Frequently Asked Questions About the 2022 AAP Guideline on the Management of Hyperbilirubinemia

To help with implementation of the 2022 AAP guideline on the management of hyperbilirubinemia, members of the authoring group with input from other members of the AAP have put together this FAQ sheet. Please contact Alex Kemper if there is a common question that should be added. Remember that these are general answers and do not replace your clinical judgement.

1. Should the phototherapy thresholds in Figure 3 (the one for babies with neurotoxicity risk factors) be used for all infants with a gestational age <38 weeks since a gestational age <38 weeks is a hyperbilirubinemia neurotoxicity risk factor?
   
   Figure 3 should be used if there are additional hyperbilirubinemia neurotoxicity risk factors besides gestational age. This is described in the text under each figure. Figure 2 provides the phototherapy thresholds for babies born at 35-37 6/7 weeks who do not have any additional hyperbilirubinemia neurotoxicity risk factors.
2. Do I automatically need to check DAT or albumin level since they might lead me to treat at a lower level?
   
   The guideline provides specific advice about when to check the DAT. DAT does not otherwise need to be checked unless there is clinical concern. Similarly, albumin does not need to be measured unless there is a reason to suspect it would be low or the baby reaches the escalation of care threshold.
3. A baby was started on phototherapy early, so getting the TSB 2 mg/dL lower than the threshold at the time that phototherapy was started seems like overkill. Is it really necessary to do that?
   
   The reason for suggesting comparing the current TSB to the threshold at the time the phototherapy was started is that it provides a way to account for two risk factors at once: earlier age at initiation of phototherapy and the current bilirubin level.1Generally, babies for whom phototherapy is started at < 24 hours are more likely to have hemolysis and are at higher risk of rebound. Another clinical prediction rule that uses the difference between the current TSB and the current threshold is available,2 and it is an option to use it to guide phototherapy discontinuation decisions. As described in the guideline, it is important to have well-coordinated follow-up after discharge.
   1. Chang PW, Newman TB. A simpler prediction rule for rebound hyperbilirubinemia Pediatrics. 2019;144(1):e20183712.
   2. Chang PW, Kuzniewicz MW, McCulloch CE, Newman TB. A clinical prediction rule for rebound hyperbilirubinemia following inpatient phototherapy. Pediatrics. 2017;139(3):e20162896.
4. Can I use the flow diagram describing follow-up after the birth hospitalization (Figure 7) to guide follow-up for infants seen in the primary care setting after discharge?
   
   The criteria for timing follow-up were based on data only from birth hospitalizations. In general, most infants in the first 5 days after birth, even as outpatients, should be similar to those still in the hospital, so the timing of follow-up for infants who have not received phototherapy as described in the flow diagram can be similar. However, it is important to use clinical judgment based on the potential risk for increased bilirubin levels based on individual patient characteristics as described in the guideline. Additional clinical judgement is needed for infants older than 5 days.
5. The guideline states that IVIG can be provided to infants with isoimmune hemolytic disease whose TSB reaches or exceeds the escalation of care threshold. Given the desirability of preventing exchange transfusion, why wouldn’t I use IVIG?
   
   As described in the technical report, the potential benefit of IVIG is unclear and it has been associated with adverse outcomes, including necrotizing enterocolitis. We recommend that all infants who require escalation of care receive hydration and intensive phototherapy. The benefits of IVIG are most likely to exceed the risks in newborns with isoimmune hemolytic disease and TSB that has exceeded the escalation of care threshold and is rising despite intensive phototherapy.
6. Are there disparities in the risk of hazardous hyperbilirubinemia or in the risk of kernicterus? If so, why?
   
   Recent data show that compared to white infants, Black infants have an increased risk of hazardous hyperbilirubinemia (≥ 30 mg/dL).¹ Because the elevated risk is not evident between 20 – 30 mg/dL, some older studies that evaluated only a broader range of hyperbilirubinemia (e.g., ≥ 20 mg/dL) reported that Black infants had an overall lower risk of hyperbilirubinemia.2 Based on these data, the 2004 AAP guideline listed Black race as being protective against significant jaundice. This has been removed from the 2022 guideline.
   
   One of the challenges in assessing the epidemiology of kernicterus in the United States is that there is no current kernicterus registry. Much understanding comes from a pilot registry that collected data from 1992-2004. Based on this, about 25% of cases of kernicterus are in Black infants, most of whom (66%) had G6PD deficiency.² The degree to which factors related to healthcare (e.g., relying on visual assessment, inadequate education of caregivers) and social drivers of health leading to incomplete follow-up contribute to the risk of hazardous hyperbilirubinemia or kernicterus is not known.²
   
