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Management of non-RhD red blood cell alloantibodies during pregnancy

Management of non-RhD red blood cell alloantibodies during pregnancy
Literature review current through: Sep 2023.
This topic last updated: Apr 10, 2023.

INTRODUCTION — Maternal alloantibodies to red blood cell (RBC) antigens other than RhD are capable of causing clinically significant hemolysis of fetal and newborn RBCs, known as hemolytic disease of the fetus and newborn (HDFN). Once an alloantibody is identified, appropriate testing and estimation of the risk to the fetus are essential to obstetric care.

This topic review discusses the clinical significance of RBC alloantibodies other than anti-RhD during pregnancy. Separate topic reviews discuss RhD alloimmunization, fetal transfusion, and postnatal management of HDFN.

(See "RhD alloimmunization: Prevention in pregnant and postpartum patients".)

(See "RhD alloimmunization in pregnancy: Overview".)

(See "RhD alloimmunization in pregnancy: Management".)

(See "Alloimmune hemolytic disease of the newborn: Postnatal diagnosis and management".)

(See "Intrauterine fetal transfusion of red cells".)

(See "Red blood cell (RBC) transfusions in the neonate".)

RBC antigens and alloimmunization in the nonpregnant patient are also presented separately. (See "Red blood cell antigens and antibodies" and "Pretransfusion testing for red blood cell transfusion" and "Red blood cell (RBC) transfusion in individuals with serologic complexity".)

TERMINOLOGY AND PATHOGENESIS

Definition of terms — The following terms are used to describe the condition that results when maternal alloantibodies cause hemolysis of fetal or neonatal red blood cells (RBCs):

HDFN – Hemolytic disease of the fetus and newborn (HDFN) refers to hemolysis of fetal or neonatal RBCs by maternal alloantibodies to a fetal RBC antigen. This condition was previously called hemolytic disease of the newborn (HDN), which reflects its initial description in newborns, before tools for assessing fetal hemolysis were available.

RhD disease – HDFN due to maternal alloantibodies to the RhD antigen is also called Rh disease of the newborn, RhD disease, and RhD HDN. This subject is discussed in detail separately. (See "RhD alloimmunization in pregnancy: Overview".)

Alloantibodies other than anti-RhD – Importantly, there are alloantibodies other than anti-RhD that can cause HDFN. These include antibodies directed against other Rh antigens, including C, c, E, and e; and antigens from other blood group systems.

Hydrops fetalis – The most severe manifestation of HDFN that occurs in utero is hydrops fetalis, in which severe anemia and extramedullary hematopoiesis in the liver and spleen lead to heart failure and generalized edema (hydrops).

Maternal alloantibodies — Development of HDFN requires a maternal exposure to an RBC antigen not expressed on maternal RBCs and generation of an alloantibody. Potential sources of exposure include the following:

Transfusion – Previous blood transfusion to the mother is a common route of exposure to RBC antigens. Transfusion of RBCs is most commonly implicated, but platelets, which may contain a small number of RBCs, may also be responsible.

Transfusion is an especially common route for the development of antibodies against the K antigen (also called KEL1 or K1) of the KEL blood group system [1,2]. K is the strongest immunogen of the KEL system and can elicit anti-K [3]. Some individuals who are negative for the K antigen will develop alloantibodies to K if they receive K-positive blood products. A likely reason is the lack of routine testing of donor blood for antigens other than ABO and RhD.

Fetomaternal bleeding – Fetomaternal bleeding is another common cause of exposure to RBC antigens. Transplacental fetomaternal bleeding may be related to miscarriage, pregnancy termination, ectopic pregnancy, antepartum vaginal bleeding from placenta previa or placental abruption, abdominal trauma, or delivery (livebirth or stillbirth). It may also occur in the absence of a recognizable inciting event.

Shared needles – Injection with needles contaminated with another person's blood has been reported to cause alloimmunization to RhD in intravenous drug users; thus, exposure is considered a potential cause of sensitization to other RBC antigens [4-6].

The likelihood of alloimmunization increases with greater volumes of allogeneic blood to which an individual is exposed; thus, transfusion is more likely to cause alloimmunization than fetomaternal bleeding. However, exposure to as little as 0.5 mL of allogeneic blood can cause alloimmunization.

Following maternal sensitization to an RBC antigen through any of the above mechanisms, subsequent exposure during a future pregnancy will elicit an antibody response of variable intensity and timing.

To cause hemolysis of fetal cells, the maternal alloantibody must be transported across the placenta; thus, antibodies of the IgG class are usually implicated.

RBC antigens of the Lewis, I, and P blood groups often elicit IgM antibodies, which are not transported across the placenta and thus are not clinically significant causes of HDFN. (See 'Prevalence of alloantibodies in pregnancy' below.)

Antibodies of the Cromer blood group system can bind to a placental protein (decay accelerating factor), which traps them in the placenta and prevents them from entering the fetal circulation [7].

Antibody specificity (the antigen to which the antibody is directed) and titer (a measure of antibody concentration in maternal blood) are helpful in estimating the risk of HDFN (algorithm 1). Antibodies to certain blood group systems are more likely to cause severe HDFN, as listed in the table (table 1). The most commonly seen antibodies with the potential to cause severe HDFN besides anti-RhD include anti-K, anti-c, and anti-E. A high antibody titer is more predictive of severe fetal anemia than a low titer [7]. (See 'Prevalence of alloantibodies in pregnancy' below.)

Some antibody subclasses, such as IgG1 and IgG3, are more efficient at causing hemolysis than others. IgG1 is transported across the placenta earlier and in larger amounts than IgG3 [8]. IgG2 and IgG4 antibodies do not normally play a significant role in RBC hemolysis. Antibody subtype classification is generally used for research purposes and not for clinical management.

