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State-of-the-Art

Should we screen newborns for glucose-6-phosphate dehydrogenase deficiency in the United States?

Abstract

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, a common X-linked enzymopathy can lead to severe hyperbilirubinemia, acute bilirubin encephalopathy and kernicterus in the United States. Neonatal testing for G6PD deficiency is not yet routine and the American Academy of Pediatrics recommends testing only in jaundiced newborns who are receiving phototherapy whose family history, ethnicity, or geographic origin suggest risk for the condition, or for infants whose response to phototherapy is poor. Screening tests for G6PD deficiency are available, are suitable for use in newborns and have been used in birth hospitals. However, US birth hospitals experience is limited and no national consensus has emerged regarding the need for newborn G6PD testing, its effectiveness or the best approach. Our review of current state of G6PD deficiency screening highlights research gaps and informs specific operational challenges to implement universal newborn G6PD testing concurrent to bilirubin screening in the United States.

Introduction

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, a common X-linked enzymopathy, plays an important role in the genesis of severe hyperbilirubinemia, acute bilirubin encephalopathy and kernicterus.1, 2 G6PD is key to the antioxidant defense of red blood cells, catalyzing the first step in the hexose monophosphate shunt and reducing nicotinamide adenine dinucleotide phosphate (NADP) to NADPH.3, 4 Because G6PD is the sole source of NADPH in red blood cells, those that are G6PD deficient are susceptible to oxidant-induced hemolysis following exposure to certain drugs, chemicals and/or infections. In a G6PD-deficient newborn, additional bilirubin produced from heme catabolism during hemolysis may contribute substantially to the bilirubin load and precipitate hazardous levels of hyperbilirubinemia.5, 6, 7, 8

The American Academy of Pediatrics (AAP) clinical practice guideline on the management of neonatal hyperbilirubinemia recognizes G6PD deficiency as a major etiologic risk factor for the development of severe hyperbilirubinemia and bilirubin-induced brain damage.9, 10 As a ‘neurotoxicity risk factor’, G6PD deficiency is an indication for lower phototherapy and exchange transfusion treatment thresholds.9, 10 Yet, newborn testing for G6PD deficiency in the United States is not routine and recommended only in jaundiced newborns receiving phototherapy whose family history, ethnicity or geographic origin suggest the possibility of the condition or for infants whose response of phototherapy is poor.9 Molecular deoxyribonucleic acid (DNA) testing for five commonly encountered,11 but not all, G6PD-deficient gene variants in the United States is included in the supplemental newborn screening programs for Pennsylvania and the District of Columbia. However, the genotyping results are frequently not known until well past the period of hyperbilirubinemia risk. US birth hospitals have limited experience in newborn screening for G6PD deficiency,12 and no consensus has emerged regarding the need for, the effectiveness of, or an approach to newborn G6PD testing. We review the current state of G6PD deficiency screening and highlight research gaps and specific operational challenges to implementing G6PD testing as a newborn screening modality in the United States.

G6PD deficiency and severe neonatal hyperbilirubinemia in the United States

Traditionally regarded as a condition limited to the Mediterranean region, Africa, the Middle East and Asia many US pediatricians and neonatologist view G6PD deficiency as having little application to their patients.13, 14, 15 Past and present migration patterns and intermarriage, however, have resulted in the emergence of G6PD deficiency as a clinically relevant concern in the United States and other Western countries as evidenced in several reports.1, 2, 3, 16, 17, 18, 19, 20, 21 The most comprehensive is the US-based pilot kernicterus registry, a database of voluntarily submitted information on 125 infants who developed kernicterus between 1992 and 2004.1, 2, 16 Twenty-six registry infants or 20.8% had G6PD deficiency, a disproportionate overrepresentation as contrasted to the estimated 4 to 7% population prevalence of G6PD deficiency in the United States.22 Not surprisingly, African American neonates comprised the majority (19 of 26, or 73%) consistent with the greater prevalence of G6PD deficiency in this population (12.2% for males; 4.1% for females).22, 23 Moreover, G6PD deficiency appeared to worsen the prognosis among the infants affected with kernicterus. Compared with the group not identified as having G6PD deficiency, more G6PD-deficient infants died (15 vs 4%) or had sepsis (31 vs 14.4%).2

