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HDFN & High Bilirubin



Fast Facts

Hyperbilirubinemia: High levels of biliurbin.

Normal Lab Values: Varies by age (in hours). Use Peditools or the charts below to view normal values. Infants with HDFN are either high risk (born before 38 weeks), or medium risk (born at 38 weeks).

A common misconception is that if a mother’s antibody titers are low, her baby will not have issues after birth. This is not always true. Even women with low titers can give birth to a baby who struggles with bilirubin after birth. As red blood cells die, they release bilirubin. In utero, bilirubin is filtered by the placenta. After birth, the baby’s liver must filter out the bilirubin. Unfortunately the newborn liver is often immature and cannot keep up with the rising bilirubin levels 1. As a result, bilirubin builds up and can become toxic. As bilirubin builds up, the infant will become jaundiced which can lead to permanent effects such as: hearing loss, bilirubin encephalopathy, kernicterus, cholestasis, and death if not treated properly. Bilirubin encephalopathy and kernicterus are both considered “never events” and should never happen with appropriate care and monitoring. High levels of bilirubin can also damage the baby teeth and may cause staining or reduced tooth enamel.

It is important that all babies with a positive Coombs test or DAT be monitored regularly for bilirubin. High bilirubin occurs frequently in babies affected by anti-A, anti-B, anti-D, anti-c, anti-E antibodies, but it can occur with any antibody. According to the American Academy of Pediatrics (AAP), Infants with HDFN are at high risk (born before 38 weeks), or medium risk (born at 38 weeks or later) for bilirubin issues and require lower phototherapy and exchange transfusion thresholds 2. Bilirubin levels due to HDFN tend to peak on days 4-9 and may require phototherapy for 2-3 weeks. Documents such as the American Academy of Pediatrics’ Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation 2 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 in the management of hyperbilirubinemia.


Tests for high bilirubin

The standard test for bilirubin is a total serum bilirubin (TSB). This value is plotted on the phototherapy or exchange transfusion graph. Infants with HDFN should be considered to have “risk factors” when assessing bilirubin levels using the standard phototherapy eligibility guidelines 2. This means that they will be either medium risk (born 38 weeks or later) or high risk (born before 38 weeks) and require treatment at lower levels. 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.

The infant’s first TSB comes from the cord blood or other testing immediately at birth. A cord bilirubin of ⩾2.05 mg/dL (pre-term) to 2.15 mg/dL (full-term) indicates need for phototherapy 3. Even in the absence of a positive DAT/IAT result, it is advised to continue monitoring bilirubin in the infant every four to six hours for at least the first 24 hours of life. “A rate of rise in bilirubin levels greater than 5 mg/dL/24 h (or >0.5 mg/dL/h) is suggestive of hemolysis in any infant; therefore, clinical jaundice (bilirubin >5 mg/dL needed to be clinically visible) in the first 24 hours strongly suggests a hemolytic process” 4. If bilirubin levels are higher than expected during the infant’s first week of life, repeat the DAT. Visible jaundice is a sign that the bilirubin level is rising, but it is a poor predictor of the concentration of bilirubin in circulation or in the brain – neonatal blood testing must occur. Visual assessments are not an acceptable way to monitor or treat an infant with HDFN.

Serum bilirubin should be assessed regularly during phototherapy. It is important to note that infants with HDFN will have rebounding hyperbilirubinemia. When phototherapy is stopped, levels will increase rapidly and the infant will frequently require additional phototherapy. To help prevent this, it is better to use continuous phototherapy vs intermittent phototherapy. Because home phototherapy is not an option for infants with HDFN, a 12 or 24 hour trial without lights before discharge is advisable to reduce hospital readmissions. During the first week of life, bilirubin should be checked daily, especially considering that bilirubin due to alloimmunization tends to peak at days four to six, but can peak as late as day 9. “If phototherapy is used for infants with hemolytic diseases or is initiated early and discontinued before the infant is 3 to 4 days old, a follow-up bilirubin measurement within 24 hours after discharge is recommended.” 2 Home phototherapy is not an option for infants with HDFN and readmission may be necessary. High bilirubin due to antibodies can persist for 2-3 weeks and should continue to be checked at least one to two times a week until a steady decrease is certain.

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.

For additional information about testing, see our Infant Testing page.


Preventative Options for High Bilirubin

As an attempt to mature the baby’s liver, some physicians are administering phenobarbital to mothers in their last 10 days of pregnancy. This has been shown to reduce the need for exchange transfusions due to high bilirubin levels 5, 6.

