Hemolytic Disease of the Fetus and Newborn
Hemolytic disease of the fetus and newborn (HDFN), also referred to as erythroblastosis fetalis, is a blood disorder in a fetus or newborn that develops when the pregnant mother’s antibodies (a blood protein produced by the immune system to fight off foreign substances) pass through the placenta during pregnancy and attack the baby's red blood cells, breaking down the baby’s red blood cells (hemolysis) at a rapid rate and causing the baby to become anemic. The formation of antibodies in the pregnant mother in response to a fetal antigen (foreign substance) is known as red cell alloimmunization. HDFN is relatively rare and occurs in approximately 3 to 80 out of 100,000 pregnancies in the United States.
About Hemolytic Disease of the Fetus and Newborn
HDFN occurs when the blood types of the pregnant mother and unborn baby are incompatible. All people have an ABO blood type (A, B, AB, or O) and an Rh factor (positive or negative). A problem may exist if the pregnant mother and baby have a different blood type and Rh factor. HDFN occurs most often when an Rh-negative mother becomes pregnant with a baby that has an Rh-positive father. An unborn baby with an Rh factor that is positive, just like their father's, can create an issue if the baby's red blood cells cross over into the Rh-negative mother. When this happens, the Rh-negative mother’s immune system flags the baby's Rh-positive red blood cells as foreign, and the pregnant mother’s immune system responds by making antibodies to fight and destroy these foreign cells. The pregnant mother’s immune system stores these antibodies in case these foreign cells are encountered, again, in a future pregnancy, and the mother is now referred to as Rh-sensitized. Rh sensitization normally isn’t a problem during the mother’s first pregnancy; however, Rh sensitization can cause problems in future pregnancies if the mother becomes pregnant with another Rh-positive baby. In future pregnancies, the mother's antibodies can pass through the placenta to fight off the Rh-positive cells in the baby's body. As the antibodies destroy the cells, the baby becomes anemic. During pregnancy, this is referred to as erythroblastosis fetalis, and once the baby is born, it becomes known as hemolytic disease of the newborn (HDN).
Symptoms of Hemolytic Disease of the Fetus and Newborn
During pregnancy, you likely won’t notice any symptoms related to HDFN. HDFN is more commonly suspected when specific abnormal findings appear on ultrasound. Signs and symptoms of HDFN often differ in each pregnancy and child.
During pregnancy, signs of HDFN may include:
- A high velocity in a blood vessel (the middle cerebral artery, or MCA) in the fetal brain; This is known as the peak systolic velocity of the MCA and can be measured using Doppler ultrasound (a special type of ultrasound that uses sound waves to estimate the blood flow through blood vessels).
- A fetal liver, spleen, or heart that is large in size; There may also be extra fluid in the fetal stomach, around the lungs, or in the scalp. These are signs of hydrops fetalis, which is an abnormal buildup of fluids in the abdomen (ascites), around the lungs (pleural effusions), around the heart (pericardial effusion), and in the skin (subcutaneous edema).
After birth, signs of HDFN may include:
- A liver and spleen that is large in size
- Pale-looking skin from having too few red blood cells (anemia)
- Severe swelling of their entire body due to hydrops fetalis; The baby may also have pale-looking skin and experience difficulty breathing.
- Yellow coloring of your baby’s umbilical cord, skin, and the whites of his or her eyes (jaundice); While your baby may not look yellow immediately after birth, jaundice can come on quickly and often appears within 24 to 36 hours.
Complications Associated With Hemolytic Disease of the Fetus and Newborn
HDFN is rarely associated with any health risks for the pregnant mother. Certain treatment options may cause side effects experienced by the pregnant mother but can be combatted with medications if necessary. However, when the pregnant mother’s antibodies attack the unborn baby’s red blood cells, those blood cells are broken down and destroyed (hemolysis), causing the baby’s body to produce bilirubin (a orange-yellow waste product that travels through the liver, gallbladder, and digestive tract before being excreted). It’s difficult for babies to get rid of bilirubin once they are born as the bilirubin can build up in the blood, tissues, and other fluids. The buildup of bilirubin in the blood (hyperbilirubinemia) can cause the baby’s skin, eyes, and other tissues to turn yellow (jaundice).
The breakdown of your baby’s red blood cells also causes your baby to become anemic. Anemia is dangerous. In anemia, your baby’s body tries to make more red blood cells very quickly. This involves the bone marrow, liver, and spleen and can cause these organs to grow in size.
Complications associated with HDFN can vary from mild to severe.
