Cochrane Database of Systematic Reviews (Protocols) || Intermittent phototherapy versus continuous phototherapy for neonatal jaundice

Intermittent phototherapy versus continuous phototherapy

for neonatal jaundice (Protocol)

Onyango AB, Suresh G, Were F

This is a reprint of a Cochrane protocol, prepared and maintained by The Cochrane Collaboration and published in The Cochrane

Library 2009, Issue 4

http://www.thecochranelibrary.com

Intermittent phototherapy versus continuous phototherapy for neonatal jaundice (Protocol)

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iIntermittent phototherapy versus continuous phototherapy for neonatal jaundice (Protocol)


[Intervention Protocol]

Intermittent phototherapy versus continuous phototherapyfor neonatal jaundice

Awuonda B Onyango1, Gautham Suresh2, Fred Were3

1Pediatrics, University of Nairobi-Kenya, Nairobi, Kenya. 2Department of Pediatrics, Neonatal Division, Dartmouth-Hitchcock Med-

ical Center, Lebanon, NH, USA. 3Department of Paediatrics and Child Health, University of Nairobi and Aga Khan University,

Nairobi, Kenya

Contact address: Awuonda B Onyango, Pediatrics, University of Nairobi-Kenya, P.O. Box 11305-00100, Nairobi, Kenya.

[email protected].

Editorial group: Cochrane Neonatal Group.

Publication status and date: Edited (no change to conclusions), published in Issue 1, 2010.

Citation: Onyango AB, Suresh G, Were F. Intermittent phototherapy versus continuous phototherapy for neonatal jaundice. Cochrane

Database of Systematic Reviews 2009, Issue 4. Art. No.: CD008168. DOI: 10.1002/14651858.CD008168.


A B S T R A C T

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effect of intermittent phototherapy compared with continuous phototherapy on the incidence of kernicterus and treatment

failure in neonates with hyperbilirubinemia.

B A C K G R O U N D

Description of the condition

Jaundice is the yellow discolouration of the skin caused by the

presence of bilirubin in the soft tissues and can result from high

levels of conjugated or unconjugated bilirubin. About 97% of

full term and preterm neonates demonstrate a biochemical hyper-

bilirubinaemia (serum bilirubin level > 1 mg/dl) and about 65%

appear clinically jaundiced (serum bilirubin > 5 mg/dl) (Maisels

1986; Keren 2008). Physiological jaundice results from a high

level of circulating unconjugated bilirubin due to accelerated red

cell break-down, reduced liver bilirubin handling capacity and in-

creased enterohepatic circulation (Horn 2006). Pathologic jaun-

dice results from conditions such as haemolytic disease of the new-

born, sepsis, and inborn errors of metabolism (Maisels 2005). Sup-

plementary feeding, percentage weight loss, ABO incompatibility

and vacuum extraction significantly increase the risk of jaundice

(Bertini 2001).

Untreated indirect hyperbilirubinaemia may result in kernicterus.

In the acute phase, the signs of kernicterus are poor feeding,

lethargy, high-pitched cry, hypertonia or hypotonia, opisthotonos

and seizures. The chronic manifestations of kernicterus include

athetoid cerebral palsy, motor delay, gaze palsy, dental dysplasia,

mental retardation and sensorineural hearing loss. When neuro-

logical signs are evident in the infant, permanent damage has al-

ready occurred, leading to death or long- term disability (AAP

2004).

Description of the intervention

In 1985, the National Institute of Child Health and Human

Development (NICHHD) reported that phototherapy was as

effective as exchange transfusion in preventing neurological se-

1Intermittent phototherapy versus continuous phototherapy for neonatal jaundice (Protocol)


mailto:[email protected]

quelae (NICHHD 1985). Since then, phototherapy has been

widely adopted as the initial therapy of choice for neonatal jaun-

dice (Knudsen 1991; Eberhard 1994). Phototherapy converts the

bilirubin through structural photoisomerization and photo-oxi-

dation into excretable products. This molecular conversion oc-

curs when bilirubin accumulating in the skin is exposed to light

of wave-lengths 425 - 475 nm (blue-green spectrum).The effec-

tiveness of phototherapy is related to the area of skin exposed,

the radiant energy, the sources and wave-length of the light (Tan

1982; Thaithumyanon 2002), and the cause and severity of jaun-

dice (Maisels 2008). The guidelines or protocols used to deter-

mine the need for phototherapy may vary from one study to the

other. Lewis et al showed that early institution of phototherapy

produced a more rapid decline in serum bilirubin levels compared

to delayed phototherapy (Lewis 1982).

