GUIA HBMF Neonato

TECHNICAL REPORT Guidance for the Clinician in Rendering Pediatric Care
Technical Report: Diagnosis and

Management of Hyperbilirubinemia in
the Newborn Infant 35 or More
Weeks of Gestation
Jonathan L. Slaughter, MD, MPH, FAAP,a Alex R. Kemper, MD, MPH, MS, FAAP,c Thomas B. Newman, MD, MPH, FAAPb
CONTEXT: Severe hyperbilirubinemia is associated with kernicterus. Informed abstract

guidance on hyperbilirubinemia management, including preventive treatment a
Center for Perinatal Research, bDivision of Primary Care Pediatrics,
thresholds, is essential to safely minimize neurodevelopmental risk. Nationwide Children's Hospital, Columbus, Ohio; and cDepartments of
Epidemiology & Biostatistics and Pediatrics, University of California,
OBJECTIVE:To update the evidence base necessary to develop the 2022 American San Francisco, San Francisco, California,
Academy of Pediatrics clinical practice guideline for management of Dr Slaughter oversaw the search strategy and drafted the technical
hyperbilirubinemia in the newborn infant $35 weeks’ gestation. report; Dr Kemper and Dr Newman participated in the evidence
review and revised the report; and all authors approved the final
DATA SOURCE: PubMed. report and agree to be accountable for all aspects of the work.
STUDY SELECTION:
English language randomized controlled trials and This document is copyrighted and is property of the American
Academy of Pediatrics and its Board of Directors. All authors have
observational studies. Excluded: case reports or series, nonsystematic filed conflict of interest statements with the American Academy of
reviews, and investigations focused on <35-weeks’ gestation infants. Pediatrics. Any conflicts have been resolved through a process
approved by the Board of Directors. The American Academy of
Pediatrics has neither solicited nor accepted any commercial
DATA EXTRACTION:
Topics addressed in the previous clinical practice guideline involvement in the development of the content of this publication.
(2004) and follow-up commentary (2009) were updated with new
Technical reports from the American Academy of Pediatrics benefit
evidence published through March 2022. Evidence reviews were from expertise and resources of liaisons and internal (AAP) and
external reviewers. However, technical reports from the American
conducted for previously unaddressed topics (phototherapy-associated Academy of Pediatrics may not reflect the views of the liaisons or
adverse effects and effectiveness of intravenous immune globulin [IVIG] the organizations or government agencies that they represent.
to prevent exchange transfusion). The guidance in this report does not indicate an exclusive course
of treatment or serve as a standard of medical care. Variations,
RESULTS: New evidence indicates that neurotoxicity does not occur until taking into account individual circumstances, may be appropriate.
bilirubin concentrations are well above the 2004 exchange transfusion All technical reports from the American Academy of Pediatrics
automatically expire 5 years after publication unless reaffirmed,
thresholds. Systematic review of phototherapy-associated adverse effects revised, or retired at or before that time.
found limited and/or inconsistent evidence of late adverse effects,
DOI: https://doi.org/10.1542/peds.2022-058865
including cancer and epilepsy. IVIG has unclear benefit for preventing
exchange transfusion in infants with isoimmune hemolytic disease, with Accepted for publication 00 00, 2022
a possible risk of harm due to necrotizing enterocolitis. Address correspondence to Jonathan L. Slaughter, MD, MPH,
FAAP. E-mail: Jonathan.Slaughter@nationwidechildrens.org
LIMITATIONS: The search was limited to 1 database and English language studies.
CONCLUSIONS: Accumulated evidence justified narrowly raising phototherapy
treatment thresholds in the updated clinical practice guideline. Limited To cite: Slaughter JL, Kemper AR, Newman TB. Technical
Report: Diagnosis and Management of Hyperbilirubinemia in
evidence for effectiveness with some evidence of risk of harm support the Newborn Infant 35 or More Weeks of Gestation. Pediatrics.
the revised recommendations to limit IVIG use. 2022;150(3):e2022058865
PEDIATRICS Volume 150, number 3, September 2022:e2022058865 FROM THE AMERICAN ACADEMY OF PEDIATRICS
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The 2022 American Academy of below which kernicterus or adverse COMPOSITION OF THE SUBCOMMITTEE
Pediatrics publication, “Clinical effects are not observed.5–11 In MEMBERS AND MEETINGS
Practice Guideline Revision: addition, large cohort studies have The subcommittee consisted of
Diagnosis and Management of suggested that phototherapy itself individuals with expertise in
Hyperbilirubinemia in the Newborn may carry some risk for patient neonatal hyperbilirubinemia and
Infant 35 or More Weeks of harm.12,13 The committee late-preterm and term newborn
Gestation,”1 builds on the previous incorporated this new evidence care, including members of multiple
2004 guideline, “Management of including each infant’s birth relevant AAP committees. The
Hyperbilirubinemia in the Newborn gestation and the presence or subcommittee was chaired by Alex
Infant 35 or More Weeks of absence of neurotoxicity risk factors R. Kemper, MD, MPH, MS, FAAP,
Gestation,”2 and a 2009 follow-up to develop new phototherapy and who appointed Thomas B. Newman,
commentary, “Hyperbilirubinemia in exchange transfusion thresholds that MD, MPH, FAAP, as vice chair in
the Newborn Infant $35 Weeks’ aim to continue to safely reduce the 2017. Jonathan L. Slaughter, MD,
Gestation: An Update With risk of kernicterus while reducing MPH, FAAP, a neonatologist, served
Clarifications.”3 The gestational age the risk of unnecessary treatment.1 as epidemiologist and
cutoff of $35 weeks was chosen methodologist. He developed the
because it includes most newborn initial evidence-review questions
infants cared for by general APPROACH TO DEVELOPING THE and evidence tables for the potential
pediatricians and other primary care UPDATED CLINICAL PRACTICE use of intravenous immune globulin
clinicians in mother-baby units and GUIDELINE (IVIG) and/or exchange transfusion.
well-baby nurseries. This guideline In January of 2014, Dr Alex Kemper Three librarians—Susi Miller, Teri
does not apply to preterm newborns was approved by the AAP Board of Ballard, and Allison Erlinger—
born <35 weeks’ gestation, who Directors as the Chair of the Clinical assisted with the primary literature
generally receive care in neonatal Practice Guideline Subcommittee on search. Kymika Okechukwu, MPA,
intensive care units (NICUs). was the AAP staff representative for
Hyperbilirubinemia. Dr Kemper was
the project. All conflicts of interest
charged with leading the update of
Hyperbilirubinemia management were disclosed at the beginning of
the hyperbilirubinemia clinical
presents a unique challenge for the process and updated throughout.
clinicians. Although rare in high- practice guideline (CPG) focused on
resource settings, kernicterus is the diagnosis and management of The subcommittee met face-to-face
deadly and leads to severe, lifelong hyperbilirubinemia in newborn in August of 2014, May of 2017, and
neurodevelopmental impairment in infants born at $35 weeks’ virtually in August of 2018.
survivors.2,4 At some patient-specific gestation. The rationale for Conference call and E-mail
threshold, severe bilirubinemia can development of an updated correspondence were frequent and
lead to bilirubin encephalopathy and guideline included the following: used to assess the quality of
kernicterus. However, the current evidence, reach consensus, and
evidence base is insufficient to 1. New evidence that bilirubin develop the final clinical practice
quantitatively derive the exact neurotoxicity does not occur guideline.
treatment threshold at which until concentrations well above
hyperbilirubinemia should be the 2004 exchange transfusion FORMULATION AND ARTICULATION OF
treated in a given infant to prevent thresholds justified raising the THE QUESTIONS ADDRESSED BY THE
kernicterus. Thus, expert opinion phototherapy treatment CLINICAL PRACTICE GUIDELINE
remains crucial to the development thresholds by a narrow range; SUBCOMMITTEE
of hyperbilirubinemia treatment and The AAP Evidence-Based Clinical
guidance. The committee’s approach 2. Increasing evidence that Practice Guidelines Development and
was to improve on the expert-driven phototherapy may have rare Implementation Manual14
2004 American Academy of but serious late adverse effects. recommends that clinical practice
Pediatrics (AAP) guideline2 and guidelines be reviewed periodically
2009 follow-up commentary3 In April 2014, the AAP Executive and updated if “literature
through the incorporation of new Committee approved the final surveillance suggests that significant
evidence. Recent, large cohort subcommittee members for the changes in clinical practice would be
investigations have provided formation of the Clinical Practice supported by strong evidence or
reassurance that there are certain Guideline Subcommittee on monitoring of implementations
total serum bilirubin concentrations Hyperbilirubinemia. suggests that the current guideline
2 FROM THE AMERICAN ACADEMY OF PEDIATRICS

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results in care that would be controlled trials on the effectiveness of diagnoses and adverse effects
unnecessarily harmful to patients.” IVIG to prevent exchange transfusion associated with phototherapy and
Since the original 2004 clinical in infants with indirect was age-limited to newborn infants
practice guideline2 and the 2009 hyperbilirubinemia, to develop an from birth to one month of age with
update with clarifications,3 new data evidence-table comparing recent the Medline limiter “newborn infant
have emerged regarding potential placebo-controlled trials of infants (birth to one month).” It was further
phototherapy-related harms with Rhesus (Rh) incompatibility to limited using the Medical Subject
(Table 1),12,13,15–17 along with previous literature on IVIG treatment Headings (MeSH) term:
evidence that the phototherapy and of infants with maternal-infant blood Phototherapy with subheading
exchange transfusion treatment group incompatibility-mediated Adverse Effects. The search strategy
thresholds from the previous 2004 hemolysis. was expanded to include
clinical practice guideline could be phototherapy (keyword) AND – any
raised to safely reduce SYSTEMATIC REVIEW PROCESS of the following MeSH terms or
overtreatment.5–11 The two systematic reviews were keywords (newborn*; neonat*;
conducted in accordance with the adverse; asthma; Asthma[MeSH];
In addition, neonatal
“Preferred Reporting Items for epilepsy; Epilepsy[MeSH]; cancer;
hyperbilirubinemia experts have
Systematic Reviews and Meta- Neoplasms[MeSH]; neuro*; seizure*;
noted the need for additional
Analysis Guideline.”18 The Seizure[MeSH]).
guidance to separate routine
epidemiologist developed questions
phototherapy from “escalation of A second search (October 1, 2018;
to guide the literature search,
care,” including more aggressive repeated March 5, 2021 and April 7,
evidence abstraction, and
phototherapy, intravenous hydration 2022) focused on the effects of
construction of the tables. The
for dehydrated infants, and the
primary literature search was phototherapy on family bonding and
potential use of IVIG and/or
assisted by librarians Susi Miller, breastfeeding. The search strategy
exchange transfusion. In recent
Teri Ballard, and Allison Erlinger. included searching Medline for
years, multiple randomized
articles indexed with either
controlled trials evaluated the
effectiveness of IVIG to prevent SEARCH STRATEGY Phototherapy[MeSH term] OR
Neonatal Jaundice[MeSH term with
exchange transfusion in infants with The epidemiologist and librarians
subheading Therapy] AND ALSO one
indirect hyperbilirubinemia from created a list of search terms and
strategies. of the following MeSH terms:
hemolysis precipitated by maternal-
Mothers/subheading psychology;
infant blood group incompatibility.
Question 1: What are the adverse Maternal Behavior; Parent-Child-
Most of the subject areas within the
clinically detectable effects of Relations; Breast Feeding;
2022 guideline update were
previously included in the 2004 phototherapy in newborns? breastmilk; Family Relations OR one
clinical practice guideline2 and/or of the following key word/phrases:
Population: Neonates born at $35 “maternal-infant bond” or “mother-
2009 commentary.3 Accordingly, for
weeks’ gestation with indirect infant separation.” Our search
most subjects, the committee
reviewed the peer-reviewed hyperbilirubinemia who are strategy also including searching for
literature for new, subsequent candidates for phototherapy. keyword “phototherapy” AND one
evidence since 2009. Complete or more of the following keywords
Intervention: Treatment with or phrases: “breastfeeding,”
systematic reviews were conducted
phototherapy. “bonding,” “separation,” “family
and new evidence-tables created for
two topics: phototherapy-related dynamics,” or “family relationships.”
Comparator: Nontreatment.
harm and the effectiveness of A final search strategy including
IVIG to prevent exchange transfusion Outcome: Increased risk of any searching for articles indexed with
in infants with adverse clinical outcome that is both of the following: Object
indirect hyperbilirubinemia. For important to neonatal patients, their attachment[MeSH term] AND
phototherapy-related harm, an families, and/or the clinicians Phototherapy[MeSH termg. Case
emerging subject that was not treating them. reports or series, nonsystematic
previously covered, the committee review articles, and manuscripts
reviewed all relevant literature without The first search (conducted May 24, focused on preterm infants born at
a date restriction. In addition, the 2018; repeated March 5, 2021 and <35 weeks’ gestation were
committee reviewed all randomized April 7, 2022) focused on medical excluded.
PEDIATRICS Volume 150, number 3, September 2022 3