During pregnancy, your baby may experience:
- Mild anemia: This can lead to a more serious form of anemia.
- Severe anemia: This can cause your baby’s liver and spleen to grow too large in size. It can also affect other organs.
- Hydrops fetalis: This occurs when your baby's organs are unable to handle the anemia. Your baby’s heart will start to fail due to the increased volume of blood that needs to be pumped by the heart to deliver the same amount of oxygen. This also causes large amounts of abnormal fluid buildup in the baby's tissues and around the organs. Babies with this condition are at risk for being stillborn.
After birth, your baby may experience:
- Severe hyperbilirubinemia and jaundice: This occurs when your baby’s liver is unable to handle the large amount of bilirubin produced. This also causes your baby’s liver to grow too large in size. Your baby will still have anemia.
- Kernicterus: This rare complication is the most severe form of hyperbilirubinemia in which the buildup of bilirubin is located in your baby’s brain. It can cause seizures, brain damage, deafness, and even death. Kernicterus should not occur if your baby is closely monitored and receives proper treatment after birth.
Diagnosing Hemolytic Disease of the Fetus and Newborn
One of the first steps in determining if the fetus may be affected by the pregnant mother’s antibodies is to verify the blood type of the baby’s father. In the cases of Rh disease, the father will be Rh negative, just like the baby’s mother, in approximately 13 out of 100 cases, which will result in the baby not being affected at all. In other cases, there is a possibility that the baby will be Rh-positive (have a different blood type than the mother), which may cause the baby to develop a low blood count (anemia) while in the womb. If the father of the baby is Rh-positive, there is approximately a 50% chance that his blood type will be of a mixed variety (heterozygous). This means that approximately half of his offspring will be Rh-negative (will experience no problems) and the other half will be Rh-positive (may develop anemia). This occurs by chance at the time of fertilization of the egg. If the father of the baby is found to be a pure-Rh-positive blood type (homozygous), then all of his children will be Rh-positive and have the possibility of being affected by the pregnant mother’s antibodies. In cases of Rh disease, a partner can be tested through a DNA blood test in a special lab. In the case of red cell alloimmunization due to other red cell antigens, a partner can be tested to see if their blood is heterozygous or homozygous through a simple blood test performed at most hospital blood banks.
Additional testing options include:
- Free fetal DNA: If the father of the baby is found to be heterozygous or if a patient's partner is not available for testing, a free fetal DNA test can be done on the pregnant mother's blood to detect the baby's blood type. Free fetal DNA is found in the pregnant woman's bloodstream as early as ten weeks of gestation due to leakage of DNA material from the placenta. Currently, the free fetal DNA test is only available in the United States for determining the Rh type of the fetus; testing for other red cell antigens is not yet available.
- Ultrasound: Doppler ultrasound (a special type of ultrasound that uses sound waves to estimate the blood flow through blood vessels) can be used to measure the speed of your baby's blood as it moves through a particular blood vessel (the middle cerebral artery, or MCA) in the baby's brain. When babies become anemic, they increase the speed of the blood that moves through their body to deliver more oxygen to their tissues. The top speed of the blood moving through the MCA is then compared to a normal value for the point in pregnancy when it is being measured. The test result is reported in multiples of the median (MoMs). A test result more than one and a half times higher than the usual value (greater than 1.5 MoMs) indicates that the baby is likely to be anemic. MCA measurements can begin as early as 16 weeks (4 months) of gestation and are typically repeated every 1 to 2 weeks.
- Cordocentesis: This test, also referred to as umbilical blood sampling, involves drawing blood from your baby while the baby is still inside your womb and is typically not performed unless the MCA Doppler assessment is abnormal. The procedure is similar to amniocentesis in that it involves placing a needle into the uterus using ultrasound for guidance. However, instead of inserting the needle into fluid surrounding the fetus to extract a sample of the fluid, the needle will be inserted into the umbilical cord to extract a sample of blood. This enables your doctor to perform a variety of tests, such as confirmation of blood type, blood count (hematocrit), the number of new blood cells being made by the baby (reticulocyte count), and the number of antibodies attached to the baby's red blood cells (direct Coombs), to predict the severity of disease in your baby.
Pregnancy With Hemolytic Disease of the Fetus and Newborn
After the initial ultrasound evaluation, you will likely be scheduled for fetal magnetic resonance imaging (MRI). A fetal MRI is similar to a CT scan but does not involve X-rays or radiation. Instead, a special magnet is used to produce images of the structures in the fetus that cannot be seen easily with ultrasound. A fetal MRI is safe for both you and your baby. You will likely need ultrasounds every 3 to 4 weeks to monitor the overall growth of your baby, examine any changes or other findings in the brain, and to determine whether your baby has developed hydrops.
