Open access peer-reviewed chapter - ONLINE FIRST

RH Groups

Written By

Amr J. Halawani

Submitted: September 22nd, 2021Reviewed: January 3rd, 2022Published: March 23rd, 2022

DOI: 10.5772/intechopen.102421

IntechOpen
Blood Groups - More Than Inheritance of Antigenic SubstancesEdited by Kaneez Fatima Shad

From the Edited Volume

Blood Groups - More Than Inheritance of Antigenic Substances [Working Title]

Prof. Kaneez Fatima Shad

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Abstract

In 1939, a mother gave birth to a stillborn baby and underwent blood transfusion with ABO-matched blood from her husband. This resulted in a hemolytic transfusion reaction (HTR). Levine and Stetson postulated that a novel antigen was present in the baby and father, which was absent in the mother. Therefore, the mother’s immune system recognized this antigen and produced antibodies against it. This condition has been known as the hemolytic disease of the newborn for a long period of time. Since the antenatal management of the fetus has been developed, the term has been modified to hemolytic disease of the fetus and newborn (HDFN). This case led to the discovery of the antibody against the first antigen of the RH blood group system, the D antigen. To date, 56 antigens have been recognized within the RH blood group system. The five main antigens are D, C, c, E, and e. As observed in the above-mentioned case, the antibodies against these antigens are implicated in HTR and HDFN.

Keywords

  • RH
  • anti-D
  • hemolytic disease of the fetus and newborn
  • antenatal and postnatal management
  • anti-D prophylaxis

1. Introduction

The RH blood group system is the most clinically significant blood group system after the ABO blood group system. It is extremely polymorphic, and to date, 56 antigens have been identified and reported by the International Society of Blood Transfusion [1]. The five main antigens of the RH blood group system are D, C, E, c, and e. Other antigens are represented in a combined form, including the ce or f antigen. Some antigens are correlated to specific ethnicities; e.g., the VS antigen is found in the Black population, which is a variant of the e antigen [2].

1.1 RH polypeptides

The antigens of the RH blood group system are encoded by two highly homologous genes, RHDand RHCE. The cDNA open reading frame of these 2 genes encodes 417 amino acids for each of the RhD and RhCE polypeptides, with a shared sequence identity of 92% (Figure 1). The difference between RhD and RhCE polypeptides is 32–35 amino acids, depending on which RHCEallele is inherited [RHce, cE, Ce, and CE] [3]. The RhD and RhCE polypeptides traverse the membrane lipid bilayer 12 times and form 6 extracellular loops, in which both NH2 and COOH termini are intracellular [4]. In addition, the RhD and RhCE proteins may act as a possible CO2 channel [5].

Figure 1.

The schematic diagram for the RH genes and their proteins. TheRHDgene comprises 10 exons (blue boxes). Two RH boxes, upstream and downstream, are flanked by theRHDgene. TheRHCEgene has the same number of exons (red boxes), but it is in the opposite orientation. Thetransmembrane 50A(TMEM50A) gene is flanked by theRHDandRHCEgenes, which are indicated by a green arrow. Each protein, RhD and RhCE, traverses the red blood cell membrane 12 times forming 6 extracellular loops. On the RhCE protein, two amino acid substitutions, Ser103Pro and Pro226Ala, are indicated in the second and fourth extracellular loops of the RhCE protein. These gave rise to the antigenic polymorphism of the C/c and E/e antigens.

Normally, the RHDgene encodes for the D antigen, whereas the RHCEgene encodes for the C, c, E, and e antigens. Eight possible haplotypes have been identified, which vary from one population to another [6]. Table 1 displays these haplotypes along with the frequencies observed in different ethnicities. For instance, Dceis the most common haplotype observed in individuals of African origin compared with that observed in individuals from England and southwestern Saudi Arabia [7, 8, 10]. By contrast, the Chinese population lacks the Dhaplotypes [9].

HaplotypeEnglish [7]Nigerian [8]Chinese [9]Saudi Arabian [10]
N = 2000N = 274N = 4648N = 3563
Dce(R0)0.02570.59080.03340.0078
DCe(R1)0.42050.06020.72980.4723
DcE(R2)0.14110.11510.18700.2736
DCE(RZ)0.002400.00410.0051
dce(r)0.38860.20280.02320.2410
dCe(r’)0.00980.03110.01890
dcE(r”)0.0119000.0001
dCE(ry)000.00360

Table 1.

