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Hemolytic Disease of the Newborn (HDN)

What is hemolytic disease of the newborn?

Hemolytic disease of the newborn (HDN) is a blood problem in newborn babies. It occurs when your baby's red blood cells break down at a fast rate. It’s also called erythroblastosis fetalis. 

  • Hemolytic means breaking down of red blood cells.
  • Erythroblastosis means making immature red blood cells.
  • Fetalis means fetus.

What causes HDN in a newborn?

All people have a blood type (A, B, AB, or O). Everyone also has an Rh factor (positive or negative). There can be a problem if a mother and baby have a different blood type and Rh factor.

HDN happens most often when an Rh negative mother has a baby with an Rh positive father. If the baby's Rh factor is positive, like his or her father's, this can be an issue if the baby's red blood cells cross to the Rh negative mother.

This often happens at birth when the placenta breaks away. But it may also happen any time the mother’s and baby's blood cells mix. This can occur during a miscarriage or fall. It may also happen during a prenatal test. These can include amniocentesis or chorionic villus sampling. These tests use a needle to take a sample of tissue. They may cause bleeding.

The Rh negative mother’s immune system sees the baby's Rh positive red blood cells as foreign. Your immune system responds by making antibodies to fight and destroy these foreign cells. Your immune system stores these antibodies in case these foreign cells come back again. This can happen in a future pregnancy. You are now Rh sensitized.

Rh sensitization normally isn’t a problem with a first pregnancy. Most problems occur in future pregnancies with another Rh positive baby. During that pregnancy, the mother's antibodies cross the placenta to fight the Rh positive cells in the baby's body. As the antibodies destroy the cells, the baby gets sick. This is called erythroblastosis fetalis during pregnancy. Once the baby is born, it’s called HDN.

Which children are at risk for HDN?

The following can raise your risk for having a baby with HDN:

  • You’re Rh negative and have an Rh positive baby but haven’t received treatment.
  • You’re Rh negative and have been sensitized. This can happen in a past pregnancy with an Rh positive baby. Or it can happen because of an injury or test in this pregnancy with an Rh positive baby. 

HDN is about 3 times more common in Caucasian babies than in African-American babies.

What are the symptoms of HDN in a newborn?

Symptoms can occur a bit differently in each pregnancy and child.

During pregnancy, you won't notice any symptoms. But your healthcare provider may see the following during a prenatal test:

  • A yellow coloring of amniotic fluid. This color may be because of bilirubin. This is a substance that forms as blood cells break down.
  • Your baby may have a big liver, spleen, or heart. There may also be extra fluid in his or her stomach, lungs, or scalp. These are signs of hydrops fetalis. This condition causes severe swelling (edema).

After birth, symptoms in your baby may include:

  • Pale-looking skin. This is from having too few red blood cells (anemia).
  • Yellow coloring of your baby’s umbilical cord, skin, and the whites of his or her eyes (jaundice). Your baby may not look yellow right after birth. But jaundice can come on quickly. It often starts within 24 to 36 hours.  
  • Your newborn may have a big liver and spleen.
  • A newborn with hydrops fetalis may have severe swelling of their entire body. They may also be very pale and have trouble breathing.

How is HDN diagnosed in a newborn?

HDN can cause symptoms similar to those caused by other conditions. To make a diagnosis, your child’s healthcare provider will look for blood types that cannot work together. Sometimes, this diagnosis is made during pregnancy. It will be based on results from the following tests:

  • Blood test. Testing is done to look for for Rh positive antibodies in your blood.
  • Ultrasound. This test can show enlarged organs or fluid buildup in your baby.
  • Amniocentesis. This test is done to check the amount of bilirubin in the amniotic fluid. In this test, a needle is put into your abdominal and uterine wall. It goes through to the amniotic sac. The needle takes a sample of amniotic fluid.
  • Percutaneous umbilical cord blood sampling. This test is also called fetal blood sampling. In this test, a blood sample is taken from your baby’s umbilical cord. Your child’s healthcare provider will check this blood for antibodies, bilirubin, and anemia. This is done to check if your baby needs an intrauterine blood transfusion.

The following tests are used to diagnose HDN after your baby is born:

  • Testing of your baby's umbilical cord. This can show your baby’s blood group, Rh factor, red blood cell count, and antibodies.
  • Testing of the baby's blood for bilirubin levels.

How is HDN treated in a newborn?

Treatment will depend on your child’s symptoms, age, and general health. It will also depend on how severe the condition is.

During pregnancy, treatment for HDN may include the following.

A healthcare provider will check your baby’s blood flow with an ultrasound.

Intrauterine blood transfusion

This test puts red blood cells into your baby's circulation. In this test, a needle is placed through your uterus. It goes into your baby’s abdominal cavity to a vein in the umbilical cord. Your baby may need sedative medicine to keep him or her from moving. You may need to have more than 1 transfusion.

Early delivery

If your baby gets certain complications, he or she may need to be born early. Your healthcare provider may induce labor may once your baby has mature lungs. This can keep HDN from getting worse.  

After birth, treatment may include the following.

Blood transfusions

This may be done if your baby has severe anemia.

Intravenous fluids

This may be done if your baby has low blood pressure.

Phototherapy

In this test, your baby is put under a special light. This helps your baby get rid of extra bilirubin.

Help with breathing

Your baby may need oxygen, a substance in the lungs that helps keep the tiny air sacs open (surfactant), or a mechanical breathing machine to breathe better.

Exchange transfusion

This test removes your baby’s blood that has a high bilirubin level. It replaces it with fresh blood that has a normal bilirubin level. This raises your baby’s red blood cell count. It also lowers his or her bilirubin level. In this test, your baby will alternate giving and getting small amounts of blood. This will be done through a vein or artery. Your baby may need to have this procedure again if his or her bilirubin levels stay high.

Intravenous immunoglobulin (IVIG)

IVIG is a solution made from blood plasma. It contains antibodies to help the baby's immune system. IVIG reduces your baby’s breakdown of red blood cells. It may also lower his or her bilirubin levels.  

What are possible complications of HDN in a newborn?

When your antibodies attack your baby’s red blood cells, they are broken down and destroyed (hemolysis).

When your baby’s red blood cells break down, bilirubin is formed. It’s hard for babies to get rid of bilirubin. It can build up in their blood, tissues, and fluids. This is called hyperbilirubinemia. Bilirubin makes a baby’s skin, eyes, and other tissues to turn yellow. This is called jaundice.

When red blood cells breakdown, this makes your baby anemic. Anemia is dangerous. In anemia, your baby’s blood makes more red blood cells very quickly. This happens in the bone marrow, liver, and spleen. This causes these organs to get bigger. The new red blood cells are often immature and can’t do the work of mature red blood cells.

Complications of HDN can be mild or severe.

During pregnancy, your baby may have the following:

  • Mild anemia, hyperbilirubinemia, and jaundice. The placenta gets rid of some bilirubin. But it can’t remove all of it.
  • Severe anemia. This can cause your baby’s liver and spleen to get too big. This can also affect other organs.
  • Hydrops fetalis. This happens when your baby's organs aren’t able to handle the anemia. Your baby’s heart will start to fail. This will cause large amounts of fluid buildup in your baby's tissues and organs. Babies with this condition are at risk for being stillborn.

After birth, your baby may have the following:

  • Severe hyperbilirubinemia and jaundice. Your baby’s liver can’t handle the large amount of bilirubin. This causes your baby’s liver to grow too big. He or she will still have anemia.
  • Kernicterus. This is the most severe form of hyperbilirubinemia. It’s because of the buildup of bilirubin in your baby’s brain. This can cause seizures, brain damage, and deafness. It can even cause death.

What can I do to prevent hemolytic disease of the newborn?

HDN can be prevented. Almost all women will have a blood test to learn their blood type early in pregnancy.

If you’re Rh negative and have not been sensitized, you’ll get a medicine called Rh immunoglobulin (RhoGAM). This medicine can stop your antibodies from reacting to your baby’s Rh positive cells. Many women get RhoGAM around week 28 of pregnancy.

If your baby is Rh positive, you’ll get a second dose of medicine within 72 hours of giving birth. If your baby is Rh negative, you won’t need a second dose

Key points about hemolytic disease of the newborn

  • HDN occurs when your baby's red blood cells break down at a fast rate.
  • HDN happens when an Rh negative mother has a baby with an Rh positive father.
  • If the Rh negative mother has been sensitized to Rh positive blood, her immune system will make antibodies to attack her baby.
  • When the antibodies enter the baby's bloodstream, they will attack the red blood cells. This causes them to break down. This can cause problems.
  • This condition can be prevented. Women who are Rh negative and haven’t been sensitized can receive medicine. This medicine can stop your antibodies from reacting to your baby’s Rh positive cells.

Tips to help you get the most from a visit to your child’s healthcare provider:

  • Know the reason for the visit and what you want to happen.
  • Before your visit, write down questions you want answered.
  • At the visit, write down the name of a new diagnosis, and any new medicines, treatments, or tests. Also write down any new instructions your provider gives you for your child.
  • Know why a new medicine or treatment is prescribed and how it will help your child. Also know what the side effects are.
  • Ask if your child’s condition can be treated in other ways.
  • Know why a test or procedure is recommended and what the results could mean.
  • Know what to expect if your child does not take the medicine or have the test or procedure.
  • If your child has a follow-up appointment, write down the date, time, and purpose for that visit.
  • Know how you can contact your child’s provider after office hours. This is important if your child becomes ill and you have questions or need advice.

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Hemolytic Disease of the Newborn

Children's hospital of philadelphia, what is hemolytic disease of the newborn (hdn).

Hemolytic disease of the newborn is also called erythroblastosis fetalis. This condition occurs when there is an incompatibility between the blood types of the mother and baby.

"Hemolytic" means breaking down of red blood cells

"Erythroblastosis" refers to making of immature red blood cells

"Fetalis" refers to fetus

What causes hemolytic disease of the newborn (HDN)?

HDN most frequently occurs when an Rh negative mother has a baby with an Rh positive father. When the baby's Rh factor is positive, like the father's, problems can develop if the baby's red blood cells cross to the Rh negative mother. This usually happens at delivery when the placenta detaches. However, it may also happen anytime blood cells of the two circulations mix, such as during a miscarriage or abortion, with a fall, or during an invasive prenatal testing procedure (such as an amniocentesis or chorionic villus sampling).

The mother's immune system sees the baby's Rh positive red blood cells as "foreign." Just as when bacteria invade the body, the immune system responds by developing antibodies to fight and destroy these foreign cells. The mother's immune system then keeps the antibodies in case the foreign cells appear again, even in a future pregnancy. The mother is now "Rh sensitized."

In a first pregnancy, Rh sensitization is not likely. Usually, it only becomes a problem in a future pregnancy with another Rh positive baby. During that pregnancy, the mother's antibodies cross the placenta to fight the Rh positive cells in the baby's body. As the antibodies destroy the red blood cells, the baby can become sick. This is called erythroblastosis fetalis during pregnancy. In the newborn, the condition is called hemolytic disease of the newborn.

Who is affected by hemolytic disease of the newborn?

Babies affected by HDN are usually in a mother's second or higher pregnancy, after she has become sensitized with a first baby. HDN due to Rh incompatibility is about three times more likely in Caucasian babies than African-American babies.

Why is hemolytic disease of the newborn a concern?

When the mother's antibodies attack the red blood cells, they are broken down and destroyed (hemolysis). This makes the baby anemic. Anemia is dangerous because it limits the ability of the blood to carry oxygen to the baby's organs and tissues. As a result:

The baby's body responds to the hemolysis by trying to make more red blood cells very quickly in the bone marrow and the liver and spleen. This causes these organs to get bigger. The new red blood cells, called erythroblasts, are often immature and are not able to do the work of mature red blood cells.

As the red blood cells break down, a substance called bilirubin is formed. Babies are not easily able to get rid of the bilirubin and it can build up in the blood and other tissues and fluids of the baby's body. This is called hyperbilirubinemia. Because bilirubin has a pigment or coloring, it causes a yellowing of the baby's skin and tissues. This is called jaundice.

Complications of hemolytic disease of the newborn can range from mild to severe. The following are some of the problems that can result:

During pregnancy:

Mild anemia, hyperbilirubinemia, and jaundice. The placenta helps rid some of the bilirubin, but not all.

Severe anemia with enlargement of the liver and spleen. When these organs and the bone marrow cannot compensate for the fast destruction of red blood cells, severe anemia results and other organs are affected.

Hydrops fetalis. This occurs as the baby's organs are unable to handle the anemia. The heart begins to fail and large amounts of fluid build up in the baby's tissues and organs. A fetus with hydrops is at great risk of being stillborn.

After birth:

Severe hyperbilirubinemia and jaundice. The baby's liver is unable to handle the large amount of bilirubin that results from red blood cell breakdown. The baby's liver is enlarged and anemia continues.

Kernicterus. Kernicterus is the most severe form of hyperbilirubinemia and results from the buildup of bilirubin in the brain. This can cause seizures, brain damage, deafness, and death.

What are the symptoms of hemolytic disease of the newborn?

The following are the most common symptoms of hemolytic disease of the newborn. However, each baby may experience symptoms differently. During pregnancy symptoms may include:

With amniocentesis, the amniotic fluid may have a yellow coloring and contain bilirubin.

Ultrasound of the fetus shows enlarged liver, spleen, or heart and fluid buildup in the fetus's abdomen, around the lungs, or in the scalp.

After birth, symptoms may include:

A pale coloring may be evident, due to anemia.

Jaundice, or yellow coloring of amniotic fluid, umbilical cord, skin, and eyes may be present. The baby may not look yellow immediately after birth, but jaundice can develop quickly, usually within 24 to 36 hours.

The newborn may have an enlarged liver and spleen.

Babies with hydrops fetalis have severe edema (swelling) of the entire body and are extremely pale. They often have difficulty breathing.

How is hemolytic disease of the newborn diagnosed?

Because anemia, hyperbilirubinemia, and hydrops fetalis can occur with other diseases and conditions, the accurate diagnosis of HDN depends on determining if there is a blood group or blood type incompatibility. Sometimes, the diagnosis can be made during pregnancy based on information from the following tests:

Testing for the presence of Rh positive antibodies in the mother's blood

Ultrasound - to detect organ enlargement or fluid buildup in the fetus. Ultrasound is a diagnostic imaging technique which uses high-frequency sound waves and a computer to create images of blood vessels, tissues, and organs. Ultrasound is used to view internal organs as they function, and to assess blood flow through various vessels.

Amniocentesis - to measure the amount of bilirubin in the amniotic fluid. Amniocentesis is a test performed to determine chromosomal and genetic disorders and certain birth defects. The test involves inserting a needle through the abdominal and uterine wall into the amniotic sac to retrieve a sample of amniotic fluid.

Sampling of some of the blood from the fetal umbilical cord during pregnancy to check for antibodies, bilirubin, and anemia in the fetus.

