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Blood Types Explained | Blood Groups (ABO) and Rh Factor Nursing Transfusions Compatibility

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Antibody Dependent Cell-mediated Cytotoxicity 

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Antibody Dependent Cell-mediated Cytotoxicity 

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Hemolytic Disease of the Newborn EXPLAINED | Rh and ABO incompatibility

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Abstract

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. Previously, HDN was known to cause fetal death in 1% of all pregnancies, but with the advent of immunoprophylactic therapies, the condition can be currently fairly well managed with fewer complications if diagnosed early. Diagnosis calls for extensive history taking, physical examination, serological studies, and imaging modalities such as pelvic ultrasound scans. To prevent the disease, earlier intravenous immunoglobulin (IVIG) should be given to pregnant Rh- women who have not been sensitized. It is also vital to understand prospective complications such as severe hyperbilirubinemia and develop appropriate remedies. Because of its great incidence and nature, HDN has been thoroughly explored, and more studies are being conducted each year, revealing new insights about the condition. This review covers the disorder's etiology, diagnosis, and management, including the most current findings as of 2021, as well as trends and prospects, to help in future research and evidence-based medical practice.

Keywords: alloimmunization, fetomaternal hemorrhage, hemolysis, immunoprophylaxis

Introduction

Hemolytic disease of the newborn (HDN), also known as Erythroblastosis fetalis, is a hemolytic disorder that primarily affects Rhesus positive (Rh+) fetuses and newborns born to Rhesus negative (Rh-) mothers. A French midwife first described the disorder in 1609; however, it was not until the 1950s when the underlying cause was clarified.1 The pathogenesis of HDN begins with the attack of fetal red blood cells (RBCs) by maternal antibodies due to incompatibility of maternal and fetal blood based on the Rhesus and ABO antigen systems. Usually, when the first child inherits paternal D antigen, whose inheritance has been shown to follow an autosomal dominant pattern, and there occurs an event that leads to mixing of maternal and fetal blood, the mother starts producing anti-D antibodies through a process referred to as alloimmunization, as she lacks the D antigen.2 Immunologically, antibody secretion initially starts with IgM, which cannot cross the placental barrier, but is then followed by isotype switching, which produces IgG antibodies. IgG antibodies can cross the placental barrier, and they do so during the second and or subsequent pregnancies, attacking the fetal RBCs and causing hemolysis and associated complications such as Hydrops fetalis and jaundice.3 Although, the IgG antibodies can enter fetal circulation through fetomaternal hemorrhage (FMH) as well.

HDN has been estimated to affect 3 to 8 for every 100,000 patients yearly. Before developing anti-D prophylaxis, it was responsible for fetal loss in 1% of all pregnancies.4 The occurrence of HDN is directly correlated with the inheritance pattern in females that results in the absence of the Rhesus (D) antigen; however, the incidence of HDN is seen to vary with ethnicity.5 For instance, it has been found that whites have the highest prevalence, and Asians and American Indians have the lowest, as illustrated in Table 1 . Furthermore, among the Rh antigens in existence, the most immunogenic one is the D antigen. It is approximated that about 10% of pregnant white women are Rh incompatible.

Table 1

Ethnicity

Prevalence by Percentage (%)

Africans

4

African-Americans

8

Whites

15-16

Eurasians

2.4

Asians

<1

Basque (Spain/France)

30-35

Because of its high prevalence and nature, HDN has been extensively studied, and more studies continue to be done each year, uncovering more concepts regarding the disorder. This review summarizes the disorder in terms of etiology, diagnosis, and management, incorporating the most recent findings as of 2021 and trends and prospects to aid in further research evidence-based medical practice.

Background

The knowledge of blood group systems is essential in clinical practice, especially for hematological disorders. The primary blood group systems in humans include the ABO and Rhesus systems. In 1904, Karl Landsteiner discovered the human blood groups. He characterized them using the Landsteiner law, which states that the corresponding antibodies are present in the plasma for each blood group antigen not present on the RBCs.6 However, this is not the case with the rhesus antigen - antigen D. Typically, anti-D antibodies are absent in both Rh+ and Rh- individuals, but when Rh- individuals are exposed to the D antigen, they start secreting the corresponding antibodies. Therefore, the presence of both D antigens and anti-D antibodies in the same person can lead to RBC agglutination and hemolysis, which is the basis of Rh incompatibility.7 ABO incompatibility also follows the same pattern, and because of that, care has to be taken when doing blood transfusions and tissue transplants. In almost all of the cases of HDN, the underlying cause is usually Rh or ABO incompatibility between the mother and the fetus, when alloimmunization occurs, and the maternal antibodies start attacking fetal RBCs. Maternal antibodies reach the fetus when IgG antibodies, following antibody isotype switching, cross the placenta and enter the fetal circulation or through FMH.2,8

A 2017 review by Ree et al stated a global shift in HDN from 1% with a death rate of 50% before introducing Rh- immunoprophylaxis in 1968 to 0.5% after its introduction. The incidences decreased further to 0.1% with the introduction of antepartum Rh D immunoprophylaxis in 1970.9 Although there is sufficient RhD immunoprophylaxis, it is still approximated that between 1 to 3 of a thousand women who are Rh- still develop alloimmunization presently.10 While a larger proportion of HDN is caused by Rh incompatibility, the Rh- phenotype is less common, although it occurs more in some ethnic groups and races than others. For instance, epidemiological studies have revealed that 15% of whites are Rh- while only 1% of Asians are Rh- ( Table 1 ).

