#45: Neonatal Hyperbilirubinemia – Their Future’s So Bright, They Gotta Wear Shades!

March 2, 2022 | By Sam Masur

Summary

Aren’t all babies a little jaundiced anyways? What’s up with those phototherapy lights? Come for the answers, stay for this de-light of a conversation with pediatrician Dr. Alison Holmes and neonatologist Dr. Tom Shimotake, both of whom have extensive experience with commonly used guidelines for neonatal hyperbilirubinemia. We will cover common and rarer etiologies of neonatal hyperbilirubinemia, the whens and hows of working up and screening, and the ins and outs of treatment.

Credits

• Writer, Infographic, Producer: Angela Y. Zhang MD
• Executive Producer: Max Cruz MD
• Showrunner: Sam Masur MD
• Cover Art: Chris Chiu MD
• Hosts: Angela Y. Zhang MD, Chris Chiu MD, Justin Berk MD
• Editor:Justin Berk MD; Clair Morgan of nodderly.com
• Guest(s): Alison Holmes MD MPH, Tom Shimotake MD

Neonatal Hyperbilirubinemia Pearls

1. Unconjugated neonatal hyperbilirubinemia is very common and can be benign, though frightening, to parents. When you have low concern for other pathophysiology, encourage feeding and supplementation to alleviate starvation jaundice.
2. Have a systematic approach to hyperbilirubinemia and keep an open mind, especially with an unexpected clinical course. A good history is key!
3. Physical exam skills can identify sources of possible hemolysis, but aren’t always the best for jaundice.
4. Equitable care practices include universal bilirubin screening at 24 hours of life, and ensuring robust follow-up after discharge from the birthing center, nursery, or NICU.
5. Be judicious with interventions and don’t initiate subthreshold phototherapy.

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Hyperbilirubinemia Show Notes

Pathophysiology & Risk Factors

• Unconjugated hyperbilirubinemia is very common in the newborn period due to high turnover of fetal red blood cells shortly after birth. Reassure parents that jaundice (physical exam finding of hyperbilirubinemia) can be normal and, according to Dr. Holmes, seen in up to 80% of breastfed infants. 
• Kernicterus, or bilirubin encephalopathy, is the main concern of neonatal hyperbilirubinemia. Kernicterus occurs when unconjugated bilirubin crosses the blood-brain barrier and deposits in the basal ganglia, causing acute and sometimes chronic neurologic damage. Clinical manifestations include lethargy, weak tone, altered mental status, and seizures.

Unconjugated Hyperbilirubinemia

Risk factors for unconjugated hyperbilirubinemia, resulting in a high indirect bilirubin, are varied and fall into several categories.

Parental Risk Factors

• ABO incompatibility between birthing parent and fetus.
• Blood group antibody mismatch between birthing parent and fetus. 
• Family history of hyperbilirubinemia. 
• Birthing parent history of gestational diabetes.

Expert pearl: Obtain a thorough set of labs from birthing parent’s prenatal care from your obstetric and family medicine colleagues, including the minor blood group antigens which are often responsible for an antibody setup.

Processes Leading to Increased Production of Bilirubin

• Hereditary spherocytosis and other RBC membrane defects.
• G6PD deficiency, PK deficiency, and other erythrocyte enzymatic defects.
• Polycythemia.
• Source(s) of increased RBC breakdown, such as a cephalohematoma.
• Sepsis.

Expert pearl: Although G6PD deficiency is classically taught to occur more often in darker-skinned populations, it is in fact a global concern and can happen in many populations that ethnic categorizations are not adequate for. Because a large percentage of kernicterus cases can be attributed to G6PD deficiency (up to 30%), it is important not to let bias determine screening and workup, especially as hemolysis from G6PD deficiency may not occur in the first few days of life.

Decreased Clearance

• Crigler-Najjar 
• Gilbert syndrome

Increased Enterohepatic Circulation leading to increased bilirubin gut absorption

• Breastmilk jaundice
• Intestinal obstruction or ileus

Finally, a common risk factor is any feeding difficulty, through which an infant does not receive enough nutrition. The pathophysiology of this starvation jaundice is unclear. Expert practice: Although sometimes termed “breastfeeding jaundice”, this term is inaccurate since this type of hyperbilirubinemia can occur with failure to feed either with breastmilk or formula.

Conjugated Hyperbilirubinemia

Conjugated hyperbilirubinemia results from cholestasis and an impaired ability to form or excrete bile. The conjugated, or direct, bilirubin should be less than 20% of the total bilirubin measurement; anything more is considered elevated. Causes include:

• Anatomical (biliary atresia, Alagille syndrome).
• Metabolic (Galactosemia).
• Infectious (hepatitis, other TORCH infections).

