Your activity: 288 p.v.
your limit has been reached. plz Donate us to allow your ip full access, Email: sshnevis@outlook.com

Screening for hyperbilirubinemia in term and late preterm newborn infants

Screening for hyperbilirubinemia in term and late preterm newborn infants
Authors:
Ronald J Wong, BA
Vinod K Bhutani, MD, FAAP
Section Editor:
Steven A Abrams, MD
Deputy Editor:
Laurie Wilkie, MD, MS
Literature review current through: Dec 2022. | This topic last updated: Oct 26, 2022.

INTRODUCTION — Nearly all newborn infants develop elevated bilirubin levels (ie, total serum or plasma bilirubin [TSB] >1 mg/dL [17 micromol/L], which is the upper limit of normal for adults). As TSB levels increase, the newborn may develop visible jaundice. Newborns with severe hyperbilirubinemia (defined as TSB >25 mg/dL [428 micromol/L] in term and late preterm newborns [gestational age ≥35 weeks]) are at risk for developing bilirubin-induced neurologic disorders (BIND). It is important to identify newborns at risk for severe hyperbilirubinemia and to provide timely and appropriate preventive therapy, if warranted.

This topic will discuss screening for unconjugated hyperbilirubinemia in term and late preterm newborns, including the approach to identifying newborns at risk for severe or progressive hyperbilirubinemia. Other related issues are discussed separately:

Pathogenesis and etiology of neonatal hyperbilirubinemia (see "Etiology and pathogenesis of neonatal unconjugated hyperbilirubinemia")

Risk factors, clinical manifestations, and neurologic complications of neonatal hyperbilirubinemia (see "Risk factors, clinical manifestations, and neurologic complications of neonatal unconjugated hyperbilirubinemia")

Management of neonatal hyperbilirubinemia (see "Initial management of unconjugated hyperbilirubinemia in term and late preterm newborns" and "Escalation of care for term and late preterm newborns with unconjugated hyperbilirubinemia")

Hyperbilirubinemia in preterm infants (gestational age [GA] <35 weeks) (see "Unconjugated hyperbilirubinemia in preterm infants <35 weeks gestation")

Conjugated (direct) hyperbilirubinemia in neonates (see "Causes of cholestasis in neonates and young infants")

DEFINITIONS — The following terms are used throughout this topic:

Benign neonatal hyperbilirubinemia is a transient and normal increase in bilirubin levels occurring in nearly all newborn infants. It was previously referred to as "physiologic jaundice."

Severe neonatal hyperbilirubinemia is defined as total serum or plasma bilirubin (TSB) >25 mg/dL (428 micromol/L). It is associated with an increased risk for developing bilirubin-induced neurotoxicity.

Extreme neonatal hyperbilirubinemia is defined as TSB >30 mg/dL (513 micromol/L). It is associated with an increased risk for developing bilirubin-induced neurotoxicity, including irreversible chronic encephalopathy.

Bilirubin-induced neurologic disorders (BIND) result from free (or unbound) bilirubin crossing the blood-brain barrier and binding to brain tissue. The spectrum of neurotoxic injury, including subtle dysfunction and acute and chronic bilirubin encephalopathy (ABE and CBE, respectively), is collectively referred to as BIND. The manifestations of BIND, ABE, and CBE are described separately. (See "Risk factors, clinical manifestations, and neurologic complications of neonatal unconjugated hyperbilirubinemia", section on 'Consequences of severe hyperbilirubinemia'.)

Assessment of neonatal hyperbilirubinemia is based upon total bilirubin rather than unconjugated bilirubin levels alone because neonatal hyperbilirubinemia is mostly due to increased bilirubin production, resulting primarily in unconjugated bilirubin that can be exacerbated by conditions causing impaired bilirubin elimination. Cholestasis, which presents with primarily elevated conjugated (direct) bilirubin, is a rare cause of neonatal hyperbilirubinemia. (See "Etiology and pathogenesis of neonatal unconjugated hyperbilirubinemia" and "Causes of cholestasis in neonates and young infants".)

BENEFITS OF SCREENING — We agree with the guidelines of the American Academy of Pediatrics (AAP) and the Canadian Paediatric Society (CPS), which recommend universal bilirubin screening before discharge in all term and late term newborns to identify newborns at risk for developing severe hyperbilirubinemia [1,2]. Links to these and other society guidelines are provided separately. (See 'Society guideline links' below.)

Rationale for screening — The rationale for screening all newborns for hyperbilirubinemia during the birth hospitalization is based upon the following:

Hyperbilirubinemia is common in newborns, with nearly all neonates having total serum or plasma bilirubin (TSB) levels above the upper limit of normal for older children and adults. Severe hyperbilirubinemia (defined as TSB >25 mg/dL [428 micromol/L]) is far less common. However, before bilirubin screening was a routine part of newborn care, approximately 1 in 600 newborns developed severe hyperbilirubinemia. The incidence has declined considerably with routine screening, presumably due to identifying and treating at-risk newborns (figure 1). Additional details regarding the epidemiology of neonatal hyperbilirubinemia, including incidence and trends over time, are provided separately. (See "Risk factors, clinical manifestations, and neurologic complications of neonatal unconjugated hyperbilirubinemia", section on 'Epidemiology'.)

If severe hyperbilirubinemia is not detected and treated in a timely manner, bilirubin may progress to extreme levels (TSB >30 mg/dL [513 micromol/L]), and consequences can be dire (ie, severe permanent neurologic injury). (See 'Consequences of hyperbilirubinemia' below and "Risk factors, clinical manifestations, and neurologic complications of neonatal unconjugated hyperbilirubinemia", section on 'Consequences of severe hyperbilirubinemia'.)

Universal screening aims to identify newborns who are at risk for developing severe hyperbilirubinemia so that treatment can be initiated before the newborn develops adverse consequences. (See 'Approach to screening' below and "Initial management of unconjugated hyperbilirubinemia in term and late preterm newborns".)

Supporting evidence — Evidence supporting universal newborn bilirubin screening comes from observational studies demonstrating that routine screening before discharge reduces the risk of severe hyperbilirubinemia (figure 1) [3-7]. Universal screening also appears to reduce hospital readmissions for neonatal hyperbilirubinemia [8,9].

Direct evidence is lacking to conclusively show that screening reduces the adverse consequences of hyperbilirubinemia (bilirubin-induced neurologic disorders [BIND]). However, indirect data suggest a strong link between severe hyperbilirubinemia and BIND [10,11]. Thus, it is reasonable to expect that reducing the incidence of severe hyperbilirubinemia will reduce the incidence of BIND.

In a clinical trial from South Africa involving 1858 healthy term and late preterm newborns who were randomly assigned to predischarge transcutaneous bilirubin screening or standard care (visual inspection for jaundice only), screening reduced the readmission rate for neonatal hyperbilirubinemia (1.4 versus 5.6 percent; relative risk [RR] 0.25, 95% CI 0.14-0.46) and reduced the incidence of severe hyperbilirubinemia (0.3 versus 1.2 percent; RR 0.27, 95% CI 0.08-0.97) [9]. Use of phototherapy during the birth hospitalization was higher in the screening group (5.2 versus 1.9 percent). Only two newborns in the trial required exchange transfusion (both in the standard care group). One newborn in the standard care group developed clinical evidence of BIND.    

Observational studies comparing universal screening with a selective testing strategy (ie, testing based upon the extent of visible jaundice and/or risk factors for hyperbilirubinemia) have generally reported that universal screening is more effective in reducing severe hyperbilirubinemia. In a large retrospective study of late preterm and term newborns, the incidence of hyperbilirubinemia exceeding the AAP-recommended threshold for exchange transfusion was lower in birth facilities that had implemented universal screening compared with facilities using a selective testing strategy (0.17 versus 0.45 percent) [4].

In another large multicenter study, the incidence of severe hyperbilirubinemia decreased after the implementation of universal screening compared with pre-implementation historical controls (0.02 versus 0.07 percent) [8]. In addition, the rate of hospital readmissions for neonatal hyperbilirubinemia decreased after implementation of universal screening.

HARMS OF SCREENING — The benefits of screening must be weighed against the potential downsides, which include:

Additional blood draws – Some newborns may require additional laboratory testing and blood draws, which can cause pain and discomfort to the newborn and may or may not ultimately lead to specific intervention or other benefit to the patient.    

Falsely concerning results (false positives) – For newborns screened using transcutaneous bilirubin (TcB) devices, there is a risk that the TcB value may overestimate the true total serum or plasma bilirubin (TSB) level. This may result in additional validation testing and, in some cases, potentially unnecessary treatment. This is a particular concern in newborns with darkly pigmented skin, for whom TcB can overestimate TSB, as discussed below. (See 'Transcutaneous bilirubin (TcB)' below.)