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4
TABLE 1 Adverse Effects of Phototherapy in Newborn Infants
Citation Participants or Notes or
Country Methods Inclusion Criteria Exclusion Criteria Interventions Outcomes Results Risk of Bias Conclusions
Asthma and
Allergies
Aspberg Retrospective 14 803 children born Children younger Multiple maternal Hospitalization for Phototherapy-associated Unable to adjust for Hyperbilirubinemia and
2007 population- between 1987 and than 2 y of age at and infant childhood asthma odds ratio (Mantel- bilirubin levels when phototherapy were
Sweden based 1999 and recorded the time of characteristics after age 2 y. Haenszel) for asthma estimating both associated with
registry in the Swedish hospital admission including requiring associations between increased odds of a
study Hospital Discharge for asthma were phototherapy hospitalization (OR: phototherapy and childhood asthma
Register as excluded because exposure were 1.27, 95% CI: 1.08–1.5) asthma. hospitalization after
hospitalized with of uncertainty of studied. after excluding infants Evaluated multiple risk age 2 y.
asthma between 2 asthma diagnosis with risk factors factors (multiple However, it was
y of age and 2001 at <2 y. (except for icterus or comparisons). impossible to
were compared to jaundice) associated distinguish the
all children in the with both asthma and phototherapy-
Swedish Medical phototherapy associated effect on
Birth Registry (n (measured asthma from that of
5 1 386 029) for confounders). jaundice.
those same years.
Aspberg Perinatal data for Numerous antenatal and Asthma as defined by Association of Adjusted for birth Phototherapy and
2010 singleton children neonatal variables singleton children phototherapy with: All year, maternal age, jaundice were both
Sweden prescribed including icterus and who received an childhood asthma parity, smoking during associated with a
antiasthmatic phototherapy. asthma (OR 1.35; 95% CI: pregnancy, and years diagnosis of asthma.
medication medication. 1.3–1.4). of involuntary However, it was
(n 5 61 256) were Asthma stated in childlessness. impossible to
compared to prescription Evaluated multiple risk distinguish the
corresponding (OR 1.42; 95% CI: factors (multiple phototherapy-
data for all 1.3–1.5). comparisons). associated effect on

singleton children Asthma on systemic There was no asthma from that of
born in Sweden corticosteroids (OR adjustment for degree jaundice.
from January 1990 1.47; 95% CI: of hyperbilirubinemia.
to June 2003 and 1.2–1.8). Phototherapy duration
surviving through A diagnosis of icterus and intensity could not
June 2005 (jaundice) was also be evaluated.
(n 5 1 338 319). associated with
Data from 3 large asthma (OR 1.45,
Swedish health 95% CI: 1.4–1.5).
registers: Swedish
Medical Birth
Register, Swedish
Prescribed Drug
Register, and
Swedish Hospital
Discharge Register.
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TABLE 1 Continued
Ku 2012 Retrospective 11 321 children born Subjects with Those with neonatal Asthma defined as: Phototherapy-associated Unable to adjust for Hyperbilirubinemia but
Taiwan cohort 1 questionable basic jaundice (exposed) at least 4 odds ratio (Mantel- bilirubin not phototherapy was
997–2000 and data (not precisely were classified as the outpatient or Haenszel) after concentrations when associated with
randomly selected defined) were study group or icteric emergency excluding children estimating increased odds of a
from the excluded. children. Those department with 5 risk factors associations between childhood asthma
Taiwanese National without (nonexposed) diagnoses of associated with phototherapy and diagnosis after age 1
Health Insurance were classified as the asthma between asthma and asthma. y.
Research Database control group or ages 1–10 y, or 1 phototherapy
(NHIRD). nonicteric children. asthma diagnosis (confounders)
during (preterm or low birth
a hospital wt, neonatal
admission between infections, other
ages 1–10 y. respiratory conditions,
PEDIATRICS Volume 150, number 3, September 2022

other birth conditions,
and sex).
(OR: 1.03; 95% CI
0.72–1.4; P 5 .958.)
Jaundice ICD-9
diagnosis-
associated odds of
asthma after
exclusion of
children with the
above risk factors
(OR: 1.64; 95% CI
1.36–1.98; P <

.001).
Sun 2013 Retrospective 11 328 children Incomplete basic Main exposure of Childhood allergic Association between Adjusted for the following There was no association
Taiwan cohort randomly selected data, such as interest was neonatal rhinitis between allergic rhinitis and: confounders: preterm/ between phototherapy
from the conflicting sex and jaundice as measured birth and 10-y of Phototherapy (RR 1.06; low birth wt, neonatal and childhood allergic
Taiwanese National uncertain birth by ICD code. age. 95% CI: 0.89–1.27) infection, other rhinitis.
Health Insurance date. Phototherapy was Diagnostic criteria for (Risk difference 2.7; respiratory conditions, Neonatal jaundice was
Research Database also recorded as a allergic rhinitis 95% CI: -4.8 to 10.1) other birth conditions, associated with a
(NHIRD) and born proxy for bilirubin were at least 3 Neonatal jaundice and sex. childhood allergic
between 1997 and concentration >15 outpatient allergic (aOR 1.46; 95% CI: Unable to adjust for rhinitis diagnosis
2000. mg/dL, at which rhinitis diagnoses, 1.2–1.7). bilirubin concentration. before age 10 y.
phototherapy charges 1 during a Phototherapy duration
were reimbursed. hospitalization, or and intensity could not
1 in an emergency be evaluated.
department.
5
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TABLE 1 Continued
6
Das 2015 Systematic 7 observational (hyperbilirubinemia Children with Neonatal Allergic rhinitis or Hyperbilirubinemia:
review studies OR icterus OR outcome hyperbilirubinemia conjunctivitis. Asthma (OR: 4.26; 95%
and meta- (n 5 101 499 total jaundice) AND assessment at <1 (cutoff level not Asthma. CI: 4.05–4.5).
analysis participants) that (phototherapy OR y of age or those defined). Eczema. Allergic rhinitis (OR:
included infants therapy OR treatment) with chronic Neonatal 5.37; 95%
with AND (allergy OR atopy illness, congenital phototherapy. CI: 4.16–6.92).
hyperbilirubinemia OR asthma OR malformation, or Phototherapy:
and/or those allergic rhinitis OR kernicterus. Asthma (OR: 3.81; 95%
receiving rhinitis OR rhino- CI: 3.53–4.11).
phototherapy in conjunctivitis OR hay Allergic rhinitis (OR:
the neonatal fever OR atopic 3.04; 95%
period and who dermatitis OR allergic CI: 2.13–4.32).
were followed up eczema)].
to 12 y.
Search terms:
[(newborn OR
infant OR
neonate*) AND
Fixed-effects Hyperbilirubinemia hyperbilirubinemia-
logistic and phototherapy associated effect
regression were both from that of
model was associated with phototherapy.
used for increased odds Risk differences and
meta-analysis of asthma and number needed to
of the allergic rhinitis. harm were not
individual However, it was calculated.
study results. impossible to

Did not identify separate the
whether
studies
adjusted for
bilirubin levels
when
estimating
associations
between
phototherapy
and allergy or
asthma
outcomes.
Did not evaluate
duration of
phototherapy
exposure. Only
2 of the 7
included

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TABLE 1 Continued
studies
(Aspberg
2007; Ku 2012)
evaluated the
effect of
phototherapy.
Wei 2015 Nested 27 693 patients within Children >1 mo of The main exposure of Allergic conjunctivitis, Association between Analyses were adjusted Phototherapy and a
Taiwan case-control the Taiwanese age, diagnosed interest was neonatal allergic rhinitis, phototherapy in for age, diagnosis of neonatal
National Health with allergic jaundice as diagnosed atopic dermatitis, infants with neonatal sex, comorbidities of jaundice were both
Insurance disease before the by ICD code. Other asthma, and jaundice and: fetal and newborn associated with 5
Research database index date of diagnoses including urticaria as Allergic conjunctivitis respiratory conditions, childhood allergic
(NHIRD) with a new neonatal jaundice phototherapy were diagnosed by ICD (aHR 1.38; (95% infections, prematurity, diseases (allergic
diagnosis of diagnosis, and examined within the code by the end of CI: 1.3–1.5). low birth wt, other conjunctivitis, allergic

neonatal jaundice those missing cohort of infants with 2008 Allergic rhinitis birth rhinitis, asthma,
from 2000 to 2007. information on sex neonatal jaundice. (aHR 1.37; conditions, and allergic dermatitis,
For each child with or age. 95% CI: 1.3–1.4) glucose-6-phosphate and urticaria).
neonatal jaundice, Asthma (aHR 1.21; dehydrogenase It was not possible to
2 children without 95% deficiency. differentiate the
neonatal jaundice CI: 1.2–1.3) There was no adjustment effects of
from the same Atopic dermatitis for degree of hyperbilirubinemia
period (aHR 1.22; 95% hyperbilirubinemia. and effects of
were randomly CI: 1.1–1.3) Phototherapy duration phototherapy on these
selected and Urticaria (aHR 1.12; and intensity could not allergic outcomes.
included in the 95% be evaluated.
nonneonatal CI: 1.03–1.2).
jaundice cohort (n All 5 allergic disease

5 55 367) were increased in
Patients with the neonatal
nonneonatal jaundice cases as
jaundice were compared to the
frequency-matched group of matched
with patients nonjaundiced
with neonatal patients).
jaundice according
to sex, age,
parental
urbanization,
parental
occupation, and
index date.
Egeberg 2016 Retrospective All children (n 5 As per inclusion Neonatal blue light Primary end-point Association between Adjusted IRRs were Although neonatal
Denmark cohort 673 614) criteria. phototherapy, was the atopic dermatitis and: mutually adjusted for jaundice was linked to
born in the 10-y neonatal jaundice, first occurrence of Phototherapy at first age, sex, neonatal an increased rate of
period between birth gestation, birth atopic dermatitis birthday phototherapy, neonatal childhood atopic
7
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8
TABLE 1 Continued
1997- 2006 and wt as recorded in the measured at first, (aIRR 1.11; 95% jaundice, birth wt, dermatitis, neonatal
recorded in the Danish National second, and fifth CI: 0.92–1.35). gestation, and season phototherapy was not
Danish National Patient Register. birthdays as Phototherapy at of birth. associated with an
Patient Register. recorded in the second P values corrected by atopic dermatitis
Danish National birthday (aIRR 1.01; the Bonferroni method diagnosis.
Patient Register. 95% with corrected 2-tailed
CI: 0.88–1.15). P value <0.008
Phototherapy at fifth considered significant.
birthday Children were followed
(aIRR 0.97; 95% from birth until either
CI: 0.88–1.08). first occurrence of
Neonatal jaundice at atopic dermatitis,
first migration, death, or
birthday (aIRR 1.13; (in 3 separate
95% analyses) their first,
CI: 1.06–1.21). second, or fifth
Neonatal jaundice at birthday.
second
birthday (aIRR 1.13;
95%
CI: 1.08–1.18).
Neonatal jaundice at
fifth
birthday (aIRR 1.12;
95%
CI: 1.08–1.16).

Kuzniewicz Retrospective 109 212 newborns Infants who did not Phototherapy (defined as Asthma (diagnosed Association of Cox proportional hazard Phototherapy use was
2018 cohort born remain in the a recorded nursing after phototherapy with models used for not associated with
Northern during 2010-2014 same hospital phototherapy flow 2 y of age: defined asthma: primary multivariable asthma, and
California, USA at system during sheet or both a as 1) at least 2 (multivariable Cox- analysis to account for phototherapy is
$35 wk’ gestation. their birth phototherapy asthma diagnoses model differing follow-up unlikely to increase or
11 Northern admission, infants procedure code and from any adjusted hazard times by infant. decrease asthma risk.
California Hospitals who did not an order for outpatient or ratio [aHR]: 1.01; Among infants within 3 Modest levels of
(Kaiser remain in the KP phototherapy). inpatient 95% CI: 0.92–1.11). mg/dL of 2009 AAP hyperbilirubinemia
Permanente [KP]) health plan for at encounter (Propensity-score aHR: phototherapy were associated with
that employed least 25 mo, and separated by $30 1.07; 95% CI: threshold, propensity an increased risk of
universal TSB infants without TSB d; and 2) at least 2 0.96–1.20.) scores for receiving asthma, but this
screening before levels. asthma medication Relative to TSB phototherapy were association was not
discharge. prescriptions in a levels of 3-5.9 mg/ used to adjust for TSB observed at higher
12-mo period dL, infants with levels before, but not bilirubin levels.
separated by $30 maximum TSB after, receipt of
d). levels between 9-17 phototherapy.
mg/dL were at a Unable to measure
significantly phototherapy duration.

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TABLE 1 Continued
increased hazard However, hospital
for asthma. phototherapy
However, there was treatment was
not a significant compared to home
increase in asthma phototherapy and
associated with there was no
maximum TSB $18 difference in the
mg/dL (no TSB outcome.
dose-effect) (aHR:
1.04; 95% CI:
0.90–1.20).
Tham 2018 Prospective Growing Up in Per inclusion criteria. Neonatal Diagnosis of eczema, Association of Adjusted for sex, No association was found
Singapore cohort Singapore Toward phototherapy for wheezing or use of phototherapy with: ethnicity, breastfeeding between either

healthy Outcomes neonatal nebulizer or Allergen sensitization levels, family history of phototherapy or
(GUSTO) study hyperbilirubinemia inhaler, and by allergy, gestational bilirubin level and
during the birth rhinitis by parental month 60 (aOR 1.1; age, maternal allergic sensitization,
hospitalization as survey 95% CI: 0.6–2.0) education levels and eczema, rhinitis,
recorded for the Atopic sensitization Eczema by month 60 mode of wheezing or nebulizer
GUSTO study. was assessed (aOR 1.3; 95% CI: delivery. or inhaler use.
through skin prick 0.7–2.3). Parental surveys at risk
testing. Rhinitis by month 60 for recall bias.
(aOR 1.0; 95% CI:
0.6–1.9).
Early onset of wheeze
and use of
nebulizer or inhaler