The mechanisms mentioned above can explain the pathophysiology of HDN. According to published research, ABO mismatch affects 15 to 25% of all pregnancies. However, only 1% of people will develop HDN.11 The response caused by ABO incompatibility is modest, most likely due to the expression of ABO blood type antigens and their presentation in several organs. With FMH, the maternal antibodies are secreted following mixing of the maternal and blood, and the most commonly involved antigen is the Rhesus/D antigen.12

Antigens in fetal blood (mainly Rh-positive inherited from the paternal side) are not found in maternal blood, which is Rh-. IgM-type antibodies are the first to form due to FMH, and because they cannot cross the placenta, the first pregnancy survives, leaving behind an already sensitized immune system.2 In the event of rhesus factor incompatibility, the fetus is at risk. At a later stage, in subsequent pregnancies, the mother's rhesus antibodies may attack the fetus's antigens, resulting in alloimmune hemolysis in the fetus. As a result, a significant amount of bilirubin is freed from the fetus's hemoglobin breakdown. The placenta transports them to the maternal circulation. They are worked on and removed by the mother once they enter her system.13,14 Nonetheless, problems may occur, increasing serum bilirubin levels, resulting in severe jaundice.

The least afflicted newborns may have mild anemia and just hyperbilirubinemia due to the ongoing effect of rhesus antibody hemolysis. Kernicterus occurs in roughly 25% of instances of fetal hyperbilirubinemia.15,16 Kernicterus is a condition caused by the buildup of bilirubin in the tissues of the central nervous system. It usually happens in the days following birth. Surviving kernicterus is typically not considered a true survival because survivors may still have developmental retardation, hypotonia, and hearing loss.17 As a result, the symptoms mentioned earlier should be sought during the physical examination of the newborn.

As with any diagnosis, the value of history and physical examination cannot be overstated. Prior history of HDN or hydrops fetalis, chorionic villus sampling, amniocentesis, antepartum hemorrhage, miscarriages, abortions, and maternal blood transfusions are all risk factors for FMH.18 Blood testing throughout the first trimester is very important. Pregnant women with blood type O should be closely examined during and after birth. It is advised that the blood type of their baby be identified as soon as possible after birth. A lady with Rh- blood type gets the Rosette test to rule out the potential of HDN.19 This test is capable of identifying alloimmunization caused by even little FMH. If there is clinical suspicion of FMH (>30 mL blood), another test known as Kleihauer-Betke acid elution is performed.19 The amount of fetal RBCs in the woman's blood is determined quantitatively by this test. A similar test can be used to evaluate whether another Rh IgG injection is necessary. Pelvic ultrasound of a pregnant woman with probable Rh incompatibility is also important in diagnosing HDN, and it is often restricted to the pelvis.13,20 Other causes of newborn jaundice and anemia must be ruled out before a definitive diagnosis of HDN can be made. As a result, traditional tube techniques and the Gel card approach can be used for diagnosis.21-23 The direct and indirect Coombs tests are two conventional techniques. The red blood cells are rinsed and centrifuged with antihuman antiglobulin in the indirect Coombs test. Agglutination occurs when immunoglobulins or complement factors are fixed to the surface of RBCs in vitro, indicating a positive test.24,25 The indirect Coombs test is used in prenatal screening to detect prenatally generated antibodies and testing before blood transfusion. It utilizes the patient's serum, which is incubated with foreign red blood cells of known antigenicity. The Coombs reagent is next added, and if agglutination occurs, the test is positive. The serum is incubated in the Red blood cell test, and the response occurs within a microtube. Non-agglutinated cells move through a gel matrix (Sephadex) to create a bottom, while bigger agglutinates remain on top.26 Singh et al discovered that the sensitivity and specificity of the two approaches were equivalent in comparative research comparing and contrasting conventional methods and gel card technology. On the other hand, the gel card technique was less time-consuming, more dependable, and the findings could be documented.27

