Neonatal jaundice explained

Neonatal jaundice
Synonyms:Neonatal hyperbilirubinemia, neonatal icterus, jaundice in newborns
Field:Pediatrics
Symptoms:Yellowish discoloration of the skin and white part of the eyes
Complications:Seizures, cerebral palsy, kernicterus
Onset:Newborns
Types:Physiologic, pathologic
Causes:Red blood cell breakdown, liver disease, infection, hypothyroidism, metabolic disorders
Diagnosis:Based on symptoms, confirmed by bilirubin
Treatment:More frequent feeding, phototherapy, exchange transfusions
Frequency:>50% of babies

Neonatal jaundice is a yellowish discoloration of the white part of the eyes and skin in a newborn baby due to high bilirubin levels. Other symptoms may include excess sleepiness or poor feeding. Complications may include seizures, cerebral palsy, or kernicterus.

In most of cases there is no specific underlying physiologic disorder. In other cases it results from red blood cell breakdown, liver disease, infection, hypothyroidism, or metabolic disorders (pathologic). A bilirubin level more than 34 μmol/L (2 mg/dL) may be visible. Concerns, in otherwise healthy babies, occur when levels are greater than 308 μmol/L (18 mg/dL), jaundice is noticed in the first day of life, there is a rapid rise in levels, jaundice lasts more than two weeks, or the baby appears unwell. In those with concerning findings further investigations to determine the underlying cause are recommended.

The need for treatment depends on bilirubin levels, the age of the child, and the underlying cause.[1] Treatments may include more frequent feeding, phototherapy, or exchange transfusions. In those who are born early more aggressive treatment tends to be required. Physiologic jaundice generally lasts less than seven days. The condition affects over half of babies in the first week of life.[2] Of babies that are born early about 80% are affected.[3] Globally over 100,000 late-preterm and term babies die each year as a result of jaundice.[4]

Sign and symptoms

Bronze baby syndrome (dark pigmentation of skin).

The primary symptom is yellowish discoloration of the white part of the eyes and skin in a newborn baby.[2] Other symptoms may include excess sleepiness or poor feeding.[2]

A bilirubin level more than 34 μmol/L (2 mg/dL) may be visible.[2] For the feet to be affected level generally must be over 255 μmol/L (15 mg/dL).[2]

Complications

Prolonged hyperbilirubinemia (severe jaundice) can result in chronic bilirubin encephalopathy (kernicterus).[5] [6] Quick and accurate treatment of neonatal jaundice helps to reduce the risk of neonates developing kernicterus.[7]

Infants with kernicterus may have a fever[8] or seizures.[9] High pitched crying is an effect of kernicterus.

Exchange transfusions performed to lower high bilirubin levels are an aggressive treatment.[10]

Causes

In newborns, jaundice tends to develop because of two factors—the breakdown of fetal hemoglobin as it is replaced with adult hemoglobin and the relatively immature metabolic pathways of the liver, which are unable to conjugate and so excrete bilirubin as quickly as an adult. This causes an accumulation of bilirubin in the blood (hyperbilirubinemia), leading to the symptoms of jaundice.

If the neonatal jaundice is not resolved with simple phototherapy, other causes such as biliary atresia, Progressive familial intrahepatic cholestasis, bile duct paucity, Alagille syndrome, alpha 1-antitrypsin deficiency, and other pediatric liver diseases should be considered. The evaluation for these will include blood work and a variety of diagnostic tests. Prolonged neonatal jaundice is serious and should be followed up promptly.[11]

Severe neonatal jaundice may indicate the presence of other conditions contributing to the elevated bilirubin levels, of which there are a large variety of possibilities (see below). These should be detected or excluded as part of the differential diagnosis to prevent the development of complications. They can be grouped into the following categories:

Unconjugated

Hemolytic

Intrinsic causes of hemolysis
Extrinsic causes of hemolysis

Non-hemolytic causes

Conjugated (Direct)

Liver causes

Post-liver

Non-organic causes

Breastfeeding jaundice

"Breastfeeding jaundice" (or "lack of breastfeeding jaundice") is caused by insufficient breast milk intake,[13] resulting in inadequate quantities of bowel movements to remove bilirubin from the body. This leads to increased enterohepatic circulation, resulting in increased reabsorption of bilirubin from the intestines.[14] Usually occurring in the first week of life, most cases can be ameliorated by frequent breastfeeding sessions of sufficient duration to stimulate adequate milk production.[15]

