Neonatal jaundice medical therapy: Difference between revisions

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==Overview==
==Overview==
The mainstay of treatment of patients with neonatal jaundice is phototherapy and blood exchange.  
The mainstay of treatment of patients with neonatal jaundice is [[phototherapy]], [[intravenous]] [[immunoglobulins]] and [[Blood transfusion|blood exchange]].  
 
 
==Medical Therapy==
==Medical Therapy==
* Phototherapy or blood transfusion are recommended by the American Academy of Pediatrics (AAP) for the treatment of neonatal jaundice.<ref name="AAP2004">{{cite journal |author=|title=Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation |journal=Pediatrics |volume=114 |issue=1|pages=297–316 |year=2004 |month=July |pmid=15231951 |doi= 10.1542/peds.114.1.297|url=http://pediatrics.aappublications.org/cgi/pmidlookup?view=long&pmid=15231951 |author1= American Academy of Pediatrics Subcommittee on Hyperbilirubinemia}}</ref>
* [[Phototherapy]] or [[blood transfusion]] are recommended by the American Academy of Pediatrics (AAP) for the treatment of neonatal jaundice.<ref name="AAP2004">{{cite journal |author=|title=Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation |journal=Pediatrics |volume=114 |issue=1|pages=297–316 |year=2004 |month=July |pmid=15231951 |doi= 10.1542/peds.114.1.297|url=http://pediatrics.aappublications.org/cgi/pmidlookup?view=long&pmid=15231951 |author1= American Academy of Pediatrics Subcommittee on Hyperbilirubinemia}}</ref>
* It is recommended to treat the newborns with phototherapy or blood transfusion in order to decrease the risk of severe hyperbilirubinemia and kernicterus development.  
* It is recommended to treat the [[newborns]] with [[phototherapy]] or blood transfusion in order to decrease the risk of severe [[hyperbilirubinemia]] and [[kernicterus]].  


