Advances to diminish global newborn kernicterus mortality.

OBJECTIVE: Initiatives, "Every Newborn Action Plans" and "Sustainable Developmental Goals," are profoundly shaping global infant mortality trends. Concurrently, professional organizations recommended curricula to prevent extreme hyperbilirubinemia (EHB) sequelae. Therefore we assessed if these efforts have successfully decreased EHB-related mortality over time. STUDY DESIGN: We used the Global Burden of Diseases 2019 database to determine neonatal and infant mortality and the burden of kernicterus from 1990-2019. RESULTS: Globally, kernicterus accounted for 2.8 million infant deaths and trended downwards significantly from 1990 to 2019. By 2019, kernicterus-related mortality was 4 and 293 per million livebirths in high (HICs) and low income countries (LICs), respectively. 82% of deaths occurred in LICs and lower-middle income-countries. Average declines of mortality rates were 6.2% and 3.0% for HICs and LICs, respectively. CONCLUSIONS: Kernicterus-related mortality has been effectively reduced to <5 per million in HICs. Skills and knowledge transfer can potentially transform frontline services to bridge discordant kernicteric outcomes worldwide.

A "Gold Standard" Test for Diagnosing and Quantifying Hemolysis in Neonates and Infants.

Identifying "gold standard" diagnostic tests can promote evidence-based neonatology practice. Hemolysis is a pathological shortening of the erythrocyte lifespan, differing from erythrocyte senescence in responsible mechanisms and clinical implications. Diagnosing hemolysis goes beyond a binary (yes vs. no) determination. It is characterized according to magnitude, and as acute vs. chronic, and genetically based vs. not. For neonates with significant hyperbilirubinemia or anemia, detecting hemolysis and quantifying its magnitude provides diagnostic clarity. The 2022 American Academy of Pediatrics (AAP) Clinical Practice Guideline on management of hyperbilirubinemia in the newborn states that hemolysis is a risk factor for developing significant hyperbilirubinemia and neurotoxicity. The guideline recommends identifying hemolysis from any cause, but specific guidance is not provided. A spectrum of laboratory tests has been endorsed as diagnostic methods for hemolysis. Herein we examine these laboratory tests and recommend one as the "gold standard" for diagnosing and quantifying hemolysis in neonates and infants.

Transcutaneous bilirubinometry versus total serum bilirubin measurement for newborns.

BACKGROUND: Jaundice is a very common condition in newborns, affecting up to 60% of term newborns and 80% of preterm newborns in the first week of life. Jaundice is caused by increased bilirubin in the blood from the breakdown of red blood cells. The gold standard for measuring bilirubin levels is obtaining a blood sample and processing it in a laboratory. However, noninvasive transcutaneous bilirubin (TcB) measurement devices are widely available and used in many settings to estimate total serum bilirubin (TSB) levels. OBJECTIVES: To determine the diagnostic accuracy of transcutaneous bilirubin measurement for detecting hyperbilirubinaemia in newborns. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL and trial registries up to 18 August 2022. We also checked the reference lists of all included studies and relevant systematic reviews for other potentially eligible studies. SELECTION CRITERIA: We included cross-sectional and prospective cohort studies that evaluated the accuracy of any TcB device compared to TSB measurement in term or preterm newborn infants (0 to 28 days postnatal age). All included studies provided sufficient data and information to create a 2 × 2 table for the calculation of measures of diagnostic accuracy, including sensitivities and specificities. We excluded studies that only reported correlation coefficients. DATA COLLECTION AND ANALYSIS: Two review authors independently applied the eligibility criteria to all citations from the search and extracted data from the included studies using a standard data extraction form. We summarised the available results narratively and, where possible, we combined study data in a meta-analysis. MAIN RESULTS: We included 23 studies, involving 5058 participants. All studies had low risk of bias as measured by the QUADAS 2 tool. The studies were conducted in different countries and settings, included newborns of different gestational and postnatal ages, compared various TcB devices (including the JM 101, JM 102, JM 103, BiliChek, Bilitest and JH20-1C) and used different cutoff values for a positive result. In most studies, the TcB measurement was taken from the forehead, sternum, or both. The sensitivity of various TcB cutoff values to detect significant hyperbilirubinaemia ranged from 74% to 100%, and specificity ranged from 18% to 89%. AUTHORS' CONCLUSIONS: The high sensitivity of TcB to detect hyperbilirubinaemia suggests that TcB devices are reliable screening tests for ruling out hyperbilirubinaemia in newborn infants. Positive test results would require confirmation through serum bilirubin measurement.