Breast milk jaundice

Whereas breastfeeding jaundice is a mechanical problem, breast milk jaundice is a biochemical occurrence and the higher bilirubin possibly acts as an antioxidant. Breast milk jaundice occurs later in the newborn period, with the bilirubin level usually peaking in the sixth to 14th days of life. This late-onset jaundice may develop in up to one third of healthy breastfed infants.[16]

  1. The gut is sterile at birth and normal gut flora takes time to establish. The bacteria in the adult gut convert conjugated bilirubin to stercobilinogen which is then oxidized to stercobilin and excreted in the stool. In the absence of sufficient bacteria, the bilirubin is de-conjugated by brush border β-glucuronidase and reabsorbed. This process of re-absorption is called enterohepatic circulation. It has been suggested that bilirubin uptake in the gut (enterohepatic circulation) is increased in breast fed babies, possibly as the result of increased levels of epidermal growth factor (EGF) in breast milk.[17] Breast milk also contains glucoronidase which will increase deconjugation and enterohepatic recirculation of bilirubin.
  2. The breast-milk of some women contains a metabolite of progesterone called 3-alpha-20-beta pregnanediol. This substance inhibits the action of the enzyme uridine diphosphoglucuronic acid (UDPGA) glucuronyl transferase responsible for conjugation and subsequent excretion of bilirubin. In the newborn liver, activity of glucuronyl transferase is only at 0.1-1% of adult levels, so conjugation of bilirubin is already reduced. Further inhibition of bilirubin conjugation leads to increased levels of bilirubin in the blood.[18] However, these results have not been supported by subsequent studies.[19]
  3. An enzyme in breast milk called lipoprotein lipase produces increased concentration of nonesterified free fatty acids that inhibit hepatic glucuronyl transferase, which again leads to decreased conjugation and subsequent excretion of bilirubin.[20]

Physiological jaundice

Most infants develop visible jaundice due to elevation of unconjugated bilirubin concentration during their first week. This is called physiological jaundice. This pattern of hyperbilirubinemia has been classified into two functionally distinct periods.[21]

  1. Term infants - jaundice lasts for about 10 days with a rapid rise of serum bilirubin up to 204 μmol/L (12 mg/dL).
  2. Preterm infants - jaundice lasts for about two weeks, with a rapid rise of serum bilirubin up to 255 μmol/L (15 mg/dL).
  1. Preterm infants - phase two can last more than one month.
  2. Exclusively breastfed infants - phase two can last more than one month.

Mechanisms involved in physiological jaundice include:

Diagnosis

Diagnosis is often by measuring the serum bilirubin level in the blood.[1] In those who are born after 35 weeks and are more than a day old transcutaneous bilirubinometer may also be used.[1] The use of an icterometer, a piece of transparent plastic painted in five transverse strips of graded yellow lines, is not recommended.[1]

Transcutaneous bilirubinometer

This is hand held, portable and rechargeable but expensive. When pressure is applied to the photoprobe, a xenon tube generates a strobe light, and this light passes through the subcutaneous tissue. The reflected light returns through the second fiber optic bundle to the spectrophotometric module. The intensity of the yellow color in this light, after correcting for the hemoglobin, is measured and instantly displayed in arbitrary units.

Pathological jaundice

Any of the following features suggests pathological jaundice:

  1. Clinical jaundice appearing in the first 24 hours or greater than 14 days of life.
  2. Increases in the level of total bilirubin by more than 8.5 μmol/L (0.5 mg/dL) per hour or (85 μmol/L) 5 mg/dL per 24 hours.
  3. Total bilirubin more than 331.5 μmol/L (19.5 mg/dL) (hyperbilirubinemia).
  4. Direct bilirubin more than 34 μmol/L (2.0 mg/dL).

The signs which help detect pathological jaundice are the presence of intrauterine growth restriction, stigma of intrauterine infections (e.g. cataracts, small head, and enlargement of the liver and spleen), cephalohematoma, bruising, signs of bleeding in the brain's ventricles. History of illness is noteworthy. Family history of jaundice and anemia, family history of neonatal or early infant death due to liver disease, maternal illness suggestive of viral infection (fever, rash or lymphadenopathy), maternal drugs (e.g. sulphonamides, anti-malarials causing red blood cell destruction in G6PD deficiency) are suggestive of pathological jaundice in neonates.