Although not associated with HDFN, naturally occurring antibodies to some RBC antigens can develop when the antigens are similar to epitopes present on microorganisms (a form of molecular mimicry). The most common example is the ABO blood group antigens A and B. Anti-A and anti-B are present in virtually all individuals who lack the corresponding antigen, due to exposure to gut bacteria; however, these antibodies are IgM and/or IgA and thus do not cross the placenta. Group O individuals are unique in that, in addition to IgM and IgA class antibodies, they form small amounts of IgG antibodies to the A and B antigens. The IgG antibodies are capable of crossing the placenta, which may contribute to HDFN [9]. (See 'ABO' below.)

Anti-M and anti-N, also due to gut microorganisms, are present in 2 to 3 percent of the general population [10]. (See 'MNS' below.)

Fetal/neonatal anemia — Fetal or neonatal anemia can only develop if the maternal antibody crosses the placenta and binds its cognate antigen on fetal RBCs. Thus, if the fetus has not inherited the implicated antigen, or the antigen is one that does not develop on fetal RBCs until after birth, hemolysis cannot occur.

RBC antigens are inherited from both parents. If the father is homozygous for the gene encoding the antigen, all of his children will be antigen-positive; if he is heterozygous, approximately half will be antigen-positive.

RBC antigens are expressed at various stages during gestation, beginning in the first trimester of pregnancy. Some antigens are not well developed on fetal or neonatal RBCs and therefore are not associated with HDFN; examples include the Lutheran system antigen Lu(b) and the Cartwright antigen Yta.

Once a maternal antibody binds to fetal RBCs, the cells can be phagocytized by reticuloendothelial macrophages in the spleen or liver, causing fetal anemia; this form of RBC destruction is referred to as extravascular hemolysis [11]. In more severe forms of HDFN, intravascular hemolysis also occurs (ie, direct lysis of RBCs within the circulation) [11].

In most forms of HDFN, RBC production (erythropoiesis) is increased in order to compensate for hemolysis [11]. A major exception occurs in HDFN due to K alloimmunization because antibodies against K antigen cause hemolysis and suppress erythropoiesis, the latter via destruction of RBC progenitor and precursor cells in the bone marrow. Anti-K thus leads to earlier and more severe anemia than many other alloantibodies.

After delivery, hemolysis can continue due to persistent maternal antibody in the neonatal circulation. Maternal antibody levels decline over approximately 12 weeks [11].

Hyperbilirubinemia is not an important problem for the fetus, because bilirubin resulting from hemolysis is transported back to the maternal circulation, where it is conjugated and cleared. After delivery, however, conjugation of bilirubin depends on the newborn liver, which cannot conjugate bilirubin efficiently. Thus, hyperbilirubinemia is a concern after delivery. (See "Unconjugated hyperbilirubinemia in neonates: Etiology and pathogenesis".)

PREVALENCE OF ALLOANTIBODIES IN PREGNANCY — Overall, alloantibodies to non-RhD red blood cell (RBC) antigens are seen in approximately 1.5 to 2.5 percent of pregnancies [12]. Other than RhD, the antigens most commonly implicated in hemolytic disease of the fetus and newborn (HDFN) are K, c, and E. The likelihood that alloantibodies will cause HDFN increases as the number of at-risk pregnancies increases. The distribution of antibody specificities depends on the population sampled and the sampling methods used.

In a large prospective series that included over 300,000 consecutive pregnancies, first trimester screening revealed an alloantibody to an antigen other than RhD in 1002 participants (approximately 1 percent), accounting for approximately one-quarter of all alloantibodies in this series [13]. The most common were anti-E, anti-K, and anti-c. Clinically significant antibodies (eg, those requiring in utero or neonatal transfusion) to antigens other than RhD occurred in 21 of 567 fetuses at risk (3.7 percent).

In a study of 110 pregnant mothers with 111 at-risk fetuses and maternal antibody titers of 16 or greater, antibodies to RhD, K, E, and c were present in 84, 18, 8, and 3 fetuses, respectively [14].

In East Asia, the relative frequency of non-RhD HDFN is higher because the proportion of RhD-negative individuals in the population is especially low.

Some "low frequency" antigens are present in such a small percentage of the population that they are not present in reagent screening cells used to detect maternal alloantibodies (table 1). Alloantibodies to these antigens may be missed by standard maternal screening, and in rare cases in which they cause hemolysis, the problem may not be detected until delivery [15]. (See "Alloimmune hemolytic disease of the newborn: Postnatal diagnosis and management".)

ALLOANTIBODIES NOT ASSOCIATED WITH HDFN — As mentioned above, maternal antibodies will not cause hemolytic disease of the fetus and newborn (HDFN) if they cannot cross the placenta (eg, IgM), or if they are directed against an antigen not expressed on fetal red blood cells (RBCs) (see 'Terminology and pathogenesis' above). This includes antibodies to the Lewis blood group antigens, the I antigens, and the P antigen P1. Maternal titers and fetal assessment for anemia are unnecessary for pregnancies associated with these alloantibodies.

Lewis — The Lewis antigens are not associated with HDFN. This includes Le(a), Le(b), and four rare associated antigens. Antibodies to Lewis antigens are IgM, and fetal RBCs lack Lewis antigens, which develop later in childhood [16]. However, Lewis antibodies commonly are detected during pregnancy and often may lead to a concern for HDFN.

I — The I antigens are not associated with HDFN. The I blood group includes "I" and "i" antigens, neither of which has been associated with HDFN. Fetal and newborn RBCs strongly express the i antigen, with only small amounts of I antigen.

P1 — The P1 antigen often elicits an IgM alloantibody in individuals who express P2; anti-P1 is not associated with HDFN. In contrast, individuals with the very rare "p" phenotype can produce clinically significant alloantibodies to other P antigens. (See 'P' below.)