Frequencies of RH haplotypes in various ethnicities.

The RhD/RhCE polypeptide is accompanied by two Rh-associated glycoproteins (RhAG) proteins. This association produces a trimer structure as a part of a macrocomplex on the red blood cell membrane proteins [11]. RhAG resembles the RhD and RhCE polypeptides with 36% identity and possesses glycosylation on the first loop. By contrast, the RhD and RhCE polypeptides are not glycosylated [12, 13].

1.2 RHD polymorphisms

The D+ antigen and Dare always denoted as Rh+ and Rh−, respectively. The presence of the D antigen in an individual means that their blood group is D+. However, a person who lacks this antigen is considered D− [14]. Normal D+ individuals have a contact RHDgene with 10 contact exons without any mutations or modifications, with RH boxes that flank the RHDgene from upstream and downstream [15] (Figure 1). Regarding D− individuals, there are various genetic mechanisms underlying this phenotype according to ethnicity. For example, in Caucasians, the entire RHDgene in the dcehaplotype is deleted, resulting in a hybrid box of both upstream and downstream RH boxes [16]. By contrast, Africans possess the pseudogene RHDΨ, which has a 37-bp duplication in intron 3 and exon 4, three missense mutations in exon 5, and a nonsense mutation with a premature stop codon in exon 6 [17].

Regarding the Asian population, D− is rare. Nevertheless, different mechanisms have been identified for the D− phenotype in this ethnicity, including the entire deletion of the RHD gene, D-elute (DEL) phenotype, and hybrid genes (such as RHD-CE(2-9)-Dand RHD-CE(3-9)-D) [18, 19, 20, 21].

1.3 Variants of the D antigen

1.3.1 Weak D

The weak D phenotype was previously designated as Du because it could only be identified by anti-D immunoglobulin (Ig) G in the antiglobulin test and not with anti-D IgM. In contrast to the normal D antigen, the numbers of antigen sites per red blood cell are less and considered quantitative D [22, 23, 24]. The intact D antigen (normal D+) has 13,000–24,000 antigen sites per red blood cell. However, the weak D antigen possesses only between 70 and 4000 sites [25].

The weak D antigen comprises all the D epitopes but with weak expression. This phenotype arose from a missense mutation in the intracellular or intramembranous domain of the RhD polypeptides. Thus, a restriction occurs during the RhD polypeptide subunit assembly, leading to a decrease in the density of the RhD polypeptides [26]. In general, individuals with weak D cannot produce anti-D compared with partial D and are treated as D+ individuals [27]. However, in rare scenarios, weak D can produce anti-D. Hence, the term has been modified to weak partial D for such phenotypes. In summary, the term “D variants” was proposed by Daniels to be used for both weak D and partial D to clear the ambiguity [28]. A website called “The Human Rhesus Base” lists all D variant alleles [29, 30].

1.3.2 Partial D

The partial D phenotype was initially classified into six categories (i.e., I–VI) according to the patterns of antibody reactions with D+ red blood cells, which already produced anti-D [31, 32]. The development of monoclonal antibodies paved the way to identify different reaction patterns. The D antigen is now defined as a mosaic or made of pieces of “epitopes.” Thirty epitopes have been identified and numbered as ep1–ep9, excluding ep7, followed by the subdivisions of these epitopes (e.g., ep8.3) [33].

This phenotype is characterized by the absence of some epitopes and is considered qualitative D [33]. Such individuals can produce anti-D when undergoing blood transfusion with a “complete” and intact normal D antigen and must be treated as D− phenotype when receiving a blood transfusion. In addition, a D− woman who is pregnant with a complete D+ child who inherits the paternal allele from his father is also at risk of developing hemolytic disease of the fetus and newborn (HDFN) [34]. The gene conversion of the two RH genes leads to the formation of a hybrid gene and the replacement of the RHDparts by the corresponding RHCEones. Furthermore, the presence of a missense mutation in the extracellular domains of the RhD polypeptides could result in the partial D phenotype [35].

1.4 Clinical significance of the RH groups

The most immunogenic antibody of the RH blood group system is the anti-D, which has been reported to cause severe hemolytic transfusion reaction (HTR). Therefore, typing for the D antigen is extremely crucial, except in a population in which D− is considered rare [36]. Of note, some D− individuals have been reported to produce anti-D antibodies when blood transfusion reaction occurs and D+ blood is transfused [37, 38, 39].