Side effects of phototherapy include temperature instability man-

ifesting as either hyperthermia or hypothermia, dehydration (Oh

1972), gastrointestinal hypermotility, diarrhoea, drowsiness, and

exanthemata (Knudsen 1991). Phototherapy has been linked

to persistent ductus arteriosus (Clyman 1978; Rosenfeld 1986;

Travadi 2006) and to increased incidence of atypical melanocytic

naevi (Csoma 2007; Bauer 2004).

Continuous phototherapy involves maintaining the jaundiced

neonate under phototherapy virtually all the time with only min-

imal interruptions (e.g. during feeding or cleaning) so as to maxi-

mize the time spent under radiant energy and hopefully minimize

the duration of phototherapy and hospital stay. Intermittent pho-

totherapy involves regular cessation of phototherapy at specific

times and for specific duration to reduce exposure to radiant en-

ergy and allow ample time for parental-infant interaction. There

is no optimal time schedule for intermittent phototherapy de-

fined in the literature and, therefore, different studies have looked

at various time intervals for their effectiveness at lowering serum

bilirubin while allowing ample time for parental-infant interac-

tion. A study by Vogl et al looked at three different intermittent

schedules: fifteen minutes on and 15 minutes off phototherapy; 15

minutes on and 30 minutes off phototherapy; 15 minutes on and

60 minutes off phototherapy (Vogl 1978). A study by Hodgman

looked at 12 hours on and 12 hours off phototherapy (Hodgman

1976). Jahrig et al also considered 12 hours on and 12 hours off

phototherapy (Jahrig 1982).

The advantages and disadvantages of intermittent and continu-

ous phototherapy remain controversial. Rubaltelli et al showed

that continuous phototherapy was more effective than intermit-

tent therapy in newborns greater than three days of age (Rubaltelli

1978). Rudenko and Kalinicheva showed that continuous pho-

totherapy had the highest efficacy in prematures that was enhanced

with the addition of alpha-tocopherol acetate (Rudenko 1990).

The study by Hodgman comparing intermittent versus continu-

ous therapy showed that continuous phototherapy was more effec-

tive but was associated with higher metabolic demands (Hodgman

1976).

Other studies have supported the use of various schedules of in-

termittent phototherapy. Vogl et al showed that intermittent pho-

totherapy was as effective as continuous phototherapy (Vogl 1978).

Wu et al demonstrated that the subsequent catch-up growth, af-

ter initial weight loss, was better in the intermittent compared to

the continuous therapy group (Wu Py 1974). Roll observed that

there was a marked reduction in the total light energy required

to decrease serum bilirubin by a certain concentration. The ”dark

periods” of the intermittent therapy would allow for evaluation of

the neonates’ skin colour, reduce stray light exposure to staff or

parents, and facilitate feeding and parent-child bonding. Increased

apoptosis and necrosis was noted with longer exposure periods and

was possibly due to increased photo-oxidation and cell damage

(Roll 2005).

Komar-Szymborska et al showed that the effectiveness of pho-

totherapy depended on the initial bilirubinaemia and was similar

in both continuous and intermittent groups (Komar-Szymborska

1994). Intermittent therapy is convenient and best suited for home

phototherapy in infants with no major risk factors (CIGNA 2008).

Lau and Fung in their study noted that the chief advantage of

intermittent treatment is the reduction of total irradiance. It was

also simple and economically attractive for developing countries

where the need is great and the resources are scarce (Lau 1984).