The disease was responsible for significant morbidity and mortality for a long time until preventative and therapeutic techniques like phototherapy, intrauterine transfusion, exchange transfusion, and amniocentesis were established. Since then, the prevalence has decreased, with a perinatal survival rate of more than 90%.28 Phototherapy is the first-line treatment method and has been the treatment of choice for more than 30 years due to fewer side effects and its efficacy in treating preterm infants.29,30 The two forms of treatment offered are prophylactic and therapeutic phototherapy. Light emission within a wavelength range of 460-490 nm in the blue-green range, maximum exposure to the infant's body, and adequate irradiance all contribute to this modality of treatment.29,31,32 Hyperbilirubinemia caused by HDN is mostly treated with phototherapy and, on rare occasions, exchange transfusion. In a 2004 research by pediatricians (AAP), recommendations were made that HDN was possible for children with the following birth weights: 2000g, 2000 to 2499 g, and bilirubin level > 171 umol/L (10 mg/dL), 2500 g, and 222 umol/L (13 mg/dL) respectively.13,33

On the other hand, exchange transfusion is suggested for extremely anemic newborns and includes replacing the baby's RBCs with antigen-negative RBCs.34 In addition, in fragile patients, a blood transfusion using ABO-matched packed RBCs may be explored.35 Studies have also found that exchange transfusion is safe, with death rates ranging from 0.53% to 4.7% per child.29,36 The side effects of exchange transfusion are severe cardiorespiratory effects, catheter and blood product problems, metabolic derangements, necrotizing enterocolitis, and intestinal perforation. Over the previous two decades, the hazards of exchange transfusions have been reported to reach up to 74%. However, the negative impact is roughly 31%. For more than 21 years, there has been no growth in morbidity and mortality, according to Steiner et al.37 Intravenous immunoglobulin (IVIG) has been proposed as an alternative for exchange transfusion and phototherapy, with some advantages. However, prophylaxis with intravenous immunoglobulin remains debatable Several studies have found that IVIG has no advantage over exchange transfusion, a more intrusive procedure.9,30,38

Furthermore, clinical data show IVIG has failed to treat a large number of ABO-HDN patients.29,34 IVIG comprises antibodies, primarily IgG, IgM, IgA, and IgE, and electrolytes, sugar, cytokines, albumin, and solvents. The proposed mechanisms of IVIG are that it inhibits antibody neutralization in newborns with ABO-HDN, therefore lowering the risk.39,40 However, all of the above therapeutic techniques have side effects. Therefore, prevention is still essential in decreasing morbidity and mortality. Also, the concern about the severity of problems and the risk of mortality has required early screening and preventative strategies during prenatal care appointments. In addition, sensitizing procedures including abortion, amniocentesis, and chorionic villus sampling should be followed with anti-D immunoglobulin prophylaxis.41,42

According to Neil Murray of ADC Fetal and Neonatal, it has been discovered that the spectrum of the HDN has broadened since its first identification.43 Previously, the situation remained constant, resulting in excessive fetal and neonatal hemolysis, hyperbilirubinemia, and severe anemia. However, with the use of standard postnatal prophylactic anti-D immunoglobulin for Rh- mothers, this condition has been significantly decreased. This therapy has shown to be one of the most effective post-modern perinatal care options.41 Blood transfusions are required for anemic newborns, and the blood must be ABO-matched and packed with red blood cells. Furthermore, the blood must be type O and Rh-and leukodepleted and irradiated.19 All of these should be present throughout the delivery.

Etiology

HDN is commonly caused by the incompatibility of the mother's and the baby's blood. Suppose the baby's blood crosses over and reaches the mother's incompatible RBCs; the mother's immune system perceives the fetal antigens as non-self and fights them by releasing antibodies that do not hesitate to attack and destroy them.2 Usually, the cross-over occurs through the placenta during pregnancy or delivery. This leads to severe complications in the baby's system, which may even lead to the ultimate demise of the baby. However, the immune system of the mother does not get rid of the antibodies. Still, it develops immunological memory, which can cause the secretion of more antibodies upon re-exposure to the antigen. As a result, HDN is likely to occur in the second and the subsequent pregnancies, even after a miscarriage or abortion.8

Diagnosis

Laboratory Studies

To diagnose and manage pregnant women with HDN, extensive laboratory and imaging practice is required. HDN is clinically indicated by: (1) rapid and severe hyperbilirubinemia or persistent hyperbilirubinemia; and (2) hemolysis on blood film results.44 It should also be noted that the extent of hematopoiesis affects the severity of the disorders.