Anti-D has also been implicated in severe HDFN, leading to fetal mortality [40]. However, since the start of the use of anti-D prophylaxis, this issue has been decreased dramatically [41]. Other antibodies of the RH blood group system, namely, anti-C, anti-c, anti-E, and anti-e, have been observed to result in severe HTR and HDFN [42]. To date, more than 50 antigens among the RH and different blood group systems have been implicated in HDFN, ranging from mild to severe [43].

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2. HDFN

2.1 HDFN pathophysiology

Maternal alloimmunization may be caused by blood transfusion with an incompatible blood group antigen or during the previous or present pregnancy, in which the fetus or neonate inherits the paternal allele of the blood group antigen that is different from the maternal allele [44]. Fetal red cell leakage via the placenta entering the maternal circulation is known as fetomaternal hemorrhage (FMH). These fetal red cells are recognized by the mother’s immune system as foreign bodies and start producing IgM antibodies against these antigens. In the subsequent pregnancy, the maternal IgG antibodies cross the placenta, attach to the fetal red cells, and sensitize them. Consequently, alloimmune destruction can be triggered by splenic macrophages, resulting in anemia with erythroblastosis. The duration of hemolysis varies and causes antenatal or postnatal complications according to the development of the blood group antigen of the fetus [45]. Extramedullary erythropoiesis subsequently occurs to compensate for the destroyed red cells [46].

In the case of mild anemia, an appropriate compensation can be achieved by the liver and spleen. However, in complicated cases, severe anemia leads to hypoxia in multiple organs as a result of difficult delivery that requires sufficient oxygen and nutrients. This subsequently leads to circulatory and liver failure. Liver failure results in a decrease in protein levels and a drop in oncotic pressure in the circulation. Moreover, heart failure increases venous pressure. These two complications lead to ascites and edema, which is recognized as hydrops fetalis that has a high rate of mortality and stillbirth babies [47].

The level of HDFN severity varies from one fetus/infant to another [48]. In most severe cases, the fetus may die in the uterus starting from approximately week 17 of pregnancy [49]. In severe cases presenting with hydrops fetalis, which has high morbidity and mortality, patients could be diagnosed prior to or after the delivery. For the earlier detection of the disease, intrauterine transfusion can be performed in the patients [50]. For moderate HDFN, hyperbilirubinemia can be observed in patients. In such cases, exchange transfusion is needed for the neonate to prevent the accumulation of excess bilirubin in the brain, which may lead to neurological damage and kernicterus. Regarding mild cases, jaundice and hemolysis can be identified in the neonatal period [51].

The hemolysis of the red cells leads to the release of bilirubin into the fetal/neonatal circulation. This released bilirubin has the ability to traverse the placenta, which is then eliminated by the maternal liver. After delivery, the unconjugated bilirubin is processed and excreted by the neonate’s liver. The enzyme diphosphate glucuronosyltransferase is released in a lesser amount owing to the immaturity of the neonate’s liver [52].

Because of fetal hemoglobin destruction, all newborns can exhibit jaundice. Therefore, newborns with severe hemolysis have an increased level of bilirubin. This excess amount can accumulate in the brain and lead to irreversible central neurological damage and death, a condition known as kernicterus [53].

Anti-D is the major cause of HDFN, and it was a major cause of fetal and neonatal morbidity and mortality before 1970. The incidence of stillbirths and infant deaths dropped after anti-D prophylaxis was developed [54]. This anti-D prophylaxis inhibits the production of the maternal anti-D antibodies after the D-mismatch pregnancies. However, partial D mothers can develop anti-D antibodies when they become pregnant with D+ antigen fetus. In this regard, such mothers need to be treated as D− and should receive anti-D prophylaxis [55].

2.2 Factors affecting HDFN immunization and severity

Many factors affect the severity of RH-HDFN, including antigenic exposure, host factors, Ig class, antibody specificity, and influence of the ABO blood group.

2.2.1 Antigenic exposure

FMH from previous pregnancy can lead to a critical increase in maternal antibody titers, leading to maternal alloimmunization. FMH could occur in approximately 93% of mothers in a small amount (as low as 0.5 mL) [56]. The risk of FMH may be elevated as a result of abdominal trauma or because of interventions, including amniocentesis. Furthermore, the occurrence of FMH may exceed 50% at delivery owing to the entry of fetal red cells into the maternal circulation via placental separation from the uterus [57].