by month 60 (aOR
0.6; 95% CI:
0.3–1.2).
No associations were
found between
bilirubin levels and
these measured
outcomes.
Kuniyoshi Systematic The systematic review Case-reports, case- Neonatal jaundice and Childhood-onset Association of Random-effects models Jaundice and
2021 review and included 19 series, systematic phototherapy. (#19-y) allergic phototherapy with: weighted by inverse phototherapy were
meta-analysis observational reviews, and meta- For studies that diseases (asthma, Asthma (OR 1.24; 95% variance estimates both associated with
studies (cohort, analyses were stratified bilirubin atopic dermatitis, CI: 1.1–1.4). were used for meta- increased odds of
case-control, cross- excluded. levels, results with allergic rhinitis, or Atopic dermatitis (OR analysis. asthma and atopic
sectional) that 5 studies were TSB >15 mg/dL were food allergies). 1.31; Did not evaluate intensity dermatitis. Jaundice,
evaluated the excluded from used. 95% CI: 1.2–1.4). or duration of but not phototherapy,
association of meta-analysis Allergic rhinitis (OR phototherapy was associated with
neonatal jaundice because no effect- 1.38; 95% exposure. allergic rhinitis.
and neonatal estimate was CI: 0.9-2.0). No studies were found
phototherapy with reported. Association of jaundice that quantitatively
9
childhood allergic with: assessed the
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10
TABLE 1 Continued
diseases. Asthma (OR 1.46; 95% association between
14 studies were CI: 1.4–1.5). either jaundice or
included in the Atopic dermatitis (OR phototherapy and food
meta-analysis for 1.3; allergies.
jaundice and 8 95% CI: 1.1–1.6). It was impossible to
studies in the Allergic rhinitis (OR separate the jaundice-
meta-analysis for 3.01; 95% associated effect from
phototherapy. CI: 0.9–10.3). that of phototherapy.
Autism
Spectrum
Disorder
Wu 2016 Retrospective 457 855 infants born Infants who died In-hospital or home ASD diagnosis either Phototherapy (aHR: 1.10; Propensity-analyses After adjustment for the
Northern Cohort at $35 wk’ during phototherapy. by ASD evaluation 95% CI: 0.98–1.24) adjusted for bilirubin confounding effects of
California, USA Study gestation who the birth center, a clinical was not associated level before sociodemographic
were recorded in hospitalization, ASD specialist with ASD in the phototherapy. factors, neither
the were transferred outside the ASD primary analysis (Cox Unable to measure phototherapy nor
Kaiser Permanente out of the KPNC center (ie, proportional hazards phototherapy duration hyperbilirubinemia
of Northern system, or were psychiatrist, model). or intensity. was a significant
California (KPNC) followed <60 d. psychologist, or Propensity-adjusted independent risk
Database Infants with at least 2 developmental sensitivity analyses factor for ASD.
(1995–2011). inpatient or pediatrician), or by also revealed no
outpatient a general association between
physician ICD pediatrician. phototherapy and ASD
diagnoses of: Hyperbilirubinemia (aHR: 1.09; 95% CI:
Trisomy 21, other was also not 0.95–1.24). This model
genetic disorders, associated with examined the effect of

or congenital ASD after phototherapy among
anomalies adjustment for only infants who had
diagnosed at <15 confounders. a TSB level within 3
d. mg/dL of the 2004 AAP
phototherapy
threshold.
TSB $20 (aHR: 1.09; 95%
CI: 0.89–1.35) was
also not associated
with ASD.
Breastfeeding
and Familial
Bonding
Kemper 1989 Prospective 101 jaundiced infants Birth wt <2500 g or Diagnosis of jaundice Mothers were Of mothers whose Risk of recall bias Mothers of infants who
Yale-New Haven observational born in 1987-1988 if infant spent >6 (mean peak bilirubin surveyed at infants received (survey). had a jaundice
Hospital, New study with with a total serum h in the ICU. in jaundiced infants 1 mo postnatal to phototherapy, 70% Difficult to determine diagnosis were more
Haven, matched bilirubin >11.99 Comparison group was 16.2 mg/dL, and assess (1) thought its use effect sizes for concerned about their
Connecticut, controls mg/dL measured infants were 55% received concerns about implied that their phototherapy since the infant’s overall health
USA before discharge. excluded if a phototherapy). jaundice and child was moderately main focus of the at 1-mo postnatal.

155 comparison bilirubin level was phototherapy, (2) to seriously ill and study was a jaundice Maternal concerns
by guest
TABLE 1 Continued
subjects who were obtained anytime termination of 74% found its use diagnosis versus no were increased if
not visually up to 1 mo breastfeeding upsetting. jaundice diagnosis. their infant received
jaundiced and who postnatal. within 1 mo 53% of mothers whose Phototherapy specific in-hospital
were seen by the postnatal, and (3) infants received data are presented as phototherapy.
same pediatrician maternal behaviors phototherapy vs 31% proportions for some It should be noted that
as the matched, consistent with the of those with outcomes. clinical practice
jaundiced infant. vulnerable child jaundiced, Although some baseline (including increased
syndrome. non–phototherapy- variables (potential phototherapy
treated infants had confounders) were utilization) and
ever left their child collected, these were parental counseling
with someone else for not used to adjust (on phototherapy and
>1 h at 1 mo estimates between breastfeeding) may
postnatal. jaundiced infants have changed over the

64% of those with receiving phototherapy 28 y since the study
breastfeeding and jaundiced was published.
interrupted in the nontreated infants.
hospital vs 36%
without interruption
had completely
stopped breastfeeding
at 1 mo
(P < .05).
84% of mothers of
jaundiced infants
completed the 1-mo
survey, as did 80% of

mothers of
comparison group
infants.
Schedle 1990 (Kantonsspital), Prospective 107 healthy, term Pregnancy Three group comparison: Denver Developmental There were no differences
County Aarau, Switzerland cohort infants, 1986-1987. complication, (1) 29 jaundiced Screening Test and in Denver scores for
Hospital >10th percentile infants with mean Ainsworth Attachment social
wt for gestation, peak TSB of 15.85 mg/ Scores at 1 y of age. contact (X2 5 0.1; P 5
congenital dL who received 2–3 .93), gross motor
malformation, or d of phototherapy and behavior (X2 5 0.5; P 5
neonatal illness. partial mother-child .77), and fine motor and
separation, (2) 40 adaptive performance
mildly jaundiced (X2 5 4.5; P 5 .10) at 1
infants with mean y of age.
peak TSB of 12.22 mg/ No significant difference in
dL who received the three study groups
neither phototherapy was found for mother-
nor separation, and child attachment at 1 y
(3) a control group of
11
by guest
12
TABLE 1 Continued
38 infants with no of age (X2 5 1.5; P 5
apparent jaundice. .83).
Measured baseline
variables were similar
in all groups except
the phototherapy
group had
significantly more
boys relative to the
other 2 groups (X2 5
0 .48;
P 5 .009).
Were unable to non–phototherapy- Treatment with neurodevelopment,
completely treated group. phototherapy as as measured by the
differentiate Small-sample size. a newborn did Denver
effect of not appear to Developmental
bilirubin and affect Screening Test at 1-
phototherapy y of age and by
since mean maternal-infant
TSB was lower attachment at 1 y of
in the age.
jaundiced
Usatin 2010 Retrospective Infants born between Newborns that The 3 study comparison Primary outcome There were small Poisson regression was Small increases in
Northern cohort 1995 and 2004 at received groups: 1) never had variables: Total increases in used to account for outpatient visits
California, USA gestation $36 wk phototherapy a TSB $12 mg/dL, 2) outpatient visits total year-1 visits for potentially confounding before age 1 were
with birth wt $2 during their initial TSB $17 to <23 mg/ during postnatal jaundiced infants variables including seen with both

kg. birth admission, dL without days 15–364 and without phototherapy mother’s age, infant’s neonatal jaundice
Patients were eligible those with birth phototherapy, and 3) total numbers of (group 2) (adjusted year, month, and (10.36) and
if they (1) never admission >48 h, TSB $17 to <23 mg/ various types of incident rate ratio hospital of birth, phototherapy (10.73)
had a TSB $12 or a conjugated or dL with phototherapy. outpatient visits at [aIRR]: 1.04; 95%: CI: gestational age, sex, that most often
mg/dL (n 5 direct bilirubin $2 ages (in days): 1.02–1.05) compared and race. occurred in the first 2
128 417) or (2) mg/dL in the first 15–59, 60–119, to infants with TSB level that qualified postnatal months.
when they had a 30 postnatal days. 120–179, 180–364. bilirubin <12 mg/dL for groups 2 or 3 Phototherapy
TSB $17 to <23 Those that were (group 1). were dichotomized at treatment and
mg/dL readmitted to the There were also slightly 17–19.9 and 20–22.9 jaundice diagnoses
(a range where hospital for any more total year-1 mg/dL and used to were associated
phototherapy reason with a visits for jaundiced adjust comparisons with only small increases
might be length of stay $96 infants with between group 2 and in first-year outpatient
discretionary) as h within the first phototherapy (group group 3 visit rates, consistent
outpatients at 2 to 14 postnatal days. 3) (aIRR: 1.03; 95%: CI: (phototherapy with mild or
7 d postnatal and Those with <4 1.01–1.06) relative to exposure). infrequent
did outpatient visits in those with jaundice The authors noted that contribution to the
(n 5 1765) or did the first year and/ and phototherapy estimates should be vulnerable child
not (group 2). interpreted in light of syndrome.

by guest
TABLE 1 Continued
(n 5 6777) receive or no visits in the For both phototherapy no correction for
inpatient second year. and untreated groups multiple comparisons.
phototherapy after of infants with
their initial birth bilirubin $17 to <23
admission. mg/dL, increases in
Kaiser Permanente of visits were greatest
Northern California during days 15–59,
Database. appeared related to
follow-up for the
diagnosis of jaundice
itself, and were not
statistically significant
in any other

measured year-1 time
periods.
The adjusted increase in
visits over group 1
(bilirubin <12 mg/dL)
were 0.36 visits in
year-1 by group 2
(jaundice and no
phototherapy) and
0.73 visits by group 3
(jaundice and
phototherapy).
The average number of

outpatient visits for
the 8 most common
sick-visit diagnostic
codes did not vary by
phototherapy use.
Waite 2016 Retrospective 4441 ever-breastfed Breastfeeds were Phototherapy for the Primary outcome At 1-mo postnatal there Potential for recall bias Phototherapy treatment
United States cohort infants born >35 never initiated or treatment of jaundice variables: was no increased due to determination of hyperbilirubinemia
of America wk’ gestation at if mothers as indicated by Any breastfeeding odds of any of phototherapy may be associated
$2200 g between answered via parental report via at 1, 2, 4, 6, 9, and breastfeeding (aOR: exposure and with a decreased odds
May-December survey that their survey at 3 wk 12 mo postnatal 1.14; 95% CI: breastfeeding history of exclusive
2005 and recorded infants received postnatal. based on maternal 0.71–1.81) in via postnatal maternal breastfeeding during
in the Centers for “other treatment Parents first indicated survey response. phototherapy-exposed survey. months 1–4 postnatal.
Disease Control for jaundice,” that their child was Secondary outcome infants. No differences The first postnatal survey Phototherapy was not
and Prevention which included ever jaundice and if variables: Exclusive in any breastfeeding at 3 wk asked the associated with a
Infant Feeding switching so, they were asked breastfeeding at 1, were noted at months respondent whether change in the odds of
Practices Study II completely to whether treatment 2, and 4 mo 2, 4, 6, and 9 the infant had jaundice any breastfeeding.
(IFPS II). Infants formula feeds. was required with postnatal based on postnatal. At 12 mo at any time since Although there was a
who received phototherapy being 1 postnatal, birth. Mothers that decrease in the odds
13
by guest
TABLE 1 Continued
14
treatments for of the treatment maternal survey phototherapy answered that their of any breastfeeding
jaundice other options. response. exposure was baby had jaundice at 12 mo postnatal, it
than phototherapy associated with a were then asked about seems unlikely that
(eg, formula) were reduced odds of any phototherapy phototherapy was the
excluded. breastfeeding (aOR: treatment. It is cause given the one-
0.58; 95% possible that some year duration between
CI:0.37–0.91). mothers may not have phototherapy-exposure
There was a reduced understood that and change in
odds of exclusive jaundice and high breastfeeding habits.
breastfeeding in bilirubin are Unclear whether among
phototherapy-exposed synonymous terms. jaundiced infants
infants (aOR: 0.69; receiving treatment
95% CI: 0.49–0.95) at phototherapy has a
1-mo postnatal. The more adverse effect
reduced odds of on breastfeeding than
breastfeeding in other interventions.
phototherapy-exposed
infants persisted at 2
and 4 mo postnatal.
Digitale 2021 Retrospective 25 853 infants born at Infants with missing Inpatient phototherapy Exclusive breast mlk No association between Emulated a randomized Phototherapy during the
Northern cohort $35-wk’ gestation data on length of during birth feeding via phototherapy and trial birth hospitalization
California, USA with birth hospital stay, hospitalization caregiver self- exclusive breast milk by only including was not associated
TSB levels from 3 TSB <3 mg/dL, or defined as presence report at 2-mo feeding at 2-mo of infants with with reduced breast
mg/dL TSB not measured of phototherapy flow well-child visit. age (aRR 0.99; 95% CI: a TSB level for which milk feeding at the 2-
below to 2.9 mg/dL were excluded. sheet in chart or Reporting feeding 0.95–1.04). phototherapy was mo well-child visit.
above 2004 AAP Infants whose first both ICD procedure infant The adjusted estimate of potentially indicated These results may not
phototherapy TSB higher than 3 code and any breast milk at the difference but not essential. apply to hospital

thresholds. mg/dL below phototherapy order. 2-mo well-child between observed Used a directed acyclic systems that do not
Medical records at 16 phototherapy visit. breast milk feeding graph (DAG) to actively support
Northern California threshold was among those who illustrate modeling maternal lactation
Hospitals (Kaiser $3mg/dL above received phototherapy assumptions. during photherapy.
Permanente [KP]) threshold excluded (average treatment Adjusted for potential Therefore, lactation
from 2013-2017. from primary effect on the treated) confounding variables support should be
analysis because (ATET) was -0.2% (95% using a modified encouraged.
phototherapy is no CI: -2.0% to 1.5%) less Poisson regression
longer optional at than that estimated if model.
those higher TSB those patients had Conducted sensitivity
concentrations. not received analyses by: (1)
phototherapy. including infants
Any breast milk feeding excluded from primary
at 2-mo: analysis because of
aRR 1.02 (95% CI: high initial TSB;
1.0–1.04) (2) imputing missing
ATET for any breast data to include infants
milk feeding at 2-mo initially excluded from
among those who primary analysis; (3)

by guest
TABLE 1 Continued
received phototherapy: analyzing infants who
11.6% (95% CI: received formula
0.1%–3.1%) before first TSB; and
(4) analyzing infants
who formula fed
before first TSB.
Estimates from
sensitivity analyses
were similar to
primary analysis
estimates.
Infant Behavior
Telzrow 1980 Obser-vational 10 low-risk term, Infants with Phototherapy at clinician Brazelton Scale Visual orientation scores The authors were unable Infants that received

