This chapter should be cited as follows:
Jackson ME, Baker JM, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.417773
The Continuous Textbook of Women’s Medicine Series – Obstetrics Module
Volume 16
The prevention and management of rhesus disease
Volume Editors:
Professor Gerard HA Visser, Department of Obstetrics and Gynaecology, University Hospital of Utrecht, Heidelberglaan 100, Utrecht 3584EA, The Netherlands
Professor Gian Carlo Di Renzo, University of Perugia, Italy
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Chapter
Hemolytic Disease from Other Incompatibilities
First published: November 2022
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INTRODUCTION
Hemolytic disease of the fetus and newborn (HDFN) is a life-threatening illness of fetuses and neonates, caused by maternal–fetal red-blood-cell antigen incompatibilities and subsequent antibody production. The clinical presentation and natural history vary from case to case, ranging from mildly symptomatic hemolysis in neonates causing self-limiting postnatal jaundice, to hydrops fetalis and perinatal mortality including stillbirth.
As discussed in other chapters, the most recognized and often most severe form of HDFN is that of rhesus disease, also known as RhD-HDFN, caused by maternal alloantibodies to rhesus antigen D (RhD). However, HDFN is far from limited to this antigenic presentation, as there are many other potential red-cell antigens that can be responsible for fetal and neonatal hemolysis due to red-cell incompatibilities.1 More than 50 other red-blood-cell antigen incompatibilities have been described to trigger HDFN.2 Some of these antigens cause a more pronounced hemolysis than others,1 and severity varies case to case. Several red-blood-cell antigens in the same red-cell group as RhD are known to be responsible, but less frequently and usually less severely. As such, rhesus antigens other than RhD including c, C, E, and e3 are often implicated, and can produce severe hemolysis. Red-blood-cell antigens from other groups known to cause severe hemolytic disease include antigens from Kell, Duffy, MNS, and Kidd blood group systems.4
Understanding the different red-cell incompatibilities and antibody production leading to HDFN is important in terms of predicting risk, monitoring and managing pregnancies and neonates at risk of the effects of hemolytic disease of the fetus and newborn. Whilst there are hundreds of possible red-cell antigen incompatibilities with the potential to cause antibody production, a much smaller proportion of these red-cell incompatibilities are clinically relevant;1 some antibodies are much more pathogenic than others, and some antigens are very low frequency. As with many antibody-mediated pathologies of the human body, the clinical relevance of antibody varies depending on the type of antibody, its titer, as well as individual differences that varies from patient to patient.
HDFN is still considered a potential cause of severe long-term morbidity5 and even mortality in the newborn, despite the introduction of Rh immunoglobulin (RhIG) to prevent notoriously severe HDFN – RhD-HDFN. Consequently, HDFN warrants education, careful monitoring, and clinical consideration worldwide.
RED-BLOOD-CELL ANTIGENS
Red-blood cells are covered in antigens, which are composed of sugars, proteins, and/or lipids.6,7 Many of these are anchored surface proteins; of which are polymorphic and for the different antigenic sites.8 The antigens can stimulate an immune response in various circumstances, including HDFN.1 Most blood group antigens are glycoproteins, and their specificity is mostly determined either by the oligosaccharide or amino acid sequence. Most blood group polymorphisms result from single nucleotide polymorphisms (SNPs)9 encoding amino acid substitutions in either a glycosyltransferase or extracellular domain of a red-cell membrane protein, and as such there are a lot of variability between people. Antigens are usually on the surface of the red blood cell to form other functions, such as cellular messaging and trafficking, and immune and complement regulation.7
Antigens are defined by the antibodies that the immune system creates in response to them.10 Such antibodies either form innately – due to physiological exposure to the corresponding antigens, or are formed as a result of exposure to non-self RBC antigens. It is the inherited presence or absence of red-cell surface antigens that defines the different blood groups of an individual.7
The nomenclature of categorizing the red-blood-cell antigens is important in labeling various blood groups and different types of red-cell antigens responsible for immune response.1 Individuals have different red-blood-cell antigens on the surface of their red cells. Some of these differences are responsible for the development of the immune response, leading to HDFN, whilst many are not.
