What is Hemolytic Disease of the Fetus and Newborn/Maternal Alloimmunization?
Maternal alloimmunization, commonly known as Rh disease or isoimmunization, occurs when a woman makes red blood cell antibodies after being exposed to a blood type different from her own. This can be a serious problem if the woman becomes pregnant with a baby who has the offending blood type. In these cases the antibodies can cross the placenta in the second or third trimester and destroy the baby’s red blood cells. This is called Hemolytic Disease of the Fetus and Newborn (HDFN).
HDFN can occur in utero and/or after birth. Fetuses affected by HDFN can become anemic. After birth, HDFN has 4 manifestations: hyperbilirubinemia, anemia, neutropenia, and thrombocytopenia.
Causes of Alloimmunization & HDFN
When a woman is exposed to blood that has different antigens than her own, her immune system sometimes responds by creating antibodies. It is still unknown why some people develop alloimmunization while others do not. Common causes of alloimmunization include:
- Blood transfusion
- Miscarriage or abortion
- Ectopic pregnancy
- Fetal-maternal hemorrhage
- Invasive procedures such as amniocentesis or chorionic villus sampling (CVS)
- Unknown causes during pregnancy
- Intravenous drug use/shared needles
HDFN is caused when an alloimmunized woman gets pregnant and has an antigen positive fetus or child. These antibodies can cross the placenta and bind to the matching antigen on the fetal blood cells. Once bound to the blood cell, the antibody destroys it causing fetal anemia. After birth, the maternal antibodies that were in the child’s blood stream can continue to attack and destroy the infant’s red blood cells for up to 12 weeks. This can cause delayed onset anemia. As the red blood cells are broken down after birth, bilirubin is released and builds up in the infant’s system (hyperbilirubinemia). Due to increased demand to produce new red blood cells, the infant may stop making other types of essential blood cells including neutrophils and thrombocytes. A low level of neutrophils causes neutropenia, which occurs in 40-50% of infants with HDFN. Low levels of platelets cause thrombocytopenia, which occurs in ~25% of infants with HDFN.
Alloimmunization occurs in approximately one to two percent of pregnancies. Approximately 300,000 children are born with HDFN every year.
Diagnosis & Monitoring
In most cases, women don’t know they have developed antibodies until they are pregnant and their routine first trimester antibody screen comes back positive. Maternal alloimmunization is diagnosed with an Indirect Coombs Test or Indirect Agglutination Test (IAT). This test looks for alloantibodies in the patient’s blood.
Once a pregnant woman is confirmed to have antibodies, she will be monitored with regular blood tests (titers) and specialized ultrasounds. If initial titer levels are below critical they should be checked every 4 weeks until 24 weeks, then every 2 weeks until delivery at 37-38 weeks. If the titer levels rise to the critical titer level of 16 for most antibodies, or 4 for anti-K, then the fetus will have MCA dopplers to monitor for fetal anemia.
MCA dopplers are done every 1-2 weeks and measure how fast the blood is flowing in the baby’s brain. If the baby is anemic, the blood will flow faster. The physician will take the peak velocity from the scan and insert it into a calculator to get an MoM value. If the MoM rises to 1.5 or higher, or signs of fetal hydrops are detected, additional monitoring and treatments are needed.
After birth, HDFN is diagnosed or ruled out with a Direct Coombs Test or Direct Agglutination Test (DAT). This test looks for alloantibodies bound to the infant’s blood. Babies with high levels of bilirubin typically undergo further testing with a DAT to determine the cause.
Symptoms of HDFN
The mother will not experience any personal symptoms with HDFN.
