Rh(D) Alloimmunization

MedlinePlus: "If your blood cells have this protein, you are Rh-positive. If you don't, you are Rh-negative." "Being Rh-negative doesn't affect your health, but it can affect the health of your fetus if you are pregnant." "If you are pregnant and are Rh-negative and your fetus is Rh-positive, it's called Rh incompatibility."

Sensitization. "Blood from your fetus can cross into your bloodstream, especially during childbirth." "If you're Rh-negative and your baby is Rh-positive, your body will react to the fetus's blood as a foreign substance. It will create antibodies (proteins) that can damage their red blood cells" (MedlinePlus). StatPearls: "Rh alloimmunization due to the D antigen is the most common cause of HDFN."

Why the first pregnancy is usually spared. "These antibodies usually don't cause problems during your first pregnancy. But Rh incompatibility may cause problems in later pregnancies if the fetus is Rh-positive. This is because the antibodies stay in your body once they have formed" (MedlinePlus). NCBI: "Initially, the maternal anti-D that is formed at the time of sensitization is of the IgM type, which can not cross the placenta. In subsequent pregnancies, a repeat encounter with the Rh D antigen stimulates the rapid production of type IgG anti-D, which can be transported across the placenta and enter the fetal circulation."

Small exposures matter. NCBI: "Only a small amount of fetal blood need enter the mother's circulation for sensitization to occur. Typically, this occurs during the delivery of the first-born Rh D-positive child." StatPearls (Kleihauer-Betke): "Only 0.01 to 0.03 mL of fetomaternal hemorrhage is required to isoimmunize the mother."

StatPearls: hemolytic disease of the fetus and newborn is "a complex and potentially life-threatening condition arising from maternal-fetal blood group incompatibility." NCBI: once in the fetal circulation, "anti-D attaches to the Rh D antigens found on the fetal RBCs, marking them to be destroyed."

Anemia and extramedullary blood production. NCBI: "The liver, spleen, and other organs increase their production of RBCs to compensate for their loss. The drive to produce RBCs causes the liver and spleen to increase in size (hepatosplenomegaly), and liver dysfunction can occur." "Immature RBCs (erythroblasts) spill into the circulation, giving rise to the alternative name of this disease, erythroblastosis fetalis."

Hydrops fetalis. StatPearls: severe fetal anemia "can cause hydrops fetalis when the fetal hemoglobin decreases to approximately <7 g/dL below the gestational age average, which is manifested by diffuse edema, pleural and pericardial effusions, and ascites." NCBI: "This condition is usually fatal, either in utero or soon after birth."

Bilirubin after birth. NCBI: "the level of bilirubin may still remain low during the pregnancy because of the ability of the placenta to remove bilirubin from the fetal circulation. However, after birth the neonate's immature liver is unable to metabolize the increased amount of bilirubin that instead accumulates in his or her blood. Within 24 hours of birth, the level of bilirubin may rise dramatically." If it keeps rising, "bilirubin may enter the brain to cause kernicterus, a potentially fatal condition that leaves permanent neurological damage in the babies that survive."

[NB] From jaundice to brain injury. CDC (archived page, last reviewed Dec 8, 2020): "When severe jaundice goes untreated for too long, it can cause a condition called kernicterus. Kernicterus is a type of brain damage that can result from high levels of bilirubin in a baby’s blood. It can cause athetoid cerebral palsy and hearing loss." "Early detection and management of jaundice can prevent kernicterus." Jaundice "usually appears first on the face and then moves to the chest, belly, arms, and legs as bilirubin levels get higher," and "Jaundice can be harder to see in babies with darker skin color." CDC sorts the warning signs into two tiers: a jaundiced baby who is very yellow, hard to wake or feeding poorly is seen the same day; a high-pitched or inconsolable cry, arching, a stiff or floppy body or strange eye movements need emergency help.

How it works. StatPearls: giving anti-D immune globulin "to Rh-negative mothers at the time of antigen exposure, eg, the birth of an Rh-positive child, blocks the primary immune response to the foreign cells. Therefore, maternal antibodies to Rh-positive cells are not produced in subsequent pregnancies, and hemolytic disease of the neonate is averted."

Who gets it. RhoGAM "is indicated for administration to Rh-negative women not previously sensitized to the Rho(D) factor, unless the father or baby are conclusively Rh-negative." Rhophylac: for "non-sensitized Rh(D)-negative women with an Rh-incompatible pregnancy." "An Rh-incompatible pregnancy is assumed if the fetus/baby is either Rh(D)-positive or Rh(D)-unknown or if the father is either Rh(D)-positive or Rh(D)-unknown" (Rhophylac label).

When (product-scoped). RhoGAM: "Antepartum prophylaxis at 26 to 28 weeks gestation." Rhophylac: routine antepartum prophylaxis "Week 28-30 of pregnancy." Postpartum: RhoGAM "Postpartum (if the newborn is Rh-positive)" — "Administer within 72 hours of delivery"; Rhophylac "Postpartum prophylaxis (required only if the newborn is Rh(D)-positive, or of unknown status)" — "Within 72 hours of birth." After a sensitizing event, RhoGAM: "Administer within 72 hours of suspected or proven exposure to Rh-positive red blood cells."

WHO (2024) differs. "For both medical and surgical abortion at < 12 weeks: Recommend against anti-D immunoglobulin administration," and "WHO only recommends antenatal prophylaxis with anti-D immunoglobulin in non-sensitized Rh-negative pregnant women at 28 and 34 weeks of gestation to prevent RhD alloimmunization in the context of rigorous research." US product labels, above, set the doses and times used in US practice.