New red-cell antigens continue to be described, named and grouped.11 Thus, the number of understood red-cell antigens is constantly growing. To ensure accuracy and consistency, an international society – International Society of Blood Transfusion (ISBT) – is entrusted to keep an up to date record and categorize red-cell antigens as they are discovered and described. In some instances, HDFN can occur without identifying the offending antigen, however the clinical scenario is consistent with HDFN. Red-cell phenotyping of both parents is indicated in this scenario to look for incompatibilities.
Nomenclature
The International Society of Blood Transfusion Working Party for Red Cell Immunogenetics and Blood Group Terminology (ISBT WP) maintains an official record of all currently recognized blood group systems.11 As of June 2021, the ISBT recognizes 43 blood group systems containing 345 red-cell antigens. As time progresses, more red-cell antigens are being described and thus our knowledge of potential antigen:antibody complexes continues to increase. The 43 systems are genetically determined by 48 genes, and not all antigens currently described fall into a set system.11
PATHOPHYSIOLOGY
HDFN is an alloimmune disease, as antibodies created by the pregnant mother act against cells on the fetus and persist into the neonatal period. HDFN predominantly occurs when the fetus or neonate inherits a red-blood-cell antigen from the father that is not present on the mother’s red blood cells. Thereafter, maternal IgG antibodies develop to a particular red-blood-cell antigen and travel across the placenta into the fetal blood stream.12 The antibodies then identify and attach to the fetal red-blood-cell antigens and cause alloimmune destruction of fetal and neonatal red blood cells by the splenic macrophages.13 The timing of hemolysis in the fetus or neonate depends on when in development the red-blood-cell antigen is expressed on the fetal or the neonatal red blood cell.14 For this reason, while many red-cell antibodies can cause problems antenatally, some do not until the postnatal period.15 Of course, alloantibodies that cannot cross the placenta to enter the fetal blood stream cannot cause disease.
Most types of HDFN require maternal previous exposure, known as sensitization, to the causative red-cell antigen that the mother does not possess, in order to develop the antibodies that subsequently cross the placenta. This can either be through previous pregnancy, or transfusion, as well as other rarer types of red-blood-cell exposures. Antibodies also develop after exposure to bacterial or viruses presenting the same antigens to the immune system within the body, such as that believed to occur in the case of the A and B blood group system, explaining why people of O blood group have naturally occurring A and B antibodies.16
Hemolysis occurs when the macrophages of the reticuloendothelial system, predominantly in the spleen and liver, identify the antigen:antibody immune complexes and destroy the cells.13,17 In the fetus, compenzation for the hemolysis occurs by extramedullary hematopoiesis to produce more red blood cells.17 If the red blood cell destruction is mild, extramedullary hematopoiesis in the liver and spleen may compensate adequately. If the red-blood-cell destruction is severe and blood production cannot compensate adequately, there will be severe anemia and due to inadequate compenzation, this can result in multi-organ hypoxia from the reduced ability to deliver oxygen and nutrients adequately, resulting in circulatory and hepatic failure.17 Liver failure causes decreased protein levels and a reduction in oncotic pressure in the circulation and heart failure causes an increase in venous pressure; the combination of which leads to generalized edema and ascites, known as hydrops fetalis, which has a high perinatal mortality rate. Lesser degrees of edema can also occur. Erythroblastosis fetalis refers to hemolysis due to HDFN in the fetus with subsequent sequelae of hydrops, anemia, and neonatal hyperbilirubinemia.17
In the postnatal period, severe neonatal hyperbilirubinemia may lead to kernicterus, causing seizures and long-term neurodevelopmental impairment.17
LABORATORY INVESTIGATIONS
Blood Smear
The findings on blood film of the fetus or neonate are suggestive of immune-mediated hemolysis and often show severe microspherocytosis and other markers of intravascular hemolysis.18
Direct Antiglobulin Test
The direct antiglobulin test (DAT) is used to evaluate for immune-mediated hemolysis including in the evaluation for potential HDFN. The DAT can be tested from the fetus (if intrauterine testing is performed), from the cord blood (representing the neonatal blood), or from the neonate after birth.19 A positive DAT is not specific for HDFN, and a negative DAT does not exclude HDFN, and thus this test result needs to be interpreted with caution. A positive neonatal DAT in the absence of abnormal jaundice has a very low positive predictive rate.20 Note that some patients will only develop late-onset hemolysis whereby blood work is initially reassuring, but there is a positive DAT. In this case the baby would still need monitoring and clinical assessment for several weeks in the postnatal period.32 This is often forgotten and is thereby a cause of preventable morbidity in our current medical environment.21 A negative DAT does not exclude the diagnosis of HDFN, particularly in the setting of ABO incompatibility or intrauterine transfusions during pregnancy.