Falsely reassuring results (false negatives) – TcB can also underestimate TSB levels, which may lead to delays in appropriate treatment for hyperbilirubinemia. Even when results are accurate, reassuring screening results (bilirubin level well below the threshold for treatment) may falsely reassure parents/caregivers and healthcare providers that the newborn is not at risk of subsequently developing significant hyperbilirubinemia. The parents/caregivers may be less likely to seek care if the newborn becomes jaundiced and healthcare providers may be less likely to recheck bilirubin levels since the initial value was normal. This is a particular concern in newborns who undergo screening and are discharged from the birth hospitalization early after birth (within the first 24 to 48 hours) and those with glucose-6-phosphate dehydrogenase (G6PD) deficiency, for whom neonatal hyperbilirubinemia can be prolonged. For all newborns, it is imperative to ensure timely follow-up and to provide clear discharge instructions about when to seek care. (See 'Subsequent evaluation and management' below and 'Outpatient follow-up' below.)

Unnecessary treatments – In theory, it is possible that some newborns with TSB levels above the treatment threshold could have spontaneous resolution of the hyperbilirubinemia during the first week after birth without intervention and without ever reaching a dangerous level. While the trajectory of hyperbilirubinemia can be predicted to some extent based upon risk factors (eg, lower gestational age [GA], hemolysis), these predictions are imperfect. Nevertheless, the treatment thresholds established by the American Academy of Pediatrics (AAP) are intended to reflect the point at which the benefits of phototherapy likely exceed its potential harms, taking into account the hour-specific TSB level, GA, and risk of bilirubin neurotoxicity [1]. These thresholds are based largely on expert opinion rather than high-certainty evidence. The potential harms of phototherapy are discussed separately. (See "Initial management of unconjugated hyperbilirubinemia in term and late preterm newborns", section on 'Adverse effects'.)

Parent/caregiver anxiety and interference with establishing breastfeeding – Parents/caregivers may experience increased worry and anxiety if their newborn requires additional blood testing. In addition, treatment may interfere with establishing breastfeeding.

Increased costs – The costs associated with newborn bilirubin screening are generally low, but may be a limitation in resource-constrained settings. Cost-effectiveness studies performed in the current era suggest that while the approach of universal screening increases costs during the birth hospitalization and post-discharge follow-up visits, these costs are partially offset by reduced costs from fewer emergency room visits, hospital readmissions, and long-term care associated with potential complications of hyperbilirubinemia (ie, chronic bilirubin encephalopathy [CBE, previously called kernicterus]) [12,13].

CONSEQUENCES OF HYPERBILIRUBINEMIA — The most severe consequence of neonatal hyperbilirubinemia is bilirubin neurotoxicity caused by free (or unbound) bilirubin crossing the blood-brain barrier and binding to brain tissue (figure 2). The spectrum of neurotoxic injuries, collectively referred to as bilirubin-induced neurologic disorders (BIND), ranges from subtle findings of neurologic dysfunction to severe permanent disability. (See "Risk factors, clinical manifestations, and neurologic complications of neonatal unconjugated hyperbilirubinemia", section on 'Bilirubin-induced neurologic disorders (BIND)'.)

Acute bilirubin encephalopathy (ABE) – ABE refers to acute signs of neurotoxicity in a newborn with severe persistent hyperbilirubinemia. Clinical findings may be subtle initially (sleepiness, mild hypotonia, high-pitched cry). Without intervention, ABE can progress to more severe manifestations (apnea, seizures, severe hypertonia) and ultimately to coma or death (table 1). ABE may be reversible, but if the high total serum or plasma bilirubin (TSB) level is not addressed promptly, it may result in permanent irreversible neurologic dysfunction. (See "Risk factors, clinical manifestations, and neurologic complications of neonatal unconjugated hyperbilirubinemia", section on 'Acute bilirubin encephalopathy (ABE)'.)

Chronic bilirubin encephalopathy (CBE) – CBE (formerly called kernicterus) is a permanent post-icteric brain injury characterized by choreoathetoid cerebral palsy, sensorineural hearing loss, gaze palsies, and other chronic neurologic impairments. (See "Risk factors, clinical manifestations, and neurologic complications of neonatal unconjugated hyperbilirubinemia", section on 'Chronic bilirubin encephalopathy (kernicterus)'.)

The most important risk factor for BIND is the severity and duration of bilirubin exposure. The risk is highest when TSB is ≥30 mg/dL. Additional risk factors are summarized in the table (table 2) and discussed separately. (See "Risk factors, clinical manifestations, and neurologic complications of neonatal unconjugated hyperbilirubinemia", section on 'Risk factors for neurotoxicity'.)

APPROACH TO SCREENING — The approach to identifying and treating newborns at risk for severe hyperbilirubinemia should be systematic [1]. We suggest performing bilirubin screening in all term and late preterm newborns prior to discharge. Screening can be performed using either a transcutaneous bilirubin (TcB) device or a laboratory total serum or plasma bilirubin (TSB) measurement. The bilirubin level is used in conjunction with assessment of the risk for development of severe hyperbilirubinemia to determine the need for further evaluation and treatment. (See 'Interpretation of bilirubin testing' below and 'Subsequent evaluation and management' below.)

Newborn bilirubin screening involves the following steps, each of which is described in greater detail in the sections below:

Perform TSB or TcB measurements at 24 to 48 hours after birth or before discharge, whichever is sooner. Newborns with visible jaundice in the first 24 hours after birth or certain other risk factors for early severe hyperbilirubinemia must be tested sooner. (See 'Bilirubin testing methods' below and 'Timing of screening' below.)

Determine the hour-specific TSB threshold for phototherapy based upon the newborn's gestational age (GA), postnatal age, and risk factors for neurotoxicity (figure 3A-B). (See 'Risk assessment' below and 'Interpretation of bilirubin testing' below.)

If screening was performed with a TcB measurement and the value is >15 mg/dL (257 micromol/L) or is within 3 mg/dL (51 micromol/L) of the phototherapy threshold, confirm with a TSB measurement. The decision to begin phototherapy is based upon the TSB value. (See 'Transcutaneous bilirubin (TcB)' below.)

If the newborn's TSB is at or above the phototherapy threshold, begin treatment urgently. (See "Initial management of unconjugated hyperbilirubinemia in term and late preterm newborns".)

If the newborn's bilirubin level is below the phototherapy threshold, calculate the difference between the hour-specific TSB phototherapy threshold and newborn's bilirubin level. Decisions regarding timing and need for follow-up testing are based upon this difference (table 3). (See 'Interpretation of bilirubin testing' below and 'Subsequent evaluation and management' below.)

Bilirubin testing methods

Advantages and disadvantages of the tests — Bilirubin screening can be performed noninvasively with a TcB device or with a laboratory measurement of TSB, which requires a blood draw. In our center, we use TSB; however, other centers predominantly rely on TcB.

A TSB measurement is the gold standard for assessing neonatal bilirubin levels and its main advantage is that it is more accurate, particularly at high bilirubin levels. In addition, it is not impacted by skin pigmentation. Its main disadvantage is that it requires a blood draw. However, if the TSB is obtained at the time of routine metabolic screening, no additional blood draw is necessary. (See 'Total serum or plasma bilirubin (TSB)' below.)

The advantages of using a TcB device are that it does not require a blood draw, it reduces laboratory costs, and it can be used to track the trend of TSB trajectory. TcB only estimates TSB and therefore it can be used as a screening tool to identify newborns who should have a TSB level measured in the laboratory. (See 'Transcutaneous bilirubin (TcB)' below.)

TcB and TSB should not be used interchangeably. If therapeutic interventions are being considered, a TcB measurement must be confirmed with a TSB measurement [1]. (See 'When to confirm with TSB' below.)

Total serum or plasma bilirubin (TSB) — TSB can be measured in the laboratory or with a point-of-care analyzer. Both methods can be performed on small-volume blood samples (≤0.3 mL), which are obtainable via a heel-stick.

Clinical laboratory testing – Analyzers used in core clinical laboratories directly measure TSB via a chemical reaction (diazo method) or spectrophotometrically. These methods are the gold standard for TSB measurement. The hour-specific percentile-based nomograms used in the 2022 American Academy of Pediatrics (AAP) clinical practice guideline are based upon TSB measurements performed by chemical laboratory analyzers utilizing the diazo method [1,3].

Interlaboratory and inter-instrument variabilities in TSB measurements have been reported [14,15]. The variability for TSB measurements within a given laboratory is usually <6 percent. It is important that laboratories perform routine quality assurance and proficiency testing, as changes, including recalibration of bilirubin assays, can result in clinically significant measurement error. This was illustrated by a study demonstrating the effects of a recalibration of a commercially-available assay that resulted in reductions in the need for phototherapy during birth hospitalizations and fewer readmissions for phototherapy [16].

