Immune Hydrops fetalis
Dr. Vinayak V. Kodur
3rd year DM resident
L.T.M. General Hospital
• Hippocrates in 400 bc, had discribed
• First clinical report - Attributed to a French midwife
who delivered twins in 1609.
• The first twin was hydropic and stillborn; the second
died of kernicterus.
• 1940 Landsteiner et al discovered Rh antigen.
• In 1941, Levine et al observed that RhD negative
mother exposed to when RhD positive erythrocytes,
she forms antibodies that cause red blood cell
• In 1948, Wiener postulated that transplacental
passage of RhD-positive fetal blood into the
maternal circulation trigger the production of
antibodies against fetal cells
• Thus it supported an immunologic rationale for
the therapeutic use of exchange transfusion.
• Freda and coworkers efficacy of anti-D IgG in
Rh negative volunteers.
• The Rh system includes antigens encoded by two
genes on chromosome 1p36.13-1p34.3.
• Although this system comprises more than 40
discrete antigens, only five of them are clinically
relevant: D, C, c, E, and e.
• “D” is dominant and in clinical sympatomatology
whenever present the person is called Rh +Ve,
while one having small dd is non effective hence
taken as Rh -Ve .
• Rh –Ve persions ---India 5- 10 % 0f population –it is
least in Japan < 2% and 15 % in Europe and USA.
Kleihauer Betke Test..
• Based on acid elution technique. Fetal and maternal
RBCs have different response to citrate acid
phosphate buffer solution.
• Maternal cells (adult Hb ) get eluded leaving behind
only cell membrane and hence appear as swollen
round large “GHOST CELLS” against normal fetal
cells whose Hb remain unaltered hence look as red
refractile round cells .
Kleihauer Betke Test
• If in 50 low power fields of maternal peripheral
blood 80 fetal RBC’s are found- it is estimated that
4ml of fetomaternal hemorrhage has occurred.
• For 1ml of fetal blood 10ug of Rh anti D is needed.
Thus 300ug anti D will be sufficient for 30 ml of fetal
blood which has entered the maternal circulation.
Characteristics of Rh -
• Saline antibodies
• Agglutinate Rh +ve RBCs
when suspended in saline.
• Appear first –before 24
weeks– and then decline
• Larger molecule.
• Can not cross placenta hence
can not cause hemolytic
disease of new born.
• Agglutinate with Rh +Ve
RBCs when suspended in
20% Albumin solution.
• Appear later than saline
antibodies & continue to
increase as pregnancy
• Small Molecule.
• It crosses the placenta.
• Causes hemolytic disease of
• Hydrops fetalis is a condition in the fetus characterized
by an abnormal collection of fluid with at least two of
(fluid beneath the skin, more than 5 mm).
(fluid in abdomen)
• Pleural effusion
(fluid in the pleural cavity, the fluid-filled space that surrounds
• Pericardial effusion
(fluid in the pericardial sac, covering that surrounds the heart)
• Hydrops fetalis is typically diagnosed during
ultrasound evaluation for other complaints such as
• Size greater than dates
• Fetal tachycardia
• Decreased fetal movement
• Abnormal serum screening
• Antenatal hemorrhage
• Hydrops fetalis is found in about 1 per 2,000 births
and is categorized as :
• Immune hydrops
• Nonimmune hydrops
• Accounts for 10-24%of cases
• Maternal antibodies against red-cells of the fetus
cross the placenta and coat fetal red cells which
are then destroyed (hemolysis) in the fetal
• Accounts for 76 -90% of cases
• Any other cause besides immune.
• 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
• Non-immune is now becoming more and more
• Isoimmunization (hemolytic disease of the newborn,
• Rh (most commonly D; also C, c, E, e)
• Kell (K1, k2, Kp, Js[B])
• Duffy (Fyb )
• Anti-D, anti-E, and antibodies directed against other
Rh antigens comprise the majority of antibodies
responsible for hemolytic disease of the newborn .