Treatment

The bilirubin levels for initiative of phototherapy varies depends on the age and health status of the newborn. However, any newborn with a total serum bilirubin greater than 359 μmol/L (21 mg/dL) should receive phototherapy.[25]

Phototherapy

Babies with neonatal jaundice may be treated with colored light called phototherapy, which works by changing trans-bilirubin into the water-soluble cis-bilirubin isomer.[26] [27] [28]

The phototherapy involved is not ultraviolet light therapy but rather a specific frequency of blue light. The light can be applied with overhead lamps, which means that the baby's eyes need to be covered, or with a device called a biliblanket, which sits under the baby's clothing close to its skin.[27]

The use of phototherapy was first discovered, accidentally, at Rochford Hospital in Essex, England, when a nurse, Sister Jean Ward, noticed that babies exposed to sunlight had reduced jaundice, and a pathologist, Dr. Perryman, who noticed that a vial of blood left in the sun had turned green. Drs Cremer, Richards and Dobbs put together these observations,[29] leading to a landmark randomized clinical trial which was published in Pediatrics in 1968; it took another ten years for the practice to become established.[27] [30] Massage therapy could be useful in addition to phototherapy in order to reduce the phototherapy duration. However, it does not appear to reduce the requirement for phototherapy in the treatment of neonatal jaundice.[31]

Recent studies from several countries show that phototherapy can safely and effectively be performed in the family's home, and since 2022 home phototherapy is recommended as an alternative to readmission to hospital in the American national guidelines.[32] [33] [34] However, there have been several reports about the possible relationship between neonatal phototherapy and the increased risk of future cancer. A recent systematic review has found that there may be a statistically significant association between phototherapy and various hematopoietic cancers (especially myeloid leukemia).[35]

Exchange transfusions

Much like with phototherapy the level at which exchange transfusion should occur depends on the health status and age of the newborn. It should however be used for any newborn with a total serum bilirubin of greater than 428 μmol/L (25 mg/dL).[25] [28]

Research

Penicillamine was studied in the 1970s in hyperbilirubinemia due to ABO hemolytic disease.[36] While tin mesoporphyrin IX may decrease bilirubin such use is not recommended in babies.[36] Preclinical studies have looked at minocycline to help prevent neurotoxicity.[36] Clofibrate may decrease the duration of phototherapy.[36] Evidence as of 2012 however is insufficient to recommend its use.[37]

