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Neonatal jaundice

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Neonatal jaundice
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Neonatal jaundice or Neonatal hyperbilirubinemia, or Neonatal icterus (from the Greek word ἴκτερος), attributive adjective: icteric, is a yellowing of the skin and other tissues of a newborn infant. A bilirubin level of more than 85 μmol/l (5 mg/dL) manifests clinical jaundice in neonates whereas in adults a level of 34 μmol/l (2 mg/dL) would look icteric. In newborns, jaundice is detected by blanching the skin with digital pressure so that it reveals underlying skin and subcutaneous tissue.[1] Jaundiced newborns have an apparent icteric sclera, and yellowing of the face, extending down onto the chest.

Neonatal jaundice can sometimes make the newborn sleepy, and interfere with feeding. Extreme jaundice can cause permanent neurological damage known as kernicterus.

In neonates, the dermal icterus is first noted in the face and as the bilirubin level rises proceeds caudal to the trunk and then to the extremities.[2] This condition is common in newborns affecting over half (50–60%) of all babies in the first week of life.[3]

Notoriously inaccurate rules of thumb have been applied to the physical exam of the jaundiced infant.[citation needed] Some include estimation of serum bilirubin based on appearance. One such rule of thumb includes infants whose jaundice is restricted to the face and part of the trunk above the umbilicus, have the bilirubin less than 204 μmol/l (12 mg/dL) (less dangerous level). Infants whose palms and soles are yellow, have serum bilirubin level over 255 μmol/l (15 mg/dL) (more serious level). Studies have shown that trained examiners assessment of levels of jaundice show moderate agreement with icterometer bilirubin measurements.[2] In infants, jaundice can be measured using invasive or non-invasive methods.

Classification

Physiological jaundice

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

Phase one
  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).
Phase two - bilirubin levels decline to about 34 μmol/l (2 mg/dL) for two weeks, eventually mimicking adult values.
  1. Preterm infants - phase two can last more than one month.
  2. Exclusively breastfed infants - phase two can last more than one month.

Causes

Mechanism involved in physiological jaundice are mainly:

  • Relatively low activity of the enzyme glucuronosyltransferase which normally converts unconjugated bilirubin to conjugated bilirubin that can be excreted into the gastrointestinal tract.[4] Before birth, this enzyme is actively down-regulated, since bilirubin needs to remain unconjugated in order to cross the placenta to avoid being accumulated in the fetus.[5] After birth, it takes some time for this enzyme to gain function.
  • Shorter life span of fetal red blood cells,[4] being approximately 80 to 90 days in a full term infant,[6] compared to 100 to 120 days in adults.
  • Relatively low conversion of bilirubin to urobilinogen by the intestinal flora, resulting in relatively high absorption of bilirubin back into the circulation.[4]

Pathological Jaundice of Neonates (Unconjugated Pathological Hyperbilirubinemia)

Any of the following features characterizes 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).

Differentiating Physiological and Pathological Jaundice

The aim of clinical assessment is to distinguish physiological from pathological jaundice. The signs which help to differentiate pathological jaundice of neonates from physiological jaundice of neonates are the presence of intrauterine growth restriction, stigma of intrauterine infections (e.g. cataracts, microcephaly, hepatosplenomegaly etc.), cephalohematoma, bruising, signs of intraventricular hemorrhage, etc. 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 hemolysis in G6PD deficiency) are suggestive of pathological jaundice in neonates.

Causes of jaundice

In neonates, jaundice tends to develop because of two factors - the breakdown of fetal hemoglobin as it is replaced with adult hemoglobin and the relatively immature hepatic metabolic pathways 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 does not clear up with simple phototherapy, other causes such as biliary atresia, PFIC, 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.

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:

Neonatal jaundice
Unconjugated bilirubinConjugated bilirubin
PathologicPhysiological jaundice of NeonatesHepaticPost-hepatic
HemolyticNon-hemolytic
Intrinsic causesExtrinsic causes

Non Conjugated

Hemolytic

Intrinsic causes of hemolysis
Extrinsic causes of hemolysis

Non-hemolytic causes

Conjugated (Direct)

Hepatic causes

Post-hepatic

Non-organic causes

Breastfeeding failure jaundice

"Breastfeeding jaundice" or "lack of breastfeeding jaundice," is caused by insufficient breast milk intake,[7] resulting in inadequate quantities of bowel movements to remove bilirubin from the body. This can usually be ameliorated by frequent breastfeeding sessions of sufficient duration to stimulate adequate milk production.