Feto- maternal haemorrhage During
• O.1mlof fetal RBCs are found in 5-15 % of
women’s circulation by 8 weeks of gestation.
• 75% cases it is always < 1ml .
• 1% show atleast 5ml fetal RBCs.
• 0.25% have more than 30ml of fetal RBCs
• Only 1.5 % women get sensitised in Antenatal
• It can be prevented by anti D therapy in
antenatal period ---at 28-30 and 34-36 weeks
of gestation and repating it after delivery.
• Fetomaternal transfusion has been documented
in 7%, 16%, and 29% of patients in their first,
second, and third trimesters, respectively.
• In the peripartum period, the incidence of
fetomaternal hemorrhage can be as high as
• As little as 0.2 mL of fetal blood is sufficient to
cause maternal anti-D sensitization.
Immune Hydrops Fetalis
• First pregnancy proceeds normally as Rh -ve mother
is usually not sensitized.
• Feto -placental maternal transfusion occurs at the
time of placental separation.
• Amnioscentesis , threatened abortion, ectopic
pregnancy, MTP, D&E, abruptio placenta, APH ,
External podalic version, IPV, LSCS, CVS.
• In subsequent pregnancy the fetal RBCs entering in
maternal circulation may be destroyed /or some of
them may have booster effect for maternal
• Maternal Immunoglobins G cross the placenta and
destroy fetal RBCs .
• In mild cases, the fetus has haemolytic disease
resulting in anaemia with mild icterus.
• In severe cases fetus develops hydrops fetalis.
• If IgG titers are high the disease process may start
even in early period of gestation --- resulting in
Degree of Risk of Developing
isoimmunisation according to period of
Gestational period %
After 1st trimester abortion 2 %
After MTP ( mid trimester ) 4-5%
At term after Delivery— Rh
2% at the time of delivery ,
7% will develop anti D antibodies by
the 6 months of delivery ,
7% get sensibilized e.g. they
develop anti D slowly and very low
titre which becomes detactable and
measurable in next prgnancy.
ABO incompetable 1.5 -2 %
Why all babies are not affected in
Rh –Ve mother
• Volume of fetomaternal trnsfusion may be too low to
• Immunological non responders ---pregnancy
induced suppression of immune system –30%.
• ABO Major group incompetability.
• Rh set up of the fetal blood may change the Rh –
antigenicity ( stimulus )
• Occasionally hydrops may be due to other
erythrocyte antigen apart from Rh D antigen.
• These include –major A.B.O. incompatibility and
minor blood group antigens ---C D E, Kell , Jk, S,
c , and Duffy.
• If issoimmunization occurs , then the titers of
antibodies are monitored at appropriate intervals
depending on the levels and rapidity with which
they are changing ( either every 2 or 4 weeks).
• In immune hydrops, excessive and prolonged
hemolysis causes anemia, which in turn stimulates
marked marrow erythroid hyperplasia
• It also stimulates extramedullary hematopoiesis in
the spleen and liver with eventual hepatic
• The precise pathophysiology of hydrops remains
• Theories includes
• Heart failure form profound anemia and hypoxia
• Portal hypertension due to hepatic parenchymal
disruption caused by extramedullary hemopoiesis
• Decreased colloid oncotic pressure resulting from
liver dysfunction and hypopreteinemia
• The degree and duration of anemia is the major
factor causing and influencing the severity of
• Secondary factors include hypoproteinemia caused
by liver dysfunction and capillary endothelial
leakage resulting from tissue hypoxia, both of these
lead to protein loss and decreased colloid oncotic
Hepatic extramedullary hematopoeisis
Decreased production of plasma proteins
Decreased plasma COP
Severe tissue hypoxia
Endothelial cell damage
Capillary leak of fluid & protein
• There may be cardiac enlargement and pulmonary
• Fluid collects in the fetal thorax, abdominal cavity,
• The placenta is markedly edematous, enlarge, and
boggy. It contains large, prominent cotyledons and
• Pleural effusions may be so severe as to restrict
lung development, which causes pulmonary
compromise after birth
• Ascites, hepatomegaly, and splenomegaly may lead
to severe labor dystocia
• Severe hydropic changes are easily seen with
• Fetuses with hydrops may die in utero from
profound anemia and circulatory failure
• One sign of severe anemia and impending death is
the sinusoidal fetal heart rate pattern
• Hydrops placental changes leading to
placentomegaly can cause preeclampsia
• The liveborn hydropic infant appears pale,
edematous, and limp at birth and usually requires
• The spleen and liver are enlarged, and there may
be widespread ecchymosis or scattered petechiae
• Dyspnea and circulatory collapse are common
Placenta of Hydropic Pregnancy
Placenta of Normal Pregnancy
• In an attempt to compensate for the fetal
hypoxia, placenta increases in size and
sometimes also penetrate deeper into the
• Thus causes the morbid adherence of
placenta and can cause the problems for
third stage of labor necessitating the manual
removal of Placenta.
