Management of Rh (D) Negative Pregnancy

1. Background/Pathophysiology

2. Initial Antenatal Workup

• Booking visit: ABO/Rh typing and indirect Coombs test (antibody screen) for all pregnant women.
• If the woman is Rh-negative and the antibody screen is negative (not yet sensitized) → she is a candidate for routine anti-D prophylaxis.
• If the antibody screen is positive → this is an already-sensitized (isoimmunized) pregnancy, which is managed very differently (see section 5).
• Determine paternal (and where available, fetal) RhD status when possible - if the father is confirmed RhD-negative, the fetus cannot be RhD-positive and prophylaxis/monitoring is unnecessary. Cell-free fetal DNA can non-invasively determine fetal RhD status in some settings.

3. Routine Antenatal Anti-D (RhIG) Prophylaxis - Non-Sensitized Rh-Negative Women

• Repeat antibody screen around 28 weeks.
• Give anti-D immunoglobulin (RhIG) at ~28 weeks' gestation (standard dose, typically 300 microg/1500 IU IM) if the antibody screen remains negative - this is the single most important intervention that reduced Rh isoimmunization rates dramatically (Robbins, Cotran & Kumar, p. 1617-1629).
• Give a further dose within 72 hours of delivery if the newborn is confirmed RhD-positive.
• Additional doses are indicated after any potentially sensitizing event, since RhIG protects for only about 12 weeks:
  • Miscarriage, threatened miscarriage, ectopic or molar pregnancy
  • Chorionic villus sampling, amniocentesis, cordocentesis
  • External cephalic version
  • Antepartum hemorrhage/placental abruption
  • Abdominal trauma
  • Intrauterine fetal death
  • RhIG is effective even if given up to 72 hours after exposure, and some benefit persists even later, so it should not be withheld solely because the window has passed (ROSEN's Emergency Medicine, Kleihauer-Betke Test section).
• First-trimester events (<12 weeks): recent 2024 ACOG guidance and SOGC Guideline No. 448 have narrowed indications - RhIG is generally recommended for surgical/procedural abortion or ectopic pregnancy but is now considered optional (shared decision-making) for early spontaneous/threatened miscarriage or medication abortion before 12 weeks, since fetomaternal hemorrhage risk is very low at this stage.
• Kleihauer-Betke test (or flow cytometry) should be performed after large sensitizing events (major trauma, abruption, third-trimester bleeding) to quantify fetomaternal hemorrhage and determine if additional RhIG doses beyond the standard dose are needed (each standard dose covers ~30 mL of fetal whole blood/15 mL fetal RBCs).

4. Delivery and Postpartum

• Send cord blood for neonatal ABO/Rh type, direct Coombs test (DAT), and bilirubin if indicated.
• If the infant is RhD-positive, give the mother RhIG within 72 hours of delivery (regardless of whether the 28-week dose was given).
• If the infant is RhD-negative, no postpartum RhIG is needed.
• Perform Kleihauer-Betke test if excessive fetomaternal hemorrhage is suspected (e.g., abruption, manual removal of placenta, cesarean delivery) to adjust RhIG dosing.

5. Management of the Already-Sensitized (Isoimmunized) Pregnancy

• RhIG is no longer useful (she is already sensitized) - management shifts to surveillance for fetal anemia.
• Quantify maternal antibody titer; a critical titer (commonly ≥1:16, lab-dependent) warrants closer fetal surveillance.
• Determine fetal RhD status (paternal genotype/zygosity or cell-free fetal DNA) - if the fetus is RhD-negative, no risk exists.
• Serial Middle Cerebral Artery (MCA) peak systolic velocity Doppler by ultrasound has replaced serial amniocentesis (spectrophotometric bilirubin/ΔOD450) as the primary non-invasive method to detect fetal anemia; rising MCA-PSV correlates with worsening anemia.
• Intrauterine transfusion (IUT) via cordocentesis is performed for moderate-to-severe fetal anemia or hydrops, typically started after 18-20 weeks, repeated every 1-4 weeks depending on fetal hematocrit decline.
• Timing of delivery is individualized based on gestational age, transfusion history, and fetal status - often around 37-38 weeks if stable, earlier if the fetus is decompensating.
• Maternal IVIG and/or plasmapheresis may be used in severe early-onset alloimmunization (history of early hydrops/fetal loss) to blunt maternal antibody transfer before IUTs are feasible. A recent individual-patient-data meta-analysis (Mustafa et al., Am J Obstet Gynecol 2024, PMID: 38588966) evaluated IVIG for severe maternal alloimmunization and found it may prolong pregnancy and delay need for IUT in select severe cases, though evidence quality is limited - this is a specialist/tertiary-center intervention, not routine care.
• After birth, the neonate is monitored for hyperbilirubinemia/kernicterus risk and may need phototherapy or exchange transfusion.

6. Key Practical Points