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HDFN and the Clinical Impact of Specific Antibodies After Birth

The most common way of confirming HDFN after birth is via Direct Agglutination Test (DAT) performed on the cord blood. However, a negative DAT cannot rule out the presence of HDFN due to maternal alloimmunization.  In some cases, the DAT may come back negative, but the infant is still severely affected. This happens most often with the anti-C, anti-c, anti-Fya, anti-Good, anti-H, anti-Jra, anti-M, and anti-Mta antibodies. If dealing with these antibodies, it is helpful to also run an Indirect Agglutination Test (IAT) to see if there are unbound antibodies in neonatal circulation. It is optional to run a titer to determine the amount. If IAT cannot be run or is inconclusive, there is also the option to run an antigen phenotype test to determine the neonate’s antigen status. A positive antigen status with a history of maternal alloimmunization means that there is a risk of HDFN and continued monitoring would be prudent.


An infant affected by HDFN is one who has a positive DAT or IAT (in the case of one of the exceptions), and at least one of the following: anemia, hyperbilirubinemia, neutropenia, and thrombocytopenia. The degree of effect can range from mild needing no or minimal treatment, to severe requiring multiple transfusions.


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HDFN can manifest itself in a variety of ways. It is most commonly identified when anemia is present. Anemia may be apparent at birth, or it may manifest as delayed onset anemia at 2-12 weeks of age. Delayed onset anemia has the potential to be fatal. All infants with HDFN must be monitored for several weeks - usually until the hemoglobin is increasing without a blood transfusion for at least 2 weeks in a row. If the infant presents with signs of anemia (mild or severe), it is wise to immediately get a hemoglobin and if necessary refer to the Emergency Department or Hematology for same-day transfusion. Some antibodies cause a suppression of bone marrow production which may lead to prolonged anemia or hyporegenerative anemia. A reticulocyte count is helpful in determining if suppression is happening or if the bone marrow is producing an adequate number of erythrocytes. Treatment options for anemia include transfusion, IVIG, erythropoietin, and folic acid. Iron supplements must never be given to infants with hemolytic anemia as these infants have normal to high iron stores and are at risk for overdose. If iron is to be administered, it can only be done after a ferritin test. 


 As a result of erythrocyte destruction, hyperbilirubinemia is a common side effect of HDFN. Hyperbilirubinemia may be treated by intensive phototherapy, administration of intravenous immunoglobulin (IVIG), and exchange transfusion. It is possible to reduce the level of hyperbilirubinemia by maternal administration of phenobarbital prior to delivery. Neutropenia and Thrombocytopenia are additional side effects of maternal alloimmunization and HDFN and should be monitored for. 

Clinical Impact of Specific Antibodies

Which Antibodies Are  Associated with HDFN?

There are antibodies that are generally accepted as either being associated with HDFN or not associated with HDFN. Would reword: Certain antibodies are generally associated with HDFN and others are not associated with HDFN. A prudent provider will conduct a literature review to ensure that his patient’s antibodies have not been found to cause HDFN. There is a widely circulated table of antibodies associated with HDFN and antibodies that are not associated with HDFN. Unfortunately there have been cases of antibodies not thought to cause HDFN which have caused fatal HDFN. Though rare, it does happen. Older lists available online will have these antibodies in the Does NOT cause HDN column, however this is not always the case. These antibodies are marked with a *.


Table 1 - Clinically Significant Alloantibodies

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Difficult Antibodies to Crossmatch

The following are antibodies which require the mother to bank her own blood. These antibodies are formed to high frequency antigens or antibodies that belong to rare phenotypes. Patients with these antibodies may need to bank their own blood for delivery, in case of IUT, or emergency. Whole blood is donated, the plasma removed, and the irradiated blood cells are given to the infant or back to the mother.
Anti-H, anti-Jra, anti-Jsb, Anti-Ku, anti-Lea, anti-Lub, anti-PP1PK also called anti-Tja.

Table 2 - Difficult Antibodies to Crossmatch

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Direct and Indirect Agglutination Test Exceptions

Some antibodies are known to have a negative IAT in the mother even though the fetus or neonate could still be affected. Certain antibodies are known to cause a negative DAT on the neonate even with a severely affected infant. The antibodies and their corresponding results are listed below.