Once a baby is born, diagnostic tests for HDN may include the following:

Testing of the baby's umbilical cord blood for blood group, Rh factor, red blood cell count, and antibodies

Testing of the baby's blood for bilirubin levels

Treatment for hemolytic disease of the newborn

Once HDN is diagnosed, treatment may be needed. Specific treatment for hemolytic disease of the newborn will be determined by your baby's doctor based on:

Your baby's gestational age, overall health, and medical history

Extent of the disease

Your baby's tolerance for specific medications, procedures, or therapies

Expectations for the course of the disease

Your opinion or preference

During pregnancy, treatment for HDN may include:

Intrauterine blood transfusion of red blood cells into the baby's circulation. This is done by placing a needle through the mother's uterus and into the abdominal cavity of the fetus or directly into the vein in the umbilical cord. It may be necessary to give a sedative medication to keep the baby from moving. Intrauterine transfusions may need to be repeated.

Early delivery if the fetus develops complications. If the fetus has mature lungs, labor and delivery may be induced to prevent worsening of HDN.

After birth, treatment may include:

Blood transfusions (for severe anemia)

Intravenous fluids (for low blood pressure)

Help for respiratory distress using oxygen, surfactant,  or a mechanical breathing machine

Exchange transfusion to replace the baby's damaged blood with fresh blood. The exchange transfusion helps increase the red blood cell count and lower the levels of bilirubin. An exchange transfusion is done by alternating giving and withdrawing blood in small amounts through a vein or artery. Exchange transfusions may need to be repeated if the bilirubin levels remain high.

Intravenous immunoglobin(IVIG). IVIG is a solution made from blood plasma that contains antibodies to help the baby's immune system. IVIG may help reduce the breakdown of red blood cells and lower bilirubin levels.  

Prevention of hemolytic disease of the newborn

Fortunately, HDN is a very preventable disease. Because of the advances in prenatal care, nearly all women with Rh negative blood are identified in early pregnancy by blood testing. If a mother is Rh negative and has not been sensitized, she is usually given a drug called Rh immunoglobulin (RhIg), also known as RhoGAM. This is a specially developed blood product that can prevent an Rh negative mother's antibodies from being able to react to Rh positive cells. Many women are given RhoGAM around the 28th week of pregnancy. After the baby is born, a woman should receive a second dose of the drug within 72 hours, if her baby is Rh positive. If her baby is Rh negative, she does not need another dose.

  • Learning Objectives

Epidemiology and pathophysiology

Fetal management, neonatal management, prevention (transfusion, rhig), correspondence, hemolytic disease of the fetus and newborn: managing the mother, fetus, and newborn.

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Meghan Delaney , Dana C. Matthews; Hemolytic disease of the fetus and newborn: managing the mother, fetus, and newborn. Hematology Am Soc Hematol Educ Program 2015; 2015 (1): 146–151. doi: https://doi.org/10.1182/asheducation-2015.1.146

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Hemolytic disease of the fetus and newborn (HDFN) affects 3/100 000 to 80/100 000 patients per year. It is due to maternal blood group antibodies that cause fetal red cell destruction and in some cases, marrow suppression. This process leads to fetal anemia, and in severe cases can progress to edema, ascites, heart failure, and death. Infants affected with HDFN can have hyperbilirubinemia in the acute phase and hyporegenerative anemia for weeks to months after birth. The diagnosis and management of pregnant women with HDFN is based on laboratory and radiographic monitoring. Fetuses with marked anemia may require intervention with intrauterine transfusion. HDFN due to RhD can be prevented by RhIg administration. Prevention for other causal blood group specificities is less studied.

Explain the fetal and infant clinical findings associated with hemolytic disease of the fetus and newborn (HDFN)

Describe the approach to pregnancy management when a mother has red cell alloimmunization

Discuss the prevention strategies for HDFN

Hemolytic disease of the fetus and newborn (HDFN) is rare condition that occurs when maternal red blood cell (RBC) or blood group antibodies cross the placenta during pregnancy and cause fetal red cell destruction. The fetal physiological consequences of severe anemia in the fetus can also lead to edema, ascites, hydrops, heart failure, and death. In less severe cases, the in utero red cell incompatibility can persist postnatally with neonatal anemia due to hemolysis, along with hyperbilirubinemia and erythropoietic suppression.

There are an estimated 3/100 000 to 80/100 000 cases of HDFN per year in the United States. 1   The maternal blood group antibodies that cause HDFN can be naturally occurring ABO antibodies (isohemagglutinins), or develop after exposure to foreign RBC; the latter are called blood group alloantibodies. For HDFN to occur, the fetus must be antigen positive (paternally inherited) and the mother must be antigen negative. Several studies have investigated the prevalence of red cell sensitization. In a large series of 22 102 females in the US, 254 (1.15%) of the women were found to have a red cell alloantibodies, of whom 18% had more than one alloantibody. 2   In the Netherlands, the prevalence of red cell alloantibodies detected in the first trimester was 1.2%. 3  

The most common cause of blood group incompatibility results from the ABO blood group system, with incompatibility present in up to 20% of infants. 4   However, because anti-ABO antibodies are predominantly IgM class, most are not effectively transported across the placenta. In addition, the A and B antigens are not well developed on fetal red blood cells. Together, this results in a low rate of clinically severe HDFN due to ABO compatibility, although the incidence of more mild disease varies from 1:150 to 1:3000, depending on the parameters used for the case definition, such as bilirubin levels or neonatal anemia. 1   Because maternal ABO antibodies are present without previous sensitization, HDFN due to ABO antibodies can occur in the first pregnancy and has a recurrence rate up to 87%. 1   It is most commonly seen in group O mothers with group A infants (European ancestry) or group B infants (African ancestry).

The most clinically significant forms of HDFN are caused by maternal blood group alloantibodies are of IgG1 and IgG subclasses, which cause hemolysis more effectively than other IgG subclasses. IgG1 and IgG3 are transported across the placenta by the Fc receptor from the second trimester onward. 5   Once in the fetal circulation, the antibody binds antigen-positive fetal red cells that are then cleared by the fetal spleen. Free hemoglobin is metabolized into bilirubin that is conjugated by the maternal liver. As anemia worsens, fetal hematopoiesis increases, termed “erythroblastosis fetalis” and organs involved in red blood cell synthesis (liver, spleen) may enlarge. In the most severe cases, portal hypertension and reduced hepatic synthesis of albumin leads to low plasma oncotic pressure, edema and ascites. “Hydrops fetalis” refers to the state of widespread effusions and associated high-output cardiac failure and death. 6   A large population-based study in Sweden found that the presence of maternal red cell antibodies was significantly associated with adverse outcomes, with a 1.4-2.4 relative risk of preterm delivery and a 1.5-2.6 relative risk of stillbirth in mothers with red cell allosensitization as compared to those without. 7  

After delivery, the passive blood group antibody can continue to affect neonatal red cells causing ongoing anemia until the maternal antibody is no longer present, which can be weeks to months after birth. In early neonatal anemia, bilirubin from red cell destruction can rise quickly because the fetal liver's metabolic machinery is not well developed. Very high levels of unconjugated bilirubin can lead to bilirubin encephalopathy, which clinically presents acutely as lethargy, and can include neurological and muscular manifestations, such as hypotonia, hypertonia, a weak suck, seizures, and/or coma. Chronic and permanent effects of kernicterus, which is permanent neuronal damage from hyperbilirubinemia, includes cerebral palsy, auditory dysfunction, intellectual, or other handicaps. 6   Infants may also enter a hypoproliferative phase of anemia due to erythropoietic marrow suppression from maternal antibody, as well as intrauterine transfusion, and simple transfusion ( Table 1 ). 8   Low erythropoietin production by the infant may also be contributory to low hemoglobin levels. 9   Late hemolysis can continue to cause low blood counts and elevated bilirubin.

Neonatal manifestations of HDFN anemia by time of onset

Neonatal manifestations of HDFN anemia by time of onset

Hb indicates hemoglobin; RBC, red blood cell; and IUT, intrauterine transfusion.

Adapted from Rath et al with permission. 8  

Maternal alloimmunization results from exposure to foreign red blood cells through previous or current pregnancy, previous transfusions, or organ transplant. During pregnancy, there is spontaneous mixing between fetal and maternal circulation (fetal–maternal hemorrhage; FMH). The mixing increases throughout the pregnancy; 3%, 12%, and 45% in trimesters I, II, and III, respectively, although the amounts of fetal blood in the maternal circulation is generally very small. Hemolytic disease of the fetus and newborn due to red cell alloantibodies rarely occurs in first pregnancies because the highest risk for FMH is later in the pregnancy, especially at delivery, and new alloantibodies are more likely to be formed after delivery. Any physical perturbation of a fetus or placenta in utero also increases the risk of FMH, such as trauma, abortion, ectopic pregnancy, amniocentesis, or multiple pregnancy. 10   Once exposed, the maternal immune system may or may not respond to foreign red cell antigens. 11   The immune response to red cell antigens is complex and not fully understood. It is clear that the RhD antigen is the most potent immunogen of all of the red cell antigens; 85% of RhD-negative individuals will sensitize (form anti-D) after challenge with a 200 mL transfusion of red cells, although more recent data suggests this is far lower. 12   Although as little as 0.1 to 1 mL of RhD-positive red cells can stimulate antibody production, the volumes of FMH are generally small, which contributes to relatively low alloimmunization rates in pregnancy. Before Rh(D) immunoprophylaxis was implemented in 1968, 16% of ABO compatible D-negative mothers with D-positive infants developed anti-D antibody. However, a much lower amount (≤2%) developed anti-D in mother/fetus pairs that were ABO incompatible because of the ABO antibody mediated clearance of fetal red cells from the maternal circulation. 13  

Although RhD remains the most prevalent cause for HDFN due to allosensitization, other red cell antigens are known to be commonly etiologic ( Table 2 ). Other antibodies that have been less commonly reported include E, k, Kp a , Kp b , Ku, Ge, M, Js a , Js b , Jk a , Fy a , Fy b , S, s, and U. 4   A Dutch case-controlled study utilizing a national database of 900 pregnant women with RBC sensitization to non-RhD red cell antibodies enumerated the risk factors for maternal allosensitization. Factors found to be associated with red cell allosensitization in the women were previous major surgery, red cell or platelet transfusion, multiparity, having had a previous male child, and operative removal of the placenta. 14  

Red blood cell antibody specificity in female population studies

Red blood cell antibody specificity in female population studies

Number of samples with antibody per 1000 samples.

Adapted from Giefman-Holtzman et al. 2  

All pregnant women should have testing performed, including a blood type (ABO, RhD) and antibody detection test (indirect antiglobulin test) that detects IgG antibodies. 15   For patients with red cell sensitization, the antibody specificity is determined and initial risk stratification occurs. Certain blood group antibodies such as anti-I, -P1, -Le a , and -Le b , may be ignored because the corresponding (cognate) antigens are incompletely developed at birth, the antibodies are typically not IgG, and clinical experience has established the rarity of their causing HDFN. 4   Women with red blood cell sensitization to clinically significant red cell antigens (such as D, E, c, K, etc) are transitioned into a pathway of more intensive diagnostic testing and monitoring. If paternity is assured, the paternal blood type is usually determined to predict fetal risk of inheriting the antigen that the maternal antibody is directed against. For most blood group systems, serological testing of the father's blood type is sufficient to predict homozygosity or heterozygosity of the antigen. For instance, anti-K and anti-k antisera can detect K and k antigens, respectively, and provide accurate prediction of the risk that the fetus has inherited the blood group antigen. For RhD, serological testing alone cannot predict the number of RhD genes that the father carries because there is no antithetical allele for the RhD gene. Thus, in the case of maternal anti-D sensitization, paternal genotyping to detect copy number of the RhD gene is recommended. 16   Fetuses may bear a 50% risk of antigen inheritance when testing identifies paternal heterozygosity for the antigen in question.. Direct fetal genotyping can determine fetal blood group expression in these settings and provide accurate prediction of fetal risk for HDFN in sensitized mothers. Red cell genotyping can be accomplished using fetal amniocyte genetic testing (obtained via amniocentesis or chorionic villus sampling), or using fetal DNA obtained from maternal serum. 17   The latter methodology has found broad appeal due to its noninvasive approach. 18  

For pregnancies at risk of HDFN due to maternal alloimmunization and possible fetal RBC expression of the cognate antigen, prenatal care by maternal–fetal medicine physicians is recommended. A detailed maternal history is useful to determine previous pregnancy outcomes, particularly for past stillbirths or hydropic fetal losses, and potential etiology of the offending red cell antibody. In addition, fetal ultrasound to determine gestational age and absence of ascites is indicated. 19  

The red cell antibody titer, or strength, helps with further stratification, although the relatively subjective nature of these assays should always be kept in mind. 20 , 21   Traditionally, serial antibody titers are used to detect ongoing sensitization, with arbitrary thresholds of increasing antibody strength used to indicate ongoing and increasing immune stimulation, presumably due to the presence of fetal red cell antigen. If there was a previously affected pregnancy, trending of the titer will not be a reliable measure of increasing sensitization. In addition, transfusion laboratories establish critical antibody titers at which the antibody strength has reached a level that may lead to significant fetal anemia (titers of 1:16-32 are commonly used). 4   However, because the Kell blood group antigens are present on early red cell precursors, a maternal anti-K of relatively low titer, such as 8, may lead to severe hypoproliferative anemia. 22   Using other techniques for antibody strength determination, such as flow cytometry, may be more precise than antibody titers. 23  

For pregnancies that have reached 16-24 weeks, or when a critical antibody titer is reached (depending on maternal history of previously affected pregnancies), fetal anemia is monitored using cerebral MCA Doppler velocity measurements every 2 weeks for risk stratification ( Figure 1 ). 19 , 24   Correlative studies support that the use of the noninvasive MCA Doppler technique as a surrogate measurement for assessing fetal anemia. 19   Doppler readings that are >1.5 multiples of the mean (MoM) are very sensitive, with a 12% false-positive rate, thus trending is important. Weekly fetal monitoring, such as ultrasound and fetal heart rate monitoring, is also often performed).

Figure 1. Diagram of fetal middle cerebral artery Doppler velocimetry testing. Adapted from Moise42 with permission.

Diagram of fetal middle cerebral artery Doppler velocimetry testing. Adapted from Moise 42   with permission.