Boston study nursery infants intrapartum or discretion (high scoring were lower in the to separate phototherapy may
Hospital for with matched who subsequently postnatal bilirubin was defined at 3, 6, and 10 d phototherapy-treated phototherapy-specific have had short-term
Women, controls received abnormalities, as >9 mg/dL before postnatal. group relative to the effects from bilirubin- changes in visual
Boston, phototherapy for including infants of 48 h postnatal and (Phototherapy was nontreated attributable or orientation.
Massachusetts, high bilirubin were Rh-positive >11 mg/dL before 72 started at an comparison group on separation-attributable Results may not apply
USA compared to 10 mothers, were h). average age postnatal days 3 (P < effects. to infants whose eyes
similar infants who excluded. of 76.5 h). .01), It was not possible for are not covered
did not receive 6 (P < .01), and 10 (P the examiners to be during phototherapy
phototherapy. < .05). Motor scores blinded to treatment or who are not
Sex, maternal were lower on day 6 group separated from their
breastfeeding (P < .05). Separate components parents.
intent, and (26 separate
rooming-in components and

proportions were 6 cluster-group
similar between scores) were assessed
groups. within the Brazelton
tests (multiple
comparisons).
Difficult to determine an
estimate of effect-size.
Decision to initiate
phototherapy was at
clinician discretion.
Mothers were discharged
at
3 d. Examinations at 6
d were performed for
the phototherapy
group within the
hospital and for the
comparison group at
home.
15
by guest
16
TABLE 1 Continued
Interrater reliability
coefficient was >0.85.
Paludetto Prospective 30 term infants Infants transferred to Phototherapy for 6 h or Brazelton Scale Visual orientation scores The mean total bilirubin Infants that received
1983 observational undergoing special care more for jaundice. scores at were lower in the levels phototherapy may
Newborn study with phototherapy for 6 nursery or with (Treated with (1) postnatal day 3 phototherapy-treated were lower in the have had short-term
Nursery of matched h or more for any neonatal phototherapy in the (day of enrollment) group relative to the comparison group (9.6 changes in visual
Second School controls jaundice (mean illness including nursery and the (treated infants nontreated [range, 3.5–14.3]) orientation.
of Medicine; bilirubin, 13.3 mg/ Rh and ABO mothers fed them were under comparison group on relative to the Results may not apply to
Naples, Italy dL) and 30 mismatch. every phototherapy an postnatal days 3 (P < phototherapy group infants whose eyes
comparison 3 h versus rooming-in average of 24 h at .005) and 4 (P < .01) (13.3 [range, are not covered
subjects matched in the first examination), and at 1 mo 8.4–17.5]). The authors during phototherapy
for sex, gestation, non–phototherapy- (2) 24 h of age (P < .05). were unable to or who are not
Apgar score, treated comparison postenrollment, separate phototherapy- separated from their
obstetric history, group.) and 3) specific effects from parents.
and father’s at 1 mo of age. bilirubin-attributable
profession. or separation-
Enrolled on attributable effects.
postnatal day 3. 26 separate components
were assessed within
the Brazelton tests
(multiple
comparisons).
Difficult to determine an
estimate of effect-size.
Although there were
general newborn unit

phototherapy
guidelines, clinicians
were free to decide
whether to start
phototherapy.
Only 12 matched pairs
were available for 12-
mo scoring follow-up.
Brazelton scorers were
unaware of treatment
assignment, but might
have noted different
levels of visible skin
jaundice in subjects.
Cancer
Cnattingius Nested 613 cases of 93 total antenatal and Lymphatic (ie, acute, Association of childhood Given number of studied Neither the use of
1995 (June) case-control lymphatic leukemia perinatal exposures chronic, lymphatic leukemia exposures, the authors phototherapy or
Sweden study were identified in were examined or unspecified with: estimated 4 or 5 neonatal jaundice was

by guest
TABLE 1 Continued
the Swedish including lymphocytic) Phototherapy (OR 1.0; significant associations found to increase the
National Cancer phototherapy and leukemia. 95% would be detected by odds of childhood
Register and the neonatal jaundice. CI: 0.5–1.8). chance alone. lymphatic leukemia.
Medical Birth Diagnoses and Physiologic jaundice The authors were unable
Register between procedures (OR 1.2; 95% CI: to adjust for degree of
1973-1989. determined by ICD 0.8–1.7). hyperbilirubinemia or
5 controls were codes. phototherapy intensity
matched to every or duration.
case by sex and
birth month and
year.
Cnattingius Nested 98 cases of myeloid Numerous antenatal and Myeloid (acute, Association of childhood Given number of studied Phototherapy and
1995 (July) case-control leukemia were perinatal exposures chronic, or myeloid leukemia exposures, significant neonatal jaundice

Sweden study identified in the were examined unspecified) with: associations might be were associated with
Swedish National including leukemia. Phototherapy (OR 7.5; detected by chance an increased odds of
Cancer Register phototherapy and 95% alone. childhood myeloid
and the Medical neonatal jaundice. CI: 1.8–31.9). leukemia. However,
Birth Register Diagnoses and Physiologic jaundice these associations
between 1973 procedures (OR 2.5; 95% CI: were no longer
and1989. determined by ICD 1.2–5.0). statistically significant
5 controls were codes. Reanalysis excluding after excluding
matched to every cases with Trisomy children with Trisomy
case by sex and 21: 21 diagnoses.
birth month and Phototherapy (OR 4.3; The authors were unable
year. 95% to adjust for degree of
CI: 0.9–21.9). hyperbilirubinemia or

Physiologic jaundice phototherapy intensity
(OR 1.7; 95% CI: or duration.
0.8–4.0).
Olsen 1996 Retrospective 66 430 neonates Supplementary Diagnosis of Diagnosis of cancer Among infants with Phototherapy diagnoses Hyperbilirubinemia was
Denmark cohort discharged with a diagnoses of hyperbilirubinemia within the Danish hyperbilirubinemia were not recorded. It not associated with
history of neonatal neonatal by ICD code. Cancer Registry. diagnoses, 87 cancers was estimated that childhood cancer. The
hyperbilirubinemia immaturity or were observed 85% to 50% of infants authors were not able
between 1977 and hemolytic disease. compared to 85 in the study received to directly estimate
1989 and recorded expected yielding phototherapy based on the effect of
in the Danish standardized a random sample of phototherapy on
Central Hospital incidence [SIR] 150 neonates with cancer.
Discharge Register. ratio51.0; 95% CI: 0.8- hyperbilirubinemia in
1.3. Copenhagen in 1981.
Leukemia (SIR 5 1.2; Average follow-up of 9.1
95% CI: 0.8-1.7) y (range 0–15 y)
(5 499 502 person-
years).
Case-control Per inclusion criteria.
17
by guest
18
TABLE 1 Continued
Berg 1997 30 cases of childhood Neonatal phototherapy Childhood malignant None of the infants The average follow-up No association was
Sweden malignant as determined by melanoma as diagnosed time detected between
melanoma between Swedish Medical Birth determined by with malignant was 18 y (range: 10- phototherapy and
1973 and 1992 and Registry. Swedish Cancer melanoma had 19). childhood malignant
120 controls Registry. received phototherapy Phototherapy melanoma.
matched by same compared to 11 of estimates were not
date of birth, same 120 controls (one- adjusted for degree of
hospital, and same tailed P value as hyperbilirubinemia or
sex. calculated in study 5 phototherapy intensity
0.08) or duration.
(Odd ratio 5 0; 95%
CI: 0–1.2). Calculated
2-tailed
P value 5 0.156).
Roman 1997 Case-control 177 cases with Infants from multiple Multiple antenatal and Leukemia or non- Association between any Phototherapy estimates Phototherapy and
Southern Leukemia or non- gestation perinatal risk factors Hodgkin’s leukemia and: were not adjusted for jaundice were not
England, UK Hodgkin’s pregnancies who including lymphoma Phototherapy (OR 0.5; degree of associated with
lymphoma and 354 died before birth phototherapy and diagnosed between 95% hyperbilirubinemia. leukemia or non-
age and sex- hospital discharge, neonatal jaundice, as the age of CI: 0.1–2.3). Hodgkin’s lymphoma in
matched controls or with identified extracted from 3 mo-30 y. Jaundice (OR 0.8; 95% CI: young adults.
identified from the chromosomal hospital medical Cases for children (0- 0.5–1.5).
medical records of anomalies or records. 14 y) extracted Additionally, no
3 hospitals. malformations. from the Childhood associations were
Cancer Research detected between
Group (1962–1992). jaundice or
Cases for young phototherapy and

adults (15–29 y) acute lymphocytic
extracted from leukemia, acute
Office of National myeloid leukemia, or
Statistics (ONS) non-Hodgkin’s
(1972-1987). lymphoma).
Podvin 2006 Case-control 595 cases born Per inclusion criteria. Multiple antenatal and Childhood leukemia Phototherapy (aOR 2.2; Estimates were adjusted Phototherapy and
Washington, between 1980-2002 perinatal risk factors diagnosis 95% for maternal age, neonatal jaundice
USA were identified including (age<20). CI: 1.0-4.9) gestation, birth wt and were associated with
from the phototherapy and Neonatal jaundice as race childhood leukemia.
Washington State neonatal jaundice. documented by ICD A secondary analysis that The authors were unable
Cancer Registry or Jaundice diagnoses code (aOR 1.4; 95% CI: excluded infants with to adjust for degree of
Cancer were documented on 1.0–1.9) Trisomy 21 found hyperbilirubinemia or
Surveillance birth certificates Neonatal jaundice as similar results. intensity or duration
System of Western before 1992. After documented on birth Phototherapy estimates of phototherapy.
Washington. 1987, ICD code-based certificate (aOR 2.1; were not adjusted for
Controls (n 5 5950) phototherapy and 95% CI: 1.2–3.8). degree of
were randomly neonatal jaundice hyperbilirubinemia.

by guest
TABLE 1 Continued
selected from birth diagnoses were
certificate records available.
of infants without
leukemia and
frequency of
controls were
matched to cases
by year.
Brewster Retrospective 77518 singleton Neonatal deaths. Received neonatal Standardized Two cases of melanoma Limited confounder No difference in skin
2010 cohort newborn infants phototherapy versus incidence ratios occurred control cancer risk was
Grampian born 1976–1990 no phototherapy. for melanoma, in phototherapy- for age, sex, calendar detected in infants
Region, that survived the basal cell, and exposed versus 16 period, and exposed to neonatal
Scotland, UK neonatal period. squamous cell skin cases in unexposed. socioeconomic phototherapy.

cancer. Standardized incidence measure within a
ratio of 1.40 (95% CI, postal code.
0.17–5.04; P 5 .834) Bilirubin level
for melanoma. No unmeasured.
cases of squamous Duration of phototherapy
cell or basal cell unmeasured.
carcinoma of skin Median follow-up of 24 y.
were observed in
exposed persons.
Newman Retrospective 449 621 newborn Death or transferred Received any neonatal Cancer diagnoses Propensity-score Cox regression models In adjusted analyses,
2016 Northern cohort infants born 1995- to phototherapy (in between postnatal adjusted hazard ratio including both there was no
California, USA 2011 at $35 wk’ another hospital hospital, day 60 and the end for any cancer after traditional statistically significant
gestation who before initial at home, or both) vs of the follow-up phototherapy: (aHR: multivariable models elevation in the risk

survived to hospital discharge. no phototherapy. period. 1.0; 95% CI: 0.7–1.6). and models for cancer. Unadjusted
discharge and were Cancer diagnosis Dose-response Examined multiple Lower limit of 95% CI for incorporating analyses did show an
followed $60 d. before 60 phototherapy variable categories of number needed to propensity-score elevated risk.
Database from 15 postnatal days. (0- none, 1-home leukemia and harm (NNH) for 10-y adjustment were used Given their elevated
Northern California <60 d of follow-up. phototherapy only, 2- other forms/sites cancer risk 1100. to adjust for potential, baseline risk for
Hospitals (Kaiser Infants born at <35 phototherapy in of cancer. For children with Down measured leukemia, children
Permanente). wk’ gestation. single admission, 3- syndrome, lower limit confounders, and with trisomy 21 may
1995-2011. phototherapy in of 95% CI for duration of follow-up. be at an even higher
multiple admits). estimated NNH for Multivariable and risk for leukemia after
leukemia 5 23. propensity-score phototherapy.
Propensity-score estimates were
adjusted hazard ratios mutually consistent.
for: Unable to measure total
Any leukemia: (aHR: duration of
1.6; 95% CI: 0.8–3.5). phototherapy
Nonlymphocytic exposure.
leukemia: (aHR: 1.9; Used a directed acyclic
19
by guest
20
TABLE 1 Continued
95% CI: 0.6–6.9). graph (DAG) to
Liver cancer: (aHR 1.4; illustrate modeling
95% CI: 0.2–12). assumptions.
In infants with $2 Cancer diagnoses were
phototherapy confirmed by a
admissions there was medical record review.
an association
between phototherapy
and acute
myelogenous leukemia
(AML) (aHR 8.5; 95%
CI 1.9–38) (note:
based on only 2 cases
of AML with $2
readmissions for
phototherapy).
Wickremasinghe Retrospective 5 144 849 infants born at Death within 60-d of Receipt of phototherapy Hospital discharge Propensity-score adjusted
2016 cohort $35 wk’ gestation birth. during a diagnosis of cancer via odds ratio for:
California, USA who survived >60 d. Cancer diagnosis hospitalization that ICD-9 code between 60- All cancer: (aOR: 1.4; 95%
California Vital before 60 began within the first d postnatal and 1 y of CI: 1.1-1.9).
Statistics/Patient postnatal days. 2 postnatal weeks as age. Myeloid leukemia: (aOR:
Discharge Dataset Infants born at <35 recorded by ICD-9 2.6; 95% CI: 1.3–5.0).
1998-2007. wk’ gestation. code for phototherapy Renal cancer: (aOR: 2.5;
(99.83, 99.83). 95% CI: 1.2–5.1).
Found NNH of 10 638 in the
general population and