===Phototherapy===
===Phototherapy===
* Phototherapy is considered as the safest intervention approach used in treatment of neonatal jaundice.
* [[Phototherapy]] is considered as the safest intervention approach used in treatment of neonatal jaundice.
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&nbsp;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.<ref>{{Cite journal
* [[Phototherapy]] showed its efficacy in lowering the level of the total [[serum bilirubin]] in all patients with neonatal jaundice regardless the underlying cause.<ref>{{cite journal |author=Amato M, Inaebnit D |title=Clinical usefulness of high intensity green light phototherapy in the treatment of neonatal jaundice |journal=Eur. J. Pediatr. |volume=150 |issue=4 |pages=274–6 |year=1991 |month=February|pmid=2029920 |doi= 10.1007/BF01955530|url=}}</ref><ref name="pmid15231986">{{cite journal| author=Ip S, Chung M, Kulig J, O'Brien R, Sege R, Glicken S et al.| title=An evidence-based review of important issues concerning neonatal hyperbilirubinemia. | journal=Pediatrics | year= 2004 | volume= 114 | issue= 1 | pages= e130-53 | pmid=15231986 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15231986  }}</ref>
| doi = 10.1136/adc.50.11.833
* [[Phototherapy]] also acts on preventing the rise of the [[bilirubin]] to the level of [[exchange transfusion]] threshold.<ref name="pmid19403502">{{cite journal| author=Newman TB, Kuzniewicz MW, Liljestrand P, Wi S, McCulloch C, Escobar GJ| title=Numbers needed to treat with phototherapy according to American Academy of Pediatrics guidelines. | journal=Pediatrics | year= 2009 | volume= 123 | issue= 5 | pages= 1352-9 | pmid=19403502 | doi=10.1542/peds.2008-1635 | pmc=2843697 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19403502  }}</ref>
| issn = 0003-9888
* The total [[bilirubin]] level should be assessed every three hours after starting the [[phototherapy]]. The efficacy of [[phototherapy]] is assessed by the drop of the [[bilirubin]] level which is the best indicator of the neonatal response to the [[phototherapy]].<ref name="pmid9917432">{{cite journal| author=Bhutani VK, Johnson L, Sivieri EM| title=Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns. | journal=Pediatrics | year= 1999 | volume= 103 | issue= 1 | pages= 6-14 | pmid=9917432 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9917432  }}</ref>
| volume = 50
* If the level of the [[bilirubin]] still high after initiating the [[phototherapy]], [[blood transfusion]] is indicated.
| issue = 11
| pages = 833–836
| last = Dobbs
| first = R H
| coauthors = R J Cremer
| title = Phototherapy.
| journal = Archives of Disease in Childhood
| date = 1975-11
| pmid = 1108807
| pmc = 1545706
}}</ref><ref>{{Cite journal
| doi = 10.1016/S0140-6736(58)91849-X
| issn = 0140-6736
| volume = 271
| issue = 7030
| pages = 1094–1097
| last = Cremer
| first = R. J.
| coauthors = P. W. Perryman, D. H. Richards
| title = INFLUENCE OF LIGHT ON THE HYPERBILIRUBINÆMIA OF INFANTS
| journal = The Lancet
| accessdate = 2010-08-01
| date = 1958-05-24
| url = http://www.sciencedirect.com.lrc1.usuhs.edu/science/article/B6T1B-497S8P6-7T/2/79532c4987c3e76cc9f804072c89252f
}}</ref>
[[Image:Jaundice phototherapy.jpg |thumb|left]]
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&nbsp;mg/dl/h in the blue light.  This suggests that blue light therapy helps reduce high bilirubin levels that cause neonatal jaundice.<ref>{{cite journal |author=Amato M, Inaebnit D |title=Clinical usefulness of high intensity green light phototherapy in the treatment of neonatal jaundice |journal=Eur. J. Pediatr. |volume=150 |issue=4 |pages=274–6 |year=1991 |month=February|pmid=2029920 |doi= 10.1007/BF01955530|url=}}</ref>


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.<ref>{{cite journal |author=Leung C, Soong WJ, Chen SJ |title=[Effect of light on total micro-bilirubin values in vitro] |language=Chinese |journal=Zhonghua Yi Xue Za Zhi (Taipei) |volume=50 |issue=1 |pages=41–5 |year=1992|month=July |pmid=1326385 |doi= |url=}}</ref>
==== Mechanism of phototherapy ====
* [[Phototherapy]] lowers the level of [[bilirubin]] in neonatal jaundice via the following mechanisms:<ref name="pmid3584465">{{cite journal| author=Ennever JF, Costarino AT, Polin RA, Speck WT| title=Rapid clearance of a structural isomer of bilirubin during phototherapy. | journal=J Clin Invest | year= 1987 | volume= 79 | issue= 6 | pages= 1674-8 | pmid=3584465 | doi=10.1172/JCI113006 | pmc=424499 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3584465  }}</ref><ref>{{cite journal |author=Leung C, Soong WJ, Chen SJ |title=[Effect of light on total micro-bilirubin values in vitro] |language=Chinese |journal=Zhonghua Yi Xue Za Zhi (Taipei) |volume=50 |issue=1 |pages=41–5 |year=1992|month=July |pmid=1326385 |doi= |url=}}</ref>
** Isomerization of [[bilirubin]] to lumirubin which is more soluble<ref>{{cite journal |author=Stokowski LA |title=Fundamentals of phototherapy for neonatal jaundice |journal=Adv Neonatal Care |volume=6 |issue=6|pages=303–12 |year=2006 |month=December |pmid=17208161 |doi=10.1016/j.adnc.2006.08.004 |url=}}</ref>
** Isomerization of [[bilirubin]] isomers to less toxic isomers (ex. 4Z and 15E)
** [[Phototherapy]] converts [[bilirubin]] into soluble polar compounds by [[4|oxidation]]
* Different sources of the light required for [[phototherapy]]: <ref name="pmid15686263">{{cite journal| author=Vreman HJ, Wong RJ, Stevenson DK| title=Phototherapy: current methods and future directions. | journal=Semin Perinatol | year= 2004 | volume= 28 | issue= 5 | pages= 326-33 | pmid=15686263 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15686263  }}</ref>
** Home [[phototherapy]]
** Sunlight exposure
** Filtered sunlight
** Fluorescent tubes
** Halogen white light
** Blue LEDs


