Relevance of the 2022 American Academy of Pediatrics Hyperbilirubinemia Guidelines for an LMIC

For decades, the American Academy of Pediatrics (AAP) guidelines on various topics, including management of neonatal hyperbilirubinemia, have been seen as the basis for guidelines globally. Although not the intent of, nor the practice endorsed by, the AAP, many times these guidelines have been adopted as guidelines in both high- and low- and middle-income countries (LMICs) without substantial modifications. Although likely appropriate in countries with similar risk profiles and resources as the United States, it has not been, and is still not, the best practice in every situation and locale globally.

The authors of this perspectives piece wish to congratulate the AAP for clearly calling out and stating this in these newest guidelines.¹  As we in Nigeria and many others have taught for decades, “the risk of kernicterus differs significantly from countries, particularly within the countries with limited resources.”¹  Equally important is to clearly state that “these guidelines, including the phototherapy and exchange transfusion (ET) thresholds, were not developed for use in LMICs where the resources described for screening, follow-up, and treatment might not be available.”¹  The new guidelines even state that in other high-income countries “local consultation” should be sought.¹ 

Risk factors for acute bilirubin encephalopathy (ABE) in neonates and adverse effects in children or adults beyond the neonatal period, best known as the kernicterus spectrum disorder, are significantly increased in Nigeria and most of Sub-Saharan Africa (SSA) and many countries in Southeast Asia (SEA). As pointed out by Bhutani et al²  in his landmark article, 24 million neonates were at risk for severe neonatal hyperbilirubinemia with sequalae in 83% of survivors of kernicterus. The increased risk for severe neonatal jaundice/hyperbilirubinemia in SSA and SEA is also highlighted in the systematic review by Slusher et al,³  which noted that the African region of the World Health Organization had an appallingly high incidence of severe neonatal jaundice as determined by clinical markers including ABE, ET, or jaundice-related death in 667.8 (95% confidence interval: 603.4–738.5) followed by SEA with 251.3 (132.0–473.2) per 10 000 livebirths in stark contrast to the Americas at 0.38 (0.21–0.67) per 10 000 livebirths. Nigeria bears much of the burden in SSA as seen in a recent article from Lagos in which neonatal jaundice or hyperbilirubinemia accounted for 12% of all neonatal deaths.⁴  The magnitude and burden attributable to individual risk factors in Nigeria were underscored in the extensive review by Olusanya et al,⁵  which included articles with publication dates ranging from 1960 to 2014. This scoping review,⁵  along with the new AAP guidelines,¹  highlights the role of glucose-6-phosphate dehydrogenase (G6PD) deficiency as an etiology of severe neonatal hyperbilirubinemia both in the United States and globally. As emphasized in many reports, the World Health Organization has recommended screening for G6PD deficiency in populations with a male prevalence of G6PD deficiency of >3% to 5%,⁶  which is far exceeded in Nigeria (16%–26%)⁶  and most other countries in SSA, some countries in Asia,⁶  and in certain populations in the United States including the African American population in which the overall male prevalence is 13% and female prevalence is 4%.¹  Of note even in the United States, routine screening for G6PD deficiency is not consistently done even in high-risk populations, such as those whose ancestries are from regions such as SSA. Unfortunately, in most of SSA and other LMICs, routine testing for G6PD deficiency remains largely unavailable and is primarily relegated to research studies. As pointed out in the new AAP guidelines, selective screening for G6PD deficiency would be an excellent example of race-conscious medicine,¹  and certainly in these authors’ opinions, screening all neonates in these high-risk populations could lead to marked improvement in the outcome of hyperbilirubinemia in newborns with G6PD deficiency, not just in the United States but globally as well.

