What is Hemolytic Disease of the Fetus and Newborn (Erythroblastosis Fetalis)?
Hemolytic disease of the fetus and newborn (HDFN), also known as erythroblastosis fetalis, happens when the blood types of a mother and baby aren’t compatible. It can become a complex and dangerous health problem for the baby both before and after birth. This happens when the fetus inherits blood group factors from the father that are missing in the mother’s blood. In certain conditions, the mother’s immune system reacts and produces antibodies against these unfamiliar factors. This process is known as alloimmunization.
These maternal antibodies can, to varying extent, pass through the placenta and into the baby’s bloodstream. Depending on the types and amounts of antibodies involved, this can lead to HDFN. The baby might develop complications like anemia (lack of enough red blood cells), jaundice (yellowing of the skin and eyes), or, in severe cases, swelling in the fetus (hydrops fetalis), or very high levels of a substance called bilirubin in the newborn’s blood, causing a disorder called kernicterus.
Despite major progress in understanding and managing HDFN, it can still cause serious health problems or death in newborns if it’s not diagnosed and treated in time. However, the development of Doppler ultrasound scans has provided noninvasive means of managing alloimmunization in pregnant women. These advancing techniques offer a more comprehensive and less invasive way of checking on the health of the fetus, reducing risks for both mother and baby.
Moreover, understanding the intricate naming system of the Rh blood group system is crucial to effectively manage Rh alloimmunization. This requires clear knowledge of different antigenic variants and their impact on clinical practice. Hence, getting a better understanding of the causes, frequency, prevention, and treatment strategies of HDFN, as well as the importance of timely intervention, is essential. This, along with the evolving diagnostic techniques, can help improve the outcome for affected pregnancies.
What Causes Hemolytic Disease of the Fetus and Newborn (Erythroblastosis Fetalis)?
Hemolytic Disease of the Newborn (HDFN) happens when a mother’s antibodies destroy the red blood cells (RBCs) of the baby inside her. This happens because of a difference in the blood groups of the mother and baby. The mother’s body may produce these antibodies if her immune system identifies the baby’s blood cells as foreign, a process known as alloimmunization. Even a tiny amount of the baby’s blood entering the mother’s bloodstream can trigger alloimmunization.
Two systems in our bodies can cause sensitization: the Rh and the ABO systems. In the case of Rh incompatibility, the mother, who is Rh-negative, sees the Rh-positive blood cells of the baby (inherited from the father) as foreign. This causes the mother’s immune system to produce antibodies, especially anti-D antibodies. As a result, if a mother gets pregnant again with another Rh-positive baby, her body can produce more antibodies because her immune system remembers the antigen, or foreign substance.
A similar process happens in ABO incompatibility. Here, the mother’s antibodies target the baby’s RBCs that have A or B antigens, which are not present in her own blood. Both of these immune responses can cause serious complications for the baby such as anemia, jaundice, or further serious conditions known as hydrops fetalis and kernicterus.
While methods to prevent Rh incompatibility have advanced, HDFN remains a global concern. The chances of an Rh-negative mother are higher in some populations. ABO incompatibility is common, but results in fewer cases of HDFN because the immune responses caused by ABO antigens are milder. Bleeding between the mother and baby, which can occur during pregnancy, delivery, or emergencies like an ectopic pregnancy or miscarriage, is crucial in causing HDFN. This is because it allows the baby’s blood to enter the mother’s bloodstream, leading to alloimmunization. Additionally, some medical procedures during pregnancy also increase the risk of bleeding between mother and baby. Therefore, it is essential to carefully manage potential sensitization in the mother to prevent HDFN.
Risk Factors and Frequency for Hemolytic Disease of the Fetus and Newborn (Erythroblastosis Fetalis)
HDFN, or Hemolytic Disease of the Fetus and Newborn, was first noticed by Dr Louis K. Diamond in 1932. It affects about 1695 out of every 100,000 live births. While around 20% of births have something called ABO incompatibility, only 1% of these end up developing HDFN.