[[Phototherapy]] works through a process of isomerization that changes trans-bilirubin into the water-soluble cis-bilirubin isomer.<ref>{{cite journal |author=Stokowski LA |title=Fundamentals of phototherapy for neonatal jaundice |journal=Adv Neonatal Care |volume=6 |issue=6|pages=303–12 |year=2006 |month=December |pmid=17208161 |doi=10.1016/j.adnc.2006.08.004 |url=}}</ref><ref>{{cite journal |author=Ennever JF, Sobel M, McDonagh AF, Speck WT |title=Phototherapy for neonatal jaundice: in vitro comparison of light sources |journal=Pediatr. Res.|volume=18 |issue=7 |pages=667–70 |year=1984 |month=July |pmid=6540860 |doi= 10.1203/00006450-198407000-00021|url=}}</ref>
==== Adverse effects of phototherapy ====
* Although [[phototherapy]] is of a high safe margin, the following adverse effects are associated with [[phototherapy]] in some cases:
** [[Skin rashes]] and [[hyperthermia]]
** Bronze baby syndrome<ref name="pmid8696003">{{cite journal| author=Rubaltelli FF, Da Riol R, D'Amore ES, Jori G| title=The bronze baby syndrome: evidence of increased tissue concentration of copper porphyrins. | journal=Acta Paediatr | year= 1996 | volume= 85 | issue= 3 | pages= 381-4 | pmid=8696003 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8696003  }}</ref>
** Increase risk of cancers in the [[neonates]] treated by [[phototherapy]]<ref name="pmid27217478">{{cite journal| author=Wickremasinghe AC, Kuzniewicz MW, Grimes BA, McCulloch CE, Newman TB| title=Neonatal Phototherapy and Infantile Cancer. | journal=Pediatrics | year= 2016 | volume= 137 | issue= 6 | pages=  | pmid=27217478 | doi=10.1542/peds.2015-1353 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27217478  }} [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27849162 Review in: Evid Based Med. 2017 Mar;22(1):39-40]</ref>
** Development of nevi <ref name="pmid23521230">{{cite journal| author=Oláh J, Tóth-Molnár E, Kemény L, Csoma Z| title=Long-term hazards of neonatal blue-light phototherapy. | journal=Br J Dermatol | year= 2013 | volume= 169 | issue= 2 | pages= 243-9 | pmid=23521230 | doi=10.1111/bjd.12335 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23521230  }}</ref>


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. Green light is not commonly used because exposure time must be longer to see dramatic results. Green light is not commonly used because it makes the babies appear sickly, which is disturbing to observers.
===Exchange transfusions===
* [[Blood transfusion]] is reserved for the patients who still have high level of [[bilirubin]] even after receiving treatment by [[phototherapy]].<ref name="AAP2004" />
* The role of [[exchange transfusion]] is to remove the [[bilirubin]] from the blood stream especially if the patient [[infants]] show complications of acute [[bilirubin]] [[encephalopathy]] or [[kernicterus]].<ref name="pmid21641482">{{cite journal| author=Johnson L, Bhutani VK| title=The clinical syndrome of bilirubin-induced neurologic dysfunction. | journal=Semin Perinatol | year= 2011 | volume= 35 | issue= 3 | pages= 101-13 | pmid=21641482 | doi=10.1053/j.semperi.2011.02.003 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21641482 }}</ref>
* [[Exchange transfusion]] has its best outcome in the patients with jaundice due to [[alloimmunization]] diseases.
* [[Exchange transfusion]] may have the following complications:
** [[Hemolytic]] reactions 
** [[Infections]] 
** [[Portal vein thrombosis]] 
** [[Electrolyte disturbances]] 
** Increase blood volume 
** [[Iron overload]] 