When fetal anemia becomes moderate to severe as indicated by Doppler MoM measurements exceeding 1.5, invasive testing via cordocentesis is done to determine fetal hematocrit. If the fetus has not reached an acceptable gestational age for delivery, and the hematocrit level is <30%, intrauterine transfusion is usually indicated. Blood products for fetal transfusion should be ready at the start of the procedure for immediate use. Intrauterine transfusion (IUT) is performed by inserting a needle into the umbilical vein using ultrasound guidance and infusion of red cells at a predetermined hematocrit level. The selection of red cell products for intrauterine transfusion is typically Group O, Rh D-negative (or -positive, depending on maternal blood group antibody), leukocyte reduced, hemoglobin S-negative, CMV-safe (CMV seronegative or leukocyte reduced), irradiated, and antigen-negative for maternal red cell antibody/antibodies. Because authors have reported that there is a risk of additional maternal red cell antibody formation after IUT, some centers have adopted providing prospectively matched Rh C, c, E, e, and K-matched transfusions. 25   Despite this, there is evidence that women undergoing Rh- and K-matched IUTs still form additional alloantibodies [to Duffy (FY), Kidd (JK) and (MNS) S blood group antigens]. 26   Following one or more IUT procedures, the fetal circulation is comprised primarily of donor red cells, as fetal marrow production is suppressed and the remaining circulating red cells are destroyed. 27   The procedure of intrauterine transfusion carries a 1%-3% risk of fetal adverse events such as infection or rupture of membranes; procedure outcomes in the early second trimester are poor. 28-30  

Small patient series have explored using maternal treatment with plasma exchange and/or intravenous immunoglobulin (IVIG) to blunt the effect of the maternal antibody on the fetal red cells with some success. 31   The American Society for Apheresis considers plasma exchange in this setting a Category II (second line therapy), with a weak grade of evidence. 32   The ultimate decision for delivery is based on the treating physician's judgement, and it is standard to maintain pregnancy until the fetus has reached a safe gestational age. For severely affected fetuses, the risk of continued monitoring and intrauterine transfusion is balanced against this, and most suggest delivery at 37-38weeks, although earlier delivery may be warranted in severe HDFN. 24  

At birth, the connection to the maternal circulation is severed, and the risk of neonatal hyperbilirubinemia increases significantly because of the immature development of the metabolic pathway to break down bilirubin in the neonatal liver. Although most jaundice in newborns is benign, management of hyperbilirubinemia is critical in the neonatal period because of the risk for bilirubin-induced encephalopathy. 33   Affected infants may need phototherapy to oxidize unconjugated bilirubin to allow for urinary excretion. For patients with known HDFN, close observation of bilirubin levels and hemoglobin is warranted to determine whether neonatal exchange transfusion is needed to wash out bilirubin and maternal antibody, and/or if transfusions are indicated to support oxygen carrying capacity to the tissues. 8   Administration of IVIG to the newborn has been used to reduce the need for exchange transfusions and phototherapy, but it does not affect the need for top off transfusions, and a Cochrane review suggests that more study is needed to determine the best use of IVIG in this setting. 8   When levels of bilirubin reach critical levels, exchange transfusion is indicated ( Table 3 ). Blood product selection is similar to that of IUT, however, because infant whole blood is also being removed, the RBC unit is usually mixed with a plasma unit to create reconstituted whole blood. After a two-volume exchange transfusion, ∼90% of the red cells have been replaced and 50% of the bilirubin has been removed. After exchange transfusion, a platelet count should be performed to monitor for iatrogenic thrombocytopenia.

Guidelines for exchange transfusion in infants 35 or more weeks gestation

Guidelines for exchange transfusion in infants 35 or more weeks gestation

During birth hospitalization, exchange transfusion is recommended if the TSB rises to these levels despite intensive phototherapy. For readmitted infants, if the TSB level is above the exchange level, repeat TSB measurement every 2-3 hours and consider exchange if the TSB remains above the levels indicated after intensive phototherapy for 6 hours.

Adapted from the Clinical Guideline for Management of Hyperbilirubinemia. 33  

Hyporegenerative anemia can last for many weeks after birth ( Table 1 ). Infants must be carefully monitored for clinical signs of ongoing anemia, whichis most likely manifested by poor feeding, the most aerobic activity for neonates. They may also have increased sleep as anemia worsens. In ongoing anemia, the reticulocyte production from the fetal bone marrow may be decreased, and other cells lines, such as neutrophils can be affected. Weekly monitoring of reticulocytes and hematocrit will help to guide decision making about transfusion, and also provide reassurance when the marrow is recovering.

Prevention of HDFN can be divided into primary and secondary measures; there are no international standards, thus, nations differ on preventative measures including dosing and dosing schedules of RhIg and approach to transfusion. Primary prevention focuses on prevention of maternal alloimmunization in the first pregnancy. This is encompassed by the policy employed by some transfusion services, or blood banks, to provide red cell transfusions to females of childbearing potential that are more highly matched than standard transfusions to prevent transfusion-induced red cell sensitization. For instance, in some European countries, K-negative RBC units are provided to women younger than 45-50 years of age. Other nations provide additional matching for antigens, such as c and E. 34   In a retrospective review in Croatia, 48% of 214 pregnancies with maternal sensitization to E, K, or c had a history of transfusion, suggesting that matching for these antigens may be protective, however, the paternal antigen status was not reported. 35   A study in the Netherlands found that a proportion of maternal sensitization to non-RhD blood groups with clinically affected offspring was due to intrauterine transfusion itself. 26   Therefore, these measures may be effective in reducing the incidence of HDFN; however, further comparative studies are needed.

Secondary prevention of HDFN focuses on the RhD RBC antigen given that RhD immune globulin (RhIg) is available to prevent naïve RhD-negative immune systems from synthesizing anti-D antibody after exposure to small amounts of RhD antigen. The risk of an RhD-negative mother becoming allosensitized can be reduced to from 16% to <0.1% by the appropriate administration of RhIg. 13   At this time, there are no other pharmaceutical therapies that can prevent blood group sensitization for other blood group antigens. The transfusion service laboratory plays a critical role in guiding therapy with RhIg. For pregnant women who are RhD-negative, RhIg is typically administered at 2 time points over the course of the pregnancy. The first dose is provided at 28 weeks gestation, as recommended by the American College of Obstetricians and Gynecologists (ACOG) because the majority of allosensitization appears to occur after this time point, and the second after delivery of an RhD-positive infant. 36   The 28 week dose reduces the rate of allosensitization to RhD from 1.5% (antenatal administration only) to 0.1%. As noted above, any procedure or trauma that increases the rate of fetomaternal hemorrhage should elicit the administration of an additional RhIg dose. The antenatal RhIg dose is increased when the volume of fetomaternal hemorrhage is found to be ≥10 mL using the Kleihauer–Betke test. Although used for many years, the Kleihauer–Betke test has been found to be imprecise, and recent attention has focused on newer technologies, such as flow cytometry to provide more accurate quantification of the FMH volume 37  

As molecular testing advances throughout the field of medicine, so does the application of blood typing using molecular techniques. In certain patients, serological reagents do not accurately detect the RhD type. The most common genetic backgrounds that account for this serological typing problem are called weak D phenotypes. Recently, authors have encouraged the use of RhD genetic testing for patients with a weak D phenotype to provide accurate and actionable results for RhD blood typing and RhIg administration. 38 , 39   Further scientific study is needed to elucidate the clinical significance of different RhD genotypes in various ethnic backgrounds and the risk factors for RhIg failure. 40   Precise determination of fetal RhD typing has been widely accepted in Europe and improved the ability to guide RhIg therapy. 18  

In conclusion, HDFN is a multifaceted disease that has distinct technical considerations over several critical time periods of fetal and neonatal development. Advances in maternal–fetal medicine, such as the inventions of RhIg, IUT and noninvasive fetal genetic testing, have led to dramatic improvements in the outcomes of HDFN and prevention of maternal allosensitization. 41   Future advances in blood typing and noninvasive testing will continue to improve the care of mothers and their offspring affected by blood group incompatibility.

Meghan Delaney, Bloodworks NW, 921 Terry Ave, Seattle, WA 98104; Phone: 206-689-6500; e-mail: [email protected] .

Competing Interests

Conflict-of-interest disclosures: M.D. has consulted for Williams Kastner and has received honoraria from Grifols/Novartis and Bioarray/Immucor; and D.C.M. declares no competing financial interests.

Author notes

Off-label drug use: IVIG is included as a therapy for mothers with HDFN. This will be discussed in brief.

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What to Know About Hemolytic Disease of the Newborn

It's a blood type mismatch reaction that can affect babies

  • Complications
  • Exams and Tests
  • When to See a Provider

Hemolytic disease of the newborn (HDN), also called erythroblastosis fetalis , is a serious immune reaction that can affect newborn babies. This condition causes rapid and severe hemolysis —the breakdown of the baby’s red blood cells (RBCs). It only occurs when there is a mismatch in blood type between the baby and the pregnant parent.

Usually, screening tests can help identify whether a baby is at risk of HDN. If there’s a risk, certain treatments can help prevent it from occurring. Symptoms of hemolysis can include swelling of the body, pale skin, yellow-appearing skin, low birth weight, and a rapid heart rate.

Timely diagnosis and treatment can help prevent death or lifelong disability that can occur secondary to HDN. Read more to learn about hemolytic disease of the newborn, its risk factors, prevention, and treatment.

eli_asenova / Getty Images

What Causes Hemolytic Disease of the Newborn?

There are many causes of hemolysis. A baby is considered a neonate during the four weeks after delivery. The most common cause of hemolysis during the neonatal phase of life is an immune response to blood type incompatibility.

The proteins on the surface of RBCs determine blood type. Every single RBC that a person has in their body has the same blood type. The proteins are defined as A, B, and Rh. A person’s blood type can be identified as A, B, AB, or O (no A or B proteins). Additionally, the presence or absence of Rh protein determines whether a person is Rh positive or Rh negative.

When a pregnant person is Rh negative, exposure to a fetus’s Rh positive blood will cause the pregnant person to produce antibodies (immune proteins) against the fetus’s RBCs. This is called Rh sensitization .

This exposure most often happens during labor and delivery. However, it can occur earlier in pregnancy, including during a miscarriage, pregnancy termination, ectopic pregnancy , or an invasive procedure such as amniocentesis or chorionic villus sampling.

The pregnancy in which the first exposure happens usually is not affected. The pregnant person is treated to prevent antibody formation. If antibodies form, they can affect future pregnancies with an Rh positive fetus. The antibodies can cross the placenta and attack the fetus’s blood, resulting in hemolysis.

The most common cause of HDN is Rh incompatibility—when the fetus is Rh positive, and the pregnant person is Rh negative. Other types of blood type incompatibility involving the A and B blood type markers may cause HDN. But the reaction tends to be milder with A or B incompatibility than it is when it occurs due to Rh incompatibility.

Symptoms of HDN

Your healthcare providers can identify risk factors for HDN before birth, but any symptoms of the condition during pregnancy would be subtle and not specific to HDN. The symptoms of HDN after a baby is born can be more obvious but not necessarily specific to this disorder. Diagnostic testing is necessary to identify the cause of any newborn distress.

Signs or symptoms of HDN before birth may include:

  • Lower than normal pregnancy weight gain 
  • Low weight of the growing fetus for gestational (pregnancy) age
  • Lower than normal fetal activity

The baby may show one or more of these signs or symptoms of HDN after birth:

  • General swelling throughout the baby's body
  • Enlarged abdomen
  • Rapid heart rate
  • Yellowish-appearing skin ( jaundice )

Severe complications can include damage to one or more organs in the body, such as the brain or kidneys. This can result in long-term disability or even death of the baby.

Complications Associated With HDN

Anemia (low numbers of healthy red blood cells) can be a serious problem, especially when RBCs break down rapidly before the body can replenish them. A deficiency of RBCs may cause insufficient oxygen supply to the body’s organs.

Bilirubin is a breakdown product of RBCs. Rapid hemolysis causes an accumulation of bilirubin in the body. This material can damage the baby’s organs.

Sometimes a serious complication called kernicterus can develop. This is an accumulation of bilirubin in the brain. It can cause permanent brain damage and may lead to learning disabilities, blindness, epilepsy , and an inability to learn how to walk or control physical movements.

HDN Exams and Tests

In addition to a physical examination, testing is an important part of diagnosing HDN. Blood tests can determine whether a baby has low RBCs, immature RBCs, or antibodies that could be destroying the RBCs. Additionally, some blood tests can identify antibodies in the pregnant person’s blood.

Diagnostic tests that can aid in identifying HDN or some of its complications are:

  • Oxygen level : Noninvasive testing with pulse oximetry can determine whether a baby is low in oxygen.
  • Heart rate : A rapid heart rate can occur when there is a low blood volume due to anemia. This can be extremely straining for a young baby’s heart.
  • Blood pressure : Low blood pressure is one of the effects of anemia.
  • Direct Coombs test : This blood test can identify antibodies on the baby’s RBCs.
  • Indirect Coombs test : This test can identify the presence of antibodies against RBC proteins in the pregnant person’s blood, and it can help identify the risk of HDN before a baby is born.
  • Bilirubin level : A high level of bilirubin in the baby’s blood or urine is a sign of hemolysis. 
  • Blood typing : A prenatal blood test can identify whether the pregnant person is Rh negative.
  • Complete blood count (CBC) : A CBC can identify a low number of RBCs in the baby’s blood.
  • Reticulocyte count : This is a measure of immature RBCs. A high reticulocyte count is a sign that the body is attempting to replace hemolyzed RBCs.

Other tests that may be necessary if there’s concern about serious complications and organ damage include brain imaging or abdominal computerized tomography (CT) scan.

What Is the Treatment for HDN?

Treatments for HDN include preventive approaches, as well as interventions that can be used if the condition isn’t adequately prevented. Survival has improved as treatments have developed, but life expectancy remains low for babies who develop this condition in areas with low access to treatment.

An Rh negative pregnant person who has developed Rh antibodies will have the pregnancy closely monitored. Ultrasound imaging can assess whether the fetus has signs of anemia.

An amniocentesis may be performed to determine if there is elevated bilirubin in the amniotic fluid surrounding the fetus. The fetus's umbilical cord blood may also be sampled to check for antibodies, bilirubin, and signs of anemia.

Sometimes the fetus is treated with an intrauterine blood transfusion before birth. A baby might need further blood transfusions after birth. Intravenous immunoglobulin may also be given to the baby to help prevent hemolysis and elevated bilirubin.

Phototherapy is a type of light therapy that can help the body eliminate excess bilirubin. Babies who have anemia may also need oxygen supplementation, intravenous fluids, and blood pressure management.

Long-Term Care

A baby who has developed organ failure due to HDN may need lifelong care. This can include anti-seizure medication if they develop epilepsy, dialysis if they develop kidney failure , or a feeding tube if they are unable to eat.

Treating Each Pregnancy

Prevention of HDN begins during a first pregnancy for a pregnant person who is Rh negative, even if the pregnancy is not carried to term. Treatment during each pregnancy can prevent the condition from occurring during subsequent pregnancies.

Can HDN Be Prevented?

While HDN is not common, it is recognized as a serious risk during pregnancy and delivery. Prenatal care routinely includes blood typing, which identifies whether a pregnant person is Rh negative, the biggest risk factor for HDN.

Normally it’s recommended for the Rh negative pregnant person to receive treatment with RhoGAM , an immune therapy that prevents antibodies from forming against Rh positive blood. Prevention of antibodies during each pregnancy is crucial so that a subsequent pregnancy will not be affected by antibodies attacking the fetus's RBCs.

RhoGAM is administered around 28 weeks of pregnancy. It is also given within 72 hours of delivery of an Rh positive baby. Sometimes it may need to be administered sooner, such as before an amniocentesis. This invasive diagnostic procedure is safe, but it carries the potential of exposure of the pregnant person to the baby’s blood.

Miscarriage or pregnancy termination can lead to a risk of subsequent HDN, so you might receive RhoGAM if you experience these as well.

What’s the Outlook for a Baby With HDN?

The outlook for a baby who develops HDN is variable. It can be nearly impossible to anticipate the severity of anemia that will develop in response to Rh incompatibility. Without treatment, the outlook can range from mild and easily treatable anemia to severe organ damage or even death.

