This Is Why Pre-discharge Newborn Testing for G6PD Deficiency in the U.S. Matters

Ramesh Vidavalur MD MBA FAAP

Dr. Vidavalur is an Assistant Professor in Clinical Pediatrics at Weill Cornell Medical College and an attending neonatologist at Cayuga Medical Center at Ithaca.

The World Health Organization’s constitution urges every nation to consider the “highest attainable standard of health as a fundamental right of every human being.” Needless to say, the right to health must be accessible to everyone without discrimination on grounds of race, age, ethnicity, or any other status. Universal newborn screening (NBS), where a small blood sample is obtained in the first few days of life and tested for a panel of metabolic and genetic diseases, offers those critical rights to vulnerable infants, helping their parents take advantage of early detection to plan coordinated care and make lifestyle modifications which can reduce morbidity and mortality.

The importance of newborn screening programs

Since its inception five decades ago, many industrialized nations have implemented NBS programs to detect various diseases. In addition to empowering parents about their child’s health, NBS programs provide safe, effective, timely, individualized healthcare to those babies affected by the early-diagnosed conditions. In this context, although individual states have different panels of NBS disorders, the United States has been a front-runner in implementing these programs nationwide. Combining close surveillance of various diseases with emerging needs, individual states consider many factors before including any new condition to the newborn screening panel list. Here are some examples of the factors that can determine the possibility of a new condition being added to the list:

  • Incidence
  • Prevalence
  • Screening test sensitivity and specificity
  • Associated morbidity and mortality
  • Effectiveness of early recognition
  • Available treatments

The debate over G6PDd inclusion in newborn screening programs

One condition that has been debated for inclusion over the past decade in United States is Glucose-6-Phosphate Dehydrogenase deficiency (G6PDd). G6PDd is one of the most common inherited conditions on the planet.  Worldwide estimates show that G6PDd affects 400 million people.  In the United States, it affects 1 in 10 African American males, compared to 1 in 50 in the general population.  The highest frequency is seen in the Southeast Asian population, and is more common in persons of African and Mediterranean descent.

Deficiency of a critical enzyme that protects red blood cells, which are a key component of the oxygen carrying system, causes the rapid breakdown of red blood cells when exposed to specific triggers such as certain foods, medications, and viral or bacterial infections. Currently there are no well-established criteria for starting a G6PDd newborn screening program, and if started, questions remain on what type of testing would need to be used. WHO recommends G6PDd quantitative screening when the population prevalence in males exceeds 3-5% 1.

Some newborns with this condition can show signs or symptoms at birth. Babies with G6PDd can develop prolonged and severe jaundice in the newborn period. The severity of jaundice can range from mildly elevated levels to a level that can cause kernicterus, a condition causing brain damage due to extreme levels of bilirubin. One study6 estimated that almost 20% of the cases of kernicterus also had G6PDd, and that this complication is more common in African American infants.

To combat this significant complication, many nations with a high incidence have instituted newborn screening programs to identify the deficiency early, to establish close surveillance, and to avoid triggering factors. A recent Scandinavian study 2 highlighted the significant role of G6PDd in the causation of high levels of bilirubin; and why we need to be vigilant about this condition in the western world to avoid chronic, rarely lethal, complications. Singapore has been doing this surveillance for the last 55 years by measuring G6PD levels in cord blood and keeping enzyme-deficient infants in the hospital for two weeks. The idea is to reduce the risk of unexpected hemolytic anemia and the resulting rapid rise in bilirubin levels. While implementing these measures raises cost concerns in low-incidence countries, it does show that early recognition of G6PDd reduces morbidity of the disease, at least in the neonatal period. One in four babies in the US Pilot Kernicterus Registry who were re-hospitalized within the first week after birth had G6PDd6. Therefore, to be effective in preventing severe hyperbilirubinemia related complications, G6PD screening results must be available to parents and primary care physicians before discharge from the birth hospital. Now, with cost concerns and uncertainties in the economic and health benefits of NBS, many countries have started to do economic evaluations to study specific NBS conditions to aid in their policy decisions.