Also, clinical conditions such as anemia, thrombocytopenia, and neutropenia are often observed in patients. The anemia can be accurately estimated using arteriole samples instead of capillary blood. Thrombocytopenia commonly accompanies exchange transfusions. It results from poor blood platelets formation and when the production is suppressed in favor of erythropoiesis. Neutropenia is mostly observed after intrauterine transfusion. It is commonly associated with increased circulating cytokines (such as granulocyte-macrophage colony-stimulating factor) and reticulocytosis, ie, increased nucleated RBCs and cell fragmentation.36,45 In addition, Rh-HDN peripheral blood smears usually show polychromasia, anisocytosis, erythroblasts, and no spherocytes.4

Furthermore, a serological test needs to be done to verify the positivity of the HDN. The results of this test may show that the baby is either directly or indirectly impacted by the variation in the mother's Coombs and antibodies. According to a recent study, the positive impact of the natural antibody test finding is related to a predictive value of 23% and a sensitivity of 86%.46 If the neonatal hemolytic syndrome is caused by antic, the direct antibody test may be negative. As a result, it is suggested that a diagnosis be made only when the indirect Coombs test has shown certainty. Table 2 summarizes the laboratory tests utilized in the diagnosis of HDN and their expected results.

Table 2

Mother's Sample

Baby's Sample

Test

Result

Test

Result

ABO/Rh Determination

A (Rh D positive)

ABO/Rh Determination

A (Rh D positive)

Antibody Screening

Positive

Polyspecific DAT

Positive

Antibody Identification

Anti-c testing

IgG/C3 Coombs

IgG positive/C3d-negative

Antigen Typing

Negative for "c" antigen

Elution

Positive

Imaging Studies

During pregnancy, the fetus should be screened for maternal red cell alloantibodies. Ultrasound should also be used, especially when intravenous transfusion is performed.48 Maternal blood samples for ABO, Rh group, and red cells should be tested throughout this phase. If alloantibodies capable of causing HDN are found, a laboratory test should be performed to validate the findings. The father's phenotype should be established to help estimate the chance of a newborn bearing the appropriate red cell antigen.49 Once fetal Rh positivity is established, fetal surveillance can be done by serial maternal pelvic ultrasounds, umbilical artery, and middle cerebral artery (MCA) dopplers. MCA dopplers are often utilized to screen for anemia in Rh+ fetuses. They are done every 1-2 weeks from the 24th week of gestation. This kind of monitoring checks for peak systolic velocity (PSV), as it is always bound to increase in anemia.50 Fetal ultrasounds are usually utilized to check for fetal ascites, soft-tissue edema, scalp edema, pleural effusion, cardiomegaly, and hepatomegaly with portal hypertension if the fetus is heavily affected.51

Patient Care and Prevention

When the testing results indicate anemia in the uterus, group O negative blood transfusion should begin. The transfused blood type O negative should be cross-matched with maternal blood. This procedure is best completed between the ages of 16 and 18.52 Furthermore, intravenous transfusion under ultrasound monitoring should be used since it is simple in a hydropic fetus and does not create more problems than intraperitoneal fetal transfusion.53 Neonates should be regularly watched after birth to look for the emergence of any late anemia between 6 and 8 weeks. This amounts to 50% of the total. However, around 25% of the newborns have the typical illness, which necessitates transfusion.54 If severe HDN is expected, the delivery should be performed by a specialized pediatrician who has received neonatal resuscitation training, and fresh blood should be made available. The earlier the IVIG is given, the lower the risk of hemolysis and the requirement for exchange transfusion.55 To prevent HDN, IVIG should be given to all Rh- women who have not already been sensitized.

To improve health care results, a solid clinician-patient connection is required. Collaboration among members of an interprofessional team, which mostly consists of an obstetrician, a primary physician, and nurses, is also needed. Because this condition is avoidable, doctors must accurately examine and screen both mother and father during the first trimester and closely monitor antibody titers in Rh- females. These antibody levels should be less than 1:16, and if they are higher, invasive testing is performed to treat them appropriately.56 Critical monitoring of the fetus using MCA Doppler provides an accurate picture of fetal anemia, determining if an intrauterine transfusion is required or not.

Potential Complications of Exchange and Transfusion

Several complications may be experienced during a blood transfusion. It is critical to have an initial understanding of such prospective difficulties to establish remedies and handle them. Severe hyperbilirubinemia, which is unpredicted by maternal prenatal antibody screening; persistent hyperbilirubinemia; and ABO incompatibility, are a few of the complications.57 Furthermore, if a mother with antibodies needs a blood transfusion, she risks a future transfusion response. One alternative solution is to tell medical staff and physicians about her past diagnosis. This may assist doctors in administering the correct diagnosis and taking care of the patient. A fetus may develop mild to severe anemia and even jaundice during pregnancy. In addition, if the baby's organs are incapable of dealing with anemia, it is at risk of developing hydrops fetalis.58 The newborn may develop kernicterus, the most severe type of hyperbilirubinemia, at birth. Potential consequences in certain situations include bacterial and viral infections such as HIV, hepatitis, and malaria. Metabolic problems such as acidosis, hypocalcemia, and hypernatremia might also occur.59

Furthermore, certain vascular problems such as thrombosis, neutralizing enterocolitis, and umbilical vessel perforation may occur. Hypothermia is also an accompanying systemic danger that severely affects the tissues.60 Table 3 summarizes some of the aforementioned potential risks.

