Hemolytic disease of the newborn (ABO) explained

ABO HDN
Specialty:	hematology/pediatrics

In ABO hemolytic disease of the newborn (also known as ABO HDN) maternal IgG antibodies with specificity for the ABO blood group system pass through the placenta to the fetal circulation where they can cause hemolysis of fetal red blood cells which can lead to fetal anemia and HDN. In contrast to Rh disease, about half of the cases of ABO HDN occur in a firstborn baby and ABO HDN does not become more severe after further pregnancies.

The ABO blood group system is the best known surface antigen system, expressed on a wide variety of human cells. For Caucasian populations about one fifth of all pregnancies have ABO incompatibility between the fetus and the mother, but only a very small minority develop symptomatic ABO HDN.^[1] The latter typically only occurs in mothers of blood group O, because they can produce enough IgG antibodies to cause hemolysis.

Although very uncommon, cases of ABO HDN have been reported in infants born to mothers with blood groups A^{[2] [3]} and B.^[4]

Presentation

Complications

• High at birth or rapidly rising bilirubin
• Prolonged hyperbilirubinemia
• Bilirubin Induced Neurological Dysfunction^[5]
• Cerebral Palsy^[6]
• Kernicterus^[7]
• Neutropenia
• Thrombocytopenia
• Hemolytic Anemia - MUST NOT be treated with iron
• Late onset anemia - Must NOT be treated with iron. Can persist up to 12 weeks after birth.^{[8] [9]}

Causes

Environmental exposure: Anti-A and anti-B antibodies are usually IgM and do not pass through the placenta, but some mothers "naturally" have IgG anti-A or IgG anti-B antibodies, which can pass through the placenta. Exposure to A-antigens and B-antigens, which are both widespread in nature, usually leads to the production of IgM anti-A and IgM anti-B antibodies but occasionally IgG antibodies are produced.

Fetal-maternal transfusion: Some mothers may be sensitized by fetal-maternal transfusion of ABO incompatible red blood and produce immune IgG antibodies against the antigen they do not have and their baby does. For example, when a mother of genotype OO (blood group O) carries a fetus of genotype AO (blood group A) she may produce IgG anti-A antibodies. The father will either have blood group A, with genotype AA or AO or, more rarely, have blood group AB, with genotype AB.

Blood transfusion: It would be very rare for ABO sensitization to be due to therapeutic blood transfusion as a great deal of effort and checking is done to ensure that blood is ABO compatible between the recipient and the donor.

Risk factors

In about a third of all ABO incompatible pregnancies maternal IgG anti-A or IgG anti-B antibodies pass through the placenta to the fetal circulation leading to a weakly positive direct Coombs test for the neonate's blood. However, ABO HDN is generally mild and short-lived and only occasionally severe because:

• IgG anti-A (or IgG anti-B) antibodies that enter the fetal circulation from the mother find A (or B) antigens on many different fetal cell types, leaving fewer antibodies available for binding onto fetal red blood cells.^[10]
• Fetal RBC surface A and B antigens are not fully developed during gestation and so there are a smaller number of antigenic sites on fetal RBCs.^[10]

Diagnosis

Routine antenatal antibody screening blood tests (indirect Coombs test) do not screen for ABO HDN. If IgG anti-A or IgG anti-B antibodies are found in the pregnant woman's blood, they are not reported with the test results, because they do not correlate well with ABO HDN. Diagnosis is usually made by investigation of a newborn baby who has developed jaundice during the first week of life.

