- Ann R Stark, MD
Ann R Stark, MD
- Professor of Pediatrics
- Vanderbilt University School of Medicine
- Rebecca Simmons, MD
Rebecca Simmons, MD
- Hallam Hurt Professor of Pediatrics
- Perelman School of Medicine University of Pennsylvania
- Children’s Hospital of Philadelphia
- Section Editors
- Steven A Abrams, MD
Steven A Abrams, MD
- Section Editor — Neonatology
- Professor, Department of Pediatrics
- Dell Medical School at the University of Texas at Austin
- Joseph I Wolfsdorf, MB, BCh
Joseph I Wolfsdorf, MB, BCh
- Section Editor — Pediatric Endocrinology
- Professor of Pediatrics
- Harvard Medical School
Glucose supply and metabolism are of central importance for growth and normal brain development in the fetus and newborn. Disorders in glucose availability or utilization can result in hypoglycemia or hyperglycemia.
The causes and management of neonatal hyperglycemia are reviewed here. Neonatal hypoglycemia is discussed separately. (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia".)
Hyperglycemia — The definition of hyperglycemia is uncertain. It is often defined as blood glucose >125 mg/dL (6.9 mmol/L) or plasma glucose >150 mg/dL (8.3 mmol/L). However, these levels are frequently observed during glucose infusions in newborns, especially in extremely preterm infants, and may not require intervention .
Most neonatologists become concerned about hyperglycemia when plasma glucose concentration (the standard laboratory test) exceeds 180 to 200 mg/dL (10 to 11.1 mmol/L). However, higher levels of hyperglycemia are required to produce the hyperosmolality and osmotic diuresis that may be clinically important. Plasma osmolality increases by 1 mosmol/L for each 18 mg/dL increase in plasma glucose concentration. Thus, a rise in glucose concentration from 110 to 200 mg/dL (6.1 to 11.1 mmol/L) only increases osmolality by 5 mosmol/L, which is a relatively small change.
Glucosuria — Glucose excretion in the urine in hyperglycemic neonates is determined by the degree of hyperglycemia and renal tubular reabsorptive capacity for glucose. Newborns have variable reabsorptive capacities for glucose, which may be particularly reduced in those who are ill or preterm.To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Louik C, Mitchell AA, Epstein MF, Shapiro S. Risk factors for neonatal hyperglycemia associated with 10% dextrose infusion. Am J Dis Child 1985; 139:783.
- Wilkins BH. Renal function in sick very low birthweight infants: 4. Glucose excretion. Arch Dis Child 1992; 67:1162.
- Cowett RM, Oh W, Schwartz R. Persistent glucose production during glucose infusion in the neonate. J Clin Invest 1983; 71:467.
- Kalhan SC, Devaskar SU. Disorders of carbohydrate metabolism. In: Neonatal-Perinatal Medicine: Diseases of the Fetus and Infant, 9th ed, Martin RJ, Fanaroff AA, Walsh MC (Eds), Elsevier Mosby, St. Louis 2011. Vol 2, p.1497.
- Meetze W, Bowsher R, Compton J, Moorehead H. Hyperglycemia in extremely- low-birth-weight infants. Biol Neonate 1998; 74:214.
- Mitanchez-Mokhtari D, Lahlou N, Kieffer F, et al. Both relative insulin resistance and defective islet beta-cell processing of proinsulin are responsible for transient hyperglycemia in extremely preterm infants. Pediatrics 2004; 113:537.
- Sunehag A, Gustafsson J, Ewald U. Very immature infants (< or = 30 Wk) respond to glucose infusion with incomplete suppression of glucose production. Pediatr Res 1994; 36:550.
- Lilien LD, Rosenfield RL, Baccaro MM, Pildes RS. Hyperglycemia in stressed small premature neonates. J Pediatr 1979; 94:454.
- Beardsall K, Vanhaesebrouck S, Ogilvy-Stuart AL, et al. Prevalence and determinants of hyperglycemia in very low birth weight infants: cohort analyses of the NIRTURE study. J Pediatr 2010; 157:715.
- Alexandrou G, Skiöld B, Karlén J, et al. Early hyperglycemia is a risk factor for death and white matter reduction in preterm infants. Pediatrics 2010; 125:e584.
- Kao LS, Morris BH, Lally KP, et al. Hyperglycemia and morbidity and mortality in extremely low birth weight infants. J Perinatol 2006; 26:730.
- Blanco CL, Baillargeon JG, Morrison RL, Gong AK. Hyperglycemia in extremely low birth weight infants in a predominantly Hispanic population and related morbidities. J Perinatol 2006; 26:737.
- Farrag HM, Cowett RM. Glucose homeostasis in the micropremie. Clin Perinatol 2000; 27:1.
- White RH, Frayn KN, Little RA, et al. Hormonal and metabolic responses to glucose infusion in sepsis studied by the hyperglycemic glucose clamp technique. JPEN J Parenter Enteral Nutr 1987; 11:345.
- Manzoni P, Castagnola E, Mostert M, et al. Hyperglycaemia as a possible marker of invasive fungal infection in preterm neonates. Acta Paediatr 2006; 95:486.
