a short presentation on the condition non immune hydrops..particularly on how to approach the case

1. Non-immune hydrops
Dr Anita Srinivasan
2nd year DM resident
Dept. of Neonatology,
Seth GSMC & KEMGH,Parel,mumbai

2. Hydrops fetalis
Hydrops 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).

3. Broadly divided into 2 categories:
Immune Hydrops &
Non-immune hydops

4. incidence
Accurate 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.

5. Causes
Hydrops 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

6. 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 .

7. 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.

8. Pathogenesis
This 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)

9. 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%

10. 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

12. Non-immune Hydrops Fetalis

13. Normal
four
Chamber
Cardiac
View

14. Pericardial Effusion
Heart

15. Body wall
edema in a
hydropic
fetus

16. www.thefetus.net Fetal Ascites

17. Hydrocele can
be an early
manifestation
in hydrops

18. Soft Tissue
shadow and
pleural
effusion in
hydropic
neonate

20. 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 ovale
Intracardiac tumors (tuberous sclerosis)
Cardiac arrhythmia
SVT, flutter, heart block, WPW syndrome
Chromosomal /Genetic Syndromes
T13, T18, T21, XO (Turners syndrome) , Noonan syndrome , multiple pterygium syndrome, Pena-Shokeir, arthrogryposis
Fetal Anemia
Alpha (α) thalassemia, parvovirus, fetal hemorrhage, G-6-PD deficiency
Infection
Parvovirus, CMV, syphilis, coxsackie virus, rubella, toxoplasmosis, herpes,varicella, adenovirus, enterovirus, influenza, listeria
Thoracic Abnormalities
Congenital cystic adenomatoid malformation (CCAM) , chylothorax, diaphragmatic hernia, mediastinal tumor, skeletal dysplasias
Twinnning
Twin to twin transfusion Severe anemia in the donor twin or high-output failure in the recipient
Tumors
Fetal 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 nephrotic
syndrome.

21. 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 hydrops
presenting after this is usually due to structural anomalies (such as cardiac and
pulmonary)

22. 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.

23. . Fetal supraventricular tachyarrhythmias (SVT) are an important cause of hydrops
which 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

24. 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.

27. 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.

28. 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 hydrops
probably share the same pathogenesis.

29. 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.

30. 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.

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

32. 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.

33. 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 fetuses
infected 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.

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

35. 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.

36. 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.

37. 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.

38. 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

39. INVESTIGATIONS
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.

41. Detailed Ultrasound Scan
Fetal Echocardiography
Doppler Blood Flow Studies
Liquor Volume Assessment (AFI)
Placental Thickness & Echogenicity

42. 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.

43. Fetal blood tests should include hemoglobin chain analysis for thalassemia and fetal
serum 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.

44. Fetal echocardiogram
Consider fetal heart rate monitoring for 12 to 24 hours if fetal
arrhythmia 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.

45. MANAGEMENT
Counseling
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.

46. 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

47. 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.

48. 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 adenomatoid
malformation 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.

49. 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

50. 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).

51. Fetal surgery is not yet commonly available in India.
Interventions performed include:
Needle aspiration
Feto-amniotic shunting
repair of congenital diaphragmatic hernia, resection of cystadenomatoid
malformation of the lung, and excision of large sacrococcygeal teratomas.
Fetal endoscopic surgery for TRAP,PLUG for cases of CDH.

52. DELIVERY
Neonatal 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).

53. Delivery
a) 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

54. 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

55. 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

56. 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.

57. CONCLUSIONS
Non-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.

58. CONCLUSIONS
The 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 fetal
interventions 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.

59. CONCLUSIONS
Neonatal 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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