Further evidence that G6PD deficiency is a relevant contributor to neonatal hyperbilirubinemia risk in the United States includes studies from Cleveland and Chicago on African American male newborns. The former study showed that G6PD-deficient infants had significantly higher total serum bilirubin (TSB) levels, were more likely to need phototherapy and comprised almost half of hospital readmissions for hyperbilirubinemia.12 The latter study reported that more G6PD-deficient neonates developed hyperbilirubinemia (>95% on Bhutani nomogram) than did G6PD-normal control subjects (14 of 64, 21.9%, vs 29 of 436, 6.7%; relative risk: 3.27; 95% confidence interval: 1.83 to 5.86).24 G6PD deficiency, exclusive breast-feeding and a predischarge transcutaneous total bilirubin 75th percentile were all significant risk factors for developing subsequent hyperbilirubinemia in this cohort.25

In the United Kingdom17 and Canada,18, 19, 20, 21 experience with newborn G6PD deficiency is similar to that of the United States. In recent surveys, G6PD deficiency was second only to ABO incompatibility and other red blood cell antibodies as an identifiable cause of severe neonatal hyperbilirubinemia (TSB>25 mg dl−1 or had an exchange transfusion) in the Canadian Paediatric Surveillance Program.20, 21 Similarly, in the United Kingdom and Ireland, G6PD deficiency independently increased the risk of bilirubin encephalopathy (odds ratio 28.2, 95% confidence interval 2.6 to 307.7, P=0.006).17 These cases occurred despite attempts to increase awareness of kernicterus risk in widely publicized guidelines for the management of hyperbilirubinemia.9, 10, 26

Clinical presentation of neonatal hyperbilirubinemia in G6PD deficiency

Clinical manifestations of G6PD deficiency during the neonatal period include (i) early- and later-onset hyperbilirubinemia, (ii) persistent or delayed resolution of significant hyperbilirubinemia (due to co-inherited gene variants of uridine 5'-diphospho-glucuronosyltransferase, UGT1A1), (iii) unpredictable hazardous hyperbilirubinemia, (iv) risk of associated sepsis, (v) kernicterus and (vi) neonatal death.1, 2 The two classic presentations of hyperbilirubinemia in G6PD-deficient neonates27, 28 are detailed below.

Acute neonatal hemolytic event

This presentation is usually characterized by acute onset of hemolysis, with a resultant rapid rise in TSB to potentially hazardous levels. The hemolysis may be precipitated by oxidative stress induced by an array of environmental agents (for example, naphthalene in moth balls, drugs) or infection,4, 8, 29, 30, 31 although it is often a challenge to ascertain the trigger.29, 30, 31 The acute onset, akin to favism seen in older patients, is usually unanticipated and frequently occurs following discharge from the birth hospital. Favism by proxy (that is, trigger exposure via breast milk) and exposure to other agents have been reported to precipitate hemolysis.32 This mode of G6PD deficiency-associated neonatal hyperbilirubinemia can result in kernicterus that may not always be preventable with current practice.33 Curiously, many newborns in this category do not develop anemia and/or reticulocytosis yet demonstrate increased levels of carboxyhemoglobin indicative of hemolysis.25, 34

Gradual onset neonatal hyperbilirubinemia and role of UGT1A1 polymorphisms

The second and more frequent mode of hyperbilirubinemia presentation in G6PD-deficient neonates couples low-grade hemolysis with genetic polymorphisms of the UGT1A1 gene that reduce UGT1A1 expression and thereby limit hepatic bilirubin conjugation.35 The resultant hyperbilirubinemia is usually moderate in degree and more gradual in onset and trajectory but occurs more frequently than in the general population. Such hyperbilirubinemia is usually responsive to phototherapy but sometimes requires exchange transfusion. Late preterm gestation, hemolysis or less efficient conjugation can upset this equilibrium further and precipitate extreme hyperbilirubinemia.36, 37

