RESUMEN
Very high unconjugated bilirubin plasma concentrations in neonates (neonatal hyperbilirubinaemia; NH) may cause neurologic damage (kernicterus). Both increased red blood cell turn-over and immaturity of hepatic glucuronidation contribute to neonatal hyperbilirubinaemia. The incidence of NH requiring phototherapy during the first week of life on the Thailand-Myanmar border is high (approximately 25%). On the Thailand-Myanmar border we investigated the contribution of genetic risk factors to high bilirubin levels in the first month of life in 1596 neonates enrolled in a prospective observational birth cohort study. Lower gestational age (<38 weeks), mutations in the genes encoding glucose-6-phosphate dehydrogenase (G6PD) and uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A1 were identified as the main independent risk factors for NH in the first week, and for prolonged jaundice in the first month of life. Population attributable risks (PAR%) were 61.7% for lower gestational age, 22.9% for hemi or homozygous and 9.9% for heterozygous G6PD deficiency respectively, and 6.3% for UGT1A1*6 homozygosity. In neonates with an estimated gestational age ≥ 38 weeks, G6PD mutations contributed PARs of 38.1% and 23.6% for "early" (≤ 48 hours) and "late" (49-168 hours) NH respectively. For late NH, the PAR for UGT1A1*6 homozygosity was 7.7%. Maternal excess weight was also a significant risk factor for "early" NH while maternal mutations on the beta-globin gene, prolonged rupture of membranes, large haematomas and neonatal sepsis were risk factors for "late" NH. For prolonged jaundice during the first month of life, G6PD mutations and UGT1A1*6 mutation, together with lower gestational age at birth and presence of haematoma were significant risk factors. In this population, genetic factors contribute considerably to the high risk of NH. Diagnostic tools to identify G6PD deficiency at birth would facilitate early recognition of high risk cases.
RESUMEN
OBJECTIVES: New point-of-care (POC) quantitative G6PD testing devices developed to provide safe radical cure for Plasmodium vivax malaria may be used to diagnose G6PD deficiency in newborns at risk of severe neonatal hyperbilirubinaemia, improving clinical care, and preventing related morbidity and mortality. METHODS: We conducted a mixed-methods study analysing technical performance and usability of the 'STANDARD G6PD' Biosensor when used by trained midwives on cord blood samples at two rural clinics on the Thailand-Myanmar border. RESULTS: In 307 cord blood samples, the Biosensor had a sensitivity of 1.000 (95% CI: 0.859 to 1.000) and a specificity of 0.993 (95% CI: 0.971 to 0.999) as compared with gold-standard spectrophotometry to diagnose G6PD-deficient newborns using a receiver operating characteristic (ROC) analysis-derived threshold of ≤4.8 IU/gHb. The Biosensor had a sensitivity of 0.727 (95% CI: 0.498 to 0.893) and specificity of 0.933 (95% CI: 0.876 to 0.969) for 30%-70% activity range in girls using ROC analysis-derived range of 4.9-9.9 IU/gHb. These thresholds allowed identification of all G6PD-deficient neonates and 80% of female neonates with intermediate phenotypes.Need of phototherapy treatment for neonatal hyperbilirubinaemia was higher in neonates with deficient and intermediate phenotypes as diagnosed by either reference spectrophotometry or Biosensor.Focus group discussions found high levels of learnability, willingness, satisfaction and suitability for the Biosensor in this setting. The staff valued the capacity of the Biosensor to identify newborns with G6PD deficiency early ('We can know that early, we can counsel the parents about the chances of their children getting jaundice') and at the POC, including in more rural settings ('Because we can know the right result of the G6PD deficiency in a short time, especially for the clinic which does not have a lab'). CONCLUSIONS: The Biosensor is a suitable tool in this resource-constrained setting to identify newborns with abnormal G6PD phenotypes at increased risk of neonatal hyperbilirubinaemia.