Georacial Epidemiological Estimates of Glucose-6-Phosphate Dehydrogenase Deficiency among Newborns in the United States.

OBJECTIVE: Glucose-6-phosphate dehydrogenase deficiency (G6PDd) is the most common inherited enzyme deficiency disorder worldwide and a major risk factor for the development of severe hyperbilirubinemia. Racial diversity of phenotypes and genotypes in affected individuals is likely to exist in the United States because of changing population demographics. The aim of the present study was to predict an empirical estimate of annual prevalence of G6PDd in newborns adjusted for geography (state of birth), maternal racial identity, and sex of the infant. STUDY DESIGN: Birth statistics (2019) from National Center for Vital Statistics and CDC-WONDER data and race-specific prevalence of G6PDd in the United States were evaluated from published sources. We developed Simpson's diversity index (DI) for each State and correlated these to rates of G6PDd in neonates. Descriptive statistics including modeled prevalence and its association with DI were assessed using the Spearman's rho correlation test. We modeled state-specific prevalence for six states (California, Washington DC, Illinois, Massachusetts, New York, and Pennsylvania) using population-level allele frequencies and race, based on Hardy-Weinberg equilibrium. RESULTS: We estimated 78,010 (95% confidence interval: 76,768-79,252) newborns had G6PDd at birth in 2019 with cumulative median prevalence of 17.3 (interquartile range: 12.4-23.2) per 1,000 live births for United States. A strong association was noted for DI and prevalence of G6PDd (p < 0.0005). Five states (Washington DC, Mississippi, Louisiana, Georgia, and Maryland) have the highest projected G6PDd prevalence, with a range of 35 to 48 per 1,000 live births. The probability of G6PDd for female heterozygotes, based on male prevalence, ranged from 1.1 to 7.5% for each cohort in the select six states. CONCLUSION: States with diverse populations are likely to have higher rates of G6PDd. These prevalence estimates exceeded by several-fold when compared with disorders screened by existing state mandated newborn screening panels. These discrepancies are further confounded by known risk of severe neonatal hyperbilirubinemia that results with G6PDd and the life-long risk of hemolysis. Combined universal newborn predischarge screening for G6PDd and bilirubin could alert and guide a clinician's practices for parental education and closer medical surveillance during the vulnerable neonatal time period. KEY POINTS: · G6PDd is a common X-linked disorder that can present with varied phenotypes among newborns.. · Prevalence of G6PDd and genotype distribution varies with sex, race, and ethnicity.. · We present regional race- and sex-based estimates of G6PDd in the United States..

Chemoprevention of bilirubin encephalopathy with a nanoceutical agent.