Table 3

Outcome

Number (%)

Cardiovascular

Bradycardia (mild)

1 (2)

Bradycardia needing CPR

1 (2)

Limb cyanosis

1 (2)

Metabolic

Hypomagnesemia

2 (4)

Hyperglycemia

7 (15)

Hematologic

Thrombocytopenia

15 (32)

Platelet Transfusion

3 (7)

Anemia

11 (23)

PRBCs Transfusion

4 (8)

Follow-up and neurological complications

Post-discharge visit for at least 1 time

35 (78)

Post-discharge follow-up for more than one year of age

25 (52)

Developmental delay and seizures

1 (4)

Spasticity

1 (4)

Hearing Deficit

1 (4)

Trends and Future Prospects

Blood typing using molecular methods is becoming more common as molecular testing becomes more widely used in medicine. Serological probes do not always correctly identify the RhD type in some individuals. Weak D phenotypes seem to be the most common genetic background that accounts for this serological typing problem. Scholars have recently advocated using RhD genetic testing for patients with a weak D phenotype to obtain accurate and actionable results for RhD blood typing and Rh Ig administration.63-65

There is still a vast capacity for improving HDN's understanding and management in both developed and developing countries. Universal research-backed guidelines regarding RBC antigen matching transfusion techniques for women before pregnancy or during intrauterine transfusion would be a good place to start.66 A critical area that needs more research is the mechanism of action of Rh immunoglobulin. We believe that a proper understanding of the roles of RBC clearance, antigen masking, modulation, and immune suppression might help develop innovative preventive prophylaxis during gestation for vaccination against Rh and non-Rh antigens. Proper understanding of the roles of fetal RBC clearance, antigen masking, antigen modulation, and immune suppression in the efficacy of Rh immunoglobulin may assist in developing innovative preventive treatments during pregnancy for vaccination against RhD and non-RhD antigens. Furthermore, more understanding of the relevance of anti-RhD or other alloantibody glycosylation patterns may be useful in the development of novel treatments and in predicting the clinical significance of current maternal alloantibodies. Another area of need is developing treatments other than intrauterine infusions to alleviate maternal alloantibodies' risks to the fetus.

Conclusion

HDN is a complex multidimensional condition with unique technical issues during numerous crucial developmental stages of the prenatal and neonatal eras. Advances in maternal-fetal medicine, including the development of IVIG, IUT, and noninvasive fetal genetic testing, have resulted in significant improvements in HDN outcomes and the avoidance of maternal allosensitization. Future advancements in blood typing and noninvasive testing will help women and their children with blood group incompatibility. Also, more attention should be given to the ethnic groups and races that are more at risk.

Disclosure

The authors report no conflicts of interest in this work.

References

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12. Tao E, Ye D, Long G, et al. Severe neonatal anemia affected by massive fetomaternal hemorrhage: a single-center retrospective observational study. [ J Maternal-Fetal Neonatal Med. 2020;1-7. doi: 10.1080/14767058.2020.1845313 [ PubMed] [ CrossRef] Google Scholar]

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48. Osonoi K, Kudo K, Kobayashi A, et al. A comprehensive evaluation including ultrasound monitoring of fetal hemolytic disease in Rhesus E incompatibility. [ Hirosaki Med J. 2020;71(1):71-74. Google Scholar]

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Hemolytic Disease of the Newborn: A Review of Current Trends and Prospects

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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 ...

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Clinical Manifestations

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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.

Monitoring

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.

Next steps

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 (HDN) is a blood problem in newborns. It occurs when your baby's red blood cells break down at a fast rate. It's also called erythroblastosis fetalis.

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ABO Incompatibility And Hemolytic Disease Of The Newborn (HDN)

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Management of maternal alloimmunization

As a rule, serial maternal antibody titers are monitored until a critical titer of 1:32, which indicates that a high risk of fetal hydrops has been reached. At this point, the fetus requires very intense monitoring for signs of anemia and fetal hydrops. In Kell alloimmunization, hydrops can occur at low maternal titers because of suppressed erythropoiesis, and, thus, a titer of 1:8 has been suggested as critical. Hence, delta-OD 450 values are also unreliable in predicting disease severity in Kell alloimmunization.

Maternal titers are not useful in predicting the onset of fetal anemia after the first affected gestation. Large differences in titer can be seen in the same patient between different laboratories, and a newer gel technique produces higher titer results than the older tube method. Therefore, standard tube methodology should be used to determine critical titer, and a change of more than 1 dilution represents a true increase in maternal antibody titer. For all the antibodies responsible for hemolytic disease of the newborn (HDN), a 4-fold increase in any antibody titer is typically considered a significant change that requires fetal evaluation.