• Mirror syndrome
• The mother develops preeclampsia along
with severe edema that is similar to that of
• Caused by vascular changes in the
swollen, hydropic placenta, this likely
related to antiangiopenic factors produced
• A history suggesting the presence of any of the
following factors should trigger an extensive
diagnostic study for hydrops fetalis:
• Maternal history
• Rh negative (d;d) blood type
• Known presence of isoimmune blood group
• Prior administration of blood products
• Risks of illicit drug use
• Family history
• Hydramnios in earlier pregnancies
• Prior hydrops fetalis
• Previous fetomaternal transfusion
• Previous fetal death
• Jaundice in other family members or in
• Treatment given in previous child if jaundiced
Manifestation Of Erythroblastosis
• Depending upon the degree of fetal RBCs haemolysis -
--It may be -
• Hydrops Fetalis: Fetus is severely affected.
• Neonatal Jaundice: Relatively less affected.
• Congenital Anaemia: mildly affected . Baby develops
anaemia ; jaundice is not so evident or mild , prognosis
• 30% cases with hydrops die in utero. (IUFD)
• Assessments generally proceed from low-risk
noninvasive tests to higher-risk invasive techniques
as required for precise and complete diagnosis to
properly manage the individual pregnancy.
Maternal laboratory studies
• Assessment of maternal blood type (red cells) and
antibody screen (identification, and quantitation
when indicated, of maternal plasma antibodies)
• Qualitative and quantitative estimates of the
proportion of red cells containing fetal hemoglobin
in the maternal circulation Kleihauer Betke test.
• Ultrasonogram with Doppler measurement of
the peak systolic velocity (PSV) in the fetal
middle cerebral artery (MCA) to assess for fetal
• At cut off point of 1.5 multiples of median, MCA-
PSV is found to correlate with moderate to severe
anemia, with a sensitivity of 100% and a false
positive rate of 12%
• An accurate and noninvasive means of diagnosing
fetal anemia in patients with Rh isoimmunization.
be an early
• Fetal 2D echocardiogram with doppler
• Amniocentesis for fetal karyotype and Liley`s
• Fetal percutaneous blood sampling to confirm
the hemoglobin just before intrauterine
• Routine antenatal Rh antibody therapy is
recommended to Rh negetive women married to
• 300 ug ,im in deltoid muscle at 28-30 weeks and
34-36 weeks of gestation.
• 100 ug, im is given after bleeding in 1st trimester.
• Higher dose if any precipitating factor or procedure
likely to cause feto placental hemorrhage.
• 300ug anti D is sufficient to neutralize 15 ml of
have fetal cell/ 30ml of whole blood.
• When a Rh(D) negative mother receives RhD-Ig
during pregnancy, especially as routine
prophylaxis at 28-30 and 34-36 weeks gestation:
• Rh(D) positive infant may be born with a positive
DCT but have no evidence of haemolysis
• Maternal sample will often show anti-D reactivity,
as the half-life of passive RhD-Ig in the absence
of significant FMH, is approximately 21 days.