Hydrops fetalis is a life-threatening condition in which the baby develops severe swelling in the body. Life expectancy is substantially lowered if a baby develops this complication.

When to Talk to a Healthcare Provider

It’s best to get prenatal care as soon as you find out you are pregnant. If you are planning to get pregnant or are at risk of pregnancy, you might be advised to start taking care of your health. This includes starting on prenatal vitamins and avoiding smoking and alcohol.

During early pregnancy, blood tests will identify your blood type. If you are Rh positive, then there is no need to worry or get treatment to prevent HDN.

If you are Rh negative, it’s highly likely that you could be carrying a fetus who is Rh positive because about 90% of the population is Rh positive. It is a dominant trait (is likely to be expressed in the fetus if the other parent is Rh positive).

Your healthcare providers would schedule your preventive treatment during your pregnancy so that you will not develop antibodies against your fetus’s Rh factor proteins.

If you are Rh negative, you need to consult a healthcare provider during each pregnancy to determine if treatment is needed, even if you are not carrying the pregnancy to term.

Hemolytic disease of the newborn (HDN) is a rare but serious condition that may develop due to blood type incompatibility between a growing fetus and the pregnant parent. The process and steps that lead to this condition usually involve sequential pregnancies of a pregnant person who is Rh negative.

During the first pregnancy, an Rh negative pregnant person develops antibodies to the fetus’s Rh positive blood. During a subsequent pregnancy, the antibodies will attack the RBCs of the developing fetus, causing hemolysis.

This immune reaction may cause anemia, organ failure, or death. Usually, HDN can be prevented with treatment that begins during each pregnancy. However, if a fetus or baby develops this condition, close observation and medical care may prevent serious consequences.

Myle AK, Al-Khattabi GH. Hemolytic disease of the newborn: a review of current trends and prospects . Pediatric Health Med Ther. 2021;12:491-498. doi:10.2147/PHMT.S327032

American College of Obstetricians and Gynecologists.  The Rh factor: how it can affect your pregnancy .

De Winter DP, Hulzebos C, Van 't Oever RM, De Haas M, Verweij EJ, Lopriore E. History and current standard of postnatal management in hemolytic disease of the fetus and newborn . Eur J Pediatr. 2023;182(2):489-500. doi:10.1007/s00431-022-04724-0

Mohan DR, Lu H, McClary J, Marasch J, Nock ML, Ryan RM. Evaluation of intravenous immunoglobulin administration for hyperbilirubinemia in newborn infants with hemolytic disease . Children (Basel) . 2023;10(3):496. doi:10.3390/children10030496

Kasirer Y, Kaplan M, Hammerman C. Kernicterus on the spectrum . Neoreviews. 2023;24(6):e329-e342. doi:10.1542/neo.24-6-e329

UC San Diego Health. Hemolytic disease of the newborn .

de Winter DP, Kaminski A, Tjoa ML, Oepkes D. Hemolytic disease of the fetus and newborn: systematic literature review of the antenatal landscape . BMC Pregnancy Childbirth. 2023;23(1):12. doi:10.1186/s12884-022-05329-z

Novoselac J, Buzina Marić K, Rimac V, Selak I, Raos M, Golubić Ćepulić B. Significance of immunohematologic testing in mother and newborn ABO incompatibility . Immunohematology. 2023;39(2):55-60. doi:10.21307/immunohematology-2023-009

By Heidi Moawad, MD Heidi Moawad is a neurologist and expert in the field of brain health and neurological disorders. Dr. Moawad regularly writes and edits health and career content for medical books and publications.  

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Health Encyclopedia

Hemolytic disease of the newborn (hdn), what is hemolytic disease of the newborn.

Hemolytic disease of the newborn (HDN) is a blood problem in newborn babies. It occurs when your baby's red blood cells break down at a fast rate. It’s also called erythroblastosis fetalis. 

Hemolytic means breaking down of red blood cells.

Erythroblastosis means making immature red blood cells.

Fetalis means fetus.

What causes HDN in a newborn?

All people have a blood type (A, B, AB, or O). Everyone also has an Rh factor (positive or negative). There can be a problem if a mother and baby have a different blood type and Rh factor.

HDN happens most often when an Rh negative mother has a baby with an Rh positive father. If the baby's Rh factor is positive, like their father's, this can be an issue if the baby's red blood cells cross to the Rh negative mother.

This often happens at birth when the placenta breaks away. But it may also happen any time the mother’s and baby's blood cells mix. This can occur during a miscarriage or fall. It may also happen during a prenatal test. These can include amniocentesis or chorionic villus sampling. These tests use a needle to take a sample of tissue. They may cause bleeding.

The Rh negative mother’s immune system sees the baby's Rh positive red blood cells as foreign. Your immune system responds by making antibodies to fight and destroy these foreign cells. Your immune system stores these antibodies in case these foreign cells come back again. This can happen in a future pregnancy. You are now Rh sensitized.

Rh sensitization normally isn’t a problem with a first pregnancy. Most problems occur in future pregnancies with another Rh positive baby. During that pregnancy, the mother's antibodies cross the placenta to fight the Rh positive cells in the baby's body. As the antibodies destroy the cells, the baby gets sick. This is called erythroblastosis fetalis during pregnancy. Once the baby is born, it’s called HDN.

Which children are at risk for HDN?

The following can raise your risk for having a baby with HDN:

You’re Rh negative and have an Rh positive baby but haven’t received treatment.

You’re Rh negative and have been sensitized. This can happen in a past pregnancy with an Rh positive baby. Or it can happen because of an injury or test in this pregnancy with an Rh positive baby. 

HDN is about 3 times more common in white babies than in African-American babies.

What are the symptoms of HDN in a newborn?

Symptoms can occur a bit differently in each pregnancy and child.

During pregnancy, you won't notice any symptoms. But your healthcare provider may see the following during a prenatal test:

A yellow coloring of amniotic fluid. This color may be because of bilirubin. This is a substance that forms as blood cells break down.

Your baby may have a big liver, spleen, or heart. There may also be extra fluid in their stomach, lungs, or scalp. These are signs of hydrops fetalis. This condition causes severe swelling (edema).

After birth, symptoms in your baby may include:

Pale-looking skin. This is from having too few red blood cells (anemia).

Yellow coloring of your baby’s umbilical cord, skin, and the whites of their eyes (jaundice). Your baby may not look yellow right after birth. But jaundice can come on quickly. It often starts in 24 to 36 hours.  

Your newborn may have a big liver and spleen.

A newborn with hydrops fetalis may have severe swelling of their entire body. They may also be very pale and have trouble breathing.

How is HDN diagnosed in a newborn?

HDN can cause symptoms similar to those caused by other conditions. To make a diagnosis, your child’s healthcare provider will look for blood types that cannot work together. Sometimes this diagnosis is made during pregnancy. It will be based on results from the following tests:

Blood test. Testing is done to look for Rh positive antibodies in your blood.

Ultrasound. This test can show enlarged organs or fluid buildup in your baby.

Amniocentesis. This test is done to check the amount of bilirubin in the amniotic fluid. In this test, a needle is put into your abdominal and uterine wall. It goes through to the amniotic sac. The needle takes a sample of amniotic fluid.

Percutaneous umbilical cord blood sampling. This test is also called fetal blood sampling. In this test, a blood sample is taken from your baby’s umbilical cord. Your child’s healthcare provider will check this blood for antibodies, bilirubin, and anemia. This is done to check if your baby needs an intrauterine blood transfusion.

The following tests are used to diagnose HDN after your baby is born:

Testing of your baby's umbilical cord. This can show your baby’s blood group, Rh factor, red blood cell count, and antibodies.

Testing of the baby's blood for bilirubin levels.

How is HDN treated in a newborn?

During pregnancy, treatment for HDN may include the following.

A healthcare provider will check your baby’s blood flow with an ultrasound.

Intrauterine blood transfusion

This test puts red blood cells into your baby's circulation. In this test, a needle is placed through your uterus. It goes into your baby’s abdominal cavity to a vein in the umbilical cord. Your baby may need sedative medicine to keep them from moving. You may need to have more than 1 transfusion.

Early delivery

If your baby gets certain complications, they may need to be born early. Your healthcare provider may induce labor once your baby has mature lungs. This can keep HDN from getting worse.  

After birth, treatment may include the following.

Blood transfusions

This may be done if your baby has severe anemia.

Intravenous fluids

This may be done if your baby has low blood pressure.

Phototherapy

In this test, your baby is put under a special light. This helps your baby get rid of extra bilirubin.

Help with breathing

Your baby may need oxygen, a substance in the lungs that helps keep the tiny air sacs open (surfactant), or a mechanical breathing machine (ventilator) to breathe better.

Exchange transfusion

This test removes your baby’s blood that has a high bilirubin level. It replaces it with fresh blood that has a normal bilirubin level. This raises your baby’s red blood cell count. It also lowers their bilirubin level. In this test, your baby will alternate giving and getting small amounts of blood. This will be done through a vein or artery. Your baby may need to have this procedure again if their bilirubin levels stay high.

Intravenous immunoglobulin (IVIG)

IVIG is a solution made from blood plasma. It contains antibodies to help the baby's immune system. IVIG reduces your baby’s breakdown of red blood cells. It may also lower their bilirubin levels.  

What are possible complications of HDN in a newborn?

When your antibodies attack your baby’s red blood cells, they are broken down and destroyed (hemolysis).

When your baby’s red blood cells break down, bilirubin is formed. It’s hard for babies to get rid of bilirubin. It can build up in their blood, tissues, and fluids. This is called hyperbilirubinemia. Bilirubin makes a baby’s skin, eyes, and other tissues to turn yellow. This is called jaundice.

When red blood cells breakdown, this makes your baby anemic. Anemia is dangerous. In anemia, your baby’s blood makes more red blood cells very quickly. This happens in the bone marrow, liver, and spleen. This causes these organs to get bigger. The new red blood cells are often immature and can’t do the work of mature red blood cells.

Complications of HDN can be mild or severe.

During pregnancy, your baby may have the following:

Mild anemia, hyperbilirubinemia, and jaundice. The placenta gets rid of some bilirubin. But it can’t remove all of it.

Severe anemia. This can cause your baby’s liver and spleen to get too big. This can also affect other organs.

Hydrops fetalis. This happens when your baby's organs aren’t able to handle the anemia. Your baby’s heart will start to fail. This will cause large amounts of fluid buildup in your baby's tissues and organs. Babies with this condition are at risk for being stillborn.

After birth, your baby may have the following:

Severe hyperbilirubinemia and jaundice. Your baby’s liver can’t handle the large amount of bilirubin. This causes your baby’s liver to grow too big. They will still have anemia.

Kernicterus. This is the most severe form of hyperbilirubinemia. It’s because of the buildup of bilirubin in your baby’s brain. This can cause seizures, brain damage, and deafness. It can even cause death.

What can I do to prevent hemolytic disease of the newborn?

HDN can be prevented. Almost all women will have a blood test to learn their blood type early in pregnancy.

If you’re Rh negative and have not been sensitized, you’ll get a medicine called Rh immunoglobulin (RhoGAM). This medicine can stop your antibodies from reacting to your baby’s Rh positive cells. Many women get RhoGAM around week 28 of pregnancy.

If your baby is Rh positive, you’ll get a second dose of medicine within 72 hours of giving birth. If your baby is Rh negative, you won’t need a second dose

Key points about hemolytic disease of the newborn

HDN occurs when your baby's red blood cells break down at a fast rate.

HDN happens when an Rh negative mother has a baby with an Rh positive father.

If the Rh negative mother has been sensitized to Rh positive blood, her immune system will make antibodies to attack her baby.

When the antibodies enter the baby's blood, they will attack the red blood cells. This causes them to break down. This can cause problems.

This condition can be prevented. Women who are Rh negative and haven’t been sensitized can receive medicine. This medicine can stop your antibodies from reacting to your baby’s Rh positive cells.

Tips to help you get the most from a visit to your child’s healthcare provider:

Know the reason for the visit and what you want to happen.

Before your visit, write down questions you want answered.

At the visit, write down the name of a new diagnosis, and any new medicines, treatments, or tests. Also write down any new instructions your provider gives you for your child.

Know why a new medicine or treatment is prescribed and how it will help your child. Also know what the side effects are.

Ask if your child’s condition can be treated in other ways.

Know why a test or procedure is recommended and what the results could mean.

Know what to expect if your child does not take the medicine or have the test or procedure.

If your child has a follow-up appointment, write down the date, time, and purpose for that visit.

Know how you can contact your child’s provider after office hours. This is important if your child becomes ill and you have questions or need advice.

Medical Reviewers:

  • Donna Freeborn PhD CNM FNP
  • Heather M Trevino BSN RNC
  • Irina Burd MD PhD
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Hemolytic Disease of the Fetus and Newborn

(rh incompatibility; erythroblastosis fetalis or neonatorum).

, MD, Main Line Health System

Rh incompatibility occurs when a pregnant woman has Rh-negative blood and the fetus has Rh-positive blood.

Rh incompatibility can result in destruction of the fetus’s red blood cells, sometimes causing anemia that can be severe.

The fetus of a women with Rh-negative blood and a man with Rh-positive blood is checked periodically for evidence of anemia.

If anemia is suspected, the fetus is given blood transfusions.

To prevent problems in the fetus, doctors give injections of Rh antibodies to women with Rh-negative blood at about 28 weeks of pregnancy, after any episode of significant bleeding, after delivery, and after certain procedures.

Pregnancy complications, such as Rh incompatibility, are problems that occur only during pregnancy. They may affect the woman, the fetus, or both and may occur at different times during the pregnancy. However, most pregnancy complications can be effectively treated.

The fetus of a woman with Rh-negative blood may have Rh-positive blood if the father has Rh-positive blood. The percentage of people who have Rh-negative blood is small and varies by ethnicity:

White people in North America and Europe: About 15%

African American people: About 8%

People of Chinese descent: About 0.3%

People of Indian descent: About 5%

Did You Know...

Antibodies

In women with Rh-negative blood, sensitization can occur at any time during pregnancy. However, the most likely time is at delivery. In the pregnancy when sensitization first occurs, the fetus or newborn is not likely to be affected. Once women are sensitized, problems are more likely with each subsequent pregnancy if the fetus’s blood is Rh-positive. In each pregnancy after sensitization, women produce Rh antibodies earlier and in larger amounts.

If Rh antibodies cross the placenta to the fetus, they may destroy some of the fetus’s red blood cells. If red blood cells are destroyed faster than the fetus can produce new ones, the fetus can develop anemia. Such destruction is called hemolytic disease of the fetus Hemolytic Disease of the Newborn Hemolytic disease of the newborn is a condition in which red blood cells are broken down or destroyed by the mother's antibodies. Hemolysis is the breakdown of red blood cells. This disorder... read more (erythroblastosis fetalis) or of the newborn (erythroblastosis neonatorum).

Jaundice in the Newborn

Usually, Rh incompatibility causes no symptoms in pregnant women.

Occasionally, other molecules on the woman's red blood cells are incompatible with those of the fetus. Such incompatibility can cause problems similar to those of Rh incompatibility.