ALLOANTIBODIES THAT CAN BE ASSOCIATED WITH HDFN — Antibodies to blood group systems that have been associated with hemolytic disease of the fetus and newborn (HDFN) are listed in the table (table 1); however, the presence of antibodies to these blood group systems does not necessarily result in HDFN. Some of these blood group systems are discussed in more detail below.

KEL — The most antigenic of the KEL group is K. K-sensitized pregnancies are responsible for approximately 10 percent of severe cases of HDFN. In a large series that included 19 K-sensitized pregnancies, severe HDFN was seen in five (26 percent) [13].

Other KEL antigens include k, Kp(a), Kp(b), Ko, Js(a), Js(b), and a large number of other rare antigens; these are rarely a cause of KEL incompatibility [17]. The genotype frequencies in White Americans are approximately: Kk (8.7 percent), kk (91.1 percent), and KK (0.2 percent) [16]. By comparison, the frequencies for African Americans are Kk (2 percent) and kk (98 percent); KK is extremely rare.

Blood transfusion is likely the most common mechanism of K sensitization in reproductive-age females. Antigen testing for K antigens is not routinely performed on blood donors in the United States, although it is in some countries (eg, Australia, the Netherlands) [18]. In one series, 8 of 12 K-sensitized individuals with K-positive newborns had a prior blood transfusion [19]. Some countries have adopted a K-matched transfusion policy for females of childbearing age in an attempt to prevent K-immunization in pregnancy [20]. Alloimmunization during a previous pregnancy may account for anti-K in gravidas who have not received a transfusion.

HDFN due to anti-K can be severe. One reason for this is the ability of anti-K to cause destruction of red blood cell (RBC) precursors and maturing erythrocytes in the bone marrow as well as circulating mature fetal RBCs (see 'Fetal/neonatal anemia' above). Anti-K can be particularly troublesome because the titer of the alloantibody correlates poorly with the likelihood of fetal anemia, and the severity of anemia can change dramatically over the course of a single week [19,21-25]. Hydrops fetalis can develop before the third trimester.

The severity of HDFN from K alloimmunization was illustrated in a large cohort study that identified 1026 K-sensitized pregnancies in the Netherlands [26]. Of these, there were 124 cases in which a mother with anti-K was pregnant with a K-positive child (in one case, twins). After exclusion of pregnancies with multiple alloantibodies, there were 92 remaining pregnancies (93 neonates) with K sensitization and signs of HDFN. Findings from these pregnancies included the following:

Intrauterine transfusion was required for 48 fetuses (52 percent). An additional neonate received a transfusion after birth.

There were three perinatal deaths related to anti-K.

Of the 16 pregnancies with titers <4, none had severe HDFN.

Use of a cutoff maternal antibody titer of 4 provided the best sensitivity (100 percent), specificity (36 percent), positive predictive value (64 percent), and negative predictive value (100 percent).

The first antibody titer obtained (median gestational age, 14 weeks) had the highest power to predict the need for transfusions, and subsequent titers did not change substantially during the pregnancies.

Other series have reported similar findings [22]. One case of fetal hydrops has been reported in the second trimester when the maternal titer was 2 [3].

Management of K-sensitized pregnancies thus requires a lower threshold antibody titer, as discussed below. (See 'KEL-sensitized pregnancy' below.)

Rh system antigens c and E — The Rh system includes many antigens other than RhD, the most clinically significant of which are "c" and "E." Other Rh antigens include "C" and "e"; there is no "d" antigen. Importantly, administration of anti-D immune globulin does not protect the mother from developing antibodies directed against these other Rh antigens. The likelihood of HDFN due to other Rh antigens was illustrated in a large series that included 118 c-sensitized pregnancies; of these, severe HDFN was seen in 12 (10 percent) [13].

The hemolytic effect of c is similar to RhD [18]. In various case series, mortality rates up to 10 percent have been reported; intrauterine transfusions have been required in 1 to 17 percent, and neonatal transfusions have been required in approximately 10 to 30 percent [27-30].

Special mention should be made of the RhD-negative pregnant individuals presenting with what appears to be anti-"C+D." The patient may actually have an antibody to the G antigen, which is present on any RBC that expresses C and/or RhD. Immunohematology reference laboratories can readily distinguish between these possibilities. The clinical importance of this distinction is that the individual may be negative for RhD and may not have been actively alloimmunized to the RhD antigen, and thus they are a candidate for anti-D immune globulin. (See "RhD alloimmunization in pregnancy: Overview".)

Antibodies against the Rh antigens C, E, and e are usually found at a low titer in conjunction with anti-RhD antibody (eg, anti-D, 128; anti-C, 2). Their presence may be additive to the hemolytic effect of the anti-D antibody on the fetus [31]. Intrauterine transfusions are only rarely reported when these antibodies occur as the sole finding [32,33].

Duffy — The Duffy antigens, Fy(a) and Fy(b), are encoded by codominant alleles, giving the phenotypes Fy(a+b+), Fy(a-b-), Fy(a+b-), or Fy(a-b+). Only anti-Fy(a) antibody has been associated with HDFN, which may range from mild to severe [34].

One study reported that 82 percent of Black individuals were Fy(a-b-), likely because Fy(b) antigen serves as a receptor for malaria [35]. (See "Protection against malaria by variants in red blood cell (RBC) genes", section on 'Duffy blood group system'.)

MNS — The MNS system contains the M, N, S, s, and U antigens, as well as 32 other rare antigens. Naturally occurring antibodies to M and N are seen in a small percentage of the general population in the absence of exposure to allogeneic blood. (See 'Maternal alloantibodies' above.)

Anti-S, anti-s, and anti-U have been reported to cause mild to severe HDFN; anti-N may cause mild hemolysis.

Anti-Mur, which is especially common in Southeast Asians, can cause mild or severe disease [36,37].