There used to be more cases of HDFN due to blood type (Rh) incompatibility, but this has declined following the introduction of a prevention method called RhD-negative immunoprophylaxis, or RhoGAM, in 1968. After RhoGAM was introduced, the rate of Rh-induced HDFN dropped from 99 per 100,000 live births down to 44 per 100,000.
Even with these measures, around 0.1% to 0.4% of women who could be at risk still develop the condition during pregnancy, likely due to antigens other than RhD. According to studies, the occurrence of HDFN can vary greatly based on ethnicity and geographical location within the United States.
- The highest reported rates are among Black female babies born in southern states, while the lowest are among White male infants born in the West or Midwest.
- In terms of ethnic breakdown, HDFN is estimated to affect 15-16% of White women, 8% of African-American women, 4% of African women, less than 1% of Asian women, and 30-35% of Spanish and French women.
Signs and Symptoms of Hemolytic Disease of the Fetus and Newborn (Erythroblastosis Fetalis)
Hemolytic Disease of the Fetus and Newborn (HDFN) can cause different symptoms depending on whether it is present antenatally (before birth) or postnatally (after birth). Antenatally, the disease is often discovered during regular prenatal screenings that test for potential Rh incompatibility, indicating a risk for the disease. After birth, the disease may cause signs like jaundice and anemia (low red blood cell count), which can appear severe within just 24 hours post-delivery.
For patients facing a risk of HDFN, doctors will need a thorough medical history, including information about parental Rh blood groups, any blood transfusions, previous pregnancies, particularly any with Rh-related blood diseases, trauma or invasive procedures, miscarriages, abortions, or Rh IgG administration. The purpose is to pinpoint any incidents that may have caused bleeding from the fetus to the mother, such as injuries, miscarriages, ectopic pregnancies (where the fetus grows outside the womb), placental detachment, molar pregnancies, or procedures related to the pregnancy.
All pregnant women are tested for blood types in their first trimester — as part of standard prenatal care. For instance, women with blood type O naturally have antibodies against blood types A and B, so their babies should be monitored for HDFN, especially after birth. Babies of mothers with Rh-positive A, B, or AB blood types aren’t at risk. Symptoms of HDFN can include fatigue, yellow skin (jaundice), enlarged liver or spleen, yellowing of the whites of the eyes, fast heart rate, rapid breathing, and low blood pressure. In severe cases, a condition called hydrops fetalis (severe swelling in the fetus or newborn) may occur, which can have a high risk of fatality.
Severe HDFN may cause hydrops fetalis due to intense anemia caused by Rh or ABO incompatibility. This condition can cause fluid build-up in the skin (edema), pericardial effusions (fluid around the heart), pleural effusions (fluid around the lungs), and ascites (fluid in the abdomen). It is often identified before birth using ultrasound imaging, which may show fluid in two or more compartments of the body. In certain severe cases, this condition can lead to cardiovascular shock during the newborn examination due to extreme anemia. Other symptoms can include shortness of breath, underdeveloped lungs, and severe respiratory or circulatory diseases. Rare conditions like pneumothorax (collapsed lung) or chylothorax (lymphatic fluid in the lungs) can also occur, posing a high mortality risk.
Untreated anemia in newborns can lead to hyperbilirubinemia with jaundice, progressing to kernicterus — a condition where a type of bilirubin (a product resulting from the breakdown of red blood cells) accumulates in the brain, leading to the death of nerve cells. This can, in turn, cause developmental delays, loss of hearing, spastic cerebral palsy, and even death. It’s essential to identify and treat HDFN as early as possible to prevent these complications.
Testing for Hemolytic Disease of the Fetus and Newborn (Erythroblastosis Fetalis)
If your doctor suspects that your baby may have Hemolytic Disease of the Fetus and Newborn (HDFN), they might conduct a prenatal diagnostic evaluation. This involves getting your blood group checked and screening for antibodies at your first prenatal visit. It helps the doctor see whether you have red blood cell (RBC) antibodies in your blood, which is key to spotting HDFN. If the test comes back positive, there’s a risk that your baby could develop HDFN.