Table 3 - Direct and Indirect Agglutination Test Exceptions

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Specific Antibodies and Their Clinical Impact


Anti-A:
Anti-A does not usually severely affect the fetus in utero, but can on occasion. It is generally less severe than anti-B. It is possible to have both anti-A and anti-B at the same time. Anti-A will cause more severe HDFN in blacks and Hispanics than in whites.

Anti-Ata: For a long time, it had been thought that anti-Ata did not cause HDFN. Anti-Ata can cause moderate HDFN requiring phototherapy. Anti-Ata can also cause hemolytic transfusion reactions. One experiment showed the survival for transfused mismatched cells is 95% at 1 hour, and 18% at 24 hours. 


Anti-B: Anti-B is also a race discriminating antibody causing more severe disease in blacks and latinos than in whites. Anti-B can affect the fetus during pregnancy if it’s warm reacting IgG type, and there have been cases requiring IUTs for anti-B. Anti-B can cause hydrops, distress requiring an emergency c-section, and severe anemia within only hours of birth.

Anti-C: One of the most important things to note about anti-C is that the direct agglutination test done on the neonate can come back negative, even with severely affected neonates. Always test the infant’s antigen phenotype and/or run an indirect agglutination test to see if there are antibodies in the neonates system. Anti-C can require IUTs and needs to be monitored carefully, especially if in combination with one of the E/e antibodies.


Anti-c: One of the most important things to note about anti-c is that the direct agglutination test done on the neonate can come back negative, but the child still be severely (or fatally) affected. Always test the neonate’s antigen phenotype and run an indirect agglutination test too. Anti-c becomes more severe if in combination with one of the E/e antibodies.

Anti-cw: Articles show that anti-Cw runs the gamut from no intervention needed to requiring IUTs, fetal hydrops, and death. Post birth interventions can range from none, to phototherapy and exchange transfusions. 


Anti-D: Rhogam is used to prevent anti-D formation. Once anti-D antibodies have been formed, Rhogam should not be administered. In rare cases, anti-D may be the result of Rhogam administered within the past 6 months. This form of anti-D will not titer higher than 16. 


Anti-Dia: Anti-Dia has been known to be undetectable on maternal indirect agglutination test during pregnancy, yet still cause issues with the infant after birth. HDFN due to Diego antibodies is more common in SE Asia and S. America, though cases have been reported in other countries. If not treated promptly, despite single phototherapy, anti-Dia can cause Kernicterus.

Anti-Dib: With anti-Dib the disease is more severe in people of East Asian descent. Anti-Dib is more likely to be severe than anti-Dia. Despite the cases of severe effects, anti-Dib can also require no treatment. 


Anti-E: Anti-E is known more for jaundice than severe anemia requiring IUTs, but IUTs are occasionally needed. In one study, the most severely affected neonate was born to a mother with titers of only 1:2. Rebounding jaundice is not unexpected with anti-E, neither is jaundice lasting several weeks. In rare cases anti-E can be naturally occurring.


Anti-e: One of the most important things to note about anti-e is that the direct agglutination test done on the newborn can come back negative, but the neonate still be severely affected. Anti-e can cause mild anemia that persists for 4 months, or severe anemia. Anti-e is known more so for jaundice than anemia requiring IUTs, though they may be needed too.

Anti-Far: Anti-Far has been implicated in causing HDFN. Anti-Far is very rare.


Anti-Fya: Anti-Fya can be mild to severe. Most of the severe cases requiring IUTs are out of Europe. An infant affected by anti-Fya can have a negative direct agglutination test but still be affected.


Anti-Fyb: HDFN from anti-Fyb is exceedingly rare. A literature review revealed only one article referencing HDFN due to anti-Fyb. 


Anti-Fyc: HFDN due to anti-Fyc also called anti-Fy3, is rare and can cause mild to moderate disease. Anti-Fy3 can only be made by individuals who are fy(a-,b-). Only 3 cases of anti-Fy3 were found in a literature review. Two of those cases were in non-negro (is there a better word)maybe non-black? people while only one was black. This was surprising because the phenotype Fy(a-,b-) that develops anti-Fy3 is most common among blacks. 


Anti-G: It is possible for an antibody screen to show anti-D and anti-C when it is actually anti-G and vice versa. It is important to distinguish because if it is actually anti-G, then the RhD negative woman can and should be given rhogam to prevent development of true anti-D. Anti-G can cause HDFN and severe anemia with a hemoglobin as low as 3. 


