Most women find out that they have a red cell antibody, or maternal alloimmunization, when their first trimester antibody screen comes back positive. This often comes as a shock since the antibodies weren’t present/detected in the previous pregnancy. Our bodies create antibodies when our immune system detects a threat such as a virus. In order to protect us, the antibodies fight off the virus. Maternal alloimmunization just means a woman has created red cell antibodies. This happens when we are exposed to a blood type that is different from ours. Our body thinks the foreign blood is a threat just like a virus so our immune system creates antibodies specifically designed to destroy the foreign blood type. This exposure to a different blood type can happen during pregnancy or childbirth or from a blood transfusion.

If you become pregnant, your baby could be at risk for hemolytic disease of the fetus and newborn or HDFN for short. HDFN happens when your antibodies cross the placenta during pregnancy and attack the unborn child’s red blood cells, causing the baby to become anemic. So, just to clarify, since the two terms can be confusing, the condition in the mother is called maternal alloimmunization and the condition in the baby is called HDFN. Thankfully, there are ways that your MFM and baby’s neonatologist can help keep your baby safe. If your baby becomes anemic in utero your doctor can resolve the anemia by giving the baby a blood transfusion while in the womb. If HDFN is left untreated it can have devastating consequences ranging from anemia and hyperbilirubinemia, to even death. With close monitoring and timely treatment, babies with HDFN can have great outcomes and lead normal, healthy lives. Unfortunately, due to the rarity of the disease and the variation in global care practices, well-managed pregnancies and ideal outcomes are not universal - but they can be!

Once your body has created red cell antibodies you will have the antibodies for the rest of your life. Remember, these antibodies were created to destroy a blood type that is different from your own, so they will not affect you or put you in danger. The only risk you should be aware of is if you need a blood transfusion. The donor blood you are given must be matched to your specific antibodies or you could be at risk for a hemolytic transfusion reaction. It is important to tell your doctors about your antibodies for the rest of your life, and especially before a blood transfusion.

The biggest risk is to your baby during pregnancy and after birth. Your antibodies can go through the placenta during pregnancy and destroy your baby’s red blood cells, causing the baby to become anemic. If fetal anemia is not treated properly, serious problems such as hydrops, organ damage, or death can occur.

If HDFN is not treated properly after birth, serious problems such as anemia, high bilirubin, brain damage, or death can occur. Infants with HDFN are also at risk for neutropenia, or for thrombocytopenia. Thankfully there are treatments that can be used to protect your baby from these risks.

The best way to protect your baby is to find a good Maternal Fetal Medicine Specialist (perinatologist) who is knowledgeable about these antibodies. You should ask to be sent to an MFM doctor if you do not already have an MFM. You can also protect your baby by educating yourself about alloimmunization and HDFN. You need to make sure that you get the proper prenatal tests, monitoring, and treatment.

Plasmapheresis and IVIG treatments may be an option for you beginning early in your pregnancy to protect the baby until he or she is big enough for an intrauterine transfusion (IUT). Talk with your doctor about these options if you have had a previous loss because of your antibodies, or a severely affected baby, or if you have a very high titer early in pregnancy (>256).

If you have had a previously affected pregnancy or you already know that you have antibodies it can be helpful to have a preconception appointment with a Maternal Fetal Medicine specialist before getting pregnant again. This is a great time to go over a care plan and do some initial testing. While a preconception appointment is helpful, it is not required or possible for women whose antibodies are discovered during pregnancy. The two main tests that the MFM might run at a preconception appointment are an antibody screen for mom, and an antigen phenotype for dad. These tests can help you and your doctor know more about potential risks during a future pregnancy and whether you should consider early intervention such as plasmapheresis and IVIG treatments. The antibody screen will detect any new antibodies that have developed since your previous delivery. Unfortunately, titer levels before pregnancy often change once you are pregnant so they don’t always reflect how your pregnancy will go. If you have questions and fears about a future pregnancy, write them down ahead of time and have them ready to ask your provider during your preconception appointment.

As previously mentioned, the biggest risk to your baby during pregnancy is fetal anemia. Untreated anemia can be fatal. The purpose of monitoring during pregnancy is to detect fetal anemia early and treat it before it becomes severe. For more detailed information about prenatal testing, see our page on Necessary and Optional Laboratory Assessments for the Mother, Father, and Fetus. Here is a handy week by week guide through an alloimmunized pregnancy.