Point-of-care testing – Point-of-care analyzers measure TSB spectrophotometrically and require minimal blood volumes (eg, capillary sample by heelstick). Many of these devices can simultaneously perform other tests (eg, blood gas analysis, blood electrolyte levels) on a single sample.

TSB measurements on these devices generally correlate well with standard laboratory analyzers, but they are less accurate when TSB is elevated. At TSB >14.6 mg/dL (250 micromol/L), these devices may underestimate TSB, and the values should be confirmed with standard core laboratory methods [17,18]. However, if the point-of-care TSB level is markedly elevated, phototherapy should be initiated while awaiting confirmatory results from the laboratory.

Additional details of bilirubin measurement are provided separately. (See "Clinical aspects of serum bilirubin determination", section on 'Measurement of serum bilirubin'.)

Transcutaneous bilirubin (TcB) — TcB measurement is performed using a hand-held device that emits light at different wavelengths and measures the difference in optical densities of light reflected back from the skin [1,19]. Although TcB measurements do not directly measure TSB, they are valid and reliable when used to screen and identify newborns who require further evaluation.

TcB devices should be used in accordance with each specific manufacturer's instructions. Generally, the forehead is the most convenient site for testing. Exposure to sunlight can impact TcB device accuracy. Therefore, in outpatient settings, when a newborn has had prior exposure to sunlight, the sternum is the preferred site since it usually has been covered. Concurrent TcB measurements at the umbilical area, iliac crests, knees, and ankles/wrists can sometimes be useful to track the progression of jaundice.  

Advantages — The advantages of using TcB for screening are that it can be performed relatively quickly, results are available immediately, it does not require a blood draw, and it may be less costly compared with TSB measurements [4,7,12,20-22].

The use of TcB for screening reduces the number of blood tests for bilirubin measurement without compromising detection of at-risk newborns [7,12,23,24].

Accuracy — There is generally a good correlation between TcB and TSB (typically within 2 to 3 mg/dL [34 to 51 micromol/L]) when the TSB level is <15 mg/dL (257 micromol/L) [20,25-28]. At TSB levels ≥15 mg/dL, TcB can substantially under- or overestimate TSB. For markedly elevated TSB levels (ie, TSB is >20 mg/dL [342 micromol/L]), many TcB devices will report "error" instead of a bilirubin value.

The magnitude and direction of the difference between TcB and TSB varies, depending on [1]:

Device used – There can be significant variability between different TcB devices, even when using the same manufacturer [27,29]. Thus, it is important that for an individual newborn, the same device is used to measure TcB levels over the course of an individual newborn's hospital stay [30]. This can be challenging if different TcB devices are used in the same care unit. In addition, when a new device is initially put into routine clinical use, its measurements should be compared with TSB levels performed in the laboratory to ensure good correlation.

Skin pigmentation – Skin pigmentation affects light reflectance which can potentially impact the accuracy of TcB readings because. Different methodologies have been developed by TcB device manufacturers to minimize this effect. However, these methods are not perfect.

TcB generally overestimates TSB in newborns with darker skin pigmentation and underestimates TSB in newborns with lighter pigmented skin [20,21,27,31-33]. In a study that evaluated 925 paired TcB and TSB levels in healthy newborns, the mean difference between the two values among African-American newborns was 1.51 mg/dL (26 micromol/L) compared with 0.84 (14 micromol/L) for the entire cohort [27]. A similar study that compared >2000 pairs of TcB and TSB measurements in Black African newborns found that TcB overestimated TSB by ≥3 mg/dL (51 micromol/L) in 43 percent of newborns [33]. These findings suggest that TcB values should be interpreted with caution in newborns with darker skin pigmentation. Nevertheless, TcB screening appears to perform better than visual assessment alone [9].

Exposure to sunlight or phototherapy – TcB accuracy is reduced with prior exposure to sunlight or phototherapy [34,35]. Some manufacturers have suggested covering an area of skin with a patch to protect it from exposure to sunlight if the newborn is in a sunny room. However, it is unclear if this is an effective strategy to mitigate this issue. TcB should not be used in newborns receiving phototherapy. (See "Initial management of unconjugated hyperbilirubinemia in term and late preterm newborns", section on 'Monitoring during phototherapy'.)

A systematic review identified 54 studies assessing the accuracy of TcB using various device compared with TSB measurements [28]. TcB cut-off values and thresholds to define hyperbilirubinemia varied considerably in the different studies. The reported sensitivity of TcB for predicting TSB ranged from 68 to 100 percent and specificity ranged from 21 to 88 percent.

Nomograms in different populations — For most of the commercially available TcB devices, nomograms have been developed that define the range of normal values and the 75th and 95th percentiles according to postnatal age [22,36-39]. Many of the available studies were performed in populations that included predominantly breastfed White newborns. However, there are available data across different racial and ethnic groups and regions of the world [22,36-48]. Systematic reviews of these studies have found that TcB nomograms vary across different populations, though all demonstrate an hourly progression to peak levels at ages three to five days and a transient plateau that is subsequently followed by decline [40,49]. Possible explanations for the variability among different studies include variability in skin pigmentation, differences in breastfeeding practices, genetic factors (eg, prevalence of glucose-6-phosphate deficiency or Gilbert syndrome in the study population), and differences in study design (eg, enrollment criteria, TcB device used).

When to confirm with TSB — TcB measurements should be confirmed with TSB measurements in the following situations [1,17,48,50-52]:  

When therapeutic interventions are being considered (phototherapy or exchange transfusion); however, phototherapy can be initiated while awaiting confirmatory TSB results.

If TcB is within 3 mg/dL (51 micromol/L) of the phototherapy threshold (figure 3A-B).

If TcB is >15 mg/dL (257 micromol/L).

If the TcB device reports an "error" message or if there is any question regarding the validity of the TcB measurement.

TcB measurements are not reliable in patients undergoing phototherapy and should not be used in this setting [1,53,54]. Management decisions regarding phototherapy should be guided by TSB values. (See "Initial management of unconjugated hyperbilirubinemia in term and late preterm newborns", section on 'Initial intervention (phototherapy)'.)

Other methods

Smart phone applications – There are a growing number of direct-to-consumer applications that are available on smart phones and other devices to assess newborn jaundice [55-57]. Most of these applications assess how yellow the newborn's sclerae or skin are using the smart phone’s digital camera. Further validation of these devices is needed before they can be recommended for routine use.

Color comparison charts – In resource-limited settings, color comparison charts or rulers are a low-cost alternative to TcB [58,59].

Timing of screening — The timing of the first bilirubin test depends upon whether the newborn has risk factors for developing early severe hyperbilirubinemia. (See 'Risk assessment' below.)

Indications for early screening – Newborns with any of the following warrant early testing [1]:

Newborns with positive direct antiglobulin test (DAT). TSB should be measured as part of the evaluation for alloimmune hemolytic disease, as discussed separately. (See "Alloimmune hemolytic disease of the newborn: Postnatal diagnosis and management", section on 'Evaluation'.)

Newborns with onset of visible jaundice within the first 24 hours after birth. This finding suggests an underlying hemolytic process. TSB measurement is appropriate in this setting.    

Newborns who have a first-degree relative with a heritable hemolytic disease (eg, glucose-6 phosphate dehydrogenase [G6PD] deficiency or hereditary spherocytosis).  

Routine screening – For all other newborns, TSB or TcB levels should be checked at 24 to 48 hours after birth or before discharge, whichever is sooner [1]. In our center, we obtain TSB levels in all newborns at the time of the newborn metabolic screen. (See "Newborn screening", section on 'When to obtain testing'.)

Clinical assessment — In addition to performing bilirubin testing, the clinician should clinically assess the newborn for risk factors for hyperbilirubinemia and visible jaundice.

Risk assessment — Newborns should be assessed for risk of developing severe or progressive hyperbilirubinemia and risk of developing bilirubin neurotoxicity. The newborn's predischarge TSB or TcB level is the strongest predictor. Other risk factors are summarized in the tables (table 2 and table 4) and are discussed in detail separately. (See "Risk factors, clinical manifestations, and neurologic complications of neonatal unconjugated hyperbilirubinemia", section on 'Risk factors'.)

Physical examination

Visual assessment for jaundice – All term and late preterm newborn infants should be routinely assessed during their birth hospitalization for the onset and progression of jaundice. Visual jaundice assessment should occur when vital signs are taken or at least every 12 hours as part of routine newborn management [1]. (See "Overview of the routine management of the healthy newborn infant".)

Newborns who develop jaundice within the first 24 hours of birth should undergo early TSB testing, as discussed above. (See 'Timing of screening' above.)