Why it is important to do this review

There is no consensus on whether intermittent phototherapy or

continuous phototherapy is the preferred method of treatment.

Intermittent therapy would be simple, economical, facilitate ad-

equate feeding and bonding, home therapy, and have minimal

adverse effects (Lau 1984; Roll 2005). Therefore, the aim of this

review is to systematically assess the available evidence from ran-

domized and quasi-randomized controlled trials for the effect of

intermittent phototherapy compared to continuous phototherapy

in reducing the incidence of kernicterus and treatment failure.

O B J E C T I V E S

To assess the effect of intermittent phototherapy compared with

continuous phototherapy on the incidence of kernicterus and

treatment failure in neonates with hyperbilirubinemia.

M E T H O D S

Criteria for considering studies for this review

Types of studies



Randomised and quasi-randomized controlled trials.

Types of participants

Infants (both term and preterm) up to the age of 30 days with

jaundice or hyperbilirubinaemia assessed clinically by the primary

physician as severe enough to require phototherapy.

Types of interventions

Intermittent phototherapy compared with continuous photother-

apy by any method and at any dose and duration as defined by

the authors.

Types of outcome measures

Primary outcomes

• Kernicterus defined as either the pathological finding of

deep-yellow staining of neurons and neuronal necrosis of the

basal ganglia and brainstem nuclei or acute or chronic

neurological deficit including athetoid cerebral palsy, impaired

upward gaze and deafness, isolated conditions like auditory

neuropathy or dyssynchrony and subtle bilirubin-induced

neurological dysfunction.

• Rate of decline of serum bilirubin (mcmol/l/h).

Secondary outcomes

• Treatment failure i.e. the need to restart phototherapy or

exchange transfusion or both

• Number of infants receiving an exchange transfusion

• Infant growth parameters e.g. weight gain (g/kg/day) and/

or length (cm/day)

• Length of hospital stay (days) during treatment for

hyperbilirubinaemia

• Infant feeding (defined as volume of feeds per day while

receiving phototherapy)

• Infant mortality - as a result of complications of

hyperbilirubinaemia

• Total duration of phototherapy - total number of hours of

phototherapy delivered

• Duration of first episode of phototherapy (hours)

• Parental satisfaction with care - qualitative assessment of

parental perception of effect of phototherapy

• Medical staff satisfaction with care - qualitative assessment

of the perception of the medical staff on the effect of

phototherapy

Side effects

• Dehydration (as defined by the authors)

• Gastrointestinal motility (defined as number of stools

passed per day)

• Incidence of patent ductus arteriosus

• Incidence of thrombocytopenia (defined as platelet count <

100,000)

• Retinal damage

• Melanocytic naevi

• Temperature instability- hypothermia/ hyperthermia

• Body rash

• Drowsiness

• Bronze discolouration of the skin

• Interference with maternal-infant interaction

Search methods for identification of studies

See: Cochrane Neonatal Group methods used in reviews

The standard search strategy of the Cochrane Neonatal Review

Group as outlined in The Cochrane Library will be used. The fol-

lowing sources will be searched for eligible reports in any language:

Electronic searches

Electronic databases to be searched will include:

• The Cochrane Central Register of Controlled Trials

(CENTRAL).

• MEDLINE (1966 to the present)

• EMBASE(1980 to the present)

• CINAHL (1982 to the present).

The search string for searching CENTRAL, and MEDLINE

via PubMed, will include the following terms: Jaundice OR

Hyperbilirubinemia OR Hyperbilirubinaemia OR Bilirubin en-

cephalopathy OR Kernicterus OR High serum bilirubin AND

Neonate OR Neonatal OR Baby OR Babies OR Child OR Infant

OR Infants OR Neonates AND Phototherapy OR Photothera-

peutic OR Phototherapeutics OR Light therapy OR Photothera-

pies.

A similar search string will be used for searching EMBASE and

CINAHL via Ovid. The search terms will be adapted to the struc-

tured vocabulary, syntax, and limits required for these databases.

