Immune and non immune Hydrops fetalis

1. APPROACH
TO
INFANTWITH
HYDROPS FETALIS
DR PRAMAN KUSHWAH
DrNB NEONATOLOGY RESIDENT

2. Introduction
 Hydrops fetalis is a Greek term that describes pathological fluid
(“ὕdur,” Greek for water) accumulation in fetal soft tissues and
serous cavities
 Defn -The presence of 2 abnormal fluid collections in the fetus
detected by ultrasound.

3.  The overall incidence of fetal hydrops reported in the literature is
between 1 in 1500 and 1 in 3000 pregnancies

4.  Features detected by ultrasound, and are defined as the presence
of 2 abnormal fluid collections in the fetus.
 These include
 ascites,
 pleural effusions,
 pericardial effusion, and
 Generalized skin edema (defined as skin thickness >5 mm)
 Other frequent sonographic findings include
 polyhydramnios
 placental thickening
 placental thickness 4 cm in the second trimester
 6 cm in the third trimester

5. Sub-types
 Hydrops fetalis is broadly classified based on etiology into
 Immune estimated 10%-24%
 Non-immune accounting for 76%-90% of cases (becoming
increasingly the main cause of Hydrops)

6. Immune
Hydrops
Fetalis
 Maternal–fetal blood group incompatibilities and production of
Red cell antibodies
 Maternal– fetal Rhesus (Rh) blood group incompatibility a/k/a Rh
Iso-immunization
 ABO blood group incompatibility (rare)
 Non-Rh(D) and non-ABO incompatibility (atypical antibodies)
Phenomenon of Rh Iso-immunisation was reported by Levine in
1941.

7. Causes
 The five antigens that make up the Rh system are D, C, c, E, and e.
 Rhesus D, c, and E are the commonest,
 Incidence of Rh D antibodies is reducing  use of anti-D
 Red cell antibodies that are now commonly associated with
immune hydrops-
 kell antibodies
 Duffy
 Lewis
 p antibodies
 Last two rarely cause hemolytic disease of the newborn
 Kell iso-immunization - mechanism for anemia is most likely
erythroid suppression rather than hemolysis (Vaughan et
al.,1994).

8. Development of
Rh-DAntibodies
 Out ofTotal Rh Positives  45% are homozygous and 55 % are
heterozygous
 First-timer Rh Iso-immune , carries 16% risk of stimulating the
maternal immune system to produce anti-D antibody
 First immune response  Anti-D IgM antibody, cannot cross
placenta, no fetal hemolysis.
 Subsequent pregnancy, if the fetus is again Rh positive
 More rapid immune response occurs
 High titers of anti-D IgG antibody,
 Antibodies rapidly crosses the placenta
 Fetal hemolysis and profound fetal anemia occurs.

10. Mechanism of
Hydrops
Fetalis
1. Maternal anti-D IgG antibody attaches itself to the Rh antigen
present on fetal red cells.
2. Chemotaxis of phagocytes into the fetal spleen
3. Destruction and hemolysis of fetal red cells
4. Increased Fetal Erythropoietin
5. Fetal bone marrow stimulated to increase red cell production
6. Marrow capacity is exhausted and extra-medullary
erythropoiesis begins
7. Red cell production occurs in the fetal liver, spleen, kidney,
adrenal glands, and intestine
8. Fetal rbcs at these sites are often immature, are nucleated, and
appear in the circulation as erythroblasts.
9. Hence, the synonym erythroblastosis fetalis for immune
hydrops

11. Risk of Iso-
immunisation

12. Pathophysiology
Majority of Rh isoimmunization lead to mild or moderate fetal or
neonatal hemolytic disease.
 Only 20% to 25% of cases result in severe hemolytic disease, with
immune hydrops
Pathophysiology is unclear and several hypothesis being
suggested
1. Congestive heart failure secondary to fetal anemia leading to
hydrops
2. Severe fetal anemia leading to extensive extramedullary
erythropoiesis, with associated hepatosplenomegaly and
distortion of intrahepatic architecture, resulting in portal and
umbilical venous distortion, portal hypertension, placental
edema, and placental hypoperfusion (Bowman, 1999).
Deteriorating hepatic synthesis, progressive hypo
albuminemia occurs, adding to the generalized edema,
anasarca, and pleural and pericardial effusions.