• Follow up of the fetus will depend on the gestational
age of the fetus, and the mother's wishes regarding
• If treatment has been successful or hydrops is
resolving spontaneously, the fetus may be followed
with repeat sonograms every 1 to 2 weeks and
• The goal of IUT is to achieve a posttransfusion
hematocrit of 50-60%.
• Indications for the first IUT:
• Ultrasound evidence of hydrops fetalis.
• cordocentesis shows severe anemia
(hemoglobin < 10 g/dL, hematocrit < 30%)
• Spectrophotometry of amniotic fluid shows
high bilirubin level,
• Give antenatal steroids for lung maturity
• Use of antibiotics and tocolytics before
procedure no evidence for it.
• Fetal paralysis with pancuronium can be done
• 20-22 gauge echogenic tip needle
• Site 1. near the placental insertion of cord
• 2. Free loop of cord
• 3. Intrahepatic portion of hepatic vein
• 4.Umbilical artery
• Fetal blood confirmed by high MCV (>110)
• Volume of blood transfused depends on
EFW, fetal hematocrit(HCT), HCT of blood
• Overall procedure related fetal loss 1%.
• Emergency delivery in 24 hrs of procedure
and subsequent perinatal death 1.8%
• HCT falls 1% per day and repeat transfusion
generally within 2 weeks.
• Usually done < 18weeks or when intravenous
transfusion technically impossible because fetal
position or location of umbilical cord.
• Infused RBCs are absorbed into the circulation of
subdiaphragmatic lymphatic lacunae and right
• Fetal respiration is important to occur.
• Complete absorption takes 150hrs (6days)
• Less effective when hydrops present
• 16-20 gauge Touhy needle used
• Needle inserted in between umbilicus and
• Catheter tip should be free in abdominal cavity
and confirmed with injected saline.
• Bowman formula for infused blood volume
= (gestation in weeks -20) * 10 ml.
Repeat transfusion generally 9-12 days
• Complications: serial IUT risk to the mother and the
fetus such as preterm labor, premature rupture of
membranes, chorioamnionitis, fetal bleeding, fetal
bradycardia, and fetal death.
• Fetomaternal hemorrhage which may increase
maternal alloimmunization and worsen the
• After one IUT, the timing of the next IUT is usually
planned arbitrarily after 2-3 weeks depending on
previous posttransfusion hematocrit, considering a
fall in hematocrit of 1% per day
• Invasive Procedures
• Drainage Procedures:
• Large Pleural Effusions
• All invasive procedures carry an inherent increased
risk of fetal demise or pre-mature labor.
• Mild Rh isoimmunisation 37 completed weeks
• Severe cases
• Last transfusion should be given 30-32 weeks
with delivery between 32-34 weeks with steroids
given to accelerate FLM.
• Intra-uterine transfusion to be continued till 35
weeks and delivery at 37 weeks
• Oral phenobarbitone can be given to mother strating
1 week prior to anticipated delivery.
• The fetus should be delivered at tertiary care center
with neonatologists and other appropriate
• There is no evidence that delivery by cesarean
section has a marked effect on outcome.
• Cord blood should be obtained at delivery for
hemoglobin concentration and direct Coombs
• A postmortem evaluation should be performed in all
cases of hydrops that result in neonatal death. One
study showed that a combined approach of a
thorough antenatal assessment and autopsy may
be more likely to determine the cause of non-
immune hydrops .
• 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
• If early in pregnancy (less than 24 weeks) with no
treatable cause the option of termination may be a
• Recurrence is uncommon unless related to blood
group incompatibility (isoimmunization) or
Grand Mother theory
• Rh –ve(dd) fetus rarely may be exposed to
maternal D antigen as result of materno fetal
haemorrhage and may become sensitized in
their intra uterine life. When such girl at her adult
age has pregnancy with Rh +ve fetus , the very
first fetus may suffer from HDFN . this
mechanism of isoimmunisation is called GRAND
• In a previously sensitized / sensibilized women the
antibody titer may rise to high level in subsequent
• This may occur in d-negative fetus also.