Testing

• Coombs - after birth baby will have a direct coombs test run to confirm antibodies attached to the infant's red blood cells. This test is run from cord blood.^[11] In some cases, the direct coombs will be negative but severe, even fatal HDN can occur.^[12] An indirect coombs needs to be run in cases of anti-C, anti-c, and anti-M. Anti-M also recommends antigen testing to rule out the presence of HDN.^[13]
• Hgb - the infant's hemoglobin should be tested from cord blood.^[11]
• Reticulocyte count - Reticulocytes are elevated when the infant is producing more blood to combat anemia.^[11] A rise in the retic count can mean that an infant may not need additional transfusions.^[14] Low retic is observed in infants treated with IUT and in those with HDN from anti-Kell
• Neutrophils - as Neutropenia is one of the complications of HDN, the neutrophil count should be checked.^{[15] [16]}
• Thrombocytes - as thrombocytopenia is one of the complications of HDN, the thrombocyte count should be checked.^[15]
• Bilirubin should be tested from cord blood.^[11]
• Ferritin - because most infants affected by HDN have iron overload, a ferritin must be run before giving the infant any additional iron.^[17]
• Newborn Screening Tests - Transfusion with donor blood during pregnancy or shortly after birth can affect the results of the Newborn Screening Tests. It is recommended to wait and retest 10–12 months after last transfusion. In some cases, DNA testing from saliva can be used to rule out certain conditions.

Treatment

The antibodies in ABO HDN cause anemia due to destruction of fetal red blood cells and jaundice due to the rise in blood levels of bilirubin a by-product of hemoglobin break down. If the anemia is severe, it can be treated with a blood transfusion, however this is rarely needed. On the other hand, neonates have underdeveloped livers that are unable to process large amounts of bilirubin and a poorly developed blood–brain barrier that is unable to block bilirubin from entering the brain. This can result in kernicterus if left unchecked. If the bilirubin level is sufficiently high as to cause worry, it can be lowered via phototherapy in the first instance or an exchange transfusion if severely elevated.

• Phototherapy - Phototherapy is used for cord bilirubin of 3 or higher. Some doctors use it at lower levels while awaiting lab results.^[18]
• IVIG - Intravenous Immunoglobulin therapy (IVIG) has been used to successfully treat many cases of HDN. It has been used not only on anti-D, but on anti-E as well.^[19] IVIG can be used to reduce the need for exchange transfusion and to shorten the length of phototherapy.^[20] The AAP recommends "In isoimmune hemolytic disease, administration of intravenous γ-globulin (0.5-1 g/kg over 2 hours) is recommended if the TSB is rising despite intensive phototherapy or the TSB level is within 2 to 3 mg/dL (34-51 μmol/L) of the exchange level . If necessary, this dose can be repeated in 12 hours (evidence quality B: benefits exceed harms). Intravenous γ-globulin has been shown to reduce the need for exchange transfusions in Rh and ABO hemolytic disease."^[18]
• Exchange transfusion - Exchange transfusion is used when bilirubin reaches either the high or medium risk lines on the normogram provided by the American Academy of Pediatrics (Figure 4).^[18] Cord bilirubin >4 is also indicative of the need for exchange transfusion.

