Hemolytic disease of the newborn (HDN) is a disease in which there is hemolysis in a newborn or fetus caused by blood-group incompatibility between mother and child.

There are a bunch of related terms:

  • Immune hydrops (Hydrops means accumulation of edema fluid in the fetus during intrauterine growth. It is not specific to HDN, but can occur in many different fetal conditions including cardiovascular conditions, chromosomal disorders like Down syndrome, non-immune fetal anemia, twin-twin transfusion, infections, tumors, and metabolic disorders. Whew.)
  • Hydrops fetalis (When the accumulation of fluid – from whatever cause – is severe and generalized, it is called hydrops fetalis.)
  • Erythroblastosis fetalis (Erythroblastosis means that early red cell precursors are showing up in the peripheral blood. This can happen in any severe anemia, not just HDN.)

Mechanism of HDN

1. Fetus inherits blood group antigens (usually Rh D antigen or ABO antigens) from the father that are foreign to the mother.
2. Fetal blood gets into mom’s circulation (either during last trimester of pregnancy, when cytotrophoblast is no longer present, or during childbirth).
3. Mom makes antibodies to these blood group antigens.
4. Antibodies cross the placenta, attack baby’s red cells, causing hemolytic anemia and its consequences.

The consequences of hemolysis are numerous. One such consequence is extramedullary hematopoiesis. If the anemia is mild, extramedullary hematopoiesis in the liver and spleen may produce enough red cells to maintain normal numbers.

Other consequences are not so happy. If the anemia is severe, the heart and liver may suffer hypoxic injury, resulting in circulatory and hepatic failure. Liver failure causes decreased protein levels (proteins are synthesized in the liver) and a reduction in oncotic pressure in the circulation. Heart failure causes an increase in venous pressure (blood is backing up behind the failing heart). If severe enough, the combination of reduced oncotic pressure and increased venous pressure leads to generalized edema and ascites, a condition called hydrops fetalis, which can be fatal. Lesser degrees of edema can also occur.

If hemolysis is severe, jaundice can occur due to accumulation of unconjugated bilirubin. Unconjugated bilirubin is water insoluble; it binds to lipids in the brain (the blood-brain barrier in the fetus is poorly developed), causing serious damage to the CNS, termed kernicterus. The affected brain is enlarged, edematous, and yellow.

Rh-mediated HDN

Rh-mediated HDN most often involves the D antigen (sometimes it involves E or c; rarely it involves e or C). The baby inherits the D antigen from father, and mom is D negative (same as saying “Rh negative”). Fetal blood gets into mom’s circulation (through trauma, ruptures in the placenta during pregnancy, medical procedures carried out during pregnancy that breech the uterine wall, or childbirth). As a result, mom makes anti-D antibodies (the amount of antibody made depends on dose of antigen received from baby! Mom only makes anti-Rh antibodies when the she has received more than 0.5- 1 mL of Rh + cells.). Just like any other developing antibody, IgM appears first, and IgG appears later. This is important because IgG can cross the placenta, but IgM can’t. So HDN is uncommon in a first pregnancy. But if the mom gets pregnant again, and the fetus inherits D again, mom will now make IgG antibodies, and HDN can happen then.

Rh-mediated HDN is diagnosed using a direct antiglobulin test (DAT). This test will be positive in the baby (baby’s cells are coated with mom’s antibodies). An indirect antiglobulin test  will be positive in mother (though if the mother has received Rhogam at 28 weeks – keep reading – the IAT will be artificially positive!). Administration of anti-D antibody (Rhogam) at 28 weeks and again within 72 hours of delivery to Rh-negative moms prevents HDN in the current pregnancy (and, if mom has not produced anti-D yet, protects future pregnancies too) by coating any circulating D+ fetal red cells before mom is able to make any anti-D antibodies! The incidence of Rh-mediated HDN has gone way down since Rhogam was developed.

In order to determine the appropriate dose of Rhogam to give the mom, you have to quantify the amount of fetomaternal hemorrhage. This is done using either the Kleihauer-Betke test or an immunophenotyping assay. We’ll discuss these tests in our next post.

ABO-mediated HDN

ABO incompatibility occurs in 20-25% of pregnancies.but laboratory evidence of hemolytic disease occurs only in 1 of 10 such infants, and the hemolytic disease is severe enough to require treatment in only 1 in 200 cases.

There are a number of reasons why ABO incompatibility is rarely serious:

1. Most anti-A and anti-B antibodies are IgM (hence they don’t cross the placenta).
2. Neonatal RBCs express A and B poorly (the expression of A and B antigens increases as the baby grows).
3. Many cells other than red cells express A and B antigens and thus sop up some of the transferred antibody.

ABO hemolytic disease occurs almost exclusively in infants of A or B type born of group O mothers. Normal anti-A and anti-B antibodies are IgM and therefore don’t cross the placenta. For reasons not understood, however, some group O women have IgG anti-A and anti-B even without prior sensitization! In this situation, a firstborn child may be affected. Fortunately, even with transplacentally acquired antibodies, lysis of infant red cells is minimal.

ABO incompatibility is diagnosed with same tests as Rh incompatibility (DAT, IAT, Kleihauer-Betke test). There’s no effective protection against ABO incompatibility reactions! Good thing they’re not very common.

Treatment of HDN

It’s obviously way better to prevent HDN than to try treat it once it’s developed. That’s why the mother’s blood type is determined very early in pregnancy, and Rhogam is administered if mom is D negative.

If HDN does develop, there are several options for treatment. Minimally affected newborns can be treated with phototherapy (as in the photo above). Light oxidizes unconjugated bilirubin (toxic) to water-soluble, readily-excreted dipyrroles (harmless). Severely affected fetuses can be treated by total exchange transfusion of the infant (through umbilical vein). The mother can be treated with plasmapheresis (which removes antibody). High-dose intravenous immunoglobulin can be used too – but the best dosage and timing are not well-defined.

Photo credit:  treehouse1977 (, under cc license.