Anti-M rarely causes fetal anemia since it is typically IgM. However, severe HDFN due to anti-M may occur if the antibody is a high-titer IgG (or a mixture of IgM and IgG) that is active at 37°C rather than room temperature [38-43]. Severely affected fetuses have been hydropic and/or have received intrauterine transfusion or transfusion after birth [44]. Consultation with the transfusion medicine service or blood bank can help to determine whether the antibody is predominantly IgG, IgM, or mixed (eg, by treating the maternal serum with dithiothreitol [DTT]) or to perform serial anti-M titers to assess for rapid increases or titers above a threshold [45,46].

Affected fetuses and newborns have shown hypoproliferative anemia out of proportion to that expected based on the antibody titer, similar to that seen with anti-K. A greater component of erythropoietic suppression rather than hemolysis may contribute to missed diagnosis [47].

A 2023 series of 17 infants with anti-M HDFN reported less reticulocytosis than infants with HDFN due to anti-D or antibodies to ABO antigens [47]. Transfusions were given to 14 of the 17 (82 percent), and the risk of premature birth, low birthweight, and dyspnea were higher than in the infants with anti-D or antibodies to ABO antigens. One infant died from severe anemia; there was a history of stillbirth or neonatal death in 7 of 39 prior pregnancies in the anti-M cohort. Antibody titers were higher at 4°C than at 37°C in five mothers.

Severe HDFN related to anti-M is most frequently reported in patients of Asian ancestry [44]. Case series, as well as our experience, have failed to reveal severe cases in North America [38,48].

P — The P system consists of the P1 and P2 antigens. Individuals with the very rare "p" phenotype can produce anti-P1+P+P(k), an antibody that has been associated with severe HDFN and recurrent early pregnancy loss [49]. Those with the P2 antigen commonly produce anti-P1 antibodies, which are IgM antibodies that do not cross the placenta. (See 'P1' above.)

ABO — The ABO system contains the A and B antigens, which are assembled on the H antigen. Type O represents the absence of A and B (ie, H alone). The A and B antigens are codominantly expressed, resulting in blood types A, B, O, and AB. Thus, an individual who is type A can be heterozygous or homozygous for the A antigen; a type B individual can be heterozygous or homozygous for B.

Naturally occurring IgM antibodies to A and B develop early in life in individuals lacking the corresponding antigen, following exposure to bacterial antigens in the gut. These IgM antibodies do not cross the placenta and do not cause HDFN. IgG antibodies directed against A and B antigens may cross the placenta and cause HDFN, particularly in group O mothers who have been exposed to a non-O fetus [50]. In contrast to other IgG alloantibodies, severe hemolysis due to ABO incompatibility is usually a problem for the neonate and rarely affects the fetus [51-55]. However, hemolysis may be particularly pronounced in group B African-American neonates, in whom the B antigen is more developed at birth than in other populations [51-53,56,57].

An issue may arise when a type A or B, RhD-negative fetus of a type O, RhD-negative mother is typed for RhD. Apparent weak RhD-positivity may be seen at the antiglobulin stage of testing due to the presence of maternal anti-A or anti-B on the surface of the neonate's red cells even though the neonate is RhD-negative. This weak RhD typing is a false positive reaction. An elution technique to remove maternal IgG can be performed using the baby's cells followed by retesting with reagent anti-D to determine the baby's RhD-type.

PREPREGNANCY COUNSELING — If a nonpregnant female is found to have an alloantibody to a red blood cell (RBC) antigen, they should be counseled regarding the potential effects of the antibody on a future pregnancy. Details of this counseling will depend on the class of the antibody (IgG versus IgM); the specificity (ie, the target antigen); and the antigen type of the biologic father, which determines the risk to the fetus.

Parental testing — Individuals with a history of hemolytic disease of the fetus and newborn (HDFN) require further testing to determine the specificity and the potential father's antigen status. In some situations, such as the detection of an anti-M antibody, further consultation with a blood bank medical director is indicated to determine if the antibody is of the IgG or IgM class. The antibody titer prepregnancy is not useful, since the titer may rise several-fold during pregnancy. If the antibody is capable of producing HDFN (eg, IgG, concerning specificity) and the potential father of the future pregnancy is known, it is reasonable to determine whether he carries the associated RBC antigen and, if so, whether he is homozygous or heterozygous for the allele.

Prevention of HDFN — HDFN can be prevented by avoiding pregnancy with fetal RBC antigen-maternal RBC antibody incompatibility. Prevention is rarely attempted because of the costs and complexities involved and because HDFN can be treated successfully in most cases. Fetal RBC antigen-maternal RBC antibody incompatibility can be avoided in the following ways:

In vitro fertilization with preimplantation genetic diagnosis – If the potential biologic father is heterozygous for the antigen, in vitro fertilization (IVF) with preimplantation genetic diagnosis (PGD) can be used to identify antigen-negative embryos, and only these embryos are considered for embryo transfer [58]. (See "Preimplantation genetic testing".)

Use of a gestational carrier – If the potential biologic father is homozygous for the antigen, the intended parents can conceive by IVF and the embryo can be carried by a gestational carrier who is not alloimmunized. (See "Gestational carrier pregnancy".)

Use of donor sperm – Sperm from an antigen-negative donor can be used for intrauterine insemination of the alloimmunized mother. (See "Donor insemination".)

PRENATAL MANAGEMENT — Our general approach to diagnosis and management of non-RhD alloimmunization in pregnancy is illustrated in the algorithm (algorithm 1) and outlined below. The efficacy of this approach has been demonstrated in several case series; however, there is limited evidence on which to base management [34,59]. This approach is consistent with recommendations of the American College of Obstetricians and Gynecologists (ACOG), which advise that the care of patients with non-RhD alloantibodies should be the same as for those with RhD alloimmunization, with the possible exception of K sensitization [12].

