Received: 29 September 2022 | Accepted: 11 January 2023
DOI: 10.1002/jhm.13046
PROGRESS NOTES
Clinical progress note: Revisions to the management
of neonatal hyperbilirubinemia
Danni Liang MD1 | Michelle D. Veters MD2
1
Division of Pediatric Hospital Medicine, Stanford University School of Medicine, Palo Alto, California, USA
2
Division of Pediatric Hospital Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
Correspondence: Danni Liang, MD, Division of Pediatric Hospital Medicine, Stanford University School of Medicine, Palo Alto, CA, USA.
Email: dannil@stanford.edu; Twitter: @dxl273
I NTR O D U C TI O N
Over 80% of newborns have jaundice.1,2 While this is typically benign,
those with high bilirubin concentrations, or hyperbilirubinemia, are at risk
of severe and permanent sequelae. Minimizing the risk of acute bilirubin
encephalopathy and the permanent disabling neurologic consequences of
kernicterus requires careful monitoring and appropriate treatment of
hyperbilirubinemia.3,4 The aim of generating guidelines for neonatal
hyperbilirubinemia is to reduce the incidence of severe hyperbilirubinemia
and kernicterus while minimizing unintended consequences such as
reduced breastfeeding, familial anxiety, and any unnecessary costs and/or
treatment.5 Since the advent of the 2004 guidelines recommending
adoption of universal bilirubin screening during birth hospitalization, the
incidence of severe hyperbilirubinemia has decreased.6–8 However, this
recommendation also led to an increase in phototherapy use, which
recent large cohort studies demonstrate a potential risk for patient harm.9
New literature regarding safe phototherapy thresholds and risk assess-
ments for escalation of care, universal bilirubin screening procedures,
hyperbilirubinemia and neurotoxicity risk factors, along with efforts to
eliminate race‐based medicine, generates the evidence for the new 2022
American Academy of Pediatrics (AAP) guideline revision.4,9,10 We
highlight key recommendations from the clinical guideline revision for
the pediatric hospitalist.
K EY REC OMME NDATIO NS
Risk factors for significant hyperbilirubinemia
and neurotoxicity
It is essential to identify the risk factors for hyperbilirubinemia and the risk
factors for neurotoxicity, which have been modified from prior guidelines.
Significant changes in the hyperbilirubinemia risk factors include removal
of race and replacement with family or genetic history of hemolytic
disease (i.e., glucose‐6‐phosphate dehydrogenase [G6PD] deficiency) and
the increasing risk for each additional week below <40 weeks gestation.
530 | © 2023 Society of Hospital Medicine wileyonlinelibrary.com/journal/jhm
Risk factors for neurotoxicity have also been adjusted: gestational age
<38 weeks, albumin <3.0 grams/deciliter, sepsis, significant clinical
instability in the prior 24 h (which replaces asphyxia, lethargy, tempera-
ture instability, and acidosis), and isoimmune hemolytic disease (i.e.,
positive direct antiglobulin test [DAT]), G6PD deficiency, or other
hemolytic conditions.3,4 Infants with hyperbilirubinemia risk factors
necessitate closer monitoring (see fig. 1 of the AAP guideline revision
for a detailed bilirubin measurement schedule for DAT‐positive infants),
and those with neurotoxicity risk factors have lower thresholds for
phototherapy and escalation of care (Tables 1 and 2).
Monitoring for hyperbilirubinemia
Infants should be visually assessed for jaundice at least every 12 h
from birth until hospital discharge. For any infant who is jaundiced
<24 h after birth, the total serum bilirubin (TSB) or transcutaneous
bilirubin (TcB) should be measured as soon as possible since these
infants are more likely to have a hemolytic cause of their jaundice.4,5
Most infants will not have any visible jaundice and only require a TSB
or TcB between 24 h and 48 h after birth or before discharge from the
birth hospital. TSB is the definitive test to guide phototherapy or
escalation‐of‐care because it is independent of factors like skin
melanin concentration, and should be obtained if the TcB is within
3 mg/dL of the phototherapy threshold or if the TcB is ≥15 mg/dL.4
Phototherapy
Compared with the previous guideline, intensive phototherapy is now
recommended at higher TSB thresholds due to new evidence that the
risk of neurotoxicity occurs well above the 2004 AAP exchange
transfusion thresholds.11–13 These new thresholds contain recom-
mendations up to 14 days of age and are made on expert
recommendations with consideration to the gestational age, age of
the infant (in hours), updated neurotoxicity risk factors, and adjust for
J. Hosp. Med. 2023;18:530–533.
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LIANG AND VETERS | 531