Role of identification of G6PD deficiency in kernicterus prevention strategies

Current kernicterus risk reduction strategies include universal predischarge bilirubin screening coupled with a systematic review of hyperbilirubinemia risk factors during the birth hospitalization and targeted timely post-discharge follow-up. Predischarge bilirubin screening may have limitations in infants with undetected G6PD deficiency. The association of G6PD deficiency in neonates with predischarge bilirubin values >75th percentile25 requires validation. Most important, predischarge bilirubin testing does not predict or identify an infant with later onset of an acute hemolytic event, nor do biologic markers of incipient neonatal hemolysis exist.

Biochemical testing for G6PD deficiency is available, suitable for use in newborns, and has the potential for application during the birth hospitalization. At two stakeholders meetings the potential effectiveness of G6PD deficiency screening to prevent severe neonatal hyperbilirubinemia in the United States was debated (A Planning Conference: Utility of Screening for G6PD Deficiency to Prevent Severe Neonatal Hyperbilirubinemia; 11—12 May, 2007, Bethesda, MD; and A Stake-Holders Conference to Determine the Feasibility of G6PD Deficiency Identification for Prevention of Severe Neonatal Hyperbilirubinemia; 28–29 July, 2009, Bethesda, MD). Research gaps and specific operational challenges related to G6PD testing as a screening modality in neonates are detailed in the paragraphs that follow.

Research gaps

Newborns are screened for G6PD deficiency in some Asian, African, Mediterranean and Middle Eastern countries, where the prevalence is high38, 39, 40, 41, 42, 43, 44 and this has diminished the incidence of favism in children.41 In addition, when combined with parental education on the risks of subsequent jaundice in an affected infant, newborn G6PD screening has been associated with a decreased incidence of severe hyperbilirubinemia and kernicterus in Singapore,43 Greece,38 Saudi Arabia,40 Philippines,44 Taiwan,39, 45 and Hong Kong.45

Nevertheless, it is unclear how relevant experiences in other countries are to the United States. Prolonged initial hospitalization of G6PD-deficient newborns in some programs43 is not practical in the United States. Moreover, predischarge bilirubin screening coupled with parental counseling on hyperbilirubinemia risk routinely practiced in most US birth hospitals will identify a substantial number of at risk neonates without G6PD testing. However, severe hyperbilirubinemia may not occur during the birth hospitalization in G6PD-deficient neonates and may not always be predicted by predischarge bilirubin measurement. Would identification of G6PD-deficient neonates during the birth hospitalization add significantly, incrementally or not at all to identifying neonates at risk and decrease the occurrence of hazardous hyperbilirubinemia in such infants?

We would expect that identification of a G6PD-deficient neonate during the birth hospitalization would heighten surveillance for significant hyperbilirubinemia by medical caregivers, who would also educate families on hyperbilirubinemia risks and ensure timely post-discharge follow-up. However, at the time of discharge, much of the onus for identifying increasing jaundice will fall on the parents. An appointment with a pediatrician, even within recommendations of the AAP9, 10 framework, may be insufficient to detect rapidly rising, exponentially progressing hyperbilirubinemia. Parents would therefore also be instructed to seek immediate medical assistance should new onset jaundice, worsening jaundice in a previously identified icteric newborn, change in behavior, feeding or sleep pattern develop. Testing this hypothesis, however, is no small task in large part because even hazardous hyperbilirubinemia as a surrogate for bilirubin encephalopathy is rare and G6PD deficiency relatively common. Data are still needed to determine whether G6PD screening could provide additional benefit in terms of reductions in adverse outcomes over current newborn hyperbilirubinemia surveillance, discharge and follow-up practices.