BACKGROUND: Targeted rapid degradation of bilirubin has the potential to thwart incipient bilirubin encephalopathy. We investigated a novel spinel-structured citrate-functionalized trimanganese tetroxide nanoparticle (C-Mn3O4 NP, the nanodrug) to degrade both systemic and neural bilirubin loads. METHOD: Severe neonatal unconjugated hyperbilirubinemia (SNH) was induced in neonatal C57BL/6j mice model with phenylhydrazine (PHz) intoxication. Efficiency of the nanodrug on both in vivo bilirubin degradation and amelioration of bilirubin encephalopathy and associated neurobehavioral sequelae were evaluated. RESULTS: Single oral dose (0.25 mg kg-1 bodyweight) of the nanodrug reduced both total serum bilirubin (TSB) and unconjugated bilirubin (UCB) in SNH rodents. Significant (p < 0.0001) UCB and TSB-degradation rates were reported within 4-8 h at 1.84 ± 0.26 and 2.19 ± 0.31 mg dL-1 h-1, respectively. Neural bilirubin load was decreased by 5.6 nmol g-1 (p = 0.0002) along with improved measures of neurobehavior, neuromotor movements, learning, and memory. Histopathological studies confirm that the nanodrug prevented neural cell reduction in Purkinje and substantia nigra regions, eosinophilic neurons, spongiosis, and cell shrinkage in SNH brain parenchyma. Brain oxidative status was maintained in nanodrug-treated SNH cohort. Pharmacokinetic data corroborated the bilirubin degradation rate with plasma nanodrug concentrations. CONCLUSION: This study demonstrates the in vivo capacity of this novel nanodrug to reduce systemic and neural bilirubin load and reverse bilirubin-induced neurotoxicity. Further compilation of a drug-safety-dossier is warranted to translate this novel therapeutic chemopreventive approach to clinical settings. IMPACT: None of the current pharmacotherapeutics treat severe neonatal hyperbilirubinemia (SNH) to prevent risks of neurotoxicity. In this preclinical study, a newly investigated nano-formulation, citrate-functionalized Mn3O4 nanoparticles (C-Mn3O4 NPs), exhibits bilirubin reduction properties in rodents. Chemopreventive properties of this nano-formulation demonstrate an efficacious, efficient agent that appears to be safe in these early studies. Translation of C-Mn3O4 NPs to prospective preclinical and clinical trials in appropriate in vivo models should be explored as a potential novel pharmacotherapy for SNH.

Economic evaluation of point of care universal newborn screening for glucose-6-Phosphate dehydrogenase deficiency in United States.

BACKGROUND AND OBJECTIVES: Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency is frequent inherited enzymopathy that poses potentially preventable risk for extreme hyperbilirubinemia (EHB) which can, rarely, lead to acute bilirubin encephalopathy, childhood kernicterus and death. We aimed to estimate quality adjusted life years (QALY) lost due to G6PD deficiency associated with EHB and economic costs to best estimate value of universal pre-discharge screening. METHODS: We did a cost utility analysis for US birth cohort utilizing pre-discharge screening decision tree model to estimate population burden and EHB outcomes, based on literature search and expert opinions. Employing human capital approach, we measured health benefits in terms of QALYs and economic losses. QALYs and costs were discounted at 3%; one-way sensitivity analysis was used for decision variables. RESULTS: We determined for USA live births of 3.86 million in 2017, 1464 cases of EHB were estimated to be due to G6PD deficiency (CI 95%; range: 1270-1656) and contributed 2 deaths (CI 95%; range 1.3-3.2) and 14 (CI 95%; range: 9.1-21.5) cases of kernicterus. Over lifetime horizon, the model predicted undiscounted and discounted gains of 165 (102-252) life years; 241 (183-433) QALYs and 16 (9.9-24.5) life years; 89 (67.9-160.5) QALYs, respectively. Assuming 50% effectiveness, benefit cost ratios ranged from 0.19 to 3.42 for diverse operational settings. The cost to prevent a single case of kernicterus was $2.7 to 6.8 million per annum with cost per QALY gained at $35,946 to $89,159. CONCLUSION: At incremental cost-effective threshold of $100,000/life year, pre-discharge screening would be expected to prove cost effective in preventing EHB related morbidities and mortality attributed to G6PD deficiency.

Hour-Specific Total Serum Bilirubin Percentiles for Infants Born at 29-35 Weeks' Gestation.