See also

• Coombs test
• Hemolytic anemia
• Hematology

Notes and References

1. Web site: Archived copy . 2007-12-09 . 2005-03-01 . https://web.archive.org/web/20050301183018/http://www.obgyn.net/english/pubs/features/presentations/panda13/ABO-Rh.ppt . dead .
2. 10.1002/pbc.20503 . 16007582 . Hemolytic disease of the newborn caused by a high titer anti-group B IgG from a group a mother . Pediatric Blood & Cancer . 45 . 6 . 861–2 . 2005 . Wang . Michael . Hays . Taru . Ambruso . Dan R. . Silliman . Christopher C. . Dickey . William C. . 44546304 .
3. 15373613 . 2000 . Jeon . H . Significant ABO hemolytic disease of the newborn in a group B infant with a group A2 mother . Immunohematology . 16 . 3 . 105–8 . Calhoun . B . Pothiawala . M . Herschel . M . Baron . B. W. . 10.21307/immunohematology-2019-587 . 38090703 . free .
4. 11508073 . 2000 . Haque . K. M. . An unusual case of ABO-haemolytic disease of the newborn . Bangladesh Medical Research Council Bulletin . 26 . 2 . 61–4 . Rahman . M .
5. 10.1038/sj.jp.7211157 . 15578034 . Definition of the Clinical Spectrum of Kernicterus and Bilirubin-Induced Neurologic Dysfunction (BIND) . Journal of Perinatology . 25 . 1 . 54–9 . 2004 . Shapiro . Steven M . 19663259 .
6. 10.1016/j.siny.2005.10.010 . 16338186 . Epidemiology of cerebral palsy . Seminars in Fetal and Neonatal Medicine . 11 . 2 . 117–25 . 2006 . Blair . Eve . Watson . Linda .
7. 10.1016/S0022-3476(48)80225-8 . 18866937 . Clinical signs and development of survivors of kernicterus due to Rh sensitization . The Journal of Pediatrics . 32 . 6 . 693–705 . 1948 . Lande . Lottie .
8. 20212966 . 2828194 . 1999 . Mitchell . S . Severe late anemia of hemolytic disease of the newborn . Paediatrics & Child Health . 4 . 3 . 201–3 . James . A . 10.1093/pch/4.3.201.
9. 10.1515/JPM.1999.014 . 10379500 . Late hyporegenerative anemia in neonates with rhesus hemolytic disease . Journal of Perinatal Medicine . 27 . 2 . 112–5 . 1999 . Al-Alaiyan . S. . Al Omran . A. . 32155893 .
10. Book: Bethesda DL. Blood Groups and Red Cell Antigens. Hemolytic disease of the newborn. National Center for Biotechnology Information. 2005. https://www.ncbi.nlm.nih.gov/books/NBK2266/.
11. 10.1136/adc.2005.076794 . 17337672 . 2675453 . Haemolytic disease of the newborn . Archives of Disease in Childhood: Fetal and Neonatal Edition . 92 . 2 . F83–8 . 2007 . Murray . N. A . Roberts . I. A G .
12. 10.1111/j.1365-3148.1995.tb00197.x . 7655573 . Three examples of Rh haemolytic disease of the newborn with a negative direct antiglobulin test . Transfusion Medicine . 5 . 2 . 113–6 . 1995 . Heddle . N. M. . Wentworth . P. . Anderson . D. R. . Emmerson . D. . Kelton . J. G. . Blajchman . M. A. . 21936425 .
13. 10.4103/0973-6247.150968 . 25722586 . 4339947 . Maternal anti-M induced hemolytic disease of newborn followed by prolonged anemia in newborn twins . Asian Journal of Transfusion Science . 9 . 1 . 98–101 . 2015 . Arora . Satyam . Doda . Veena . Maria . Arti . Kotwal . Urvershi . Goyal . Saurabh . free .
14. Web site: Archived copy . 2017-02-15 . 2021-03-09 . https://web.archive.org/web/20210309053500/https://www.ucsfbenioffchildrens.org/pdf/manuals/42_Hemol.pdf . dead .
15. 2494315 . 1989 . Koenig . J. M. . Neutropenia and thrombocytopenia in infants with Rh hemolytic disease . The Journal of Pediatrics . 114 . 4 Pt 1 . 625–31 . Christensen . R. D. . 10.1016/s0022-3476(89)80709-7.
16. 14413526 . 1960 . Lalezari . P . Neonatal neutropenia due to maternal isoimmunization . Blood . 15 . 236–43 . Nussbaum . M . Gelman . S . Spaet . T. H. . 2. 10.1182/blood.V15.2.236.236. free .
17. 10.1111/vox.12061 . 23802744 . Iron status in infants with alloimmune haemolytic disease in the first three months of life . Vox Sanguinis . 105 . 4 . 328–33 . 2013 . Rath . M. E. A. . Smits-Wintjens . V. E. H. J. . Oepkes . D. . Walther . F. J. . Lopriore . E. . 24789324 .
18. 15231951 . Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation . 2004 . American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. . Pediatrics . 114 . 1 . 297–316 . 10.1542/peds.114.1.297.
19. 10.3109/14767050903544751 . 20092394 . Intravenous Immunoglobulin therapy for anti-E hemolytic disease in the newborn . The Journal of Maternal-Fetal & Neonatal Medicine . 23 . 9 . 1059–61 . 2010 . Onesimo . Roberta . Rizzo . Daniela . Ruggiero . Antonio . Valentini . Piero . 25144401 .
20. 10.1136/fn.88.1.F6 . 12496219 . 1755998 . Systematic review of intravenous immunoglobulin in haemolytic disease of the newborn . Archives of Disease in Childhood: Fetal and Neonatal Edition . 88 . 1 . F6–10 . 2003 . Gottstein . R .