Universal pre-discharge G6PDd newborn testing economic evaluation

Recently, albeit using the limited available data on prevalence, morbidity, health benefits, and costs, we did an empirical economic evaluation of pre-discharge G6PDd universal newborn testing for birth hospitalizations in the United States 3. From our modelling and analysis, out of 3.7 million annual births, we can expect around 78,000 to 82,000 newborns to have G6PDd, with more than two-thirds of them being African American newborns (~52,000 newborns). Considering the current incidence of newborns with bilirubin levels high enough to be at or above the threshold for treatment with a life-saving blood transfusion, we predict that G6PDd is associated with 1,500 of these newborns and can lead to a minimum of 14 (range 9-21) cases of kernicterus.

If the current kernicterus estimates of 1 per 100,000 is to be believed, there would be a minimum of 37 cases annually 4,5.  Health Resources and Services Administration estimates the occurrence is between 20-108 cases per annum. Applying previous estimates from the contribution of G6PDd 6 to these overall cases, at least 8 cases could be due to an underlying diagnosis of G6PDd. Although evidence is lacking regarding the impact of screening on the improvement in bilirubin-related outcomes in the newborn period in cases of G6PDd, historical studies looking at effectiveness of universal bilirubin screening before discharge might give some clues. Applying the projected impacts of universal newborn screening on the incidence of kernicterus (45-73% reduction as per HRSA report), we did a cost effectiveness analysis to understand the value of pre-discharge testing for G6PDd. At an assumed 50% effectiveness, the benefit-cost ratios ranged from 0.19 to 3.42.  We concluded that at a cost-effectiveness threshold of $100,000 per saved life year, pre-discharge testing might be cost-effective if implemented nationally.

Figure 1

In another study (unpublished), we looked at the number of estimated G6PDd-deficient newborns in the United States (Figure 1). We concluded that there is disproportionate prevalence depending on race across the states (Figure 2).  Our estimates are based on a recent population study that looked at racial and sex differences in prevalence of G6PDd among military recruits 7.  Currently only Pennsylvania and Washington D.C. perform genetic testing for G6PDd as part of their NBS program.  As a nation, if you take the WHO prevalence threshold rates for starting a program, both the non-Hispanic black male and female populations qualify for universal newborn screening with prevalence rates of 11.2% and 4.7%, respectively.  The top five states with the highest expected number of G6PDd infants are California, Texas, New York, Florida and Illinois. (Figure 3)

Although experts agree that kernicterus in developed countries should be considered a “never event,” it continues to occur for different reasons. We emphasize that eliminating one more risk factor, such as G6PDd, could save a considerable amount of long-term neurodevelopmental disabilities in the affected population and their families.  This is especially true if it happens in the high-risk, socio-economically disadvantaged population, where there are already considerable healthcare disparities. We conclude that any intervention that is ethically and evidentially justified to reduce the rare burden of hazardous bilirubinemia, and subsequent kernicterus spectrum disorder, based outcomes is a noble one. Pre-discharge testing for G6PDd is such an intervention.

Figure 2

Figure 3


  1. WHO Working Group Glucose-6-phosphate dehydrogenase deficiency. Bull World Health Organ. 1989;67:601–11
  2. Kristensen L, Lai AB, Ebbesen F, Donneborg ML. A greater awareness of children with glucose-6-phosphate dehydrogenase deficiency is imperative in western countries. Acta Paediatr. 2021 Jun;110(6):1935-1941. doi: 10.1111/apa.15803. Epub 2021 Feb 15. PMID: 33560519.
  3. Vidavalur R, Bhutani VK. Economic evaluation of point of care universal newborn screening for glucose-6-Phosphate dehydrogenase deficiency in United States. J Matern Fetal Neonatal Med. 2021 Feb 24:1-9. doi: 10.1080/14767058.2021.1892067. Epub ahead of print. PMID: 33627013-
  6. Johnson L, Bhutani VK, Karp K, Sivieri EM, Shapiro SM. Clinical report from the pilot USA Kernicterus Registry (1992 to 2004). J Perinatol. 2009 Feb;29 Suppl 1:S25-45. doi: 10.1038/jp.2008.211. PMID: 19177057
  7. Lee J, Poitras BT. Prevalence of glucose-6-phosphate dehydrogenase deficiency, U.S. Armed Forces, May 2004-September 2018. MSMR. 2019 Dec;26(12):14-17. PMID: 31860324.