Diagnosis of Rh Incompatibility

Blood tests

If the woman's blood contains Rh antibodies, Doppler ultrasonography

At the first visit to a doctor during a pregnancy, all women are screened to determine what their blood type is, whether they have Rh-positive or Rh-negative blood, and whether they have Rh antibodies or other antibodies to red blood cells.

Doctors usually assess the risk of women with Rh-negative blood becoming sensitized to Rh factor and producing Rh antibodies as follows:

If the father is known and is available for testing, his blood type is determined.

If the father is unavailable for testing or if he was tested and he has Rh-positive blood, a blood test called cell-free fetal nucleic acid (DNA) testing can be done to determine whether the fetus has Rh-positive blood. For this test, doctors test small fragments of the fetus's DNA, which are present in the pregnant woman's blood in tiny amounts (usually after 10 to 11 weeks).

If the father has Rh-negative blood, no further testing is needed.

Doppler ultrasonography

Prevention of Rh Incompatibility

As a precaution, women who have Rh-negative blood are given an injection of Rh antibodies at each of the following times:

At 28 weeks of pregnancy

Within 72 hours after delivery of a baby who has Rh-positive blood, even after a miscarriage or an abortion

After any episode of vaginal bleeding during pregnancy

After amniocentesis Amniocentesis Prenatal testing for genetic disorders and birth defects involves testing a pregnant woman or fetus before birth (prenatally) to determine whether the fetus has certain abnormalities, including... read more or chorionic villus sampling Chorionic Villus Sampling Prenatal testing for genetic disorders and birth defects involves testing a pregnant woman or fetus before birth (prenatally) to determine whether the fetus has certain abnormalities, including... read more

Sometimes, when large amounts of the fetus's blood enters the woman's bloodstream, additional injections are needed.

The antibodies given are called Rho(D) immune globulin. This treatment works by making the woman's immune system less able to recognize the Rh factor on red blood cells from the baby, which may have entered the woman’s bloodstream. Thus, the woman's immune system does not make antibodies to the Rh factor. Such treatment reduces the risk that the fetus's red blood cells will be destroyed in subsequent pregnancies from about 12 to 13% (without treatment) to about 0.1%.

Treatment of Rh Incompatibility

For anemia in the fetus, blood transfusions

Sometimes early delivery

If the fetus has Rh-negative blood or if results of tests continue to indicate that the fetus does not have anemia, the pregnancy can continue to term without any treatment.

If anemia is diagnosed in the fetus, the fetus can be given a blood transfusion before birth by a specialist at a center that specializes in high-risk pregnancies. Most often, the transfusion is given through a needle inserted into a vein in the umbilical cord. Usually, additional transfusions are given until 32 to 35 weeks of pregnancy. Exact timing of the transfusions depends on how severe the anemia is and how old the fetus is. Timing of delivery is based on the individual woman's situation.

Before the first transfusion, women are often given corticosteroids if the pregnancy has lasted 23 or 24 weeks or longer. Corticosteroids help the fetus's lungs mature and help prevent the common complications that can affect a preterm newborn Preterm (Premature) Newborns A preterm newborn is a baby delivered before 37 weeks of gestation. Depending on when they are born, preterm newborns may have underdeveloped organs that are not be ready to function outside... read more .

The baby may need additional transfusions after birth. Sometimes no transfusions are needed until after birth.

presentation on hemolytic disease of newborn

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hemolytic disease of newborn

Hemolytic disease of newborn

Aug 25, 2014

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Hemolytic disease of newborn. Objectives. Definition &amp; characteristics ABO vs Rh hemolytic disease of the newborn Pathogenesis Incidence Blood types of mother and baby Severity of disease Laboratory data Prevention Rh immune globulin Tests for feto-maternal hemorrhage

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Presentation Transcript

Objectives • Definition & characteristics • ABO vs Rh hemolytic disease of the newborn • Pathogenesis • Incidence • Blood types of mother and baby • Severity of disease • Laboratory data • Prevention • Rh immune globulin • Tests for feto-maternal hemorrhage • Exchange transfusion protocol

Hemolytic disease of newborn Hemolytic disease of the new born and fetus (HDN) is a destruction of the red blood cells (RBCs) of the fetus and neonate by antibodies produced by the mother It is a condition in which the life span of the fetal/neonatal red cells is shortened due to maternal allo-antibodies against red cell antigens acquired from the father

Antibodies • Five classes of antibodies • IgM • IgG • IgA • IgD • IgE • Blood groups specific antibodies are • IgG and • IgM

Biochemistry of antibodies • Made from four polypeptide chains • Two light (L) chains • Two identical heavy (H) chains • Each class has immunologically distinct heavy chain

Biochemistry of antibodies

Blood group antibodies • Blood group antibodies can be classified as • Naturally occurring and immune antibodies • Depending on presensitization • Cold and warm antibodies • Thermal range of antibodies • Most natural Abs are cold & some e.g wide thermal range like Anti A and Anti B • Most immune Abs are warm and can destroy red cell in-vivo • Complete and incomplete antibodies • Depends on agglutination of saline suspended red cells • IgM is complete antibody; most naturally occurring antibodies are complete and of IgM class • IgG is incomplete antibody

Antibodies of ABO system • Anti- A • Naturally occurring • Immune • Anti- B • Naturally occurring • Immune • Anti- A1 • Anti- H

Antibodies of Rh system • Naturally occurring • Anti- E • Occasionally anti-D and anti C • Immune antibodies • D antibodies are more immunogenic • Other are anti c, E, e, C. • Most common is anti- E • After anti- D, anti- c is the common cause of HDN (The vast majority of Rh antibodies are IgG and do not fix complement)

Antibodies from other blood group systems • Anti- K • Kell blood group system • Usually is immune antibody • Warm Ab • Anti- Jka • Kidd blood group system • Usually is immune antibody • Warm Ab

Complement • Complements are series of proteins, present in plasma as an inactive precursors • When activated and react sequentially with each other they mediate destruction of cells and bacteria • Complement activation involves two stages • Opsonization • Lytic stage

Complement • Antibodies can fix complement and cause rapid destruction of red cells • Destruction depends on the amount of antibody and complement • In ABO- incompatible transfusion no surviving A or B red cells can be seen after 1 hour of transfusion • Why? • Remember naturally occurring Abs. are IgM and fix complement mediating the hemolysis

Disease mechanism - HDN • There is destruction of the RBCs of the fetus by antibodies produced by mother • If the fetal red cells contains the corresponding antigen, then binding of antibody will occur to red cells • Coated RBCs are removed by mononuclear phagocytic system

Neonatal liver is immature and unable to handle bilirubin Unconjugated bilirubin Conjugated bilirubin Coated red blood cell are hemolysed in spleen

Pathogenesis; before birth

Pathogenesis; after delivery

Clinical features • Less severe form • Mild anemia • Severe forms • Icterus gravis neonatorum (Kernicterus) • Intrauterine death • Hydrops fetalis • Oedematous, ascites, bulky swollen & friable placenta • Pathophysiology • Extravascular hemolysis with extramedullary erythropoiesis • Hepatic and cardiac failure

Hemolytic disease of newborn HDN BOFORE BIRTH • Anemia (destruction of red cells) • Heart failure • Fetal death AFTER BIRTH • Anemia (destruction of red cells) • Heart failure • Build up of bilirubin • Kernicterus • Severe growth retardation

P N Blood film of a fetus affected by HDN showing polychromasia and increased number of normaoblasts

Rh HEMOLYTIC DISEASE OF NEWBORN • Antibodies against • Anti-D and less commonly anti-c, anti-E • Mother is the case of anti-D is Rh -ve (negative) • Firstborn infant is usually unaffected • Sensitization of mother occurs • During gestation • At the time of birth • All subsequent offspring inheriting D-antigen will be affected in case of anti-D HDN

Pathogenesis Fetomaternal Hemorrhage Maternal Antibodies formed against Paternally derived antigens During subsequent pregnancy, placental passage of maternal IgG antibodies Maternal antibody attaches to fetal red blood cells Fetal red blood cell hemolysis

Diagnosis and Management • Cooperation between • Pregnant patient • Obstetrician • Her spouse • Clinical laboratory

Recommended obstetric practice • History; including H/O previous pregnancies or and disease needing blood transfusion • ABO and Rh testing • Antibody detection; • To detect clinically significant IgG Ab which reacts at 370C • Repeat testing required at 24 or 28 weeks if first test negative • Antibody specificity • Parental phenotype • Amniocyte testing

Antibody titres • Difference of 2 dilutions or score more than 10 is significant • Amniocentesis and cordocentesis • Concentration of bilirubin • Spectrophotometric scan • Indirect method • Increasing or un-change OD as pregnancy advance shows worsening of the fetal hemolytic disease • Fetal blood sample can be taken and tested for • Hb, HCT, blood type and DCT (Direct Coombs test) Percutaneous Umbilical blood sampling

Prevention of Rh- HDN • Prevention of active immunization • Administration of corresponding RBC antibody (e.g anti-D) • Use of high-titered Rh-Ig (Rhogam) • Calculation of the dose • Kleihauer test for fetal Hb

Mechanism of action • Administered antibodies will bind the fetal Rh- positive cells • Spleen captured these cells by Fc-receptors • Spleen remove anti-D coated red cells prior to contact with antigen presenting cells “antigen deviation”

The Kleihauer test • The identification of cells containing haemoglobin F depends on the fact that they resist acid elution to a greater extent than do normal cells, they appear as isolated, darkly stained cells among a background of palely staining ghost cells. • The occasional cells that stain to an intermediate degree are less easy to evaluate; some may be reticulocytes because these also resist acid elution to some extent.

ABO HEMOLYTIC DISEASE OF NEW BORN • For practical purpose, only group O individuals make high titres IgG • Anti-A and anti-B are predominantly IgM • ABO antibodies are present in the sera of all individuals whose RBCs lack the corresponding antigens

ABO HDN contd. • Signs and symptoms • Two mechanism protects the fetus against anti-A and anti-B • Relative weak A and B antigens o fetal red cells • Widespread distribution of A & B antigen in fetal tissue diverting antibodies away from fetal RBCs • Anemia is most of the time mild • ABO- HDN may be seen in the first pregnancy • Laboratory findings • Differ from Rh- HDN; microspherocytes are characteristic of ABO- HDN • Bilirubin peak is later; 1- 3 days after birth • Collection of cord blood and testing eluates form red cells will reveal anti-A or anti-B • Treatment • Group O donor blood for exchange transfusion which is rarely required

HDN- due to other antibodies • Anti-c • Usually less severe than that cause by Anti-D • Anti-K • May cause severe fetal anemia • Blood transfusion for the treatment should lack the appropriate antigen

Summary. • Hemolytic disease of newborn occurs when IgG antibodies produced by the mother against the corresponding antigen which is absent in her, crosses the placenta and destroy the red blood cells of the fetus. • Proper early management of Rh- HDN saves lives of a child and future pregnancies • ABO- HDN is usually mild • Other blood group antigens can also cause HDN

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An ongoing problem: Rhesus hemolytic disease of the newborn - A decade of experience in a single centre

Affiliations.

  • 1 Department of Pediatrics, Istanbul University Faculty of Medicine, Istanbul, Turkey. Electronic address: [email protected].
  • 2 Department of Pediatrics, Division of Neonatology, Istanbul University Faculty of Medicine, Istanbul, Turkey.
  • 3 Department of Obstetrics and Gynecology, Division of Perinatology, Istanbul University Faculty of Medicine, Istanbul, Turkey.
  • PMID: 38490905
  • DOI: 10.1016/j.pedneo.2024.02.004

Background: The objectives were to evaluate the descriptive features of newborns with a diagnosis of Rhesus (Rh) hemolytic disease, to determine the morbidity and mortality rates, to evaluate the treatment methods and the factors affecting treatment requirements and clinical outcomes during a ten-year period at a tertiary center.

Methods: Newborn infants who had a positive direct Coombs test and/or had a history of intrauterine transfusion (IUT) due to Rh hemolytic disease were included. The data regarding the prenatal, natal and postnatal periods were collected from hospital records.

Results: A total of 260 neonates were included of which 51.2% were female. The mean ± standard deviation gestational age was 36.9 ± 2.7 weeks. The rate of preterm birth was 41.2%. Of 257 mothers whose obstetric medical history could be accessed, 87.2% were multigravida, whereas 76.3% were multiparous. Among mothers who had a reliable history of anti-D immunoglobulin prophylaxis (n=191), 51.3% had not received anti-D immunoglobulin prophylaxis in their previous pregnancies. The antenatal transfusion rate was 31.7% and the frequency of hydrops fetalis was 8.8%. While combined exchange transfusion (ET) and phototherapy (PT) was performed in 15.4% of the babies, the majority either needed phototherapy only (51.1%) or no treatment (33.5%). The mortality rate was 3.8 % (n = 10), and nine babies out of these 10 were those with severe hydrops fetalis.

Conclusion: This study showed that Rh hemolytic disease is still a major problem in developing countries. Multiple comorbidities may occur in addition to life threatening complications, including hydrops fetalis, anemia and severe hyperbilirubinemia. High rates of multiparity and low rates of anti-D immunoglobulin prophylaxis are potential barriers for the eradication of the disease. It should be remembered that Rh hemolytic disease is a preventable disease in the presence of appropriate antenatal follow-up and care facilities.

Keywords: Exchange transfusion; Intrauterine transfusion; Neonatal mortality; Phototherapy; Rhesus hemolytic disease.

Copyright © 2024 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.

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KATHERINE A. M. SNYDER, MD, AND ADAM D. VOELCKERS, MD

Am Fam Physician. 2024;109(3):212-216

This is part I of a two-part article on newborn skin. “ Newborn Skin: Part II. Birthmarks ,” appears in this issue of AFP .

Author disclosure: No relevant financial relationships.

Rashes in the newborn period are common and most are benign. Infections should be suspected in newborns with pustules or vesicles, especially in those who are not well-appearing or have risk factors for congenital infection. Congenital cytomegalovirus infection can cause sensorineural hearing loss and neurodevelopmental delay. Skin manifestations of cytomegalovirus may include petechiae due to thrombocytopenia. The most common skin manifestations of early congenital syphilis are small, copper-red, maculopapular lesions located primarily on the hands and feet that peel and crust over three weeks. Erythema toxicum neonatorum and neonatal pustular melanosis are transient pustular rashes with characteristic appearance and distribution. Neonatal acne is self-limited, whereas infantile acne may benefit from treatment. Milia can be differentiated from neonatal acne by their presence at birth. Cutis marmorata and harlequin color change are transient vascular phenomena resulting from inappropriate or exaggerated dilation of capillaries and venules in response to stimuli.

Skin findings in newborns can present a diagnostic challenge in distinguishing common, benign rashes from those associated with infection, malignancy, or systemic syndromes. When clinicians evaluate the newborn rash, the most important skill is to recognize when further evaluation is necessary because early diagnosis and treatment can have a significant impact on morbidity and mortality. Part I of this article reviews the presentation, prognosis, and treatment of the most common rashes and skin changes that present during the first four weeks of life. Part II of this article, which appears in this issue of American Family Physician , discusses the identification and management of birthmarks that appear in newborns. 1

Transient Rashes

Infectious causes of transient rashes, such as Candida infections or congenital cytomegalovirus, should be a primary consideration. A rash consistent with one of the classic benign presentations in the well-appearing newborn can be monitored for resolution. Risk factors for congenital infections should be considered before the diagnosis of a benign rash.