While visual assessment for jaundice remains an important part of the approach to assessing risk of severe hyperbilirubinemia and assessing progression, clinicians should recognize that visual assessment of jaundice is not a reliable way to estimate the degree of hyperbilirubinemia, as discussed separately. (See "Risk factors, clinical manifestations, and neurologic complications of neonatal unconjugated hyperbilirubinemia", section on 'Jaundice'.)

Other concerning physical findings:

Significant bruising (see "Neonatal birth injuries", section on 'Bruising and petechiae')

Cephalohematoma (see "Neonatal birth injuries", section on 'Cephalohematoma')

Findings concerning for Down syndrome (see "Down syndrome: Clinical features and diagnosis", section on 'Dysmorphic features')

Macrosomia (eg, in a newborn of a diabetic mother) (see "Infants of women with diabetes")

Feeding assessment — Exclusively breastfed newborns are at greater risk for developing hyperbilirubinemia due to suboptimal intake [1]. A feeding assessment, including frequency and quality of breastfeeding, and assessment of urine and stool output, should reviewed for every newborn. (See "Initiation of breastfeeding", section on 'Assessment of intake'.)

Family history — The family history and ancestry should be reviewed with particular attention to inherited hemolytic disorders such as G6PD deficiency. Clinicians should ask if the newborn's siblings or parents required treatment for jaundice in infancy. However, in many affected individuals, the family history is negative. Thus, inquiring about newborn's ancestry can inform risk. The prevalence of G6PD deficiency varies by region and ethnicity, with higher prevalence among Kurdish Jews; Black individuals from sub-Saharan Africa or Brazil; African-Americans; and people from Thailand, Sardinia, Greece, South China, and India (figure 4). (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)  

INTERPRETATION OF BILIRUBIN TESTING

Approach — Bilirubin values are interpreted relative to the hour-specific thresholds for treatment, which vary depending upon the newborn's gestational age (GA) and other risk factors for neurotoxicity (table 2) [1] (see "Initial management of unconjugated hyperbilirubinemia in term and late preterm newborns"):

Phototherapy thresholds – Total serum or plasma bilirubin (TSB) thresholds for initiating phototherapy are summarized in the figures:

In newborns without risk factors for neurotoxicity (other than GA) (figure 3A)

In newborns with at least one risk factor for neurotoxicity (other than GA) (figure 3B)

Exchange transfusion thresholds – Thresholds for exchange transfusion are summarized in the figures:

In newborns without risk factors for neurotoxicity (figure 5A)

In newborns with risk factors for neurotoxicity (figure 5B)

The predischarge bilirubin level can be used to guide subsequent management using the following steps:

Step 1 – Use the appropriate hour-specific nomogram to determine the hour-specific TSB threshold for phototherapy:

For newborns without risk factors for neurotoxicity (other than GA) (figure 3A)

For newborns with one or more risk factor for neurotoxicity (other than GA) (figure 3B)  

Step 2 – If the newborn's predischarge bilirubin level is at or above the treatment threshold, begin treatment urgently. Note that if screening is performed with transcutaneous bilirubin (TcB) and the value is >15 mg/dL (257 micromol/L) or is within 3 mg/dL (51 micromol/L) of the treatment threshold, it should be confirmed with a TSB measurement (see 'When to confirm with TSB' above). TSB values should be used to decide on whether to initiate phototherapy. However, if the TcB is above the treatment threshold, phototherapy should be initiated while awaiting TSB confirmation. (See "Initial management of unconjugated hyperbilirubinemia in term and late preterm newborns".)

Step 3 – If the newborn's bilirubin level is below the treatment threshold, calculate the difference between the hour-specific TSB threshold for phototherapy and newborn's bilirubin level.

Decisions regarding timing of follow-up and need for repeat testing are based upon the difference between the hour-specific phototherapy threshold and newborn's bilirubin level (step 3, above), as summarized in the table (table 3) and discussed below. (See 'Subsequent evaluation and management' below and 'Outpatient follow-up' below.)

In general, the smaller the difference, the greater the risk of subsequently developing severe hyperbilirubinemia. A difference of <2 mg/dL (34 micromol/L) warrants close follow-up and possibly treatment. (See 'Approach based upon bilirubin level' below.)

In addition, when two or more bilirubin levels are available, the rate of rise can help identify patients at higher risk of subsequently developing severe hyperbilirubinemia. Rapidly rising bilirubin levels (ie, increasing by ≥0.3 mg/dL [5 micromol/L] per hour in the first 24 hours or ≥0.2 mg/dL [3 micromol/L] per hour thereafter) suggest an underlying hemolytic process. (See 'Testing for hemolysis' below.)

The approach described above is different from previous guidance from the American Academy of Pediatrics (AAP) in which screening and intervention was a two-step process guided by a different hour-specific nomogram that used "risk zones" to categorize the newborn's risk [3].

Support for the newer approach comes from a study of nearly 150,000 newborns who underwent bilirubin screening and were discharged from the birth hospitalization, of whom 1.8 percent (2623 newborns) subsequently exceeded the phototherapy threshold [60]. Newborns with predischarge TSB levels ≤1 mg/dL (17 micromol/L) below the phototherapy threshold had a 56 percent probability of subsequently needing treatment, whereas if the difference was >7 mg/dL (120 micromol/L), the probability of subsequently needing treatment was extremely low (0.008 percent). The difference from the phototherapy threshold was more accurate in predicting subsequent need for treatment compared with the older risk zone categorization approach.

SUBSEQUENT EVALUATION AND MANAGEMENT

General considerations — For newborns undergoing bilirubin screening, subsequent evaluation and management during the birth hospitalization must address the following clinical decisions:

Does the newborn require treatment of hyperbilirubinemia?

Is additional evaluation warranted to identify the cause of hyperbilirubinemia (eg, hemolysis)?

Should the bilirubin level be rechecked and if so, when?

Can the newborn be discharged, or should they remain in the hospital?

When should outpatient follow-up occur?

The following sections provide guidance on these issues. In general, decisions should take into account the following considerations (table 3):

How close the newborn's predischarge total serum or plasma bilirubin (TSB) or transcutaneous bilirubin (TcB) level is to the treatment threshold. In general, the smaller the difference, the greater the risk of subsequently developing severe hyperbilirubinemia. (See 'Interpretation of bilirubin testing' above.)

Whether there are other risk factors for severe hyperbilirubinemia (table 4).

The newborn's postnatal and gestational age.

Type of feeding (breastfeeding versus formula) and adequacy of intake.

Family support.

Whether follow-up can be ensured.

Values and preferences of the parents/caregivers.

In general, earlier follow-up is required for newborns born at <38 weeks gestational age (GA) and those with additional risk factors for severe hyperbilirubinemia (table 4) [1]. TSB levels typically peak between 72 and 96 hours after birth [61,62]. Newborns who are discharged prior to the anticipated peak (ie, before 72 hours) require earlier follow-up to assess for jaundice and decide whether a repeat bilirubin level is needed.

Determining the timing for follow-up is particularly challenging when the newborn is discharged just prior to a weekend or a holiday. Under these circumstances, clinicians should use their judgment. As an example, when discharging a formula-fed newborn with a GA of 41 weeks whose TSB level at screening was well below the treatment threshold and without additional risk factors (table 4), it is acceptable to discharge the newborn on a Friday and schedule the follow-up visit on the following Monday or Tuesday. On the other hand, when discharging a newborn with multiple clinical risk factors (eg, predischarge TSB close to the treatment threshold, GA <38 weeks, and exclusively breastfed), the newborn should be seen the following day, regardless of weekends or holidays. If appropriate follow-up cannot be arranged, discharge should be delayed until follow-up can be ensured or the period of greatest risk for hyperbilirubinemia has passed (72 to 96 hours of age).

Approach based upon bilirubin level

Bilirubin approaching the exchange transfusion threshold – Newborns with TSB levels that are approaching or above the threshold for exchange transfusion (figure 5A-B) require escalation of care, as discussed separately. (See "Escalation of care for term and late preterm newborns with unconjugated hyperbilirubinemia".)

Bilirubin at or above phototherapy threshold – For newborns with bilirubin levels at or above the threshold for treatment (figure 3A-B), phototherapy should be initiated promptly [1]. If screening was performed with TcB, it should be confirmed with a TSB measurement in this setting since decisions regarding phototherapy should be guided by the TSB value not the TcB (see 'When to confirm with TSB' above). However, phototherapy should be initiated while awaiting TSB confirmation. Details of treatment are provided separately. (See "Initial management of unconjugated hyperbilirubinemia in term and late preterm newborns".)

Additional laboratory evaluation is generally warranted for newborns who require treatment of hyperbilirubinemia during the birth hospitalization, as discussed below. (See 'Additional laboratory evaluation' below.)