If you’re found to be Rh-positive, there’s no need for extra tests. But if you’re Rh-negative, your doctor will need to check your antibody screen again before giving you anti-D immune globulin, which prevents RHD. They will also do certain tests to see if the antibodies in your blood could potentially harm your baby. Some antibodies are harmless, but others (like anti-K and anti-c) could cause problems and, if present, you might need to see a specialist.
In cases where the antibody levels are significant, the father’s RBC antigens (proteins on the surface of the cells) may also be checked. A positive result means that DNA tests should be done on the baby—these are preferable via cell-free DNA if available. The main aim of these tests is to see if your baby is Rh-positive and could therefore have HDFN. Assessment of fetal anemia (a lack of red blood cells) is then performed with a Doppler scan of the baby’s middle cerebral artery (MCA).
The MCA Doppler helps to gauge if there’s greater blood flow in the baby’s brain, which is a sign of anemia. This test is done every 1 to 2 weeks from 24 weeks gestation. If the results suggest fetal anemia, your doctor will consider more invasive testing and potential treatment. Note, however, these MCA Doppler findings can sometimes be less accurate after 34 to 35 weeks.
You might also have an ultrasound scan to look for signs of hydrops fetalis—severe swelling in the baby due to HDFN. The most common signs of this condition early in pregnancy are a build-up of fluid in the abdomen and thick skin on the baby’s head, neck, thorax, and abdomen. Various other signs and symptoms may develop as the pregnancy progresses.
Finally, if your baby was born and is known to have had hemolytic disease, they’ll need to be checked regularly for anemia and jaundice. This is done by monitoring their bilirubin levels, which can rise rapidly in babies with hemolysis—a condition where red blood cells are destroyed faster than they can be produced. This can be done through a skin test or blood test. A positive direct antibody test (DAT) of the baby’s blood can confirm HDFN, though a separate test called an indirect antiglobulin test might be needed for a more definitive diagnosis.
Treatment Options for Hemolytic Disease of the Fetus and Newborn (Erythroblastosis Fetalis)
When Hemolytic Disease of the Fetus and Newborn (HDFN) is identified or suspected during pregnancy, a specialist in maternal and fetal medicine should be consulted for proper management, which might include procedures such as intrauterine transfusions (blood transfusion directly into the baby) and special care during delivery. Every 2 weeks, the specialist may need to sample the baby’s blood to determine their hemoglobin level. This procedure is known as cordocentesis. If the baby’s hemoglobin is significantly low, an intrauterine transfusion may be required.
There is ongoing debate about the best time to deliver a baby when HDFN is present. The main aim is to delay delivery until the baby can survive outside the womb. Usually, if HDFN is mild, carrying the pregnancy to 37 or 38 weeks is considered acceptable. However, if HDFN is severe, special treatment plans must be considered, weighing the advantages and disadvantages of early delivery versus undergoing multiple procedures during pregnancy. In such cases, some experts recommend delivery at 32 weeks, when the chances of neonatal survival are high. Others suggest continuing intrauterine transfusions until 36 weeks, with the delivery taking place at 37 or 38 weeks.
After birth, HDFN is typically managed by treating hyperbilirubinemia (excess bilirubin in the blood, which can cause jaundice) and anemia (a lack of healthy red blood cells). Severe cases, which may require immediate treatment at delivery, may warrant blood transfusions, fluid drains, and breathing support. This treatment usually requires ABO-matched red blood cells (RBCs). The most common treatment for HDFN that isn’t associated with severe complications (hydrops fetalis) is phototherapy, and if necessary, exchange transfusions (where baby’s blood is replaced with fresh blood), depending on the bilirubin levels.
