Isoimmunization & Fetal Hydrops Gillor Moshe Kaplan Medical Center.

Isoimmunization & Fetal Hydrops

Gillor Moshe

Kaplan Medical Center

Hydrops Fetalis- Definition

- General fetal edema

- Accumulation of fluid in ≥2 body cavities:• Pleural• Pericardial• Peritoneal• Soft tissue - subcutaneous

• Mostly coupled with placentomegaly & polyhydramnios

Pathophysiology

Dysregulation of the net fluid movement

between the vascular & interstitial spaces:

•Primary heart failure

•High cardiac output failure - anemia

•Decreased colloid oncotic pressure

•Increased capillary permeability

•Obstruction of venous and lymphatic flow

Appearance of hydrops

Pericardial effusion

Ascites

Polyhydramnios

Scalp edema

Pleural effusions

Oligohydramnios

Hydrops Fetalis- Etiology

ImmuneImmune Non-immuneNon-immune

Hydrops Fetalis- Etiology

ImmuneImmune Non-immuneNon-immune10%-15%10%-15% 85%-90%85%-90%

RhD Isoimmunization in pregnancy

Introduction• 29 known blood groups

• >600 known red cell antigens (Ag’s)

• Exposure to foreign red cell Ag’s → anti–red cell antibodies(Ab’s) → red cell alloimmunization

• These Ab’s may cross the placenta →– Fetal anemia – Hyperbilirubinemia– Hydrops fetalis

Historic landmarks1609- Hemolytic disease of the fetus and newborn (HDFN) was first described by a French midwife

1939- An Ab was identified in a mother to a stillborn (Levine)

1941- RhD Ab’s in an RhD(-) mother serum & HDFN of her newborn (Levine)

1945- Amniotic fluid bilirubin assessment is an indirect measurement for the degree of fetal hemolysis (Liley)

1964- Anti-D prophylaxis (Freda)

1981- Intravascular fetal transfusion (Rodeck)

2000- Noninvasive detection of fetal anemia by Doppler ultrasound of the fetal middle cerebral artery (MCA)

2002- Fetal typing via cell free DNA in maternal plasma

Incidence• 15% of whites are Rh(-)

• Father is Rh(+) 85% of cases with 40% homozygous → ~60% of

infants are Rh(+)

• Only 16% isoimmunization (mostly postpartum) *

• In Rh(-) alloimmunized mother:– 25% mild-moderate HDFN – 25% hydrops fetalis

• Males are x13 more likely to develop hydrops & x3 more likely

to die* Before the introduction of anti-D prophylaxis

Incidence- cont.• Anti red cell Ab’s are found in 1% of pregnancies• Anti-D prophylaxis shifted the cause of HDFN to less

common red cell antigens

  Incidence of maternal anti-red cell antibodies associated with hemolytic disease of the fetus and newborn

(HDFN) in a Dutch population of pregnant women. (From van der Schoot CE, Tax GH, Rijnders RJP, et al: Prenatal typing of Rh and Kell blood group system antigens: The edge of the watershed. Trans Med Rev 17:31, 2003.)

)Kell( )Kidd()Duffy(

Pathophysiology

• Feto-maternal hemorrhage (↑ w GA)

• Materno-fetal hemorrhage (‘grandmother theory’)

• IgG response

• ABO incompatibility is protective

• Ab’s can be detected 5-16W post- exposure

• 50% of alloimmunized are “sensibilized” = Ab levels are very low and can’t be detected

• Fetal anemia→ ↑ CO + extramedullary hematopoesis

• Hydrops is a late finding. Pathophysiology unknown (↓ oncotic P/ iron overload/ ↑ capillary permeability)

Primary immune response (IgM)

Secondary immune response (IgG)

Transplacental passage of IgG

Fetal red cell IgG binding

Hemolysis

Anemia Degredation products

Jaundice

Extramedullaryerythropoesis

Deficient hepaticfunction

Ascites

Hydrops

CHF

Secondary exposure

Prevention

• Anti-D Ig ↓ alloimmunization by 90% postpartum & 2→0.1% in 3rd trimester

• 300μg counteract 30ml of Rh(+) blood or 15ml RBCs

• Anti-D Ig t½ = 16 days

• Risk from anti-D Ig is minimal/absent → whenever there is a doubt → anti-D Ig should be administered

Prevention- indications:

• At 28 weeks

• After delivery (within 72h, ±KB )• After abortion

• Abdominal trauma

• Maternal bleeding

• Invasive procedures

Prevention- cont.

• Failure of prevention= 0.1-0.2%

• Currently, no prophylactic Ig exists for

other forms of red cell alloimmunization

• For subsequent pregnancy- PGD

Diagnosis

• Indirect Coomb’s• Ab titer• Critical titer→ 1:8 – 1:32• Paternity status (zygosity)• Determine fetal genotype:

– AC (CVS→↑FMH)– ccff DNA in maternal plasma

ccff- circulating cell free fetal

Diagnosis- cont.

