Maternal-fetal blood group incompatibility refers to an alloimmune condition that arises between the mother and the fetus due to differences in red blood cell antigens, occurring during the fetal period and early neonatal period. Starting from the 30th day of gestation, fetal red blood cells begin to express antigens. As gestational age increases, both the likelihood and quantity of fetal red blood cells entering the maternal circulation rise, with approximately 50% of these antigens inherited from the father being recognized as foreign by the maternal immune system. Once fetal red blood cells enter the maternal circulation, the maternal immune system may produce antibodies, which then cross the placenta into the fetal bloodstream and destroy fetal red blood cells, leading to hemolytic disease of the fetus and newborn (HDFN).
Etiology
Human red blood cell antigens have various subtypes, but the most common blood group systems causing maternal-fetal blood group incompatibility are the Rh and ABO systems. ABO blood group incompatibility has a high incidence but rarely causes significant fetal hemolysis, with generally mild cases requiring little special management during pregnancy. In contrast, Rh incompatibility is less common but can lead to severe HDFN and is a major cause of fetal immune hydrops. Therefore, this section focuses on Rh maternal-fetal blood group incompatibility.
The Rh blood group antigens are determined by three closely linked allelic genes located on chromosome 1, and over 40 Rh system antigens have been identified. Among these, five antigens—D, E, C, c, and e—are clinically significant, with the D antigen being the most important. Based on the presence or absence of the D antigen on red blood cells, individuals are categorized as Rh-positive or Rh-negative.
Under normal conditions, fetal red blood cells do not cross the placenta; they typically enter the maternal circulation only when placental damage occurs, such as during pregnancy or delivery. The primary immune response to initial antigen exposure is slow, predominantly producing IgM antibodies, which do not cross the placenta. Additionally, the absence of naturally occurring substances similar to Rh antigens in the environment makes sensitization unlikely during the first pregnancy. However, in subsequent pregnancies, a sensitized mother can rapidly produce IgG antibodies capable of crossing the placenta, leading to fetal red blood cell destruction and HDFN. Other blood group incompatibilities, such as MNS system incompatibility, have similar pathogenesis to the Rh system but with a lower incidence.
Clinical Manifestations
The clinical manifestations of Rh incompatibility-related hemolytic disease typically present early, with severe and prolonged courses. During the fetal period, symptoms include anemia, heart failure, hydrops fetalis, or intrauterine fetal death. In the neonatal period, affected infants may present with anemia, hemolytic jaundice, and kernicterus, and severe cases can lead to neonatal death.
Diagnosis
Maternal-fetal blood group incompatibility can be clinically diagnosed during pregnancy based on medical history, blood group testing, Rh antibody monitoring, and ultrasound findings. However, definitive diagnosis often relies on neonatal testing.
Diagnosis During the Fetal Period
Medical History and Blood Group Testing
Women with a history of neonatal jaundice or hydrops fetalis, miscarriage, premature delivery, intrauterine fetal death, or blood transfusion are advised to undergo blood group and antibody testing with their partners before conception. Crossmatching of blood groups is recommended during the first antenatal visit for women without high-risk factors.
Rh Antibody Monitoring
The maternal indirect Coombs test is used to evaluate Rh antibody titers. An Rh antibody titer >1:32 suggests a high risk of fetal hemolysis. However, the severity of fetal hemolysis may not directly correlate with antibody titers, as factors such as placental barrier permeability and fetal tolerance to hemolysis also play roles.
Ultrasound Examination
Ultrasound is an effective tool for assessing fetal anemia. Findings such as ascites, generalized edema, or polyhydramnios may indicate severe fetal anemia. Doppler ultrasound of the middle cerebral artery peak systolic velocity (MCA-PSV) in mothers with blood group incompatibility is used to screen for severe fetal anemia. An MCA-PSV >1.5 multiples of the median (MoM) indicates the possibility of severe anemia.
Sampling via Puncture
If severe fetal anemia is highly suspected, cordocentesis (fetal blood sampling) may be performed with preparations for potential intrauterine transfusion. This allows for timely treatment upon confirmation.
Diagnosis During the Neonatal Period
Neonates with hemolytic anemia often present with pallor, edema, or heart failure, followed shortly by jaundice, which typically peaks within 24–48 hours. After birth, maternal-fetal blood group incompatibility can be confirmed through tests for blood group typing, bilirubin levels, direct Coombs test, serum free antibodies, or antibody release from neonatal red blood cells. Additionally, peripheral blood tests assessing hemoglobin level, hematocrit, reticulocyte count, and the presence of nucleated red blood cells provide insights into the degree of hemolysis and anemia.
Impact on Mother and Fetus/Neonate
Impact on the Mother
Maternal-fetal blood group incompatibility can lead to polyhydramnios, increasing the risks of premature rupture of membranes, preterm birth, placental abruption, and postpartum hemorrhage. In cases of fetal hydrops, pregnant women are at risk of developing mirror syndrome and preeclampsia.
Impact on the Fetus
The fetus may experience intrauterine anemia and heart failure, which increase the risks of intrauterine death and long-term neurological damage.
Impact on the Neonate
Neonates may develop anemia, jaundice, kernicterus, or may not survive.
Management
Management During Pregnancy
Plasma Exchange for the Mother
For women with a history of multiple episodes of alloimmune hemolysis resulting in intrauterine fetal death prior to 20 weeks of gestation, early plasma exchange during the first trimester may be attempted to create opportunities for intrauterine transfusion. However, the efficacy of this approach remains uncertain.
Intrauterine Fetal Transfusion
For fetuses with severe anemia, intrauterine transfusion may be performed before 34–35 weeks of gestation. The goal is to correct anemia and prevent the development of fetal hydrops.
Pregnancy Termination
Termination of pregnancy may be considered after 34 weeks of gestation once fetal lung maturity has been achieved. Before delivery, a multidisciplinary consultation involving transfusion medicine specialists, neonatal intensive care unit (NICU) teams, and other relevant disciplines is recommended to thoroughly assess maternal and fetal risks and develop a comprehensive plan.
Neonatal Monitoring and Treatment
Neonates should be monitored for anemia, progression of jaundice, and potential heart failure. Mild cases may be managed with non-surgical treatments such as phototherapy, and selective use of albumin, corticosteroids, hepatoprotective medications, phenobarbital, or intravenous immunoglobulin (IVIG). For neonates with severe anemia or jaundice, blood transfusion or exchange transfusion may be considered.
Prevention
For Rh-negative pregnant women who have not been sensitized, the administration of anti-D immunoglobulin can prevent Rh incompatibility. It is advisable to administer anti-D immunoglobulin at 28 weeks of gestation and within 72 hours after delivery. Anti-D immunoglobulin is also recommended after situations such as ectopic pregnancy, threatened miscarriage, inevitable miscarriage, or invasive prenatal diagnostic procedures.