Searching other resources

Abstracts presented in the past years at the annual meetings of

the European Society for Paediatric Research and The Society

for Pediatric Research will be searched from the journal Pediatric

Research and Abstracts On Line.



On-going trials will be searched at the WHO clinical trials reg-

istry platform, and specifically at the following websites:http://

www.clinicaltrials.gov and http://www.controlled-trials.com.

Hand searches of the reference lists of all pertinent reviews and

studies found will be done.

Where possible authors of identified trials will be contacted to find

out if they are aware of other published or unpublished trials.

Data collection and analysis

Selection of studies

The lead review author will perform the search for trials with the

assistance of the Cochrane Neonatal Review Group. Two review

authors will independently screen the titles and abstracts obtained

from the electronic searches to create a pool of eligible studies. The

lead review author will obtain the full articles of the latter, which

both review authors will then independently scrutinize for rele-

vance using a standardized eligibility form with predefined inclu-

sion criteria. The criteria for relevance will be based on the study

design, participants, interventions and outcomes. Possible dupli-

cate publications will be assessed by comparing author names, lo-

cation and setting, specific details of the intervention, numbers

of participants and their baseline data, date and duration of the

study. We will attempt to obtain data sets that are as complete as

possible.

Data extraction and management

For included studies, data will be extracted concerning study iden-

tity (title, authors, reference), design, methodology, eligibility,

quality, clinical features of the population, interventions and out-

comes, and treatment effects, using specially designed data collec-

tion forms. For studies that were initially considered eligible for

inclusion, but which were excluded after reading the full report,

the reason for exclusion will be documented.

All data will be extracted independently by two review authors,

compared, and any discrepancies resolved by discussion or, if nec-

essary, through contact with the primary investigators. Unresolved

disagreements will be referred for arbitration by the third review

author or mentor. We will request from the primary investigators

any unreported data on study outcomes, if necessary. To the ex-

tent possible, outcome data will be extracted on all patients ran-

domised.

Assessment of risk of bias in included studies

The risk of bias for each included trial will be assessed indepen-

dently by two review authors using the Cochrane ”Risk of Bias”

tool, with any disagreement(s) resolved by discussion.

The risk of bias will be assessed based on the following:

• Sequence generation

• Allocation concealment

• Blinding of participants, personnel and outcome assessors

• Incomplete outcome data

• Selective outcome reporting

• Other potential sources of bias e.g. sources of funding

The judgement for each entry will involve answering a question,

with answers ’Yes’ for low risk of bias, ’No’ for high risk of bias,

and ’Unclear’ for either lack of information or uncertainty over

the potential for bias.

Measures of treatment effect

Data analysis will be done using the RevMan 5. If it is possible to

conduct a meta-analysis of identified trials, the effect measures for

binary outcomes will be the relative risk (RR), and absolute risk

difference (RD), each with 95% confidence interval (CI). For the

primary outcome(s), number needed to treat (NNT), or number

needed to harm (NNH), will be calculated. For continuous out-

comes, the effect measures will be the weighted mean difference

(WMD) or, if the scale of measurement differs across trials, the

standardised mean difference (SMD), each with 95% CI.

Assessment of heterogeneity

If it is possible to conduct a meta-analysis, the amount of hetero-

geneity of treatment effect across trials will be estimated using the I2 statistic and the chi-squared statistic. If substantial heterogeneity

is present, its source(s) will be explored, considering differences in

design or clinical features of the trials.

Subgroup analysis and investigation of heterogeneity

Analyses will be performed among subgroups to determine if re-

sponses differ according to the following:

• Gestational age: term ( ≥ 37 weeks) vs. preterm (< 37

weeks)

• Aetiology of the jaundice (haemolytic vs. no identified

hemolysis)

• Radiant energy, as defined by the authors

• Various regimens of intermittent phototherapy

• Trial validity (industry funded vs. non-industry funded

trials)

Sensitivity analysis

The effect of risk of bias on the meta-analysis and on studies with

high risk of bias, will be examined by performing a sensitivity anal-

ysis. The aim will be to estimate how outcomes change according

to small variations in the data and methods.