Specific operational challenges related to G6PD screening

As noted, some international studies document a benefit of newborn G6PD screening in high-risk populations. However, challenges exist for successful implementation of newborn G6PD screening in the United States.

When and where to screen?

The majority of G6PD-deficient neonates in the US Pilot Kernicterus Registry were rehospitalized within the first week after birth.2 Therefore, to be effective in preventing severe hyperbilirubinemia G6PD screening results must be available to parents and caretakers before discharge from the birth hospital. This necessitates testing in the birth hospital laboratory to ensure parents receive adequate instruction before discharge on the condition, related hyperbilirubinemia risk, jaundice assessment and follow-up care. To meet the typical 48-h (or shorter) birth hospitalization discharge target, most birth hospitals would need to set up a daily G6PD testing service with a quick turnaround time, a facility currently available in few hospitals in the United States.

The University Hospitals of Cleveland implemented a G6PD screening program in which a primary objective was to have fluorescent spot test results available before discharge.12 Only male newborns of high-risk groups, primarily African American, or with a family history of G6PD deficiency were screened. Of 673 males born during a 5-month period in 2007, 453 (67%) were screened, of whom 57 (12.6%) had abnormal findings. All but two results were reported within 48 h. While the effectiveness of this approach in altering care and reducing readmissions for hyperbilirubinemia was not studied, this report supports the feasibility of newborn screening with rapid turnaround time in the United States and the implementation of a parental education program. Two recent independently published quantitative G6PD screening program results from Israel also demonstrate the feasibility of enzyme activity assessments with a short turnaround time.24, 46 The use of samples drawn at the time of routine metabolic screening and shipped to a central laboratory may be cost efficient but will not provide the timely results needed for counseling before discharge. Moreover, exposure to heat en route to a central laboratory may affect the accuracy of biochemical G6PD testing.47

Whom to screen?

A second challenge is whether screening should be (i) targeted to high-risk groups or (ii) universal. Targeted screening is clearly possible and proven effective as in Sephardic Jewish newborns at high risk for G6PD deficiency at the Shaare Zedek Medical Center in Jerusalem. Newborns at risk were identified at birth according to mother’s family geographic origin and a routine cord blood specimen was collected. A qualitative test was run once daily on those babies born during the previous 24 h and the results made available by noon. Parents were given a verbal explanation and written instructions. Of the 12 000 live births during 2008, 276 of 2548 (10.8%) tested infants were G6PD deficient. Of males, 197/1062 (18.5%) were G6PD deficient, compared with 79/1183 (6.7%) of females. During 2008, no exchange transfusions were performed in G6PD-deficient newborns and no cases of kernicterus were identified, compared with 12 exchange transfusions performed on G6PD-deficient neonates in the prior decade (unpublished data M. Kaplan, 2010). At that time, in Israel in general there were on an average 140 000 deliveries per year. Three cases of kernicterus occurred during the decade before 2008 including one death, all in G6PD-deficient newborns.

In the United States, high-risk populations would include primarily African Americans and families with ancestral roots in the Mediterranean Basin, Middle East and Asia. A targeted approach would reduce screening program costs by not testing low-risk newborns, but overall cost-effectiveness would depend on the proportion of high-risk groups in the population.48 The World Health Organization Working Committee49, 50 suggested that G6PD screening be instituted in population groups with a male G6PD incidence of 3 to 5% or more. Assuming a 12% incidence in African American males,23 a hospital with 50% African American births can be expected to meet that threshold G6PD deficiency rate. The pilot G6PD screening program in Cleveland which serves a large at-risk African–American population studied a targeted approach.12 Newborns were assigned the ethnicity of their mother as determined by maternal self-identity on questionnaire and screened if they had an at-risk ethnic background or family history of G6PD deficiency.12