When indicated, amniocentesis can be performed as early as 15 weeks' gestation (rarely needed in first affected pregnancy before 24 weeks' gestation) to determine fetal genotype and to assess the severity. Maternal and paternal blood samples should be sent to the reference laboratory with amniotic fluid sample to eliminate false-positive results (from maternal pseudogene or Ccde gene) and false-negative results (from a rearrangement at the RHD gene locus in the father).

Fetal Rh-genotype determination in maternal plasma has become routine in many European countries and is being offered in the United States.Fetal cell-free DNA accounts for 3% of total circulating maternal plasma DNA, is found as early as 38 days of gestation, and is derived from apoptosis of the placental cytotrophoblast layer. The mean half-life of circulating fetal DNA is on average less than 30 minutes, and maternal plasma is subjected to filtration and microcentrifugation to remove all cellular elements before testing. This eliminates false-positive results from engrafted fetal cells of previous pregnancies in maternal lymphoid organs.

Cell-free fetal DNA is subjected to real-time polymerase chain reaction (PCR) for the presence of RHD gene-specific sequences and has been found to be accurate in 99.5% of cases. The SRY gene (in the male fetus) and DNA polymorphisms in the general population (in the female fetus) are used as internal controls to confirm the fetal origin of the cell-free DNA.A panel of 92 single-nucleotide polymorphisms (SNPs) is compared between maternal sample from buffy coat and plasma. A difference of more than 6 SNPs confirms presence of fetal DNA and the validity of the test in a female fetus. False-negative results being most undesirable and consequential are due to partial or weak D phenotypes. They are detected by using at least two RHD-specific exon primers and run in duplicates.

Fortunately, cell-free fetal DNA testing for determining the genotype for other red blood cell antigens such as c,C, e, E and Kell is also now found to be highly reliable and accurate.

Serial amniocentesis is begun at 10-14 day intervals to monitor the severity of the disease in the fetus. All attempts should be made to avoid transplacental passage of needle which can lead to fetomaternal hemorrhage (FMH) and a further rise in antibody titer. Serial delta-OD 450 values are plotted on the Queenan chart or the extended Liley chart to evaluate the risk of fetal hydrops. Early ultrasonography is performed to establish correct gestational age. Frequent ultrasonographic monitoring is also performed to assess fetal well-being and to detect moderate anemia and early signs of hydrops.

Slopes for peak systolic velocity in middle cerebral artery (MCA) for normal fetuses (dotted line), mildly anemic fetuses (thin line), and severely anemia fetuses (thick line).

With acquisition of experience in performing MCA Doppler study, serial amniocentesis for detecting fetal anemia has been used to lesser extent.

During the period when intrauterine peritoneal transfusion was the only means of treatment, newborns were routinely delivered at 32 weeks' gestation. This approach resulted in a high incidence of hyaline membrane disease and exchange transfusions. With the advent of intravascular transfusion (IVT) in utero, the general approach to the severely affected fetus is to perform IVT as required until 35 weeks' gestation, with delivery planned at term. Establishment of lung maturity is difficult in these fetuses because of contamination of amniotic fluid with residual blood during transfusion; however, if delivery is planned prior to 34 weeks' gestation, maternal steroid administration to enhance fetal lung maturity is indicated.

In addition, excess amniotic fluid bilirubin levels cause false elevation on the fluorescence depolarization TDx fetal lung maturity test, version II (TDX-FLMII); therefore, other tests to determine fetal lung maturity should be used, such as infrared spectroscopy, lamellar body count, phosphatidylglycerol quantitation or lecithin/sphingomyelin (L/S) ratio.

Liley first described intraperitoneal transfusion (IPT) in 1963. A Tuohy needle is introduced into the fetal peritoneal cavity under ultrasonographic guidance. An epidural catheter is threaded through the needle. A radiopaque medium is injected into the fetal peritoneum. The proper placement is confirmed by delineation outside of bowel or under the diaphragm or by diffusion in fetal ascites. Packed red blood cells (RBCs) at a hemotcrit (Hct) of 75-80% that are CMV-negative, less than 4-days-old, group O, Rh-negative, Kell-negative, leukoreduced, irradiated with 25 Gy to prevent graft versus host disease, and cross-matched with maternal serum are injected in 10-mL aliquots to a volume calculated by the following formula:

IPT volume = (gestation in weeks - 20) × 10 mL

Residual hemoglobin (Hb) in the fetus is estimated to allow for proper spacing of IPT and selection of gestation of delivery by the following formula:

Hb g/dL = 0.85/125 × a/b × 120 - c/120

In the formula, a is the amount of donor RBC Hb transfused, b is the estimated fetal body weight, and c is the interval in days from the time of transfusion to the time of donor Hb estimation.