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Required blood work for the Father

The father should have his blood drawn to look at his antigen phenotype. The antigen phenotype will tell you and your doctor if your baby could have the antigen, or blood type, that your antibodies may destroy. This test is a simple blood draw which will show if he is homozygous, heterozygous or negative for the antigen. If the man is homozygous, then each of his children have a 100% chance of being positive for the antigen. If he is heterozygous, then each child has a 50% chance of being positive for the antigen and if he is negative for the antigen then his children have a 0% chance of being antigen positive. Only antigen positive babies are at risk for HDFN. An antigen negative baby is completely safe from the mother’s antibodies. This is why it is so important to know if the baby is antigen positive or negative. Occasionally, doctors or laboratories may mistakenly run an antibody screen for the father instead of the antigen phenotype, so the results must be checked carefully to make sure that the antigen was tested.

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Antibody Screen and Titer

Once you are pregnant, your initial first trimester blood work will include an antibody screen with reflex for ID and Titer. This blood draw will show which antibodies you have and what your antibody titers are. The titer level shows the amount of antibodies in your blood. If your initial titer is below the critical level you will have blood drawn every 4 weeks until 28 weeks, then every 2 weeks, to see what your titer is. From 36 weeks until delivery titers are run weekly. It is common for antibody levels to increase in the third trimester as both maternal and fetal blood volumes increase, which is why titers are drawn more frequently after 28 weeks. In some cases, maternal antibodies may not recognize the fetal antigens until late third trimester and then rapidly increase. If titers increase, it may mean it’s time for an early delivery.

If your titer (or quant in the UK) goes above the critical level (4 for Kell, 16 for others) or has a 4-fold increase, then you should have weekly MCA scans instead. High titer levels in the hundreds or thousands may mean you are a candidate for IVIG and plasmapheresis treatments, both of which are started during the first trimester.

Anemia requiring intrauterine blood transfusion is possible at titers below 4 with anti-Kell antibodies. Some doctors debate if there is a safe critical level for anti-Kell, or if scans should be initiated regardless of titer with anti-Kell.

Occasionally a patient will have a prior history of being positive for a specific antibody but her new antibody screen might be negative. This does not mean that the antibodies have gone away or that the woman is “cured”. It simply means that the level of antibodies in her blood is so low that the antibodies are undetectable; the medical term for this phenomenon is antibody evanescence. Learn more about Necessary and Optional Testing for the Mother, Father, and Fetus.

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Cell Free Fetal DNA Test

CffDNA testing offers parents a noninvasive way to find out whether a baby is antigen positive or negative. This test requires a blood sample from the mother. Fetal DNA that is found floating in maternal circulation is pulled out and tested for the antigen. cffDNA can be used for pregnancies complicated by anti-Kell, anti-D, anti-C, anti-c, anti-E, and anti-e antibodies. If the baby is negative, weekly MCA scans are unnecessary. If the baby is antigen positive, MCA scans may be required depending on titer levels. The cffDNA test can also help a healthcare provider decide on when to deliver the baby (ie an at risk baby would be delivered at an earlier gestation than an antigen negative baby). The results can also help determine if there is a need for RhD Immune Globulin (Rhogam) in an Rh- mother. While this test is available to women all over the world regardless of where they live, in most cases the blood drawn for testing must be shipped overseas to the Netherlands. Overall accuracy of the test is over 99%. It may need to be repeated if it is performed at an early gestation (9-14 weeks) or if the baby is female. Read more about cffDNA testing and get the forms here.

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MCA Scans

MCA scans are used to monitor pregnancies where the mother has had a previously affected baby or if the titers are at a critical level. An MCA scan is a special ultrasound that measures how quickly the baby’s blood is flowing through the middle cerebral artery in the brain. If the blood is flowing too fast it means your baby is probably anemic. During your MCA scan the sonographer or MFM will get a PSV (peak systolic velocity) number, which is the speed at which the blood is flowing. The PSV number and your baby’s gestational age will be used to calculate the MoM (multiples of median.) An MoM score shows whether your baby is anemic and whether your baby needs treatment or not. To calculate your baby’s MoM, use this handy tool. An MoM under 1.5 means your baby is not anemic enough to warrant treatment. Once the MoM reaches 1.5 or over, your MFM should prepare for an intrauterine blood transfusion or delivery (whichever is safest for your particular situation). MCA scans are usually done every 1-2 weeks starting between 16-18 weeks but can be done as early as 14-16 weeks for women with aggressive antibodies. The safest approach for your baby is to have weekly MCA scans since fetal anemia can develop within a matter of days. Learn more about MCA scans.