A recent study in 2020 found that vitamin C supplementation during the last month of pregnancy can significantly reduce newborn bilirubin levels 7. This has not been studied to see if vitamin C supplementation will work for hyperbilirubinemia due to HDFN.


Treatment Options for High Bilirubin

Treatment options for hyperbilirubinemia are discussed in depth below, 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 8.

The American Academy of Pediatrics recommends against the use of home phototherapy because the home lights are not as strong as the lights used in the hospital.

Phototherapy

Intervention for hyperbilirubinemia includes phototherapy based on cord bilirubin, serial determinations, and the rate of rise. A cord bilirubin of ⩾2.05 mg/dL (pre-term) to 2.15 mg/dL (full-term) indicates need for phototherapy 3. Serum bilirubin should be assessed regularly during phototherapy. It is important to note that infants with HDFN will have rebounding hyperbilirubinemia. When phototherapy is stopped, levels can increase rapidly and the infant will frequently require additional phototherapy. To help prevent this, it is better to use continuous phototherapy vs intermittent phototherapy. Because home phototherapy is not an option for infants with HDFN, a 12 or 24 hour trial without lights before discharge is advisable to reduce hospital readmissions.

Intravenous Immune Globulin (IVIG)

The implementation of intravenous immune globulin (IVIG) in the newborn is employed by many neonatal units in the treatment of HDFN after birth 9. IVIG is given when bilirubin levels are rising despite intensive phototherapy, or when levels are approaching the levels necessitating an exchange transfusion. The American Academy of Pediatrics recommends the use of intravenous immuneglobulin (IVIG) to reduce bilirubin levels – “RECOMMENDATION 7.1.4: 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 (Fig 4).If necessary, this dose can be repeated in 12 hours (evidence quality B: benefits exceed harms) 2.” Early studies indicated that high-dose IVIG (0.5g/kg IV immediately after HDFN is confirmed) does reduce serum bilirubin levels and subsequent need for exchange transfusion 10. A recent meta-analysis confirmed these findings in studies where IVIG doses ranged from 0.5g/kg to 1.5g/kg in one to three administrations 11. Adverse effects of IVIG can include: fever, allergic reactions, rebound hemolysis, and fluid overload 12. IVIG can affect the efficacy of some live-virus vaccines for 11-12 months. This can affect administration of the rotavirus vaccine.

Exchange Transfusion

Exchange transfusion should be conducted if bilirubin reaches or exceeds critical levels as shown below (infants with HDFN are medium or high risk)45. A cord bilirubin level of >5 mg/dL, or a rate of rise in serum bilirubin of more than 0.5-1 mg/dL/h is predictive of the ultimate need for exchange transfusion 13. IVIG may prevent the need for an exchange transfusion if initiated early enough.

Metalloporphyrins

While phototherapy and exchange transfusions are effective treatments for hyperbilirubinemia after it forms, much can be done to optimize treatment of infants with HDFN to prevent and eliminate the development of kernicterus. Studies are currently underway on a multitude of pharmacotherapeutic agents to prevent or treat neonatal hyperbilirubinemia, including metalloporphyrins. The increased hemolysis occuring in infants with HDFN is associated with increased bilirubin production and a greater risk for neurologic injury. Preventing the formation of bilirubin via heme oxygenase (the rate-limiting enzyme responsible for the production of bilirubin), is possible with both natural and synthetic metalloporphyrins 14. Clinical studies of SnMP show that it prevents excessive hyperbilirubinemia and reduces the duration and need for phototherapy in both term and near-term infants 15. The use of metalloporphyrins reduces the risk of Kernicterus and BIND, however side effects such as photosensitivity and potential inhibition of several other enzymes that have essential roles in metabolism have been known to occur 15. While multiple metalloporphyrins have been studied in animal models, only two have been studied in human neonates: tin protoporphyrin (SnPP) and tin mesoporphyrin (SnMP). SnPP was highly efficacious, but abandoned due to its photosensitizing properties 4. SnMP can be used at lower doses with minimal photoreactivity 14. Metalloporphyrins are currently being studied and administered on a compassionate basis, particularly in regards to patients with religious objections to blood products 16.

For additional articles relating to hyperbilirubinemia and treatment options, see our additional reading by topic page.


Lasting Consequences of Poorly Managed High Bilirubin

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 2. This condition commonly develops during the first week of life, but can occur as late as the third week 17. 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 17. 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 2. 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 18, 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) 19. 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 20. 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 2. 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 20, though in rare cases, cholestasis can result from inappropriate iron administration 21. While cholestasis is most commonly seen with HDFN due to anti-D 20, it can happen with HDFN due to other alloantibodies as well 22, 23.