When present in the context of the fetus and/or newborn, a positive DAT demonstrates the presence of maternal antibody on the neonate’s red blood cells. In this test, agglutination of RBCs from the neonate, when suspended with serum that contains antibodies to immunoglobulin G (IgG) – The Coombs reagent, indicates the presence of maternal antibody on the red-blood-cell surface.19
The DAT may not detect sensitized red blood cells in ABO HDFN, because the A and B antigens are less well developed in neonates than in older children and adults. In addition, the antigenic sites are fewer and farther apart on neonatal RBCs, making agglutination with the Coombs reagent difficult19 Coombs regent is antihuman globulin with polyclonal specific for human immunoglobulins and human complement system factors.22 Additionally, it is important to note that in infants with HDFN who have received intrauterine transfusions as treatment of fetal anemia and hydrops, the DAT may be negative because the presence of donor red blood cells make agglutination more difficult.19 Cord blood is often used to identify the infant's blood type and to perform a DAT. However, a false positive DAT may occur due to contamination of the cord blood sample with Wharton's jelly.19 In most cases, confirmation of cord blood testing should be done with specimens obtained directly from the neonate.
ABO INCOMPATIBILITY CAUSING HDFN
ABO incompatibility is the leading cause of neonatal jaundice and the most common form of HDFN,23 albeit for the most part, not the most severe. A person’s “blood group” is often thought of as an ABO system, which itself is only one of 43 systems as explained above. In the ABO system, there are four main blood groups: A, B, AB, and O. A and B are antigens, whilst O refers to the lack of immunogenic antigen in this blood system. The ABO system is somewhat unique in the pathogenesis of the development of alloantibodies. Unlike most other red-cell antigen systems, individuals naturally begin to make A and/or B antibodies to the antigens that they do not possess at approximately 3–6 months of age.24 This occurs due to the immune response to A and B antigens on microorganisms thought to present themselves through environmental exposures, which very closely resemble the corresponding blood group antigen.16 As a result, ABO HDFN can occur with the first pregnancy without any prior foreign antigen exposure, unlike other types of HDFN. Thus in ABO HDFN, birth order or pregnancy number does not predispose to worsening disease, and occurs almost exclusively in mothers with blood type O.24 While not the most severe, ABO-HDFN is the most common form of HDFN, and is the leading cause of neonatal jaundice.23 In extremely rare circumstances it can cause fetal disease in pregnancy leading to hydrops, but this has only been reported in several case reports,25 and are thought to be uniquely associated with a high titer of IgG antibody to the corresponding antigen. More information about this is detailed below.
The ABO blood group system is additionally complicated as there are several subtypes with differing antigenicity.16 For the A blood group, there are two known antigenic subtypes, A1 and A2. The B group does not have subtypes. This means that the serum of type A2 blood group would contain anti-B and anti-A1 antibodies. The subtyping in the A group antigens creates subtypes in the AB groups as well. The A1 antigen is the most antigenic and thus when the fetus is the A1 blood group and the mother is the O blood group, the risk is highest for symptomatic ABO incompatibility.16 Note that in most cases the subtype of the A1 antigen is not clarified, however in practice ABO HDN is more common due to A fetal blood type, as opposed to B.