Symptoms in the fetus can include:
- Decreased movement
- Increased MCA-PSV Doppler readings
- Fluid build up under the skin or around internal organs (fetal hydrops)
- Echogenic bowels
Symptoms in the infant with HDFN include:
- Jaundice (hyperbilirubinemia)
- Pale skin, lips, and nail beds, rapid heart rate, difficulty feeding, excessive sleepiness or fussiness (anemia)
- Frequent colds or infections (neutropenia)
- Easy bruising or bleeding (thrombocytopenia)
Treatments for HDFN Before Birth
Pregnant women with extremely aggressive antibodies may begin IVIG and plasmapheresis to delay the onset of fetal anemia. Once a fetus with HDFN is anemic, the only treatment is an intrauterine blood transfusion (IUT) or delivery with a blood transfusion after birth.
Treatments for HDFN After Birth
After birth, the newborn’s cord blood will be tested to see if the baby has been affected by the mother’s antibodies. This includes a DAT and hemoglobin and bilirubin level. Depending on the results, additional tests may be needed.Treatment for infants with HDFN who have high bilirubin levels can include: phototherapy, intravenous immunoglobulin (IVIG), and exchange transfusion. Treatment for anemic infants with HDFN can include: blood transfusions, folic acid, and erythropoietin. Iron is not an acceptable treatment for infants with HDFN due to their already elevated iron levels. In general, once babies are discharged from the hospital they receive weekly hemoglobin tests to check for delayed onset anemia and regular bilirubin testing.
Although HDFN does not pose risks to alloimmunized women, the antibodies she formed will be with her for the rest of her life. This is why it is important for alloimmunized women to inform their care providers of their antibody status. If the patient needs a blood transfusion, the donor blood must be matched to the patient’s antibodies. If a patient with alloantibodies receives blood that is not matched to his/her antibody status, the transfused blood cells are destroyed by the patient’s immune system and can cause a hemolytic transfusion reaction (HTR). HTRs can result in a variety of problems, including: systemic inflammatory response, low blood pressure, kidney failure, and even death. Alloantibodies are the second leading cause of fatal HTRs.
Recovery & Outcomes
Infants are generally cleared of HDFN when weekly blood draws reveal that the hemoglobin or hematocrit is rising for 2 weeks in a row without a blood transfusion. At this point the infant no longer has issues with hyperbilirubinemia, and further blood draws for anemia are no longer necessary.
Long-term outcomes for infants with HDFN are favorable. The largest predictor of reduced neurological outcomes was the appearance of fetal hydrops. The LOTUS study (the largest cohort study of children who received IUTs) followed 291 children ages 2-17 years old and found that “the overall incidence of neurodevelopmental impairment was 4.8% (14/291)1”. Previous studies show similar or improved neurological outcomes for infants treated with IUTs. In 1993 Doyle et al reported 35 of 38 infants (92%) treated with IUTs had no sensorineural disability at 2 years of age 2. In 1998 Hudon looked at 40 infants with HDFN due to anti-D who were treated with IUTs. All 40 showed normal neurodevelopmental outcomes at >5 years of age 3. In 1999 Grab et. al., also showed no moderate or severe neurological impairment in 35 infants who had received IUTs 4. Severe hydrops may be associated with a higher risk of impairment 5, 6. For infants who did not develop hydrops and who were not treated with IUTs, normal outcomes should be expected.
Considerations for Subsequent Pregnancies
Though cost is generally a prohibitive factor, options exist to prevent alloimmunization entirely in subsequent pregnancies. This includes:
- In-vitro fertilization (IVF) with preimplantation genetic testing (PDG) in the case of a heterozygous paternal genotype for the offending red cell antigen32
- Gestational carrier using an embryo conceived via IVF
- Donor sperm used in intrauterine insemination (IUI) from a donor who does not carry the offending red cell antigen.
If a woman intends to become pregnant again, prenatal monitoring and potential interventions can be discussed and planned ahead of time with a supportive provider. This may include IVIG and plasmapheresis beginning in the first trimester and assessment for eligibility in new clinical trials such as the Unity trial. For women with previously affected pregnancies requiring IUTs, referral to a specialist with extensive experience in IUTs, IVIG and plasmapheresis may be considered and pre-pregnancy consultation should be initiated.
Further Reading & Resources
Allo Hope Foundation www.allohopefoundation.org