INFECTIOUS CAUSES

Congenital infections may present with vesicles or pustules and can generally be distinguished based on presentation ( Table 1 ) . 2 – 8 Diffuse papular or vesicular rashes due to bacterial infections will often be associated with clinical signs of sepsis. 2

Congenital Candida infections are rare and cause a desquamating, maculopapular, papulopustular, or erythematous diffuse rash that presents at birth or in the first week of life. Prompt treatment with systemic antifungals can prevent disseminated candidemia. 3

Herpes simplex virus (HSV) is a potentially devastating infection for the newborn and can be effectively treated with prompt recognition. Most newborns who are infected with HSV in the peripartum period have a birthing parent with no known history of HSV. Neonatal HSV can present with disseminated disease, central nervous system disease, or cutaneous infection of the skin, eyes, and mouth. HSV skin vesicles typically present at approximately 12 days of life and are associated with lethargy and fever in an ill-appearing child. 4 An evaluation for HSV in these cases should not be delayed.

Congenital cytomegalovirus infections can cause sensorineural hearing loss and neurodevelopmental delay. Presentation is variable; 90% of newborns affected by cytomegalovirus are asymptomatic. Skin manifestations may include petechiae due to thrombocytopenia. Newborns with symptoms are more likely to suffer permanent sequelae. 5 Diagnostic testing in newborns is performed with a saliva sample in the first two to three weeks of life. 6

Previously considered a rare disease, congenital syphilis has steadily increased in incidence and geographic distribution since 2013. 7 The most common skin manifestations of early congenital syphilis are small, copper-red, maculopapular lesions located primarily on the hands and feet that peel and crust over three weeks. 7 Diagnosis is based on a quantitative comparison of nontreponemal serologic titers in the birthing parent and neonate. 7 Penicillin is the treatment of choice. 8

ERYTHEMA TOXICUM NEONATORUM

Erythema toxicum is a benign rash that may cause a caregiver to have concern that it is a more serious condition ( Figure 1 ) . It is the most common pustular newborn rash and affects approximately one-half of newborns; it is more common in those who are full-term. 9 , 10 Lesions may be present at birth but more often appear in the first few days of life. 11 Lesions may present as papules, followed by the development of small pustules with a large red base that are not in groups and are located on the face, trunk, and extremities. Lesions are not found on the palms or soles. 2 Diagnosis is made clinically in well-appearing newborns, although a peripheral smear that contains eosinophils may help confirm the diagnosis. 2 No treatment is required, and the rash should resolve with no scarring in one to two weeks.

presentation on hemolytic disease of newborn

TRANSIENT NEONATAL PUSTULAR MELANOSIS

Transient neonatal pustular melanosis is more common in newborns with skin containing higher levels of melanin. It is a pustular rash that is present at birth. The pustules rupture and leave a characteristic pigmented macule ( Figure 2 ) . The rash is diagnosed clinically by lesions that may appear on the forehead, behind the ears, and on the neck, trunk, and extremities, including the palms and soles. 12 Hyperpigmentation may persist for weeks to months before fading. 2

presentation on hemolytic disease of newborn

NEONATAL AND INFANTILE ACNE

Neonatal acne presents with closed comedones on the forehead, nose, and cheeks that may appear pustular ( Figure 3 ) . It is not present at birth, but develops in the first four weeks of life. 13 Neonatal acne is thought to be a result of sebaceous gland stimulation from newborn exposure to adult levels of endogenous hormones. Infantile acne generally presents after six weeks, lasts for six to 12 months, and may be more inflammatory in nature. 14 Infantile acne does not require further evaluation in the absence of other signs of hormonal excess. Infantile acne rarely requires treatment; however, topical antimicrobials or retinoids may be used in consultation with a specialist for severe or refractory cases and concerns for scarring. 15

presentation on hemolytic disease of newborn

Milia consists of tiny, pearly white to yellow cysts located on the forehead, nose, and cheeks, although they can appear in other locations ( Figure 4 ) . They are secondary to retained keratin and present at birth in up to one-half of newborns. Treatment is not needed. 2 , 16

presentation on hemolytic disease of newborn

Transient Vascular Phenomena

Transient vascular phenomena are visual representations of inappropriate or exaggerated dilation of normally formed blood vessels in response to an environmental stimulus.

CUTIS MARMORATA

Cutis marmorata is a physiologic phenomenon that presents as a reticular, bluish rash with symmetrical distribution on the trunk and extremities ( Figure 5 ) . It is caused by the dilation of capillaries and venules in response to cold temperatures. It can occur for weeks after birth and will disappear in warm temperatures. 17

presentation on hemolytic disease of newborn

Cutis marmorata telangiectatica congenita is a serious vascular anomaly that mimics physiologic cutis marmorata. Although the rash may appear similar in both conditions, cutis marmorata telangiectatica congenita should be considered if there is skin atrophy, ulceration, or unilateral distribution. 17 Referral is indicated when the diagnosis is uncertain.

HARLEQUIN COLOR CHANGE

Harlequin color change affects up to 10% of newborns, especially those who are preterm or small for gestational age. 18 It presents as transient, clearly demarcated areas in which one-half of the body is pale, and the other is plethoric. It generally appears between the third and fifth day of life, can persist from 30 seconds to 20 minutes, and may disappear when the newborn cries. 19 It is a benign, cutaneous condition that is thought to be secondary to vasomotor instability from an immature hypothalamus. It requires no specific evaluation or treatment. 19 , 20

This article updates a previous article on this topic by O’Connor, et al. 2

Data Sources: A PubMed search was completed using the terms congenital infections, erythema toxicum neonatorum, transient neonatal pustular melanosis, neonatal and infantile acne, milia, cutis marmorata, harlequin color change, and key terms for diagnosis and management. The search included meta-analyses, randomized controlled trials, clinical trials, and reviews. The Cochrane database, UpToDate, Essential Evidence Plus, and the TRIP database were also searched. Search dates: November 2022 to February 2023, May to June 2023, and December 2023.

The authors thank the patients’ families who allowed their newborns to be photographed for this article.

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Kabani N, Kimberlin DW. Neonatal herpes simplex virus infection. Neoreviews. 2018;19(2):e89-e96.

Kabani N, Ross SA. Congenital cytomegalovirus infection. J Infect Dis. 2020;221(suppl1):S9-S14.

Fowler KB, Boppana SB. Congenital cytomegalovirus infection. Semin Perinatol. 2018;42(3):149-154.

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Centers for Disease Control and Prevention. Congenital syphilis. Accessed July 1 1, 2023. https://cdc.gov/std/treatment-guidelines/congenital-syphilis.htm

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Greydanus DE, Azmeh R, Cabral MD, et al. Acne in the first three decades of life: an update of a disorder with profound implications for all decades of life. Dis Mon. 2021;67(4):101103.

Serna-Tamayo C, Janniger CK, Micali G, et al. Neonatal and infantile acne vulgaris: an update. Cutis. 2014;94(1):13-16.

Eichenfield LF, Krakowski AC, Piggott C, et al.; American Acne and Rosacea Society. Evidence-based recommendations for the diagnosis and treatment of pediatric acne. Pediatrics. 2013;131(suppl 3):S163-S186.

Gallardo Avila PP, Mendez MD. Milia. StatPearls . Updated January 31, 2023. Accessed November 15, 2022. https://www.ncbi.nlm.nih.gov/books/NBK560481/

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Hemolytic disease of the fetus and newborn: systematic literature review of the antenatal landscape

Derek p. de winter.

1 Department of Pediatrics, Division of Neonatology, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, The Netherlands

2 Department of Immunohematology Diagnostic Services, Sanquin Diagnostic Services, Amsterdam, The Netherlands

Allysen Kaminski

3 OPEN Health, Bethesda, MD USA

4 Present address: The George Washington University, Washington, DC, USA

May Lee Tjoa

5 Janssen Pharmaceuticals, Raritan, NJ USA

Dick Oepkes

6 Division of Fetal Medicine, Department of Obstetrics, Leiden University Medical Center, K-06-35, PO Box 9600, Leiden, 2300 RC The Netherlands

Associated Data

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Prevention of pregnancy-related alloimmunization and the management of hemolytic disease of the fetus and newborn (HDFN) has significantly improved over the past decades. Considering improvements in HDFN care, the objectives of this systematic literature review were to assess the prenatal treatment landscape and outcomes of Rh(D)- and K-mediated HDFN in mothers and fetuses, to identify the burden of disease, to identify evidence gaps in the literature, and to provide recommendations for future research.

We performed a systematic search on MEDLINE, EMBASE and clinicaltrials.gov. Observational studies, trials, modelling studies, systematic reviews of cohort studies, and case reports and series of women and/or their fetus with HDFN caused by Rhesus (Rh)D or Kell alloimmunization. Extracted data included prevalence; treatment patterns; clinical outcomes; treatment efficacy; and mortality.

We identified 2,541 articles. After excluding 2,482 articles and adding 1 article from screening systematic reviews, 60 articles were selected. Most abstracted data were from case reports and case series. Prevalence was 0.047% and 0.006% for Rh(D)- and K-mediated HDFN, respectively. Most commonly reported antenatal treatment was intrauterine transfusion (IUT; median frequency [interquartile range]: 13.0% [7.2–66.0]). Average gestational age at first IUT ranged between 25 and 27 weeks. weeks. This timing is early and carries risks, which were observed in outcomes associated with IUTs. The rate of hydrops fetalis among pregnancies with Rh(D)-mediated HDFN treated with IUT was 14.8% (range, 0–50%) and 39.2% in K-mediated HDFN. Overall mean ± SD fetal mortality rate that was found to be 19.8%±29.4% across 19 studies. Mean gestational age at birth ranged between 34 and 36 weeks.

These findings corroborate the rareness of HDFN and frequently needed intrauterine transfusion with inherent risks, and most births occur at a late preterm gestational age. We identified several evidence gaps providing opportunities for future studies.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12884-022-05329-z.

Despite advances in the prevention of pregnancy-related red blood cell immunization and management and treatment of pregnancies affected by hemolytic disease of the fetus and newborn (HDFN) over recent decades, the disease still poses a significant risk in affected pregnancies [ 1 , 2 ]. HDFN is caused by maternal alloimmunization through exposure to incompatible red blood cell antigens of the fetus or through incompatible blood transfusion [ 1 , 3 ]. The then-formed immunoglobulin G (IgG) antibodies are actively transported across the placenta and can cause fetal hemolysis and anemia. When untreated, progressive fetal anemia results in hydrops fetalis and ultimately fetal demise. If the fetus survives, persistent hemolysis causes neonatal anemia and hyperbilirubinemia, which—when untreated—ultimately leads to a severe cerebral condition (“kernicterus”).

No cure exists for HDFN. Hence, interventions have focused on its prevention and minimizing adverse effects of associated complications [ 1 , 4 ]. Through transfusing women within the reproductive ages with Kell-negative donor blood, if possible, and through the introduction of Rhesus (Rh) immunoglobulin prophylaxis, the occurrence of red blood cell alloimmunization and the prevalence of Rh(D)- and K-mediated HDFN has decreased [ 1 , 4 – 6 ]; however, the gap between anti-Rh(D) supply and demand is large in low-income countries and is below the optimal threshold in high-income countries [ 7 ]. Additionally, the disease still poses a significant risk for mortality and morbidity in developing countries, whereas it is considered treatable with good outcomes in developed countries. Serological monitoring, ultrasonography, and Doppler imaging decreased the need for risky and invasive diagnostic procedures [ 3 , 8 – 12 ]. Antenatal treatment, however, still relies predominantly on (often serial) intrauterine transfusion (IUT)—an invasive procedure that carries maternal and fetal risks [ 13 , 14 ].

Considering improvements in HDFN care, the objectives of this systematic literature review were to assess the prenatal treatment landscape and outcomes of Rh(D)- and K-mediated HDFN in mothers and fetuses to identify the burden of disease, to identify evidence gaps in the literature, and to provide recommendations for future research. Secondarily, we aim to determine the humanistic and economic burden of HDFN.

Search strategy

We conducted a systematic literature review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [ 15 ] and MOOSE Reporting Guidelines for Meta-Analysis of Observational Studies [ 16 ] to address prespecified research questions (Table S 2 ). To assess the treatment landscape, articles published between January 1, 2005, and March 10, 2021 were searched (Additional file 2 : Appendix S1) in the MEDLINE and EMBASE databases and ClinicalTrials.gov using ProQuest (Fig.  1 ). The search strategy included descriptions of the disease, possible interventions and clinical outcomes. No limitations were set on studies reporting on cases managed before January 1, 2005. Searches for clinical outcomes were performed for journal articles and conference abstracts indexed in EMBASE. Duplicates were removed automatically. We also manually searched reference lists of pertinent systematic literature reviews of cohort studies and our personal libraries for potentially relevant articles.

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Flowchart of the Article Selection Process. SLR, systematic literature review.  * From authors’ personal library.  † From eligible SLRs of cohort studies 

Study selection

Two independent reviewers (D.P.D.W. and A.K.) (Table S 3 ) [ 17 ] reviewed the titles/abstracts in Rayyan ( https://rayyan.ai/ ) and then full texts in Microsoft Excel. Citations were independently evaluated to determine whether or not studies fulfilled inclusion and exclusion criteria. The project director (D.O.) and the project team adjudicated decisions. Randomized or nonrandomized trials; retrospective or prospective observational studies, including cohort, case-control, or cross-sectional studies; modelling studies; systematic reviews of cohort studies (to identify primary studies only); and case reports and case series of women and/or their fetuses, infants, or children experiencing or having experienced Rh(D)- and/or K-mediated HDFN were included. Studies or patient groups within studies where HDFN was caused by alloimmunization to antigens other than Rh(D) only and/or K only, such as c, e, E, Duffy (Fy), Kidd (Jk), MNS (S), or Gerbich, were excluded as the risk of prenatal disease is regarded as relatively low. Non–English-language articles were excluded, as were notes, editorials, and commentaries; nonsystematic reviews; reports of populations, interventions, outcomes, or study designs not of interest; publication types not of interest; indexed conference abstracts; and reports of animal or preclinical studies. The review was registered with PROSPERO before data were abstracted.

Two independent reviewers (D.P.D.W. and A.K.) abstracted data (i.e., study reference; study design; patient characteristics; HDFN treatment patterns; clinical outcomes [eg, fetal anemia, hydrops fetalis, and adverse events]; intravenous immunoglobulin [IVIG] efficacy; mortality; and prevalence) from studies that fulfilled inclusion and exclusion criteria. All abstracted data underwent quality control by the project director (D.O.), who screened 10% of included/excluded articles. The methodological quality (risk of bias) of the selected studies was assessed by 2 independent reviewers (D.P.D.W. and A.K.) using the JBI Critical Appraisal Checklist for Case Reports [ 18 ], the JBI Critical Appraisal Checklist for Case Series [ 19 ], the Newcastle-Ottawa Scale for retrospective and prospective cohort studies [ 20 ], the Checklist for Reporting Results of Internet E-Surveys (CHERRIES) for questionnaires [ 21 ], and lastly the NICE checklist for randomized controlled trials (RCTs).

