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.

Screening Neonates at Risk for Hypoglycemia

Symptoms of hypoglycemia are well defined in older individuals; however, they may be difficult to discern in a neonate. Adult guidelines highlight the utility of Whipple’s triad to verify hypoglycemia: symptoms consistent with hypoglycemia, documented low plasma glucose during symptoms, and resolution of symptoms with normalization of plasma glucose. ^, These criteria cannot be applied to neonates. Thus a high index of suspicion is needed, in addition to repeated plasma glucose measurements in neonates at risk, to recognize and confirm neonatal hypoglycemia and to prevent adverse consequences. In a neonate, hypoglycemia may present as a wide range of clinical manifestations including fussiness, hypothermia, apnea, lethargy, and seizure activity.

Neonates that should be screened for hypoglycemia include those with symptoms suggestive of hypoglycemia and those with risk factors for either transient or prolonged hypoglycemia. Risk factors include prematurity, low birth weight, small or large for gestational age, infants of diabetic mothers, suspected infection, maternal medications such as beta blockers, exposure to perinatal stressors, midline congenital defects, and a family history of hypoglycemia disorders ( Table 23.1 ).

Plasma glucose concentrations should be assessed using a laboratory-­based method. Although point-of-care glucose meters provide a rapid and convenient method to measure plasma glucose at the bedside, one should be aware that there is a limitation in accuracy, with an error margin in the setting of hypoglycemia of up to ±15 mg/dL. Thus it is important to confirm the presence of hypoglycemia using a lab-based assay prior to embarking on further evaluation. Furthermore, it should be noted that whole-blood glucose values are approximately 15% lower than plasma glucose concentrations, and additionally, a delay in sample processing can result in further reduction of glucose up to 6 mg/dL/hour due to red blood cell glycolysis.

Neonates at Risk for Persistent Hypoglycemia and Indications for Evaluation

The PES hypoglycemia guidelines identify four categories of neonates at high risk of persistent hypoglycemia that require evaluation (see Table 23.1 ): (1) neonates with severe hypoglycemia (i.e., those requiring intravenous dextrose and those with an episode of symptomatic hypoglycemia), (2) neonates unable to maintain plasma glucose >60 mg/dL by the third day of life, (3) neonates with family history of a genetic form of hypoglycemia, and (4) neonates with a congenital syndrome known to be associated with hypoglycemia (Beckwith-Wiedemann syndrome, panhypopituitarism).

Given the confounder of transitional neonatal hypoglycemia in the immediate postnatal period, diagnostic evaluation should be deferred until at least the third day of life. Failure to perform a diagnostic fast prior to hospital discharge greatly increases the risk of delaying definitive diagnosis and treatment and thus increases the likelihood of neurologic sequelae.

Initial Treatment and Stabilization

Once neonatal hypoglycemia is recognized, the first step is to stabilize the patient. In neonates with suspected congenital hypoglycemia disorders, effort should be made to maintain plasma glucose greater than or equal to 70 mg/dL to minimize repercussions of prolonged hypoglycemia. This can be done with an intravenous bolus of dextrose-containing fluids, typically 2 mL/kg of 10% dextrose solution, followed by starting a glucose infusion rate and gradually up-titrating to meet requirements to maintain a plasma glucose of 70 mg/dL. Per the PES guidelines, for infants without a suspected congenital hypoglycemia disorder, plasma glucose should be maintained above 50 mg/dL in the first 48 hours of life and above 60 mg/dL beyond the first 48 hours of life. The decision to have a lower glucose target for infants without a suspected congenital hypoglycemia disorder was made to balance the risk of transient hypoglycemia with the risk of intervention. If an infant is requiring an intravenous glucose infusion to maintain normoglycemia beyond 48 hours of life, a formal evaluation for a hypoglycemia disorder in consultation with a pediatric endocrinologist is indicated.

There is no role for glucocorticoid therapy to treat neonatal hypoglycemia, and as such, it should be avoided. Glucocorticoids are ineffective at treating hypoglycemia unless the hypoglycemia is due to adrenal insufficiency, and they can have harmful side effects including iatrogenic adrenal suppression.

Evaluation of Persistent Hypoglycemia: The Diagnostic Fast

The purpose of pursuing a diagnostic evaluation is to identify the underlying mechanism of the hypoglycemia and subsequently provide tailored treatment. A thorough history should be conducted including pregnancy, birth, and family history. Close attention should be paid to clues on the physical examination that may suggest a particular diagnosis—for example, facial midline defects such as cleft lip or palate and micropenis are suggestive of hypopituitarism, whereas omphalocele, hemihypertrophy, and macroglossia are consistent with Beckwith-Wiedemann syndrome. A carefully monitored diagnostic fast should be conducted in order to obtain a blood specimen, or critical sample, at the time of hypoglycemia. Alternatively, the sample can be obtained opportunistically if a spontaneous episode of hypoglycemia is captured. This is not a “safety fast” (performed to ensure that a patient with a known hypoglycemia disorder can fast long enough to be safely discharged home) but a “diagnostic fast” for a neonate who has been determined to have persistent hypoglycemia and in whom a cause is being investigated; a pediatric endocrinologist should be involved at this point if possible.

The critical sample measures alternative fuels and counterregulatory hormones and should be obtained when the plasma glucose is 50 mg/dL or below in order to prevent false positive results. Alternatively, the fast can be stopped if the β-hydroxybutyrate is >2.5 mmol/L. During a diagnostic fast, feeds are held and glucose support is slowly withdrawn (if necessary) while closely monitoring glucose levels. Once the glucose reaches 50 mg/dL or lower, it should be confirmed using a laboratory-based assay, and once confirmed, the critical sample is obtained. A complete critical sample measures glucose, β-hydroxybutyrate, free fatty acids, insulin, C-peptide, cortisol, growth hormone, lactate, ammonia, bicarbonate, insulin-like growth factor binding protein 1, acylcarnitine profile, total and free carnitine, and urine organic acids. If a complete critical sample is unable to be obtained, at minimum one should obtain plasma glucose, bicarbonate, β-hydroxybutyrate, lactate, and free fatty acids at the time of hypoglycemia, because these alone can provide significant metabolic clues to the underlying diagnosis ( Fig. 23.1 ).

Differential Diagnosis Based on the Critical Sample .

This algorithm outlines how the characteristic biomarkers obtained in a critical sample are useful in determining the underlying cause of neonatal hypoglycemia. BOHB , Betahydroxybutyrate; FFA , free fatty acids.

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