External links

Notes and References

  1. Web site: Jaundice in newborn babies under 28 days. NICE. 11 December 2017. October 2016.
  2. Web site: Neonatal Hyperbilirubinemia. Merck Manuals Professional Edition. 11 December 2017. en-CA. August 2015.
  3. Web site: Jaundice in newborn babies under 28 days Guidance and guidelines. NICE. 11 December 2017. October 2016.
  4. Olusanya . BO . Teeple . S . Kassebaum . NJ . The Contribution of Neonatal Jaundice to Global Child Mortality: Findings From the GBD 2016 Study. . Pediatrics . February 2018 . 141 . 2 . e20171471 . 10.1542/peds.2017-1471 . 29305393. free .
  5. Juetschke, L.J. (2005, Mar/Apr). Kernicterus: still a concern. Neonatal Network, 24(2), 7-19, 59-62
  6. Colletti. JE. Kothari. S. Kothori. S. Jackson. DM. Kilgore. KP. Barringer. K . An emergency medicine approach to neonatal hyperbilirubinemia . Emerg. Med. Clin. North Am. . 25 . 4 . 1117–35, vii . November 2007 . 17950138 . 10.1016/j.emc.2007.07.007.
  7. Watchko . JF . Hyperbilirubinemia and bilirubin toxicity in the late preterm infant . Clin Perinatol . 33 . 4 . 839–52; abstract ix . December 2006 . 17148008 . 10.1016/j.clp.2006.09.002 . 2019-09-26 . 2017-08-08 . https://web.archive.org/web/20170808143902/http://unmfm.pbworks.com/w/file/fetch/37751502/Hyperbilirubinemia%20and%20Bilirubin%20Toxicity%20in%20the%20Late%20Preterm%20Infant.pdf . dead .
  8. Shah. Z. Chawla. A. Patkar. D. Pungaonkar. S . MRI in kernicterus . Australasian Radiology . 47 . 1 . 55–7 . March 2003 . 12581055 . 10.1046/j.1440-1673.2003.00973.x .
  9. Malik. BA. Butt. MA. Shamoon. M. Tehseen. Z. Fatima. A. Hashmat. N. Seizures etiology in the newborn period . Journal of the College of Physicians and Surgeons--Pakistan . 15 . 12 . 786–90 . December 2005 . 16398972.
  10. Gómez. M. Bielza. C. Fernández del Pozo . JA. Ríos-Insua. S . 14514900. A graphical decision-theoretic model for neonatal jaundice . Med Decis Making . 27 . 3 . 250–65 . 2007 . 17545496 . 10.1177/0272989X07300605 .
  11. Gilmour. Susan M. December 2004. Prolonged neonatal jaundice: When to worry and what to do. Paediatrics & Child Health. 9. 10. 700–704. 10.1093/pch/9.10.700. 1205-7088. 2724143. 19688078.
  12. An osteopathic approach to reduction of readmissions for neonatal jaundice. https://archive.today/20130415161902/http://www.osteopathicfamilyphysician.org/article/S1877-573X(12)00187-6/abstract. dead. 2013-04-15. Click. R. Dahl-Smith. J. Fowler. L. DuBose. J. Deneau-Saxton. M. Herbert. J. Osteopathic Family Physician. 5. 1. January 2013. 10.1016/j.osfp.2012.09.005. 17–23.
  13. Book: Lynn C. Garfunkel. Jeffrey . Cynthia Christy. Mosby's pediatric clinical advisor: instant diagnosis and treatment. 14 June 2010. 2002. Elsevier Health Sciences. 978-0-323-01049-8. 200–.
  14. Leung. A. K.. Sauve. R. S.. 1989-12-01. Breastfeeding and breast milk jaundice. Journal of the Royal Society of Health. 109. 6. 213–217. 0264-0325. 2513410. 10.1177/146642408910900615. 38974909.
  15. Web site: CDC. 2020-11-13. Jaundice. 2021-07-12. Centers for Disease Control and Prevention. en-us.
  16. Hyperbilirubinemia in the Term Newborn. American Family Physician. 65. 4. 599–606. 2002-02-15. Dennis. Maj Beth L.. Porter. Meredith L.. 11871676.
  17. Kumral. A. Ozkan H . Duman N . etal . Breast milk jaundice correlates with high levels of epidermal growth factor. Pediatr Res. 2009. 66. 2. 218–21. 10.1203/pdr.0b013e3181ac4a30. 19617811. free.
  18. Arias. IM. Gartner LM . Seifter S . Furman M . Prolonged neonatal unconjugated hyperbilirubinemia associated with breast feeding and a steroid, pregnane-3(alpha), 20(beta)-diol in maternal milk that inhibits glucuronide formation in vitro. J Clin Invest. 1964. 43. 11. 2037–47. 10.1172/jci105078 . 14228539 . 441992.
  19. Murphy. J F. Hughes I. Verrier Jones ER. Gaskell S. Pike AW. Pregnanediols and breast-milk jaundice. Arch Dis Child. 1981. 56. 6. 474–76. 10.1136/adc.56.6.474. 7259280. 1627473.