INTRODUCTION: As preterm infants are susceptible to hyperbilirubinemia, they require frequent close monitoring. Prior to initiation of phototherapy, hour-specific total serum bilirubin (TSB) percentile cut-points are lacking in these infants, which led to the current study. METHODS: A multi-site retrospective cohort study of preterm infants born between January 2013 and June 2017 was completed at 3 NICUs in Ontario, Canada. A total of 2,549 infants born at 290/7-356/7 weeks' gestation contributed 6,143 pre-treatment TSB levels. Hour-specific TSB percentiles were generated using quantile regression, further described by degree of prematurity, and among those who subsequently received phototherapy. RESULTS: Among all infants, at birth, hour-specific pre-treatment, TSB percentiles were 36.1 µmol/L (95% confidence interval [CI]: 34.3-39.3) at the 40th, 52.3 µmol/L (49.4-55.1) at the 75th, and 79.5 µmol/L (72.1-89.6) at the 95th percentiles. The corresponding percentiles were 39.3 µmol/L (35.9-43.2), 55.4 µmol/L (52.1-60.2), and 87.1 µmol/L (CI 70.5-102.4) prior to initiating phototherapy and 24.4 µmol/L (20.4-28.8), 35.3 µmol/L (31.1-41.5), and 52.0 µmol/L (46.1-62.4) among those who did not receive phototherapy. Among infants born at 29-32 weeks, pre-treatment TSB percentiles were 53.9 µmol/L (49.4-61.0) and 95.5 µmol/L (77.5-105.0) at the 75th and 95th percentiles, with respective values of 48.7 µmol/L (43.0-52.3), and 74.1 µmol/L (64.8-83.2) for those born at 33-35 weeks' gestation. CONCLUSION: Hour-specific TSB percentiles, derived from a novel nomogram, may inform how bilirubin is described in preterm newborns. Further research of pre-treatment TSB levels is required before clinical consideration.

A New Hour-Specific Serum Bilirubin Nomogram for Neonates ≥35 Weeks of Gestation.

OBJECTIVE: To develop a statistically rigorous, hour-specific bilirubin nomogram for newborns based on a very large data set; and use it prospectively as a replacement for the 1999 Bhutani nomogram. STUDY DESIGN: This was a retrospective analysis of first total serum bilirubin (TSB) measurements from 15 years of universal bilirubin screening during birth hospitalizations at 20 Intermountain Healthcare hospitals. Hour-specific TSB values were assembled into a nomogram by percentile, and subgroups were compared. RESULTS: The information obtained included robust data in the first 12 hours after birth (which was not included in the 1999 nomogram), general agreement with the 1999 nomogram for values in the first 60 hours, but higher 75th and 95th percentile TSB values thereafter in the new version, no difference in TSB between male and female infants, higher TSB values among earlier gestation neonates (350/7-366/7 weeks vs ≥37 weeks, P < .0001), and lower TSB values in neonates of Black race (P < .0001) and higher values in neonates of Asian race (P < .001). CONCLUSIONS: An updated and more informative Bhutani neonatal bilirubin nomogram, based on 140 times the number of subjects included the 1999 version, is now in place in our health care system.

A novel point-of-care device for measuring glucose-6-phosphate dehydrogenase enzyme deficiency.

Extreme hyperbilirubinemia can cause bilirubin neurotoxicity. Infants with glucose-6-phosphate dehydrogenase (G6PD) deficiency can develop hemolysis and thus are at high risk. We evaluated a device that quantitatively measures G6PD activity kinetically using digital microfluidics (DMF). Intra- and inter-instrument and -day imprecision (CVs) were first assessed. G6PD activity in 86 samples was then measured and compared between DMF and 2 reference methods. Overall DMF reproducibility was 3.8% over 5 days by 2 operators on 2 instruments. Mean intra- and inter-instrument variabilities were 3.6% and 3.9%, respectively (n = 28), with a user variability of 4.3%. Mean G6PD activity was 6.40±4.62 and 6.37±4.62 U/g hemoglobin for DMF and Reference Methods 1 (n = 46) and 12.15±3.86 and 11.48±1.55 for DMF and 2 (n = 40), respectively, and strongly correlated (r = 0.95 and 0.95) with mean biases of +0.04±2.90 and +0.67±1.55 for methods 1 and 2, respectively. The novel device could be used for early newborn G6PD screening.