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 2, 8. 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 2. 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 2. It is important that the direct serum bilirubin should not be subtracted from the TSB when making decisions about exchange transfusions 2. For additional articles relating to bronze baby syndrome, see our additional reading by topic page.

References

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  2. 2. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation [published correction appears in Pediatrics. 2004 Oct;114(4):1138]. Pediatrics. 2004;114(1):297–316. doi:10.1542/peds.114.1.297
  3. 3. AlaaEldin A. Zeitoun, Hala F. Elhagrasy, Doaa M. Abdelsatar. Predictive value of umbilical cord blood bilirubin in neonatal hyperbilirubinemia. Egyptian Pediatric Association Gazette. 2013; 61 (1):23-30 https://doi.org/10.1016/j.epag.2013.04.006.
  4. 4. Thilo, Elizabeth. Hemolytic Disease of the Newborn. Cancer Therapy Advisor; Pediatrics.
  5. 5. Trevett TN Jr, Dorman K, Lamvu G, Moise KJ Jr. Antenatal maternal administration of phenobarbital for the prevention of exchange transfusion in neonates with hemolytic disease of the fetus and newborn. Am J Obstet Gynecol. 2005;192(2):478–482. doi:10.1016/j.ajog.2004.08.016
  6. 6. Venkatnarayan K, Sankar MJ, Agarwal R, Paul VK, Deorari AK. Phenobarbitone in Rh hemolytic disease of the newborn: a randomized double-blinded placebo-controlled trial. J Trop Pediatr. 2013;59(5):380–386. doi:10.1093/tropej/fmt032
  7. 7. M. Khadem al-hosseini, S.T. Rahideh, A. Saadati, N. Rahmati, F. Azadeh, L. Janani, F. Shidfar. The effect of vitamin C supplementation in the last month of pregnancy on neonatal bilirubin levels; A double-blind randomized clinical trial. Complementary Therapies in Medicine 2020;50. doi:10.1016/j.ctim.2020.102359
  8. 8. Bertini G, Dani C, Fonda C, Zorzi C, Rubaltelli FF. Bronze baby syndrome and the risk of kernicterus. Acta Paediatr. 2005;94(7):968–971. doi:10.1111/j.1651-2227.2005.tb02020.x
  9. 9. Rath ME, Smits-Wintjens VE, Walther FJ, Lopriore E. Hematological morbidity and management in neonates with hemolytic disease due to red cell alloimmunization. Early Hum Dev. 2011;87(9):583–588. doi:10.1016/j.earlhumdev.2011.07.010
  10. 10. Rübo J, Albrecht K, Lasch P, et al. High-dose intravenous immune globulin therapy for hyperbilirubinemia caused by Rh hemolytic disease. J Pediatr. 1992;121(1):93–97. doi:10.1016/s0022-3476(05)82551-x
  11. 11. Cortey A, Elzaabi M, Waegemans T, Roch B, Aujard Y. Efficacité et tolérance des immunoglobulines polyvalentes dans l'hyperbilirubinémie néonatale par incompatibilité ABO. Méta-analyse [Efficacy and safety of intravenous immunoglobulins in the management of neonatal hyperbilirubinemia due to ABO incompatibility: a meta-analysis]. Arch Pediatr. 2014;21(9):976–983. doi:10.1016/j.arcped.2014.02.005
  12. 12. Schulz S, Wong RJ, Vreman HJ, Stevenson DK. Metalloporphyrins - an update. Front Pharmacol. 2012;3:68. Published 2012 Apr 26. doi:10.3389/fphar.2012.00068
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  21. 21. Ree IMC, Smits-Wintjens VEHJ, van der Bom JG, van Klink JMM, Oepkes D, Lopriore E. Neonatal management and outcome in alloimmune hemolytic disease. Expert Rev Hematol. 2017;10(7):607–616. doi:10.1080/17474086.2017.1331124
  22. 22. Cholestasis in a neonate with ABO haemolytic disease of newborn following transfusion of ABO group-specific red cells compatible with neonatal serum: inspissated bile syndrome. Blood Transfus. 2014;12(4):621‐623. doi:10.2450/2014.0099-14
  23. 23. Macher S, Wagner T, Rosskopf K, et al. Severe case of fetal hemolytic disease caused by anti-C(w) requiring serial intrauterine transfusions complicated by pancytopenia and cholestasis. Transfusion. 2016;56(1):80‐83. doi:10.1111/trf.13367

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