A vaginal delivery is safe for babies with HDFN. Most women with a baby in utero with DHFN will be allowed to go into spontaneous labor near their due date. In some cases, you may be required to delivery earlier if your baby experiences complications. Your healthcare provider may choose to induce labor once your baby’s lungs have matured.
Treating Hemolytic Disease of the Fetus and Newborn
During pregnancy, treatment for HDFN may include:
- Intrauterine blood transfusions: If your MCA Doppler MoM is high (greater than 1.5 MoMs), your doctor may suggest proceeding with a cordocentesis (umbilical blood sampling) and possible intrauterine blood transfusion for your baby, which is typically performed at the time of the first cordocentesis to minimize the risk of puncture of the umbilical vein. At the time of the initial cordocentesis, a small sample of blood is taken from the baby's umbilical cord, and a rapid assessment of the hematocrit (baby's blood count) will be performed in the same room. Since most babies are very active inside the womb, your doctor will likely administer medication that will temporarily keep your baby still during the procedure so that the doctor may give the baby a blood transfusion. These drugs are usually administered into the umbilical cord after the initial blood sample is obtained. By giving this medication, blood transfusions to the baby are much easier for the doctor and much safer for your baby. The effects of these drugs usually last between 2 to 3 hours. At that time, you will begin to feel the baby move again. Because the baby’s own blood cells will be damaged by antibodies, the baby will likely need several transfusions before birth. The number of transfusions varies but ranges between 2 and 8. These procedures are usually performed 2 to 3 weeks apart until approximately 35 weeks (8 months and 3 weeks) of gestation.
- Intravascular transfusion: If the initial blood count indicates that the baby is very anemic (hematocrit of less than 30%), your doctor will typically begin an intravascular transfusion, which is a type of intrauterine transfusion where the blood is injected directly into the umbilical cord. Once the correct amount of blood is injected, the needle is removed.
- Intraperitoneal transfusion: Often an additional amount of blood will be placed into the baby's abdomen in a type of procedure known as an intraperitoneal transfusion. The blood placed into the abdomen is absorbed slowly into the baby's blood vessels over a 10-day to 2-week period. This allows the baby to have a better blood count when the next intrauterine transfusion is scheduled. Intraperitoneal transfusions can also be used to give blood to an unborn baby as early as 15 weeks of gestation when the umbilical cord is too small to perform an intravascular transfusion.
- Plasmapheresis: On rare occasions, due to an extremely high antibody titer (type of blood test that determines the presence and level of antibodies) or a previous history of an extremely ill fetus early in pregnancy, your doctor may feel that specialized treatments are necessary in an attempt to delay the need for the first intrauterine transfusion. At around 10 to 12 weeks of gestation, you may be scheduled for plasmapheresis. During this procedure, a tube will be placed into a vein and your blood will be washed with a specialized machine. This machine removes the liquid part of your blood (plasma) that contains the problem antibodies. The liquid portion is then replaced with albumin (a sterile protein solution made from human blood). The plasmapheresis is usually performed 3 times every other day. The major risk to plasmapheresis involves a low blood calcium level. This may cause some tingling in your lips, but rarely requires treatment. Typically, your antibody titer will drop by half after the 3 plasmapheresis procedures are performed. Plasmapheresis procedures usually take several hours and are scheduled in the hospital to be completed as an outpatient (you will not have to stay in the hospital overnight). Because your body will recognize the reduction in antibodies present after plasmapheresis, it will try to replace the antibodies. To prevent this, your doctor may prescribe intravenous immune globulin (IVIG). This is a solution made from blood plasma and contains the immunoglobins (antibodies) from plasma of over 1,000 blood donors. All donors have been tested for hepatitis and HIV, and none of these infections have been reported in patients who have received IVIG. The IVIG will fool your body into thinking that you do not need to produce more anti-red cell antibodies. Additionally, it may prevent the remaining antibodies from crossing over to your baby. Typically, you will be admitted for 2 days after your last plasmapheresis so that the first two doses of IVIG can be administered.