• F/U on severity of HDFN:– AC– Fetal blood sampling (a.k.a PUBS or

cordocentesis)→ 1-2% fetal loss, 50% FMH– US:

• Hydrops→ -7g% Hb• Splenic perimeter & hepatic length

– US Doppler

PSV in MCA

• Mainstay of surveillance for fetal anemia

• Fetal anemia causes:

– ↑CO – ↓blood viscosity– Blood flow centralization

• Begin at 18W

• After 35W → ↑False (-)

↑blood velocity

Treatment- Intrauterine transfusion

• Umbilical cord or intrahepatic portion of UV

• Fetal blood sampling for initial Hct

• Fetal paralysis (e.g. vecuronium)

• Fresh (<1W old), O(-), CMV(-), HIV(-), HCV(-), leukoreduced, irradiated, cross-matched, Hct 75% PC

• PSV in MCA is not predictive after 2nd Tx.

Treatment- Intrauterine transfusion

• Transfusion is not preformed past 35W

• Complications:– Procedure related fetal death ~5% – Emergent CS (5% after 32W)– Transient fetal bradycardia– PPROM is rare

• Alternative Tx.:IVIG Plasmapheresis

Clinical management

1:32טיטר < 1:32טיטר >

>W24 לחזור על - טיטר כל חודש

<W24 לחזור על – טיטר כל שבועיים

1:32טיטר <

יילוד במועד

בדיקת סוג דם, קומבס וטיטר נוגדנים בביקור הראשון בהריון

, עירוי HDFNאם ברקע תוך רחמי או החלפת דם בילוד אין קורלציה

בין הטיטר ורמת האנמיה

בירור סוג דם וגנוטיפ של האב

אנטיגן (-) באב אבהות ודאית

יילוד במועד

גנוטיפ הטרוזיגוטי באב

גנוטיפ הומוזיגוטי באב

MCA ב-PSVמדידת פעם בשבוע החל משבוע

18

MOM 1.5מדידה > כן לא

דיקור חבל טבור Hctלקביעת

עוברי

עירוי דם תוך > Hctרחמי אם 30%

פעם בשבוע. MCAמעקב זרימות ב- ΔOD450 לבשלות ריאתית ו- AC 35בשבוע

יילוד בשבוע 37

עובר בשל ΔOD450 לא בגבול

עליון

עובר לא בשלΔOD450בגבול עליון

יילוד בשבוע 36

עובר לא בשל ΔOD450לא בגבול עליון

תוך ACלחזור על שבועיים

AC/ccffDNA 14בשבוע

אנטיגן (-) לעובר

אנטיגן (+) לעובר

Hydrops fetalis- Etiology

Non-immune (87%) Immune (13%)

– Malformations• Cardiac (structural, CM, tumor, arrhythmia)

• Chest (diaphragmatic hernia, CCAM, 1⁰ chylothorax)

• Abdomen (tumor, obstruction, prune belly syn.)

• Placenta (TTTS, chorangioma)

• Misc. (sacrococcygeal teratoma, cystic hygroma)

– Chromosomal/genetic (trisomy 21, 45X0, triploidy, Noonan)

– Infectious (TORCH, Parvovirus, Listeria)

– Metabolic (lysosomal/glycogen storage diseases, hypothyroidism)

– Hematologic (α-thalassemia, Diamond Blackfan, FMH)

NIHF- Management

• Etiology dependent

• At term- delivery

• Treatment options include:– Conversion in heart failure caused by

SVT

– Intrauterine transfusion for fetal anemia caused by Parvovirus

Cardiovascular

• Isolated cardiac defect is uncommon, bad

prognosis

• Arrhythmias – SVT, atrial fibrillation/flutter, VT

(rare) elevated systemic venous pressure NIHF

treatment with antiarrhythmic drugs such as

digoxin, flecanaide,...

• A-V block – Anti Ro Ab., structural defect

poor prognosis

Hematology

HemoglobinopathiesHemoglobinopathies

thalassemia –deficiency of globin chain synthesis (Hb Bart’s dis)

• The most common cause of hydrops in southeast Asia

• Prenatal diagnosis of the gene mutation is possible

Hematology

• Enzyme def.- Pyruvate kinase def. & G6PD def.

• Diamond-Blackfan syn.– aplastic anemia

• Acquired causes: Fetal maternal hemorrhage

Infection• Viral, parasitic and bacterial causes• 5-10% of NIHF• Parvovirus, CMV, Syphilis & Toxoplasma• Parvovirus:

– Aplastic anemia, myocarditis– Transmission rate of 30%, IUFD rate of 5-10%– Cordocentesis– fetal anemia w/o reticulocytosis– Hydrops can be treated by intrauterine

transfusion of packed red blood cells– Can resolve spontaneously (1/3 of cases)

Twins

• TTTS – complicates 25% of monochorionic twins

• The ‘recipient’ fetus– hypervolemia -high output cardiac failure

• Twin reversed arterial perfusion (TARP)– Acardiac twin. The ‘pump twin’ perfuse an acardiac parasitic twin– leads to high output cardiac failure

Hydrops Fetalis- Maternal Complications

• Increased incidence of preeclampsia (mirror syndrome)

• Preterm labor because of polyhydramnios

• Post partum hemorrhage

Management Hydrops Fetalis-• Mother:

– CBC– Blood type, indirect Coombs– KB– TORCH, VDRL, Parvovirus– Hb electrophoresis

• Fetus:

– General survey + PSV in MCA– Echocardiography– AC for karyotype & cultures (toxo., CMV, parvovirus)

Questions?

Kleihauer-Betke

MBV(ml) x mHct x KB(%)

Fetal blood volume = nHct

300μg anti-D should protect an average size mother from 30ml of fetal whole blood

Spectral analysis of amniotic fluid