1285 in children with
trisomy 21.
Adjusted for the Adjusted phototherapy
presence of a analyses may slightly
jaundice indicated increase the risk
diagnosis, but that of cancer in the
unable to first postnatal
control for year.
bilirubin
concentration,
which is also
associated
with a cancer
diagnosis.
Phototherapy
duration was
not
measurable.

by guest
TABLE 1 Continued
Propensity-score
adjustment to
adjust for
potential,
measured
confounders.
95% Cis were
narrow
showing
precise
estimates.
Auger 2019 Retrospective 786 998 infants born Cancer diagnosis The exposure was Hospitalization for Propensity-score Unable to adjust for Neonatal phototherapy
Quebec, cohort between 2006 and before age 2 mo defined solid or adjusted hazard ratios bilirubin concentration, may be associated
Canada 2016. or less than 2 mo as a 3-category hematopoietic for: which is also with a slightly

Dataset of discharge of follow-up. variable: childhood Any cancer: associated with a increased risk of solid
abstracts from all Infants with missing phototherapy, tumors between 2 mo (Phototherapy versus no cancer diagnosis. tumors in childhood.
Quebec hospitals: gestational age or untreated jaundice, or and 11 y of age. exposure: aHR: 1.16; Phototherapy duration It was not possible to
“Maintenance and birth wt. no exposure 95% CI: 0.9–1.6). was not measurable. rule out increasing
Use of Data for the Phototherapy at birth or (Phototherapy versus Propensity-score bilirubin concentration
Study of Hospital during admissions in untreated jaundice: adjustment to adjust as a potential
Clientele Registry the first 28 postnatal aHR: 1.07; 95% CI: for potential, confounder, since a
of Quebec.” days, as recorded by 0.8–1.5). measured jaundice diagnosis
Canadian (Untreated jaundice confounders. was also associated
Classification of versus no exposure: Fine-Gray subdistribution with cancer, bilirubin
Health Interventions aHR: 1.09; 95% CI: hazard model to allow concentrations were
procedure codes 0.9–1.3). for estimation of not available, and
(1.YZ.12.JA-DQ). Any cancer at 4-–1 y: probability of cancer phototherapy would

Jaundice diagnosis (Phototherapy versus no over time (cumulative likely be initiated at
recorded via ICD-10 exposure: aHR 2.21; incidence function higher bilirubin levels
codes (P58, P59). 95% CI 1.5–3.3) [CIF]), while compared to
(Phototherapy versus accounting for death untreated jaundice.
untreated jaundice: as a competing risk. Adjusted hazard ratios
aHR 2.21; 95% CI for any cancer and for
1.3–3.7). solid tumor cancers,
Late onset solid tumors, but not for
between age 4 and 11 hematopoietic
y: cancers, significantly
(Phototherapy versus no increased with age for
exposure: aHR: 2.26; infants exposed to
95% CI: 1.3–3.8) phototherapy.
(Phototherapy versus
untreated jaundice:
aHR: 2.21; 95% CI:
1.2–4.3).
The cumulative incidence
of childhood cancer
21
by guest
TABLE 1 Continued
22
was higher for infants
with phototherapy
(25.1 per 100 000
person-years)
and untreated jaundice
(23.0 per 100 000)
compared to
unexposed infants
(21.6 per 100 000).
Seppala 2020 Case-control 2037 cases with 8 cases and 82 Multiple antenatal and Childhood cancer Association between Analyses were adjusted Phototherapy was not
Finland childhood cancer controls due to perinatal risk factors. (age <20 y) as childhood cancer and for maternal age, associated with
diagnosed from missing birth wt Prematurity associated diagnosed from phototherapy: maternal smoking, and childhood cancer.
Finnish Cancer or gestation variables were the the All newborns (aOR 1.11; number of
Registry between data. main exposure Finnish Cancer 95% CI: 0.91-1.35). pregnancies.
1996-2014. variables of interest. Registry. Term newborns (aOR Phototherapy estimates
5 sex and year- Perinatal conditions and 1.17; 95% CI: 0.91- were not adjusted for
matched controls procedures, including 1.49). degree of
(n 5 10 185) for phototherapy, were hyperbilirubinemia or
each case from secondary exposures phototherapy intensity
Finnish Medical of interest. or duration.
Birth Registry.
Digitale 2021 Retrospective 139 100 infants born Patients who died or Received any neonatal Cancer diagnoses Propensity-score Cox regression models Adjusted analyses,
Northern cohort at were transferred phototherapy during between postnatal adjusted hazard ratio incorporated detected no significant
California, USA >35 wk’ gestation to another hospital birth hospitalization day 60 and the end for any cancer propensity-score elevation in the
from 1995-2017 before initial or readmission of the follow-up afterphototherapy: adjustment to adjust baseline risk for
with qualifying hospital discharge versus no inpatient period. (aHR: 1.13; 95% CI: for potential, cancer.

bilirubin . phototherapy. Required 2 total 0.8–1.5). measured
concentration 3 Cancer diagnosis cancer diagnoses Propensity-score confounders,
mg/dL below to 4.9 before 60 at different adjusted hazard ratios (including bilirubin
mg/dL above the postnatal days or departments to for: concentration) and
2004 AAP only had a reduce false- Any hematopoietic duration of follow-up.
phototherapy secondary cancer positive diagnoses. cancer: (aHR: 1.17; Unable to measure total
threshold. diagnosis. Time of cancer 95% CI: 0.7–1.8). duration or intensity of
Database from <60 d of follow-up. diagnosis defined Solid tumors: (aHR: 1.01; phototherapy
Northern California Infants born at <35 as date of initial 95% CI: 0.7–1.6). exposure.
Hospitals (Kaiser wk’ gestation. ICD cancer Analyses specifically
Permanente). diagnosis. looking for an
*Note: This is an Examined multiple increase in cancer
extension of the categories of risk after age 4 y
Newman 2016 hematopoietic were also negative.
cohort with an cancers, solid
additional 453 786 tumors, and other
person-years of cancers.
follow-up

by guest
TABLE 1 Continued
Bugaiski- Retrospective 342 172 infants born Neonates who died or Phototherapy performed First pediatric Preterm birth and Unable to adjust for Adjusted analyses
Shaked 2022 cohort at $32 wk’ were diagnosed during the first 2 wk hospitalization with maternal age adjusted bilirubin concentration indicated that
Soroka gestation born with any postnatal as defined any diagnosis of hazard ratios for: when estimating phototherapy may
University 1998-2018. malignancy before by neoplasm Childhood malignancies associations between slightly increase the
Medical Center, Perinatal database of 30-d postnatal. ICD-9 code for (malignant or (aHR 1.89; 95% CI: phototherapy and risk of childhood
Be’er-Sheva, obstetric and phototherapy benign). 1.4–2.7) neoplasms. malignancies and
Israel neonatal discharge diagnosis (Z9983). Benign tumors: (aHR: Phototherapy intensity benign tumors cancer
summary data 1.27; 95% CI: 1.02–1.6) and duration were not in the first postnatal
merged with Childhood malignancies measurable. year.
hospitalization in term-infants: (aHR: Used Israeli Ministry of It was not possible to
records from 1.84; 95% CI: 1.2–2.7) Health national cancer rule out increasing
Soroka University registry to cross- bilirubin concentration
Medical Center. reference and verify as a potential
child malignancy confounder or to

diagnoses that were in evaluate the impact of
database. phototherapy intensity
Median follow-up of or duration on
9.5 y (range 0–18 y). outcomes.
Insulin-
Dependent
Diabetes
Mellitus
Dahlquist Case-control 6487 cases born Twins, infants born of Phototherapy as A diagnosis of Adjusted odds of type 1 Multivariable logistic Phototherapy was
2003 1973–1997 who diabetic mothers, recorded in database. childhood diabetes diabetes regression analyses associated with type I
Sweden were recorded in and infants whose Jaundice was also as recorded in the in infants who had adjusted for birth diabetes in 2 Swedish
the Swedish county of birth evaluated as an Swedish Childhood received phototherapy year, preterm birth, counties with high

Childhood Diabetes was unknown, exposure. Diabetes Registry. in 2 high-risk counties newborn respiratory diabetes prevalence,
Registry and also with high type I symptoms, and blood following adjustment
linked with the diabetes prevalence: group immunization. for measured
Swedish Medical (aOR 1.95; (95% CI: Unable to adjust for confounding variables.
Birth Registry. 1.2–3.2). bilirubin concentration This association was not
2.8 million births for Association between or phototherapy observed in all other
comparison. phototherapy and duration or intensity. Swedish counties in
diabetes in all other adjusted analyses.
counties: (aOR 1.06; The analysis did not
95% CI 0.8–1.4). attempt to separate
Unadjusted association the jaundice-
between therapy and associated effect from
diabetes, irrespective that of phototherapy.
of diagnosis: (OR 3.79;
(95% CI: 3.1– 4.6).
Unadjusted association
between jaundice
diagnosis and
23
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TABLE 1 Continued
24
diabetes: (OR 1.13;
95% CI 1.01–1.3).
Newman Retrospective 499 642 infants born Infants who died In-hospital or home Type-1 diabetes Association between any Propensity-analyses There was no evidence of
2016 cohort at $35 wk’ during birth phototherapy. diagnosis defined phototherapy and type adjusted increased type 1
Northern gestation who hospitalization, as either $2 1 diabetes: (aHR 1.06; for bilirubin level diabetes risk in
California, USA were recorded in who were encounters 95% CI: 0.8 to 1.5). before phototherapy. children who had
the transferred, and (inpatient or Adjusted incidence rate Unable to measure received phototherapy.
Kaiser Permanente of who were followed outpatient) with a ratio (aIRR) for phototherapy duration
Northern California <60 d after birth. diagnosis of type 1 phototherapy:1.03 or intensity.
(KPNC) Database diabetes or 1 (95% CI: 0.8–1.4)
(1995–2011). encounter and corresponding to an
either $2 estimated excess risk
hemoglobin A1c of 0.58 (95% CI, 4.7
levels $6.5% or a to 5.9) per 100 000
pharmacy record person-years.
indicating insulin Propensity-adjusted Cox
prescription. model-derived
Diagnoses obtained association between
from KPNC virtual phototherapy and type
data warehouse I diabetes:
and diabetes Restricted model that
registry. included only those
with $1 TSB between
3 and 14.9 mg/dL
from 2004 AAP
phototherapy
threshold (aHR 0.95;

95% CI, 0.60–1.5)
Inclusive model of all
subjects with
dichotomous variable
for any TSB level
exceeding 2004 AAP
(aHR 0.91; 95% CI:
0.7–1.3).
Melanocytic
Nevi
Bauer 2004 Cross-sectional 1812 white children Per inclusion criteria. Neonatal phototherapy Total body nevus Multiple linear Limited data are No association was found
Germany study aged as determined by counts and regression analysis presented in between phototherapy
2–7 y attending parent survey. pigmentary did not identify an this brief report. Thus, as reported via parent
day care centers characteristics association between we are unable to survey and childhood
in 2 German cities were assessed in neonatal phototherapy calculate measures melanocytic nevus
in 1998. all participating and the number of of effect size. count at ages 2–7 y.
Note: this very brief children (52.9% melanocytic nevi in A standardized interview Limitations include the
report describes a boys). children (P 5 .21). of parents included potential for recall

by guest
TABLE 1 Continued
secondary analysis The number of vacation questions bias attributable to
of a 1998 study days in the sun (P < of national origin, sun the survey design and
(Wiecker et al .001) and an at-home exposure history, sun an inability to
Cancer. 2003; outdoors activity protection, and history adequately control for
97:628-638) score of neonatal jaundice. potential confounders
designed to (P 5 .03) were Risk of recall bias from at the time of
examine the associated with the use of survey to phototherapy.
association of sun increased childhood determine
exposure and melanocytic nevi. phototherapy. Limited
nevus counts in control for potential
parents with confounders at the
childhood time of phototherapy
development of due to survey design.

melanocytic nevi. Unable to adjust for
specific bilirubin
concentrations in
phototherapy-treated
infants versus
unexposed infants.
Matichard Case-control Eighteen 8- to 9-y-old Per inclusion criteria. Neonatal phototherapy Total nevus count and Multivariate analysis A variance model was An association was found
2006 children who were for jaundice. nevus count by using a variance used to adjust for age, at ages 8–9 between
Necker born from 1994 to size in millimeters model demonstrated skin/eye/hair neonatal phototherapy
Hospital, Paris, 1995 and treated (mm) at ages 8–9 an associated classifications, and exposure and an
France with phototherapy y. increase in nevi of survey-reported solar increased 2-5 mm
for jaundice at size 2-5 mm (P < exposure. nevus count. There
birth and 40 age- .001), but not an Effect sizes for was no association

matched increase in total multivariate analysis between phototherapy
schoolchildren who nevus count. are not reported. and total nevus count.
had not received Reported solar exposure Multiple comparisons. Limitations include a
neonatal was associated with The evaluations were nonblinded
phototherapy. an increase in the performed by the examination and the
total nevus count (P same dermatologist inability to control for
5 .02) and age (P 5 but at different confounders and
.02) and freckles (P locations: at the bilirubin concentration
5 .03) were hospital for those in both groups at the
associated with an receiving phototherapy time of potential
increase in 2–5 mm and at a school for phototherapy exposure
nevi. the nonexposed shortly after birth.
comparator group.
Thus, the evaluation
was not blinded.
Mahe 2008 Retrospective 828 9-y-old children at Children absent from Neonatal phototherapy Melanocytic nevus No difference in the Statistical analysis was No association was found
France cohort 52 French primary school on the day for neonatal jaundice count as melanocytic nevus done between phototherapy
schools in May- of the skin as determined by a performed by 2 count was detected by X2 test. as reported via
June 2007. examination. standardized survey between students that A standardized interview parent/child survey
25
by guest
TABLE 1 Continued
26
of parents and dermatologist- reported phototherapy of parents included and melanocytic nevus
children. trained nurses. exposure versus questions count at age 9 y.
unexposed students of sun exposure Limitations include the
(mean± SD nevus history, sun protection, potential for recall
count of 16.8±9.8 in and history of bias because of the
exposed vs 16.7±10.5 neonatal phototherapy. survey design, an
in unexposed). Risk of recall bias from unblinded analysis,
Skin phototype, skin the use of survey to and an inability to
color, eye color, and determine adequately control for
number of sunburn phototherapy. Limited potential confounders
episodes were control for potential at the time of
associated with nevus confounders at the phototherapy.
count. time of phototherapy
attributable to survey
design. Unable to
adjust for specific
bilirubin
concentrations in
phototherapy-treated
infants versus
unexposed infants.
Evaluation was not
blinded.
Csoma 2011 Cross-sectional 58 pairs of twins (15 Per inclusion criteria. Neonatal blue light Melanocytic lesions In the multivariable Examining dermatologists This twin comparison
The University twin study monozygotic pairs, phototherapy as as determined by linear regression and ophthalmologists study demonstrated
of Szeged, 43 dizygotic) and recorded in the skin examination. analysis, neonatal were blinded to the an association