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Amniocentesis

This is an older method of estimating fetal anemia. The most up to date guidance recommends the use of non-invasive MCA scans to monitor fetal anemia instead. Due to the increased risk of fetal-maternal hemorrhage and increasing titers, amniocentesis is rarely used except for determining fetal antigen status. Medical articles recommend that cffDNA testing be used to determine fetal antigen status whenever possible. Today most women are declining the amniocentesis and choosing to determine fetal antigen status with the cffDNA test or monitor as if the baby is antigen positive (MCA scans).

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Additional monitoring options

Ultrasounds, Biophysical Profiles, and NSTs, are utilized throughout the pregnancy to monitor the baby as well. It’s important to note that these tests cannot detect fetal anemia (only MCA scans can), but they can provide important information about the baby’s well-being. You will also have weekly non-stress tests from 32 weeks until you deliver.

Kick counts are the only at home method for mom to monitor the baby. If you notice a change in the baby’s normal activity level, it is important to go in and be monitored.

One of the good things about HDFN is that there are treatment options and ways to keep your baby safe. Babies have better outcomes when fetal anemia is discovered and treated before it becomes severe.

If patients are closely monitored during pregnancy, doctors will know if/when the baby becomes anemic. Once your baby has a 1.5 or over MoM during an MCA scan it means that the baby needs a blood transfusion. If you are already well into your third trimester, your doctor might choose to deliver and then give your baby a blood transfusion right after birth. If you are at an earlier gestation and delivery is not a safe option, your doctor should schedule an intrauterine blood transfusion or refer you to an MFM who is experienced performing IUTs.

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Intrauterine Transfusion (IUT)

When you see the term IUT, it means an Intrauterine Blood Transfusion. Currently this is the only universally accepted treatment for anemia in utero. This is a delicate procedure involving blood testing and a blood transfusion for the baby in utero. When the baby does not have enough red blood cells for his body to work properly, heart failure, fluid build up, and organ damage can occur. Trained doctors who have experience performing the procedure usually have great results with IUTs. About 75% of babies with hydrops survive, while more than 90% of babies without hydrops survive (19). For this reason it is important that an IUT take place BEFORE the baby develops hydrops. When the MoM values are at or over 1.5, it is time for the doctor to perform an IUT even if there are no signs of hydrops or fluid accumulation. IUTs are generally done between 16 and 35 weeks. In some cases an IUT can be done as early as 15 weeks if the baby is already anemic and the provider has experience performing early IUTs. IUTs performed before 20 weeks come with higher risks, especially if performed by an MFM who does not have experience doing the procedure at such early gestations. However, fetal anemia left untreated is fatal which means IUTs are necessary for babies who become anemic early in the second trimester. If your MFM does not have experience performing early IUTs you can ask for a referral to a different MFM when early IUTs are needed. After 35 weeks, the IUT procedure becomes riskier than simply delivering the baby and transfusing after birth.

Timing of IUTs is a very important part of your care and often has a big impact on your baby’s outcome. As previously mentioned, the first IUT is determined based on your MCA scans and MoM. If your doctor waits too long after an MoM of 1.5 or higher to perform the IUT it can be dangerous for your baby. The timing of the second IUT is based on your baby’s beginning (before the procedure) and ending (after the procedure) hematocrit from the first IUT and MCA scans. Usually the second IUT is done 10-14 days after the first but it can be done as soon as 48 hours after the first if necessary. Subsequent IUTs are often performed 2-3 weeks apart depending on your baby’s ending hematocrit and overall health. Your doctor will use a formula to determine how long the transfused blood will last.

As your baby’s blood is destroyed by your antibodies it is replaced with antigen negative donor blood via IUTs. Since the donor blood is antigen negative it will not be destroyed by your antibodies, but your baby will need more blood as he grows. Usually by the third IUT babies are 100% donor blood. The baby’s body knows that an outside source is providing new blood regularly so his bone marrow stops producing new blood. Because the bone marrow is suppressed, infants with HDFN are at risk for hyporegenerative anemia and late onset anemia. Additional tests after birth will be used to closely monitor your baby.