Antibody screening — Routine screening for antibodies to red blood cell (RBC) antigens, as well as ABO testing, should be performed early in pregnancy, typically at the first prenatal visit; this will include screening for anti-RhD as well as a number of other antibodies [60]. Testing is done by incubating maternal serum with selected RBCs, known as the antibody screen, by the indirect antiglobulin (IAT, also called Coombs) method. This testing is highly accurate and relatively inexpensive. If no clinically significant alloantibodies are detected, antepartum antibody screening usually is not repeated, because clinically significant, late-onset alloimmunization is rare, on the order of 0.18 percent or less [13,60-65].

The results of maternal antibody screening and antibody identification are compared with any prior data that are available. If one or more alloantibodies are detected, paternal RBC antigen typing is recommended.

Follow up a positive antibody screen — If the maternal antibody screen identifies an alloantibody, the potential for causing clinically significant hemolytic disease of the fetus and newborn (HDFN) must be assessed (algorithm 1). Relevant information includes a history of HDFN in previous pregnancies with the same biologic father; the likelihood of HDFN for the implicated antigen specificity; the maternal alloantibody class (IgG versus IgM) and level of antibody in maternal plasma; and when appropriate, determination fetal RBC antigen status. Antibody titration provides information about whether the antibody concentration is above a critical threshold value. However, after this titer is reached, further assessment of antibody titer does not correlate well with the likelihood or severity of HDFN.

Evaluate the antibody — The maternal antibody is evaluated as follows (algorithm 1):

Eliminate inconsequential antibodies – If the antibody is IgM or has never been associated with HDFN (table 1), the fetus is not considered at risk and no further testing is needed.

For clinically significant antibodies, determine maternal antibody level

Maternal antibody titer – The antibody titer can give an estimation of the antibody concentration in maternal blood. A higher titer correlates with a higher antibody concentration in maternal blood, and an increasing titer suggests ongoing stimulation of maternal antibody production. We consider a fourfold increase in a current titer when compared with a previous titer, run in parallel, as a meaningful increase suggestive of continuing maternal antibody production.

The antibody titer is the reciprocal of the greatest dilution of maternal serum at which the antibody agglutinates RBCs that express the corresponding antigen. It is calculated from measuring RBC agglutination with serial dilutions of maternal plasma.

Titration is used if a maternal alloantibody is found and the fetus is potentially at risk for expressing the antigen. A titer above a critical threshold value predicts an increased likelihood of HDFN, and HDFN is extremely unlikely at a titer below a critical threshold. However, the titer does not correlate linearly with the risk of HDFN or the severity of hemolysis, which provides the rationale for additional testing if the titer exceeds the critical threshold. Titration is considered unreliable for predicting the likelihood of HDFN if a prior pregnancy with the same father was associated with HDFN, and a high antibody titer does not correlate well with the severity of hemolysis in any setting.

Titration of a clinically important maternal alloantibody can be done simultaneously with determination of fetal antigen status or sequentially, depending on the clinical setting. Both pieces of information are used in deciding whether serial monitoring for fetal anemia is needed.

If a past pregnancy was complicated by HDFN, subsequent pregnancies are at high risk of recurrence. Antibody titration should still be undertaken, as cases associated with high titers in association with a previous early second trimester fetal loss may be candidates for treatment with intravenous immune globulin [66]. However, the converse is not true; a previous unaffected pregnancy cannot be used to eliminate the possibility of an affected fetus, because the father may be heterozygous for the antigen, there may be a different father, or sensitization to the antigen may have occurred at the time of a prior delivery or miscarriage.

The critical titer is the titer below which the risk of HDFN is unlikely and fetal testing or monitoring is not required. The critical titer is lower for anti-K (of the KEL system) than for other antibodies. An antibody titer at or above the critical titer should prompt noninvasive monitoring for fetal anemia if the fetus carries the corresponding antigen (the fetal antigen status should be determined by amniocentesis if it is not already known) (algorithm 1).

Most laboratories follow guidance from the Association for the Advancement of Blood & Biotherapies (AABB), which considers 16 the critical titer. It is generally agreed that additional fetal evaluation can be deferred at titers of 4 or below. A titer of 16 should prompt close fetal monitoring (eg, with fetal middle cerebral artery peak systolic velocity [MCA-PSV]), if the fetus is antigen-positive, because rare cases of severe fetal anemia occur at this level.

An exception is a K (of the KEL system)-alloimmunized pregnancy, in which clinically significant fetal anemia has been seen with lower titers (see 'KEL' above). We use a critical titer of ≥4 for K-immunized pregnancies. (See 'KEL-sensitized pregnancy' below.)

As long as the antibody titer remains below the critical titer, additional evaluation of the fetus can be deferred and the patient evaluated with serial antibody titers. The interval between titers varies from two to four weeks, depending upon the previous titer measurement and the gestational age. Titers should be drawn more frequently when the titer is borderline or rising and in the third trimester when the risk of erythroblastosis is highest. Except in K-affected pregnancies, it is not necessary to perform serial titers before 18 to 20 weeks of gestation, because of the low risk of severe fetal anemia early in pregnancy.

Once noninvasive assessment of fetal anemia is initiated, management decisions are based on this assessment rather than on laboratory testing of the maternal antibody. (See 'Assessing for fetal anemia' below.)

Determine fetal antigen status — Determining fetal antigen status aids decision making if the maternal alloantibody titer is at or above a critical threshold. (See 'Evaluate the antibody' above.)

In many cases, fetal antigen status can be determined non-invasively (eg, by testing the father if he is homozygous for the target antigen) (algorithm 1). Paternal antigen status is determined by serologic typing of his RBCs with a reagent antibody or by DNA testing in the case of RhD. Importantly, however, data on the rates of non-paternity suggest a range of 2 to 5 percent [67].