13. Non- Immune
Hydrops
1. Accounts for 80 - 90% of cases
2. Any other cause besides immune.
3. No identifiable circulating antibody to any red cell antigen.
4. No common mechanism is responsible for the signs of hydrops.
5. Pathogenesis associated with failure of the interstitial fluid (the
liquid between the cells of the body) to return into the venous
system
 As 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

14. Causes
 ConditionsAssociated with NIH (This list is not exhaustive)
 Cardiac
 Cardiomyopathy, Ebstein's anomaly, pulmonary atresia, coarctation
of the aorta, hypoplastic left heart, completeAV 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

15.  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

16.  Difficult to find a plausible explanation for the development of
hydrops in every case - which may represent chance associations.
 However, as a general rule,
 HF presenting before 24 weeks is usually due to chromosomal
aberrations
 Hydrops presenting after this is usually due to structural anomalies
(such as cardiac and pulmonary)

17.  More than 100 causes or associations of NIHF have been found.
 10 to 20% of cases are idiopathic
 Seven major categories:
1. Cardiovascular Pathologies (35 %)
2. Chromosomal Anomalies (20 %)
3. Anemia (15 %)
4. Malformation Syndromes (15 %)
5. Infections (10 %)
6. Liver Diseases (5 %)
7. Miscellaneous Causes (5 %)

18. Pathogenesis

19. Cardiac causes
A. STRUCTURAL DEFECTS
1. KARYOTYPIC ABNORMALITIES
 Coarctation of aorta withTurner syndrome
 Arterioventricular canal and septal defects with Down syndrome
B. FUNCTIONAL DEFECT
1. Fetal supraventricular tachyarrhythmias (SVT)
1. Important cause of hydrops
2. Detected by fetal echocardiography
3. Amenable to therapy
2. Congenital heart block (CHB)
1. > 60% of pregnancies complicated by collagen disease (esp. lupus).
2. Maternal ANA attack fetal collagen in conduction bundle
3. Not all fetuses with CHB are affected

20. CHROMOSOMAL
 GENETIC SYNDROMES (1/3rd of cases of NIHF)
1. Most common -Turner syndrome – typified by ultrasound finding
of cystic hygromas
2. Prognosis is poor in most of cases due to associated structural,
functional, and metabolic defects
3. complete family history is important to rule out known inherited
disorder
4. Hemoglobinopathies
5. Inborn errors of metabolism (rare)

21. SEVERE
FETALANEMIA
A. ALPHA -THALASSEMIA (Hb Barts)
 Fetal anemia leading to hypoxia and high output cardiac failure
 South East Asia, 86 % (25/29) of hydrops were due to Hb Bart’s.
B. FETAL HEMORRHAGE
1. Intracranial bleeding from AV malformation or sacrococcygeal
teratoma
2. Fetal-maternal hemorrhage (abruptio or placental tumours such as
chorioangioma)
3. Hemolysis (Spherocytosis,G6PD or PKD)
4. Failed erythropoiesis (marrow dysfunction  Parvovirus B19,
leukemia, pure red cell aplasia).

