10.5 Rh(D) Alloimmunization & Hemolytic Disease of the Fetus and Newborn
Key Takeaways
Rh(D)-negative patients without anti-D antibodies receive 300 mcg of Rho(D) immune globulin at about 28 weeks and within 72 hours after delivery of an Rh(D)-positive infant.
One 300-mcg vial covers about 30 mL of fetal whole blood (15 mL of fetal red cells); a Kleihauer-Betke test or flow cytometry after delivery or trauma determines whether more vials are needed.
Anti-D immune globulin is also given for bleeding, trauma, ectopic or molar pregnancy, amniocentesis, CVS, and external cephalic version, while ACOG (2024) suggests forgoing it for abortion or loss before 12 weeks.
In a sensitized pregnancy, a critical anti-D titer (commonly 1:16) triggers middle cerebral artery peak systolic velocity Doppler; a value above 1.5 MoM suggests moderate-to-severe fetal anemia.
Anti-Kell antibodies can cause severe fetal anemia at low titers because they suppress fetal red-cell production, so a lower critical titer (1:8) and Doppler surveillance are used.
Pathophysiology
When an Rh(D)-negative person is exposed to Rh(D)-positive fetal red cells, through fetomaternal hemorrhage at delivery, bleeding, trauma, or procedures, they can form anti-D antibodies. The first affected pregnancy is usually spared because the primary response is slow and mostly IgM. In later Rh(D)-positive pregnancies, IgG anti-D crosses the placenta and coats fetal red cells, causing hemolysis, fetal anemia, extramedullary hematopoiesis, and in severe cases hydrops fetalis (high-output heart failure, ascites, edema) and fetal death. After birth, the newborn develops hyperbilirubinemia that can lead to kernicterus.
About 15% of White, 5%–8% of Black, and fewer than 1% of Asian individuals are Rh(D)-negative. Since anti-D immune globulin was introduced, Rh alloimmunization has fallen dramatically, but it still occurs with missed doses, unrecognized bleeding, and inadequate dosing.
Prevention with Rho(D) Immune Globulin (RhIG)
Routine Prophylaxis
- First prenatal visit: ABO, Rh(D) type, and antibody screen for everyone.
- About 28 weeks: Repeat the antibody screen and give 300 mcg RhIG to unsensitized Rh(D)-negative patients (it protects for about 12 weeks).
- After delivery: If the newborn is Rh(D)-positive (or unknown), give 300 mcg within 72 hours; if missed, it can still be given up to 28 days later.
Additional Indications (unsensitized Rh(D)-negative patients)
- Ectopic pregnancy and molar pregnancy.
- Spontaneous or induced abortion or pregnancy loss at 12 weeks or later (ACOG's 2024 Clinical Practice Update suggests forgoing routine Rh testing and RhIG before 12 weeks).
- Antepartum bleeding, abdominal trauma, and stillbirth.
- Amniocentesis, chorionic villus sampling, and external cephalic version.
- A 50-mcg dose is sometimes used for first-trimester events when RhIG is given.
Quantifying Fetomaternal Hemorrhage
One 300-mcg vial neutralizes about 30 mL of fetal whole blood (15 mL of fetal red cells). A screening rosette test after delivery identifies larger hemorrhages, and a Kleihauer-Betke test or flow cytometry quantifies them to calculate the number of vials. Quantification is especially important after abdominal trauma, abruption, or stillbirth.
Weak D
Many people with a serologic "weak D" phenotype have RHD genotypes (weak D types 1, 2, or 3) that let them be managed as Rh(D)-positive, avoiding unnecessary RhIG. Genotyping is recommended when serologic weak D is found.
Managing the Sensitized Pregnancy
Once anti-D (or another clinically significant antibody) is found, RhIG no longer helps. Management aims to detect fetal anemia early.
- Antibody titer: Repeat roughly every 4 weeks until about 24 weeks, then every 2 weeks. A critical titer, commonly 1:16 (range 1:8–1:32 by laboratory), is the level associated with a significant risk of fetal hydrops.
- Determine fetal antigen status: Test the reproductive partner. If the partner is Rh(D)-negative, the fetus is Rh(D)-negative and unaffected. If the partner is heterozygous or unknown, determine fetal RHD status by cell-free DNA in maternal blood or by amniocentesis.