Anti-Ge2: Anti-Gerbich 2 antibodies can be both warm and cold reacting, IgG and IgM type. This means that some forms of anti-Ge2 may cross the placenta while others will not. The vast majority of studies show anti-Ge2 to be harmless to the infant, however a literature review reveals that there are cases where it has caused Hemolytic Disease of the Fetus and Newborn. This means the antibodies crossed the placenta and attached to the fetal blood cells. 


Anti-Gonzales aka anti-Go(a): One infant was born with severe HDFN due to anti-Goa. She had an exchange transfusion on day 1. Anti-Goa can cause jaundice shortly after birth and exchange transfusions may be required. Even with aggressive phototherapy, bilirubin due to anti-Goa can require additional exchange transfusions. In cases without exchange transfusion, prolonged hyperbilirubinemia is known to occur with anti-Goa. 


Anti-Good: Very little is known about anti-Good. The Good antigen is so scarce that it has been tested against over 1400 samples and was not found. It is known that the direct agglutination test may be negative with anti-Good and still cause severe HDFN. The original Mrs. Good (who the antigen was named after) lost 4 children to HDFN with titers of 1:8 that ended at 1:16 (in saline) 3 months after the last birth.


Anti-H: The first case of HDFN due to anti-H was recorded in 2013 to a Bombay phenotype mother. Previously it was only theorized that anti-H could exist. The infant had a negative DAT, but still had signs of hemolysis. High bilirubin and need for an exchange transfusion caused significant problems. To optimize neonatal care and outcome anticipating anemia and hyperbilirubinemia with this rare blood type would allow earlier notification to the blood bank so they can find appropriate blood before it is needed. Blood from the mother may need to be stored or donated to the infant. 


Anti-Jka: Kidd antibodies are frequently difficult to detect. The cases where anti-Jka has caused a problem are few and far between. Of the 4 cases of HDFN from anti-Jka mentioned in one article, only 2 required exchange transfusion. After two intrauterine deaths from anti-Jka, the authors treated the infant with immediate exchange transfusion upon birth. While anti-Jka is usually mild, it can cause severe HDFN. In an article by Matson, despite exchange transfusion at 3 days old, the infant developed kernicterus. The authors again recommend early exchange transfusions with anti-Jka to avoid Kernicterus. The criteria used for monitoring anti-D affected pregnancies were effective in detecting severe HDFN due to anti-Jka. Kidd antigens are also found on the kidneys. 


Anti-Jkb: Anti-Jkb is rarely associated with severe HDFN, even with high titers. As of 2014, only 13 cases have been reported, and the potential reasons for the low incidence of severe HDFN still remain unclear. Most cases of HDFN due to anti-Jkb are mild-to-moderate, and usually have a good prognosis. Anti-Jkb usually displays mild clinical symptoms. However, there is an article that reports the second case of HDFN due to anti-Jkb with severe symptoms and a fatal outcome. The infant was admitted at 4 days old being lethargic and having high pitched crying. The total bilirubin was 46.1 mg/dL.  It should be noted that iso bilirubin peaks days 4-6. This infant was at the peak time, and the high pitched crying is a sign of kernicterus (brain damage due to bilirubin), which can be fatal. The authors say that pediatricians should be aware of the course of hemolytic jaundice due to anti-Jkb and be ready to treat with active therapeutic interventions instead of a wait and see approach.


Anti-Jkc: Anti-Jk3 is made by individuals with the rare JK-null phenotype. This is Jk (a-b-). This single antibody recognizes both Jka and Jkb antigens. Anti-Jk3 can cause HDFN in pregnancy and will hemolyse donor blood in a blood transfusion. In two reported cases of anti-Jk3, the infants were treated with phototherapy. No transfusions were necessary.