If the father is negative for the implicated antigen (and paternity is assured), the fetus will be antigen negative and no further testing/monitoring is required.

If the father is positive for the antigen, serology or DNA testing can determine whether he is homozygous or heterozygous.

If the father is homozygous for the implicated antigen (and paternity is assured), the fetus is assumed to be obligate positive, and testing to determine fetal antigen status is unnecessary; the fetus should be monitored for anemia. (See 'Assessing for fetal anemia' below.)

If the father is heterozygous (or status unknown or paternity uncertain), the fetus may be positive for the antigen, and fetal antigen testing can be performed either by cell-free DNA testing of maternal blood or testing amniocytes via amniocentesis.

Cell-free DNA testing of maternal blood, also referred to as noninvasive prenatal testing/screening (NIPT/NIPS), can determine fetal KEL and Rh antigens (such as C, c, or E) [68-72]. Consultation with prenatal genetic counselors, transfusion medicine physicians, or laboratory personnel regarding the availability of noninvasive testing may be helpful.

If cell-free DNA testing is not available, we perform amniocentesis to type amniocytes if/when the maternal alloantibody titer is at or above the critical value (≥4 for K, ≥16 for other antigens). (See 'Evaluate the antibody' above.)

In some situations, the patient may be reluctant to undergo amniocentesis because of concerns for risk for fetal loss or enhanced alloimmunization [73]. In these cases, clinicians will often offer serial MCA Doppler scans for fetal surveillance. The patient should be counseled that MCA Doppler has been associated with a false positive rate for the detection of fetal anemia of 12 percent. A falsely elevated peak systolic velocity would lead to an unnecessary cordocentesis to assess the fetal hematocrit with an associated 1 to 2 percent rate of fetal loss.

For fetuses at risk of anemia based on fetal antigen status and maternal alloantibody titer, noninvasive assessment for fetal anemia using middle cerebral artery (MCA) Doppler scanning is required. (See 'Assessing for fetal anemia' below.)

KEL-sensitized pregnancy — Unlike other alloantibodies, the critical titer and timing of testing is more stringent for pregnancies in which the mother produces antibodies to the K antigen of the KEL system. The rationale is that, in addition to causing hemolysis, anti-K suppresses erythropoiesis, leading to more severe fetal anemia [20]. In a large review series that included over 1000 K-sensitized pregnancies, a critical titer of 4 provided the best sensitivity and specificity for predicting the need for intrauterine transfusion [26]. Using this cutoff, the positive predictive value was 64 percent (approximately two of three fetuses would require transfusion) and no cases of severe HDFN were missed. We use a titer of ≥4 as the trigger for initiating Doppler monitoring of a K-positive fetus (algorithm 1). (See 'Assessing for fetal anemia' below and 'KEL' above.)

Earlier Doppler assessment of the fetal MCA-PSV is the preferred tool for determination of fetal anemia in K-sensitized pregnancies (eg, at 18 weeks of gestation rather than 22 to 24 weeks) [14,74,75]. If MCA-PSV is above 1.5 multiples of the median (MoM), then cordocentesis for fetal hematocrit and/or hemoglobin and confirmation of blood type should be performed; transfusion is performed at the same time, if needed. This is done earlier in gestation for K-sensitized pregnancies compared with other alloantibodies [22].

Assessing for fetal anemia — Assessment for fetal anemia is appropriate in pregnancies determined to be at risk of HDFN based on a maternal alloantibody titer that is rapidly rising or at or above the critical titer and expression of the corresponding antigen on fetal RBCs.

Noninvasive testing – For noninvasive assessment for fetal anemia, Doppler scanning of the fetal MCA-PSV has emerged as the best tool [14,73,74,76,77]. This test is based on the principle that in the anemic fetus, oxygen delivery to the brain is preserved by increasing cerebral flow of this low viscosity blood. Ultrasound alone should not be used for detection of fetal hydrops as a screen for fetal anemia. Fetal hydrops does not occur until the fetal hemoglobin has dropped to very low levels. In addition, hydrops fetalis may not be present in the early second trimester fetus despite the presence of significant anemia [78].

In severely anemic fetuses, the fetal heart rate may show a sinusoidal pattern. (See "Intrapartum fetal heart rate monitoring: Overview", section on 'Sinusoidal pattern'.)

Invasive testing – If the MCA-PSV is above 1.5 MoM for the gestational age, invasive testing using cordocentesis to obtain a fetal blood sample for fetal hemoglobin measurement is performed.

Tables for converting the MCA-PSV to a MoM based on gestational age are provided at www.perinatology.com [79]. The sensitivity of an increased MCA-PSV for moderate or severe fetal anemia is approximately 100 percent regardless of the cause of the anemia, with a false positive rate of 12 percent [14,76].

The gestational age at which to initiate serial MCA Doppler scans depends on whether there has been a previously affected pregnancy [80].

If a previous pregnancy was associated with HDFN or the current pregnancy has K incompatibility, MCA scanning is initiated at 18 weeks of gestation, regardless of the maternal antibody titer (ie, determination of the maternal antibody titer is not required).

If there has not been a previously affected pregnancy, K incompatibility is not present, and the maternal antibody titer is at or above the critical titer, MCA scanning is initiated at 22 to 24 weeks of gestation. The exception to this recommendation would be if a very high antibody titer is detected (eg, >1:256), in which case we would initiate MCA Doppler scans earlier, although there are no data to guide practice in this situation.

Additional aspects of Doppler evaluation, such as optimization of testing, frequency of testing, and indications for invasive measurement of fetal hemoglobin levels, are similar to those in RhD-alloimmunized pregnancies and discussed in detail separately. (See "RhD alloimmunization in pregnancy: Management", section on 'Assess for severe anemia using MCA-PSV in fetuses at risk'.)