Ultraviolet light therapy may increase the risk of or skin moles, in childhood. While an increased number of moles is related to an increased risk of skin cancer,<ref>{{cite journal |author=Pullmann H, Theunissen A, Galosi A, Steigleder GK |title=[Effect of PUVA and SUP therapy on nevocellular nevi (author's transl)] |language=German |journal=Z. Hautkr. |volume=56 |issue=21 |pages=1412–7 |year=1981 |month=November|pmid=7314762 |doi= |url=}}</ref><ref>{{cite journal |author=Titus-Ernstoff L, Perry AE, Spencer SK, Gibson JJ, Cole BF, Ernstoff MS|title=Pigmentary characteristics and moles in relation to melanoma risk |journal=Int. J. Cancer |volume=116 |issue=1 |pages=144–9 |year=2005|month=August |pmid=15761869 |doi=10.1002/ijc.21001 |url=}}</ref><ref>{{cite journal |author=Randi G, Naldi L, Gallus S, Di Landro A, La Vecchia C |title=Number of nevi at a specific anatomical site and its relation to cutaneous malignant melanoma |journal=J. Invest. Dermatol.|volume=126 |issue=9 |pages=2106–10 |year=2006 |month=September |pmid=16645584 |doi=10.1038/sj.jid.5700334 |url=}}</ref> 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.
=== Intravenous Immunoglobulins (IVIG) ===
* According to the American Academy of Pediatrics (AAP), [[IVIG]] are recommended in the patients with neonatal jaundice due to [[Hemolytic disease of newborn|hemolytic diseases]] and [[Alloimmunity|alloimmunization]].<ref name="AAP2004" />  
* [[Intravenous immunoglobulin]] may reduce the need of [[exchange transfusion]] when they are introduced to patients with [[alloimmunization]] diseases like Rh hemolytic disease and ABO incompatibility disease.<ref name="pmid12496219">{{cite journal| author=Gottstein R, Cooke RW| title=Systematic review of intravenous immunoglobulin in haemolytic disease of the newborn. | journal=Arch Dis Child Fetal Neonatal Ed | year= 2003 | volume= 88 | issue= 1 | pages= F6-10 | pmid=12496219 | doi= | pmc=1755998 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12496219  }}</ref>  
*  Preferred regimen: IVIG 500 mg/kg every 2 hours
==References==
{{Reflist|2}}


Increased feedings help move bilirubin through the neonate’s metabolic system.<ref>Wood, S. (2007, March). Fact or fable?. Baby Talk, 72(2).</ref>
​​
 
{{WH}}
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.
{{WS}}
 
Brief exposure to '''indirect''' sunlight each day and increased feeding are also helpful. A newborn should not be exposed to direct[[sunlight]] because of the danger of [[sunburn]], which is much more harmful to a newborn's thin skin than that of an adult.
 
If the neonatal jaundice does not clear up with simple [[phototherapy]], other causes such as [[biliary atresia]], PFIC, bile duct paucity, Alagille's syndrome, alpha 1 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.


===Exchange transfusions===
[[Category:Medicine]]
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 umol/l ( 25&nbsp;mg/dL ).<ref name="AAP2004" />
[[Category:Gastroenterology]]
==References==
[[Category:Up-To-Date]]
{{Reflist|2}}
[[Category:Pediatrics]]
[[Category:Pediatrics]]
[[Category:Hepatology]]
[[Category:Hepatology]]
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[[Category:Neonatology]]
[[Category:Neonatology]]
[[Category:Overview complete]]
[[Category:Overview complete]]
[[Category:Disease]]  
[[Category:Disease]]
 
{{WH}}
{{WS}}

Latest revision as of 22:57, 29 July 2020

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:

Overview

The mainstay of treatment of patients with neonatal jaundice is phototherapy, intravenous immunoglobulins and blood exchange.