Breast Milk jaundice

Whereas breast feeding 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.[8]

  • First, at birth, the gut is sterile, 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.[9] Breast milk also contains glucoronidase which will increase deconjugation and enterohepatic recirculation of bilirubin.
  • Second, 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.[10] However, these results have not been supported by subsequent studies.[11]
  • Third, 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.[12]

Despite the advantages of breast feeding, there is a strong association of breast feeding with neonatal hyperbilirubinemia and thus risk of kernicterus, though this is uncommon. Serum bilirubin levels may reach as high as 30 mg/dL. Jaundice should be managed either with phototherapy or with exchange blood transfusion as is needed. Breast feeds however need not be discontinued. The child should be kept well hydrated and extra feeds given.

Non-invasive measurement of jaundice

Clinical Assessment

This method is less accurate and more subjective in estimating jaundice.

Ingram icterometer: In this method a piece of transparent plastic known as Ingram icterometer is used. Ingram icterometer is painted in five transverse strips of graded yellow lines. The instrument is pressed against the nose and the yellow colour of the blanched skin is matched with the graded yellow lines and bilirubin level is assigned.

Transcutaneous bilirubinometer: This is hand held, portable and rechargeable but expensive and sophisticated. 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.

Treatment

The bilirubin levels for initiative of phototherapy varies depends on the age and health status of the newborn. However, any newborn with a totlial serum bilirubin greater than 359 μmol/l ( 21 mg/dL) should receive phototherapy.[13]

Phototherapy

The use of phototherapy was first discovered, accidentally, at Rochford Hospital in Essex, England. The ward sister (Charge Nurse) of the premature baby unit firmly believed that the infants under her care benefited from fresh air and sunlight in the courtyard. Although this led to the first noticing of jaundice being improved with sunlight, further studies only progressed when a vial of blood sent for bilirubin measurement sat on a windowsill in the lab for several hours. The results indicated a much lower level of bilirubin than expected based on the patient's visible jaundice. Further investigation lead to the determination that blue light, wavelength of 420-448 nm, oxidized the bilirubin to biliverdin, a soluble product that does not contribute to kernicterus. Although some pediatricians began using phototherapy in the United Kingdom following Dr. Cremer's publishing the above facts in the Lancet in 1958, most hospitals only began to regularly use phototherapy ten years later when an American group independently made the same discovery.[14][15]

newborn infant undergoing (white light) phototherapy to treat neonatal jaundice

Infants with neonatal jaundice are treated with colored light called phototherapy. Physicians randomly assigned 66 infants 35 weeks of gestation to receive phototherapy. After 15±5 the levels of bilirubin, a yellowish bile pigment that in excessive amounts causes jaundice, were decreased down to 0.27±0.25 mg/dl/h in the blue light. This suggests that blue light therapy helps reduce high bilirubin levels that cause neonatal jaundice.[16]

Exposing infants to high levels of colored light changes trans-bilirubin to the more water soluble cis-form which is excreted in the bile. Scientists studied 616 capillary blood samples from jaundiced newborn infants. These samples were randomly divided into three groups. One group contained 133 samples and would receive phototherapy with blue light. Another group contained 202 samples would receive room light, or white light. The final group contained 215 samples, and were left in a dark room. The total bilirubin levels were checked at 0, 2, 4, 6, 24, and 48 hours. There was a significant decrease in bilirubin in the first group exposed to phototherapy after two hours, but no change occurred in the white light and dark room group. After 6 hours, there was a significant change in bilirubin level in the white light group but not the dark room group. It took 48 hours to record a change in the dark room group’s bilirubin level. Phototherapy is the most effective way of breaking down a neonate’s bilirubin.[17]

Phototherapy works through a process of isomerization that changes trans-bilirubin into the water-soluble cis-bilirubin isomer.[18][19]

In phototherapy, blue light is typically used because it is more effective at breaking down bilirubin (Amato, Inaebnit, 1991). Two matched groups of newborn infants with jaundice were exposed to intensive green or blue light phototherapy. The efficiency of the treatment was measured by the rate of decline of serum bilirubin, which in excessive amounts causes jaundice, concentration after 6, 12 and 24 hours of light exposure. A more rapid response was obtained using the blue lamps than the green lamps. However, a shorter phototherapy recovery period was noticed in babies exposed to the green lamps(1). Green light is not commonly used because exposure time must be longer to see dramatic results(1).

Ultraviolet light therapy may increase the risk of skin moles, in childhood. While an increased number of moles is related to an increased risk of skin cancer,[20][21][22] it is not ultraviolet light that is used for treating neonatal jaundice. Rather, it is simply a specific frequency of blue light that does not carry these risks.

