1. HEMOLYTIC DISEASE OF NEWBORN
Assoc. Prof. Dr. Victoria ATANASOVA, MD, PhD
Clinic of Neonatology
UMHAT, Pleven

2. BACKGROUND
1609 – A French midwife reported hemolytic disease of the newborn (HDN) in a set of twins
1932 → Relationship among fetal hydrops, jaundice, anemia, and erythroblasts in the circulation (Diamond & coll.)
═► erythroblastosis fetalis
1940 → Rh blood group system (Landsteiner & Weiner) → the cause of disease (Levine)
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3. Anti-D prophylaxis in Bulgaria – since 1977 !!!
BACKGROUND
1966 – the history of anti-D immunoglobulin G (IgG) prophylaxis starts
→ 1971 (WHO) – protocol of anti-D prophylaxis
→ 1998 (American Association of Blood Banks and the American College of Obstetrics and Gynecologists) – the WHO-recommendation was reinforced
Anti-D prophylaxis in Bulgaria – since 1977 !!!
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4. DEFINITION
BLOOD GROUP INCOMPATIBILITY
= ISO-SENSITIZATION / ISO-IMMUNISATION
= HEMOLYTIC DISEASE OF THE FETUS AND NEWBORN
Incompatibility between the blood of the mother ant fetus according to some antigens (Ags) which are available in the fetus blood (inherited from the father) and missing in the mother blood
═► Immuno aggressive condition of the mother in regard to the fetus
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5. TYPES OF INCOMPATIBILITY
Rh-incompatibility – most often
→ 10% from all pregnancies
→ 1 : deliveries in the past (before anti-D-prophylaxis)
Types Rh-Ag: D, E and C (Fisher & Race); The most often Rh-conflict → D-Ag
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6. TYPES OF INCOMPATIBILITY
ABO-incompatibility
→ mother – О / baby А (90%) or В (10%)
Rh-Ags expression – in red blood cells (RBCs) and is missing in RBCs progenitors ↕
A- and B-Ags are widely expressed in various tissues besides RBCs
Incompatibility under other Ags - M, N, Hr, Kell, Kidd, Duffy etc. – rare cases and difficult to prove
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7. PATHOPHYSIOLOGY
Antibody (Ab) production against some of RBCs-Ags – 2 or more Ags-stimuli :
І – strong enough → primary immune response
ІІ – anamnestic immune response, with significantly lower blood amount
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8. Ways of exposure of mother to foreign RBC-Ags:
PATHOPHYSIOLOGY
Ways of exposure of mother to foreign RBC-Ags:
Massive exposure:
Transfusion of incompatible blood
During the delivery, abruptio placentae, ectopic pregnancy
Surgery interventions
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9. Ways of exposure of mother to foreign RBC-Ags:
PATHOPHYSIOLOGY
Ways of exposure of mother to foreign RBC-Ags:
Minimal exposure:
Abortion – spontaneous or therapeutic
Through the placenta during the pregnancy – in the 75% of pregnancies and increases to the term (< 0,1 mL)
Prenatal diagnostic procedures (amniocentesis, chorionic villus sampling, and cordocentesis)
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10. PATHOPHYSIOLOGY
Primary immune response: initial exposure of the mother to a foreign Ag → Abs of the IgM isotype (mother sensitization)
Secondary immune response → Abs of the IgG isotype across the placenta to the fetus► + fetal RBCs (after 20th GW) → fetal liver and spleen → extravasal hemolysis
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11. PATHOPHYSIOLOGY
Prolonged hemolysis Anemia ↑ bil → jaundice (in the newborn only!) ↑ medullary and extra medullary hemopoiesis (liver, spleen, skin, placenta) Liver dysfunction → hypoproteinemia
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12. PATTERNS OF DIFFERENT KINDS OF ISOIMMUNIZATIONS
Rh incompatibility:
Usually from the second pregnancy
Transplacental transfer of Abs of the IgG isotype after the 20th GW
Trends to aggravate in each subsequent pregnancy
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13. PATTERNS OF DIFFERENT KINDS OF ISOIMMUNIZATIONS
ABO-incompatibility:
Anti-A and anti-В-Abs (IgM) – normal finding in individuals with О blood group = primary sensitization
Minimal amount of fetal RBCs
→ complete sensitization
═► ½ of the cases – from the first pregnancy
Anti-A and anti-В-Abs attach to the fetal RBCs in the later stages (usually to the birth)
No trends to become progressively worst with each pregnancy
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14. PATTERNS OF DIFFERENT KINDS OF ISOIMMUNIZATIONS
Kell-incompatibility:
Kell-Ags are expressed on the surface of RBC-progenitors
→ hemolysis + erythropoiesis suppression
Rare causes – Duffy- и MNS-incompatibility
No cases of incompatibility under Lewis- и Р-Ags
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15. Signs of hemolytic anemia:
PATHOGENESIS
Signs of hemolytic anemia:
Anemia with erythroblastosis
Hyperbilirubinemia
Fetal hydrops
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16. PATHOGENESIS
Progressive anemia with compensatory response of hemopoiesis
Usually in Rh-incompatibility