A C K N O W L E D G E M E N T S

Dr. Awuonda B. B. Onyango was awarded a Reviews for Africa

Program Fellowship (www.mrc.ac.za/cochrane/rap.htm), funded

by a grant from the Nuffield Commonwealth Program, through

The Nuffield Foundation.

The Cochrane Neonatal Review Group has been funded in part

with Federal funds from the Eunice Kennedy Shriver National

Institute of Child Health and Human Development National In-

stitutes of Health, Department of Health and Human Services,

USA, under Contract No. HHSN267200603418C.

Thank you to Dr. Roger Soll for his support throughout the de-

velopment of this review.

R E F E R E N C E S

Additional references

AAP 2004

American Academy of Pediatrics Subcommittee on

Hyperbilirubinemia. Management of hyperbilirubinemia

in the newborn infant 35 or more weeks of gestation.

Pediatrics 2004;114(1):297–316.

Bauer 2004

Bauer J, Buttner P, Luther H, Wiecker TS, Mohrle M,

Garbe C. Blue light phototherapy of neonatal jaundice does

not increase the risk for melanocytic nevus development.

Archives of Dermatology 2004;140(4):493–4.

Bertini 2001

Bertini G, Dani C, Tronchin M, Rubaltelli F. Is breastfeeding

really favoring early neonatal jaundice?. Pediatrics 2001;107

(3):e41.

CIGNA 2008

Home phototherapy for hyperbilirubinemia.

http://www.cigna.com/customer_care/healthcare_

professional/coverage_positions/medical/mm_

0025_coveragepositioncriteria_phototherapy_for_

hyperbilirubinemia.pdf (Accessed 26th Sept 2008).

Clyman 1978

Clyman RI, Rudolph AM. Patent ductus arteriosus: a new

light on an old problem. Pediatric Research 1978;12(2):

92–4.

Csoma 2007

Csoma Z, Hencz P, Orvos H, Kemeny L, Dobozy A,

Dosa-Racz E, et al.Neonatal blue-light phototherapy could

increase the risk of dysplastic nevus development. Pediatrics

2007;119(5):1036–7.

Eberhard 1994

Eberhard BA, Drew JH. Perhaps vigintiphobia should only

apply to infants with Rhesus erythroblastosis. Journal of

Paediatrics and Child Health 1994;30(4):341–4.

Hodgman 1976

Hodgman JE. Clinical application of phototherapy in

neonatal jaundice. Birth Defects Original Article Series 1976;

12(2):3–10.

Horn 2006

Horn AR, Kirsten GF, Kroon SM, Henning PA, Moller G,

Pieper C, et al.Phototherapy and exchange transfusion for

neonatal hyperbilirubinemia: neonatal academic hospitals’

consensus guidelines for South African hospitals and

primary care facilities. South African Medical Journal 2006;

96(9):819–24.

Jahrig 1982

Jahrig K, Jahrig D, Meisel P. Dependence of the efficiency

of phototherapy on plasma bilirubin concentration. Acta

Paediatrica 1982;71(2):293–9.

Keren 2008

Keren R, Luan X, Friedman S, Saddlemire S, Cnaan

A, Bhutani VK. A comparison of alternative risk-

assessment strategies for predicting significant neonatal

hyperbilirubinemia in term and near-term infants. Pediatrics

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Knudsen 1991

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Ugeskr Laeger 1991;153(15):1044–6.

Komar-Szymborska 1994

Komar-Szymborska M, Szymborski J, Madela K, Bajkacz

M. Use of phototherapy in newborns with pathological

jaundice. Wiad Lek 1994;47(7-8):284–7.

Lau 1984

Lau SP, Fung KP. Serum bilirubin kinetics in intermittent

phototherapy of physiological jaundice. Archives of Disease

in Childhood 1984;59(9):892–4.

Lewis 1982

Lewis HM, Campell RH, Hambleton G. Use or abuse of

phototherapy for physiological jaundice of newborn infants.

