Immune Hydrops fetalisDr. Vinayak V. Kodur3rd year DM resident

L.T.M. General Hospital

History• Hippocrates in 400 bc, had discribed

erythroblastosis fetalis• 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 hemolysis.

History• 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.

• Some basics in Microbiology..

Rh Antigen• 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.

DCT and ICT

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.

Kleihauer Betke Test..

Characteristics of Rh -Immunoglobins

• IgM

• 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 advances.

• Small Molecule.• It crosses the placenta.• Causes hemolytic disease of

newborn .

Hydrops Fetalis

Hydrop 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

(fluid in abdomen) • Pleural effusion

 (fluid in the pleural cavity, the fluid-filled space that surrounds the lungs)

• Pericardial effusion (fluid in the pericardial sac, covering  that surrounds the heart)

• Polyhydramnios• Placentomegaly

Hydrop fetalis• 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

Etiology

• Hydrops fetalis is found in about 1 per 2,000 births and is categorized as :• Immune hydrops• Nonimmune hydrops

Immune 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 spleen.

Non-immune hydrops• 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 system .

• Non-immune is now becoming more and more common.

Hematologic causes • Isoimmunization (hemolytic disease of the

newborn, erythroblastosis) • Rh (most commonly D; also C, c, E, e) • Kell (K1, k2, Kp, Js[B]) • ABO • MNSs • 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 Antenatal Period

• 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

period .• 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.

Rh Sensitization• 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 50%.

• 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 sensitization.

Immune Hydrops• 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 IUFD.

Degree of Risk of Developing isoimmunisation according to period of

gestationGestational period %

After 1st trimester abortion 2 %

After MTP ( mid trimester ) 4-5%

At term after Delivery— Rh competability

16%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 sensitise.

• 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 )

Hydrops fetalis • 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).

Pathophysiology • 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 dysfunction

Pathophysiology • The precise pathophysiology of hydrops remains

unknown

• 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

Pathophysiology • The degree and duration of anemia is the

major factor causing and influencing the severity of ascites

• 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 pressure

Pathophysiology Severe anemia

Hepatic extramedullary hematopoeisis

Decreased production of plasma proteins

Decreased plasma COP

Pathophysiology Congestive heart failure

Increased central venous pressure

Increased capillary hydrostatic pressure

Pathophysiology Severe tissue hypoxia

Endothelial cell damage

Capillary leak of fluid & protein

DecreasedCOP

IncreasedCVP

Capillary leak

Increasedfluid effluxfrom intravascularspace

Pathophysiology • There may be cardiac enlargement and

pulmonary hemmorrhage

• Fluid collects in the fetal thorax, abdominal cavity, or skin

• The placenta is markedly edematous, enlarge, and boggy. It contains large, prominent cotyledons and edematous villi

Pathophysiology • 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 sonography

Pathophysiology • 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

Pathophysiology • The liveborn hydropic infant appears pale,

edematous, and limp at birth and usually requires resuscitation

• 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

Associated complication

• Polyhydramnios• Placenta abruption• Uterine atony• Pre-mature labour• Hydropic, theickened placenta (> 6 cm)• Retained placenta• Preeclapsia

Associated complication

• 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.

Associated complication

• Mirror syndrome• The mother develops preeclampsia along

with severe edema that is similar to that of the fetus

• Caused by vascular changes in the swollen, hydropic placenta, this likely related to antiangiopenic factors produced by hyperplacentosis

History • 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 antibodies • Prior administration of blood products • Risks of illicit drug use

History • Family history

• Hydramnios in earlier pregnancies • Prior hydrops fetalis • Previous fetomaternal transfusion• Previous fetal death • Jaundice in other family members or in

previous child • Treatment given in previous child if jaundiced

or hydropic.

Manifestation Of Erythroblastosis Fetalis

• 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 is good.

• 30% cases with hydrops die in utero. (IUFD)

Laboratory Studies

• 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.

Laboratory Studies• Ultrasonogram with Doppler measurement of

the peak systolic velocity (PSV)  in the fetal middle cerebral artery (MCA) to assess for fetal anemia.

• 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.

Normal four

Chamber Cardiac

View

Pericardial Effusion

Heart

Body wall edema in a hydropic

fetus

Fetal Ascites

Hydrocele can be an early manifestation in hydrops

Laboratory Studies

• Fetal 2D echocardiogram with doppler• Amniocentesis for fetal karyotype and Liley`s

chart• Fetal percutaneous blood sampling to confirm

the hemoglobin just before intrauterine transfusion.

Liley’s chart

Prophylaxis

Immunoprophylaxis• Routine antenatal Rh antibody therapy is

recommended to Rh negetive women married to Rh+ve partner.

• 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.

Antepartum Monitoring

• 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.

Algorithm

Algorithm

Treatment

Treatment Intrauterine Blood Transfusion

• Blood Transfusion to Fetus

• Intra-peritoneal

• Intra-venous

• Umbilical Vein

• Hepatic Vein

Intrauterine Transfusion

• 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,

Intra-venous..• 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

Intra-venous..• Fetal blood confirmed by high MCV (>110)• Volume of blood transfused depends on

EFW, fetal hematocrit(HCT), HCT of blood transfused

• 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.

Intra-peritoneal..• 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 lymphatic duct

• Fetal respiration is important to occur.

• Complete absorption takes 150hrs (6days)

Intra-peritoneal• Less effective when hydrops present• 16-20 gauge Touhy needle used• Needle inserted in between umbilicus and

bladder• 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

IUT..• 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 outcome.

IUT

• 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

Treatment • Invasive Procedures

• Drainage Procedures:• Shunts

• Large Pleural Effusions• Ascities

• All invasive procedures carry an inherent increased risk of fetal demise or pre-mature labor.

Delivery• 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.

Delivery• The fetus should be delivered at tertiary care

center with neonatologists and other appropriate specialists.

• 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 testing

Delivery

• 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 .

Counseling

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.

Counseling

• 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.

Thank You

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 MOTHER THEORY.

Amnestic Response

• In a previously sensitized / sensibilized women the antibody titer may rise to high level in subsequent pregnancy.

• This may occur in d-negative fetus also.