Estimated disease burden and lost economic productivity due to glucose-6-phosphate dehydrogenase deficiency in Nigerian newborns.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency rarely manifests as extreme hyperbilirubinemia [EHB, total serum/plasma bilirubin > 25 mg/dL (428 µmol/L)]. It is a major preventable cause of newborn morbidity and mortality. In resource-constrained communities of Nigeria, experts have observed its significant clinical burden. We accessed a previously published pooled model of G6PD deficiency and determined its prevalence, subsequent risk of EHB, kernicterus, and death to be 26.4% [95% confidence interval (CI): 19.5, 33.2%]; 33.3% (95%CI: 16.6, 50%); and 22.7% (95% CI: 16.5, 28.9%), respectively. The total number of disability-adjusted life years (DALYs) lost to symptomatic G6PD deficiency was 54,251 (95% CI: 6,039, 189,149). Estimated national average economic deficits due to mortality and disability ranged from $309 to $584 million. G6PD deficiency, when symptomatic in Nigerian newborns, is a significant disease burden, placing 1% of annual births at increased risks of neonatal mortality and morbidity, which contribute to significant economic productivity losses.

Does provider access to technology improve health care? Evidence from a national distribution of phototherapy in Rwanda.

This study assessed a large-scale national distribution of phototherapy (PT) for infants at risk for severe hyperbilirubinemia. We combined healthcare data for infants with jaundice (using local clinical definitions) with a randomized roll-out of PT devices to estimate the causal effect of the national distribution. Pre-intervention, <3.0% of infants were diagnosed as jaundiced, 41.7% of these infants were not tested for bilirubin, and 17.5% and 34.3% were treated with direct sunlight or standard PT, respectively. We found that providing hospitals with PT devices increased care practices: infants with jaundice were more likely to receive PT [+6.26 percentage points (pp)], and less likely to receive sunlight (-6.96 pp) or standard (irradiance < 30 µW/cm2/nm) PT (-14.0 pp). However, the intervention did not affect the low diagnosis rate. Our findings suggest that complementary investments in improving diagnosis and monitoring of bilirubin levels increases the benefits of expanding provider access to PT devices.

Neonatal hyperbilirubinemia management: Clinical assessment of bilirubin production.

The predominant cause of elevated total/plasma bilirubin (TB) levels is from an increase in bilirubin production primarily because of ongoing hemolysis. If undiagnosed or untreated, the risk for developing extreme neonatal hyperbilirubinemia and possibly bilirubin-induced neurological dysfunction (BIND) is increased. Since carbon monoxide (CO) and bilirubin are produced in equimolar amounts during the heme catabolic process, measurements of end-tidal CO levels, corrected for ambient CO (ETCOc) can be used as a direct indicator of ongoing hemolysis. A newly developed point-of-care ETCOc device has been shown to be a useful for identifying hemolysis-associated hyperbilirubinemia in newborns. This review summarizes the biology of bilirubin production, the clinical utility of a novel device to identify neonates undergoing hemolysis, and a brief introduction on the use of ETCOc measurements in a cohort of neonates in China.

Clinical decision support tool for phototherapy initiation in preterm infants.

OBJECTIVE: Adherence to guidelines for phototherapy initiation in preterm infants was 39% in our academic NICU (61% of phototherapy was initiated at total bilirubin (TB) levels below recommended thresholds). We hypothesized that adoption of an electronic health record integrated clinical decision support (CDS) tool would improve adherence to phototherapy guidelines. STUDY DESIGN: We developed and implemented Premie BiliRecs (PBR), a novel CDS tool for phototherapy initiation in preterm infants from 27 through 34 weeks postmenstrual age. The primary outcome measure was the proportion of phototherapy initiation events consistent with recommended TB thresholds. RESULT: Following the implementation of PBR, adherence to guidelines for phototherapy initiation in preterm infants increased to 69.8% (p < 0.001), an improvement of 77%. There was no increase in the incidence of severe hyperbilirubinemia nor exchange transfusions. CONCLUSION: The adoption of PBR was associated with improved adherence to phototherapy guidelines in preterm infants without increased adverse events.