Phototherapy, a treatment that uses light to break down bilirubin in the body, was introduced in the 1970s and is now the preferred treatment for hyperbilirubinemia. This treatment is started based on a risk guide that includes biological and clinical factors. One of the significant benefits of phototherapy is that it can prevent the need for more invasive procedures, like exchange transfusions. However, the effectiveness of phototherapy depends on several factors, including the specific light wavelength, intensity, the total exposure time, and the bilirubin level at the beginning of treatment.
In conditions of severe anemia, an exchange transfusion may be required. This procedure involves replacing a significant portion of the baby’s red blood cells with new ones, to prevent further hemolysis (breaking down of red blood cells). If the baby’s bilirubin level remains high despite intensive phototherapy, or if there are signs of bilirubin encephalopathy (a severe condition where bilirubin accumulates in the brain), an exchange transfusion may be recommended.
Other treatments such as intravenous immunoglobulin (IVIG) therapy and other agents have been considered but are still controversial. IVIG in the infant can help decrease the breakdown of antibody-coated red blood cells, potentially reducing the bilirubin levels in the blood. However, it’s important to note that none of these other treatments have been adopted as routine practice yet.
What else can Hemolytic Disease of the Fetus and Newborn (Erythroblastosis Fetalis) be?
If a baby shows signs of long-term, severe, or early jaundice and anemia, Hemolytic Disease of the Fetus and Newborn (HDFN) should be considered as a possible cause. However, there are also other reasons an infant might have jaundice and high bilirubin levels. These might include:
- Natural newborn jaundice
- Premature birth
- Jaundice related to breast milk or breastfeeding
- G6PD deficiency
- Thalassemia
- Sepsis (a severe infection)
- Birth trauma
- Gilbert syndrome
- Hypothyroidism
When a baby has too much amniotic fluid (polyhydramnios), conditions related to swallowing difficulty, kidney issues, or a blockage in the intestines could be the cause. Another potential problem is placentomegaly, where the placenta is abnormally large, likely due to an imbalance in the fluid level.
Sometimes, despite having the same symptoms as HDFN, certain conditions like anemia or sacrococcygeal teratoma may cause complications including placentomegaly and polyhydramnios. It is also possible for Hydrodrops fetalis, an abnormal accumulation of fluid in the fetus, to be caused by nonimmune issues, making up most cases. This can occur due to a range of heart, chromosomal, lymphatic issues, genetic disorders, birth defects or infections.
Blue or purple skin color (cyanosis) that does not improve with oxygen is a red flag for heart disease in babies. Having low muscle tone (hypotonia) could indicate congenital myopathy or hypothyroidism. Other symptoms like liver enlargement (hepatomegaly), heart disease (cardiomyopathy), and abnormal facial features could hint at metabolic storage diseases. Skin inflammation (dermatitis) together with or without hepatosplenomegaly may indicate TORCH infections such as toxoplasmosis, rubella, cytomegalovirus, and herpes simplex.
Other potential diagnoses that need to be kept in consideration include:
- Parvovirus-B19
- Bart hemoglobin
- Alpha-globin chain mutation
- Twin-twin transfusion
- Spherocytosis (a certain type of anemia)
- Microangiopathic hemolytic anemia (blood disorder)
- Hereditary enzyme deficiencies
- Chronic fetomaternal hemorrhage
- Alpha thalassemia (blood disorder)
What to expect with Hemolytic Disease of the Fetus and Newborn (Erythroblastosis Fetalis)
In general, the outlook for Hemolytic Disease of the Fetus and Newborn (HDFN) is positive if it’s identified and treated quickly. Although delays in care can sometimes result in long-term nerve damage, this outcome is now quite rare thanks to improvements in monitoring and preventive measures for HDFN.
In cases where a woman has had a previous pregnancy affected by alloimmunization (where the mother’s immune system produces antibodies against the baby’s blood cells), the outlook for subsequent pregnancies hingest on how successful interventions are in preventing fetal hydrops (a serious condition where abnormal amounts of fluid build up in the baby’s tissues and organs).