Although maternal self-reported ethnicity is widely used as a surrogate for newborn’s race51 and apropos for X-linked conditions, such as G6PD deficiency, such assignment still often oversimplifies and misclassifies racial ancestry,51 particularly as immigration and interracial unions increase in frequency, and may lead to missed cases of G6PD deficiency. It would be vital to know how many cases of G6PD deficiency might be missed if targeted screening was used. Targeted screening may also be viewed as discriminatory and place screening programs, hospitals and providers at malpractice risk for missed cases.48

The advantage of universal screening by biochemical methods is the detection of virtually all enzyme-deficient males (hemizygotes) and homozygous females. In the United States, an overall 4 to 7% incidence of the condition22 coupled with4 million annual births could yield a substantial number of infants with G6PD deficiency via universal screening. Among African Americans males of whom 11 to 13% are G6PD deficient,22, 23 one would predict between 32 000 and 39 000 hemizygous G6PD-deficient males would be identified each year. Moreover, universal screening can be expected to identify affected neonates born to parents who have intermarried between ethnic groups with resultant mixing of genes, as well as those born to individuals from geographic areas where G6PD deficiency is common.51 Such individual neonates may be missed during screening of targeted high-risk groups. Participants of the Stakeholders meeting favored a universal approach if need for screening was evident.

How to screen?

Biochemical screening assays. Screening for G6PD deficiency should be performed in the steady state and not in the hemolytic or immediate post-hemolytic phase. Screening can be readily accomplished using one of a variety of qualitative or quantitative tests. Many are commercially available, or may be set up in an individual hospital laboratory. Both qualitative and quantitative tests of enzyme activity are based on the reduction of NADP to NADPH which, in turn, reflects G6PD activity. Of the screening tests available, the World Health Organization recommends the fluorescent spot test.50 In this test, the generation of NADPH is visually detected directly under ultraviolet light. The test is designed to identify primarily those with severe enzyme deficiency. Quantitative measurements determine the amount of NADPH produced spectrophotometrically and will identify infants through the entire spectrum of deficient, (intermediate in females) and normal values, an approach favored by Stakeholder meeting participants.

Biochemical testing should accurately identify hemizygous males and homozygous females. Unfortunately, heterozygous females may not be accurately recognized using either qualitative or quantitative biochemical methods.24, 30, 46, 52 Standard biochemical G6PD testing assays represent an average of the deficient and sufficient red blood cell pools in heterozygous females and may give a normal or intermediate reading that is falsely reassuring.53 Even the use of intermediate enzyme activity thresholds is associated with the misclassification of female heterozygotes as sufficient in over 50% of cases.6 More importantly, a heterozygous female reported as enzymatically normal may harbor a sizable population of G6PD-deficient and potentially hemolyzable red blood cells that represent a substantial reservoir of bilirubin.53 Molecular screening is the only way to definitively identify a G6PD-deficient heterozygote,4 but this method may not lend itself to effective newborn screening (see section on biochemical vs molecular screening below). Even with a normal G6PD screening test, female neonates of high-risk ethnic groups would need to be monitored for the appearance of jaundice, to detect the heterozygous subset that may develop hemolysis and subsequent marked hyperbilirubinemia.53, 54

G6PD enzyme deficiency may also be difficult to detect by quantitative or qualitative biochemical methods in an individual who is undergoing or recovering from an acute hemolytic episode. During acute hemolysis, older, G6PD-deficient erythrocytes are removed from the circulation, leaving younger, G6PD-sufficient cells intact. This problem may result in falsely normal testing in newborns with severe hyperbilirubinemia. A solution to this problem in a suspect neonate would be to repeat the test several months later. Alternatively, molecular analysis offers a powerful and accurate means of diagnosis.4 However, one would either have to suspect a known mutation, such as G6PD A− in African Americans and G6PD Mediterranean in individuals of Mediterranean origin, or alternatively perform gene sequencing in which the specific mutation would be identified.