22. Malformation
syndromes
 Can involve any of the major system
1. PULMONARY - CCAM
 M/C thoracic lesion associated with hydrops.
 Abnormal capillary-alveolar development
 Functionless cystic lung masses  space occupying lesion
 Compression and underdevelopment of normal lung tissue
 Hypoplastic lung, shifting of mediastinum and heart, obstruction of
cardiac venous return, central venous hypertension  leading to
hydrops in severe cases.
 Other pulmonary causes of hydrops probably share the same
pathogenesis

23. 2. GASTROINTESTINAL - CONGENITAL DIAPHRAGMATIC HERNIA (CDH)
 Herniated bowel or liver causing intrathoracic mass effect similar to CCAM.
 Other causes with same pathogenesis- Esophageal Atresia, MidgutVolvulus, Meconium Peritonitis, Duodenal
Diverticulum, Intestinal Duplication, Malrotation, And Imperforate Anus.
3. RENALAND UROLOGIC
 Finnish nephrosis leading to severe hypoproteinemia, hypoplastic kidney(s), polycystic kidneys, renal vein
thrombosis, bladder outlet obstruction, and dysplastic kidneys.
4. NEUROLOGIC MALFORMATIONS are a rare cause of hydrops which includes encephalocele,
porencephaly with absent corpus callosum, fetal intracranial hemorrhage, and vein of Galen aneurysm.
5. 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.

24. INTRAUTERINE
INFECTIONS
 CAUSES IMPLICATED
 Toxoplasmosis, Rubella, Cytomegalovirus, Herpes simplex, Syphilis
(collectively known as “TORCHS”), Coxsackie virus and Parvovirus
B19
 POSSIBLE MECHANISMS
 fetal anemia from hemolysis,
 suppressed erythropoesis and myelopoiesis,
 fetal myocarditis and fetal hepatitis.
 Parvovirus B19
 one third of all cases of NIHF
 red cell aplastic crisis leading to severe anemia
 risk of fetal death of 15% at 13-20 weeks and 6 % after 20 weeks
 PROGNOSIS
 SYPHILIS - very poor prognosis
 Parvovirus B19 and other - self limited and may resolve
spontaneously and 85% of fetuses treated by in-utero transfusion
survive.

25. Twin –Twin
Transfusion
 Imbalance in blood flow due to anastomoses in placentas of
monochorionic twin pregnancies
 In severe cases, one or both twins may develop Hydrops
 Recipient twin  hypervolemia and rise central venous
pressure
 Laser therapy - best available therapeutic approach
 Selective termination via umbilical cord coagulation
 Radiofrequency ablation of the acardiac twin for severe cases

26. APPROACH

27.  Diagnostic challenge
 To establish the etiology
 To determine appropriate therapy and timing of
delivery.
 (cause of hydrops can be determined in ONLY about 60-85% of
cases including postnatal evaluation)

28. Presentation
FETAL PRESENTATION DURING ROUTINE ULTRASOUND
EVALUATION
 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

29. Maternal
complications
 MATERNAL PRESENTATION–
 Edema , hypertension, proteinuria
 Condition can quickly deteriorate into fulminant pre- eclampsia and
eclampsia.
 Mirror syndrome – An uncommon complication in which the mother
develops edema that “mirrors” that of her hydropic fetus –
necessitates urgent delivery.
 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 causing morbid adherence of placenta causing
problems for third stage of labor necessitating the manual
removal of Placenta.

30. OBSTETRIC
COMPLICATIONS  Polyhydramnios  If a/w maternal respiratory distress
 Preterm birth  Tocolytic agents <24 weeks
Prostaglandin InhibitorOR Serial Amnioreduction
Inutero Ductus closure, PPROM,Abruption NEC,

31. Investigations
 Initial investigations include an indirect Coombs test to exclude
immune causes,
 followed by-
 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;
 screening for toxoplasmosis, rubella, CMV, herpes simplex (TORCH)
and other infections infection during pregnancy.

33. Sonography
Fetal hydrops is not seen sonographically until the fetal hematocrit has fallen to
below one-third of its normal range
Axial image of a fetus demonstrating scalp
edema due to immune hydrops
Axial image demonstrating abdominal ascities
and edema of the abdominal wall in a fetus with
immune hydrops.

