How Alloimmunization Happens & How It Causes HDFN

When a person (men can become alloimmunized too) is exposed to a blood type that is different from his/her own, the body recognizes the foreign blood and creates antibodies to remove it. This is a natural part of your immune system and works very well for fighting off viruses and bacteria, however the body also uses this system to cleanse itself of any foreign blood cells. For these examples we will use anti-E, but the information applies to any red blood cell antibody. Just swap the E with whatever antigen you need to. Anti-E is an antibody that is made when you are exposed to the E antigen. You can be exposed through blood transfusion, pregnancy, shared needles, a specific type of E.Coli, or some antibodies can even be naturally occurring. Regardless of how you were exposed, the antibodies can cross the placenta. If that happens, the antibodies will look for the specific antigen that they are matched with - our anti-E antibodies will look for the E antigen. Antibodies and antigens fit like a lock and key, the E antibodies can only attach to the E antigen, not the little e antigen, not the K antigen, only the E antigen. If the baby does not have the matching antigen, the baby is completely safe and will not develop HDFN. This is the only way to 100% guarantee that baby will not develop HDFN. Even babies born to mothers with low titers can still have HDFN. Only antigen negative babies are guaranteed to not develop HDFN. Testing dad and/or doing cffDNA testing for baby's E status is very important.

My baby is antigen positive, now what do the antibodies do?
After the antibodies have crossed the placenta, they will latch on to a blood cell with the matching antigen and destroy it. That is their only job, to kill things that do not belong and remove them from the body. If the antibodies destroy too many blood cells, the baby becomes anemic. Untreated anemia can be fatal. To prevent this, a critical titer of 16 was established. In a first affected pregnancy, if the titers remain below 16, the antibodies are unlikely to cause moderate-severe anemia and the baby does not need additional monitoring. If you have a titer of 16 or higher, then the baby is considered at a higher risk for anemia and you receive weekly MCA scans. These MCA scans are special ultrasounds to check for anemia. If the MCA scans show a high value, the doctors give baby a blood transfusion. Current medical literature from multiple countries and sources (6 total) all recommend delivery at 37-38 weeks regardless of what your titer levels are. Even if your titers are low, even if your titers are stable, even if your MCA scans are good, after 37 weeks there is more risk to keeping the baby in than out.

Ok, so after I have the baby, is everything good?
If you have a baby who is antigen positive, the risk does not end at birth. All of the antibodies that had already crossed the placenta stay in the baby's blood stream after the cord is cut. These antibodies can survive and continue to destroy the baby's blood cells for up to 12 weeks, so many babies have weekly monitoring until then. The doctors can determine if the baby is at risk for HDFN by running a Direct (and in some cases an Indirect) Agglutination Test, also called a Direct Coombs Test. This test determines if there are antibodies bound to (and attacking) the baby's blood cells (Direct), or if there are antibodies floating around in the baby's bloodstream (Indirect). Once a baby is found to be Coombs positive, extra tests are run to check for the four main complications for babies with HDFN.

What's the first thing HDFN does?
Immediately after birth the birth, the concern is high bilirubin levels. Bilirubin is formed when blood cells die, so as the antibodies destroy the baby's blood cells, the bilirubin builds up. Before delivery, the placenta filtered out the bilirubin. After birth, that job falls to the baby's liver. The liver is immature and does not do a good job filtering out the bilirubin, as a result the bilirubin builds up. The baby's blood-brain barrier is not fully developed yet at birth and bilirubin is toxic to the brain. All together (the immature liver and the immature blood-brain barrier), this is why the treatment levels are lower in babies who are 12 hours old vs those who are 12 days old. Bilirubin due to HDFN is considered to be more neurotoxic than bilirubin due to other causes. For this reason, babies with HDFN are considered to be at high risk (born before 38 weeks) or medium risk (born 38 weeks or later) for damage from high bilirubin. As a result, babies with HDFN need phototherapy treatment at lower levels. If the bilirubin isn't controlled with lights, they will use IVIG (a medication) or an exchange transfusion to remove the bilirubin.  Most babies are over bili issues by 3 weeks old, and it is common for a child with HDFN to need lights for 10 -14 days or even longer.

What is the next thing HDFN does?
The antibodies can anemia. There are 3 types of anemia due to the antibodies: early onset, delayed onset, and hyporegenerative. In early onset anemia, the anemia is present at birth or within the first two weeks. These babies frequently come out anemic due to an elevated MoM score indicating delivery at/after 35 weeks, or after a failed IUT. In some cases, the anemia is missed on MCA scan and is picked up at birth. Like all anemia, this is treated with blood transfusion. Unlike in adults and other babies, anemia due to HDFN is NOT treated with iron. As the blood cells die, the iron is stored and recycled in the baby's body causing iron to build up. This is often exacerbated by transfusing iron-rich adult blood. Giving iron supplements to an infant with HDFN can be very dangerous. This is why the medical literature recommends a ferritin test before iron supplementation for infants with HDFN. Delayed onset anemia is anemia that happens 2-12 weeks after birth. Weekly hemoglobin checks are a must according to the medical literature. During the time period of 2-6 weeks is when many babies need their first transfusion, and unfortunately some of them die or have permanent damage from anemia that was not caught in time. This tragedy is completely preventable with a weekly hemoglobin check. Usually after 6 weeks, if the baby hasn't had a transfusion, they won't need one, but the doctors should be monitoring just in case. Monitoring stops when baby has had two hemoglobin increases in a row.

What are the other two things that HDFN causes?
The two other side effects of HDFN are neutropenia (40-50% of babies) and thrombocytopenia (25% of babies with HDFN). These happen because the baby is so busy making new red blood cells that it stops making white blood cells (neutrophils) and platelets (thrombocytes). When neutropenia or thrombocytopenia happen in infants with HDFN, there is usually extra monitoring and precautions that the parents will need to take, but these conditions generally do not require treatment.

Now what?
After 12 weeks old, or whenever the baby is cleared from HDFN, the baby is usually perfectly healthy with no lasting side effects (assuming the proper monitoring and prompt treatment for any issues that did arise). Unless the baby experienced severe anemia or extremely high levels of bilirubin before treatment, there are no long-term neurological effects and the child does not have any issues. You can have a perfectly normal infant and child after HDFN.