Molecular DNA screening. Molecular screening is not practical at present for birth hospitalization testing given the infrastructure requirements, cost and technical expertise required. As performed by current G6PD screening programs in Pennsylvania and District of Columbia, G6PD genotyping requires the use of a centralized core laboratory with a highly skilled technical staff, incurs the cost of sample transport and is associated with a significant delay in reporting results, typically when the infant is 10 to 14 days of age, well beyond the birth hospitalization and typical period of hyperbilirubinemia risk. Moreover, these programs identify only the common mutations (G6PD A−; G6PD Mediterranean; G6PD Kaiping; G6PD Canton) thought to comprise up to 90% of affected neonates in the United States.11 Less frequent variants, which could be detected by simple biochemical tests, are not detected.

Interpreting the results of screening. Any screening test has false-positive and false-negative results. In hemizygous males, G6PD screening tests are reliable, interpretation straightforward, and the number of false positives or false negatives minimal. Using a quantitative enzyme assay performed on umbilical cord blood in African American males, the mean value for 64 G6PD-deficient infants was 2.7±1.1 U g−1 Hb, range 0.4 to 6.6 U g−1 Hb, while that for 436 G6PD normal neonates was 21.8±2.9 U g−1 Hb, range 14.5 to 33.8 U g−1 Hb.39 There was no overlap between the groups. The problem of female heterozygotes with a normal biochemical test result has been discussed above. Females of population subgroups at high risk for G6PD deficiency must be followed vigilantly for the development of jaundice, regardless of the outcome of the G6PD screening.

Parental instruction. Parental education about G6PD deficiency, neonatal hyperbilirubinemia, jaundice assessment and when to seek pediatric care is critical to the success of any G6PD screening program. Most individuals with G6PD deficiency will lead perfectly normal lives, especially if they avoid hemolytic triggers including fava beans, naphthalene-stored clothes or offending drugs.4 Similarly, the majority of G6PD-deficient neonates will not develop significant jaundice, extreme hyperbilirubinemia will be unusual, and kernicterus will be rare. In the Chicago based study of African Americans,25 approximately one in five G6PD-deficient newborn males developed a TSB >95th percentile on the hour-specific bilirubin nomogram.55 The mean peak TSB was 14.3±3.4 mg dl−1, although these values do not represent the natural peak, because phototherapy had been instituted in many instances. No infant progressed to extreme hyperbilirubinemia, required exchange transfusion or developed kernicterus. Therefore, although many families will be told that their infant has G6PD deficiency, the majority will be unaffected during the neonatal period and for their entire lives.

Proposed research on newborn G6PD screening in the United States

Kernicterus continues to occur in the United States and G6PD deficiency remains an important cause. Despite this recognition, it is unclear whether knowledge of G6PD status in the immediate newborn period will alter neonatal outcomes. Early detection of G6PD deficiency is relevant to determining phototherapy and exchange transfusion treatment thresholds and may enhance risk assessment for subsequent severe hyperbilirubinemia. Study is needed to determine whether the addition of birth hospital-based newborn G6PD testing to standard hyperbilirubinemia risk evaluation, including predischarge bilirubin testing (2009) and parental instruction, will further decrease the risk of marked hyperbilirubinemia and associated morbidities in the United States. Given the rare occurrence of bilirubin encephalopathy, it will be difficult to prove or disprove the value of G6PD screening to prevent kernicterus. Instead, measures of severe (>20 mg dl−1) or extreme (>25 mg dl−1) hyperbilirubinemia levels will need to be used as proxies for risk. We propose a hypothetical model to interpret G6PD screening data concurrent with bilirubin testing (Table 1) and call for a national multi-center study whose primary objective would be to evaluate standard predischarge hyperbilirubinemia risk assessment against the dual screening model (bilirubin and G6PD testing) to prevent (i) severe or extreme hyperbilirubinemia and/or (ii) readmission to hospital for phototherapy. Follow-up in both arms of the study would be based on 2004 AAP guidelines9 and as clarified.10 Other specific aims could address: (i) the relationship between G6PD status determined during the birth hospitalization and the natural history of neonatal jaundice; (ii) how the knowledge of G6PD status in the newborn period influences immediate care, follow-up and ultimate hyperbilirubinemia severity; (iii) whom to screen; and (iv) how best to screen and whether screening for G6PD deficiency is of value without concurrent screening for UGT1A1 polymorphisms? Of key relevance would be determining the costs and benefits of routine G6PD screening on reducing the population burden of hazardous hyperbilirubinemia. The substantial contribution G6PD deficiency makes to the current incidence of kernicterus in the United States underscores the merit of such study.