2.2.2 Host factors

With respect to the undefined genetic factors that lead to complications, the capability of antibody production differs in response to antigenic exposure [58]. For example, approximately 85% of D− individuals produce alloanti-D antibodies when transfused with blood containing D+ red cells. However, if anti-D prophylaxis has been administered to D− mothers, the remaining 16% will be at the risk of HDFN after pregnancy with D+ babies [59].

2.2.3 Ig class

Among the Ig classes (IgG, IgM, IgA, IgE, and IgD), only IgG has the ability to cross the placenta. The IgG1 and IgG3 subclasses are more efficient in causing red cell intravascular hemolysis compared with the IgG2 and IgG4 subclasses [60].

2.2.4 Antibody specificity

As previously described in this chapter, among all red cell antibodies, anti-D is the most immunogenic. Moreover, anti-C, anti-c, and anti-E are also potent antibodies that can cause moderate to severe HDFN. Anti-c and anti-E may lead to severe HDFN, which require management and treatment [61].

2.2.5 Influence of the ABO group

Of note, the incidence of detecting FMH is decreased when the mother is ABO-incompatible with the fetus. The rate of D immunization has been reported to be less in mothers with major ABO incompatibility with the fetus. This may be caused by the clearance of hemolysis that occurs due to the presence of ABO-incompatible D+ fetal red cells in the maternal circulation prior to the identification of fetal D+ red cells by the mother’s immune system [57].

2.3 Anti-D prophylaxis

Anti-D prophylaxis is also known as RH immune globulin. In 1965, the success of the anti-D prophylaxis was reported; the prophylaxis was given to D− mothers after the delivery of the D+ newborn [62]. Anti-D prophylaxis has become the backbone therapy to preclude any clinical significance of RH-HDFN. However, the mode of action regarding how these prophylaxis works remain unclear [63].

Anti-D prophylaxis contains a natural product derived from human plasma that helps in the prevention of sensitization events; therefore, there might be a risk of infectious disease transmission [64]. In general, male blood donors are used and re-exposed to a small volume of the D antigen. As a consequence, the anti-D antibody is then developed by the immune system of the donors, followed by plasma collection and processing [65].

Anti-D prophylaxis was only administered to D− mothers postnatally, and in the 1970s, the prophylaxis was modified to include an antenatal dose for the additional prevention of any sensitizing event of RH-HDFN [66].

Different anti-D prophylaxis routines are used in different countries, in which most of them administer the antenatal dose at 34 weeks. The current regimen is by administering two doses to the D− or partial D mothers who are pregnant with D+ babies. The first dose of the anti-D prophylaxis should be administered to D− mothers within 28–34 weeks of pregnancy, which could decrease the antenatal immunization [67, 68]. A total of 92% of mothers were shown to have become sensitized after week 28 [64]. If sensitization events occur, anti-D prophylaxis must be immediately administered within 72 h [69].

The second dose of anti-D prophylaxis must be given within 72 h of delivery to all D− mothers. This dose has reduced the burden of RH-HDFN by approximately 95% in the last 52 years [70]. Indeed, the second dose was initially introduced in the first routine of anti-D prophylaxis [66]. The recommended dosage of anti-D is 300 mg [49]. A larger dose might be given depending on the magnitude of FMH to reduce the risk of sensitization. The dose is typically calculated depending on the magnitude of FMH either using the Kleihauer-Betke test or flow cytometry. Cellular assays might be performed to predict the severity of HDFN, including antibody-dependent cellular cytotoxicity assay, monocyte monolayer assay, and chemiluminescence [71].

2.4 Antenatal screening (fetus at risk)

In general, the recommended routine testing for ABO and D grouping on a maternal blood sample is performed in the first trimester to predict the severity of HDFN. Antibody screening is also performed. Antibody screening must be performed frequently during pregnancy to identify any emerging antibodies. The early investigation of any new antibodies could assist in the monitoring and management of HDFN [72].