Data from eligible studies were characterized as representative, which included data from studies that accurately reflected the characteristics of the larger group (e.g., larger case series, retrospective or prospective studies, RCTs), or were characterized as nonrepresentative, which included data from studies that reflected a small proportion of the characteristics of the larger group (e.g., case reports or small case series, or studies in a subset of the larger group, such as cases treated with IUT or only cases with hydrops fetalis). When possible, we aggregated information reported in a similar manner. For unique outcomes, we highlighted information from generalizable studies. Where appropriate, data were summarized as percentage (mean ± standard deviation [SD] or range) or median (interquartile range [IQR]) for patient groups or patient populations (e.g., Rh[D] or Kell, Rh[D] treated with IVIG or Rh[D] not treated with IVIG). Case reports and case series were excluded from prevalence analyses.

An assessment of the available findings was conducted to identify evidence gaps, and recommendations to fill unmet needs were formulated. Results pertinent to mothers and fetuses are reported herein. Neonatal outcomes will be reported in a separate article.

Humanistic and economic burden

A separate objective of this systematic review is to determine the humanistic and economic burden of HDFN. We conducted a systematic search using the same criteria as previously mentioned (Additional file 2 : Appendix S2). We selected studies reporting on quality of life, humanistic burden, economic burden, health care resource use, and direct and indirect costs. The review process was performed according to the PRISMA and MOOSE guidelines and similar as previously stated.

Data sources

In addition to the 2,538 articles identified through searches of MEDLINE and EMBASE, we identified 3 articles from our personal libraries (Fig.  1 ). The search on ClinicalTrials.gov did not yield any additional results to the search on MEDLINE and EMBASE. Overall, 2,363 of the 2,541 total articles were excluded on the basis of title and abstract review, and 119 were excluded on the basis of full-text review. Besides the 59 articles that remained, we identified 1 article from a review of applicable systematic reviews of cohort studies.

Study characteristics

Among the 60 eligible studies that were included in our analysis (Table S 1 ), [ 2 , 22 – 80 ] nearly half were retrospective cohort studies ( n  = 27 [45%]), followed by case reports and case series ( n  = 21 [35%]), prospective cohort studies ( n  = 7 [12%]), observational cohort studies ( n  = 3 [5%]), and RCTs and questionnaires ( n  = 1 [2%] each). More studies included patients with only Rh(D)-mediated HDFN ( n  = 26) than only K-mediated HDFN ( n  = 7); 27 studies included patients with Rh(D)- or K-mediated HDFN. Studies were conducted across 25 countries, most commonly The Netherlands ( n  = 12), followed by Turkey and the United States ( n  = 6 each). The 60 studies comprised 146 patient groups, including mothers, neonates, and fetuses. Of these patient groups, 46 were single patients extracted from case reports. Mean (range) group size, including case reports, was 36.5 (SD ± 68.7, range 1.0–334.0). The reported patient groups included cases managed between 1985 and 2019.

Methodological quality of the studies

Of the 14 included case reports, 7 received a perfect score (8/8) using the JBI Critical Appraisal Checklist for Case Reports. Median score among case reports was 7.5 [IQR: 6.0–8.0]. Two of the seven included case series received a perfect score among the applicable questions. Median score among case series was 5.0 [IQR: 5.0–8.5]. Twenty-one of 30 retrospective cohort studies were rated as good quality, 8 as fair, and 1 as poor. All 8 included prospective studies were rated as good quality. The randomized controlled trial by Santos et al. was rated as having low risk of bias in all 4 domains—selection bias, performance bias, attrition bias, and detection bias. Tables S 4 a-e contains a detailed overview of the methodological quality of the selected studies.

Diagnostic testing

Diagnostic testing data were available for 59 of the 60 studies. The most commonly reported diagnostic testing method was ultrasound ( n  = 20; median [IQR]: 100% [100–100%]), followed by percutaneous umbilical cord sampling ( n  = 17; 100% [100–100%]); anti-D and/or anti-K antibody titer ( n  = 16; 100% [100–100%]); fetal hemoglobin ( n  = 15; 100% [100–100%]); Coombs/antiglobulin testing ( n  = 15; 100%); cell-free DNA testing ( n  = 8; 100% [80–100%]); amniocentesis ( n  = 7; 100% [50–100%]); free antibody testing, antibody release testing, and gel card technique ( n  = 2; 100%); and magnetic resonance imaging ( n  = 2; 100% [56.5–100%]).

Prevalence of D- and K-mediated HDFN

The mean ± SD prevalence of Rh(D)-mediated HDFN (requiring any form of treatment) as reported in 5 studies [ 23 , 29 , 45 , 47 , 54 ] was 0.047%±0.037% among all pregnancies that were managed and delivered in the centers of the 5 selected studies (Fig.  2 ). The reported prevalence of K-mediated HDFN (requiring any form of treatment) among all pregnancies managed and delivered in the centers reporting in 2 retrospective studies was 0.006% [ 45 , 47 ]. No data were available for the prevalence of early-onset HDFN (requiring intervention before 24 weeks of pregnancy) in the selected studies. The gestational age at first IUT was between 25 and 27 weeksand the mean gestational age at birth between 34 and 36 weeks (Table  1 ) amongst all selected studies [ 2 , 22 – 80 ].

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Prevalence of Rh(D)-mediated HDFN (Requiring a Form of Treatment) Among All Referred Pregnancies [ 18 , 24 , 40 , 42 , 49 ]. D, Rh(D); HDFN, hemolytic disease of the fetus and newborn; Rh, Rhesus; SD, standard deviation

Patient Characteristics Among 155 HDFN Groups, Including Mothers, Neonates, and Fetuses, From 60 Included Studis

Means, medians, and exact gestational age as reported in each study were used to calculate mean (range)

HDFN  Hemolytic disease of the fetus and newborn, IUT  Intrauterine transfusion

a Of the 155 patient groups, 46 (29.7%) groups were single patients from case reports

b Does not include 1 study [ 2 ] in which the reported percentage of the patient group fell within gestational age ranges (i.e., < 259 days and 259–294 days)

Frequencies of antenatal management strategies

Antenatal treatment data were available for 24 studies (Table S 8 ) [ 24 , 25 , 29 , 30 , 33 – 37 , 42 , 43 , 48 , 51 , 52 , 56 , 58 – 63 , 65 , 71 , 80 ]. The most commonly reported antenatal treatment across these studies was IUT ( n  = 9 with representative data [ 25 , 29 , 33 , 36 , 37 , 56 , 59 , 60 , 65 ]; n  = 3 with nonrepresentative data [ 35 , 58 , 62 ].

Intrauterine transfusions

Among the 9 studies with representative data, IUTs were given at a median frequency of 13.0% (IQR: 7.2–66.0) among pregnancies with a positive anti-Rh(D) screening that were monitored prenatally with ultrasonography. Three of these studies monitored pregnancies with a positive anti-Rh(D) screening and a risk-stratification using the antibody titers and/or antibody-dependent cellular cytotoxicity values above cut-off value, and might therefore overestimate the frequency of IUTs [ 56 , 59 , 60 ]. In these three studies, the frequency of IUTs was 64.7% (range 59.2–66) [ 56 , 59 , 60 ]. Number of IUTs was reported by only two of these studies with a median of 2 (range 0–4) [ 56 , 59 ]. IUTs were required in 76.8% of pregnancies, as reported in 63/82 collective cases [ 36 , 56 , 60 ].

The frequency of IUTs in pregnancies with a positive anti-Rh(D) screening monitored without serological cut-off values was 11.2% (range, 4.5–58.6) in the collective cases (42/376) reported by 5 studies [ 25 , 29 , 33 , 37 , 65 ]. The number of IUTs required was only reported by 1 study with a mean of 2.4 (SD not reported) [ 33 ]. Data on the need for IUTs in pregnancies with K-alloimmunization without serological cut-offs were reported by 1 study and was 12.5% in 1/8 reported cases [ 25 ].

Alternative management strategies

Use of IVIG alone was reported in 1 study with representative data [ 48 ]. In this case series of 3 severely affected pregnancies, 2 (Rh[D], n  = 1; Kell, n = 1) resulted in live births without IUT; the third (Rh[D] + anti-C) was treated with IUT but resulted in a post-procedure intrauterine death.

Use of IUT + IVIG was reported in 4 studies ( n  = 1 with representative data[ 61 ]; n  = 3 with nonrepresentative data [ 35 , 42 , 62 ]). In the one study with representative data, 3.2% of the Rh(D) alloimmunization cases and 4.3% of the Kell alloimmunization cases were treated with IUT + IVIG [ 61 ].

Use of other treatments (therapeutic plasma exchange [TPE]; maternal plasma exchange ± high-dose IVIG; TPE + IVIG + IUT; TPE + immunoadsorption + IVIG + IUT; plasmapheresis + IUT; and plasmapheresis + IVIG + IUT) were reported in 10 studies with a total of 38 cases [ 24 , 30 , 34 , 36 , 43 , 51 , 52 , 63 , 71 , 80 ]. Plasmapheresis + IVIG + IUT was the most commonly reported treatment regimen across these 10 studies.Two of these studies did not report gestational age at start of the treatment, at first IUT (if applicable) and at birth [ 36 , 80 ]. The remaining 8 studies, including 20 cases total, reported the mean gestational age at treatment initiation (13.0 ± 5.7 weeks). 17/20 cases required an IUT for fetal anemia. The mean gestational age at first IUT was 24.2 ± 3.1 weeks, with a median of 4 IUTs (range 1–8) administered. Gestational age at birth was 34.4 ± 3.1 weeks [ 30 , 34 , 43 , 51 , 52 , 63 , 71 ]. In the series of 20 cases, one patient received plasmapheresis, which was started a week after the first IUT at a gestational age of 27 weeks [ 43 ]. In all other cases, the alternative treatment was started prior to the occurrence of fetal anemia. The indications to start the alternative treatment option in the 20 cases were previous intrauterine fetal death ( n  = 11), neonatal hydrops fetalis and/or death ( n  = 4), marked elevation in antibody titer ( n  = 4), and suspected fetal anemia after initial IUT ( n  = 1).

Clinical outcomes of mothers and fetuses

The most commonly reported maternal/fetal clinical outcome across studies was hydrops fetalis ( n  = 19 with representative data [ 23 , 28 , 31 , 32 , 41 , 42 , 47 , 49 , 51 , 53 , 59 , 64 , 66 , 67 , 69 , 75 , 76 , 79 , 80 ] (Table S 8 ); n  = 10 with nonrepresentative data [ 24 , 39 , 40 , 44 , 46 , 52 , 55 , 68 , 70 , 74 ]). The rate of hydrops fetalis among pregnancies with Rh(D)-mediated HDFN treated with IUT was 14.9% (range, 0–50%) in 72/483 reported cases [ 31 , 32 , 49 , 53 , 66 , 76 , 79 ]. The rate of hydrops fetalis among pregnancies with K-mediated HDFN treated with IUT was 39.2% in 49/125 reported cases [ 69 , 75 , 76 , 79 ]. Five studies reported on the rate of hydrops fetalis in all pregnancies monitored for Rh(D)- and or K-alloimmunization, with or without the need for antenatal treatment. The rate of hydrops fetalis in these studies was 7.3% in 17/232 collective cases.

Severe fetal anemia was reported in 1 study with representative data [ 28 ] (Table S 8 ) and 11 studies with nonrepresentative data [ 30 , 39 , 42 – 44 , 46 , 52 , 63 , 68 , 74 , 80 ]. In the 1 cohort study with representative data, 100% of 22 successful IUTs performed in Rh(D)- or K-mediated HDFN cases within 20 weeks of gestation were considered severely anemic (≥ 5 SDs from the fetal hemoglobin reference value of 15 g/dL; 1 SD = 1 g/dL difference from reference value) [ 28 ]. Adverse events or procedure-related complications were commonly reported after IUTs or other treatments for Rh(D)- and/or K-mediated HDFN ( n  = 11 studies with representative data [ 28 , 33 , 47 , 51 , 53 , 63 , 64 , 66 , 69 , 72 , 80 ] (Table S 8 ); n  = 2 studies with nonrepresentative data [ 68 , 73 ]). Bradycardia was the most frequently reported post-IUT complication per procedure, and adverse serological outcomes were the most frequently reported post-IUT complication per fetus, although adverse serological outcomes were reported in only 1 study [ 33 ] (Fig. S 2 ).

IVIG efficacy

Assessment of IVIG efficacy in women and fetuses affected by HDFN was based on treatment response in 6 studies [ 24 , 30 , 34 , 48 , 62 , 80 ] and associated mortality in 3 studies [ 35 , 42 , 63 ] (Table S 8 ). Collectively, findings indicate that IVIG delayed or prevented IUT. IVIG-associated fetal mortality ranged from 0 to 50% across the 3 studies reporting this outcome [ 35 , 42 , 63 ].

Fetal mortality

The overall mean ± SD fetal mortality rate was 19.8% ± 29.4% across 19 studies, including representative case reports [ 28 , 31 , 35 , 42 , 43 , 45 , 47 , 49 , 53 , 63 , 64 , 66 , 68 , 69 , 73 , 75 , 76 , 78 , 80 ] (Table S 8 ). Head-to-head comparison of mortality rates between the different treatment strategies is limited by variation in potential patient characteristics between the groups. Employed treatment strategies for HDFN take into account previous obstetrical history, for example 75% of cases in the “IUT + other” group had a history of fetal or neonatal death due to HDFN. Together, these will influence the outcomes of HDFN in the current pregnancy and limit our capability of mortality rate comparison.

In addition to the 1457 articles identified in the systematic search, one additional article was identified from personal libraries (Fig. S 2 ). Based on the title/abstract screening 1435 articles were excluded. Full-text screening was performed in the remaining 23 records of which 22 were excluded. Healthcare utilization was reported by only one study with a median of duration of phototherapy of 4-4.5 days and a median length of stay of 6.5–7.5 days [ 65 ].

Main findings

We found that the prenatal burden and need for treatment remains relatively high – we estimated that 13% of pregnancies monitored for Rh(D) or K-alloimmunization required one or more IUTs – despite advances in the identification and care for pregnancies at risk of HDFN. Strikingly, the rate of hydrops fetalis in pregnancies requiring an IUT was found to be 14.9% for Rh(D)-mediated HDFN and 39.2% in K-mediated HDFN. As the occurrence of hydrops fetalis was previously found to be associated with impaired neurodevelopmental outcomes [ 81 ] still much is to gain in the timely identification of pregnancies at-risk and the timely detection and treatment of fetal anemia to prevent hydrops fetalis. The average gestational age at first IUT was 27 weeks, which was possibly delayed by using IVIG and/or plasmapheresis although evidence on this in the included studies is limited. Although IUT is a regarded as a relatively safe procedure in experienced hands, its invasive nature still poses serious risks to the mother and fetus. Fetal loss rate increases when procedures need to be done early in gestation (i.e., < 22 weeks) [ 13 ]. It is also noteworthy that the average gestational age at birth in the present analyses was approximately 35 weeks for Rh(D)- and/or K-mediated HDFN, which is considered late preterm and might also represent that early delivery is frequently employed in the management of pregnancies at risk of fetal anemia although we were unable to extract data on this from the included studies. But, late preterm birth has the potential for serious consequences, such as increased risk for short- or long-term respiratory issues [ 82 – 84 ], readmission [ 82 ], death [ 82 , 84 , 85 ], and neurocognitive impairment in late adulthood [ 86 , 87 ].