Bilirubin near threshold – Newborns with bilirubin levels that are approaching the treatment threshold (ie, <2 mg/dL [34 microL/L] below the phototherapy threshold (figure 3A-B)) are at high risk of subsequently needing treatment [1,60]. A TcB value in this range should be confirmed with a TSB measurement. (See 'When to confirm with TSB' above.)

The approach to management depends on the newborn's age [1]:

<24 hours old – Newborns with near-threshold TSB values within the first 24 hours of birth are likely to have a hemolytic condition (eg, alloimmune hemolytic disease of the newborn, glucose-6-phosphate dehydrogenase [G6PD] deficiency). Additional evaluation is warranted, as discussed below. (See 'Testing for hemolysis' below.)

Discharge should be delayed, and TSB should be repeated in four to eight hours.

In many cases, it is reasonable to initiate phototherapy early (ie, at near-threshold TSB values rather than waiting for TSB to cross the treatment threshold), particularly if the newborn has ABO or Rh incompatibility and/or has a rapidly rising bilirubin level (ie, increasing by ≥0.3 mg/dL [5 micromol/L] per hour in the first 24 hours or ≥0.2 mg/dL [3 micromol/L] per hour thereafter). (See "Initial management of unconjugated hyperbilirubinemia in term and late preterm newborns", section on 'Thresholds for treatment' and "Alloimmune hemolytic disease of the newborn: Postnatal diagnosis and management", section on 'Management approach'.)

≥24 hours old – Newborns with near-threshold TSB values beyond the first 24 hours of birth are at high risk and warrant close follow-up. TSB should be repeated in 4 to 12 hours.

If there are risk factors for early and/or severe hyperbilirubinemia (table 4) or if the TSB is rising rapidly (ie, increasing by ≥0.3 mg/dL [5 micromol/L] per hour in the first 24 hours or ≥0.2 mg/dL [3 micromol/L] per hour thereafter), it may be reasonable to initiate phototherapy early (ie, at near-threshold TSB values rather than waiting for TSB to cross the treatment threshold). Such decisions should be individualized depending on the nature of the risk factor and parent/caregiver preference. (See "Initial management of unconjugated hyperbilirubinemia in term and late preterm newborns", section on 'Thresholds for treatment'.)

Decisions regarding discharge are also individualized. Options include delaying discharge, discharging with home phototherapy (if the patient meets criteria), or discharging without phototherapy but with close outpatient follow-up. (See 'Outpatient follow-up' below and "Initial management of unconjugated hyperbilirubinemia in term and late preterm newborns", section on 'Home phototherapy'.)

Bilirubin moderately below threshold – Newborns with bilirubin levels that are between 2 to <7 mg/dL (34 to 120 micromol/L) below the phototherapy threshold (figure 3A-B) are still at risk for subsequently needing treatment and generally warrant follow-up [1].

TcB values in this range should be confirmed with TSB if the TcB is >15 mg/dL (257 micromol/L) or within 3 mg/dL (51 micromol/L) of the phototherapy threshold. (See 'When to confirm with TSB' above.)

Most newborns in this category can be discharged home provided follow-up is ensured. (See 'General considerations' above.)

The timing of follow-up and need for repeat bilirubin testing is as follows (table 3) [1]:

If the bilirubin is 2.0 to <3.5 mg/dL (34 to <60 micromol/L) below the phototherapy threshold – Recheck bilirubin (with TSB or TcB) in the outpatient setting in 8 to 24 hours. (See 'Outpatient follow-up' below.)

If the bilirubin is 3.5 to <5.5 mg/dL (60 to <94 micromol/L) below the phototherapy threshold – Recheck with TSB or TcB in the outpatient setting in one to two days. (See 'Outpatient follow-up' below.)

If the bilirubin is 5.5 to <7 mg/dL (94 to <120 micromol/L) below the phototherapy threshold – Follow-up depends upon the timing of discharge:

-For newborns discharged at <72 hours after birth, outpatient follow-up should occur within 48 hours.

-Newborns discharged at ≥72 hours after birth can be seen at the initial well-newborn visit within three to five days after discharge, provided no new concerns arise before then. (See "Overview of the routine management of the healthy newborn infant", section on 'Follow-up visit'.)

The need for repeat bilirubin testing during the outpatient visit is based upon the clinical assessment at that time (signs of jaundice, feeding adequacy, weight trajectory, parent/caregiver concerns). (See 'Outpatient follow-up' below.)

Bilirubin well below threshold – Newborns with predischarge bilirubin levels >7 mg/dL (120 micromol/L) below the phototherapy threshold (figure 3A-B) have a low risk of developing severe hyperbilirubinemia [1,60]. Additional testing is generally not required during the birth hospitalization. If the newborn is discharged from the birth hospitalization at ≥72 hours after birth, follow-up specifically related to hyperbilirubinemia is not required unless new concerns arise (eg, feeding difficulties, parent/caregiver concern for jaundice). For newborns discharged at <72 hours, follow-up should occur within two to three days. (See 'Outpatient follow-up' below.)

Additional laboratory evaluation

Testing for hemolysis — Additional evaluation for an underlying hemolytic process is warranted if any of following are present:

Early-onset jaundice (within first 24 hours after birth).

Requirement for phototherapy or exchange transfusion during the birth hospitalization.

Near-threshold bilirubin levels within the first 48 hours after birth (ie, within 2 mg/dL [34 micromol/L] of the phototherapy threshold) (figure 3A-B).

Rapidly rising TSB levels (ie, increasing by ≥0.3 mg/dL [5 micromol/L] per hour in the first 24 hours or ≥0.2 mg/dL [3 micromol/L] per hour thereafter).

ABO incompatibility, regardless of the direct antiglobulin test (DAT).

Family history of an inherited hemolytic disorder.

In these circumstances, the following tests should be performed:

Complete blood cell count (CBC), reticulocyte count, and peripheral blood smear – (See "Overview of hemolytic anemias in children", section on 'Laboratory testing'.)

Evaluation for alloimmune hemolytic disease of the newborn – This generally includes comparing the newborn's blood type to the mother's and for newborns with incompatible blood types, performing a direct antiglobulin test (DAT, formerly called Coombs). Additional details are provided separately. (See "Alloimmune hemolytic disease of the newborn: Postnatal diagnosis and management", section on 'Evaluation'.)

Evaluation for G6PD deficiency – G6PD testing should be performed if there is clinical concern for hemolysis (ie, any of the findings listed above) but DAT is negative. The prevalence of G6PD deficiency is highest among African, Southern European, Middle Eastern, Chinese, or Southeast Asian populations (figure 4). However, testing for G6PD is warranted even without a suggestive ancestry.

Most laboratories provide qualitative G6PD testing rapidly; however, the results may not accurately identify deficiency. Quantitative testing may take longer to result. Point-of-care testing is available in some settings [63]. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Confirmatory tests' and "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Point of care tests under investigation'.)

If there is a high level of clinical concern for G6PD, tests should be ordered urgently. While awaiting results, management and counseling should be provided to the parents/caregivers including avoidance of agents that can trigger hemolysis in the newborn [64]. Parents/caregivers should also be informed at the time of discharge from the birth hospitalization that the newborn is at risk for subsequently having a rapid and dramatic increase in bilirubin level and they should be instructed to seek medical attention is the newborn has an increase in the degree of visible jaundice or other concerning symptoms (eg, poor feeding, lethargy, abnormal cry).

End-tidal carbon monoxide (CO) concentration, corrected for ambient CO (ETCOc) – If available at the birth center, ETCOc can be a helpful noninvasive tool for confirming active hemolysis in newborns. ETCOc provides a noninvasive assessment of bilirubin production because the breakdown of heme results in the production of equimolar quantities of bilirubin and CO [65-69]. Elevated ETCOc values (>1.7 ppm) can identify newborns with increased bilirubin production due to hemolysis (regardless of etiology) [70]. Commercial ETCOc monitors are available and have been evaluated at a number of institutions as safe and feasible screen for hemolysis [71-73].

Conjugated (direct) hyperbilirubinemia — Physiologic hyperbilirubinemia is not associated with increased conjugated (or direct) bilirubin levels. Conjugated (direct) hyperbilirubinemia is indicative of cholestasis. If the direct bilirubin is >1 mg/dL (17.1 micromol/L), the newborn should undergo evaluation for causes of cholestasis, including biliary atresia, as discussed separately. (See "Approach to evaluation of cholestasis in neonates and young infants".)

Sepsis is another important cause of conjugated (direct) hyperbilirubinemia. Evaluation for sepsis may be warranted if there are other concerning clinical signs or risk factors for neonatal sepsis. The approach to evaluating for sepsis in newborns is discussed separately. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Evaluation and initial management'.)