Maternal antibody titer testing is performed if IgG antibody screening is positive. Each antibody has a certain titer, which varies as per the antibody. If this titer is below a certain level, further management for HDFN is not necessary [73]. Titer measurement can also be beneficial to distinguish between immune and passive anti-D. Nevertheless, the severity of HDFN cannot be reliably determined [74]. If the maternal antibody level is higher than the critical titer, paternal RHDzygosity testing may be required.

2.4.1 Predicting D phenotype from DNA

2.4.1.1 Paternal RHDzygosity testing

The management of all immunized mothers is possible via paternal RHDzygosity testing, which detects the copy number of the father’s gene. This identifies the father’s zygosity status and paternity. Nowadays, various techniques have been used for RHDzygosity testing. These include real-time polymerase chain reaction (PCR), digital PCR, and mass spectrometry [75, 76, 77, 78].

When fathers are homozygous for the deletion of the entire RHDgene, i.e., D−, there is no risk of HDFN within the current or subsequent pregnancies. By contrast, when fathers are D+ carrying both the alleles of positive RHDgene (homozygous, e.g., DCe/DCe), then the fetus will definitely be D+. The fetus has a 50% possibility of being D+ in case the father’s genotype is hemizygous (e.g., DCe/dce). Therefore, further analysis using noninvasive prenatal testing (NIPT) is required [77].

Some methods assess the hybrid Rhesus box expressed in D− individuals, which results from the entire RHDgene deletion in Caucasians. It mainly targets the cdehaplotype; therefore, such a method cannot be applied to the samples of African ethnicity [79]. A total of 59% of Nigerians [8] possess the Dcehaplotype [see Table 1].

2.4.1.2 Fetal genotyping

Amniocentesis is a risky and invasive procedure for obtaining fetal DNA. It can increase the risk of alloimmunization and miscarriage. Instead, NIPT is nowadays performed for fetal genotyping. The approach is now followed globally and is performed by detecting cell-free fetal DNA extracted from the maternal plasma [80, 81].

Fetal genotyping is a noninvasive technique based on cell-free fetal DNA circulating in the maternal plasma, which is derived from a maternal blood sample. This approach assists in identifying different blood group alleles and predicting the corresponding antigens, including D, C, c, E, and e, in addition to KEL1 antigens [82, 83].

If the mother is D− and the fetus is D+, anti-D prophylaxis may be administered. By contrast, if the fetus is D−,the D− mother does not need to receive the prophylaxis. Therefore, this avoids unnecessary injections in the mother; moreover, it appears to be cost-effective to save treatment for the mothers in actual need [84]. Thus, the approach of fetal genotyping could be cost-effective [85].

2.5 Antenatal management

2.5.1 Ultrasonography

Amniocentesis has been replaced by the middle cerebral artery (MCA) Doppler ultrasonography for predicting the severity of fetal anemia. At present, this method is routinely used by obstetricians for investigating fetal anemia by observing an increase in the velocity of blood flow in MCA in anemic fetuses compared with normal ones [86, 87]. In the case of severe anemia, fetal blood sampling (FBS) can be performed along with cordocentesis. Under ultrasound guidance, FBS is normally performed with a needle to obtain fetal blood; this procedure is considered an invasive procedure [88].

2.5.2 Intrauterine transfusion

For severely HDFN-affected fetuses, intrauterine transfusion provides blood to the fetus via the umbilical vein under ultrasound guidance. Fetuses must be administered Oblood (unless fetal ABO type is known), which is also KEL-1 negative, leuko depleted, plasma depleted, hemoglobin S negative, cytomegalovirus seronegative, and ≤5 days old [89]. Furthermore, citrate phosphate dextrose is the anticoagulant used in these blood units to prevent problems arising from using different anticoagulants. Gamma irradiation is performed to eliminate any residual leukocytes that may lead to graft-versus-host disease [89].

Fetal hemoglobin and hematocrit level measurement along with crossmatching is performed to ensure that safe compatible blood is transfused to the fetus. All blood units are normally prewarmed to 37°C before being transfused. Interestingly, intrauterine transfusion has been reported to reduce prenatal death and stillbirth resulting from HDFN by 75–90% [90, 91].

2.6 Postnatal screening (newborn/infant at risk)

The serological investigation is performed after a sample is withdrawn from the cord blood at birth. This sample is used to detect HDFN, which may help arrange for probable transfusion.