Lancet 1982;2(8295):408–10.



Maisels 1986

Maisels MJ, Gifford KL. Normal serum bilirubin levels in

the newborn and the effect of breastfeeding. Pediatrics

1986;78(5):837–43.

Maisels 2005

Maisel MJ. Jaundice. In: McDonald MG, Mullet MD,

Seshia MM editor(s). Avery’s neonatology: pathophysiology

and management of the newborn. Philadelphia: Lippincott

Williams & Wilkins, 2005:768–846.

Maisels 2008

Maisels MJ, McDonagh AF. Phototherapy for neonatal

jaundice. New England Journal of Medicine 2008;358(9):

920–8.

NICHHD 1985

National Institute of Child Health and Human

Development randomized, controlled trials of phototherapy

for neonatal hyperbilirubinemia. Pediatrics 1985;75(2 pt

2):385–441.

Oh 1972

Oh W, Karecki H. Phototherapy and insensible water loss in

the newborn infant. American Journal of Diseases of Children

1972;124(2):230–2.

Palmer 1983

Palmer DC, Drew JH. Jaundice: a 10 year review of 41,000

live born infants. Australian Paediatric Journal 1983;19(2):

86–9.

Roll 2005

Roll EB. Bilirubin-induced cell death during continuous

and intermittent phototherapy and in the dark. Acta

Paediatrica 2005;94(10):1437–42.

Rosenfeld 1986

Rosenfeld W, Sadhev S, Brunot V, Jhaveri R, Zabaleta I,

Evans HE. Phototherapy effect on the incidence of patent

ductus arteriosus in premature infants: prevention with

chest shielding. Pediatrics 1986;78(1):10–4.

Rubaltelli 1978

Rubaltelli FF, Zanardo V, Granati B. Effect of various

phototherapy regimens on bilirubin decrement. Pediatrics

1978;61(6):838–41.

Rudenko 1990

Rudenko EB, Kalinicheva VI. Comparative evaluation

of the effectiveness of various schedules of phototherapy

in premature newborn infants with hyperbilirubinemia.

Pediatriia 1990, (4):58–61.

Tan 1982

Tan KL. The pattern of bilirubin response to phototherapy

for neonatal hyperbilirubinemia. Pediatric Research 1982;16

(8):670–4.

Thaithumyanon 2002

Thaithumyanon P, Visutitatmanee C. Double phototherapy

in jaundiced term infants with haemolysis. Journal of the

Medical Association of Thailand 2002 Nov;85(11):1176–81.

Travadi 2006

Travadi J, Simmer K, Ramsay J, Doherty D, Hagan R.

Patent ductus arteriosus in extremely preterm infants

receiving phototherapy: does shielding the chest make a

difference? A randimised, controlled-trial. Acta Paediatrica

2006;95(11):1418–23.

Vogl 1978

Vogl TP, Hegyi T, Hiatt IM, Polin RA, Indyk L.

Intermediate phototherapy in the treatment of jaundice

in the premature infant. Journal of Pediatrics 1978;92(4):

627–30.

Wu Py 1974

Wu PY, Lim RC, Hodgman JE, Kokosky MJ, Teberg AJ.

Effect of phototherapy in preterm infants on growth in the

neonatal period. Journal of Pediatrics 1974;85(4):563–6.∗ Indicates the major publication for the study

W H A T ’ S N E W

Last assessed as up-to-date: 16 June 2009.

Date Event Description

11 November 2009 Amended Minor reference edits



H I S T O R Y

Protocol first published: Issue 4, 2009

C O N T R I B U T I O N S O F A U T H O R S

Awuonda B Onyango has been the main review author involved in identifying the topic for review, writing the protocol and taking the

project forward.

Gautham Suresh and Fred Were have been involved in all stages of writing the protocol, from the draft stage to the final version.

D E C L A R A T I O N S O F I N T E R E S T

None known



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Cochrane Database of Systematic Reviews (Protocols) || Intermittent phototherapy versus continuous phototherapy for neonatal jaundice