  20. Poland. R L. Schultz GE . Gayatri G . High milk lipase activity associated with breastmilk jaundice. Pediatr Res. 1980. 14. 12. 1328–31. 10.1203/00006450-198012000-00011. 6782543. free.
  21. Porter. Meredith L.. Dennis. Maj Beth L.. 2002-02-15. Hyperbilirubinemia in the Term Newborn. American Family Physician. 65. 4. 599–606. 11871676. 0002-838X.
  22. McDonagh . A. F. . 21269991 . Movement of Bilirubin and Bilirubin Conjugates Across the Placenta . 10.1542/peds.2006-3669 . Pediatrics . 119 . 5 . 1032–1033; author 1033 1033 . 2007 . 17473108.
  23. https://books.google.com/books?hl=en&lr=&id=ulR9AuVcJOIC&oi=fnd&pg=PA45 Page 45
  24. Harrison . K. L. . Fetal Erythrocyte Lifespan . 10.1111/j.1440-1754.1979.tb01197.x . Journal of Paediatrics and Child Health . 15 . 2 . 96–97 . 1979 . 485998. 5370064 .
  25. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation . Pediatrics . 114 . 1 . 297–316 . July 2004 . 15231951 . 10.1542/peds.114.1.297. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. free .
  26. Stokowski LA . 31233601 . Fundamentals of phototherapy for neonatal jaundice . Adv Neonatal Care . 6 . 6 . 303–12 . December 2006 . 17208161 . 10.1016/j.adnc.2006.08.004 .
  27. Jones. Clay. Separating Fact from Fiction in the Not-So-Normal Newborn Nursery: Newborn Jaundice. Science-Based Medicine. 9 May 2014.
  28. Book: Wolkoff, Allan W.. Longo. Dan L.. Kasper. Dennis L.. Harrison's principles of internal medicine.. 2012. McGraw-Hill. New York. 978-0071748896. 18th. Chapter 303: The Hyperbilirubinemias.
  29. CREMER . RJ . PERRYMAN . PW . RICHARDS . DH . Influence of light on the hyperbilirubinaemia of infants. . Lancet . 24 May 1958 . 1 . 7030 . 1094–7 . 10.1016/s0140-6736(58)91849-x . 13550936.
  30. Lucey. J. Ferriero. M. Hewitt. J. Prevention of hyperbilirubinemia of prematurity by phototherapy.. Pediatrics. June 1968. 41. 6. 1047–54. 10.1542/peds.41.6.1047. 5652916. 41816888.
  31. Abdellatif . Mohammed . Massage therapy for the treatment of neonatal jaundice: A systematic review and network meta-analysis . Journal of Neonatal Nursing . February 2020 . 26 . 1 . 17–24 . 10.1016/j.jnn.2019.09.002 . free .
  32. Anderson . Candice Megan . Kandasamy . Yogavijayan . Kilcullen . Meegan . August 2021 . The efficacy of home phototherapy for physiological and non-physiological neonatal jaundice: A systematic review . Journal of Neonatal Nursing . 28 . 5 . en . 312–326 . 10.1016/j.jnn.2021.08.010. 238646014 .
  33. Pettersson . M. . Eriksson . M. . Albinsson . E. . Ohlin . A. . 2021-05-01 . Home phototherapy for hyperbilirubinemia in term neonates—an unblinded multicentre randomized controlled trial . European Journal of Pediatrics . en . 180 . 5 . 1603–1610 . 10.1007/s00431-021-03932-4 . 1432-1076 . 8032579 . 33469713.
  34. Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation . 10.1542/peds.2022-058859. free . 2022-09-20 . Pediatrics. 2022 . 35927462 . Kemper . A. R. . Newman . T. B. . Slaughter . J. L. . Maisels . M. J. . Watchko . J. F. . Downs . S. M. . Grout . R. W. . Bundy . D. G. . Stark . A. R. . Bogen . D. L. . Holmes . A. V. . Feldman-Winter . L. B. . Bhutani . V. K. . Brown . S. R. . Maradiaga Panayotti . G. M. . Okechukwu . K. . Rappo . P. D. . Russell . T. L. . 150 . 3 .
  35. Abdellatif, Mohammed, et al. "Association between neonatal phototherapy and future cancer: an updated systematic review and meta-analysis." European Journal of Pediatrics (2022): 1-13
  36. Mancuso . Cesare . 21001248 . Bilirubin and brain: A pharmacological approach . Neuropharmacology . May 15, 2017 . 118 . 113–123 . 10.1016/j.neuropharm.2017.03.013 . 28315352 .
  37. Gholitabar . M . McGuire . H . Rennie . J . Manning . D . Lai . R . Clofibrate in combination with phototherapy for unconjugated neonatal hyperbilirubinaemia. . The Cochrane Database of Systematic Reviews . 12 December 2012 . 12 . 3 . CD009017 . 10.1002/14651858.CD009017.pub2 . 23235669. 6426433 .

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