IPT is repeated when the fetal Hb is estimated to have dropped to 10 g/dL. Usually, a second IPT is performed 10 days after the first transfusion in order to raise the Hb above 10 g/dL. Then another transfusion is performed every 4 weeks until the time of planned delivery at 34-35 weeks' gestation. Fetal diaphragmatic movements are necessary in order for absorption of RBC to occur. This approach is of no value for a moribund nonbreathing fetus. Maternal complications include infection and transplacental hemorrhage, whereas fetal complications are overtransfusion, exsanguination, cardiac tamponade, infection, preterm labor, and graft versus host disease. Survival rates after IPT approached approximately 75% with the help of ultrasonography.

Direct IVT has become a preferred route of fetal intervention because of the higher rate of complications and limited effectiveness of IPT in a hydropic fetus. Rodeck first successfully performed IVT in 1981. With ultrasonographic guidance, a 20-22 gauge needle is introduced into an umbilical vein at the cord insertion into the placenta or into its intrahepatic portion, and a fetal blood sample is obtained. The blood sample is confirmed to be of fetal origin by rapid alkaline denaturation test. All the relevant fetal tests (eg, blood type, direct antibody test, reticulocyte count, platelet count, Hb level, Hct level, serum albumin level, erythropoietin level) are performed. If the Hb level is less than 11 g/dL or if the Hct level is less than 30%, an IVT is started. The position of the needle is confirmed by noting the turbulence in the fetal vessel on injection of saline. The fetus is frequently paralyzed with pancuronium and given fentanyl 10 mcg/kg to prevent the displacement of the needle by fetal movements. Maternal medication varies from local anesthetic only, to routine indomethacin and conscious sedation, to spinal epidural analgesia.

The transfusion is performed in 10-mL aliquots to a volume of approximately 50 mL/kg estimated body weight using ultrasonography or until an Hct level of 40% is reached. The procedure is promptly discontinued if cardiac decompensation is noted on ultrasonography findings. Severely anemic fetuses do not tolerate acute correction of their Hct to normal values, and the initial Hct should not be increased by more than 4-fold at the time of first IVT. They should then be monitored every 2-7 days. The IVT is repeated when it reaches a value that reflects critical anemia in the fetus. A loss of 1% of transfused cells per day can be anticipated.

Some centers perform repeat transfusion at intervals of 10 days, 2 weeks, and every 3 weeks. Others transfuse based on an anticipated decline in fetal hemoglobin of 0.4 g/dL/day, 0.3 g/dL/day, and 0.2 g/dL/day for first, second, and third transfusion intervals, respectively.The peak systolic MCA velocity has been used to time the second transfusion, with a threshold of 1.32 MOM.After the first intrauterine transfusion, the presence of red blood cells with adult hemoglobin suppress erythropoiesis and improve oxygen delivery, which is responsible for the poor correlation between peak MCA velocity and severity of fetal anemia. Some centers have found a beneficial effect of combined IVT and IPT transfusion on interval to repeat transfusion.

In addition to the complications of IPT, transient fetal bradycardia, cord hematoma, umbilical vein compression, and fetal death have been reported during IVT. However, IVT has many advantages, including immediate correction of anemia and resolution of fetal hydrops, reduced rate of hemolysis and subsequent hyperinsulinemia, and acceleration of fetal growth for nonhydropic fetuses who are often growth retarded. IVT is the only intervention available for moribund hydropic fetuses and those with anterior placenta. The risk of fetal loss is about 0.8% with IVT versus 3.5% per procedure for IPT, and the overall survival rate is 88%.

Recently washed maternal RBCs have been successfully used as a source of antigen-negative RBCs in the event of rare incompatibility but also have been routinely used because of benefits such as decreased risk for sensitization to new red cell antigens, a longer circulating half-life being fresh, and decreased risk of transmission of viral agents.Mother can donate a unit of red cells after the first trimester.

Management of first affected pregnancy.

Management of pregnant women with previously affected fetus.

Initial attempts to suppress Rh antibody production with Rh hapten, Rh-positive RBC stroma, and administration of promethazine were unsuccessful. Extensive plasmapheresis with partial replacement using 5% albumin (therapeutic plasma exchange) and intravenous immunoglobulin (IVIG) or the administration of IVIG at 1 g/kg body weight weekly has been shown to be moderately effective. The mechanism of action appears to be blockage of Fc receptors in the placenta, reducing antibody transport across to the fetus, Fc receptors on the phagocytes in the fetal reticuloendothelial system, and feedback inhibition of maternal antibody synthesis. However, antibody-dependent cell-mediated cytotoxicity and rebound elevation of antibody concentration, alteration of placental blood flow during the procedure, and postpartum hemorrhage have been noted after plasma exchange.

Similar regimens of tests and treatment are used in the management of pregnancies affected by nonRhD alloimmunization, such as anti-Rhc, anti-K (K1), and anti-M. Once the mother is diagnosed with an antibody associated with hemolytic disease, an indirect Coombs titer is performed, along with paternal testing for involved antigen and zygosity. Maternal titers are repeated (monthly until 28 weeks' gestation and then every 2 wk) until a threshold for fetal anemia is reached (1:8 for Kell and 1:32 for rest).