Anti-Jra: This is an antibody to a high frequency antigen. Blood from the mother may need to be stored or donated to the infant. The first case of fatal HDFN from anti-Jra was reported in 2008. The authors of the case study recommend close monitoring of pregnant women with a high-titer anti-Jr(a), especially those with an incompatible transfusion history and/or multiple pregnancies. Most cases of HDFN from anti-Jra are mild, but severe cases do occur. The DAT can be negative yet the infant still become anemic. Upon an IAT, anti-Jra was found with a titer 1:8 in an infant whose DAT was negative. This occurs because infants can have low Jra antigen density immediately postpartum; the antigens aren't fully developed and in large quantities at birth. Anti-Jra can inhibit the formation of new blood cells in addition to destroying the blood cells. This makes it harder for the infant to recover from anemia. Anti-Jra can be difficult to identify in the mother and may cause HDFN in the first affected pregnancy. Anti-Jra can be treated with IUTs and may not cause hyperbilirubinemia. Jra- blood can be difficult to find. Blood from the mother may need to be stored or donated to the infant. 


Anti-Jsa: This antibody belongs to the Kell blood group and may cause suppression of erythropoiesis. The first case of hydrops from anti-Jsa was reported in 2005. What is startling to note about this was that the mother's IAT was NEGATIVE despite the infant having hydrops and a positive DAT with a strength of 3+. The woman had lost an infant before due to hydrops, the cause of which was never identified. Further testing revealed the woman to be Jsa- and the neonate Jsa+. Both maternal and fetal blood reacted with Jsa+ cells and they were able to identify the antibody as anti-Jsa. Delayed onset anemia was found on day 14 and the infant was treated with a transfusion, phototherapy and erythropoietin. In addition to the red blood cells being hemolyzed, erythroid and myeloid precursors are inhibited.  


Anti-Jsb: This antibody belongs to the Kell blood group and may cause suppression of erythropoiesis. This is an antibody to a high frequency antigen. Blood from the mother may need to be stored or donated to the infant. Prior to 1995, anti-Jsb was not known to cause HDFN. Doctors then reported a patient with a high anti-Jsb titer that caused hydrops and death, followed by a pregnancy treated with multiple IUTs. In one case they treated the fetus with IUTs with blood donated from the mother. Knowledge and availability of this rare blood type is a must. Multiple times the infant in utero and after birth was transfused with blood from the mother. It is difficult to gauge severity of anti-Jsb off of a titer. Erythropoietin has been used to treat anti-Jsb. 


Anti-Kell: Anti-Kell suppresses the fetal production of blood cells. Kell antigens are found on the surface of progenitor cells, and anti-Kell will destroy them in addition to the red blood cells. Anemia is the big concern here, and severe anemia can be caused regardless of titer. A titer of 2 has been known to require IUTs. Infants with HDFN due to anti-Kell may not experience hyperbilirubinemia. A lack of hyperbilirubinemia does not indicate a lack of severe anemia.

Anti-k (cellano): This antibody belongs to the Kell blood group and may cause suppression of erythropoiesis. Anti-k is extremely rare and should be managed the same as anti-K. In 1989, Bowman reported on their first known case of anti-k being severe enough that IUTs were required to prevent hydrops. This showed that anti-k can cause HDFN requiring IUTs. In another article, a woman had two stillborn babies from hydrops due to anti-k with a titer of 4. Another woman had a titer of 16 and the infant had hyperbilirubinemia but required no treatment. This shows the variability of the effects of anti-k at different titers, and the need for close monitoring before and after birth.


Anti-Kpa: This antibody belongs to the Kell blood group and may cause suppression of erythropoiesis. Anti-Kpa is usually mild and does not generally require transfusions. In one case it did cause HDFN and needed a transfusion when the infant was 18 days old.


Anti-Kpb: This antibody belongs to the Kell blood group and may cause suppression of erythropoiesis. Long believed to not be a clinically significant antibody, there have been cases of anti-Kpb causing HDFN and requiring intervention. 


Anti-Ku: This antibody belongs to the Kell blood group and may cause suppression of erythropoiesis. The Kell system has a rare null phenotype called K0, where the red blood cells lack all Kell antigens. In this case individuals can produce anti-Ku. Anti-Ku reacts with the K, k, Kpa, Kpb, Jsa, Jsb antigens. Anti-Ku can cause severe HDFN requiring IUTs. Recombinant erythropoietin has been used successfully on infants affected by anti-Ku. Anti-Ku individuals require transfusions with only K0 blood or they are at risk for a severe, possibly fatal transfusion reaction. Blood from the mother may need to be stored or donated to the infant. Is the technical name anti-Ku or anti-K0?