- Doyle LW, Cheong JL, Ehrenkranz RA, Halliday HL. Early (< 8 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants. Cochrane Database Syst Rev 2017; 10:CD001146.
- Srinivasan G, Singh J, Cattamanchi G, et al. Plasma glucose changes in preterm infants during oral theophylline therapy. J Pediatr 1983; 103:473.
- al-Rubeaan K, Ryan EA. Phenytoin-induced insulin insensitivity. Diabet Med 1991; 8:968.
- Rubio-Cabezas O, Ellard S. Diabetes mellitus in neonates and infants: genetic heterogeneity, clinical approach to diagnosis, and therapeutic options. Horm Res Paediatr 2013; 80:137.
- Støy J, Steiner DF, Park SY, et al. Clinical and molecular genetics of neonatal diabetes due to mutations in the insulin gene. Rev Endocr Metab Disord 2010; 11:205.
- De Franco E, Flanagan SE, Houghton JA, et al. The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study. Lancet 2015; 386:957.
- von Mühlendahl KE, Herkenhoff H. Long-term course of neonatal diabetes. N Engl J Med 1995; 333:704.
- Hermann R, Laine AP, Johansson C, et al. Transient but not permanent neonatal diabetes mellitus is associated with paternal uniparental isodisomy of chromosome 6. Pediatrics 2000; 105:49.
- Shield JP. Neonatal diabetes: new insights into aetiology and implications. Horm Res 2000; 53 Suppl 1:7.
- Kamiya M, Judson H, Okazaki Y, et al. The cell cycle control gene ZAC/PLAGL1 is imprinted--a strong candidate gene for transient neonatal diabetes. Hum Mol Genet 2000; 9:453.
- Temple IK, Shield JP. Transient neonatal diabetes, a disorder of imprinting. J Med Genet 2002; 39:872.
- Mackay DJ, Callaway JL, Marks SM, et al. Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57. Nat Genet 2008; 40:949.
- Chen R, Hussain K, Al-Ali M, et al. Neonatal and late-onset diabetes mellitus caused by failure of pancreatic development: report of 4 more cases and a review of the literature. Pediatrics 2008; 121:e1541.
- Thomas P, Ye Y, Lightner E. Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy. Hum Mol Genet 1996; 5:1809.
- Carmody D, Bell CD, Hwang JL, et al. Sulfonylurea treatment before genetic testing in neonatal diabetes: pros and cons. J Clin Endocrinol Metab 2014; 99:E2709.
- Gloyn AL, Pearson ER, Antcliff JF, et al. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med 2004; 350:1838.
- Gloyn AL, Cummings EA, Edghill EL, et al. Permanent neonatal diabetes due to paternal germline mosaicism for an activating mutation of the KCNJ11 Gene encoding the Kir6.2 subunit of the beta-cell potassium adenosine triphosphate channel. J Clin Endocrinol Metab 2004; 89:3932.
- Vaxillaire M, Populaire C, Busiah K, et al. Kir6.2 mutations are a common cause of permanent neonatal diabetes in a large cohort of French patients. Diabetes 2004; 53:2719.
- Slingerland AS, Hattersley AT. Activating mutations in the gene encoding Kir6.2 alter fetal and postnatal growth and also cause neonatal diabetes. J Clin Endocrinol Metab 2006; 91:2782.
- Hattersley AT, Ashcroft FM. Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy. Diabetes 2005; 54:2503.
- Pearson ER, Flechtner I, Njølstad PR, et al. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med 2006; 355:467.
- Landau Z, Wainstein J, Hanukoglu A, et al. Sulfonylurea-responsive diabetes in childhood. J Pediatr 2007; 150:553.
- Babenko AP, Polak M, Cavé H, et al. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med 2006; 355:456.
- Smith SB, Qu HQ, Taleb N, et al. Rfx6 directs islet formation and insulin production in mice and humans. Nature 2010; 463:775.
- Scharfmann R, Polak M. Transcribing neonatal diabetes mellitus. N Engl J Med 2010; 362:1538.
- Stoffers DA, Zinkin NT, Stanojevic V, et al. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet 1997; 15:106.
- Dodge JA, Laurence KM. Congenital absence of islets of Langerhans. Arch Dis Child 1977; 52:411.
- Blum D, Dorchy H, Mouraux T, et al. Congenital absence of insulin cells in a neonate with diabetes mellitus and mutase-deficient methylmalonic acidaemia. Diabetologia 1993; 36:352.
- Winter WE, Maclaren NK, Riley WJ, et al. Congenital pancreatic hypoplasia: a syndrome of exocrine and endocrine pancreatic insufficiency. J Pediatr 1986; 109:465.
- Baumeister FA, Engelsberger I, Schulze A. Pancreatic agenesis as cause for neonatal diabetes mellitus. Klin Padiatr 2005; 217:76.
- Delépine M, Nicolino M, Barrett T, et al. EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nat Genet 2000; 25:406.
- Thornton CM, Carson DJ, Stewart FJ. Autopsy findings in the Wolcott-Rallison syndrome. Pediatr Pathol Lab Med 1997; 17:487.