If the MCA-PSV indicates possible severe anemia, or if a fetal ultrasound indicates signs of hydrops fetalis (eg, ascites, pleural effusion, skin edema, pericardial effusion), cordocentesis for measurement of the fetal hemoglobin level is indicated, with availability of blood for transfusion if needed, as done for pregnancies with RhD alloimmunization. This subject, as well the selection and preparation of RBCs, are discussed in detail separately:

Cordocentesis – (See "Fetal blood sampling".)

Intrauterine transfusion – (See "Intrauterine fetal transfusion of red cells".)

Postnatal transfusion – (See "Alloimmune hemolytic disease of the newborn: Postnatal diagnosis and management" and "Red blood cell (RBC) transfusions in the neonate".)

RBC compatibility testing and modifications – (See "Red blood cell transfusion in infants and children: Selection of blood products".)

SPECIAL POPULATIONS — Additional circumstances that may complicate the evaluation and management of a pregnancy include autoimmune hemolytic anemia (AIHA) in the mother, recent anti-D immune globulin administration, alloantibodies to high frequency antigens, and the use of donor gametes or gestational carriers.

Warm autoimmune hemolytic anemia — Warm autoimmune hemolytic anemia (AIHA) is caused by an autoantibody to a red blood cell (RBC) antigen that causes variable hemolysis in the mother. These autoantibodies generally cause a positive direct antiglobulin (Coombs) test (DAT) and may be present in the mother's plasma, complicating the interpretation of alloantibody screening. AIHA must be distinguished from the nonpathologic positive DAT, which occurs in 1 in 1000 hospitalized patients and in 1 in 36,000 normal blood donors. (See "Warm autoimmune hemolytic anemia (AIHA) in adults".)

Warm AIHA is often exacerbated during pregnancy [81,82]. In some cases, the autoantibody may cross the placenta and cause shortened survival of the fetal RBCs. Occasionally, the autoantibody mimics allo-anti-Rh(e), which may be transported across the placenta. However, we are unaware of cases of severe HDFN; thus, serial fetal middle cerebral artery peak systolic velocity (MCA-PSV) scans are not needed in this setting.

If sufficient autoantibodies are transported across the placenta to cause anemia in the fetus, exchange transfusion may be required shortly after delivery. Other interventions (eg, phototherapy, intravenous immune globulin [IVIG]) are discussed in detail separately. (See "Unconjugated hyperbilirubinemia in term and late preterm newborns: Initial management".)

Recent anti-D immune globulin — Administration of anti-D immune globulin (also called Rho[D] or Rho[D] immune globulin) is not harmful for individuals with other alloantibodies, but it may cause confusion in the interpretation of other testing if the details are not communicated to the transfusion service and/or immunohematology laboratory.

Timing of administration – Administration of anti-D immune globulin is safe in patients with antibodies to other Rh or non-Rh antigens, and testing for other alloantibodies can be performed as long as the transfusion service is aware that anti-D immune globulin has been administered. Importantly, administration of anti-D immune globulin should not be withheld or delayed during the evaluation or treatment of other maternal alloantibodies.

Potential misinterpretation of maternal antibody screeningAnti-D immune globulin is made from human plasma and rarely may contain antibodies to other Rh antigens besides RhD, which could make it appear that an alloantibody is present when it is not. Unlike an alloantibody that is continually produced by the mother, other antibodies in the anti-D immune globulin will not cause any problems for the fetus because the dose to which the fetus is exposed is small.

Lack of protection from other Rh alloantibodies – Administration of anti-D immune globulin does not provide prophylaxis against HDFN due to other Rh antigens (eg, C, c, E). Thus, if a pregnant patient has alloantibodies to one of these other Rh antigens, she should be managed as if the fetus is potentially at risk for HDFN. (See 'Prenatal management' above.)

High frequency antigen — One issue that warrants additional discussion is the presence of an alloantibody directed against an antigen present in a high frequency of the population; it may be difficult to obtain blood for transfusion that lacks the corresponding antigen. Examples include the KEL blood group antigens k or Kp(b), U antigen, and the Colton blood group antigen Co(a). Identifying the antibody specificity, as well as any underlying clinically significant antibodies being masked by its presence, in a timely manner, is essential so that donor blood is available should fetal transfusion be required prior to delivery or the mother and/or the newborn require transfusion postpartum.

Options for identifying units of blood for fetal/neonatal transfusion in the setting of maternal alloantibodies to high frequency antigens include the following:

If the mother is medically able, she may donate units of blood. One series reported the donation of up to six units in pregnancy [83].

The mother's siblings can be tested. There is a 25 percent chance that a sibling's cells will be compatible with the mother's serum if both parents are heterozygous for the corresponding low frequency antigen (they must also be ABO compatible).

The cells can be frozen and then thawed if necessary for transfusion for the mother, fetus, and/or the neonate (if ABO compatible), if a blood center is available that offers this service. Consideration should be given to aliquoting the unit to allow for more efficient use early in gestation. Alternatively, the transfusion service can contact the American Rare Donor Registry to inquire if frozen units lacking the high frequency antigen in question can be found. Such units could then be held or shipped to the local facility and stored for future use.

If compatible blood cannot be obtained and intrauterine or exchange transfusion becomes imperative, group O red blood cells that are heterozygous for the high frequency antigen (eg, K+k+ when anti-k is present) are preferred to blood from a donor who is homozygous for the implicated antigen.

IVF/donor egg or sperm/gestational carrier — Management of pregnancies involving a donor gamete or a gestational carrier is based on the predicted antigen status of the fetus and the known antibody status of the gestational carrier. These pregnancies are managed as described above. (See 'Prevention of HDFN' above.)

PROGNOSIS — The outcome of pregnancies complicated by alloimmunization has been greatly improved by the availability of methods for fetal assessment and intrauterine transfusion.