Before having an IUT patients should ask their health care provider for details such as who will be performing an IUT, if a referral to a different facility is needed, how many transfusions the doctor performs per year, and how the doctor decides the timing of future IUTs.

Shortly before you go to have an IUT, your blood will be drawn and tested to see if you have developed any new antibodies. Your doctor will order donor blood for the baby that matches your antibodies in order to avoid a transfusion reaction. IUTs are done in the hospital, usually in a surgical suite. IUT procedures vary by doctor and hospital. Since IUTs carry a risk of infection, many doctors choose to give antibiotics as a regular part of care for IUT. In general, patients can expect conscious sedation and pain medication during the procedure. Your doctor will use an anesthetic such as lidocaine to numb your skin before inserting the needle. The doctor will then stick a needle through your uterus and into the umbilical cord using ultrasound guidance. The baby will be given a sedative and/or a paralytic medication at the beginning of the procedure. The paralytic will keep your baby still during the IUT in order to prevent injury. Your doctor will monitor your baby’s heartbeat periodically. If the baby is under too much stress, the procedure will be stopped and further action (such as immediate delivery) may be taken. Once the needle is in, a sample of the baby’s blood will be taken and the hemoglobin (or hematocrit) will be checked. This is called a cordocentesis or percutaneous umbilical cord blood sampling (PUBS), and it tells the doctor how anemic the baby is and how much blood will be needed. Once the amount of blood is decided, the doctor gives that exact amount to the baby and takes a final hemoglobin reading to see how successful the transfusion was. The needle is removed and it is off to recovery to rest and wait for the medications to wear off.

The doctor should continue to monitor the baby for a few hours before sending you home. Some doctors prefer an overnight stay, while others do not. Depending on the doctor, you may be asked to be on bed rest, or reduced activity for a day or two before resuming your normal routine.

Normal hemoglobin increases from about 10 to 11 g/dL at 17 weeks, to about 14 to 15 g/dL at term. If a baby's hemoglobin is 2 g/dL lower than normal, he is considered mildly anemic, 2-7 g/dL lower is considered moderately anemic, and anything 7 g/dL or more below normal is considered severely anemic. Some doctors do their calculations using hematocrit instead of hemoglobin. The general rule is that hematocrit is three times the hemoglobin number.
Note: If the baby has had IUTs, the state required newborn blood screening may be off. The blood sample that is run may be testing donor blood and not the infant’s actual blood. It is also common for the infant’s blood type to change as he or she gets older. For this reason, the standard newborn blood screening should be repeated once the baby has been transfusion free for at least 3 weeks. Read more about intrauterine transfusions.

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Is There Anything I Can Do To Prevent Fetal Anemia?

Women often want to know if there is anything they can do to keep their babies safe from their antibodies, such as changing their diet or taking certain supplements. Unfortunately, mothers cannot do anything to prevent their baby from developing HDFN. For women with extremely aggressive antibodies there are some preventative treatment options that could delay the need for IUTs. These treatments are called plasmapheresis and IVIG. There are also non-invasive treatments to mature both the fetal liver and lungs before delivery - a huge help for infants who may be delivered prematurely or who are expected to struggle with hyperbilirubinemia.

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Intravenous Immunoglobulin (IVIG) with Plasmapheresis

IVIG is not a replacement for an IUT, but it may delay the need for an IUT and get the baby to a gestation when an IUT is possible. IVIG is an infusion of mostly IgG immunoglobulins that is made by extracting the immunoglobulins from the plasma of ~1,000 donors. IVIG is usually done between 12 and 20 weeks. It is also sometimes used after birth to treat high bilirubin.

IVIG is usually done once per week and is administered slowly through an IV, or a port depending on how often you need to receive treatment. IVIG can be administered at the hospital, outpatient infusion center, doctor’s office or at home by a home care nurse. It can cause side effects such as headache, nausea, vomiting, fever and fatigue. Many women experience headaches and migraines from the IVIG. Healthcare providers may be able to give medications for symptom relief. It is also important to stay well hydrated to reduce these side effects. Some women have an allergic reaction to the IVIG. If this is the case, clinicians will try using a different brand of IVIG. Some women find that they have no reaction after switching brands. Most women receive an antihistamine and acetaminophen before a transfusion to mitigate side effects.