Both A and B groups, patients also develop the respective antibodies to the antigens they do not possess, however are not normally at risk of HDFN as these antibodies are almost always IgM and thus do not cross the placenta and therefore cannot cause fetal or neonatal disease.17 There have been several case reports of ABO incompatibility HDN occurring in mothers who are A or B who have a fetus of differing ABO blood group other than O.26 This is slightly more common with an A2 subtype A blood group mother, and a B blood group infant. There has been a single case report of a B blood group mother having an A1 blood group infant with severe hemolytic disease.26 In these instances, significant hemolysis has been restricted to the neonatal period, and this has not been described to cause fetal disease.
ABO HDFN is usually mild and self-limiting, resulting in postnatal jaundice that often meets the threshold to require phototherapy. It is thought that ABO incompatibility generally causes a milder disease than some other types of HDFN as the antibody produced has several antigenic sites other than just red blood cells to associate with, thus leaving fewer antibodies to associate with the red blood cells. In addition, because infant red blood cells A and B antigens are not fully developed until later in life, so there are fewer antigenic sites on the red blood cells.14
Hemolysis to the degree to cause kernicterus, or even neonatal anemia, is not common in the setting of ABO incompatibility, in the absence of other co-morbid hemolytic disorders increasing the bilirubin such as G6PD deficiency. Fetal consequences of ABO HDFN in the antenatal period are exceptionally rare, likely due to the timing of the development of this red-cell antigen group, later in pregnancy. In a study looking at preterm infants,27 ABO incompatibility causes more problems in babies born in the third trimester than the second trimester, indicating the timing of the development of maternal alloantibodies.27 Hydrops fetalis as a consequence of HDFN due to ABO red-cell antigens is very rare.
ABO incompatibility occurs in 15–20% of pregnancies, with evidence of sensitization – defined by a positive DAT – in approximately 3–4% of these pregnancies, and yet less than 1% of those at risk develop clinically significant hemolysis thereafter.14 The reasoning for this is thought to be similar to the reason that ABO incompatibility produces only a mild hemolytic disease detailed above, and due to the differing antigenicity of A1 and A2 in the A blood group.
In very rare instances, ABO incompatibility has been implicated as the cause of severe fetal anemia and perinatal morbidity.25 In a case series in Africa, two cases of O blood group women with high IgG anti-B antibodies, with fetuses of blood group B have been described to cause severe fetal hemolytic disease and hydrops. These pregnancies resulted in preterm labor with evidence of fetal anemia and hydrops and no other alloantibodies identified. Both of the aforementioned pregnancies were in people of African descent, and it is believed that ABO incompatibility is perhaps more severe in this ethnic cohort.25
Rhesus Disease and ABO Incompatibility
Interestingly, co-morbid ABO incompatibility and RhD-HDFN usually produces milder disease than would be expected when compared with cases of RhD-HDFN with ABO compatibility. The etiology of this is not entirely understood, however it is believed that the macrophage of IgG tagged ABO incompatible red cells, reduced the immunogenicity caused by Rh(D) and thus results in less antibody formation.14
OTHER NON-RHD ANTIGENS CAUSATIVE OF HDFN
Alloantibodies to non-RhD red-blood-cell antigens are thought to be present in 1.5 to 2.5 percent of all pregnancies28 and can be identified by screen during the pregnancy. This of course does not include anti-A or anti-B, as these antibodies are innate. Different alloantibodies are more common in various geographical populations due to the differing antigenic geographical distribution, which of course is changing with time.29 In a large population-based study in the Netherlands, approximately 1 in 80 pregnancies were found to have a positive antibody screen, and 1 in 300 found to have clinically significant antibodies other than anti-D known to cause disease.30 The most common antibodies were anti-E, anti-K, and anti-c. Of the pregnancies identified, 3.7% required in-utero transfusion due to life-threatening hemolytic disease affecting the fetus.30 This study demonstrates the importance of understanding the other antibodies that can cause HDFN, and also of first-trimester screening.