Strengths and limitations

A strength of this systematic review and corresponding analyses is the minimal limitation on study design criteria. Overall, 35% of the studies included in our analyses were case reports or case series, validating the rarity of HDFN. By including case reports and case series, we were able to identify and aggregate data on treatment types (e.g., plasmapheresis and plasma exchange) that were not typically reported in larger cohort studies. But, inclusion of case reports and case series might also be regarded as a limitation as it may skew and overestimate the results as, given the rarity of HDFN, the most severe cases are generally reported in literature. Our estimates might therefore not truly mirror the population level data.

Also, we were unable to quantify heterogeneity (using e.g. the I 2 -statistic) due to the descriptive nature of this systematic review and consequent lack of reported comparisons between interventions. However, a certain level of heterogeneity may be expected due to differences in available management options, treatment protocols, prevalence of Rh(D)- and K-negativity, geographical location and sociodemographic differences. These differences may be approached by the varying frequencies of, for instance, IUTs and rate of hydrops fetalis between included studies.

Our analyses are further limited by the strict prespecified inclusion of only Rh(D)- or K-mediated HDFN populations. By applying this criterion, 7 studies were excluded from analyses—despite high quality of evidence and outcomes of interest—because Rh(c) populations were mixed with Rh(D) or Kell populations, or the population was not well defined [ 88 – 94 ]. We were unable to stratify the data per alloimmunization type with the data provided in these articles. One of these studies represented the only prospective study with long-term outcomes [ 89 ], thereby also indicating the lack of data on long-term outcomes and the need for further research on the topic.

Interpretation

Almost all studies included in these analyses were conducted in high-income countries, which have adequate resources for screening, prophylaxis and preventative measures for alloimmunization, and referral to specialized fetal therapy centers. Outcome data on HDFN-complicated pregnancies from less privileged or less organized societies are lacking and, if analyzed, likely are less favorable. This well-known bias in outcome reporting indicates an important evidence gap and signifies the need for international collaboration to gain a better understanding of the global burden of HDFN and to pave the way for potential wide-spread improvements. To add to that, we also found that the evidence for frequency of use and effectiveness of alternative treatment options such as IVIG, plasmapheresis, and plasma exchange on disease severity and the prevention of fetal anemia is limited in the included studies. Also, as previously mentioned it is likely that the most severe cases are reported in literature due to the rarity of the disease. Taken together, future research should aim to gain more exact insight into the employed treatment options and its efficacy and clinical outcomes of mothers, fetuses, and neonates affected by HDFN through an international retrospective and/or prospective registry through the collection of data on diagnostics, antenatal and postnatal treatments and short- and long-term clinical outcomes of mothers, fetuses, and neonates. Such an international effort will pave the way for long sought after answers.

A separate objective of this systematic review, as previously mentioned, was to ascertain the economic and humanistic burden of HDFN. However, through the systematic approach only one study reporting on healthcare utilization was included. This dearth of information indicates another major gap in knowledge, particularly as it relates to the impact of HDFN on a pregnant individual’s quality of life and the potential downstream consequences of high-risk pregnancy on family planning decisions, as well as on the healthcare system.

To conclude, we found that the clinical burden of Rh(D)- and K-mediated HDFN remains relatively high, with 13% of pregnancies monitored for Rh(D)- or K-alloimmunization requiring an IUT and most births occurring at a late preterm gestational age. We identified several important evidence gaps that provide opportunities for future studies to further improve the clinical care of HDFN.

Acknowledgements

Dipen Patel and Chandrasekhar Boya of OPEN Health contributed to this work. Medical writing and editorial support were provided by Maribeth Bogush, PhD, of Peloton Advantage, LLC, an OPEN Health company, in accordance with Good Publication Practice (GPP3) guidelines, and funded by Janssen Pharmaceuticals.

Systematic review registration

PROSPERO 2021 CRD42021234940 Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021234940 .

Abbreviations

Authors’ contributions.

DPDW, AK, ML, and DO contributed to the study design. AK conducted the search. DPDW and AK independently reviewed eligible studies, extracted data, evaluated the methodological quality, and performed analyses. The manuscript was written by DPDW. DPDW, AK, ML, and DO were involved in revising the manuscript. All authors approved the final version for publication.

Funding for this systematic literature review was provided by Janssen Pharmaceuticals (Raritan, NJ, USA). The authors had access to relevant aggregated study data and other information (e.g., study protocol, analytic plan and report, and validated data tables) required to understand and report research findings. The authors take responsibility for the presentation and publication of the research findings, have been fully involved at all stages of publication and presentation development, and are willing to take public responsibility for all aspects of the work. All individuals included as authors and contributors who made substantial intellectual contributions to the research, data analysis, and publication or presentation development are listed appropriately. The role of the sponsor in the design, execution, analysis, reporting, and funding is fully disclosed. The authors’ personal interests, financial or non-financial, relating to this research and its publication have been disclosed.

Availability of data and materials

Declarations.

Not applicable.

Derek P. de Winter: PhD program funded by Momenta Pharmaceuticals, Inc., which was acquired by Johnson & Johnson; coordinating investigator for a phase 2 trial ( {"type":"clinical-trial","attrs":{"text":"NCT03842189","term_id":"NCT03842189"}} NCT03842189 ) of a new drug for the treatment of HDFN, which is sponsored by Janssen Pharmaceuticals.

Allysen Kaminski: Former employee of OPEN Health, which was retained by Janssen Pharmaceuticals to conduct the study.

May Lee Tjoa: Employee and stockholder of Janssen Pharmaceuticals.

Dick Oepkes: Former principal investigator for a phase 2 trial ( {"type":"clinical-trial","attrs":{"text":"NCT03842189","term_id":"NCT03842189"}} NCT03842189 ) of a new drug for the treatment of HDFN, which is sponsored by Janssen Pharmaceuticals.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

IMAGES

  1. Hemolytic Disease Of The Newborn Abo

    presentation on hemolytic disease of newborn

  2. Hemolytic disease of the newborn (HDN)

    presentation on hemolytic disease of newborn

  3. Hemolytic disease of the newborn

    presentation on hemolytic disease of newborn

  4. PPT

    presentation on hemolytic disease of newborn

  5. PPT

    presentation on hemolytic disease of newborn

  6. PPT

    presentation on hemolytic disease of newborn

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COMMENTS

  1. Hemolytic Disease of the Newborn

    Hemolytic disease of the fetus and newborn (HDFN) is an immune-mediated red blood cell (RBC) disorder in which maternal antibodies attack fetal or newborn RBCs.[1][2] HDFN can cause significant morbidity and mortality, especially in limited healthcare resource settings. Effects of HDFN range from mild anemia to hydrops fetalis in the fetus and hyperbilirubinemia and kernicterus in the newborn ...

  2. Hemolytic disease of the newborn

    The fetus compensates by producing large numbers of immature erythrocytes, a condition known as erythroblastosis fetalis, hemolytic disease of the newborn, or hydrops fetalis. Hydrops refers to the edema and fetalis refers to the lethal state of the infant. In Rh incompatibility, the hemolysis usually begins in utero.

  3. Hemolytic Disease of the Newborn: A Review of Current Trends and

    Hemolytic disease of the newborn (HDN), also known as Erythroblastosis fetalis, is a hemolytic condition that predominantly affects rhesus-positive fetuses and infants born to rhesus-negative mothers.The pathophysiology of HDN begins with maternal antibodies attacking fetal red blood cells following alloimmunization due to rhesus or ABO incompatibility between the maternal and fetal blood.

  4. Hemolytic Disease of the Newborn (HDN)

    Key points about hemolytic disease of the newborn. HDN occurs when your baby's red blood cells break down at a fast rate. HDN happens when an Rh negative mother has a baby with an Rh positive father. If the Rh negative mother has been sensitized to Rh positive blood, her immune system will make antibodies to attack her baby.

  5. Hemolytic Disease of the Newborn

    Hemolytic disease of the newborn is also called erythroblastosis fetalis. This condition occurs when there is an incompatibility between the blood types of the mother and baby. "Hemolytic" means breaking down of red blood cells. "Erythroblastosis" refers to making of immature red blood cells. "Fetalis" refers to fetus.

  6. PDF Hemolytic Disease of the Newborn

    The disease is more common and more severe in African-American infants. Unlike Rh, ABO disease can occur in first pregnancies, because anti-A and anti-B antibodies are found early in life from exposure to A- or B-like antigens present in many foods and bacteria. (2) Clinical presentation: generally less severe than with Rh disease.

  7. Hemolytic disease of the fetus and newborn: managing the mother, fetus

    Hemolytic disease of the fetus and newborn (HDFN) affects 3/100 000 to 80/100 000 patients per year. It is due to maternal blood group antibodies that cause fetal red cell destruction and in some cases, marrow suppression.

  8. Hemolytic Disease of the Newborn Clinical Presentation

    Spherocytosis. Rare. Frequent. A French midwife was the first to report hemolytic disease of the newborn (HDN) in a set of twins in 1609. In 1932, Diamond and colleagues described the relationship among fetal hydrops, jaundice, anemia, and erythroblasts in the circulation, a condition later called erythroblastosis fetalis.

  9. Hemolytic Disease of the Fetus and Newborn: Historical and Current

    Abstract. Hemolytic disease of the fetus and newborn (HDFN) is an immune-mediated disorder affecting neonates globally, with a range of clinical presentations from severe and life threatening to mild or even asymptomatic. Historically, HDFN has been responsible for a large proportion of perinatal mortality, and, despite advances in diagnosis ...

  10. Hemolytic Disease of the Newborn

    Treatment. Hemolytic disease of the newborn is a condition in which red blood cells are broken down or destroyed by the mother's antibodies. Hemolysis is the breakdown of red blood cells. This disorder may occur if a mother's blood is incompatible (not a match) with her fetus's blood. The diagnosis is based on blood tests of the mother and ...

  11. What to Know About Hemolytic Disease of the Newborn

    Hemolytic disease of the newborn (HDN), also called erythroblastosis fetalis , is a serious immune reaction that can affect newborn babies. This condition causes rapid and severe hemolysis —the breakdown of the baby's red blood cells (RBCs). It only occurs when there is a mismatch in blood type between the baby and the pregnant parent.

  12. Hemolytic disease of the newborn

    Hemolytic disease of the newborn (HDN) used to be a major cause of fetal loss and death among newborn babies. The first description of HDN is thought to be in 1609 by a French midwife who delivered twins—one baby was swollen and died soon after birth, the other baby developed jaundice and died several days later. For the next 300 years, many similar cases were described in which newborns ...

  13. Hemolytic Disease of the Fetus and Newborn

    Hemolytic disease of the fetus and newborn (HDFN) is an immune-mediated disorder affecting neonates globally, with a range of clinical presentations from severe and life threatening to mild or even asymptomatic. Historically, HDFN has been responsible for a large proportion of perinatal mortality, and, despite advances in diagnosis and management, this morbidity and mortality has not been ...

  14. Hemolytic Disease of the Newborn (HDN)

    Hemolytic disease of the newborn (HDN) is a blood problem in newborn babies. It occurs when your baby's red blood cells break down at a fast rate. It's also called erythroblastosis fetalis. Hemolytic means breaking down of red blood cells. Erythroblastosis means making immature red blood cells. ...

  15. Hemolytic disease of the newborn: Video & Anatomy

    Summary. Hemolytic disease of the newborn is a condition that occurs when fetal red blood cells are destroyed by the mother's antibodies that cross the placenta. This can lead to anemia (a shortage of red blood cells), jaundice ( yellowing of the skin and eyes), and other fetal problems. Hemolytic disease of the newborn can develop during ...

  16. Hemolytic disease of the newborn

    Hemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis fetalis, is an alloimmune condition that develops in a fetus at or around birth, when the IgG molecules (one of the five main types of antibodies) produced by the mother pass through the placenta.Among these antibodies are some which attack antigens on the red blood cells ...

  17. Hemolytic Disease of the Fetus and Newborn

    Such destruction is called hemolytic disease of the fetus (erythroblastosis fetalis) or of the newborn (erythroblastosis neonatorum). When red blood cells are destroyed, a yellow pigment called bilirubin is produced. When many red blood cells are destroyed, bilirubin can accumulate within the skin and other tissues.

  18. Hemolytic Disease of the Newborn (HDN)

    Hemolytic disease of the newborn (HDN) is a blood problem in newborn babies. It occurs when your baby's red blood cells break down at a fast rate. It's also called erythroblastosis fetalis. Hemolytic means breaking down of red blood cells. Erythroblastosis means making immature red blood cells. Fetalis means fetus.

  19. PPT

    Summary. • Hemolytic disease of newborn occurs when IgG antibodies produced by the mother against the corresponding antigen which is absent in her, crosses the placenta and destroy the red blood cells of the fetus. • Proper early management of Rh- HDN saves lives of a child and future pregnancies • ABO- HDN is usually mild • Other blood ...

  20. Haemolytic disease of the newborn

    Neonatal paediatricians continue to recognise a number of different presentations of neonatal haemolysis, many of which are considerably more subtle than the traditional "neonatal emergency" presentation of severe Rh D disease. ... Waldron P, de Alarcon P. ABO hemolytic disease of the newborn: a unique constellation of findings in siblings ...

  21. Hemolytic Disease of the Newborn: Symptoms and Treatment

    The cause of hemolytic disease of the newborn is an incompatibility of blood types between mother and baby. Everyone has a blood type : either A, B, AB, or O. Along with a type, you also have an ...

  22. Hemolytic disease of newborn

    Hemolytic disease of the newborn is also called erythroblastosis fetalis. This condition occurs when there is an incompatibility between the blood types of the mother and baby. "Hemolytic" means breaking down of red blood cells "Erythroblastosis" refers to making of immature red blood cells "Fetalis" refers to fetus. 3.

  23. An ongoing problem: Rhesus hemolytic disease of the newborn

    Background: The objectives were to evaluate the descriptive features of newborns with a diagnosis of Rhesus (Rh) hemolytic disease, to determine the morbidity and mortality rates, to evaluate the treatment methods and the factors affecting treatment requirements and clinical outcomes during a ten-year period at a tertiary center. Methods: Newborn infants who had a positive direct Coombs test ...

  24. Newborn Skin: Part I. Common Rashes and Skin Changes

    Part I of this article reviews the presentation, prognosis, and treatment of the most common rashes and skin changes that present during the first four weeks of life. Part II of this article ...

  25. Hemolytic disease of the fetus and newborn: systematic literature

    HDFN Hemolytic disease of the fetus and newborn, IUT Intrauterine transfusion. a Of the 155 patient groups, 46 (29.7%) groups were single patients from case reports. ... The authors take responsibility for the presentation and publication of the research findings, have been fully involved at all stages of publication and presentation ...