Plasmapheresis is a procedure where the blood is removed from the mother, the blood cells are returned, and the antibody-rich plasma is removed. This can decrease the amount of antibodies in the blood and lower the antibody titer. Plasmapheresis is usually done with IVIG for maximum effectiveness. Read more about IVIG and plasmapheresis.

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M281 aka Nipocalimab

There is currently a clinical trial being conducted for pregnant women with anti-D and anti-Kell antibodies. Many providers do not know about this study, so if you are interested in participating in the trial you can share the information and discuss it with your healthcare providers. Trial sites are open around the world and are currently accepting patients with a history of severe maternal alloimmunization.

M281 is a monoclonal antibody that is also called Nipocalimab. It is designed to prevent Hemolytic Disease of the Fetus and Newborn by reducing how many antibodies are in mom's system (lowering titers), and by blocking the antibodies from crossing the placenta. It is an IV infusion given every week. While the study is only for anti-D and anti-Kell, the two most aggressive antibodies, it should work for all antibodies once the trial is finished and the drug given final approval.

M281 Trial Criteria

• Anti-D antibodies with a titer of 1:32 or higher - OR - anti-Kell antibodies with a titer of 1:4 or higher.
  
• Between 8 and 13 weeks gestation.
  
• Previous pregnancy with problems occurring at or before 24 weeks including:
  
• Severe anemia at the time of IUT - OR -
  
• Hydrops fetalis with MoM over 1.5 - OR -
  
• Loss with placenta/pathology reports indicating severe HDFN.

If a patient does not meet the trial criteria, there is a second trial going on to assess the outcomes of alloimmunized pregnancies. No medication is given and patients can enroll at any gestation. This trial is just keeping track of test results and how pregnancy outcomes. Read more about M281 and other trials.

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Phenobarbital

Phenobarbital is a pill that the mother takes orally 3 times per day for the last 10 days of pregnancy. It is used to mature the baby's liver and to improve liver function after birth. When blood cells break down, they turn into bilirubin, which is removed by the liver. Getting the liver to mature faster can help reduce the amount of hyperbilirubinemia and reduce related complications. Read more about phenobarbital.

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Steroids

Steroids do not treat anemia, but they may be given to the mother to mature the baby’s lungs in case of early delivery. If a patient is having IUTs, steroids may be given before an IUT, and again before birth. The important thing for providers and patients to remember is that steroids artificially lower the MoM score - they make the baby seem better when in fact he is still anemic. An IUT should never be delayed because of a decrease in MoM after steroid administration. Read more about steroids and the effect on fetal blood flow.

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Erythropoietin

Erythropoietin is not commonly given to the mother for the treatment of alloimmunization. It is used in the few rare cases when women cannot be transfused with blood products. Read more.

Women with antibodies usually give birth between 35 and 38 weeks, but the exact timing of delivery depends on your specific situation and what is safest for your baby. Even if titers are low, the majority of alloimmunized women deliver early. This is because the risks of staying in the womb become higher than the risks associated with an early birth/delivery. Having antibodies does not automatically mean you must have a c-section.

For women who have not needed an IUT, multiple articles support induction at 37-38 weeks. The ACOG Practice Bulletin 192 (USA) says delivery between 37 and 38 weeks is reasonable if there are signs of mild hemolysis. This could be an increase in titers, or an MoM of 1.3 or higher. The RCOG green top 65 guidelines (UK) also suggests delivery at 37-38 weeks for women whose blood levels have been stable throughout pregnancy.

Babies who have had IUTs are often born earlier (24-37 weeks). For most doctors, the goal is to reach 35 weeks; anything after is a bonus. The exact timing of your delivery will depend on your unique case and your doctor. The vast majority of alloimmunized women are not allowed to go to 40 weeks due to increased risk of stillbirth and increased difficulty monitoring the baby.

