New Roles for Albumin/Globulin Ratio in the Early-Onset Hyperbilirubinemia among Infants Born Weighing 1,000 to 2,499 Grams

Abstract

Introduction Early-onset hyperbilirubinemia (EOH) is a clinical issue for premature infants. We predicted that EOH management would be improved by fast results from common laboratory tests. Total serum bilirubin (TSB) level and the albumin/globulin ratio may contribute to improving the management of EOH.

Objective The aim of the study is to examine the relationship between EOH and perinatal variables among infants born weighing 1,000 to 2,499 g.

Study Designs A single center study was undertaken at Ohta Nishinouchi Hospital between April 1, 2016 and January 31, 2022, using blood samples prospectively collected from infants admitted to the neonatal intensive care unit that were assessed by univariate analyses and multivariate logistic regression analysis. Due to a correlation between gestational age (GA) and birth weight (BW), each variable was entered separately into Model 1 (including GA) and 2 (including BW).

Results A total of 508 infants were analyzed (270 in the non EOH group and 238 in the EOH group). No infants experienced feto-maternal transfusion syndrome or hemolytic diseases such as blood type (ABO or Rh) incompatibility or glucose-6-phosphate dehydrogenase deficiency during perinatal period. Significant relationships were observed between EOH and BW (p <0.01, odds ratio [OR], 0.997; 95% confidence interval [CI], 0.996–0.997), albumin (p <0.01, OR, 0.278; 95% CI, 0.129–0.599), albumin/globulin ratio (p <0.01, OR, 2.695; 95% CI, 1.378–5.270), TSB (p <0.01, OR, 2.774; 95% CI, 1.795–4.287), and antenatal corticoid therapy (p = 0.02, OR, 1.852; 95% CI, 1.108–3.097) in Model 2. Per receiver operating characteristic curves, an albumin/globulin ratio of 1.84 could predict EOH at a sensitivity of 50.0% and specificity of 75.6% (AUC = 0.652, p <0.01, 95% CI, 0.603–0.700).

Conclusion Albumin/globulin ratio among infants born weighing 1,000 to 2,499 g may be a useful indicator of EOH.

Key Points

• Early-onset hyperbilirubinemia (EOH) is a clinical issue for premature infants.

• EOH management expected to be improved through the use of common laboratory tests.

• Albumin/globulin ratio among low birth weight infants may be a useful indicator of EOH.

Keywords

albumin/globulin ratio - early-onset hyperbilirubinemia - low birth weight infants - neonatal intensive care unit

Authors' Contributions

All authors have participated in clinical study design and interpretation. T.I. drafted the first version of the manuscript. T.I. and S.Y. analyzed the data of the study. Y.K. and S.Y. collected the data of the study (including medical treatment) and revised a part of the manuscript critically. T.I. and Y.N. reviewed the manuscript critically. All authors read and approved the final manuscript. All authors contributed equally.