postnatal age as demonstrated by thresholds for infants 35–39
weeks gestation slanting upwards over time.3–5 Table 1 provides
recommendations based on infants with no known hyperbilirubine-
mia neurotoxicity risk factors, whereas Table 2 is used for infants with
at least 1 neurotoxicity risk factor other than gestational age. Families
and providers may opt to use lower thresholds with consideration of
4
individual circumstances.
A hemoglobin, hematocrit, or complete blood count should be
obtained for all infants requiring phototherapy to assess for anemia
and to provide a baseline prior to initiating phototherapy. A DAT
should also be obtained for those with a positive or unknown
maternal antibody screen or whose mother is blood type O.4,5
The TSB should be measured within 12 h of starting photo-
therapy for hospitalized patients. The patient's age, presence of
neurotoxicity risk factors, TSB concentration, and TSB trajectory
should guide the frequency of TSB monitoring during phototherapy.
If an infant has a rapid rate of increase (≥0.3 mg/dL/h in the first 24 h
or ≥0.2 mg/dL/h thereafter), it may be due to a hemolytic condition
and DAT should be measured. G6PD activity should be measured for
infants with suspected hemolysis of unknown cause.4,14

T A B L E 1 Phototherapy thresholds and exchange transfusion thresholds for infants with no neurotoxicity risk factors from the American
Academy of Pediatrics (AAP) Guideline Revision.4
Age in hours (AH)
12 AH 24 AH 36 AH 48 AH 72 AH 96 AH 120 AH

Gestational age 35 weeks 8.5 10.6 12.5 14.2 16.8 18.6 18.7
(weeks)
16.3 18.0 19.3 20.7 22.9 24.5 24.7

36 weeks 9.0 7.4 13.1 14.8 17.5 19.3 19.4

17.5 15.2 20.6 21.9 24.1 25.6 25.7

37 weeks 9.6 8.0 13.6 15.4 18.1 20.0 20.2

18.7 15.7 21.8 23.1 25.3 26.6 26.8

38 weeks 10.1 8.5 14.2 16.0 18.8 20.7 20.9

19.7 16.2 22.8 24 26 27 27

39 weeks 10.6 8.5 14.8 16.6 19.5 21.5 21.6

19.7 16.2 22.8 24 26 27 27

≥40 weeks 11.1 8.5 15.3 17.0 19.8 21.8 21.8

19.7 16.2 22.8 24 26 27 27

Note: Numbers in each large cell reflect the phototherapy threshold (top) and exchange transfusion threshold (bottom); all threshold values are displayed
in units of milligrams/deciliter (mg/dL).

T A B L E 2 Phototherapy thresholds and exchange transfusion thresholds for infants with 1+ neurotoxicity risk factors other than gestational
age from the American Academy of Pediatrics (AAP) Guideline Revision.4
Age in hours (AH)
12 AH 24 AH 36 AH 48 AH 72 AH 96 AH 120 AH

Gestational age 35 weeks 6.9 8.9 10.6 12.2 14.6 16.1 16.3
(weeks)
14.6 16.1 17.4 18.5 20.1 21.1 21.3

36 weeks 7.4 9.4 11.2 12.8 15.4 17 17.1

15.2 16.7 17.9 19.1 20.9 22.1 22.1

37 weeks 8.0 10 11.9 13.5 16.1 17.9 18

15.7 17.2 18.5 19.7 21.7 23.1 23.3

≥38 weeks 8.5 10.5 12.4 14 16.6 18.2 18.2

16.2 17.6 19.0 20.1 22.1 23.5 23.5

Note: Numbers in each large cell reflect the phototherapy threshold (top) and exchange transfusion threshold (bottom); all threshold values are displayed
in units of milligrams/deciliter (mg/dL).