RHESUS BLOOD GROUP ANTIGENS OTHER THAN RHESUS D
Whilst RhD causes the majority of HDFN within the rhesus blood group system, there are other rhesus antigens known to frequently cause varying degrees of hemolytic disease in fetuses and newborns. The most recognized of these are anti-E, e, C, c, and G1. Rhesus antigens are expressed as part of the antigen components of erythroid cells only, and are not present on other human cells. There are currently 49 described antigens in the rhesus blood group system,11 with a much small subset known to cause HDFN. Specifically anti-c, anti-C, anti-e, anti-E, and G are commonly implicated.14
Anti-c tends to be the most clinically significant after D and can cause severe HDFN.31 Moderate HDFN can be caused by differing subtypes, anti-Cw32 and anti-Cx.33 Rh alloantibodies that are typically associated with mild HDN include anti-C,32 anti-E,34 and anti-e.35 Anti-C is the most common of these.32
The G antigen of the rhesus blood group system is also known to cause HDFN, however less commonly causes problematic disease.36 The G antigen is found on cells that either D or C positive, and red blood cells not expressing either of these antigens are also by default G-negative. The antibody is often found in addition to anti-D and/or anti-C.36 Anti-G itself is, if anything associated, with mild disease but in combination with anti-D or anti-C can worsen the HDFN.37
KELL BLOOD GROUP ANTIGENS
The Kell blood group system contains many antigens that are highly immunogenic.38 There are 25 antigens recognized by the ISBT.11 The KEL gene is found on chromosome 7. Kell antigens are transmembrane glycoproteins present not only on red cells, but on myeloid tissue, lymphoid cells, muscle, and nerve cells.38 One of their functions is to produce constriction of vessels. Kell alloantibodies are the second most common cause of severe HDFN, after RhD-HDFN.39 The K antigen is by far the most clinically significant and immunogenic RBC antigen.38 Kell has the potential to cause severe HDFN early in pregnancy due to its early presentation on antenatal cells. Kell antibodies are known to produce a severe form of HDFN.38,40 Severe anti-K-mediated HDFN may develop very early in pregnancy, often presenting with evidence of hydrops at less than 20 weeks of gestation.40,41 Other Kell antigens causing HDFN include anti-k, anti-Kpa, anti-Kpb,, anti-Jsa, anti-Jsb, and anti-U19.38
Postnatally, anti-K-mediated HDFN is characterized more frequently by anemia than by hyperbilirubinemia, compared with HDFN caused by anti-D or other types of Rh alloantibodies.38
Previous transfusion is a common cause for the development of Kell autoantibodies due to the prevalence of genetic polymorphisms from the donor population,42 however sensitization can also occur in pregnancy.
DUFFY BLOOD GROUP ANTIGENS
The Duffy blood group system consists of a group of glycoproteins on the surface of red blood cells, endothelial cells, epithelial cells of the lungs and kidneys.43 There are currently five Duffy antigens recognized by the ISBT11– Fya, Fyb, Fy3, Fy5, and Fy6. Like rhesus antigens, the gene location is on chromosome 1.44 Fya and Fyb are the most clinically relevant in the development of alloantibodies and thus hemolytic disease. The Duffy antigens have a role in the immune system whereby they function as chemokines to attract immune cells to specific areas of the body.44 They also act as receptors for several species of malaria, and thus their distribution has a geographical significance pending on the incidence of malaria. A weakened form of Fyb has also been described,45 however is not known to be implicated in DFN.
Fya is expressed on fetal red blood cells from 6 weeks of gestation, whilst Fyb expression is higher after birth and reaches significant levels at 6 weeks of age.43 Fya is 20 times more immunogenetic than Fyb, and this in combination with its earlier antenatal presentation on the red cell, tends to cause a more severe form of HDN than Fyb.46 However, these alloantibodies most commonly cause mild-moderate disease if implicated in HDFN. In fact, Fyb has only been described in only a few case reports to cause HDFN.45,46 Rarely such cases have been reported to cause severe antenatal anemia, however in rare instances this has been described, with high titers of the antibody, and intrauterine transfusions have thus been indicated.46
Anti-Fy3 and anti-Fy5 are rare alloantibodies that have been described in transfusion reactions, particularly in the sickle cell population. They have not been described to causes HDFN. Anti-Fy6 has not been described in human population and thus has not been implicated in HDFN.43
MNS BLOOD GROUP ANTIGENS
The MNS system of blood group antigens consists of 42 red-cell antigens recognized by the ISBT11. This group of antigens are glycophorins in the membrane of red blood cells, and function as receptors function as receptors for cytokines, bacteria and viruses.48 These antigens are also expressed in the kidney and epithelial cells. There is emerging evidence that some species of malaria may use these antigens as well in their pathogenesis, thus further explain the geographical variation.
