Current perspectives on neonatal hypoglycemia, its management, and cerebral injury risk

Figures & data

Figure 1 The gluconeogenic, glycolytic, glycogenolysis, and glycogen synthesis pathways.

Abbreviations: TCA, tricarboxylic acid cycle; UDP, uridine diphosphate.

Table 1 Infants at risk of hypoglycemia

Maternal conditions

Diabetes in pregnancy (pregestational/gestational)

Medication (β-blockers)

Neonatal conditions

Prematurity

Intrauterine growth retardation

Large for gestational age – infant of diabetic mother

Perinatal asphyxia

Infection

Polycythemia

Hypothermia

Parenteral nutrition

Syndromes – Beckwith–Wiedemann, Timothy, Laron, Sotos

Table 2 Metabolic and endocrine causes of neonatal hypoglycemia

Hyperinsulinism	Transient
	Infant of diabetic mothers
	Perinatal asphyxia
	Rhesus hemolytic disease
	Intrauterine growth restriction
	Beckwith-Wiedemann syndrome
	Congenital
	Mutations in ABCC8, KCNJ11, GLUD1, GCK, HADH SLC16A1, HNF4A, UCP2 genes
Deficiency of counter-regulatory hormones	Isolated growth hormone deficiency
	Congenital adrenal hyperplasia
	ACTH deficiency
	Familial glucocorticoid deficiency
	Cortisol deficiency
Disorders of gluconeogenesis	Fructose-1, 6-bisphosphatase deficiency
	Phosphoenolpyruvate carboxykinase deficiency
	Pyruvate carboxylase deficiency
Disorders of galactose metabolism	Galactosemia
Disorders of hepatic glycogen synthesis	Glycogen storage disease
Disorders of fructose metabolism	Hereditary fructose intolerance
Disorders of amino acid metabolism	Maple syrup urine disease
	Propionic acidemia
	Methylmalonic acidemia
	Tyrosinemia
Disorders of fatty acid metabolism	Defects in β-oxidation
	MCAD deficiency
	LCHAD deficiency
	SCHAD deficiency
Disorders of carnitine metabolism	Primary carnitine deficiency
	CPT-I deficiency
	CACT deficiency
	CPT-II deficiency
Defects in ketone body synthesis and utilization	HMG-CoA synthase deficiency
	HMG-CoA lyase deficiency
	β-ketothiolase deficiency
	SCOT deficiency
Hypoinsulinemic hypoglycemia	Activating AKT2 mutation
Defects in glucose transport	GLUT 1/2/3 transporter defects

Abbreviations: ACTH, adrenocorticotropic hormone; CACT, carnitine-acylcarnitine translocase; CPT, carnitine palmitoyltransferase; LCHAD, long-chain 3-hydroxyacyl-coenzyme A dehydrogenase; MCAD, medium-chain acyl-CoA dehydrogenase; SCHAD, 3-hydroxyacyl–coenzyme A dehydrogenase; SCOT, succinyl-CoA:3-ketoacid-coenzyme A transferase 1.

Table 3 Investigations for cases of severe/persistent hypoglycemia

Sample	Test
Blood	Glucose
	Insulin/C-peptide
	Ketone bodies
	Free fatty acids
	Lactate
	Ammonia
	Amino acids
	Acyl carnitine profile
	Cortisol
	Growth hormone
	Blood gas
	Bicarbonate
	Liver function test
Urine	Reducing substances
	Ketone bodies
	Amino acids
	Organic acids

Figure 2 Outline of the management of congenital hyperinsulinism.

Abbreviation: PET, positron emission tomography.

Table 4 Risk factors and neurodevelopmental outcome of infants with hypoglycemia

No	Authors	Study and subjects	Threshold values for NHBI	Findings	Risk factors
1	Lucas et al^Citation56	Preterm 30.5±2.7 weeks Birth weight < 1,850 g (n=661)	<2.6 mmol/L	At 18 months mental developmental scores lower by 14 points, motor developmental score lower by 13 points. Increased risk of CP or developmental delay. RR 3.5 (95% CI: 1.3–9.4)	Recurrent hypoglycemia for 5 or more days
2	Koh et al^Citation53	Full term Asymptomatic	<2.6 mmol/L	Abnormal evoked potentials Reversible CNS injury	Asymptomatic
3	Stenninger et al^Citation93	IDM Term 38.2±1.4 weeks Asymptomatic (n=28)	< 1.5 mmol/L	At 8 years – increased minimal brain dysfunction and deficits in attention, motor control, and perception	Asymptomatic
4	Duvanel et al^Citation94	Preterm/SGA 31.9 week (27–34 weeks), 1,160 g (585–1,680 g) (n=85)	<2.6 mmol/L	At 3.5 and 5 years of age Lower psychomotor scores Reduced head circumference	Recurrent hypoglycemia
5	Filan et al^Citation95	Transient HH, IUGR, sepsis, IDM 36–40 weeks (n=4)	0.7–1.5 mmol/L	MRI (day 4–7) Occipital cerebral injury Motor delay, microcephaly, visual impairment in one patient. Three cases normal	Hyperinsulinism
6	Alkalay et al^Citation96	Symptomatic hypoglycemia (n=89)	<1.4 mmol/L	CNS injury in 21% (95% CI: 14–27)	Symptomatic hypoglycemia
7	Tam et al^Citation97	Term infants at risk for NE (n=94)	<2.6 mmol/L	At 1 year, increased corticospinal tract injury by 3.7-fold. 15-point lower cognitive and language scores	At risk for NE

Note: Asymptomatic and symptomatic hypoglycemias have been reported to be associated with varying grades of brain injury in both preterm and full-term infants.

Abbreviations: CI, confidence interval; CNS, central nervous system; CP, cerebral palsy; HH, hyperinsulinemic hypoglycemia; IDM, infants of diabetic mothers; IUGR, intrauterine growth restriction; MRI, magnetic resonance imaging; NE, neonatal encephalopathy; NHBI, newborn hypoglycemic brain injury; RR, relative risk; SGA, small for gestational age.

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