Screening and Work-Up

Physical Exam

• Jaundice spreads cephalo-caudally, i.e. head-to-toe. 
• On skin exam, good rule of thumb for correlating bilirubin levels to the line between jaundice and unjaundiced skin: head = 5; belly button = 10; legs = 15. 
• Look for jaundice in conjunctivae, nail beds, and sublingual mucosa. 
• Be sure to look for findings that indicate risk for hemolysis, such as bruising or cephalohematoma. Expert pearl: in contrast to normal findings of scalp edema which will depress, a cephalohematoma feels like a water balloon that bounces back.
• Just because you don’t see any clinical findings doesn’t mean that there isn’t any hyperbilirubinemia – have a low suspicion to check a bilirubin, and/or implement universal 24-hour of life screening as below.

Labs 

• Obtain cord blood at birth if you’re concerned about an ABO/antigen setup.
• If an infant looks jaundiced before 24 hours of life, obtain a transcutaneous bilirubin.
• At 24 hours of life, all newborns should have a transcutaneous bilirubin screen. Expert opinion: this may reduce health inequities seen in the underdiagnosis of jaundice in darker-skinned infants, although more root-cause solutions would be needed to mitigate disparities in outpatient management (Darling et al., 2017).

Expert opinion: Consider obtaining a TcB meter in your outpatient practice (Kilmarten et al, 2020).

When to check a serum bilirubin?

• Transcutaneous bilirubin is reliable for lower bilirubin levels under 13, and usually predicts bilirubin within 2 points. Therefore, if bilirubin level is either 1) within 2 points of a “lightable” level as determined by Bilitool or NCNC (below), and/or 2) over 13, check a serum bilirubin.
  • Although TcBs can be inaccurate for darker-skinned infants (Taylor et al., 2014), the rules above will help mitigate any health inequity resulting from device error.

What to do with the bilirubin measurement?

Use an algorithm (and the bilirubin rate of rise) to determine whether the bilirubin level needs intervention, e.g. phototherapy or exchange transfusion. Existing algorithms are:

• BiliTool 
  • Standard of care based on AAP 2004 guidelines.

• • Expert opinion: without standardized and consistent practice within a hospital system, can result in human error, e.g. assigning to the wrong risk category. 

• • Sneak peek: Watch for new hyperbilirubinemia guidelines coming out in late 2022!
• Northern California Neonatal Consortium (NCNC) Hyperbilirubinemia Treatment Guidelines 
  • Based on newer data since 2004, these guidelines adjusted treatment thresholds and allowed slightly higher bilirubin levels in all cases but the most high-risk infants when deciding to initiate phototherapy or exchange transfusion.
• Using these algorithms can guide intervention threshold, which depends on gestational age and risk factors, despite a historically circulated threshold of 20 (see “Vignitiphobia: A One-Act Play”).
• Studies have shown kernicterus to occur around an average bilirubin of >39  mg/dL. Expert opinion: Although providers should certainly intervene well before this threshold, knowing that average levels have to be very high to cause kernicterus gives providers more room to observe an infant before trying an intervention that has its own risk.

Treatment

Since the advent of Rhogam to prevent hemolytic disease of the newborn, rates of exchange transfusion have dropped, while rates of phototherapy have risen. 

Supplementation 

• Supplementation of expressed breast milk with donor breast milk or formula can be helpful in treating or preventing mild hyperbilirubinemia.
• Expert opinion: While many parents are concerned their infant is not feeding in the first 24 hours, this period is considered practice; in fact, many babies don’t latch until after this period. Begin to consider supplementation during these first 24 hours if the infant has other risk factors, like being SGA.
• When deciding whether to supplement in the hospital or in clinic, use the NEWT nomogram to determine excessive weight loss, and ask birthing parent whether their milk has come in.

• Expert opinion: Frame supplementation as a “transient” medical intervention, after which parents can resume preferred method of feeding.

Phototherapy 

Phototherapy utilizes specific wavelengths of light on the skin to convert bilirubin into an excretable water-soluble compound. In principle, should administer as much blue wavelength light to as much surface area as possible, thereby limiting time spent under lights. Sometimes this can be achieved with multiple banks of light with a “bili blanket” underneath to provide extra sources of light. Sometimes, phototherapy can also be done with a home machine. Stress to parents that phototherapy uses non-UV light. Although sunlight has been shown to decrease bilirubin, the risks of hyperthermia and the variability in sunlight for now do not outweigh the benefits and needs more research (Horn et al., 2020) – thus, parents should not expose their infants to sunlight for hyperbilirubinemia.

