Neonatal hypoglycaemia

Abstract

Low blood concentrations of glucose (hypoglycaemia) soon after birth are common because of the delayed metabolic transition from maternal to endogenous neonatal sources of glucose. Because glucose is the main energy source for the brain, severe hypoglycaemia can cause neuroglycopenia (inadequate supply of glucose to the brain) and, if severe, permanent brain injury. Routine screening of infants at risk and treatment when hypoglycaemia is detected are therefore widely recommended. Robust evidence to support most aspects of management is lacking, however, including the appropriate threshold for diagnosis and optimal monitoring. Treatment is usually initially more feeding, with buccal dextrose gel, followed by intravenous dextrose. In infants at risk, developmental outcomes after mild hypoglycaemia seem to be worse than in those who do not develop hypoglycaemia, but the reasons for these observations are uncertain. Here, the current understanding of the pathophysiology of neonatal hypoglycaemia and recent evidence regarding its diagnosis, management, and outcomes are reviewed. Recommendations are made for further research priorities.

Keywords: Endocrinology; Neonatology; Neuropathology; Perinatology.

Figure 1

Centiles of plasma and interstitial concentrations of glucose over the first five days in healthy term newborns. The 10th centile, in the period from two to 48 hours after birth, is about 2.6 mmol/L. Adapted and reproduced with permission from Harris et al

Figure 2

Postnatal adaptations to support glucose homeostasis. Catecholamines, cortisol, and thyroxine stimulate lipolysis in adipose tissue and glucagon secretion from pancreatic α cells. Pancreatic β cells transition from constitutive to mature glucose regulated insulin secretion, which involves a rise in the glucose set point for release of insulin and greater suppression of insulin as blood concentrations of glucose fall. The decreasing insulin to glucagon ratio after birth is a key stimulus for hepatic glucose output, triggering both glycogenolysis (release of glucose from stored glycogen) and synthesis of glucose (gluconeogenesis) from glycerol (product of lipolysis), lactate, and other precursors, including gluconeogenic amino acids (eg, alanine). Increasing hepatic fatty acid oxidation on the first day not only provides substrate for ketogenesis but also generates more cofactors and ATP in the liver to support gluconeogenesis. Increasing fatty oxidation in peripheral tissues produces more gluconeogenic precursors

Figure 3

Schematic model of cellular mechanisms in neuroglycopenia. Suppression of glycolysis from reduced neuronal uptake of glucose depletes intracelluar pyruvate, which in turn reduces production of oxaloacetate by the citric acid cycle and pyruvate carboxylase. Replenishment of oxaloacetate by aspartate transaminase (AST) generates excess glutamate, an excitatory neurotransmitter. Increasing amounts of glutamate in the extracellular fluid around neurons causes sustained neuronal excitation by glutamate receptors. High calcium (Ca²⁺) influx initiates excitotoxicity, including hyeractivation of poly-ADP-ribose-polymerase 1 (PARP-1), contributing to mitochondrial damage and cytosolic depletion of nicotinamide adenine dinucleotide (NAD+). An increase in free zinc (Zn²⁺) stimulates excess reactive oxygen species by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. NADH=reduced nicotinamide adenine dinucleotide; acetyl-CoA=acetyl coenzyme A