- Stoffers DA, Stanojevic V, Habener JF. Insulin promoter factor-1 gene mutation linked to early-onset type 2 diabetes mellitus directs expression of a dominant negative isoprotein. J Clin Invest 1998; 102:232.
- Bennett CL, Christie J, Ramsdell F, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 2001; 27:20.
- Sellick GS, Barker KT, Stolte-Dijkstra I, et al. Mutations in PTF1A cause pancreatic and cerebellar agenesis. Nat Genet 2004; 36:1301.
- Senée V, Chelala C, Duchatelet S, et al. Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism. Nat Genet 2006; 38:682.
- Senée V, Vattem KM, Delépine M, et al. Wolcott-Rallison Syndrome: clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity. Diabetes 2004; 53:1876.
- Njølstad PR, Søvik O, Cuesta-Muñoz A, et al. Neonatal diabetes mellitus due to complete glucokinase deficiency. N Engl J Med 2001; 344:1588.
- Colombo C, Porzio O, Liu M, et al. Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus. J Clin Invest 2008; 118:2148.
- Støy J, Edghill EL, Flanagan SE, et al. Insulin gene mutations as a cause of permanent neonatal diabetes. Proc Natl Acad Sci U S A 2007; 104:15040.
- Edghill EL, Flanagan SE, Patch AM, et al. Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood. Diabetes 2008; 57:1034.
- Besser RE, Flanagan SE, Mackay DG, et al. Prematurity and Genetic Testing for Neonatal Diabetes. Pediatrics 2016; 138.
- Sunehag AL, Haymond MW, Schanler RJ, et al. Gluconeogenesis in very low birth weight infants receiving total parenteral nutrition. Diabetes 1999; 48:791.
- Collins JW Jr, Hoppe M, Brown K, et al. A controlled trial of insulin infusion and parenteral nutrition in extremely low birth weight infants with glucose intolerance. J Pediatr 1991; 118:921.
- Kanarek KS, Santeiro ML, Malone JI. Continuous infusion of insulin in hyperglycemic low-birth weight infants receiving parenteral nutrition with and without lipid emulsion. JPEN J Parenter Enteral Nutr 1991; 15:417.
- Beardsall K, Vanhaesebrouck S, Ogilvy-Stuart AL, et al. Early insulin therapy in very-low-birth-weight infants. N Engl J Med 2008; 359:1873.
- Binder ND, Raschko PK, Benda GI, Reynolds JW. Insulin infusion with parenteral nutrition in extremely low birth weight infants with hyperglycemia. J Pediatr 1989; 114:273.
- Vaucher YE, Walson PD, Morrow G 3rd. Continuous insulin infusion in hyperglycemic, very low birth weight infants. J Pediatr Gastroenterol Nutr 1982; 1:211.
- Alsweiler JM, Harding JE, Bloomfield FH. Tight glycemic control with insulin in hyperglycemic preterm babies: a randomized controlled trial. Pediatrics 2012; 129:639.
- Fuloria M, Friedberg MA, DuRant RH, Aschner JL. Effect of flow rate and insulin priming on the recovery of insulin from microbore infusion tubing. Pediatrics 1998; 102:1401.
- Poindexter BB, Karn CA, Denne SC. Exogenous insulin reduces proteolysis and protein synthesis in extremely low birth weight infants. J Pediatr 1998; 132:948.
- Hays SP, Smith EO, Sunehag AL. Hyperglycemia is a risk factor for early death and morbidity in extremely low birth-weight infants. Pediatrics 2006; 118:1811.
- Stensvold HJ, Strommen K, Lang AM, et al. Early Enhanced Parenteral Nutrition, Hyperglycemia, and Death Among Extremely Low-Birth-Weight Infants. JAMA Pediatr 2015; 169:1003.
- Auerbach A, Eventov-Friedman S, Arad I, et al. Long duration of hyperglycemia in the first 96 hours of life is associated with severe intraventricular hemorrhage in preterm infants. J Pediatr 2013; 163:388.
- Yoo HS, Ahn SY, Lee MS, et al. Permissive hyperglycemia in extremely low birth weight infants. J Korean Med Sci 2013; 28:450.
- Soghier LM, Brion LP. Multivariate analysis of hyperglycemia in extremely low birth weight infants. J Perinatol 2006; 26:723.
- McKinlay CJ, Alsweiler JM, Ansell JM, et al. Neonatal Glycemia and Neurodevelopmental Outcomes at 2 Years. N Engl J Med 2015; 373:1507.
- Parenteral administration of glucose
- - Prematurity
- - Sepsis
- - Stress
- Neonatal diabetes mellitus
- - Transient
- - Permanent
- - Preterm infants
- Reduction of glucose infusion rate
- Insulin therapy
- - Routine early insulin therapy
- - Risk of hypoglycemia
- - Dose and target glucose levels
- - Monitoring
- - Titration and discontinuation
- - Adherence of insulin to plastic tubing
- Amino acid infusion
- Our approach
- SUMMARY AND RECOMMENDATIONS