While on phototherapy, continue to feed patients at regular intervals to prevent further starvation jaundice, check bilirubin levels up to every 4 hours (via serum bilirubin – transcutaneous bilirubin is not a reliable measurement until approximately 24 hours after phototherapy cessation), and examine patients for clinical signs of bilirubin encephalopathy.

Important note: Phototherapy cannot be used for conjugated/direct hyperbilirubinemia! This will result in hyperpigmentation of the skin known as “bronze baby” and will not resolve the underlying pathology.

Phototherapy is not a wholly benign intervention, and thus should only be used when indicated by the “lightable” threshold, as opposed to prophylactically to prevent bilirubin from reaching threshold. Phototherapy has been associated with increased risk for childhood seizures (excluding febrile seizures). Other multifactorial risks of phototherapy are controversial, with research evolving over time. Some data have shown that families of infants who received phototherapy were more likely to worry that their infant was sick and display high healthcare utilization; other data have shown no change or even slight increase in breastfeeding. A previous correlation of phototherapy with different kinds of childhood cancer has been disproved with recent data. 

In premature infants, and extremely low birth weight infants, phototherapy should be used with even more caution given their under-developed skin. Discuss the use of cycled phototherapy for these ELBW infants. Arnold et al. found that cycling phototherapy (15 minutes on for every hour) reduced duration of therapy by over half, with minimal changes in peak bilirubin level.

Exchange Transfusion

Exchange transfusion is reserved for more severe cases of hyperbilirubinemia. Expert pearl: After the advent of Rhogam, it is now much more rare, perhaps a few times a year, to initiate exchange transfusion in the NICU. Exchange transfusion replaces patient with donor blood to remove bilirubin, offending antibodies, and replenish red blood cell stores; it is usually performed until the patient’s total blood volume is replaced twice.

Other Treatment Modalities/Honorable Mentions

Mixed data exist on the use of IVIG and albumin; can be considered as a temporizing measure to a more data-driven intervention, although neither of these are implemented into standard of practice.

Stopping Treatment, then Home

If unconjugated bilirubin paradoxically stays constant or continues to rise during intervention, this may suggest ongoing hemolysis and requires further work-up. 

If the bilirubin is dropping as expected, intervention can be discontinued once bilirubin levels are below threshold. Depending on the bilirubin level at time of phototherapy cessation, the likelihood of a rebound hyperbilirubinemia can be calculated using gestational age and “starting threshold-ending TSB” difference. Because the risk for rebound hyperbilirubinemia is relatively low (Chang and Newman found that when phototherapy is stopped at a bilirubin of 2 mg/dL below the starting threshold, the rebound probability was 2.5%), there is often no need to stay inpatient to monitor rebound hyperbilirubinemia, as long as there is a robust outpatient follow-up plan. Considering health equity is paramount to mitigate barriers to outpatient follow-up.

Preparing for discharge should include a follow-up plan for assessing jaundice and hyperbilirubinemia based on infant risk nomograms and predischarge bilirubin risk zone nomogram. Because the two nomograms of infant and bilirubin risk can be confusing, new research may result in a composite nomogram using a Δ-TSB value (difference between the last pre-discharge serum bilirubin and the AAP phototherapy threshold) and a simpler prediction value.

Goal

Listeners will explain the basic pathophysiology, diagnosis, and management of neonatal hyperbilirubinemia to improve both inpatient care and outpatient follow-up. 

Learning Objectives

After listening to this episode listeners will be able to…  

1. Explain the basic pathophysiology and etiologies of unconjugated and conjugated hyperbilirubinemia.
2. Recognize physical exam findings and timing of appropriate labs for hyperbilirubinemia.
3. Find the algorithms that guide management for hyperbilirubinemia according to the latest guidelines.
4. Describe risks and benefits of supplementation, phototherapy, and exchange transfusion.
5. Understand the basics of outpatient follow-up for hyperbilirubinemia.
6. Describe the health inequity inherent in workup, diagnosis, and management of hyperbilirubinemia.

Disclosures

Dr. Holmes and Dr. Shimotake report no relevant financial disclosures. The Cribsiders report no relevant financial disclosures. 

Citation

Zhang AY, Holmes A, Shimotake T, Cruz M, Masur S, Chiu C, Berk J. “#45: Neonatal Hyperbilirubinemia – Their Future’s So Bright, They Gotta Wear Shades!”. The Cribsiders Pediatric Podcast. https:/www.thecribsiders.com/ March 2, 2022.