Complications of intrauterine transfusion have declined over time, as described in a retrospective analysis involving 589 fetuses at a referral center in the Netherlands [84]:

In the 255 fetuses undergoing 741 intrauterine transfusions between 1988 and 2000, the overall perinatal survival was 88.6 percent.

In the 334 fetuses undergoing 937 intrauterine transfusions between 2001 and 2015, the overall perinatal survival improved to 97 percent.

A multiple regression model determined that procedure-related complications (including fetal/neonatal death) were not associated with fetal hydrops. Comparable data have been presented for K-sensitized pregnancies, although some series report a lower survival rate for HDFN due to K than for RhD sensitization [22].

In a large series of over 300,000 pregnancies, those newborns at risk of HDFN due to alloantibodies other than anti-RhD were more likely to have icterus than those not at risk (25 versus 10 percent) and to be treated with phototherapy (17 versus 5 percent) [13].

There remains a very small risk of HDFN in pregnancies in which an alloantibody was not detected on first trimester screening. In the large series of over 300,000 pregnancies, eight cases of severe HDFN that occurred in patients with a negative screen were due to anti-c and/or anti-E, resulting in an overall risk of antibody screen-negative severe HDFN of 2 in 100,000 pregnancies [13]. Seven neonates required exchange transfusion, and two had permanent brain damage from kernicterus or intracerebral bleeding.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Transfusion and patient blood management" and "Society guideline links: Rh disease in pregnancy".)

SUMMARY AND RECOMMENDATIONS

Pathogenesis – Hemolytic disease of the fetus and newborn (HDFN) requires maternal exposure to an allogeneic red blood cell (RBC) antigen, which can occur through prior transfusion, previous pregnancy (via fetomaternal hemorrhage), or sharing needles. Fetal RBC antigens arise from a paternally inherited gene. To cause hemolysis, a corresponding maternal alloantibody must cross the placenta; therefore, IgG, but not IgM, can cause fetal hemolysis. Fetal anemia occurs primarily by phagocytosis of antibody-coated RBCs by reticuloendothelial macrophages in the fetal spleen and liver. (See 'Terminology and pathogenesis' above.)

Implicated antigens – HDFN can result from alloantibodies to RhD, other Rh antigens, and antigens from other blood group systems. Maternal alloantibodies to non-RhD antigens are seen in approximately 1.5 to 2.5 percent of pregnancies. The most commonly implicated antigens are c, E, and the K antigen of the KEL blood group (table 1). Anti-K antigen causes earlier and more severe HDFN than others. (See 'Prevalence of alloantibodies in pregnancy' above and 'KEL' above.)

Counseling – Females with alloantibodies to RBC antigens should be counseled regarding the possibility of HDFN. Individuals with a history of HDFN require further testing to determine the antibody class (IgM or IgG), specificity, and the potential father's antigen status. There are few interventions to prevent non-RhD HDFN (preimplantation genetic testing, gestational carrier, donor insemination). (See 'Prepregnancy counseling' above.)

Screening – Routine screening for antibodies to RBC antigens, as well as ABO testing, should be performed early in pregnancy, typically at the first prenatal visit; this will include screening for anti-RhD as well as other antibodies. Administration of anti-D immune globulin (also called Rho[D] immune globulin) to an RhD-negative mother at 28 weeks gestation should not be delayed while performing the evaluation for other non-RhD alloantibodies. If no clinically important alloantibodies are detected, antepartum antibody screening usually is not repeated. (See 'Antibody screening' above.)

Evaluation of antibodies – If the maternal antibody screen identifies an alloantibody and the fetus is potentially at risk for expressing the antigen, titration is performed (algorithm 1). The potential for causing clinically significant hemolysis depends on the antibody class (IgG versus IgM), titer or other quantification, and specificity. A titer above a critical threshold value predicts an increased likelihood of HDFN; however, the titer does not correlate linearly with the risk of HDFN or the severity of hemolysis, and additional testing is required if the titer exceeds the critical threshold. (See 'Follow up a positive antibody screen' above and 'Evaluate the antibody' above.)

The critical titer for anti-K is more stringent than other alloantibodies because anti-K suppresses erythropoiesis in addition to causing hemolysis. (See 'KEL-sensitized pregnancy' above.)

Evaluation, prevention, and management of RhD alloimmunization are discussed separately. (See "RhD alloimmunization in pregnancy: Overview" and "RhD alloimmunization: Prevention in pregnant and postpartum patients" and "RhD alloimmunization in pregnancy: Management".)

Fetal assessment – Assessment for fetal anemia is appropriate in pregnancies with a maternal alloantibody that is rapidly rising or at or above the critical titer when fetal RBCs express the antigen (algorithm 1). Doppler scanning of the fetal middle cerebral artery peak systolic velocity (MCA-PSV) has emerged as the best tool for noninvasive assessment. (See 'Determine fetal antigen status' above and 'Assessing for fetal anemia' above.)

Neonatal transfusion – Invasive testing for fetal anemia and fetal and neonatal transfusion are discussed separately. (See "Fetal blood sampling" and "Intrauterine fetal transfusion of red cells" and "Red blood cell (RBC) transfusions in the neonate".)

Caveats – Additional circumstances that may complicate the evaluation and management include maternal autoimmune hemolytic anemia (AIHA), recent anti-D immune globulin, alloantibodies to high frequency antigens, and use of donor gametes or a gestational carrier. (See 'Special populations' above.)

ACKNOWLEDGMENTS

The UpToDate editorial staff acknowledges extensive contributions of Arthur J Silvergleid, MD, to earlier versions of this and many other topic reviews.

The UpToDate editorial staff also acknowledges Melanie S Kennedy, MD, and David W Cohen, MA, MT(ASCP)SBB, who contributed to earlier versions of this topic review.

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