Maternal Alloimmunization and HDFN:

An overview for providers

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Neonatal Presentation of HDFN

The risks of HDFN do not end at delivery. Monitoring and management must be just as vigilant after birth as during pregnancy in order to prevent neonatal harm and infant death. Maternal alloantibodies which have crossed the placenta remain in the infant’s circulation and can attach to the infant’s red blood cells for up to 12 weeks after birth. For this reason, follow-up in newborns whose cord blood confirms the presence of maternal antibodies is essential for several weeks after discharge from the hospital, even in the absence of visible indications of anemia.

Infants with either a positive DAT or who are antigen positive in the case of a DAT exception antibody, and who have signs of anemia, hyperbilirubinemia, or some other consequence of HDFN are considered to be affected by HDFN. It is not required that an infant be treated (via transfusion etc) in order for them to be considered affected and diagnosed with HDFN. Affected infants must be monitored for ongoing and delayed anemia and other signs of HDFN. This poses a unique challenge when consistent, quality care must continue across multiple providers including maternal-fetal medicine specialists, neonatologists, hematologists and pediatricians. Unfortunately many infants do not receive proper monitoring and follow up care for HDFN and preventable infant deaths are still occurring today.

HDFN can manifest itself in a variety of ways, including: hyperbilirubinemia, neutropenia, thrombocytopenia, anemia, and more.

Hyperbilirubinemia

The destruction of red blood cells causes the release of bilirubin. In utero the bilirubin is filtered via the placenta; after birth the neonatal liver assumes the role of removing bilirubin. Due to the neonatal liver’s immature metabolic pathways 44, high levels of bilirubin can rapidly build up in the neonate’s system causing jaundice which can lead to permanent effects such as: bilirubin encephalopathy, kernicterus, cholestasis, and death if not treated properly. A total serum bilirubin level at or above the exchange transfusion level should be considered a medical emergency and intensive phototherapy, IVIG, and preparation for an exchange transfusion should be commenced immediately. Elevated levels of bilirubin have been associated with hearing loss in the neonate. Therefore, newborn screening for hearing loss (standard of care in most states) would appear warranted in children with HDFN. Follow-up screening at 1 and 2 years of age should be considered. Hyperbilirubinemia due to other causes typically peaks during days 1-3 of life, while hyperbilirubinemia due to HDFN tends to peak on days 4-6. Documents like the American Academy of Pediatrics’ Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation exist to help prevent and reduce the complications of hyperbilirubinemia. These guidelines should be followed closely to prevent neonatal harm. Tools such as Peditools provide clinical tools to assist the provider in the management of hyperbilirubinemia. Infants with HDFN should be considered to have “risk factors” when assessing bilirubin levels using standard phototherapy eligibility guidelines 45. Treatment options for hyperbilirubinemia are discussed in depth on the Infant interventions page and include: phototherapy, IVIG, exchange transfusion, and some clinical trials with tin mesoporphyrin. Phototherapy treatment may result in the development of Bronze Baby Syndrome in infants with elevated direct bilirubin levels. Bronze Baby Syndrome may increase the risk of complications due to hyperbilirubinemia such as Kernicterus 59. For additional articles relating to the consequences of hyperbilirubinemia listed below, see our additional reading by topic page.

Bilirubin encephalopathy

Infants with HDFN are at higher risk for developing bilirubin encephalopathy. Bilirubin encephalopathy develops when bilirubin moves from the bloodstream into the brain and refers to the acute manifestations of bilirubin toxicity in the first weeks after birth 45. This condition commonly develops during the first week of life, but can occur as late as the third week 75. Signs of bilirubin encephalopathy include: extreme jaundice, an absent startle reflex, poor feeding or sucking, lethargy, hypotonia, a high-pitched cry, irritability, and a hyperextended back and neck 75. Complications of bilirubin encephalopathy include: nerve deafness, damage to the tooth enamel (enamel dysplasia, and discoloration of the teeth), and brain damage.

