracheal intubation and supportive care will be needed in almost all infants as they are usually premature and have cardiorespiratory compromise possibly due to hypoplastic lungs, hyaline membrane disease, pleural effusions, pulmonary edema, sepsis, perinatal depression, hypoxia, or acidosis,

an experienced neonatalogist should be present as intubation is often difficult due to airway and chest wall edema as well as serous cavity effusions

Neonatal Management

high-frequency ventilator and high airway pressure settings will often be needed to achieve adequate oxygenation,

umbilical artery and vein lines may help with administration of various agents and allows monitoring of blood gases and arterial and venous pressures,

cautious use of inotropic agents, diuretics, blood products, albumin, and fluids to maintain an adequate cardiac function without fluid overload or soft-tissue edema

once the neonate is stabilized, promptly transfer the baby to NICU,

this is followed by full physical examination aided by relevant echocardiographic, and radiologic investigations to exclude structural malformation, and hematologic tests to rule out sepsis, biochemical and karyotypic anomalies; the placenta should be sent for histology and culture,

specific treatment is based on the underlying etiology and appropriate referral to the relevant pediatric subspecialist including clinical geneticist and pediatric surgeon.

CONCLUSIONSNon-immune hydrops fetalis is an uncommon but serious disorder associated with an overall poor prognosis. The exact pathophysiology of NIHF is still obscure, but a raised central venous pressure is an important prerequisite to the development of hydrops.

The pregnant woman with newly diagnosed hydrops should be promptly referred to a subspecialist feto-maternal medicine unit with a multidisciplinary team.

This team usually consists of perinatologists, neonatologists, clinical geneticists, and other pediatric sub-specialists all of whom are better trained to deal with this condition and provide parents with accurate information and psychological support. This is important because of the vast array of causes, some of which are rare and prognosis obscure, the extensive investigations required with their potential risks to both fetus and mother, and the detailed nature of counseling that is required in helping parents make complex management decisions.

CONCLUSIONSThe ultrasonographic detection of hydrops fetalis is usually straightforward, but its etiology may be elusive depending on the vigour in which a diagnosis is pursued. Detailed prenatal diagnostic investigations allow identification of disorders which may be amenable to treatment, and avoidance of inappropriate invasive fetalinterventions in cases associated with a poor outcome.

Fetal interventions include both medical and surgical modalities. Fetal surgery is still in its infancy applicable to only a few conditions, but is only available in selected centers and potential risks may outweigh its benefits. Trials are underway and will provide a clearer picture about efficacy and risks of fetal surgery in the near future.

CONCLUSIONSNeonatal management of NIHF requires a skilled and coordinated resuscitation team backed by a well equipped NICU.

Parents should be offered a postmortem after the death of their hydropic fetus or neonate, because an autopsy will allow identification of the underlying cause in the majority of cases and facilitate counseling, prediction of recurrence rates, and management of future pregnancies.

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Santolaya J, Alley D, Jaffe R, Warsof SL. Antenatal classification of hydrops fetalis. Obstet Gynecol 1992;79:256-9.

Anadakumar C, Biswas A, Wong YC, Chia D, Annapourna V, Arulkumaran S, Ratnam S. Management of non-immune hydrops: 8 years' experience. Ultrasound ObstetGynecol 1996;8:196-200.

Poeschmann RP, Verheijen RHM, VanDongen WJ. Differential diagnosis and causes of nonimmunological hydrops fetalis: a review. Obstet Gynecol Surv 1991;46:223-31.

Rodriquez MM, Chaves F, Romaguera RL, Ferrer PL, delaGuardia C, Bruce JH. Value of autopsy in nonimmune hydrops fetalis: series of 51 stillborn fetuses. Pediatr DevelPath 2002;5:365-374.

VanMaldergem L, Jauniaux E, Forneau C, Gillerot Y. Genetic causes of hydrops fetalis. Pediatrics 1992;89:81-6.

McCoy MC, Katz VL, Gould N, Kuller JA. Non-immune hydrops after 20 weeks' gestation: review of 10 years' experience with suggestions for management. ObstetGynecol 1995;85:578-82

Jauniaux E, VanMaldengem L DeMinter C, Moscoso G, Gillerot Y. Non-immune hydrops fetalis associated with genetic abnormalities. Obstet Gynecol 1990;75:568-72