When a baby with HDFN is born he is removed from direct contact with his mother’s antibodies but the risk to the baby does not end at birth. The antibodies that were in the baby’s blood stream before the cord was cut will stay in his system and can continue to affect him for ~12 weeks (possibly longer if the mother has had IUTs). Risks to the infant include anemia, hyperbilirubinemia, neutropenia, and thrombocytopenia. Just like during pregnancy, untreated anemia can be fatal. If the newborn’s bilirubin levels are not managed appropriately, there is a risk of neurological damage. Neutropenia can make an infant more susceptible to infections, while thrombocytopenia can make the infant bruise or bleed more easily. Most of these complications should not have lasting effects on the infant if they are detected with the necessary lab tests and treated appropriately.

Many patients feel unprepared and are unaware of what to expect once the care of the baby is transferred from the MFM/perinatologist to the neonatologist/pediatrician after birth. Parents should expect their child to need multiple blood tests after birth, either through heel pricks, venous blood draws or testing infant’s cord blood. It can be scary or disturbing for parents to see their child hooked up to IVs and monitors or under phototherapy lights.

Below we have listed the problems that HDFN causes after birth and the different treatment options available for infants with HDFN. Most babies do not need all of the treatments listed. Some babies with HDFN simply need to be closely monitored for a few days while others need more invasive treatments. Infants born with HDFN may spend several days or weeks in the NICU. Some need no NICU time and are able to stay with the mother to receive monitoring and phototherapy treatment. The amount of time in hospital varies from child to child. Infants born to mothers with low titers may still need NICU time or other treatment. Titers are not accurate predictors of how the infant will do after birth or what treatments may be required. In general, infants are kept and closely monitored for 4-7 days and the majority of infants are home with their family by week 3.

There are 4 main problems that hemolytic disease of the newborn causes after birth: anemia, hyperbilirubinemia, neutropenia, and thrombocytopenia. For additional reading on each of these topics, please see our Additional Reading by Topic page.

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Anemia

Anemia happens when red blood cells are destroyed. Infants born to mothers with antibodies have what is called hemolytic anemia. Hemolytic anemia is caused solely by red blood cell destruction. Hemolytic anemia cannot be treated with iron. Iron supplements must be avoided for babies with hemolytic anemia unless a ferritin test is given. Even if an infant is not anemic at birth or in the hospital, there is still a risk of anemia developing later; this is called delayed onset anemia. After the umbilical cord is cut, the antibodies will remain in the infant’s bloodstream, continue to bind to red blood cells, and cause hemolysis for up to 12 weeks. Anemia is checked for with routine hemoglobin or CBC tests until ~12 weeks of age. Untreated anemia can be fatal. If anemia is a concern, a consultation with a pediatric hematologist may help. It is important to note that anemia cannot be ruled out or diagnosed based on visual signs alone. Only a hemoglobin or hematocrit can diagnose or rule out anemia. Visual signs of anemia include: a pale complexion (especially lips and fingernail bed), excess sleepiness, difficulty feeding, and a fast heart rate. If parents notice these signs in their child, the child should be seen by a qualified medical professional for a hemoglobin check and assessment for anemia. Read more about hemolytic anemia, delayed onset anemia and hyporegenerative anemia.

Anemia Treatments

Transfusion
A transfusion of red blood cells involves inserting an IV into your infant and slowly giving them additional blood. It is a highly effective, immediate treatment for anemia. These are generally done later with antibody babies and may be referred to as “top up transfusions”. This kind of transfusion will not remove the antibodies, but it will put in new blood that is antigen negative into the infant. If a mother has anti-Kell, then her child needs to receive Kell negative blood or the maternal antibodies will destroy the donor blood too. An easy way to remember what a transfusion does is to think of it as topping off the infant so that she has enough blood until she can start making her own blood. The risks of a RBC transfusion are lower than with an exchange transfusion.

Erythropoietin
Erythropoietin is sometimes given after birth to help prevent hyporegenerative anemia and decrease the need for a transfusion. It promotes the formation of red blood cells by the bone marrow. In IUT babies and those with HDFN due to anti-Kell alloimmunization, the bone marrow is often suppressed, causing low levels of erythropoietin. As a result, red blood cells are not being made as quickly as they should be. Erythropoietin is administered on a schedule in order to promote the creation of blood cells. Read more about erythropoietin here.

Iron
Iron should not be given to your baby unless your baby’s ferritin level is checked first. Giving iron to babies with HDFN without testing the ferritin levels first can be dangerous. Always get a ferritin test before giving iron.