Kernicterus

While bilirubin encephalopathy refers to the acute manifestation of bilirubin toxicity, kernicterus is the chronic and permanent clinical sequelae of bilirubin toxicity 45. Kernicterus is NOT associated with any degree of cognitive impairment (mental disability), however survivors are often left trapped in a body that does not function as it should. This disease, listed as one of 27 medical errors that should never happen 73, continues to occur despite being completely preventable. Kernicterus is a spectrum which can include some or all of the following: movement disorders (athetoid cerebral palsy, dystonia, myoclonus that impairs the ability to sleep, vestibular instability), seizures, visual impairments (gaze abnormalities, nystagmus, strabismus, cortical visual impairment), digestive impairment (GERD, reflux, impaired digestion, impaired ability to swallow or eat orally), dental (dental enamel dysplasia or hypoplasia), and hearing impairment (including auditory neuropathy spectrum disorder) 74. Individuals living with kernicterus are affected to varying degrees. Some live with mild hearing loss, behavioral challenges, and/or clumsiness while other might be mistaken for someone with spastic quadriplegia.

Cholestasis

Cholestasis occurs in up to 13% of infants with HDFN 58. Cholestasis can be identified with an elevated direct or conjugated bilirubin level. If the direct or conjugated bilirubin is elevated, additional evaluation for the cause of cholestasis is recommended 45. When other causes of cholestasis have been ruled out in a DAT positive infant, HDFN as a cause of cholestasis should be strongly considered. This can be due to iron overload from intrauterine transfusions 58, though in rare cases, cholestasis can result from inappropriate iron administration 56. While cholestasis is most commonly seen with HDFN due to anti-D 58, it can happen with HDFN due to other alloantibodies as well 76, 77.

Bronze Baby Syndrome

This is a rare complication that occurs in infants with cholestatic jaundice where they develop dark, grayish-brown discolored skin, blood, and urine. Infants who have received phototherapy with an elevated direct-reacting or conjugated bilirubin level may develop the bronze-baby syndrome 45, 59. Bronze baby syndrome has few consequences, but it can be disturbing to parents. Phototherapy is not contraindicated in infants with bronze baby syndrome, however providers should be aware that cholestasis will decrease the efficacy of phototherapy 45. For this reason, exchange transfusion may be considered at lower levels if intensive phototherapy is not working and the total serum bilirubin (TSB) is high or rising despite phototherapy 45. It is important that the direct serum bilirubin should not be subtracted from the TSB when making decisions about exchange transfusions 45. For additional articles relating to bronze baby syndrome, see our additional reading by topic page.

Neutropenia

Neutropenia as a result of maternal alloimmunization has been documented since 1960 and still occurs in 45% of infants with HDFN 80 today. Koenig et al notes that, “the marked increase in erythropoiesis in fetuses with Rh hemolytic disease can be accompanied by a down-modulation of neutrophil and platelet production” 78. While all hydropic infants in Koenig’s paper were neutropenic, hydrops is not a requirement for neutropenia - even mildly affected infants with HDFN can be neutropenic. Neutropenic infants are at higher risk for infection and may require treatment for neutropenia; Recombinant Human Granulocyte Colony-Stimulating Factor has been used in some cases 79. Providers should make parents aware of the increased risk and encourage them to take precautions with their children. Neutropenia due to HDFN can persist for a year in some cases. In addition to neutropenia, leukopenia has also been known to occur 95. For additional articles relating to neutropenia, see our additional reading by topic page.

Thrombocytopenia

Thrombocytopenia is another lesser-known complication of HDFN, affecting 26% of fetuses 81 and infants 82. Risk factors include IUTs, small for gestational age, and lower gestational age at birth. Hydropic infants are more likely to be thrombocytopenic, though thrombocytopenia occurs in non-hydropic infants as well. Infants with thrombocytopenia experience bruising and bleeding easier than other infants. In severe cases, platelet transfusions are utilized. “Thrombocytopenia is an independent risk factor for perinatal mortality. Mortality in fetuses that were severely thrombocytopenic and severely hydropic was 67%.” 81For additional articles relating to thrombocytopenia, see our additional reading by topic page.

