NEONATAL HYPOGLYCEMIA

Definition The numerical definition varies from institution to institution: – Numbers based on population studies of plasma glucose concentrations during first hours of life with hypoglycemia defined as a plasma glucose level more than 2 SD below the population mean Most institutions use plasma glucose <40mg/dl on the 1 st day of life and less than 40-50mg/dl after 24 hours of life Physiologic definition: when glucose supply for cells is inadequate to meet glucose demands

Incidence Estimated to be 10% of live births if first feeding is delayed for more than 3-6 hours after birth Percentage is even higher for at-risk populations: – Preterm infants – SGA infants – LGA infants – Infants of diabetic mothers

Pathophysiology Newborns have high brain-to-body weight ratio -> higher glucose demand Impaired establishment of normal glucose homeostasis during transition from intrauterine to extrauterine life -> hypoglycemia Normal glucose homeostasis requires supply to meet demands Supply is dependent on adequate stores of glycogen, gluconeogenesis precursors, functioning hepatic enzymes, and a functioning endocrine system Demands depend on the metabolic rate of the infant, which can be increased in times of stress (i.e. sepsis, asphyxia)

Clinical Manifestations Asymptomatic Tachypnea Apnea Respiratory distress Tachycardia Bradycardia Jitteriness Lethargy Hypotonia Weak suck Temperature instability Seizures

Etiology  Diminished glucose production  Increased glucose utilization from hyperinsulinemia  Increased glucose utilization without hyperinsulinemia  Metabolic Disorders  Endocrine Disorders  Other

Diminished Glucose Production  Premature infants have diminished reserves because glycogen is deposited during the 3rd trimester of pregnancy  Infants with intrauterine growth restriction (IUGR) and who are SGA have reduced glycogen stores because of:  Low intrauterine insulin levels  Chronic intrauterine hypoxia

Increased Glucose Utilization Due to Hyperinsulinemia  Infant of a diabetic mother  Maternal intrapartum treatment with glucose  Beckwith-Wiedemann syndrome  Insulinoma

Infant of a Diabetic Mother  Intermittent maternal hyperglycemia -> fetal hyperglycemia and hyperinsulinemia -> hypoglycemia once intrauterine glucose supply from mother is interrupted  Hypoglycemia occurs in 27% of infants of diabetic mothers (IDMs)  Happens in the first few hours of life  Most common in macrosomic IDMs  Premature &/or SGA IDMs are also at higher risk

Beckwith-Wiedemann Syndrome  Fetal overgrowth syndrome with characteristic features:  Macroglossia  Growth >90%  Abdominal wall defects  Ear creases/pits  Renal abnormalities  Hemi-hyperthrophy  Hyperplasia of organs (such as the pancreas)

Beckwith-Wiedemann Syndrome  Incidence: 1 in 15,000 births  Etiology: Sporadic mutation (85%), AD (15%)  50% have transient hypoglycemia caused by hyperinsulinemia from hyperplasia of the pancreas  Increased risk for malignancy:  Wilms tumor, hepatoblastoma, neuroblastoma, gonadoblastoma  Monitored with abdominal US and alpha-fetoprotein q6months until 6 y/o

Insulinoma  Tumor of the pancreas that produces too much insulin  Very rare in children  Most are benign tumors, only about 5-10% are malignant  Treatment is surgical  If unable to surgically remove, treat with diazoxide or octreotide to reduce insulin secretion

Increased Glucose Utilization Without Hyperinsulinemia  States of stress such as hypothermia, perinatal asphyxia, sepsis, and heart failure increase usage and depletion of glycogen stores  Polycythemia - increased utilization of glucose by the increased mass of RBCs

Metabolic Disorders  Inborn errors of metabolism:  Defects in carbohydrate metabolism Glycogen Storage Disease Glycogen Synthase Deficiency Galactosemia Fructose Intolerance  Defects in amino acid metabolism Maple Syrup Urine Disease Propionic Acidemia Methylmalonic Acidemia  Defects in ketogenesis and fatty acid oxidation

Endocrine Disorders  Deficiency or malfunctioning of the hormones that regulate glucose homeostasis:  Cortisol  Growth hormone  Glucagon  Epinephrine  Thyroid  These could be associated with hypothalamic, pituitary, or adrenal insufficiency