Increased feedings help move bilirubin through the neonate’s metabolic system.[23]

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.

Sunlight

Natural sunlight also serves as an effective form of treatment as it also contains the optimal wavelengths. In one study it what is 6 times more effective than bilirubin lamps due to the difference in light intensities. according to the American pediatric Association babies that use sunlight for therapy may be at risk for getting cold since they are mostly naked in order to absorb the sunlight, it should not be taken outdoors since they will be exposed to higher ultraviolet radiation. (http://www.ncbi.nlm.nih.gov/m/pubmed/11722753)

Exchange transfusions

Much like with phototherapy the level at which exchange transfusions 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 ).[13]

Complications

Prolonged hyperbilirubinemia (severe jaundice) can result into chronic bilirubin encephalopathy (kernicterus).[24][25] Quick and accurate treatment of neonatal jaundice helps to reduce the risk of neonates developing kernicterus.[26]

Infants with kernicterus may have a fever[27] or seizures.[28] High pitched crying is an effect of kernicterus. Scientists used a computer to record and measure cranial nerves 8, 9 and 12 in 50 infants who were divided into two groups equally depending upon bilirubin concentrations. Of the 50 infants, 43 had tracings of high pitched crying.[29]

Exchange transfusions performed to lower high bilirubin levels are an aggressive treatment.[30]

Guidelines

American Academy of Pediatrics has issued guidelines for managing this disease, which can be obtained for free.[31]
National Institute for Health and Care Excellence (NICE) has issued guidelines for the recognition and treatment of neonatal jaundice in the United Kingdom.[32]