Medical Therapy

Phototherapy

Mechanism of phototherapy

Adverse effects of phototherapy

Exchange transfusions

Intravenous Immunoglobulins (IVIG)

References

  1. ↑ 1.0 1.1 1.2 American Academy of Pediatrics Subcommittee on Hyperbilirubinemia (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. Unknown parameter |month= ignored (help)
  2. ↑ Amato M, Inaebnit D (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. Unknown parameter |month= ignored (help)
  3. ↑ Ip S, Chung M, Kulig J, O'Brien R, Sege R, Glicken S; et al. (2004). "An evidence-based review of important issues concerning neonatal hyperbilirubinemia". Pediatrics. 114 (1): e130–53. PMID 15231986.
  4. ↑ Newman TB, Kuzniewicz MW, Liljestrand P, Wi S, McCulloch C, Escobar GJ (2009). "Numbers needed to treat with phototherapy according to American Academy of Pediatrics guidelines". Pediatrics. 123 (5): 1352–9. doi:10.1542/peds.2008-1635. PMC 2843697. PMID 19403502.
  5. ↑ Bhutani VK, Johnson L, Sivieri EM (1999). "Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns". Pediatrics. 103 (1): 6–14. PMID 9917432.
  6. ↑ Ennever JF, Costarino AT, Polin RA, Speck WT (1987). "Rapid clearance of a structural isomer of bilirubin during phototherapy". J Clin Invest. 79 (6): 1674–8. doi:10.1172/JCI113006. PMC 424499. PMID 3584465.
  7. ↑ Leung C, Soong WJ, Chen SJ (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. Unknown parameter |month= ignored (help)
  8. ↑ Stokowski LA (2006). "Fundamentals of phototherapy for neonatal jaundice". Adv Neonatal Care. 6 (6): 303–12. doi:10.1016/j.adnc.2006.08.004. PMID 17208161. Unknown parameter |month= ignored (help)
  9. ↑ Vreman HJ, Wong RJ, Stevenson DK (2004). "Phototherapy: current methods and future directions". Semin Perinatol. 28 (5): 326–33. PMID 15686263.
  10. ↑ Rubaltelli FF, Da Riol R, D'Amore ES, Jori G (1996). "The bronze baby syndrome: evidence of increased tissue concentration of copper porphyrins". Acta Paediatr. 85 (3): 381–4. PMID 8696003.
  11. ↑ Wickremasinghe AC, Kuzniewicz MW, Grimes BA, McCulloch CE, Newman TB (2016). "Neonatal Phototherapy and Infantile Cancer". Pediatrics. 137 (6). doi:10.1542/peds.2015-1353. PMID 27217478. Review in: Evid Based Med. 2017 Mar;22(1):39-40
  12. ↑ Oláh J, Tóth-Molnár E, Kemény L, Csoma Z (2013). "Long-term hazards of neonatal blue-light phototherapy". Br J Dermatol. 169 (2): 243–9. doi:10.1111/bjd.12335. PMID 23521230.
  13. ↑ Johnson L, Bhutani VK (2011). "The clinical syndrome of bilirubin-induced neurologic dysfunction". Semin Perinatol. 35 (3): 101–13. doi:10.1053/j.semperi.2011.02.003. PMID 21641482.
  14. ↑ Gottstein R, Cooke RW (2003). "Systematic review of intravenous immunoglobulin in haemolytic disease of the newborn". Arch Dis Child Fetal Neonatal Ed. 88 (1): F6–10. PMC 1755998. PMID 12496219.

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