Other Causes  Maternal drugs such as terbutaline, labetalol, propranolol -> inhibit glycogenolysis and gluconeogenesis  Neurohypoglycemia:  GLUT1 transport protein facilitates glucose diffusion across blood vessels into the brain and CSF  Deficiency in GLUT1 results in low CSF glucose, but blood glucose levels are normal  Rare disorder that presents as 2-3 months with seizures, developmental delay, and acquired microcephaly

Evaluation  Blood glucose should be monitored for infants at risk for hypoglycemia:  Premature infants  SGA infants  LGA infants  IDMs  Infants whose mothers were treated with beta adrenergic agents or beta blockers  Infants under stress requiring more intensive care (i.e. sepsis, asphyxia)

Evaluation  Monitor glucose within first 1-2 hours of life or with signs consistent with hypoglycemia  Surveillance should be continued in infants with glucose <40 until feedings well established and levels have stabilized  Low Chemstrips (glucose oxidase reagent strips for rapid screening) should be confirmed with serum glucose level processed by the lab

Evaluation  Determining Etiology:  Consider prenatal/perinatal history  Check growth parameters  Perform a careful physical exam  Screen for sepsis if suspected

Evaluation  If hypoglycemia persists for >1 week, endocrine and metabolic disorders should be suspected Consult endocrinology At the time of hypoglycemia, obtain: ACTH/cortisol levels Growth hormone levels Insulin levels Free fatty acids Ketones Pyruvate Lactate

Evaluation The following should also be obtained, but can be obtained at anytime: TSH/T4 levels Serum amino acids Urine organic acids Acylcarnitine profile

Management  Anticipation and prevention is key  In infants who are premature or too ill to feed, begin parenteral glucose infusion at a rate of at least 6mg/kg/min  Glucose (mg/kg/min) = (% glucose in solution x 10) x (rate of infusion per hour) / (60 x weight in kg)

Healthy asymptomatic infants  Try feeding orally with either formula, breastmilk, or D10W  Use of formula or breastmilk better than D10W because they provide carbohydrates as well as protein and fats that are metabolized more slowly to provide a sustained supply of substrate  Recheck glucose in mins after the feeding and continue to feed q2-3 hrs  Blood glucose should be followed before each feed for hours

Symptomatic infants or infants with very low glucose concentrations  Start parenteral glucose infusions on:  Symptomatic infants  Infants with a glucose of <20-25  Infants who do not tolerate enteral feedings  Infants whose blood sugar remains <40 after a trial of oral feeding

Symptomatic infants or infants with very low glucose concentrations:  Start with a bolus of 2-4ml/kg of D10W  Then begin a glucose infusion of at least 6mg/kg/min  Check blood glucose mins after bolus to determine if another bolus is needed, and adjust rate of dextrose concentration to maintain plasma glucose >45mg/dl  Follow blood glucose every 1-2 hours until stable, then can space out monitoring as needed  When the glucose concentration is stable for hrs, the glucose infusion rate can be tapered slowly by % each time the feeds are advanced and the pre- prandial blood glucose is >50-60 mg/dl

Persistent Hypoglycemia (> 7 days)  Corticosteroids stimulate gluconeogenesis and reduces peripheral glucose utilization  should be considered in infants who remain hypoglycemic after 2-3 days of glucose infusion of >12mg/kg/min  Glucagon can also be used during severe hypoglycemia as a temporizing measure in infants with adequate glycogen stores (i.e. NOT in SGA or premature infants)  Diazoxide/Somatostatin/Octreotide inhibits insulin release for those with persistent hypoglycemia and hyperinsulinemia

Persistent Hypoglycemia (> 7 days)  Human growth hormone for infants with growth hormone deficiency  Nifedipine – case reports have shown some success with few side effects  Subtotal pancreatectomy for hyperinsulinemia  hypoglycemia recurs in up to 1/3 of patients  40-60% develop DM later in life

Prognosis  Symptomatic hypoglycemia can result in brain injury  Most common sequelae are:  Disturbances in neurological development and intellectual function  Motor deficits (spasticity and ataxia)  Seizures * May be related to the underlying etiology of the hypoglycemia  There is inconclusive evidence on the effect of asymptomatic hypoglycemia on neurodevelopment