OUTPATIENT FOLLOW-UP — Appropriate follow-up after discharge is essential, particularly in infants discharged within the first 48 hours after birth, as bilirubin levels have rarely reached their peak levels by this age. (See "Etiology and pathogenesis of neonatal unconjugated hyperbilirubinemia", section on 'Peak TSB levels and time to resolution'.)

At the time of discharge, a follow-up appointment is scheduled, the timing of which is determined by the predischarge bilirubin level, other risk factors, and age at discharge, as summarized in the table (table 3) and discussed above. (See 'Subsequent evaluation and management' above.)

Documented hand-off should be provided to the newborn's designated healthcare provider. Information and instructions are given to the family on when and whom to contact for medical issues (eg, jaundice and adequacy of feeding) [1]. (See 'Information for patients' below.)

Follow-up clinical assessment — At the follow-up appointment, the following should be assessed:

Newborn's current weight and percent change from their birth weight. (See "Overview of the routine management of the healthy newborn infant", section on 'Weight loss'.)

Adequacy of intake. (See "Initiation of breastfeeding", section on 'Assessment of intake'.)

Pattern of voiding and transition of stool color.

Visual inspection for cephalocaudal jaundice progression. (See "Risk factors, clinical manifestations, and neurologic complications of neonatal unconjugated hyperbilirubinemia", section on 'Jaundice'.)

Repeat bilirubin testing

Who to test — The need for further bilirubin measurements is based upon the newborn's risk for developing treatment-level hyperbilirubinemia.  

Repeat testing based upon predischarge bilirubin level – In some cases, the newborn may require repeat testing based upon the results of initial screening performed during the birth hospitalization. The approach to determining the need for follow-up testing in this setting depends upon the predischarge bilirubin level and additional risk factors, as summarized in the table (table 3) and discussed in detail above. (See 'Subsequent evaluation and management' above.)

In these cases, the plan for repeating a bilirubin measurement in the outpatient setting should be clearly communicated to the parents/caregivers and outpatient provider. For newborns being discharged when outpatient follow-up is unavailable (eg, during a weekend or holiday), a mechanism should be in place for the newborn to have their bilirubin level checked.

Repeat testing based upon clinical assessment during the first outpatient visit – Repeat bilirubin testing may also be warranted based upon the clinical assessment during the outpatient visit. Some clinicians use office-based TcB devices. Testing decisions are based chiefly upon:

Whether the newborn appears jaundiced.

Interval medical history (weight change and feeding history).

Hyperbilirubinemia risk factors (table 4) – A single clinical risk factor in isolation is generally not sufficient to warrant repeat total serum or plasma bilirubin (TSB) testing. However, clinicians should have a lower threshold for checking the TSB level in newborns with any of these risk factors, particularly if the newborn appears jaundiced.

Evaluation of prolonged neonatal jaundice – Newborns with prolonged neonatal jaundice should have total and direct bilirubin levels checked. The expected course of neonatal hyperbilirubinemia differs depending on type of feeding (see "Etiology and pathogenesis of neonatal unconjugated hyperbilirubinemia", section on 'Peak TSB levels and time to resolution'):

For formula-fed newborns, persistence of jaundice after seven days of age is unusual and warrants evaluation.

For breastfed newborns, jaundice may persist until age 10 to 14 days. Persistent jaundice beyond age 14 days is unusual and warrants further evaluation.

Patients presenting with persistent or recurrent unconjugated hyperbilirubinemia beyond seven days after birth may have an underlying inherited condition (eg, glucose-6-phosphate dehydrogenase [G6PD] deficiency, other inherited hemolytic anemia, Gilbert syndrome). (See "Etiology and pathogenesis of neonatal unconjugated hyperbilirubinemia", section on 'Causes of significant unconjugated neonatal hyperbilirubinemia'.)

Cholestatic conditions (eg, biliary atresia) also are a consideration in the differential diagnosis of persistent neonatal hyperbilirubinemia. These can easily be distinguished based upon an elevated conjugated (direct) bilirubin level. (See 'Conjugated (direct) hyperbilirubinemia' above and "Causes of cholestasis in neonates and young infants".)

The management of unconjugated hyperbilirubinemia that persists or recurs after the newborn is one week old is reviewed separately. (See "Initial management of unconjugated hyperbilirubinemia in term and late preterm newborns", section on 'Special circumstances'.)

Test to perform — For newborns who warrant repeat bilirubin measurements, testing may be performed with either TSB or noninvasively using a transcutaneous bilirubin (TcB) device. (See 'Bilirubin testing methods' above.)

Most of the studies supporting use of TcB were performed in the inpatient setting. These data are discussed above. (See 'Transcutaneous bilirubin (TcB)' above.)

There are fewer data on the reliability and accuracy of TcB in the outpatient setting [52,74-77]. In the available reports, TcB values generally correlated with TSB levels (usually within 2 to 3 mg/dL [34 to 51 micromol/L]) [74-76]. The direction of the difference between TcB and TSB values in these studies differed (in some, TcB underestimated TSB; whereas in others, TcB slightly overestimated TSB), reflecting that different TcB devices perform slightly differently from one another. In most studies, a TcB value <13 to 14 mg/dL (222 to 239 micromol/L) reliably identified newborns with TSB values <17 mg/dL (291 micromol/L) [74,76].

TcB devices have the same limitations in the outpatient setting as they do in the inpatient setting and the criteria for confirming with TSB are the same, as outlined above. (See 'When to confirm with TSB' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neonatal jaundice".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Jaundice in babies (The Basics)")

Beyond the Basics topics (see "Patient education: Jaundice in newborn infants (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Rational for universal bilirubin screening – Hyperbilirubinemia is common and benign in most newborns. Severe hyperbilirubinemia (defined as total serum or plasma bilirubin (TSB) >25 mg/dL [428 micromol/L] in term and late preterm newborns [gestational age [GA] ≥35 weeks]) may lead to severe permanent neurologic injury if it is not detected and treated promptly. The goals of universal bilirubin screening are to identify newborns at risk for severe hyperbilirubinemia and to provide timely and appropriate preventive therapy. (See 'Benefits of screening' above and 'Consequences of hyperbilirubinemia' above.)

Approach to screening – For all term and late term newborns, we suggest routine predischarge bilirubin screening rather than no screening or selective screening (ie, testing only if the newborn appears jaundiced and/or has risk factors for hyperbilirubinemia) (Grade 2C). Observational data suggest that universal screening reduces the incidence of severe hyperbilirubinemia (figure 1). (See 'Benefits of screening' above.)

Our suggested approach is as follows (see 'Approach to screening' above):

Testing methods – Screening can be performed with either total serum bilirubin (TSB) or transcutaneous bilirubin (TcB). (See 'Bilirubin testing methods' above.)

If screening is performed with TcB, the measurement should be confirmed with TSB if (see 'When to confirm with TSB' above):

-Therapeutic intervention is being considered (phototherapy or exchange transfusion); however, phototherapy can be initiated while awaiting confirmatory TSB results. TcB measurements are not reliable for patients undergoing phototherapy and should not be used in this setting.

-TcB is within 3 mg/dL (51 micromol/L) of the phototherapy threshold (figure 3A-B).

-TcB is >15 mg/dL (257 micromol/L).

-TcB device reports an "error" message or if there is any question regarding the validity of the TcB measurement.

Timing of screening – The timing of the first bilirubin test depends upon whether the newborn is at risk for developing early severe hyperbilirubinemia (see 'Timing of screening' above):

-Early screening – Testing at <24 hours after birth is warranted in newborns who have a positive direct antiglobulin test (DAT), early onset of jaundice (within the first 24 hours after birth), or a first-degree relative with a heritable hemolytic disease (eg, glucose-6 phosphate dehydrogenase [G6PD] deficiency).

-Routine screening – For all other newborns, screening is performed at 24 to 48 hours after birth or before discharge, whichever is sooner. If TSB is used for screening, it is typically performed at the time of the newborn metabolic screen.    

Clinical assessment – In addition to bilirubin testing, the clinician should assess the newborn for (see 'Clinical assessment' above):

-Risk factors for severe or progressive hyperbilirubinemia (table 4) and bilirubin neurotoxicity (table 2) (see 'Risk assessment' above)

-Visible jaundice and other concerning physical examination findings (see 'Physical examination' above)

-Adequacy of feeding (see 'Feeding assessment' above)

-Family history and ancestry (see 'Family history' above)

Interpretation of bilirubin testing – Bilirubin values are interpreted relative to the hour-specific thresholds for treatment, which vary depending upon gestational age (GA), and other risk factors for bilirubin neurotoxicity (table 2 and figure 3A-B). The approach is summarized in the table (table 3) (see 'Interpretation of bilirubin testing' above):

Subsequent evaluation and management

Determining need for treatment – Newborns with bilirubin levels at or above the threshold for treatment (figure 3A-B and figure 5A-B), should begin urgent treatment, as discussed separately. (See "Initial management of unconjugated hyperbilirubinemia in term and late preterm newborns".)  