Fetal antigen typing is performed via amniocentesis or cell-free fetal DNA in maternal plasma if the father is found to be heterozygous (100% for K1, 65% for M). When the fetus is known to be antigen positive, surveillance for severe fetal anemia is performed, with weekly MCA Doppler screening as early as 16-18 weeks and IUT is carried out if it exceeds 1.5 MOM with a delivery by 38 weeks' gestation.

Maternal alloantibodies to paternal leukocytes have been shown to result in Fc blockade and to reduce the severity of fetal hemolytic anemia. This may be used in the future.

Management of the sensitized neonate

Mild hemolytic disease accounts for 50% of newborns with positive direct antibody test results. Most of these newborns are not anemic (cord hemoglobin [Hb] >14 g/dL) and have minimal hemolysis (cord bilirubin < 4 mg/dL). Apart from early phototherapy, they require no transfusions. However, these newborns are at risk of developing severe late anemia by 3-6 weeks of life. Therefore, monitoring their Hb levels after hospital discharge is important.

Moderate hemolytic disease accounts for approximately 25% of affected neonates. Moderate hemolytic disease of newborn is characterized by moderate anemia and increased cord bilirubin levels. These infants are not clinically jaundiced at birth but rapidly develop unconjugated hyperbilirubinemia in the first 24 hours of life. Peripheral smear shows numerous nucleated RBCs, decreased platelets, and, occasionally, a large number of immature granulocytes. These newborns often have hepatosplenomegaly and are at risk of developing bilirubin encephalopathy without adequate treatment. Early exchange transfusion with type-O Rh-negative fresh RBCs with intensive phototherapy is usually required. Use of IVIG in doses of 0.5-1 g/kg in a single or multiple dose regimen have been able to effectively reduce need for exchange transfusion.

Severe hemolytic disease accounts for the remaining 25% of the alloimmunized newborns who are either stillborn or hydropic at birth. The fetal hydrops is predominantly caused by a capillary leak syndrome due to tissue hypoxia, hypoalbuminemia secondary to hepatic dysfunction, and high-output cardiac failure from anemia. About half of these fetuses become hydropic before 34 weeks' gestation and need intensive monitoring and management of alloimmunized gestation as described earlier. Mild hydrops involving ascites reverses with IVTs in only 88% of cases with improved survival but severe hydrops causing scalp edema and severe ascites and pleural effusions reverse in 39% of cases and are associated with poor survival.

Management of ABO incompatibility

Management of hyperbilirubinemia is a major concern in newborns with ABO incompatibility. The criteria for exchange transfusion and phototherapy are similar to those used in Rh alloimmunization. IVIG has also been very effective when administered early in the course. Tin (Sn) porphyrin a potent inhibitor of heme oxygenase, the enzyme that catalyzes the rate-limiting step in the production of bilirubin from heme, has been shown to reduce the production of bilirubin and reduce the need for exchange transfusion and the duration of phototherapy in neonates with ABO incompatibility.

Tin or zinc protoporphyrin or mesoporphyrins have been studied in newborns. They must be administered intramuscularly in a dose based on body weight, and their effectiveness appears to be dose related in all gestations.Their possible toxic effects include skin photosensitization, iron deficiency, and possible inhibition of carbon monoxide production. Their use in Rh hemolytic disease of newborn has not been reported. Their routine use cannot be recommended yet because of lack of long-term safety data.

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hemolytic disease of the newborn treatment

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Hemolytic Disease of the Newborn Treatment & Management

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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.

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A visual of HDN during the first pregnancy, after delivery, and the subsequent pregnancy.

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Josephson CD, Sloan SR. Pediatric transfusion medicine. In: Hoffman R, Benz EJ, Silberstein LE, et al, eds. Hematology: Basic Principles and Practice. 7th ed. Philadelphia, PA: Elsevier; 2018:chap 121.

Niss O, Ware RE. Blood disorders. In: Kliegman RM, St. Geme JW, Blum NJ, Shah SS, Tasker RC, Wilson KM, eds. Nelson Textbook of Pediatrics. 21st ed. Philadelphia, PA: Elsevier; 2020:chap 124.

Simmons PM, Magann EF. Immune and non-immune hydrops fetalis. In: Martin RJ, Fanaroff AA, Walsh MC, eds. Fanaroff and Martin's Neonatal-Perinatal Medicine: Diseases of the Fetus and Infant. 11th ed. Philadelphia, PA: Elsevier; 2020:chap 23.

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Hemolytic disease of the newborn: MedlinePlus Medical Encyclopedia

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Hemolytic disease of the newborn (HDN) is a blood disorder in a fetus or newborn infant. In some infants, it can be fatal.