References

  1. ^ a b c Click, R; Dahl-Smith, J; Fowler, L; DuBose, J; Deneau-Saxton, M; Herbert, J (January 2013). "An osteopathic approach to reduction of readmissions for neonatal jaundice". Osteopathic Family Physician. 5 (1). doi:10.1016/j.osfp.2012.09.005.
  2. ^ a b Madlon-Kay, Diane J. Recognition of the Presence and Severity of Newborn Jaundice by Parents, Nurses, Physicians, and Icterometer Pediatrics 1997 100: e3
  3. ^ "Neonatal Jaundice" (PDF). Intensive Care Nursery House Staff Manual. UCSF Children's Hospital. 2004. Retrieved 26 July 2011. {{cite conference}}: Unknown parameter |booktitle= ignored (|book-title= suggested) (help)
  4. ^ a b c Page 45 in: Obstetrics & Gynaecology, by B. Jain, 2002. ISBN 8180562107, 9788180562105
  5. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1542/peds.2006-3669, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1542/peds.2006-3669 instead.
  6. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1111/j.1440-1754.1979.tb01197.x, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1111/j.1440-1754.1979.tb01197.x instead.
  7. ^ Lynn C. Garfunkel; Jeffrey; Cynthia Christy (2002). Mosby's pediatric clinical advisor: instant diagnosis and treatment. Elsevier Health Sciences. pp. 200–. ISBN 978-0-323-01049-8. Retrieved 14 June 2010.
  8. ^ http://www.aafp.org/afp/2002/0215/p599.html
  9. ^ Kumral, A; Ozkan H; Duman N; et al. (2009). "Breast milk jaundice correlates with high levels of epidermal growth factor". Pediatr Res. 66: 218–21. doi:10.1203/pdr.0b013e3181ac4a30. {{cite journal}}: Explicit use of et al. in: |author4= (help)
  10. ^ Arias, IM; Gartner LM; Seifter S; Furman M (1964). "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. 43: 2037–47. doi:10.1172/jci105078.
  11. ^ Murphy, J F (1981). "Pregnanediols and breast-milk jaundice". Arch Dis Child. 56: 474–76. doi:10.1136/adc.56.6.474. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  12. ^ Poland, R L; Schultz GE; Gayatri G (1980). "High milk lipase activity associated with breastmilk jaundice". Pediatr Res. 14: 1328–31. doi:10.1203/00006450-198012000-00011.
  13. ^ a b American Academy of Pediatrics Subcommittee on Hyperbilirubinemia (July 2004). "Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation". Pediatrics. 114 (1): 297–316. doi:10.1542/peds.114.1.297. PMID 15231951.
  14. ^ Dobbs, R H; R J Cremer (November 1975). "Phototherapy". Archives of Disease in Childhood. 50 (11): 833–836. doi:10.1136/adc.50.11.833. ISSN 0003-9888. PMC 1545706. PMID 1108807.
  15. ^ Cremer, R. J.; P. W. Perryman; D. H. Richards (1958-05-24). "INFLUENCE OF LIGHT ON THE HYPERBILIRUBINÆMIA OF INFANTS". The Lancet. 271 (7030): 1094–1097. doi:10.1016/S0140-6736(58)91849-X. ISSN 0140-6736. Retrieved 2010-08-01.
  16. ^ Amato M, Inaebnit D (February 1991). "Clinical usefulness of high intensity green light phototherapy in the treatment of neonatal jaundice". Eur. J. Pediatr. 150 (4): 274–6. doi:10.1007/BF01955530. PMID 2029920.
  17. ^ Leung C, Soong WJ, Chen SJ (July 1992). "[Effect of light on total micro-bilirubin values in vitro]". Zhonghua Yi Xue Za Zhi (Taipei) (in Chinese). 50 (1): 41–5. PMID 1326385.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ^ Stokowski LA (December 2006). "Fundamentals of phototherapy for neonatal jaundice". Adv Neonatal Care. 6 (6): 303–12. doi:10.1016/j.adnc.2006.08.004. PMID 17208161.
  19. ^ Ennever JF, Sobel M, McDonagh AF, Speck WT (July 1984). "Phototherapy for neonatal jaundice: in vitro comparison of light sources". Pediatr. Res. 18 (7): 667–70. doi:10.1203/00006450-198407000-00021. PMID 6540860.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  20. ^ Pullmann H, Theunissen A, Galosi A, Steigleder GK (November 1981). "[Effect of PUVA and SUP therapy on nevocellular nevi (author's transl)]". Z. Hautkr. (in German). 56 (21): 1412–7. PMID 7314762.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  21. ^ Titus-Ernstoff L, Perry AE, Spencer SK, Gibson JJ, Cole BF, Ernstoff MS (August 2005). "Pigmentary characteristics and moles in relation to melanoma risk". Int. J. Cancer. 116 (1): 144–9. doi:10.1002/ijc.21001. PMID 15761869.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  22. ^ Randi G, Naldi L, Gallus S, Di Landro A, La Vecchia C (September 2006). "Number of nevi at a specific anatomical site and its relation to cutaneous malignant melanoma". J. Invest. Dermatol. 126 (9): 2106–10. doi:10.1038/sj.jid.5700334. PMID 16645584.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  23. ^ Wood, S. (2007, March). Fact or fable?. Baby Talk, 72(2).
  24. ^ Juetschke, L.J. (2005, Mar/Apr). Kernicterus: still a concern. Neonatal Network, 24(2), 7-19, 59-62
  25. ^ Colletti, JE; Kothari, S; Kothori, S; Jackson, DM; Kilgore, KP; Barringer, K (November 2007). "An emergency medicine approach to neonatal hyperbilirubinemia". Emerg. Med. Clin. North Am. 25 (4): 1117–35, vii. doi:10.1016/j.emc.2007.07.007. PMID 17950138.
  26. ^ Watchko, JF (December 2006). "Hyperbilirubinemia and bilirubin toxicity in the late preterm infant". Clin Perinatol. 33 (4): 839–52, abstract ix. doi:10.1016/j.clp.2006.09.002. PMID 17148008.
  27. ^ Shah, Z; Chawla, A; Patkar, D; Pungaonkar, S (March 2003). "MRI in kernicterus". Australas Radiol. 47 (1): 55–7. doi:10.1046/j.1440-1673.2003.00973.x. PMID 12581055.
  28. ^ Malik, BA; Butt, MA; Shamoon, M; Tehseen, Z; Fatima, A; Hashmat, N (December 2005). "Seizures etiology in the newborn period". Journal of the College of Physicians and Surgeons--Pakistan. 15 (12): 786–90. PMID 16398972.
  29. ^ Vohr, BR; Lester, B; Rapisardi, G (August 1989). "Abnormal brain-stem function (brain-stem auditory evoked response) correlates with acoustic cry features in term infants with hyperbilirubinemia". J. Pediatr. 115 (2): 303–8. doi:10.1016/S0022-3476(89)80090-3. PMID 2754560.
  30. ^ Gómez, M; Bielza, C; Fernández del Pozo, JA; Ríos-Insua, S (2007). "A graphical decision-theoretic model for neonatal jaundice". Med Decis Making. 27 (3): 250–65. doi:10.1177/0272989X07300605. PMID 17545496.
  31. ^ American Academy of Pediatrics. "AAP Issues New Guidelines for Identifying and Managing Newborn Jaundice". Retrieved 4 July 2009.
  32. ^ "Neonatal jaundice (CG98)". Retrieved 23 May 2013.
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