Folic Acid
Folic acid is commonly given to babies with HDFN. Active hemolysis consumes folate, and replacing the folate can help stimulate red blood cell production.

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Hyperbilirubinemia

Hyperbilirubinemia is the medical term for high levels of bilirubin. Sometimes parents are told “the baby is jaundiced.” Bilirubin is released when blood cells are destroyed. It builds up in the infant’s blood system and can cause problems for the child’s brain and organs. Bilirubin levels tend to peak on days 4-6 after birth for infants with HDFN. Clinicians and parents need to expect and watch for rebounding bilirubin levels. Infants with HDFN tend to have a decrease in bilirubin levels when on phototherapy lights, but the levels can rapidly increase when the lights are removed. This can occur up to 3-4 days after removal from lights, so continued bilirubin checks are needed even after phototherapy treatment has ended. Infants with HDFN are at high or medium risk for bilirubin complications, never low risk. High bilirubin levels as an infant can damage tooth enamel and hearing. Untreated hyperbilirubinemia can lead to brain damage, delayed onset anemia for up to 12 weeks after birth, so your baby should have weekly blood tests until hemoglobin or kernicterus, BIND, or even death. Jaundice with signs like an arched back, high-pitched crying, or excessive sleepiness is considered a medical emergency and the child should be taken to the Emergency Room if not currently hospitalized. Read more about hyperbilirubinemia or read more about Kernicterus.

Hyperbilirubinemia Treatments

Phototherapy
Phototherapy is the treatment for high levels of bilirubin (hyperbilirubinemia). It involves the administration of blue light with a wavelength of approximately 450nm. The infant lies inside an incubator with blue lights over him. In some cases, a wrap around light blanket may be used. Phototherapy changes bilirubin into a water soluble form which is easier for the neonate to excrete, thus reducing the bilirubin level. Phototherapy lights are most effective when left on for a period of time. What clinicians try to avoid is having an infant on lights for 12 hours, off overnight, and then back on in the morning. It is best to keep the lights on until the bilirubin is at a safe level and declining regularly. Doctors will wean the infant off of the lights by removing 1 light at a time, and testing for rebounding bilirubin levels. If the infant rebounds, parents should expect the infant to go back under lights. Once the infant isn't rebounding, and bilirubin is decreasing on its own, hyperbilirubinemia is no longer a concern. Read more about phototherapy.

Intravenous Immunoglobulin (IVIG)
IVIG is used as a treatment for high levels of hyperbilirubinemia. It is an infusion of mostly IgG immunoglobulins that is made by extracting the immunoglobulins from the plasma of ~1,000 donors. IVIG is usually done when bilirubin levels are at or near the threshold for exchange transfusion or when levels are still rising despite phototherapy. IVIG can be used to avoid the need for an exchange transfusion. Read more about IVIG.

Exchange Transfusion
Exchange transfusions are done as a treatment for dangerously high levels of bilirubin and kernicterus. An exchange transfusion will quickly and efficiently remove much of the bilirubin in the infant’s system. Quick treatment is essential for reducing the risk of permanent brain damage. Exchange transfusions carry more risk than a regular transfusion. In this transfusion, providers will gradually remove all of the infant's blood and replace it with donor blood. This is usually done twice, in what's called a double volume exchange. Exchange transfusions do remove some of the antibodies and can be very helpful when treating HDFN. A study has shown that exchange transfusion reduces the need for top up transfusions 8-fold. Read more about exchange transfusions.

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Neutropenia

Neutropenia is a reduced level of neutrophils, a specialized kind of white blood cell. Neutropenia is often detected on a CBC and is a common side effect of HDFN. Infants with neutropenia may not be able to fight infections and extra precautions will have to be taken to avoid anyone in the household getting sick. Neutropenic infants may need antibiotics or hospitalization in order to fight infections. Neutropenia does not have any visible signs and must be diagnosed with a CBC. If neutropenia is a concern, a consultation with a pediatric hematologist may help. Infants with HDFN may remain neutropenic for up to 1 year after birth. Read more about neutropenia.

Neutropenia Treatments

Neutropenia due to HDFN does not usually require treatment, but Recombinant Human Granulocyte Colony-Stimulating Factor has been used in some cases.