Anemia

Maternal alloantibodies which have crossed into the fetal circulation remain and can attach to the infant’s red blood cells for up to 12 weeks after birth. For this reason, follow-up in newborns whose cord blood confirms the presence of maternal antibodies is essential until hemoglobin is increasing without a blood transfusion for at least two consecutive weeks, even in the absence of visible indications of anemia. Depending on the specific antibody and it’s reactions, anemia due to HDFN can manifest itself in one of three ways: early onset anemia, delayed onset anemia, and hyporegenerative anemia. No matter which form of anemia presents, iron is not an acceptable treatment for an infant with HDFN. Improperly monitored and untreated anemia can lead to heart failure and death in infants who are several weeks old. For additional articles relating to all of these types of anemia, see our additional reading by topic page.

Early onset anemia

Early onset anemia is anemia that is present at birth or before week 2. This anemia, caused by antibody mediated hemolysis, may be detected during a cord blood sample, or as part of other follow up testing. Infants who are in the NICU may struggle with feeding, failure to thrive, or cardiovascular complications. For these infants it is often not a matter of if they will need a transfusion, but when. Correcting the anemia early (at higher hemoglobin levels) may reduce stress on the infant’s body, reduce prematurity issues, and help improve latch for oral feeds. Infants with early onset anemia will have an elevated bilirubin, and a normal or elevated reticulocyte count 44. It is important to note that while early onset anemia occurs within the first 2 weeks of life, it does not resolve within the first two weeks of life. Early onset anemia can become hyporegenerative anemia and all infants with early onset anemia must be monitored weekly until the hemoglobin is increasing without intervention for 2-3 weeks in a row.

Delayed onset anemia

Delayed onset anemia is anemia that presents between 2-12 weeks of life. This anemia is still caused by antibody mediated hemolysis and may be worsened by a natural decline of hemoglobin levels. It is not uncommon for infants to need their first transfusion at 2-4 weeks of age. Infants with delayed onset anemia may have a normal or elevated bilirubin count, along with a normal or high reticulocyte count 44. Delayed onset anemia can happen to all infants with HDFN regardless of which antibody the mother has, even if the fetus was not treated with IUTs. Treatment options for infants with delayed onset anemia include folic acid, blood transfusion, and erythropoietin 13, 38.

Hyporegenerative anemia

Hyporegenerative anemia is a unique form of anemia due to HDFN that happens due to a combination of factors. Antibody mediated hemolysis is still in play, however bone marrow suppression either by IUTs and transfusions, or by specific antibody action is a major factor. Antibodies such as anti-Kell and anti-M are known to cause bone marrow suppression making it harder for the infant to regenerate blood cells destroyed by maternal antibodies. These infants usually have a normal bilirubin level along with a low reticulocyte count, and may also have erythropoietin deficiency 83. Hyporegenerative anemia is treated via erythropoietin to increase reticulocyte count 33, 69, 70.

Iron

A special consideration in these infants is the use of iron in HDFN. Infants with HDFN do not suffer from iron-deficiency anemia 49. A 2013 paper 49 found that ferritin levels are highly elevated at birth in neonates with HDFN. “Iron overload occurred in 70% of neonates at birth and in 50% and 18% at the age of 1 and 3 months, respectively.” 49 Do not administer iron supplements without first confirming the ferritin level 49, 50, 51. Inappropriate administration of iron in infants with HDFN can result in iron overload 46 and adverse events such as cholestasis 56, portal hypertension, coagulopathy abnormal liver enzymes, free-radical damage 57, liver damage, or death. For infants with severe iron overload, chelation therapy with desferrioxamine is an option to prevent or reduce organ damage 51, 52, 53, 54. Folic acid can be safely given to neonates with HDFN 46. If hyporegenerative anemia is a concern, Erythropoietin can be used either alone or in combination with desferrioxamine if iron overload is a concern 55. For additional articles relating to iron, see our additional reading by topic page.

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