   To help address the inequities, the 2022 guideline recommends: (1) all newborns have their bilirubin level measured at least once prior to discharge, (2) the timing of follow-up and the need for repeat bilirubin testing after discharge be guided by that measurement, (3) follow-up and key bilirubin risk information be transmitted to the clinician who will be responsible for follow-up, and (4) specific caregiver education, including when to seek care and potential triggers for hemolysis (e.g., oxidative stresses) to avoid. To aid with caregiver education, members of the guideline committee revised the AAP’s handout “Jaundice in Newborns: Parent FAQs” to include the following advice: “Also, let your baby's doctor know if you eat fava beans (broad beans) or use any of the following products: mothballs, antibiotics, henna, or herbal remedies. Eating fava beans and using these products should be avoided because in rare cases this can cause severe jaundice.” The intent of including antibiotics in this list is to ensure they are reviewed for their potential to cause hemolysis and does not preclude their use for nursing mothers if otherwise safe. The guideline also recommends that clinicians be aware of the risk of G6PD deficiency.
   1. Wickremasinghe AC, Kuzniewicz MW, Newman TB. Black race is not protective against hazardous bilirubin levels. J Pediatr. 2013;162(5):1068-1069.
   2. Okolie F, South-Paul JE, Watchko JF. Combating the Hidden Health Disparity of Kernicterus in Black Infants: A Review. JAMA Pediatr. 2020;174(12):1199-1205.
7. Why not test all newborns for G6PD deficiency? The guideline recommends that we consider race. Doesn’t that go against the AAP’s goal of not practicing race-based medicine?
   
   Although G6PD deficiency is an important cause of kernicterus, accounting for an estimated 1 in 5 cases in the United States,1 the guideline committee did not recommend universal G6PD deficiency screening. Some newborn screening programs include G6PD deficiency testing. However, the results often do not come back soon enough to inform care. There is no national consensus regarding the need for G6PD deficiency screening because the degree to which it could improve outcomes is unclear.1 Because G6PD deficiency is relatively common and hazardous hyperbilirubinemia is rare, universal testing could also lead to potential harm (e.g., bilirubin over-testing, prolonged hospital stays). Given the gaps in evidence, the guideline committee chose to focus on universal caregiver education about triggers for hemolysis (e.g., oxidative stresses) in G6PD deficient neonates and close follow-up of all infants.
   
   The guideline committee recognized the disparity in the risk of hazardous hyperbilirubinemia and kernicterus among Black infants and that 75% of G6PD deficiency related kernicterus in the United States Pilot Kernicterus Registry was reported in Black neonates.2 The guideline committee decided to highlight the proportion of Black individuals in the United States with G6PD deficiency by listing the prevalence. The guideline does state that the risk based on “genetic ancestry from a population in which the condition is prevalent (e.g., Sub-Saharan Africa, Middle East, Mediterranean, Arabian Peninsula, and Southeast Asia) can be helpful in predicting risk.” The corresponding prevalence for individuals in the United States with these genetic ancestries was not listed because the data are not available. The guideline committee recognizes that many individuals do not know their genetic ancestry and that over even a small number of generations in the United States, genetic ancestry may have little meaning. The guideline committee did not intend to promote race-based medicine but was concerned about the disparity, in recognition of hazardous hyperbilirubinemia and kernicterus previously observed and documented in people of color, which is mediated in part by G6PD deficiency.
   
   The guideline committee hopes that new studies help elucidate the role of G6PD deficiency testing, including how the results could be used to decrease the risk of kernicterus. The guideline committee also understands that given the frequency of hazardous hyperbilirubinemia or kernicterus, such studies will be difficult to do. At a minimum, however, establishing a national kernicterus registry could help advance the field.
   
   Since the publication of the guideline, New York has passed a mandate for G6PD deficiency testing (https://ahpnetwork.com/g6pd-provider-fact-sheet/). This legislation had advocacy support from the G6PD Deficiency Foundation. The mandate requires diagnostic testing for G6PD deficiency for infants who:
   • “Present with hemolytic anemia
   • Present with hemolytic jaundice
   • Present with early-onset increasing neonatal jaundice persisting beyond the first week of life (bilirubin level greater than the 40th percentile for age in hours).
   • Are admitted to the hospital for jaundice following discharge
   • Have a familial, racial, or ethnic risk of G6PD deficiency (African, Asian, Mediterranean, or Middle Eastern ancestry)”
     
     The approach to developing these criteria has not been described and no studies are available yet regarding the impact of this mandate on healthcare delivery or health outcomes. We do know that in many cases G6PD deficiency will be identified after the main period of risk for kernicterus has passed and that many infants with G6PD deficiency will be identified with uncertain benefit.
     1. Watchko JF, Kaplan M, Stark AR, Stevenson DK, Bhutani VK. Should we screen newborns for glucose-6-phosphate dehydrogenase deficiency in the United States. J Perinatol. 2013;33:499-504.
     2. Okolie F, South-Paul JE, Watchko JF. Combating the hidden health disparity of kernicterus in Black infants: a review. JAMA Pediatr. 2020;174(12):1199-1205.