Severe anemia (up to 20% of cases)
→ Intrauterine fetal death
→ Early neonatal death
Moderate anemia (in 80% of cases)
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17. PATHOGENESIS Hyperbilirubinemia due to hemolysis
typical for mild cases of Rh- and especially for АВО-incompatibility
Early and rapidly progressive jaundice
Indirect fraction of bilirubin (pervade into all tissues)
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18. PATHOGENESIS Genesis of fetal hydrops:
Anemia (Hgb < 40 g/l; Hct < 0,15)
Excessive extra medullary hepatic hemopoiesis
→ hepatic and umbilical venous obstruction
↓ placental perfusion
→ edematous placenta
→ diminished placental
perfusion
Hypoxic injure of myocardium and vessels
→ (congestive) cardiac failure
Tissue hypoxia → capillary leak syndrome
Liver damage
+ portal hypertension
→ ascites, ↓ albuminemia
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19. CLINICAL PRESENTATION
Intrauterine fetal death (macerated, edematous fetus, 20th-30th GW)
Swelling (hydrops fetalis, immune hydrops)
Premature delivery (26th-28th GW)
Hydramnion
Massive edema – visceral cavities, subdermal, placenta
Severe anemia (Hgb < 40 g/l); erythroblastemia
Hypoproteinemia
Hemorrhagic syndrome
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20. CLINICAL PRESENTATION
Jaundice
Term neonates
Hyperbilirubinemia
Yellow colored amniotic fluids, umbilical cord, vernix
T-bil (umbilical blood) > 51 mcmol/l
Early and progressive jaundice
CNS injury (kernicterus)
Liver dysfunction
Hemorrhagic syndrome
Hypoproteinemia
Tick bile syndrome (mechanical / obstructive jaundice)
Anemia (continuous hemolysis !)
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21. CLINICAL PRESENTATION
Anemia
Anemia fetalis gravis (~ 5% of cases of Rh- incompatibility)
Hgb g/l at birth
Hemorrhagic syndrome → DIC
Severe hypoglycemia
Often → tick bile syndrome
Moderate anemia (continuous hemolysis !)
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22. LABORATORY STUDIES Signs of hemolytic state: Metabolic disturbances:
Anemia
Indirect hyperbilirubinemia
Reticulicytosis
Erythroblastosis
↑ LDH
Metabolic disturbances:
Hypoglycemia
Electrolyte disturbances (Са++, К+)
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23. LABORATORY STUDIES Serologic tests:
Indirect Coombs test and direct antibody test
In Rh-incompatibility (+)
In АВО-incompatibility – (+) in 20-40% of newborns only
Indirect antiglobulin test (serum from the newborn + adult А- or В-RBCs) – in АВО- incompatibility
IgG1, IgG2, IgG3
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24. PRENATAL DIAGNOSIS Of the pregnant woman:
Pregnancy in Rh(-)-♀ from Rh(+)-♂ with suspect of isoimmunisation situations in ♀
At Ob-gyn risk – still birth, spontaneous abortion, previous child with HDN, child with neurodevelopmental delay
Serial serologic testing
→ Abs critical level = 1/32
In Kell incompatibility – 1/8 !!!
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25. PRENATAL DIAGNOSIS Fetus:
Examination of amniotic fluids by amniocentesis (optical density, bilirubin level) → Liley (1961)
Pic systolic blood pressure in arteria cerebri media (Doppler) → grade of fetal anemia
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26. Indices of severe fetal hemolytic disease:
PRENATAL DIAGNOSIS
Indices of severe fetal hemolytic disease:
Previous children with HDN
Increasing of mother Abs level
Increasing of amniotic bilirubin level
US-data of fetal hydrops (ascites, edema, effusions, worsened biophysical profile, decreased fetal Hgb)
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27. DIFFERENCIAL DIAGNOSES
Congenital infections (Parvovirus В19, Toxoplasmosis, Lues, CMV)
Inborn errors of metabolism (hypothyreoidismus congenita, thyrosinemia)
Fetal cardiac problems (cardiac tumors, arrhythmia)
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28. LATE COMPLICATIONS Bilirubin encephalopathy (Kernicterus)
Late anemia – causes:
Blood transfusions of adult RBCs → ↓ ЕРО
Circulating iso-Abs → continuing hemolysis
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29. ANTENATAL TREATMENT Interruption of pregnancy ~ 32nd GW
Treatment of mother alloimmunisation:
Medication and bio suppression of iso-Ab production – non effective
Plasmaferesis, IVIG – moderately effective
Intrauterine blood transfusion:
Intraperitoneal (Liley, 1963)
Intravasal (Rodeck, 1981)
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30. POSTNATAL TREATMENT
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31. PREVENTION of HDN In pregnancies at-risk: Serologic screening
Bio prophylaxis with specific (anti-D) immunoglobulin:
In 28th GW
Up to 72nd postnatal hour
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32. PREVENTION of HDN
In non-sensitized women after event associated with trans placental hemorrhage:
After abortion,
Ectopic pregnancy,
Amniocentesis,
chorionic villus sampling,
Late fetal death...
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