ABO Incompatibility in Pregnancy

Overview

Mechanism

Which Pregnancies Are at Risk?

• Mother is blood group O
• Fetus/infant is blood group A, B, or AB

Why Can the First Baby Be Affected?

Why Is ABO HDN Usually Mild?

1. Antigen density: A and B antigens are expressed on many cell types (not just red cells), so transferred maternal IgG antibody is "mopped up" by tissues outside the circulation, reducing the amount attacking fetal red cells.
2. Complement regulation: Fetal red cells express complement regulatory proteins that limit destruction.
3. Concurrent ABO incompatibility actually protects against Rh sensitization: If fetal Rh-positive cells enter an ABO-incompatible mother's circulation, they are rapidly coated by preformed anti-A/anti-B IgM isohemagglutinins and cleared before the mother can mount an anti-D response. — Robbins, Cotran & Kumar Pathologic Basis of Disease

Clinical Features

Neonatal Presentation

• Unexplained hyperbilirubinemia in a group A or B infant born to a group O mother is the classic clue
• Mild macrocytic anemia with modest reticulocytosis
• Spherocytes prominent on peripheral smear (unlike Rh HDN)
• Hepatosplenomegaly is uncommon
• Rare severe cases: fetal hydrops has been reported with very high anti-A or anti-B titers — Creasy & Resnik's Maternal-Fetal Medicine

Laboratory Diagnosis

1. Direct Antiglobulin Test (DAT/Coombs) on fetal/neonatal red cells: usually weakly positive (less strongly positive than in Rh HDN)
2. Indirect Antiglobulin Test: maternal serum should contain high-titer IgG anti-A or anti-B
3. Elution study: eluate from neonatal red cells should contain anti-A or anti-B antibody
4. Blood film: prominent spherocytosis
5. Bilirubin levels: serial monitoring postnatally

Note: Unlike Rh HDN, there is no useful antenatal titer threshold to guide fetal surveillance — maternal anti-A/anti-B titers do not reliably predict disease severity. — Henry's Clinical Diagnosis and Management

Antenatal Considerations

• Routine antibody screening at the first prenatal visit detects clinically significant alloantibodies (Rh, Kell, Duffy, Kidd, etc.), but ABO antibodies are naturally occurring and not routinely titered antenatally for this reason.
• A history of a previous infant affected by ABO HDN with hydrops should prompt enhanced surveillance in subsequent pregnancies (MCA PSV Doppler monitoring).
• MCA PSV >1.5 MoM → cordocentesis ± intrauterine transfusion (for severe cases)

Management

Antenatal

• No specific antenatal intervention is generally needed
• No effective prophylaxis exists (unlike RhIG for Rh disease)
• Enhanced fetal surveillance if prior severe case (hydrops)

Postnatal

• Phototherapy for hyperbilirubinemia (mainstay of treatment)
• Intravenous immunoglobulin (IVIG): can reduce the need for exchange transfusion in severe neonatal jaundice due to ABO HDN
• Exchange transfusion: reserved for severe hyperbilirubinemia unresponsive to phototherapy/IVIG; use group O red cells with AB plasma (compatible with both A and B antigens)
• Simple top-up transfusion: for significant anemia

Key Distinctions: ABO vs. Rh HDN

Summary

Sources of Anti-D (Causes of Rh Sensitization)

1. Fetomaternal Hemorrhage (FMH) — Most Important

Most women have <1 mL of fetal blood in their circulation post-delivery; however, intrapartum FMH >30 mL occurs in ~1% of pregnancies. — Henry's Clinical Diagnosis and Management by Laboratory Methods