Publication History

Received: 13 February 2022

Accepted: 11 April 2022

Article published online:
25 May 2022

• References

• 1 Keren R, Luan X, Friedman S, Saddlemire S, Cnaan A, Bhutani VK. A comparison of alternative risk-assessment strategies for predicting significant neonatal hyperbilirubinemia in term and near-term infants. Pediatrics 2008; 121 (01) e170-e179
• 2 Arnold C, Pedroza C, Tyson JE. Phototherapy in ELBW newborns: does it work? Is it safe? The evidence from randomized clinical trials. Semin Perinatol 2014; 38 (07) 452-464
• 3 Watchko JF, Tiribelli C. Bilirubin-induced neurologic damage—mechanisms and management approaches. N Engl J Med 2013; 369 (21) 2021-2030
• 4 Morris BH, Oh W, Tyson JE. et al; NICHD Neonatal Research Network. Aggressive vs. conservative phototherapy for infants with extremely low birth weight. N Engl J Med 2008; 359 (18) 1885-1896
• 5 Cashore WJ. Bilirubin and jaundice in the micropremie. Clin Perinatol 2000; 27 (01) 171-179
• 6 Bratlid D. Criteria for treatment of neonatal jaundice. J Perinatol 2001; 21 (Suppl. 01) S88-S92
• 7 Newman TB, Liljestrand P, Escobar GJ. Combining clinical risk factors with serum bilirubin levels to predict hyperbilirubinemia in newborns. Arch Pediatr Adolesc Med 2005; 159 (02) 113-119
• 8 Itabashi K, Miura F, Uehara R, Nakamura Y. New Japanese neonatal anthropometric charts for gestational age at birth. Pediatr Int 2014; 56 (05) 702-708
• 9 Malek A, Sager R, Kuhn P, Nicolaides KH, Schneider H. Evolution of maternofetal transport of immunoglobulins during human pregnancy. Am J Reprod Immunol 1996; 36 (05) 248-255
• 10 Metzger BE, Gabbe SG, Persson B. et al; International Association of Diabetes and Pregnancy Study Groups Consensus Panel. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 2010; 33 (03) 676-682
• 11 Brown MA, Magee LA, Kenny LC. et al; International Society for the Study of Hypertension in Pregnancy (ISSHP). Hypertensive disorders of pregnancy: ISSHP classification, diagnosis, and management recommendations for international practice. Hypertension 2018; 72 (01) 24-43
• 12 NIH Consensus Development Panel on the Effect of Corticosteroids for Fetal Maturation on Perinatal Outcomes. Effect of corticosteroids for fetal maturation on perinatal outcomes. JAMA 1995; 273 (05) 413-418
• 13 Perlman JM, Wyllie J, Kattwinkel J. et al; Neonatal Resuscitation Chapter Collaborators. Part 7: neonatal resuscitation: 2015 International consensus on cardiopulmonary resuscitation and emergency cardiomuscular care science with treatment recommendations. Pediatrics 2015; 136 (Suppl. 02) S120-S166
• 14 Nakamura H, Yonetani M, Uetani Y, Funato M, Lee Y. Determination of serum unbound bilirubin for prediction of kernicterus in low birthweight infants. Acta Paediatr Jpn 1992; 34 (06) 642-647
• 15 Wiberg N, Källén K, Olofsson P. Base deficit estimation in umbilical cord blood is influenced by gestational age, choice of fetal fluid compartment, and algorithm for calculation. Am J Obstet Gynecol 2006; 195 (06) 1651-1656
• 16 American Academy of Pediatrics. Practice parameter management clinical practice guideline. Subcommittee on Hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004; 114: 297-316
• 17 Amin SB, Wang H. Bilirubin Albumin Binding and Unbound Unconjugated Hyperbilirubinemia in Premature Infants. J Pediatr 2018; 192: 47-52
• 18 Hulzebos CV, Dijk PH, van Imhoff DE. et al; BARTrial Study Group. The bilirubin albumin ratio in the management of hyperbilirubinemia in preterm infants to improve neurodevelopmental outcome: a randomized controlled trial—BARTrial. PLoS One 2014; 9 (06) e99466
• 19 Oh W, Stevenson DK, Tyson JE. et al; NICHD Neonatal Research Network Bethesda MD. Influence of clinical status on the association between plasma total and unbound bilirubin and death or adverse neurodevelopmental outcomes in extremely low birth weight infants. Acta Paediatr 2010; 99 (05) 673-678
• 20 Cashore WJ, Oh W, Brodersen R. Reserve albumin and bilirubin toxicity index in infant serum. Acta Paediatr Scand 1983; 72 (03) 415-419
• 21 Holloway P, Stoddart H. Biochemistry in medicine-reference intervals: the use of biochemical analysis for diagnosis and management. In: Warrell DA. ed. Oxford Textbook of Medicine. Oxford University Press: ; New York: 2010: 5429-5450
• 22 Newman TB, Xiong B, Gonzales VM, Escobar GJ. Prediction and prevention of extreme neonatal hyperbilirubinemia in a mature health maintenance organization. Arch Pediatr Adolesc Med 2000; 154 (11) 1140-1147
• 23 Boamah LM, Balistreri WF. Evaluation of Patients with Possible Liver Dysfunction. In: Kliegman RM. ed. Nelson Textbook of Pediatrics. Elsevier Saunders: ; Philadelphia: 2011: 1378
• 24 Hintz SR, Stevenson DK, Yao Q. et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Is phototherapy exposure associated with better or worse outcomes in 501- to 1000-g-birth-weight infants?. Acta Paediatr 2011; 100 (07) 960-965
• 25 Travadi J, Simmer K, Ramsay J, Doherty D, Hagan R. Patent ductus arteriosus in extremely preterm infants receiving phototherapy: does shielding the chest make a difference? A randomized, controlled trial. Acta Paediatr 2006; 95 (11) 1418-1423
• 26 Tozzi-Ciancarelli MG, Amicosante G, Menichelli A, Di Giulio S, Del Principe D. Photodynamic damage induced by bilirubin on human platelets: possible relevance to newborn pathology. Biol Neonate 1985; 48 (06) 336-340
• 27 Dani C, Cecchi A, Bertini G. Role of oxidative stress as physiopathologic factor in the preterm infant. Minerva Pediatr 2004; 56 (04) 381-394