Like the ABO system, naturally occurring antibodies to M and N occur in a very small percentage of cases, in the absence of previous antigenic exposure.1 The most clinically relevant antigens in this group include for HDFN include M, N, S, U, Mia, and Mta.48,49 Of the MNS antibodies, anti-S is more common than anti-s, but both are capable of causing severe hemolysis. Less common causes of HDN include anti-M, anti-N, anti-U, anti-Mia, anti-Mta, and anti-Ena.48
Anti-M antibodies are typically not clinically significant, but can cause severe HDFN in rare instances.50,53 Anti-U is rare, but is described to cause a severe HDFN in African populations.1,53 Anti-S most often causes mild HDFN, but it can result in extreme hyperbilirubinemia needing exchange transfusion as described in several individual cases51 thought to be due to high antibody titer. Anti-Mur alloantibodies are more common in Southeast Asia and are known to cause mild or severe disease.52 A low-prevalence antigen in this group has recently been described to cause a case of severe post-natal hemolytic disease – anti-Sara.54
OTHER
We have detailed some of the more commonly implicated antigens and corresponding antibodies in HDFN, however many other antigens can cause HDFN. Several are not commonly recognized as they occur in low prevalence. There are many case reports in the literature of rarer antibodies causing severe hemolytic disease of the newborn of reviewing the literature when rare cases arise. Some examples of these causing severe hemolytic disease include but are not limited to anti-HJK55 (no ISBT group), anti-Co(a)56 (from the Colton blood group), anti-Ge3 (from the Gerber blood group),57 anti-Mia (from the Mittenberger blood group).58
Whilst Kidd blood group antigens are commonly associated with transfusion reactions, they are much less common as a cause of hemolytic disease of the newborn.59,60 Anti-Jka and anti-Jkb are rarely responsible for severe HDN.61 Anti-Jk3 is also a rare cause of HDN, however was fatal in the first described case in the Kidd family.59
MANAGEMENT IN PREGNANCY
Screening
In most high-income countries, pregnant women are routinely screened in the first trimester for antibodies using a relatively inexpensive antibody screen. Testing is typically performed by an indirect antibody test by incubating maternal serum with red blood cells. If positive, the antibody is identified and clinical relevance is assessed based on the type of antibody. As previously mentioned, not all alloimmune antibodies cause HDFN. Not only is the antibody identification important when assessing risk for HDFN, and thus the monitoring and treatment, which may be required, the titer of the antibody is also relevant. For clinically relevant antibodies, the titer or antibody concentration is next determined by serial dilution studies. In those pregnancies with an alloimmune antibody identified early in pregnancy, and considered at risk of fetal compromise, close monitoring with repeat blood tests and fetal ultrasonography to investigate for anemia looking at the flow velocity in the fetal middle cerebral artery (MCA). Generally, repeat titers are performed every 4 weeks, and if the “critical titer” is exceeded, the patient is referred to maternal–fetal medicine center for close surveillance and if needed and potential fetal or neonatal treatment. The critical titer for non-RhD, non-Kell antibodies is generally accepted as 32,30,62 though will vary from case to case.
Monitoring
Alloantibody titers are measured if a pregnancy is identified as having a clinically relevant alloantibody and the fetus could be carrying the antigen. Unfortunately, titers can be difficult to interpret, and do not correspond linearly with chance and severity of disease.64 Nonetheless, monitoring the titer is important to determine frequency of fetal monitoring and risk to the fetus of severe anemia.