- Intravenous immune globulin (IVIG): This is a solution made from blood plasma and contains the immunoglobins (antibodies) from plasma of over 1,000 blood donors. All donors have been tested for hepatitis and HIV, and none of these infections have been reported in patients who have received IVIG. IVIG is administered intravenously over 6 to 8 hours. The first treatment is administered the day of your last plasmapheresis and repeated the following day. This means a two-day hospital stay is required for the IVIG treatments. After the initial 2 treatments, treatments are administered one time per week by a home visiting nurse until your baby reaches 20 weeks of gestation. The common side effect of IVIG is severe headache, which can usually be prevented by taking two extra-strength acetaminophen tablets (Tylenol® ) before each injection of IVIG. In some cases, a headache can become as severe as a migraine and may require admission to the hospital. This is more likely to occur when you receive the first two doses of the IVIG after the plasmapheresis. After these initial doses, the risk for developing a severe headache is much lower. Other side-effects of IVIG may include nausea or a mild rash on the palms of your hands. In some cases, if your blood type is A, B, or AB, you may develop anemia, yourself, as a result of the IVIG. In these cases, your doctor will likely order that blood counts be checked periodically at the time of the IVIG administration. HDFN can be prevented. Almost all women will have a blood test to identify their blood type early in pregnancy. If you are Rh-negative and have not been sensitized, you will receive medicine (Rh immunoglobulin) to help prevent your antibodies from reacting to your baby’s Rh-positive cells. All pregnant women should receive Rh immunoglobulin at around 28 weeks (6.5 months) of gestation. If your baby is Rh-positive, you’ll receive a second dose of medicine within 72 hours of giving birth. If your baby is Rh-negative, you won’t need a second dose.
Evaluation After Birth
After birth, treatment for your baby may include:
- Assistance with breathing: Your baby may need oxygen, artificial surfactant (a mixture of fat and proteins made in the lungs that coats the alveoli, or air sacs, to prevent them from sticking together and not opening), or a mechanical breathing machine (ventilator) to breathe more efficiently.
- Blood transfusions: This may be necessary to treat severe anemia.
- Intravenous fluids: This can help raise blood pressure and may be necessary to treat low blood pressure.
- Intravenous immunoglobulin (IVIG): This is a solution made from blood plasma and contains the immunoglobins (antibodies) from plasma of over 1,000 blood donors. All donors have been tested for hepatitis and HIV, and none of these infections have been reported in patients who have received IVIG. IVIG reduces your baby’s breakdown of red blood cells and may also lower their bilirubin levels.
- Phototherapy: This is a form of light treatment that involves placing your baby under a special set of blue lights that can help lower the bilirubin levels in your baby’s blood. Your baby’s skin and blood absorb these light waves, which change bilirubin into products that can pass more easily through the baby’s system.
- Exchange transfusion: When phototherapy fails to keep your baby’s bilirubin levels low, this procedure is performed to remove the parts of your baby’s blood that have a high bilirubin level. The blood that is removed becomes replaced with fresh blood that has a normal bilirubin level, which raises your baby’s red blood cell count and lowers their bilirubin level. During this procedure, the doctor alternates giving and getting small amounts of blood from the baby. This is usually accomplished using a special tube that is placed in the umbilical cord stump. Your baby may need to undergo this procedure again if their bilirubin levels remain high.
- Top-up transfusion: After your baby is discharged, you should be scheduled to meet with a pediatric hematologist (a doctor who specializes in the study of blood, blood-forming organs, and blood disease). This doctor will want to evaluate your baby weekly to check the blood count and the reticulocyte count (a measure of how quickly the baby is making new red blood cells). Visits to your primary pediatrician should still occur for routine newborn and pediatric care. In some babies, a top-up transfusion (adding blood without taking blood) may be required to treat the baby’s anemia that has returned due to the continued presence of the antibodies left over from the baby’s time in the womb. This usually occurs at 3 to 4 weeks of age. Typically, a baby with HFDN only needs one top-up transfusion; however, some babies may require several. Once your baby begins adequately making their own red blood cells (increasing reticulocyte count), top-up transfusions are no longer necessary.
Care Team Approach
The Comprehensive Fetal Care Center, a clinical partnership between Dell Children's Medical Center and UT Health Austin, takes a multidisciplinary approach to your child’s care. This means you and your child will benefit from the expertise of multiple specialists across a variety of disciplines. Your care team will include fetal medicine specialists, obstetricians, neonatologists, sonographers, palliative care providers, fetal center advanced practice providers, fetal center nurse coordinators, genetic counselors, and more, who work together to provide unparalleled care for patients every step of the way. We collaborate with our colleagues at The University of Texas at Austin and the Dell Medical School to utilize the latest research, diagnostic, and treatment techniques, allowing us to identify new therapies to improve treatment outcomes. We are committed to communicating and coordinating your care with your other healthcare providers to ensure that we are providing you with comprehensive, whole-person care.