Hungary one set of dizygotic neonatal medical Uveal melanocytic blue light subjects’ neonatal blue between neonatal blue
triplets aged chart. lesions as phototherapy was light phototherapy light phototherapy
3–30 y between Icterus/jaundice, and determined by significantly treatment history. exposure and
January-April 2008 prematurity as detailed associated with Twin comparison controls increased numbers of
at The University of recorded in neonatal ophthalmic increased melanocytic for many antenatal both melanocytic skin
Szeged, Hungary. charts. examination. nevi prevalence: and genetic variables and uveal lesions.
In each pair, one twin (standardized coefficient: present before
had received 0.158; 95% CI: potential phototherapy
phototherapy for 0.003–0.352; P 5 .47) exposure.
neonatal jaundice (unstandardized b Were able to determine
and the other had coefficient: 0.076). receipt of
not. Age (standardized phototherapy exposure
coefficient: 0.503; 95% via chart review.
CI: 0.051–0.101; P < Subjects or parents were
.0001) and number of surveyed on family
subtropical/tropical skin lesion history, sun
holidays (0.178; 95% exposure and
CI: 0.012–0.332; P 5 protection habits.
.035) were also These risk factors

by guest
TABLE 1 Continued
associated with along with age and
increased skin lesion pigmentary traits were
prevalence. adjusted for in the
Neonatal blue light multivariable analyses.
phototherapy was Multivariable linear
associated with an regression for skin
increased odds of lesions (natural log of
benign pigmented skin lesions was
ocular lesions (aOR: normally distributed)
3.778; 95% CI: and multivariable
1.694–8.423; logistic regression for
P 5 .001). uveal lesions (not
normally distributed).

Wintermeier Case-control 52 white, 5- to 6-y-old Per inclusion criteria. Neonatal blue light Melanocytic nevus The median nevus count Limited control for No association was found
2014 children who were phototherapy count at age 5–6 y in potential confounders at ages 5–6 between
Ludwig- previously exposed exposure. by a single children with at the time of neonatal phototherapy
Maximilian to neonatal blue investigator. phototherapy was 17 phototherapy. Unable exposure and
Hospital in light phototherapy Cafe-au-lait macules, compared to 18.5 in to adjust for specific melanocytic nevus
Munich, after birth at congenital nevi, the matched bilirubin count. Limitations
Germany Ludwig-Maximilian and freckles were nonexposed concentrations in include a nonblinded
Hospital in Munich, assessed comparator group (P phototherapy-treated outcome examination
Germany and separately. 5 .18) (Mann-Whitney infants versus and the inability to
52 nonexposed U test). unexposed infants. adjust for confounders
children who were A higher count of cafe- A history of family history and bilirubin
matched on age, au-lait macules (mean of skin cancer, sun concentration in both
gender, gestational 0.5) were noted in the exposure, and sun groups shortly after

age at birth, and phototherapy exposed protection was birth, the time of
skin phototype. children relative to obtained by parental potential phototherapy
the nonexposed survey. exposure.
(mean 0.2) Blinding of the
(P 5 .001). examining
Skin phototype (P 5 .05), dermatologist to
duration of sunny phototherapy exposure
vacations was not noted.
(P 5 .02), and
vacations in sunny
areas (P 5 .03) were
associated with
increased melanocytic
nevi.
Lai 2016 Systematic 5 observational Studies were Neonatal phototherapy Melanocytic nevus Those with previous DerSimonian and Laird This meta-analysis of
review studies (n 5 2921 excluded if they for count. phototherapy were random-effects models published studies did
and meta- total subjects) that were not cohort, hyperbilirubinemia. not found to have a were used to calculate not demonstrate a
analysis evaluated the case-control, or significantly higher a weighted mean significantly higher
association of cross-sectional mean melanocytic difference. mean number of
27
by guest
28
TABLE 1 Continued
neonatal designs or if mean nevus count: There was both clinical melanocytic nevi after
phototherapy with values and (Weighted mean heterogeneity and exposure to neonatal
melanocytic nevi standard difference: 0.32; 95% significant statistical phototherapy. However,
development. deviations of nevi CI: -0.67 to 1.31; P 5 heterogeneity between there was a great
(Bauer 2004, Csoma counts were not .53). the 5 studies degree of
2011, Mahe 2008, included or (I2569.1%; P 5 .01). heterogeneity between
Matichard 2006, calculable from the Visual inspection of the the included studies.
Wintermeier 2014.) presented data. funnel plot could not
Search terms: (4 reviews excluded exclude publication
(“photo- and bias.
therapy”[Mesh] 1 excluded for Formal Egger’s test failed
AND blue light*) insufficient to provide strong
AND information.) evidence of a small-
(“nevus, study effect (P 5 .09).
pigmented”[Mesh]
OR moles OR
melanocytic nevi).
Neurologic
Maimburg Retrospective 70 230 singleton Children with missing Information on exposure Information on Treatment with Cox proportional hazard Phototherapy for
2016 Denmark cohort children born information on to phototherapy for epilepsy and phototherapy for regression models hyperbilirubinemia in
between February phototherapy hyperbilirubinemia febrile seizures hyperbilirubinemia accounted for newborn infants was
1998 and May 2003 status was obtained from a were obtained was associated with observed follow-up associated with an
as recorded in the (n 5 40), birth maternal from ICD-10 an increased hazard time of each subject increased risk of
Danish National outcome questionnaire at 6 mo diagnoses within for developing and adjusted for epilepsy for males in
Birth Cohort (n 5 9), and twins postnatal. the Danish epilepsy in early potential, measured early childhood. No
(DNBC). (n 5 15). When estimating the risk National Hospital childhood (aHR: 1.66; confounders (gender, excess risk for febrile

of epilepsy, children Registry (DNHR). 95% CI: 1.23–2.24). birth gestation, seizures was seen. A
were followed from Phototherapy treatment socioeconomic status, limitation was the
postnatal day 29 until was not associated maternal risk factors inability to adjust for
onset of epilepsy, with febrile seizures during pregnancy, and bilirubin concentration
death, or end of the (aHR: 1.04; 95% CI: maternal age, parity, in both groups at the
follow-up in August 0.86-1.27). infertility treatment). time of potential
2010. In the analyses The increased hazard of Were unable to adjust for phototherapy
for the risk of febrile epilepsy was present bilirubin exposure.
seizure, children were for boys (aHR: 1.98; concentrations at the
followed from 95% CI: 1.40–2.78) but time of potential or
postnatal day 90 until not for girls (aHR: actual phototherapy
onset of febrile 1.14; 95% CI: exposure.
seizure, death, or 5 y, 0.64–2.02). Maternal survey response
whichever came first. for phototherapy was
validated via a medical
record review of a
random 100-patient
sample of infants born
at Aarhus University

by guest
TABLE 1 Continued
Hospital, which
revealed 96%
agreement.
Newman Retrospective 496 632 infants born Exceeded 2009 AAP Dichotomous variable for Primary outcome: $1 Phototherapy-associated Cox proportional hazard Neonatal phototherapy
2018 Northern cohort at $35 wk’ exchange any phototherapy encounter with a hazard ratio for and Poisson treatment is
California, USA gestation in transfusion within the hospital or seizure diagnosis Seizure regression models associated with a
1995–2011 and thresholds at home. plus $1 AED (aHR: 1.22; 95% CI: were used to adjust slight risk in
followed $60 d. (n 5 1773) and prescription. 1.05–1.42; for TSB concentrations childhood seizures
Kaiser Permanente of those with seizure Secondary P 5 .009). and other measured, diagnosed after $60
Northern California diagnoses at <60 outcomes: other Use of phototherapy potential confounders. d postnatal following
Database of 15 d postnatal (n 5 combinations of increased during the Cox models accounted for adjustment for
hospitals. 1237). $1 or $2 study period from observed follow-up bilirubin
Died during birth encounters with 2.4% in 1995% to time of each subject. measurements.

admission. seizure or epilepsy 15.9% in 2011. Propensity-score adjusted Boys are more likely than
diagnoses and $1 More boys experienced model estimates were girls to both receive
AED prescriptions. both phototherapy similar to Cox model phototherapy
and also seizures, but estimates. treatment of
there was no effect Additional analyses hyperbilirubinemia
modification showed that bilirubin and to be diagnosed
(interaction) between concentrations of with childhood
sex and phototherapy 20–24.9 mg/dL only seizure.
exposure. became significantly
Adjusted 10-y excess associated with
risks per 1000 infants seizure-diagnoses in
associated with adjusted models when
phototherapy were 2.4 the phototherapy-

(95% CI: 0.6–4.1) exposure variable was
overall, 3.7 (95% CI: removed.
1.2–6.1) for boys, and Did not have data on the
0.8 (95% CI: -1.7 to duration or intensity of
3.2) for girls. phototherapy.
aHR, adjusted hazard ratio; aRR, adjusted relative risk; AED, antiepileptic drug; ICD, International Classification of Diseases; aIRR, incidence rate ratio; TSB; total serum bilirubin; ASD, autism spectrum disorder; ATET, average treatment
effect on the treated.
Question: What are the adverse clinically detectable effects of phototherapy in newborns?
Population: Neonates born at $35 weeks’ gestation with hyperbilirubinemia who are candidates for phototherapy
Intervention: Treatment with phototherapy
Comparator: Nontreatment
Outcome: Increased risk of any adverse clinical outcome that is important to neonatal patients, their families, and/or the clinicians treating them
Excluded: case reports/series, nonsystematic review articles, manuscripts focused on preterm infants born at <35 weeks’ gestation
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TABLE 2 IVIG to Prevent Exchange Transfusion in Infants With Indirect Hyperbilirubinemia
Citation and Participants or Notes or
Setting Methods Inclusion Criteria Exclusion Criteria Interventions Outcomes Results Risk of Bias Conclusions
ABO Isoimmu-
nization
Miqdad 2004 Randomized 112 newborn infants As per inclusion Randomized to Exchange Exchange The investigators IVIG treated
Riyadh, Saudi controlled trial born in a single- criteria. phototherapy transfusion transfusion risk and clinicians infants with
Arabia center between plus 500 mg/kg (conducted in in IVIG exposed: were not ABO
2000-2002 at $36 IVIG or both groups if 7.1%. blinded to incompatibility
wk’ gestation with phototherapy the serum Risk in placebo treatment. were less
ABO incompatibility alone. bilirubin was group: 28.6%. The control group likely to
and a positive $20 mg/dL). Risk ratio: had an receive an
direct antiglobulin (Exchange 0.25 additional exchange
test (DAT) with transfusion was (95% CI: trigger for transfusion
serum bilirubin also conducted 0.09–0.7). exchange than those in
rate of increase in the Risk difference: transfusion the control

$0.5 mg/dL/hour. phototherapy- 21.4 based on group. It
only control (95% CI: 35.1 bilirubin rate of should be
group [not the to 7.8). increase. This noted that by
IVIG group] if No adverse events increased the design, the
the serum noted. likelihood that control group
bilirubin rate of infants in the had an
increase was control group increased
$0.5 mg/dL/ might qualify opportunity to
hour). for exchange qualify for an
transfusion. exchange
transfusion
(bilirubin rate
of rise $0.5

mg/dL/hour
or serum
bilirubin $20
mg/dL),
relative to the
IVIG treated
group
(exchange
transfusion
only for
serum
bilirubin $20
mg/dL). The
number of
infants in the
control group
that were
exchanged
31
by guest
TABLE 2 Continued
32
because of
bilirubin rate
of increase
($0.5 mg/dL/
hr) rather
than a serum
bilirubin $20
mg/dL was
not reported.
Rhesus (Rh)
Isoimmun-
ization
R€ubo 1992 Randomized 32 term and preterm As per inclusion Randomized to Exchange Exchange The investigators IVIG treated
Germany controlled trial newborn infants criteria. phototherapy transfusion transfusion risk and clinicians infants with
with positive direct plus 500 mg/kg (conducted if in IVIG exposed: were not Rh-isoimm-
antiglobulin tests IVIG, as soon as bilirubin 12.5%. blinded to unization were
born at 11 German Rh- iso- concentrations Risk in placebo treatment. less likely to
children’s hospitals immunization exceeded the group: 68.8%. Randomization receive an
between 1989-1990. was established modified curves Risk ratio: concealment exchange
Treatment began and informed of Polaceka by 0.18 and allocation transfusion
as soon as Rh- consent more than 2 (95% CI: process not than those in
isoimmunization obtained, or to mg/dL). 0.05–0.69). described. the control
was established phototherapy Risk difference: Noted that 1 child group.
and consent was alone. -56.3% in each group The authors
obtained. (95% CI: -84.2 was excluded reported that
to -28.4). for unnamed the difference
No adverse events protocol in birth wt or

noted. violations. The age between
study was groups was
originally not
planned for 34 statistically
infants. significant.
However,
there was no
report of the
number of
infants by
specific
gestational
age. Of the 13
infants that
received
exchange
transfusion, 8
were >2.5 kg
birth wt term

by guest
TABLE 2 Continued
infants and 5
were <2.5 kg
preterm
infants.
Dagoglu 1995 Randomized 41 newborn infants As per inclusion Randomized to Exchange Exchange The investigators IVIG treated
Istanbul, controlled trial (mean gestational criteria. phototherapy transfusion transfusion risk and clinicians infants with
Turkey age: 36.1 wk) with plus 500 mg/kg (conducted if in IVIG exposed: were not Rh- isoimm-
Rh- incompatibility IVIG as soon as the increase of 20%. blinded to unization were
and a positive DAT possible after total bilirubin Risk in placebo treatment. less likely to
who were admitted birth (usually exceeded 1 mg/ group: 75%. receive an
to a single-center within 2 h) or dL/hour or Risk ratio: exchange
between August to phototherapy when, during 0.27 transfusion
1992- and June alone. the first 72 h, (95% CI: than those in
1994. Phototherapy was the total 0.11–0.66). the control

Mean gestation of initiated when concentration Risk difference: group
treated group: 36.1 bilirubin exceeded 20 55% Mothers of
wk; SD: 2.3. concentrations mg/dL in term (95% CI: -80.8 to enrolled
Mean gestation of exceeded the infants or 18 -29.17). infants
untreated group: relevant curves mg/dL in No adverse events received 2–3
36.1 wk; SD: 1.7. of Oski and infants noted. in-utero
Naiman.b weighing more transfusions
IVIG treatment was than 2000 g). on average,
usually before
administered delivery for
within 2 h treatment of
postnatal. Rh-mediated
hemolysis.