- At or above the critical titer with an antigen-positive fetus: Begin middle cerebral artery peak systolic velocity (MCA-PSV) Doppler every 1–2 weeks from about 16–18 weeks. Anemic fetuses have thinner, faster-flowing blood, so MCA-PSV above 1.5 multiples of the median (MoM) predicts moderate-to-severe anemia.
- Elevated MCA-PSV or hydrops: Cordocentesis to measure fetal hematocrit and intrauterine transfusion of O-negative, irradiated, cytomegalovirus-safe red cells at a fetal therapy center.
- Delivery: Usually at about 37–38 weeks, earlier if transfusions are required; the newborn may need phototherapy, exchange transfusion, or top-up transfusions.
A history of a previously affected fetus or newborn skips titer-based monitoring and goes directly to MCA Doppler surveillance, because titers do not predict severity in later pregnancies.
Other Red-Cell Antibodies
| Antibody | Clinical Significance |
|---|---|
| Anti-Kell (K1) | Causes severe anemia by suppressing fetal red-cell production as well as hemolysis; titers correlate poorly, so a lower critical titer (1:8) and early MCA Doppler are used. Often follows prior transfusion |
| Anti-c, anti-E, anti-Fya (Duffy), anti-Jka (Kidd) | Can cause HDFN; managed like anti-D |
| Anti-Lewis, anti-I, anti-P | Usually IgM; do not cause HDFN |
| ABO incompatibility (mother type O, infant A or B) | Common but usually mild neonatal jaundice; not prevented by RhIG and does not require antenatal monitoring |
Clinical Pitfalls
- The 28-week dose does not replace the postpartum dose. If the newborn is Rh(D)-positive, give anti-D immune globulin after delivery even though the patient received it at 28 weeks.
- Passive anti-D after RhIG: An antibody screen done within weeks of RhIG often shows a low anti-D titer (usually 1:4 or less) from the injection itself. This passive antibody is not sensitization and does not mean further doses should be withheld; check the timing of the last dose.
- Partner testing: If the reproductive partner is confirmed Rh(D)-negative, the fetus is Rh(D)-negative, but routine prophylaxis is still commonly given because paternity cannot always be confirmed.
- Consent: Rho(D) immune globulin is a pooled plasma product, so explain it and obtain consent; some patients, including some Jehovah's Witnesses, may decline blood-derived products.
- Timing of the antibody screen: Draw the 28-week antibody screen before giving RhIG, so the result reflects true sensitization.
- Every pregnancy restarts the process: Rh(D)-negative, unsensitized patients need the same screening and prophylaxis in each new pregnancy.
A 28-year-old G2P1 who is Rh(D) negative with a negative antibody screen at 28 weeks delivers an Rh(D)-positive infant. A postpartum rosette screen is positive, and the Kleihauer-Betke test estimates a fetomaternal hemorrhage of 50 mL of fetal whole blood. How should anti-D immune globulin be dosed?
None, because she already received a dose at 28 weeks
One 300-mcg vial, the standard dose after every delivery
A single 50-mcg vial within 72 hours of delivery
Three 300-mcg vials within 72 hours of delivery
A 32-year-old at 20 weeks has anti-D antibodies with a titer of 1:64. Her partner is heterozygous for RhD, and cell-free DNA shows that the fetus is RhD positive. What is the most appropriate surveillance?
Give 300 mcg of anti-D immune globulin now to suppress the antibodies.
Serial middle cerebral artery peak systolic velocity Doppler every 1–2 weeks.
Repeat the antibody titer monthly and deliver at 40 weeks.
Weekly nonstress tests starting now.
A 24-year-old who is Rh(D) negative and unsensitized has a complete spontaneous abortion at 7 weeks. She asks whether she needs a 'Rh shot.' According to ACOG's 2024 Clinical Practice Update, what is the best response?
Rh testing and anti-D can be forgone before 12 weeks, though it may be offered if she requests it.
She must receive 300 mcg within 72 hours, or her next Rh-positive pregnancy will be affected.
She should receive anti-D immune globulin every 12 weeks until her next pregnancy begins.
She needs a Kleihauer-Betke test to quantify fetal cells before anyone can decide.
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