Possible Complications When Diagnosed with Hemolytic Disease of the Fetus and Newborn (Erythroblastosis Fetalis)
Severe Hemolytic Disease of the Newborn (HDFN) can lead to complications such as Immune Hydrops Fetalis and Kernicterus. Kernicterus, a condition resulting from excessive bilirubin in a baby’s brain, initially shows symptoms like weak muscle tone or poor reflex for sucking. These symptoms can advance to irritability and rigid muscles along with awkward neck and body postures. If ignored, kernicterus could result in permanent effects like cerebral palsy, hearing problems, inability to move the eyes upwards, and intellectual impairments. To prevent HDFN from worsening to these degrees, it’s crucial to identify and treat the condition early.
In addition to these, HDFN can also lead to
- Bradycardia (slow heart rate)
- Limb cyanosis (blue coloring of arms or legs due to lack of oxygen)
- Metabolic abnormalities
- Thrombocytopenia (low count of platelets, the blood cells that help clotting)
- Anemia (low red blood cells or hemoglobin)
Preventing Hemolytic Disease of the Fetus and Newborn (Erythroblastosis Fetalis)
Anti-D immune globulin refers to a type of medicine used to protect women with Rh-negative blood — a certain type of blood that may cause problems during pregnancy. Since the introduction of this medicine, there has been a significant drop, about 80% to 90%, in the occurrence of Rh-hemolytic disease, a condition that affects newborns and causes their red blood cells to break down too fast. It also reduced death rates by two-thirds.
Anti-D immune globulin is typically given to Rh-negative mothers when they’re exposed to Rh-positive blood — possibly when they give birth to an Rh-positive child. This medicine helps stop the mother’s body from reacting adversarially to these foreign cells, known as an immune response. As a result, the mother doesn’t create harmful antibodies during following pregnancies, thus preventing the hemolytic disease from affecting the newborn. However, Rh-related issues still surface in areas that lack access to anti-D immune globulin.
A typical dose of this medicine, 300 mcg, can successfully protect the mother after exposure to 15 mL of the baby’s Rh D-positive blood cells. This dose is usually given once around the 28th week of pregnancy, and it stays effective until the 40th week due to its half-life of about 12 weeks. A second dose is applied after birth if the newborn’s blood type is Rh-positive. However, if a woman comes into contact with more than 15 mL of Rh D-positive blood cells from the baby, her body may still react, creating harmful antibodies. Hence, after delivery, a specific test (erythrocyte rosette screen) is conducted to identify whether more than 2 mL of the baby’s whole blood is present in the mother’s circulation.
On finding a positive result in the initial test, a more detailed test is performed to calculate the percentage of the baby’s red blood cells in the mother’s blood. This test, known as the Kleihauer-Betke acid-elution test, determines if additional doses of the Anti-D immune globulin should be given, especially when standard doses may not be enough. This may happen if an unusual amount of blood passes from the fetus to the mother due to conditions like heavy bleeding during pregnancy or abdominal trauma.
In certain situations such as a miscarriage, ectopic pregnancy (where the growing foetus is not in the uterus), termination procedures, or amniocentesis (a procedure that allows checking for problems with the baby), dosage adjustments may be considered based on how far along the pregnancy is.
There should be a clear understanding amongst Rh-negative women about routine lab testing and rh-D immunoprophylaxis- preventive medicine to protect against this Rh dispute between mother’s and baby’s blood- to ensure the right steps are taken.
Parents of newborns should be given enough information regarding the signs and symptoms of hyperbilirubinemia, a condition that may occur due to hemolytic disease, causing a high level of a yellow substance in the baby’s blood that may require further attention. They should also be educated about neonatal jaundice, a common condition seen in newborns that makes their skin and eyes look yellow. The parents should be clearly instructed about follow-up visits, lab tests, and signs that require medical attention.