Repeat bilirubin testing and timing of outpatient follow-up – For newborns whose screening results are below the treatment threshold, the need for repeat testing and the timing of follow-up are based upon the difference between the phototherapy threshold and the newborn's predischarge TSB level. The smaller the difference, the greater the risk of subsequently developing severe hyperbilirubinemia. In general, earlier follow-up is required for newborns with risk factors for severe hyperbilirubinemia (table 4) or if discharge occurs before 72 hours (table 3). (See 'Approach based upon bilirubin level' above.)

Evaluation for hemolysis – Hemolysis is suggested by any of following:

-Early-onset jaundice (within first 24 hours after birth)

-Requirement for phototherapy or exchange transfusion during the birth hospitalization

-Near-threshold bilirubin levels within the first 48 hours after birth (ie, within 2 mg/dL [34 micromol/L] of the phototherapy threshold) (figure 3A-B)

-Rapidly rising TSB levels (ie, increasing by ≥0.3 mg/dL [5 micromol/L] per hour in the first 24 hours or ≥0.2 mg/dL [3 micromol/L] per hour thereafter)

-ABO incompatibility

-Family history of an inherited hemolytic disorder

If any of these are present, additional testing should include complete blood cell count, reticulocyte count, peripheral blood smear, direct antiglobulin test (DAT), testing for G6PD deficiency. If available at the birth center, end-tidal carbon monoxide measurement is a helpful noninvasive tool for confirming hemolysis. (See 'Testing for hemolysis' above.)

Outpatient follow-up – The follow-up assessment after discharge includes (see 'Follow-up clinical assessment' above):

Current weight and percent change from birth weight (see "Overview of the routine management of the healthy newborn infant", section on 'Weight loss')

Assessing adequacy of intake and pattern of voiding and stooling (see "Initiation of breastfeeding", section on 'Assessment of intake')

Examination for presence/extent of jaundice

A follow-up bilirubin level should be obtained if the predischarge level warranted repeat testing (table 3), or if concerns arise after discharge (jaundice, feeding difficulties, weight trajectory, parent/caregiver concerns). (See 'Repeat bilirubin testing' above.)