Anti-Lan: Until 2013, only 3 cases have been reported of anti-Lan causing HDFN and all have been deemed mild, however there has also been one severe case of HDFN from anti-Lan requiring IUTs. For this reason monitoring titers followed by MCA scans is important.


Anti-Lea: This is an antibody to a high frequency antigen. Blood from the mother may need to be stored or donated to the infant. Lewis antibodies are rarely implicated in HDFN. For a long time, they were on the list for not causing HDFN. However there are both cold and warm reacting versions of these antibodies. The warm reacting IgG type antibodies can cause HDFN. Both anti-Lea and anti-Leb have been found to cause cases of mild HDFN. Anti-Lea can also result in a positive DAT but require no treatment. This is because anti-Lea can cross the placenta, but there are such low levels of lewis antigens on the blood cells.


Anti-Leb: Lewis antibodies are rarely implicated in HDFN. For a long time, they were on the list for not causing HDFN. However there are both cold and warm reacting versions of these antibodies. The warm reacting IgG type antibodies can cause HDFN. Both anti-Lea and anti-Leb have been found to cause cases of mild HDFN. Anti-Leb can cross the placenta, but there are such low levels of lewis antigens on the blood cells that IUTs are rarely needed.

Anti-Lub: This is an antibody to a high frequency antigen. Blood from the mother may need to be stored or donated to the infant. Around 1957 the first two examples of anti-Lub were described. It had long been predicted that anti-Lutheran B would exist, but there had never been a reported case before. There are a couple of articles that talk about freezing blood from the pregnant woman herself, compatible siblings or unrelated individuals' red blood cells. This was used for anti-Lutheran b, anti-PP1Pk, and a rare genotype of anti-c. Anti-Lub can cause mild Hemolytic Disease of the Newborn. One article suggests that the Lutheran antigens are only weakly expressed at birth and that may be why there are no severe cases of HDFN from anti-Lub in the literature. A second article says that Lub antigen is weaker in fetuses than adults, and was not detected in a fetus of 9 weeks, despite having inherited Lub antigens from both parents. Additional articles confirm weak expression of the Lub antigen at 8 and 10 months of age.  Lutheran antigens are found on the surface of the cells that become blood cells, so anti-Lutheran may destroy the progenitor cells before they even turn into red blood cells. Because the precursor cells do not have hemoglobin, less bilirubin is released, which may mean that jaundice can be less common in infants, but the underlying anemia may still be present. This is similar to anti-Kell and anti-M antibodies. Cord blood grouping on infants was found to give a “appreciable, highly significant, occurrence of false negatives in Lua grouping”. This suggests that cord blood typing may not be accurate for the Lutheran antigens. In summary, not much is known about anti-Lub or how exactly it works in relation to hemolytic disease of the newborn and fetus. There is a lot of theory, but little is known for certain except that anti-Lub has not caused a severe case of HDFN to date, though infants have required phototherapy from it. No cases of intrauterine transfusion, hydrops, or death from anti-Lub have been found in the literature, however this is a clinically significant antibody capable of causing disease and should be monitored. 


Anti-Lw: There is some talk that anti-Lw should actually be anti-Lwa and that anti-Nea is actually anti-Lwb because it belongs to the Landsteiner-Wiener blood group as well. HDFN due to anti-Lw is usually mild. Anti-Lw has only been implicated in 1 case of severe HDFN.

Anti-M: Anti-M can be naturally occurring, but may be developed in response to blood mixing. This makes it important to determine the M antigen status of the father. Anti-M can run the gamut of needing no intervention after birth to needing transfusions, exchange transfusions, and dealing with lasting anemia. Anti-M can also cause delayed onset anemia. One woman reported repeated stillbirths due to anti-M. After an affected pregnancy, IVIG and plasmapheresis can be done during pregnancy. M antigens are found on the surface of the cells that will become RBCs, so anti-M will destroy the progenitor cells before they turn into red blood cells. Because the RBC precursors (the progenitor cells) do not have hemoglobin, less bilirubin is released. Less bilirubin being released means that jaundice can be less common in infants, but the underlying anemia may still be severe. Anti-M can also have a negative DAT but the infant still be severely affected.

Anti-Mta: Anti-Mta has been implicated in HDFN. The first case of HDFN due to anti-Mta was reported in 1972. Like other antibodies in the MNS group, anti-Mta can cause anemia even with a negative DAT.