532 | CLINICAL PROGRESS NOTE: NEONATAL HYPERBILIRUBINEMIA
Infants should continue feeding to promote bilirubin clear-
ance and avoid dehydration. When possible, breast milk is
encouraged for its health benefits and to maintain the mother's
supply. Adequately hydrated breastfed infants should not
routinely receive formula supplementation.4 Brief supplementa-
tion with formula may be considered to assist in declining
bilirubin levels more rapidly and reduce the risk of readmission
for phototherapy in some clinical scenarios. 4,5 Intravenous fluids
are not recommended unless hydration cannot be maintained
enterally or if escalation‐of‐care is needed.4 Further workup and/
or neonatology consultation is recommended for infants requiring
escalation‐of‐care, whose bilirubin is not responding appropri-
ately to phototherapy, and those with direct or conjugated
4
hyperbilirubinemia.
Escalation‐of‐care
When the TSB reaches or exceeds 2 mg/dL below the exchange
transfusion threshold (Tables 1 and 2), escalation‐of‐care should be
initiated. These infants should receive intravenous hydration,
emergent intensive phototherapy, and neonatology consultation
regarding exchange transfusion.4 A STAT total and direct bilirubin,
complete blood count, albumin, chemistries, and type and crossmatch
should be obtained for all infants requiring escalation‐of‐care. The
TSB should be measured at least every 2 h from the start to the end
of the escalation‐of‐care period. Return to regular phototherapy
management is appropriate once the TSB is below the escalation‐of‐
care threshold.4
Discontinuation of phototherapy
Phototherapy may be discontinued when the TSB is “at least 2 mg/dL
below the hour‐specific threshold at the initiation of phototherapy.”4
For patients with risk factors for rebound hyperbilirubinemia (e.g.,
gestational age <38 weeks, <48 h of life at initiation of phototherapy,
hemolytic disease, phototherapy during birth hospitalization), longer
durations of phototherapy are an option.
A follow‐up bilirubin level after phototherapy may be
indicated depending on the risk of rebound hyperbilirubinemia.
Infants who exceeded the phototherapy threshold during birth
hospitalization should have a repeat bilirubin level 1 day after
discontinuation of phototherapy. Those who exceeded the
phototherapy threshold and had additional risk factors (i.e.,
phototherapy prior than 48 h of age, positive DAT, suspected or
known hemolytic disease) should have a repeat TSB 6‐12 h and 1
day after discontinuation of phototherapy.4 Infants who did not
receive phototherapy during their birth hospitalization but
exceeded the phototherapy threshold after discharge should
either have their bilirubin level measured 1–2 days after
discontinuation of phototherapy or clinical follow‐up within
1–2 days after phototherapy to determine whether a bilirubin
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level is needed.4 Physician assessment of the necessity in
obtaining a bilirubin level should consider the infant's hyperbilir-
ubinemia and neurotoxicity risk factors, oral intake, weight gain,
and relationship of TSB to phototherapy threshold at the time of
discontinuation. The TcB may be measured instead of TSB if
phototherapy has been discontinued for at least 24 h.4
Follow‐up for infants who have not received
phototherapy
Timing of post‐discharge follow‐up is determined by the age of the
infant and the difference between the phototherapy threshold and
TSB/TcB measurement,4 allowing the clinician to individualize care
and incorporate both the gestational age and neurotoxicity risk
factors into management decisions. It is important to note that the
discharge recommendations in fig. 7 of the AAP guideline revision
apply only to infants at least 12 h of age who have not received
phototherapy. For infants <12 h of age, repeat bilirubin should be
obtained at 24–48 h of age.4
LIMITA TION S
Limitations of this guideline are the lack of specific guidance in lab
monitoring frequency after the initiation of phototherapy, general-
izability to low‐resource countries, and considerations of barriers to
care (e.g., proximity to a provider, ability to perform home
phototherapy, and socioeconomic limitations).
CONCLUSIONS
The AAP guideline revision represents important changes in
the risk assessment and management of hyperbilirubinemia that
present opportunities for resource stewardship through
decreased overdiagnosis and overtreatment while balancing the
risk of severe sequelae such as acute bilirubin encephalopathy
and kernicterus. Additionally, the revised guidelin removes
fallacies in race‐based recommendations and highlights the
importance of the mother‐infant relationship. Use of this
clinical guideline may decrease unnecessary hospitalizations
while recognizing those at higher risk of severe
hyperbilirubinemia.
CONFLIC T OF INTEREST STATEM ENT
The authors declare no conflict of interest.
ORC I D
Danni Liang http://orcid.org/0000-0001-7048-9620
TW I TT ER
Danni Liang @dxl273

LIANG AND VETERS
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How to cite this article: Liang D, Veters MD. Clinical
progress note: Revisions to the management of neonatal
hyperbilirubinemia. J Hosp Med. 2023;18:530‐533.
doi:10.1002/jhm.13046