  1. Kemper AR, Newman TB, Slaughter JL, et al. Clinical Practice Guideline Revision: Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation. Pediatrics 2022; 150.
  2. Guidelines for detection, management and prevention of hyperbilirubinemia in term and late preterm newborn infants (35 or more weeks' gestation) - Summary. Paediatr Child Health 2007; 12:401.
  3. Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns. Pediatrics 1999; 103:6.
  4. Kuzniewicz MW, Escobar GJ, Newman TB. Impact of universal bilirubin screening on severe hyperbilirubinemia and phototherapy use. Pediatrics 2009; 124:1031.
  5. Mah MP, Clark SL, Akhigbe E, et al. Reduction of severe hyperbilirubinemia after institution of predischarge bilirubin screening. Pediatrics 2010; 125:e1143.
  6. Darling EK, Ramsay T, Sprague AE, et al. Universal bilirubin screening and health care utilization. Pediatrics 2014; 134:e1017.
  7. Wainer S, Parmar SM, Allegro D, et al. Impact of a transcutaneous bilirubinometry program on resource utilization and severe hyperbilirubinemia. Pediatrics 2012; 129:77.
  8. Eggert LD, Wiedmeier SE, Wilson J, Christensen RD. The effect of instituting a prehospital-discharge newborn bilirubin screening program in an 18-hospital health system. Pediatrics 2006; 117:e855.
  9. Okwundu C, Bhutani VK, Smith J, et al. Predischarge transcutaneous bilirubin screening reduces readmission rate for hyperbilirubinaemia in diverse South African newborns: A randomised controlled trial. S Afr Med J 2020; 110:249.
  10. Newman TB, Kemper AR. Avoiding Harm From Hyperbilirubinemia Screening. JAMA Pediatr 2019; 173:1208.
  11. Watchko JF, Maisels MJ. Avoiding Harm From Hyperbilirubinemia Screening. JAMA Pediatr 2019; 173:1209.
  12. McClean S, Baerg K, Smith-Fehr J, Szafron M. Cost savings with transcutaneous screening versus total serum bilirubin measurement for newborn jaundice in hospital and community settings: a cost-minimization analysis. CMAJ Open 2018; 6:E285.
  13. Xie B, da Silva O, Zaric G. Cost-effectiveness analysis of a system-based approach for managing neonatal jaundice and preventing kernicterus in Ontario. Paediatr Child Health 2012; 17:11.
  14. Vreman HJ, Verter J, Oh W, et al. Interlaboratory variability of bilirubin measurements. Clin Chem 1996; 42:869.
  15. Lo SF, Doumas BT, Ashwood ER. Performance of bilirubin determinations in US laboratories--revisited. Clin Chem 2004; 50:190.
  16. Kuzniewicz MW, Greene DN, Walsh EM, et al. Association Between Laboratory Calibration of a Serum Bilirubin Assay, Neonatal Bilirubin Levels, and Phototherapy Use. JAMA Pediatr 2016; 170:557.
  17. Grohmann K, Roser M, Rolinski B, et al. Bilirubin measurement for neonates: comparison of 9 frequently used methods. Pediatrics 2006; 117:1174.
  18. Barko HA, Jackson GL, Engle WD. Evaluation of a point-of-care direct spectrophotometric method for measurement of total serum bilirubin in term and near-term neonates. J Perinatol 2006; 26:100.
  19. Hulzebos CV, Vitek L, Coda Zabetta CD, et al. Screening methods for neonatal hyperbilirubinemia: benefits, limitations, requirements, and novel developments. Pediatr Res 2021; 90:272.
  20. Bhutani VK, Gourley GR, Adler S, et al. Noninvasive measurement of total serum bilirubin in a multiracial predischarge newborn population to assess the risk of severe hyperbilirubinemia. Pediatrics 2000; 106:E17.
  21. Maisels MJ, Kring E. Transcutaneous bilirubinometry decreases the need for serum bilirubin measurements and saves money. Pediatrics 1997; 99:599.
  22. Maisels MJ, Kring E. Transcutaneous bilirubin levels in the first 96 hours in a normal newborn population of > or = 35 weeks' gestation. Pediatrics 2006; 117:1169.
  23. van den Esker-Jonker B, den Boer L, Pepping RM, Bekhof J. Transcutaneous Bilirubinometry in Jaundiced Neonates: A Randomized Controlled Trial. Pediatrics 2016; 138.
  24. Konana OS, Bahr TM, Strike HR, et al. Decision Accuracy and Safety of Transcutaneous Bilirubin Screening at Intermountain Healthcare. J Pediatr 2021; 228:53.
  25. Slusher TM, Angyo IA, Bode-Thomas F, et al. Transcutaneous bilirubin measurements and serum total bilirubin levels in indigenous African infants. Pediatrics 2004; 113:1636.
  26. Fine KL, Carey WA, Schuster JAW, et al. Defining the limitations of transcutaneous bilirubin measurement in late preterm newborns. J Perinatol 2017; 37:658.
  27. Taylor JA, Burgos AE, Flaherman V, et al. Discrepancies between transcutaneous and serum bilirubin measurements. Pediatrics 2015; 135:224.
  28. Okwundu CI, Saini SS. Noninvasive methods for bilirubin measurements in newborns: A report. Semin Perinatol 2021; 45:151355.
  29. Ebbesen F, Vandborg PK, Trydal T. Comparison of the transcutaneous bilirubinometers BiliCheck and Minolta JM-103 in preterm neonates. Acta Paediatr 2012; 101:1128.
  30. Dam-Vervloet AJ, van Erk MD, Doorn N, et al. Inter-device reproducibility of transcutaneous bilirubin meters. Pediatr Res 2021; 89:770.
  31. Wainer S, Rabi Y, Parmar SM, et al. Impact of skin tone on the performance of a transcutaneous jaundice meter. Acta Paediatr 2009; 98:1909.
  32. Samiee-Zafarghandy S, Feberova J, Williams K, et al. Influence of skin colour on diagnostic accuracy of the jaundice meter JM 103 in newborns. Arch Dis Child Fetal Neonatal Ed 2014; 99:F480.
  33. Olusanya BO, Imosemi DO, Emokpae AA. Differences Between Transcutaneous and Serum Bilirubin Measurements in Black African Neonates. Pediatrics 2016; 138.
  34. Ho SR, Lin YC, Chen CN. The Impact of Phototherapy on the Accuracy of Transcutaneous Bilirubin Measurements in Neonates: Optimal Measurement Site and Timing. Diagnostics (Basel) 2021; 11.
  35. Nagar G, Vandermeer B, Campbell S, Kumar M. Effect of Phototherapy on the Reliability of Transcutaneous Bilirubin Devices in Term and Near-Term Infants: A Systematic Review and Meta-Analysis. Neonatology 2016; 109:203.
  36. Kaplan M, Maisels MJ. Natural history of early neonatal bilirubinemia: a global perspective. J Perinatol 2021; 41:873.
  37. Varvarigou A, Fouzas S, Skylogianni E, et al. Transcutaneous bilirubin nomogram for prediction of significant neonatal hyperbilirubinemia. Pediatrics 2009; 124:1052.
  38. De Luca D, Romagnoli C, Tiberi E, et al. Skin bilirubin nomogram for the first 96 h of life in a European normal healthy newborn population, obtained with multiwavelength transcutaneous bilirubinometry. Acta Paediatr 2008; 97:146.
  39. Fouzas S, Mantagou L, Skylogianni E, et al. Transcutaneous bilirubin levels for the first 120 postnatal hours in healthy neonates. Pediatrics 2010; 125:e52.
  40. Kaplan M, Bromiker R. Variation in Transcutaneous Bilirubin Nomograms across Population Groups. J Pediatr 2019; 208:273.
  41. Engle WD, Lai S, Ahmad N, et al. An hour-specific nomogram for transcutaneous bilirubin values in term and late preterm Hispanic neonates. Am J Perinatol 2009; 26:425.
  42. Sanpavat S, Nuchprayoon I, Smathakanee C, Hansuebsai R. Nomogram for prediction of the risk of neonatal hyperbilirubinemia, using transcutaneous bilirubin. J Med Assoc Thai 2005; 88:1187.
  43. Bental YA, Shiff Y, Dorsht N, et al. Bhutani-based nomograms for the prediction of significant hyperbilirubinaemia using transcutaneous measurements of bilirubin. Acta Paediatr 2009; 98:1902.
  44. Yu ZB, Dong XY, Han SP, et al. Transcutaneous bilirubin nomogram for predicting neonatal hyperbilirubinemia in healthy term and late-preterm Chinese infants. Eur J Pediatr 2011; 170:185.
  45. Akahira-Azuma M, Yonemoto N, Mori R, et al. An hour-specific transcutaneous bilirubin nomogram for Mongolian neonates. Eur J Pediatr 2015; 174:1299.
  46. Han S, Yu Z, Liu L, et al. A Model for Predicting Significant Hyperbilirubinemia in Neonates From China. Pediatrics 2015; 136:e896.
  47. Bromiker R, Goldberg A, Kaplan M. Israel transcutaneous bilirubin nomogram predicts significant hyperbilirubinemia. J Perinatol 2017; 37:1315.
  48. Engle WD, Jackson GL, Sendelbach D, et al. Assessment of a transcutaneous device in the evaluation of neonatal hyperbilirubinemia in a primarily Hispanic population. Pediatrics 2002; 110:61.
  49. De Luca D, Jackson GL, Tridente A, et al. Transcutaneous bilirubin nomograms: a systematic review of population differences and analysis of bilirubin kinetics. Arch Pediatr Adolesc Med 2009; 163:1054.
  50. Taylor JA, Burgos AE, Flaherman V, et al. Utility of Decision Rules for Transcutaneous Bilirubin Measurements. Pediatrics 2016; 137.
  51. Schumacher RE. Transcutaneous bilirubinometry and diagnostic tests: "the right job for the tool". Pediatrics 2002; 110:407.
  52. Engle WD, Jackson GL, Stehel EK, et al. Evaluation of a transcutaneous jaundice meter following hospital discharge in term and near-term neonates. J Perinatol 2005; 25:486.
  53. Casnocha Lucanova L, Matasova K, Zibolen M, Krcho P. Accuracy of transcutaneous bilirubin measurement in newborns after phototherapy. J Perinatol 2016; 36:858.
  54. Gothwal S, Singh N, Sitaraman S, et al. Efficacy of transcutaneous bilirubinometry as compared to serum bilirubin in preterm newborn during phototherapy. Eur J Pediatr 2021; 180:2629.
  55. Enweronu-Laryea C, Leung T, Outlaw F, et al. Validating a Sclera-Based Smartphone Application for Screening Jaundiced Newborns in Ghana. Pediatrics 2022; 150.
  56. Shaw SC, Devgan A. Bilirubin estimation from smartphone imaging of skin of newborns. Acta Paediatr 2020; 109:2822.
  57. Aune A, Vartdal G, Bergseng H, et al. Bilirubin estimates from smartphone images of newborn infants' skin correlated highly to serum bilirubin levels. Acta Paediatr 2020; 109:2532.
  58. Lee AC, Folger LV, Rahman M, et al. A Novel Icterometer for Hyperbilirubinemia Screening in Low-Resource Settings. Pediatrics 2019; 143.
  59. Olusanya BO, Slusher TM, Imosemi DO, Emokpae AA. Maternal detection of neonatal jaundice during birth hospitalization using a novel two-color icterometer. PLoS One 2017; 12:e0183882.
  60. Kuzniewicz MW, Park J, Niki H, et al. Predicting the Need for Phototherapy After Discharge. Pediatrics 2021; 147.
  61. Dennery PA, Seidman DS, Stevenson DK. Neonatal hyperbilirubinemia. N Engl J Med 2001; 344:581.
  62. Maisels MJ. What's in a name? Physiologic and pathologic jaundice: the conundrum of defining normal bilirubin levels in the newborn. Pediatrics 2006; 118:805.
  63. Wong RJ, Montiel C, Kunda M, et al. A novel point-of-care device for measuring glucose-6-phosphate dehydrogenase enzyme deficiency. Semin Perinatol 2021; 45:151356.
  64. Kaplan M, Hammerman C, Bhutani VK. Parental education and the WHO neonatal G-6-PD screening program: a quarter century later. J Perinatol 2015; 35:779.
  65. Stevenson DK, Fanaroff AA, Maisels MJ, et al. Prediction of hyperbilirubinemia in near-term and term infants. Pediatrics 2001; 108:31.
  66. Stevenson DK, Vreman HJ. Carbon monoxide and bilirubin production in neonates. Pediatrics 1997; 100:252.
  67. Bartoletti AL, Stevenson DK, Ostrander CR, Johnson JD. Pulmonary excretion of carbon monoxide in the human infant as an index of bilirubin production. I. Effects of gestational and postnatal age and some common neonatal abnormalities. J Pediatr 1979; 94:952.
  68. Vreman HJ, Stevenson DK, Oh W, et al. Semiportable electrochemical instrument for determining carbon monoxide in breath. Clin Chem 1994; 40:1927.
  69. Stevenson DK, Vreman HJ, Oh W, et al. Bilirubin production in healthy term infants as measured by carbon monoxide in breath. Clin Chem 1994; 40:1934.
  70. Bhutani VK, Srinivas S, Castillo Cuadrado ME, et al. Identification of neonatal haemolysis: an approach to predischarge management of neonatal hyperbilirubinemia. Acta Paediatr 2016; 105:e189.
  71. Castillo Cuadrado ME, Bhutani VK, Aby JL, et al. Evaluation of a new end-tidal carbon monoxide monitor from the bench to the bedside. Acta Paediatr 2015; 104:e279.
  72. Christensen RD, Lambert DK, Henry E, et al. End-tidal carbon monoxide as an indicator of the hemolytic rate. Blood Cells Mol Dis 2015; 54:292.
  73. Bahr TM, Shakib JH, Stipelman CH, et al. Improvement Initiative: End-Tidal Carbon Monoxide Measurement in Newborns Receiving Phototherapy. J Pediatr 2021; 238:168.
  74. Maisels MJ, Engle WD, Wainer S, et al. Transcutaneous bilirubin levels in an outpatient and office population. J Perinatol 2011; 31:621.
  75. Wickremasinghe AC, Karon BS, Cook WJ. Accuracy of neonatal transcutaneous bilirubin measurement in the outpatient setting. Clin Pediatr (Phila) 2011; 50:1144.
  76. Ercan Ş, Özgün G. The accuracy of transcutaneous bilirubinometer measurements to identify the hyperbilirubinemia in outpatient newborn population. Clin Biochem 2018; 55:69.
  77. Kumra T, Weaver SJ, Prather K, et al. Correlation of Transcutaneous and Serum Bilirubin Measurements in the Outpatient Setting. Clin Pediatr (Phila) 2018; 57:231.
Topic 5008 Version 67.0

References