2.6.1 ABO grouping

The forward ABO blood group typing may be observed with weak reactions with anti-A and anti-B antisera in infants compared with adults and older children [57]. This is because the ABO antigens of newborn infants are not entirely developed and may take 510 years to reach the adult levels [92]. Furthermore, reverse ABO grouping is not feasible because infants do not produce ABO antibodies at that age.

2.6.2 D typing

In rare cases, an infant’s red cells strongly bind to the maternal anti-D antibody, resulting in a false-negative type of D or what is known as blocked RH [93]. Anti-D can be identified from the eluant of these red cells, and typing these eluted red blood cells should be observed for any reaction with the anti-D antibody.

2.6.3 Direct antiglobulin test (DAT)

DAT is very crucial in diagnosing HDFN. A positive DAT demonstrates a sensitization reaction in which an infant’s red cells are coated by maternal IgG antibodies. No correlation has been observed between the severity of HDFN and the reaction strength. Moreover, other laboratory or clinical manifestations for hemolysis can also lead to positive DAT. This could be owing to the mother receiving the anti-D prophylaxis [57].

2.6.4 Elution

Performing the elution test in the case of positive DAT is not essential as a routine procedure. As previously mentioned, eluant is the solution for blocked RH [57, 93].

2.7 Infant management

2.7.1 Phototherapy

This procedure is used to treat anemic newborns with mild to moderate HDFN and who have elevated levels of bilirubin. Phototherapy is performed using a blue-green light, with wavelength ranging from 460 to 490 nm [94]. Natural direct sunlight has been reported to have the same wavelength and can be beneficial to reduce jaundice, although it is not recommended because it may increase the risk of sunburn [95, 96].

Bilirubin is a lipophilic molecule that absorbs light and is metabolized into two isomers, which are less lipophilic (in other words, water-soluble) and less toxic to the brain. These can then be excreted via the urine without the requirement of enzymatic glucuronidation [97]. Overall, phototherapy is an effective procedure and can adequately conjugate bilirubin. Furthermore, it may assist reduce the requirement of blood transfusion [57].

2.7.2 Exchange transfusion

Exchange transfusion may be performed in newborns who demonstrate severe anemia with hyperbilirubinemia or heart failure. During pregnancy, the fetal liver is unable to metabolize the unconjugated bilirubin. Therefore, this unconjugated bilirubin, made by the fetus, is crossed the placenta and metabolized by the maternal disposal system. After delivery, this system is no longer used as well as the infant’s liver is immature and cannot metabolize the unconjugated bilirubin efficiently. Therefore, the high level of bilirubin in the newborn may lead to kernicterus, which is the accumulation of bilirubin in the brain.

The assessment of hemoglobin and bilirubin levels is essential to determine the requirement of exchange transfusion in neonates. This is performed for removing bilirubin and maternal antibodies from neonates [98, 99]. Exchange transfusion is indicated at a critical level of bilirubin (i.e., ≥100 μmol/L), depending on the neonatal age.

Exchange transfusion is the replacement of neonatal blood by whole blood or equivalent, with the concurrent removal of bilirubin and maternal antibodies. However, this procedure is labor-intensive and time-consuming. Therefore, its use has become rare owing to the use of anti-D prophylaxis and phototherapy [50].

2.7.3 Red cell transfusion

Infants may receive red cell transfusion immediately after delivery for several weeks to treat severe anemia. The same criteria that are used for intrauterine transfusion and exchange transfusion must be applied for blood transfusion. Newborns must be closely monitored for any clinical signs of ongoing anemia, particularly if the infant is malnourished or sleeps heavily [98].

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3. Conclusion

In summary, RH is the most highly variable blood group system. The antigens of this system have many variants that include the D variants such as weak D and partial D. The antibodies of this system can cause HTR due to incompatibility during a blood transfusion. Furthermore, their antibodies can lead to fetal red cell sensitization and destruction, causing moderate to severe HDFN. Nowadays, owing to the development of the latest technologies, the antenatal management of fetuses has become feasible along with postnatal management. Anti-D prophylaxis can now be administered antenatally at gestational weeks 28–34. At-risk pregnancies can also be monitored noninvasively using MCA ultrasonography and fetal genotyping.

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Conflict of interest

The author declares no conflict of interest.

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Written By

Amr J. Halawani

Submitted: September 22nd, 2021Reviewed: January 3rd, 2022Published: March 23rd, 2022