Most blood bank laboratories and clinical guidelines follow recommendations from the Association for the Advancement of Blood & Biotherapies (AABB), which consider 16 the critical titer. It is generally agreed that additional fetal evaluation can be deferred at titers of 4 or below. Thus, a titer of 16 or above should prompt close fetal monitoring such as that with fetal middle cerebral artery peak systolic velocity to look for signs of severe anemia.63
Counseling
If a pregnancy is identified to have a clinically relevant alloantibody with potential to cause HDFN, it is important to counsel the parents appropriately for this and possible future pregnancies. Expectations and management of the current pregnancy as well the implication to future pregnancies with the same antigen set up are all important issues to address. Sensitization is known to increase with each pregnancy, and thus the degree of disease can worsen in subsequent pregnancies. If a nonpregnant woman is found to have an alloantibody to an RBC antigen, she should be counseled regarding the potential effects of the antibody on a future pregnancy. If possible, the father’s antigen class (heterozygosity or homozygosity of the allele) is helpful in prognosticating the risk in further pregnancies. This is discussed in a later chapter. There are few interventions that may be offered to prevent severe HDFN in a woman with an alloantibody and a father who carries the corresponding antigen, such as preimplantation genetic diagnosis, gestational carrier, and donor insemination.
CONCLUSION
Hemolytic disease of the fetus and newborn is a common and potentially life-threatening clinical entity for the fetus and neonate. There are many antigen:antibody complexes responsible for clinical disease with some being more common and clinically significant than others. An understanding of these antigens and antibodies is important in managing affected pregnancies, counseling, and planning for future pregnancies. High- and low-frequency antigens can produce antibodies causing HDFN and thus must be understood. High-frequency antigens such as those in ABO incompatibility cause the majority of HDFN, however often with the least severe disease, many of which do not require active management, whilst some do. Severe disease, affecting the fetus early in life, is often caused by antibodies to high-frequency antigens in the rhesus and Kell blood group systems – such as anti-D, anti-Kell, and anti-c, however less common antigens are also implicated and can lead to severe HDFN, as described above. Despite our understanding of red-cell antigens, there are still some cases where the causative antigen and antibody complex are not identified, but are nonetheless treated as HDN due to their presentation. Although RhD-HDFN remains the most severe and one of the most common forms of HDFN, it remains important to understand and recognize the other causes and clinical presentations, as HDFN continues to be a cause of significant morbidity and mortality.
PRACTICE RECOMMENDATIONS
- ABO incompatibility is the most common type of HDFN. It usually results in mild self-limiting postnatal hyperbilirubinemia often requiring post-natal treatment with phototherapy. In rare instances it may cause clinically significant anemia in neonates.
- The ability of an antibody to cause fetal hemolytic disease depends on the time at which the corresponding antigen becomes evident on the surface of the red blood cell due to fetal development.
- Anti-D, anti-Kell, and anti-c are the most common causes of HDFN affecting the fetus, however many less frequent antigens can cause antibodies and clinically significant disease in-utero.
- Pregnancies identified with a positive antibody screen and/or identification need to be monitored with caution for signs of fetal hemolytic disease. Titers can be used serially to monitor for risk during the pregnancy, as well as fetal signs of anemia including ultrasound.
- Severe HDFN often is life-threatening and requires intra-uterine transfusion.
- Many antibodies can cause isolated post-natal HDFN – including ABO antibodies, as well as antibodies to Duffy, MNS, and other antigens.
- A negative DAT does not exclude alloimmune hemolysis in the neonate, and a positive DAT does not confirm clinically significant HDFN. The DAT is usually helpful, but needs to be interpreted with caution.
- Neonates with post-natal symptoms of clinically significant HDFN need to be followed until the antibody titer is presumed to be low enough to not cause further disease – typically for at least 6–8 weeks, depending on the clinical scenario.
- Red-cell phenotyping at reference laboratory is recommended if the clinical scenario is suggestive of HDFN with no antibody identified. Case reports are also useful in understanding these cases.
- Monitoring affected pregnancies and neonates remains crucial to prevent poor neonatal outcomes from hyperbilirubinemia and/or anemia.
CONFLICTS OF INTEREST
The author(s) of this chapter declare that they have no interests that conflict with the contents of the chapter.
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