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Thrombocytopenia

Thrombocytopenia is defined as a platelet count of less than 150 x 109/L. This value is the same regardless of age. Thrombocytopenia is detected with a CBC and can be a side effect of HDFN due to maternal alloimmunization. Infants with thrombocytopenia may bruise or bleed more easily. If severe enough, platelet transfusion may be ordered. Bruising is the only visual sign of thrombocytopenia; it must be diagnosed with a CBC. If thrombocytopenia is a concern, a consultation with a pediatric hematologist may help. Read more about thrombocytopenia.

Thrombocytopenia treatments

Thrombocytopenia due to HDFN rarely requires treatment. If severe enough, platelet transfusions may be ordered.

At a minimum, all infants born to alloimmunized mothers need to have a Direct Agglutination Test (DAT, also called a direct Coombs Test), hemoglobin, and bilirubin test run on the cord blood at birth. These tests will help confirm or rule out the presence of HDFN. If the baby’s DAT is positive, or if the baby is antigen positive, then he or she needs to be monitored for signs of HDFN. Some of the results can indicate a separate issue that has not been caused by HDFN.

While in the hospital, the baby will have multiple bilirubin checks every 4-12 hours, especially during days 4-6 when hyperbilirubinemia due to HDFN tends to peak. You can also expect that the baby will have his reticulocyte count, neutrophil count, and thrombocyte count tested regularly. If the doctor is considering iron supplements for the baby, a ferritin level must checked first. Giving iron to babies with HDFN without testing the ferritin levels first can be dangerous. Always get a ferritin test before giving iron.

Babies with HDFN are at risk for delayed onset anemia for up to 12 weeks after birth, so your baby should have weekly blood tests until hemoglobin or hematocrit is going up steadily on its own without a blood transfusion. Once this happens, your baby is safe and no longer has HDFN.

As a convenience to parents, the Allo Hope Foundation offers a printable package which includes a record of care where parents can keep track of their child’s results as well as see the normal laboratory values for each of the tests listed above. If these tests are not offered, parents should request them along with a referral to a pediatric hematologist if needed. For more detailed infant testing and the normal lab values, please see Necessary Laboratory Assessments for Infants Exposed to Maternal Alloantibodies.

There is good news - over 90% of the babies born to women with alloimmunization survive, and most of them do so with no long-term effects. However, while most of the babies have no ill-effects, poor outcomes can still happen. Here are a couple of studies that talk about the long term neurological (brain) and cardiovascular (heart) outcomes.

In the LOTUS study by Lindenburg and Smits-Wintjens, 291 children who had had IUTs due to HDFN were tested between ages 2-17. Cerebral palsy was found in 6 children (2.1%), severe development delay was found in 9 (3.1%), and bilateral deafness in 3 children (1%). The overall rate of neurodevelopmental impairment was 4.8% or 14/291. The factor that was the most likely to result in neurological impairment was the development of severe hydrops. Preventing fetal hydrops is the strongest predictor for neurodevelopment.

Long-term Cardiovascular Outcome following Fetal Anemia and Intrauterine Transfusion by Wallace, Dalziel, et al reports that cardiovascular development may be altered after exposure to fetal anemia and IUTs. These changes may persist into adulthood and possibly increase the risk of cardiovascular disease. Adults who received an IUT as a baby were found to have “smaller left ventricular volumes, increased relative left ventricular wall thickness, and decreased myocardial perfusion at rest.” These adults also had “increased low frequency-to-high frequency ratio on assessment of heart rate variability and reduced high-density lipoprotein concentration”. Study limitations include: IUT babies were compared with siblings who were not exposed to antibodies. IUT children were born at earlier gestational ages which may account for some of the changes.

Read more about long-term outcomes for children who experienced HDFN.

Absolutely! You will always have antibodies, even when you are not pregnant or when your titer is very low, but your antibodies do not have to limit your family size. It has been thought that subsequent pregnancies are affected at earlier gestations, and more severely, however that is not always the case. With improvement in care practices, and new treatment options, there are several choices available if you wish to have more children. While there are many ways to grow your family, there are also alternatives to natural conception that avoid the risk of HDFN altogether. If you want to learn more about how to prepare for another alloimmunized pregnancy, talk to your doctor before you get pregnant again. Alloimmunization does not have to limit your family size - you DO have options.