Table 1 A proposed dual screening model to interpret G6PD screen data with bilirubin screen

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Acknowledgements

This manuscript derives in part from the US Stakeholders meeting convened on 28–29 July 2010 to determine the feasibility of identification of G6PD deficiency to prevent severe hyperbilirubinemia sponsored by the Health Research Services HRSA/NNSGRC. We thank the participants of this Stakeholders Meeting for their thoughtful suggestions and ideas. These individuals include: Duane Alexander (National Institute of Health, NIH), Hani Atrash and Wanda Barfield (Center for Disease Control, CDC), Stan Berberich (Iowa Program, HRSA Newborn Screening), Vinod K Bhutani (Lucile Packard Children’s Hospital at Stanford University), George Buchanan (University of Texas Southwestern Medical School), (Roger Eaton Massachusetts Program, HRSA Newborn Screening), Jim Eckman (Emory University, Atlanta, GA), Bertil Glader (Lucile Packard Children’s Hospital at Stanford University), Alice Gong (University of Texas Health Science Center at San Antonio), Greg Gosch (Luminex), Jeffrey S Gould (Lucile Packard Children’s Hospital at Stanford University), Nancy S Green (Columbia University, New York, NY), Scott Grosse (CDC), Judy Hall (Lucile Packard Children’s Hospital at Stanford University), Harry Hannon (CDC, Quality assurance), Jim Hanson (NIH), Keith Hoots (NHLBI), Carolyn Hoppe (Children’s Hospital of Oakland Research Institute, Oakland, CA), Rodney Howell (NIH), Lois Johnson (Pennsylvania Center for Kernicterus), Michael Kaplan (Shaare-Zadek Hospital, Jerusalem, Israel), Fred Lorey (CDC, Newborn Screening), Marie Mann (HRSA), Mary Nock (Macdonald Hospital, Case Western Reserve University), Kwaku Ohene-Frempong (Children’s Hospital of Philadelphia, University of Pennsylvania), Richard Olney (CDC), Vamsee Pamula (Advanced Liquid Logics, Durham, NC), Michele Parisi (NIH), Leela Phillip and Family (Patient with G6PD and Kernicterus with her family), Michele Puryear (HRSA), Tonse NK Raju (NICHD), Keld Sorenson (Luminex), Ann R. Stark (Safe and Healthy Beginnings Initiative, American Academy of Pediatrics, Baylor College of Medicine), David K Stevenson (Lucile Packard Children’s Hospital at Stanford University), Brad Therrell (NNSGRC), Tina Urv (NIH), Peter van Dyck (HRSA, MCHB) and Jon F Watchko (Magee Women’s Hospital, University of Pittsburgh). We gratefully appreciate the individual contributions of Drs Nancy S Green, Bertil Glader, Marie Mann, Bradley Therrell and Lois Johnson, and their constructive critique of an earlier version of this manuscript. We thank Rohan Vilms and Diana Wise (research assistants) at the Stanford University. We also acknowledge and thank Stella Gengania-Dina and Ronald J Wong for their administrative support at the Stanford University.

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Watchko, J., Kaplan, M., Stark, A. et al. Should we screen newborns for glucose-6-phosphate dehydrogenase deficiency in the United States?. J Perinatol 33, 499–504 (2013). https://doi.org/10.1038/jp.2013.14

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Keywords

  • glucose-6-phosphate dehydrogenase
  • severe neonatal hyperbilirubinemia
  • kernicterus

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