34. Sagittal image demonstrating edema of the scalp
and face in a fetus with immune hydrops
Hydrocele can be early manifestation in
Hydrops

35. Axial image demonstrating abdominal ascites in a
fetus with immune hydrops

36. Fetal Echo
Axial image demonstrating a
pericardial effusion
in a fetus with immune hydrops
• Consider fetal heart rate monitoring for 12 to 24 hours if fetal
arrhythmia is suspected

38. Doppler Blood
FlowStudies
 The use of Doppler sonography to predict fetal anemia has been
more successful (Mari et al., 1995).
 Elevated peak systolic velocity (PSV) measured in the middle
cerebral artery (MCA) is associated with an increased likelihood of
fetal anemia

39.  Initiated at 16–18 weeks of gestation
 Reliability decreases after 35 weeks of gestation
 MCA-PSV >1.5 MoM = severely anemic fetus.
 Sensitivity =100% (95% CI) for moderate or severe anemia
 False-positive rate of 12%(Mari et al)

41. Diagnostic
Invasivemethod
 Previously invasive methods were used to diagnose
alloimmunization.
 Critical titer levels indicative of high risk of fetal anemia,
 as ≥ 1:16 for anti-RhD
 ≥ 1:8 for anti-Kell10,
 Serial AMNIOCENTESIS for bilirubin levels to estimate the
severity of hemolysis.
 Spectrophotometry was used to quantify bilirubin level, which
was expressed as the change in optical density (OD) at a
wavelength of 450 nm (OD450).
 These values were plotted on Liley’s curve or Queenan’s curve (<
27 weeks) to predict fetal anemia

43. Amniocentesis
andCVS
 AMNIOCENTESIS
 Fetal karyotyping, amniotic fluid culturing,
 PCR (polymerase chain reaction) for infections, testing for
thalassemia, and determination of the lecithin-sphingomyelin (L/S)
ratio.
 Fetal liver function and metabolic testing if indicated.
 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
 analysis of fetal or neonatal blood or urine.
 Histological examination of fetal tissues.
 KARYOTYPING can be performed with chorionic villous sampling
(CVS) or with fluid obtained from one of the fetal cavities.

46. PERCUTANEOUS
UMBILICALBLOOD
SAMPLING (PUBS)
 PUBS OR CORDOCENTESIS
 most accurate method for diagnosis of Fetal Anemia
 Include hemoglobin chain analysis for thalassemia and fetal serum
albumin level
 done if MCA velocity >= 1.5 MoM
 INTRAUTERINETRANSFUSION is done as a part of the same
procedure after obtaining the Hb/Hct values
To summarize
 SCREENING: MCA DOPPLER
 DIAGNOSTIC &THERAPEUTIC: PUBS

47. Management
 Immediately referred to a tertiary care center, with trained
perinatologists to perform intrauterine transfusions and
neonatologists care.
 Arrangements to perform PUBS and possible intrauterine fetal
transfusion should be expedited as rapidly as possible
 Antenatal corticosteroid if GA between 24 and 34 weeks, to
reduce the complications of prematurity .
 option of elective termination should be discussed with the
parents if the gestational age is less than 24 week.

51. Fetal
Intervention
INTRAUTERINETRANSFUSION
INDICATION: - Main indication for IUT is fetal anemia due to red cell
allo-immunization
 MCA-PSV >1.5 MoM and/or
 If signs of hydrops are present
 The intrauterine transfusions can be done via 3 access points
 Intraperitoneal
 Via Umbilical cord
 Via Intrahepatic portion of UmbilicalVein

52. Transfusion
volume
calculation
 A commonly used formula for the volume of blood to be
transfused is
 whereVT is volume of blood transfused, 150 is a placental
correction factor, and EFW is estimated fetal weight in kilograms
(Kaufman and Paidas, 1994).
 Fetoplacental volume (V) :
 0.1 mL volume/g of estimated fetal weight
 Fetal erythrocyte treatment has also been reported to be
successful in nonimmune etiology

54. Fetal
monitoring
 POST - IUT
 Sonographic surveillance should be instituted, depending on the
gestational age.
 Daily fetal testing with nonstress tests or biophysical profiles is
reasonable for all potentially viable fetuses.
 With sonographic evidence of resolution of hydrops, testing can
be decreased to twice weekly.
 Sonographic surveillance for appropriate fetal growth should
continue every 2 weeks