Other risk factors such as isoimmune hemolytic disease also play a role in LMICs as they do in the United States.²  However, that role is exaggerated by the widespread lack of affordable Rh immunoglobulin and sometimes lack of even prenatal blood typing. In addition, suboptimal comprehensive and continual care of newborns partly because of lack of electricity, rapid reliable bilirubin measurements, widespread unavailability of high-quality transcutaneous bilirubinometers, consistent effective phototherapy, and cost of health care also change the landscape for neonates with hyperbilirubinemia in LMICs.⁵  Finally, lack of appropriate maternal education, late arrival of neonates born outside the hospital who are often kept indoors for extended periods of time, and the use of substances known to cause hemolysis in newborns with G6PD deficiency are all the factors contributing to the high risk of kernicterus spectrum disorder.⁵ 

Data from Lagos,⁴  as well as data from many other articles in LMICs, highlight the need for guidelines specifically for Nigeria and LMICs on the basis of risk factors and available resources. The guidelines for Nigeria and many other LMICs would likely vary within the countries because risk and resources are not uniformly distributed. In a rural hospital, it would not be advisable to wait until the total serum bilirubin (TSB) level is ∼16 mg/dL before starting phototherapy in a 48-hour-old neonate if the hospital has only intermittent electricity, is using phototherapy with fluorescent bulbs of unknown irradiance that have not been replaced for many months, and is several hours from a better resourced hospital. In a hospital in a large city in the same country that has high-quality phototherapy known to have an irradiance of 30 microwatts/cm²/nm, reliable constant power, availability of Coombs testing and G6PD screening, rapid reliable turnaround TSB levels done on microsamples, and an immediately accessible blood bank, waiting until ∼16 mg/dL in a 48-hour old neonate may well be appropriate.

Since the 2004 AAP guidelines with age-in-hours and risk factors included, we have supported and encouraged the development of local guidelines modeled after these guidelines but that also factor in the unique risk factors and resources. We see the 2022 guidelines as an improvement of the older guidelines. Specific improvements include not only the clear call out to routinely screen neonates belonging to high-risk ethnic groups for G6PD deficiency but also the inclusion of clear additional guidelines based on (a) neurotoxic risk factors, (b) evaluation and treatment of neonates at risk for isoimmune hemolytic disease shortly after birth if not previously screened while continuing to emphasize the recommendation to screen all pregnant mothers for ABO and Rh (D) type and (c) recommendation to use TSB to determine the need for treatment as well as continued support for intensive phototherapy. We see these new guidelines once again as appropriate scaffolding for other countries to build on should they choose to do so. For many regions within SSA, and certainly in most facilities in high-risk countries such as Nigeria, that will mean moving the curves down to lower TSB levels to begin phototherapy and performing ETs at a lower TSB level than currently recommended on the basis of these new AAP guidelines. Another concern of using these new guidelines globally beyond adjusting the curves is highlighted by the work of members of our research team(s) who are currently studying why some neonates in Nigeria have ABE with relatively low TSB levels, whereas others do not get apparent ABE with TSB levels well above recommended ET levels; therefore, at least in LMICs, we are not confident that the statement that “bilirubin neurotoxicity does not occur until well above the 2004 guidelines”¹  is true for all neonates. As recommended, those working in LMICs should develop screening and follow-up procedures that are feasible and sustainable for newborns at risk and those postphototherapy.

We agree, as stated in the new AAP guidelines,¹  that direct sunlight should be discouraged in favor of either intensive electric phototherapy or effective phototherapy with appropriately filtered sunlight (previously shown to be safe and efficacious⁷ ) used only when needed under approved protocols and with careful monitoring to assure the neonate does not become too cold or hot. We will continue to work in collaboration with researchers around the globe to increase availability of effective phototherapy at lower cost with units designed for LMICs in addition to upscaling filtered sunlight phototherapy where or as appropriate.

Maternal prenatal education, routine newborn follow-up 2 to 3 days after birth, availability of low-cost reliable instruments and tools for screening and measuring bilirubin, institution of G6PD screening where indicated, and affordable widely available intensive phototherapy⁸  are all essential if we are to eliminate the scourge of severe hyperbilirubinemia and the death and disability that ensue in LMICs.