Anti-N: Anti-N can cause HDFN. While anti-N can be naturally occurring, 78% of anti-N antibodies are IgG and can cross the placenta, while only 22% were IgM, so the significance of anti-N should not be dismissed.


Anti-PP1PK (aka anti-Tja): This is an antibody to a high frequency antigen. Blood from the mother may need to be stored or donated to the infant. Anti-PP1k antibody carries a high risk of repeated abortion during the first and second trimester. It can be treated with plasmapheresis, IVIG, IUTs and delivery at a set time. IVIG begun at 6 weeks and continued to 30 weeks led to an infant that was not anemic. In another case, IVIG was begun at 8 weeks. Anti-PP1Pk is known to cause growth retardation.


Anti-S: Anti-S is more common than anti-s, but both can cause severe HDFN. Anti-S is capable of causing rapid red blood cell destruction. Anti-S can be naturally occurring, due to this, the father needs to be tested for the S antigen. It is possible that both parents could be negative for S, in which case, the anti-S would be naturally occurring and would not harm the fetus because the fetus would be negative for S like both parents. Anti-S that is not naturally occurring but that occurs because of blood mixing, can be fatal. In 1952 there were two examples of anti-S causing HDFN, one of which was fatal. Despite the potential to be very severe, anti-S is not always fatal. An infant with anti-S experienced a hematocrit drop and rise in bilirubin but required no treatment.

Anti-s: Anti-S is more common than anti-s, but both can cause severe HDFN. Although approximately 10% of the population is SS and capable of forming anti-s, there are very few examples. In one article, there were 3 examples of anti-s to date and the authors reported the fourth case which was fatal at 39 weeks. In all 3 examples, titers were only 1:8. In spite of low titer, anti-s is capable of rapid red blood cell destruction, causing severe HDFN. In another article, the infant had severe HDFN and required 2 exchange transfusions. In one 1972 article documenting mild HDFN due to anti-s, the titer was 1:16, and the infant had a cord bilirubin of 3.0, yet was not treated. Current practices would have put the infant under phototherapy lights. With multiple examples of anti-s causing issues at low titer, it begs the question of if 1:16 is the appropriate critical titer for this antibody.


Anti-Tja aka anti-PP1Pk: This is an antibody to a high frequency antigen. Blood from the mother may need to be stored or donated to the infant. Anti-PP1k antibody carries a high risk of repeated abortion during the first and second trimester. It can be treated with plasmapheresis, IVIG, IUTs and delivery at a set time. IVIG begun at 6 weeks and continued to 30 weeks led to an infant that was not anemic. In another case, IVIG was begun at 8 weeks. Anti-PP1Pk is known to cause growth retardation.


Anti-U: Anti-U is a rare antibody that has been found exclusively in blacks. Destruction due to anti-U can be just as severe as due to anti-D. Severity can range from no treatment needed, to phototherapy, or stillbirth.


Anti-U1a: This antibody belongs to the Kell blood group and may cause suppression of erythropoiesis. Anti-U1a was first reported in 1994. Like other antibodies in the Kell family, anemia is the biggest risk. There may need to be a transfusion for anemia while jaundice is not severe enough to even need phototherapy.


Anti-Vel: Anti-Vel can be difficult to identify. A newborn developed severe jaundice at 3 hours old with HDFN, anemia, and an enlarged liver. The infant received two transfusions. Antibodies detected in pregnancy must be identified in order to properly manage any issues due to rare antibodies. In another infant, severe jaundice and reticulocytosis was found due to anti-Vel.

Anti-Verweyst (anti-Vw): Anti-Vw was previously on the list of antibodies that would not cause HDFN, however literature review has revealed that anti-Vw can cause severe HDFN requiring multiple exchange transfusions. HDFN due to anti-Vw can be treated with IVIG.

Anti-Wra: Anti-Wra can cause severe HDFN. Like anti-Dia, anti-Wra has been known to be undetectable on maternal indirect agglutination test during pregnancy, yet still cause issues with the infant after birth. Specialized testing may be required.


Anti-Zd: So far this antibody/antigen combo has only been found in 1 family. Anti-Zd is a warm reacting antibody that crosses the placenta, and can cause HDFN requiring an exchange transfusion.