2. Sensitizing Events During Pregnancy (Antenatal)

• Spontaneous miscarriage / threatened abortion (risk increases with gestation; >7–8 weeks gestation carries meaningful risk)
• Induced / therapeutic abortion (surgical or medical)
• Ectopic pregnancy (surgical or medical management)
• Amniocentesis — RhIG is recommended following this invasive procedure
• Chorionic villus sampling (CVS) — higher risk than amniocentesis
• Cordocentesis / fetal blood sampling
• Antepartum haemorrhage (placenta praevia, abruption)
• External cephalic version (ECV)
• Abdominal trauma (road traffic accidents, blunt trauma)
• In utero procedures (fetal transfusion, shunt insertion)
• Intrauterine death / fetal death in utero
• Hydatidiform mole

3. Blood Transfusion

• Transfusion of Rh(D)-positive red blood cells to an Rh(D)-negative recipient
• Transfusion of Rh(D)-positive platelet concentrates (platelets carry trace red cell stroma expressing D antigen)
• Accidental incompatible transfusion — managed with RhIG after exchange transfusion with Rh-negative blood (1 vial RhIG per 15 mL packed red cells or 30 mL whole blood transfused). — Henry's Clinical Diagnosis and Management

4. Other / Unusual Sources

• Needle sharing (intravenous drug use) — historically documented
• Organ transplantation from an Rh(D)-positive donor
• Bone marrow transplantation
• Skin grafting (very rarely)

Timing of Anti-D Formation

• At first exposure: a primary immune response generates IgM anti-D (does not cross the placenta); this takes weeks to develop.
• At re-exposure (subsequent pregnancy or transfusion): a brisk IgG anamnestic response occurs rapidly — IgG crosses the placenta and causes haemolytic disease of the fetus and newborn (HDFN).
• This is why Rh disease is rare in the first pregnancy but severe in subsequent ones (unlike ABO HDN).

Why This Matters: Prevention with RhIG

• 28 weeks' gestation (routine antenatal prophylaxis — 300 μg)
• Within 72 hours of delivery (dose calculated by Kleihauer–Betke or flow cytometry to quantify FMH)
• After any of the antenatal sensitizing events listed above

Sources of RhIG Used for Prophylaxis

1. Human Plasma from Donors with Anti-D — The Primary Source

Historical donors (original source):

• Rh(D)-negative women who had been naturally sensitized to the D antigen through a previous Rh(D)-positive pregnancy — i.e., women who had already developed anti-D.
• As RhIG use became widespread and successful, fewer women were naturally sensitized → this donor pool shrank drastically over time.

Current donors (predominant source today):

• Deliberately alloimmunized Rh(D)-negative male donors — D-negative male volunteers are intentionally injected with small doses of D-positive red blood cells, causing them to form high-titer anti-D antibodies.
• These donors undergo repeated apheresis plasma donations and are periodically boosted with D-positive RBCs to maintain sufficiently high anti-D titers for manufacturing.
• Using males avoids the ethical issue of sensitizing women of childbearing potential.

"Manufacturers resorted to deliberately alloimmunizing D-negative male donors with D-positive RBCs to ensure an adequate supply… Throughout the course of their donation career, it is often necessary to boost these donors with D-positive RBCs to elevate antibody titers." — AABB Association Bulletin #24-02

Notable historical donor:

2. Manufacturing Process

1. Pooling — plasma from multiple screened donors is pooled
2. Fractionation — cold ethanol (Cohn) fractionation isolates the IgG fraction
3. Viral inactivation and reduction — solvent/detergent treatment, nanofiltration, pasteurisation
4. Quality testing — potency (anti-D titer), sterility, safety testing
5. Formulation — prepared in standard doses (see below)

3. Available Formulations and Manufacturers

4. Why Recombinant Anti-D Does Not Yet Exist

• Difficulty replicating the exact IgG1 glycosylation pattern required for the immune suppression mechanism
• Monoclonal anti-D candidates in trials have shown insufficient potency or breadth of D-epitope coverage
• The mechanism of RhIG action (passive antibody suppression vs. active immune tolerance) is still not fully understood

5. The Global Shortage Problem

• Declining pool of alloimmunized donors (success of RhIG has reduced natural sensitization)
• Manufacturing deviations affecting production capacity
• Increased global demand
• Geopolitical and supply chain factors

Summary