Elalfy 2011 Randomized 90 newborns with Rh- Perinatal asphyxia, Randomized at 12 Exchange Exchange The investigators IVIG-treated
Cairo, Egypt controlled trial isoimmunization neonatal sepsis, h to 500 mg/kg transfusion transfusion risk and clinicians infants with
who were born at or presence of IVIG plus (conducted per in IVIG exposed were not Rh-
>38weeks’ hematomas. phototherapy the 2004 AAP (inclusive of blinded to incompatibility
gestation with (n 5 23 exchange low- and high- treatment. were less
serum bilirubin assigned; transfusion dose treatment Parents were able likely to
increasing by 0.5 n 5 25 thresholds if groups): 5%. to refuse receive an
mg/dL/hour and/or treated), 1 g/kg the bilirubin Risk in placebo assigned exchange
required IVIG plus was increasing group: 22%. treatment after transfusion
phototherapy in phototherapy by $1 mg/d/ Risk ratio: study than those in
the first 12 h (n 5 22 hour). 0.23 enrollment and the control
postnatal, who assigned; (95% CI: receive group.
were not yet n 5 15 treated) 0.05–0.97). treatment in a It should be
eligible for or phototherapy Risk difference: different group. noted that the
exchange only (n 5 45 17% Small sample sizes original
transfusion and assigned; (95% CI: -30.3 to in the high- and randomization
who were admitted n 5 50 -3.7). low-dose assignment
to a single center treated). The 2 IVIG-treated treatment was not
between March Parents of 5 infants who groups reduced followed for
33
by guest
TABLE 2 Continued
34
2009 and January infants received an the power for all enrolled
2010. assigned to the exchange comparison of infants. An
intervention transfusion the effect of intention to
group were were both in low- vs high- treat analysis
reassigned to the low-dose dose IVIG was not
the control (500 mg/kg) dosing for provided and
group when group. preventing authors did
their parents Risk difference exchange not respond
refused IVIG between high- transfusion. to emailed
and 5 babies versus low-dose queries
assigned to the treatment of requesting
high-dose IVIG preventing an one. No data
group were exchange on outcomes
assigned to the transfusion: -8% according to
low-dose IVIG (95% CI: -18.6 to original
group per 2.63). treatment
parental Note: risk ratio not assignment
wishes. calculable were
Parental because of no provided.
reasoning for events in high- None of the
refusing dose group. mothers of
treatment or No adverse events enrolled
switching noted. infants had a
dosage groups history of
was not antenatal IVIG
provided. treatment or
in utero

transfusion.
Smits-Wintjens Randomized, 80 newborn infants Infants with Randomized to Primary: need for Exchange Double-blinded. No difference in
2011 double-blinded, born at $35 wk’ perinatal phototherapy exchange transfusion risk Adequate exchange
Leiden, placebo- gestation and asphyxia (5-min and IVIG, 750 transfusion (per in IVIG exposed allocation transfusion
Netherlands controlled trial admitted to a Apgar <3 or mg/kg within 4 the 2004 AAP infants: 17.1%. concealment. risk or in
single center cord pH <7.0), h postnatal, or recommended Risk in placebo Inadequate power: measured
between 2006 and hemolytic phototherapy exchange group: 15.4%. confidence secondary
2010 with maternal disease other plus the same transfusion Risk ratio: 1.11 interval outcomes
and neonatal than rhesus D vol of a 5% levels) and the (95% CI: includes were detected
testing consistent or c, and dextrose number of 0.41–3.01). clinically between
with Rhesus D- or rhesus placebo. exchange Risk difference: meaningful groups
anti C-mediated hemolytic Both groups transfusions 1.69% absolute risk randomized to
hemolytic disease disease received per infant. (95% CI: -14.5% reduction -14%). IVIG treatment
of the newborn presenting intensive white Secondary: to 17.8%). versus
(HDN). >4 h after light duration of No differences placebo.
Rhesus HDN defined birth. phototherapy phototherapy between groups
as (1) a maternal with an and hospital in secondary
antibody-dependent intensity of stay, maximum outcomes.

by guest
TABLE 2 Continued
cellular cytotoxicity 12 to 20 lW/cm2 serum bilirubin No adverse events
test with a>50% per nm given concentrations, noted.
result (comparable by air shield and need for
with an antibody and Ohmeda red-cell
titer of >1:64)c lamps in transfusion in
and (2) a combination the first 3 mo
direct antiglobulin with blue-light postnatal.
test with positive bilirubin
results caused by blanket
antirhesus D or c phototherapy
antibodies in the (30 lW/cm2 per
fetus/neonate of a nm).
rhesus D or c-

negative mother.
Santos 2013 Randomized, 92 newborn infants Hydrops fetalis, Randomized to Primary: need for Exchange Double-blinded. No difference in
Rio de double-blinded, born at $32 wk’ cardiac phototherapy exchange transfusion risk Adequate exchange
Janeiro, Brazil placebo- gestation admitted instability, plus IVIG, 500 transfusion (at in IVIG-exposed allocation transfusion
controlled trial to a single-center severe mg/kg over 2-h a serum infants: 13%. concealment. risk or in
between April 2006 asphyxia, other shortly after bilirubin Risk in placebo Inadequate power: measured
and June 2009 non-Rh red birth, versus concentration group: 15.2%. confidence secondary
with a positive DAT blood cell phototherapy of 20 mg/dL or Risk ratio: interval outcomes
whose mothers antibodies, plus the same increase $0.5 0.857 includes were detected
where Rh- initial bilirubin vol of a normal mg/dL/hour). (95% CI: clinically between
alloimmunized. >4 mg/dL and/ saline placebo. Secondary: peak 0.32–2.36). meaningful groups
Mean gestation of or cord Both groups bilirubin, Risk difference: absolute risk randomized to
treated group: 36.5 hematocrit received high- phototherapy reduction -16%). IVIG treatment

2.17%
wk; SD: 1.5. <30%. intensity blue duration, length (95% CI: -16.4% versus
Mean gestation of fluorescent of stay, drug, or to 12.1%). placebo.
placebo group: phototherapy. drug No differences
36.1 wk; SD: 1.6. administration between groups
related adverse in secondary
effects or outcomes.
events. No adverse events
noted.
Rh- and ABO
isoimmu-
nization
Alpay 1999 Randomized 116 term newborn As per inclusion Randomized to Exchange Exchange The investigators IVIG treated
Ankara, Turkey controlled trial infants with ABO criteria. conventional transfusion transfusion risk and clinicians infants with
(RCT) and/or Rh phototherapy (conducted if in IVIG exposed: were not ABO or Rh-
incompatibility plus a single serum bilirubin 13.8%. blinded to incompatibility
with bilirubin 1 g/kg dose of exceeded 16.96 Risk in placebo treatment. were less
>11.9 mg/dL, IVIG or to mg/dL and group: 37.9%. Randomization likely to
positive DAT, and conventional increased $1 Risk ratio: assignment was receive an
35
by guest
TABLE 2 Continued
36
reticulocyte count phototherapy mg/dL/hour 0.36 done by a exchange
$10% who were alone. despite (95% CI: neonatologist transfusion
admitted to a IVIG treatment was phototherapy). 0.18–0.75). different from than those in
single-center initiated soon Duration of Risk difference: those the control
between March after the phototherapy. 24.1% conducting the group.
1992 and inclusion Duration of (95% CI: -39.5% study. The majority of
November 1996. criteria were hospitalization. to -8.82%). Randomization study subjects
Mean postnatal age met. Duration of concealment had ABO
of treated group: phototherapy and allocation incompatibility
51.5 h; SD: 26.7. and duration of process not (80%),14%
Mean postnatal age hospitalization otherwise had Rh incom-
of untreated group were shorter in described. patibility, and
54.3 h; SD: 30.5. the IVIG-treated 6% had ABO
group (P < .05). and Rh
No adverse events incompa-
were reported. tibility.
Tanyer 2001 Quasi-randomized 61 full-term newborn Contributing risk Assigned by order Exchange Exchange The investigators IVIG treated
Ankara, Turkey trial infants admitted to factors (such of admission to transfusion transfusion risk and clinicians infants with
a single center as sepsis, drug phototherapy (conducted if in IVIG exposed were not Rh-, ABO-, or
between January use by plus 500 mg/kg bilirubin (inclusive of blinded to subgroup
1996 and mothers) that multiple-dose exceeded limits single- and treatment. incompatibility
November 1998 could raise IVIG treatment on included multiple-dose Treatment were less
with Rh-, ABO-, or bilirubin (daily on 3- table [20 mg/dL treatment assignment was likely to
subgroup- concentrations. consecutive for low-risk groups): 7.5%. per order of receive an
incompatibility, days), infants at Risk in placebo admission exchange
bilirubin phototherapy >2500 g; 18 group: 33.3%. rather than by transfusion
concentrations plus single-dose mg/dL for low- Risk ratio: a randomization than those in

below the 500 mg/kg IVIG risk infants at 0.23 process. the control
exchange treatment, or 2000–2499 g]). (95% CI: Small sample sizes group.
transfusion criteria phototherapy 0.06–0.78). in the multiple- The majority of
at admission, and alone. Risk difference: and single-dose study subjects
a positive DAT. Initial IVIG doses -25.8 treatment had ABO
were (95% CI: -47.6% to groups reduced incompatibility
administered -4.1). the power for (55.7%), 29.5%
between 2–4 h Risk difference comparison of had Rh incom-
of admission. between the effect of patibility, 3.3%
multiple- vs multiple- versus had subgroup
single-dose single-dose IVIG incom-
treatment of dosing for patibility, and
preventing an preventing 11.5% had
exchange exchange more than 1
transfusion: transfusion. incompatibility
-15% (95% CI: type.
-30.7 to 0.65).
Note: risk ratio not
calculable due

by guest
TABLE 2 Continued
to no events in
multidose
group.
No adverse events
noted.
Nasseri 2006 Randomized 34 newborn infants at Sepsis, glucose-6- Randomized to Exchange Exchange The investigators IVIG treated
Mashdad, Iran controlled trial a single center phosphate phototherapy transfusion transfusion risk and clinicians infants with
between dehydrogenase plus 500 mg/kg (conducted if in IVIG exposed: were not ABO or
October 2003 and (G6PD) IVIG within 2 h serum bilirubin 17.7%. blinded to Rh-isoimm-
October 2004 who deficiency, or of admission was $20 mg/dL Risk in placebo treatment. unization were
were other illnesses and then every or for a rate of group: 64.7%. Manuscript less likely to
Born at $37 wk’ that could 12 h for 3 total rise >1 mg/dL/ Risk ratio: describes receive an
gestation with Rh- result in doses or to hour). 0.27 randomization exchange
or ABO- increased phototherapy (95% CI: 0.09–0.8). in multiple transfusion

incompatibility and bilirubin alone. Risk difference: -47.1 places, but also than those in
had a positive DAT concentrations. (95% CI: -76.1 describes the the control
and a serum to -18.0). study as a group.
bilirubin rate of No adverse events prospective, The majority of
increase >0.5 mg/ noted. case-control study subjects
dL/hour. study in the had ABO
Methods incompatibility
section. (62%). The
Randomization remaining
concealment 38% had Rh-
and allocation incom-
process not patibility.

described.
Systematic
Reviews
Walsh 2009 Systematic review Manuscripts on As per inclusion IVIG administration Effective reduction The authors noted Search terms IVIG is relatively
neonatal criteria. to patients with of serum a large degree specified. Loose safe and
hyperbilirubinemia isoimmune bilirubin of heterogeneity inclusion effective
and hemolytic concentrations. between criteria based means of
immunoglobulin. jaundice. Avoidance of studies. Overall, on broad reducing the
Restricted to exchange they concluded search. need for
humans, newborn transfusion. that IVIG is a exchange
infants, and relatively safe transfusion.
English. and effective There is a
Included 7 means of large degree
randomized reducing the of
controlled trials need for heterogeneity
and exchange between the
3 prospective transfusion. included
observational studies.
studies, 2 Note: This review
37
by guest
TABLE 2 Continued
38
retrospective was
reviews, and a conducted
single case series. before the
placebo-
controlled
RCTs by
Santos and
Smit-Wintjens.
Zwiers 2018 Systematic review Randomized trials of IVIG treatment of Primary: need for Overall, found that Reported that There was a
IVIG for treatment alloimmune exchange IVIG reduced overall RCT great deal of
of alloimmune thrombo- transfusion. exchange evidence was of heterogeneity
hyperbilirubinemia cytopenia. transfusion. low quality. between
of the newborn Infants in all arms Risk ratio: 0.35 Only two RCTs studies. Five
infant. Trials must of the included (95% CI: (Santos 2013 studies were
have used studies received 0.25–0.49). and Smits- restricted to
predefined criteria intensive Risk difference: Wintjens 2011), Rh-disease,
for IVIG use and phototherapy. 0.22 both on Rh- one study was
exchange (95% CI: -0.27 to alloimm- restricted to
transfusion. -0.16). unization, used ABO disease,
(included 9 RCTs Two placebo- a placebo. and three
published between controlled RCTs enrolled
1992 and 2013; 658 of infants with patients with
total participants). Rh-incompatibility both ABO and
Risk ratio: 0.98 Rh incom-
(95% CI: patibility. The
0.48–1.98). systematic
review

conclusions
were based
primarily on
the 2 placebo-
controlled
trials of
infants with
Rh-disease
(Santos 2013;
Smits-Wintjens
2011).
The most recent,
placebo-
controlled
trials did not
demonstrate a
reduced risk
for exchange

by guest
TABLE 2 Continued
transfusion in
Rh-positive
infants after
IVIG treatment.
Overall, there is
weak evidence
that IVIG may
reduce the
need for
exchange
transfusion.
Non-Rh
mediated

forms of
hyperbilir-
ubinemia
including ABO
incompatibility
are not well
studied.
Question: What is the effectiveness of IVIG for prevention of exchange transfusion in infants with indirect hyperbilirubinemia?
Population: Neonates born at $35 weeks’ gestation with isoimmunization and hyperbilirubinemia who are at risk of exchange transfusion
Intervention: Treatment with IVIG
Comparator: Nontreatment with IVIG
Outcome: Need for exchange transfusion
Included: randomized controlled trials, quasi-randomized trials, and systematic reviews that include randomized trials
a

