Neonatal Hypoglycemia

Introduction

Normal brain function depends on a continuous supply of glucose, the principal metabolic fuel of the human brain, from the bloodstream. Low plasma glucose concentrations, and as a consequence, low brain glucose availability result in cerebral energy failure, neuronal death, and irreversible brain damage. The developing brain is particularly vulnerable to the deleterious effects of hypoglycemia, as demonstrated by the high frequency of neurodevelopmental deficits in children with congenital hypoglycemia disorders. Thus it is critically important to screen, identify, and treat neonates with persistent hypoglycemia.

During fetal development, facilitated diffusion of glucose from the maternal circulation to the fetal circulation guarantees an appropriate supply of glucose to the fetus. The abrupt interruption of maternal glucose transfer to the baby at delivery imposes a need for the newborn infant to independently control plasma glucose concentrations by adjusting insulin secretion and mobilizing counterregulatory responses. These “fasting systems” are intact and functional in the newborn period and provide defense against hypoglycemia when working properly. The “fasting systems” include hepatic glycogenolysis, hepatic gluconeogenesis, and fatty acid oxidation. These processes are all coordinated by endocrine counterregulatory hormones; insulin suppresses these processes whereas glucagon, cortisol, epinephrine, and growth hormone are stimulating. Fasting adaptation’s essential function is to maintain the brain’s fuel supply. The redundancy in hormonal signaling provides for additional layers of security to prevent hypoglycemia. Hepatic glycogenolysis provides energy for only a few hours; beyond that, hepatic gluconeogenesis provides glucose for energy requirements. During extended fasting, lipolysis and fatty acid oxidation mobilize fatty acids and generate ketones as an alternative fuel source for the brain. Hypoglycemia beyond the immediate newborn period is often a consequence of a defect in fasting adaptation.

It is essential to identify neonates with hypoglycemic disorders prior to newborn hospital discharge, because there is a high risk of long-term morbidity. Specifically, persistent and repeated episodes of hypoglycemia in the neonatal period lead to irreversible brain injury and developmental disabilities. In addition to prompt stabilization, early identification of the precise etiology of hypoglycemia allows for tailored interventions to minimize hypoglycemic events and ultimately improve long-term outcomes.

In this chapter, we will review the evaluation and management of neonates with persistent hypoglycemia with a special emphasis on hyperinsulinism (HI), the most common cause of persistent hypoglycemia in neonates and infants.

Transitional Neonatal Hypoglycemia

There is a transitional period immediately after birth when mean plasma glucose concentrations fall in normal newborn infants from 70 to 80 mg/dL (close to maternal glucose values) to 55 to 60 mg/dL. ^, There is evidence that suggests that this transitional period of lower glucose concentrations in normal newborns is explained by a lower threshold for glucose-stimulated insulin secretion and thus should be considered as “transitional neonatal hyperinsulinism.” This includes observations that during the period that plasma glucose is low in normal newborns, lipolysis and ketogenesis are suppressed and liver glycogen reserves are maintained, as shown by the large glycemic responses elicited by administration of glucagon or epinephrine. An important feature of transitional neonatal hypoglycemia in normal newborns is that the hypoglycemia progressively improves over the first few days of life and the plasma glucose concentration reaches the normal range for older infants and children by the third to fourth day of life. Additionally, the plasma glucose concentration in transitional hypoglycemia is impressively stable and relatively unaffected by initial feeds, which has been demonstrated in multiple studies. ^{, ,} Of prime importance, however, is that transitional neonatal hypoglycemia is self-limited, and in the absence of other factors, the hypoglycemia should resolve within the first 3 days of life as the threshold for glucose-stimulated insulin secretion rises and fasting adaptation mechanisms become fully functional.

The process of beta cell maturation after birth may be impacted by perinatal factors resulting in a prolongation of this state of hyperinsulinism. This is a specific entity known as perinatal stress-induced hyperinsulinism, a distinct form of hyperinsulinism that spontaneously resolves within the first few weeks of life, although it sometimes persists for a few months. Perinatal factors associated with perinatal stress-induced hyperinsulinism include birth asphyxia, maternal preeclampsia, prematurity, intrauterine growth retardation, and other peripartum stress. Up to 50% of neonates in these at-risk categories may be affected. Hyperinsulinism secondary to perinatal stress can be as severe as the genetic permanent forms and is also associated with a high risk for neurodevelopmental deficits.

In 2015, the Pediatric Endocrine Society (PES) published recommendations for evaluation and management of neonatal hypoglycemia. The purpose of this publication was to provide guidance beyond the immediate stabilization period. The PES recommendations highlight the importance of differentiating transitional neonatal hypoglycemia from persistent hypoglycemia disorders, because failure to identify these at-risk neonates can lead to devastating consequences from repeated and prolonged episodes of hypoglycemia and resultant brain damage. The recommendations also emphasize the need for evaluation to determine the underlying etiology of persistent hypoglycemia in order to provide tailored treatment to optimize patient care and minimize long-term morbidity.