55. Delivery
 Pregnancies not to be allowed beyond 37 to 38 weeks
 premature delivery indicated if
 hydrops does not improve
 if fetal testing non-reassuring despite correction of fetal anemia
 Delivery by cesarean
 Because of the risk of soft-tissue dystocia associated with hydrops
 Minimize chances of maternal and fetal trauma.
 A trial of labor may be reasonable in cases in which the fetal
anemia has been adequately corrected, and in which the hydropic
features improve.
 In carefully selected and monitored cases, up to 80% of fetuses
with immune hydrops may successfully deliver vaginally
(Bowman, 1999).

56. Neonatal
Management
HYPOPLASTIC LUNGS, HYALINE MEMBRANE DISEASE,
PLEURAL EFFUSIONS, PULMONARY EDEMA, SEPSIS,
PERINATAL DEPRESSION, HYPOXIA, OR ACIDOSIS
Immediate neonatal endotracheal intubation and
supportive care in almost all infants
Cautious use of inotropic agents, diuretics, blood products, albumin, and
fluids to maintain an adequate cardiac function without fluid overload or
soft-tissue edema,
High-frequency ventilator and high airway pressure settings will often be
needed to achieve adequate oxygenation
Umbilical lines help with administration of various agents, monitoring of
blood gases and arterial and venous pressures.

57.  Once the neonate is stabilized
 Full physical examination
 Relevant echocardiographic, and radiologic investigations to
exclude structural malformation
 Hematologic tests to rule out sepsis, biochemical and karyotypic
anomalies;
 Placenta should be sent for histology and culture,
 Specific treatment is based on the underlying etiology
 Appropriate referral to the relevant pediatric subspecialist including
clinical geneticist and pediatric surgeon.
 No Surgical management described.

58. Fetal
intervention
 OTHER FORMSOF FETAL INTERVENTION (esp. NIHF)
1. Medical therapy for the mother to correct fetal arrhythmias .
Digoxin administration to pregnant women has been
successful in the treatment of fetal arrhythmias, with resolution
of hydrops in some cases (Knilans, 1995).
2. Fetal thoracentesis may be performed under sonographic
guidance with resolution of pleural effusions (Jones, 1995).
3. Thoracoamniotic shunt if repeat thoracentesis are needed
4. Other - Open fetal surgical resection of thoracic masses or
sacrococcygeal teratoma (Bullard andHarrison, 1995).
…..However, very few data is available confirming whether such
invasive approaches have a significant impact on fetal or neonatal
outcome…..

59. Recurrence
risk
 A postmortem examination indicated in all cases of NIHF
 This will maximize the number of cases in which a definite
underlying cause is identified and will facilitate appropriate
genetic counseling and prediction of recurrence risk (Steiner,
1995).
 Recurrence of idiopathic NIHF is rare, Patients should therefore be
made aware that, while idiopathic NIHF is extremely rare,
recurrences can and do occur.

60. Long term
outcome
 Long-term neurodevelopmental outcome after IUT for hemolytic
disease : the LOTUS study
 Neurodevelopmental outcome till least 2 years of age was
assessed.
 Primary outcome was the incidence of neurodevelopmental
impairment defined as at least one of the following:
 cerebral palsy,
 severe developmental delay,
 bilateral deafness, and/or
 blindness.

61. Take home
message
 Identify the cause of Hydrops
 MCA Doppler in monitoring and treatment of fetal Anemia
 Improvement in prognosis and long term outcome on use of IUTs.
 Optimal timing of delivery
 Capable NICU team and a tertiary centre
 Anticipation of Preterm delivery and RDS

62. Hydrops to Hope – Journey of Jacoby – one of a twin diagnosed with non immune hydrops – Altogether
spent 16 months in the NICU and Cleveland Clinic Children's Hospital for Rehabilitation before finally
going home…..

63. ThankYou