Polacek K. Die fruhzeitige Indikationstellung zur Austausch-transfusion bei hamolytischen Neugeborenerkrankungen. Monatsschr Kinderheilkd. 1963;111:6-10; and Polacek K. Das universale Diagramm zur Behandlung der Hyperbilirubina-
mie der Neugerborenen. Padiatrische Praxis. 1984;29:1-3.
b
Oski FA, Naiman JL: Erythroblastosis fetalis. In: Oski FA, Naiman JL, eds. Hematologic Problems in the Newborn. Philadelphia: WB Saunders Company;1982:283-346.
c
Oepkes D, van Kamp IL, Simon MJ, Mesman J, Overbeeke MA, Kanhai HH. Clinical value of an antibody-dependent cell-mediated cytotoxicity assay in the management of Rh D alloimmunization. Am J Obstet Gynecol. 2001;184(5):1015-1020.
Table 2 References:
1. Alpay F, Sarici SU, Okutan V, et al. High-dose intravenous immunoglobulin therapy in neonatal immune hemolytic jaundice. Acta Paediatr. 1999 Feb;88(2):216–219
2. Dagoglu T, Ovali F, Samanci N, Bengisu E. High-dose intravenous immunoglobulin therapy for rhesus hemolytic disease. J Int Med Res. 1995 Jul–Aug;23(4):264–271
3. Elalfy MS, Elbarbary NS, Abaza HW. Early intravenous immunoglobin (two-dose regimen) in the management of severe Rh hemolytic disease of newborn—a prospective randomized controlled trial. Eur J Pediatr. 2011
Apr;170(4):461–467
4. Miqdad AM, Abdelbasit OB, Shaheed MM, et al. Intravenous immunoglobulin G (IVIG) therapy for significant hyperbilirubinemia in ABO hemolytic disease of the newborn. J Matern Fetal Neonatal Med. 2004 Sep;16(3):163–166
5. Nasseri F, Mamouri GA, Babaei H. Intravenous immunoglobulin in ABO and Rh hemolytic diseases of newborn. Saudi Med J. 2006 Dec;27(12):1827–1830
6. R€ubo J, Albrecht K, Lasch P, et al. High-dose intravenous immune globulin therapy for hyperbilirubinemia caused by Rh hemolytic disease. J Pediatr. 1992 Jul;121(1):93–97
7. Santos MC, Sa C, Gomes SC Jr, et al. The efficacy of the use of intravenous human immunoglobulin in Brazilian newborns with rhesus hemolytic disease: a randomized double-blind trial. Transfusion. 2013 Apr;53(4):777–782
8. Smits-Wintjens VE, Walther FJ, Rath ME, et al. Intravenous immunoglobulin in neonates with rhesus hemolytic disease: a randomized controlled trial. Pediatrics. 2011 Apr;127(4):680–686
9. Tanyer G, Siklar Z, Dallar Y, et al. Multiple dose IVIG treatment in neonatal immune hemolytic jaundice. J Trop Pediatr. 2001 Feb;47(1):50–53
10. Walsh S, Molloy EJ. Toward evidence based medicine for pediatricians. Is intravenous immunoglobulin superior to exchange transfusion in the management of hyperbilirubinaemia in term neonates? Arch Dis Child. 2009
Sep;94(9):739–741
11. Zwiers C, Scheffer-Rath ME, Lopriore E, et al. Immunoglobulin for alloimmune hemolytic disease in neonates. Cochrane Database Syst Rev. 2018 Mar 18;3:CD003313
39
Question 1: What are the adverse
clinically detectable effects of
phototherapy in newborns?
The search produced 45

manuscripts. Eighteen were
excluded: 12 did not report clinically
relevant phototherapy-related
outcomes, 2 compared phototherapy
modalities rather than outcomes,
1 focused on preterm infants born
at <35 weeks’ gestation, 1 was a
case report, 1 a case series, and 1 a
nonsystematic review article.
A review of the selected
manuscripts yielded 14 additional
publications which were included.
An evidence table (Table 1) details
the study design of and evidence
derived from each of the 38
included manuscripts forquestion 1.
Summary: Phototherapy is
associated with a significant yet low
overall risk of potential harm.
FIGURE 1
Evidence grading. Childhood seizures are one of the
most serious, but infrequent,
conditions (adjusted 10-year excess
Question 2: How effective is IVIG for immunoglobulin*). Commentaries,
risk of 2.4; 95% confidence interval
preventing exchange transfusion in editorials, and letters were
[CI]: 0.6, 4.1 per 1000 phototherapy-
infants with indirect excluded.
treated infants) associated with
hyperbilirubinemia?
After the initial search produced phototherapy.12 Although the topic is
Population: Neonates born at $35 multiple randomized trials, the understudied, there is some evidence
weeks’ gestation with that phototherapy may limit familial
article inclusion criteria were
isoimmunization and bonding with the infant. Therefore,
subsequently limited to
hyperbilirubinemia who are at risk treatment thresholds must attempt to
randomized controlled trials,
for exchange transfusion. balance the risk of adverse effects of
quasi-randomized trials, and
phototherapy with its possible
systematic reviews that included
Intervention: Treatment with IVIG. benefit at reducing the risk of total
randomized trials.
serum bilirubin concentrations at
Comparator: Nontreatment with which exchange transfusion is
IVIG. SELECTION OF INCLUDED EVIDENCE recommended and/or neurotoxicity
References obtained from Medline has been found.
Outcome: Need for exchange
via the search process were initially
transfusion. Question 2: How effective is IVIG
selected on the basis of the article
for preventing exchange
The search, initially performed on title and abstract and the prewritten
transfusion in infants with indirect
May 24, 2018 and repeated March inclusion criteria for each question. hyperbilirubinemia?
5, 2021 and April 7, 2022, included Each reference was reviewed by 2
MeSH term Hyperbilirubinemia or reviewers (JLS and ARK), and a The search produced 13 manuscripts.
keyword hyperbilirubinemia AND – third reviewer (TBN) was the Two were excluded because they
any of the following MeSH terms or deciding vote in instances of were not randomized trials, quasi-
keywords (Immunoglobulins, disagreement. The first 2 reviewers randomized trials, or systematic
Intravenous[MeSH]; IVIG; subsequently reviewed the full texts reviews inclusive of randomized
intravenous immunoglobulin*; of the included articles. trials. An evidence table (Table 2)

by guest
details the study design of and an unclear definition of NEC grade, a tables, were written by the
evidence derived from each of the 11 large degree of heterogeneity (eg, epidemiologist.
included manuscripts for question 2. proportion of small for gestational
age infants) between available All members of the subcommittee then
Summary: IVIG may not be effective studies, and an incomplete reviewed all recommendation drafts
in preventing exchange transfusion description of the evaluated studies and offered amendments before a final
for infants with severe Rh disease. including the baseline severity of acceptance of all recommendations by
Larger, randomized, placebo- illness in infants who were treated vote of the entire subcommittee. The
controlled trials are needed to with IVIG, as compared to untreated derived language for each
confirm this finding. The effect of infants with hyperbilirubinemia.19 recommendation reflected the strength
IVIG for non-Rh-mediated hemolysis Despite these limitations, the signal of graded evidence.
including ABO incompatibility is for IVIG-related harm from
understudied. There is a large increased NEC must be considered, GRADING OF THE EVIDENCE
degree of heterogeneity between because observational studies are The identified evidence for each
available trials, which are all of low often better powered than recommendation within the clinical
to moderate quality. Thus, there is a randomized trials to pick up rare, practice guideline was appraised and
need for well-designed placebo- serious adverse drug events. Given
summarized per AAP policy.14 Then a
controlled trials. There were no an unclear but potential benefit
level of evidence, from strongest to
IVIG-related safety concerns from IVIG in preventing exchange
weakest, was assigned (Fig 1).14 This
reported in the included randomized transfusion and limited evidence of
information is provided in
trials. However, observational an increased NEC risk, the risks and
Supplemental Appendix B of the
investigations have reported benefits of IVIG must be carefully
clinical practice guideline.1
associations between IVIG and considered. The 2022 guideline notes
necrotizing enterocolitis (NEC). that clinicians may consider the
administration of IVIG to infants with CONCLUSIONS
Figueras-Aloy et al conducted a
retrospective cohort investigation in isoimmune hemolytic disease (ie, A systematic approach combining
Barcelona, Spain, and found an positive direct antiglobulin test [DAT]) the best available evidence and
association between IVIG and risk of who have not initially responded to expert opinion, when necessary, was
NEC (odds ratio [OR]: 31.66; 95% photherapy with a reduction in total used to generate an updated
CI: 3.25–308.57) but no increase in bilirubin only in circumstances when guideline for the diagnosis and
mortality.19 The authors attempted the TSB is rising despite intensive management of hyperbilirubinemia
to adjust for severity of illness using phototherapy or within 2 to 3 mg/dL in neonates $35 weeks’ gestation.
propensity scoring PS, but it does of the exchange level and there is The committee’s approach was to
not appear that all of the included concern that a timely exchange improve on the expert-driven 2004
variables (eg, peak bilirubin transfusion will be difficult.1
AAP guideline2 and 2009 follow-up
concentration or exchange commentary3 through the
transfusion) were measured before GENERATION OF RECOMMENDATIONS incorporation of new evidence. The
the receipt of IVIG, as should be All first drafts of recommendations committee has developed new
done when using propensity scoring were created by members of the phototherapy and exchange
to mimic a randomized trial. subcommittee that were assigned as transfusion treatment
Although care practices mostly content experts and authors for recommendations that should
seemed similar to the United States, each subsection of the guideline. In reduce the numbers of infants
they did administer phenobarbital many instances, these
unnecessarily treated with
to infants receiving phototherapy. recommendations were closely
phototherapy while at the same
A meta-analysis that included the adapted from similar
Figueras-Aloy et al investigation time ensuring that infants at
recommendation statements in the
specifically evaluated the association 2004 guideline and/or the 2009 higher risk for bilirubin-associated
between IVIG and NEC and reported commentary by reviewing and neurotoxicity, on the basis of
a higher incidence of NEC after IVIG incorporating any new evidence on serum bilirubin concentrations,
infusion for hyperbilirubinemia (OR: each previous recommendation gestational age, and neurotoxicity
4.53; 95% CI, 2.34–8.79) with no topic, when available. The original risk factors, will receive proper
increase in mortality.20 However, drafts of recommendations for the 2 treatment to prevent
the study was limited by inclusion questions, as derived from the hyperbilirubinemia-associated
of multiple nonrandomized studies, systematic reviews and evidence harm.1
PEDIATRICS Volume 150, number 3, September 2022 41

by guest
ACKNOWLEDGMENTS Nationwide Children’s Hospital,
We thank librarians Susi Miller, Teri Columbus, Ohio.
Ballard, and Allison Erlinger at
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2022 by the American Academy of Pediatrics
FUNDING: No external funding.
FINANCIAL/CONFLICT OF INTEREST DISCLOSURES: Dr Newman reported providing expert witness consultation in medical malpractice litigation. No other
disclosures were reported.
REFERENCES 8. Newman TB, Liljestrand P, Jeremy RJ, https://www.aap.org/en-us/

1. Kemper AR, Newman TB, Slaughter JL, et al; Jaundice and Infant Feeding Study professional-resources/quality-
et al. Clinical practice guideline revision: Team. Outcomes among newborns with improvement/clinical-practice-
Management of hyperbilirubinemia in the total serum bilirubin levels of 25 mg guideline-manual/Pages/default.aspx.
per deciliter or more. N Engl J Med. Accessed May 30, 2019
newborn infant 35 or more weeks of ges-
tation. Pediatrics. 2022;150(3):e2022058859
2006;354(18):1889–1900 15. Auger N, Laverdiere C, Ayoub A, Lo E,
9. Gamaleldin R, Iskander I, Seoud I, et al. Luu TM. Neonatal phototherapy and
2. Maisels MJ, Baltz RD, Bhutani VK, et al;
Risk factors for neurotoxicity in new- future risk of childhood cancer. Int
American Academy of Pediatrics Subcom- J Cancer. 2019;145(8):2061–2069
borns with severe neonatal hyperbiliru-
mittee on Hyperbilirubinemia. Manage-
binemia. Pediatrics. 16. Newman TB, Wickremasinghe AC, Walsh
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newborn infant 35 or more weeks of EM, Grimes BA, McCulloch CE, Kuznie-
10. Vandborg PK, Hansen BM, Greisen G, wicz MW. Retrospective cohort study of
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TECHNICAL REPORT Guidance for the Clinician in Rendering Pediatric Care

Technical Report: Diagnosis and

CONTEXT: Severe hyperbilirubinemia is associated with kernicterus. Informed abstract

2 FROM THE AMERICAN ACADEMY OF PEDIATRICS

PEDIATRICS Volume 150, number 3, September 2022 3

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