Hypoglycemia guidelines: AAP vs PES

Reviewed by Paul S Thornton, MD, and David Adamkin, MD

The topic of hypoglycemia in neonates and children has generated significant debate of late, with the American Academy of Pediatrics (AAP) and the Pediatric Endocrine Society (PES) having advanced apparently conflicting guidelines.^1,2 To avoid over-screening of healthy infants and children without discharging babies who may have glucose-regulation problems beyond the first days of life, the community pediatrician is perhaps best served by observing the AAP's approach for the first 48 hours, with increased vigilance consistent with the PES approach thereafter.³

Introduction

The disconnect between the 2 societies' guidelines comes as little surprise, considering the paucity of evidence regarding clinically significant levels of neonatal hypoglycemia (NH) and the lack of consensus regarding a specific level or range to define hypoglycemia in the first 2 days of life.⁴

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In reviewing NH studies to date, confounding factors such as variable definitions of hypoglycemia and lack of control groups make it impossible to define a specific plasma glucose (PG) concentration or duration that can predict permanent neurologic injury in high-risk infants.^5-7 Although it is known that symptoms and long-term neurological damage occur within a range of low plasma glucose values of varying duration and severity,¹ it is also critically important to remember that factors such as the presence of the alternative brain fuels beta-hydroxybutyrate (BOHB) and lactate, as well as hypoxia or ischemia, can affect whether brain injury will occur in conjunction with hypoglycemia.²

Hypoglycemia is defined as a glucose concentration low enough to cause signs or symptoms of impaired brain function (neuroglycopenia).⁸ Various authors have noted that the generally adopted plasma glucose concentration historically used to define NH for all infants, <47 mg/dL, lacks rigorous scientific justification.

Who, when, how?

To help determine which infants to screen, at what intervals, and what glucose levels to target during the first 48 hours of life, the AAP examined whether specific ranges of plasma glucose levels have been associated with neurodevelopmental harm in long-term follow-up studies (Table 1¹).³ Recommended values for intervention are somewhat arbitrary, the AAP concedes, but designed to provide a margin of safety above glucose concentrations associated with clinical signs.

The PES guidelines differ in that they expand the list of whom to screen and recommended that the target for treatment (not screening) in these at-risk babies is 50 mg/dL if being treated by feeding and 70 mg/dL if treated by intravenous (IV) glucose (Table 2).²

NEXT: Signs and symptoms

To help physicians recognize hypoglycemic disorders that persist beyond 48 hours and prevent brain damage in at-risk infants, the PES analyzed mean glucose levels found in newborns in establishing its guidelines, while also slightly broadening the list of at-risk infants.²

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When diagnosing hypoglycemia, the PES highlights the following issues:

• One should only use PG concentrations determined by a clinical laboratory method (not a point-of-care analyzer);

• Whole-blood glucose values are approximately 15% lower than PG concentrations; and

• Red-cell glycolysis occurring during sample processing delays can cut glucose concentration by up to 6 mg/dL hourly.

Signs and symptoms

Clinical signs of NH - ranging from cyanosis to seizures - are nonspecific and common to sick neonates. Additional nonspecific symptoms may include jitteriness, apneic episodes, tachypnea, lethargy, poor feeding, and weak crying.

Who's at risk?

The AAP and PES guidelines concur that infants at highest risk for NH include those who are:

• Late preterm (LPT; 34-36 weeks);

• Small for gestational age (SGA);

• Large for gestational age (LGA); and

• Infants of diabetic mothers (IDM).

Babies at increased risk for persistent hypoglycemia (lasting beyond the first 2 days of life) also include those with the following characteristics, says the PES:

• Postmature delivery;

• Family history of genetic forms of hypoglycemia (such as congenital hyperinsulinism or hypopituitarism);

• Congenital syndromes (such as Beckwith-Wiedemann);

• Abnormal physical features (such as midline facial deformations, microphallus); and

• Perinatal stress (birth asphyxia/ischemia, cesarean delivery, maternal preeclampsia/eclampsia or hypertension, meconium aspiration syndrome, erythroblastosis fetalis, polycythemia, hypothermia).

Both guidelines agree that only infants who show clinical manifestations or who are otherwise known to be at risk require blood glucose measurements.^1,2 In such cases, the AAP recommends measuring plasma or blood glucose concentration as soon as possible (point of care) - in minutes, not hours - while keeping in mind that breastfed term infants have lower PG concentrations but higher concentrations of ketone bodies than do formula-fed infants.^9,10 These higher ketone concentrations may allow breastfed infants to tolerate lower plasma glucose concentrations without showing NH symptoms.

NEXT: Workup and investigation

Workup/Investigation

For children with confirmed persistent hypoglycemia or those needing IV glucose to treat hypoglycemia, say PES guidelines, workup/investigation should include the following (Table 3²):

• Thorough history. Include timing of episode, in context of food, birth weight, gestational age, and family history.

• Physical exam. Seek evidence of hypopituitarism, glycogenosis, adrenal insufficiency, or Beckwith-Wiedemann syndrome.

• Specimen or "critical sample." Whenever possible, obtain at time of spontaneous presentation of hypoglycemia <50 mg/dL after 48 hours of life and before treatment that might alter intermediary metabolites and hormone levels is given. Readily available assays for PG, insulin, BOHB, and lactate are useful for distinguishing categories of hypoglycemia disorders. Consider reserving extra plasma for specific tests (such as plasma cortisol, growth hormone, or free fatty acids.

• Provocative fasting test. If a spontaneous episode of glucose <50 mg/dL does not occur in a patient in whom workup is warranted, a 6-hour fast should be performed. Additionally, if the patient is unable to maintain PG >60 mg/dL, then further consideration of a persistent hypoglycemic disorder should be entertained.

Managing persistent hypoglycemia

Neonates with persistent hypoglycemia: Because recurrent PG levels of 50 mg/dL to 70 mg/dL can blunt awareness of hypoglycemia and impair hepatic glucose release (a condition known as hypoglycemia-associated autonomic failure (HAAF),¹¹ PES treatment targets aim to maintain PG concentration within the normal range of 70 mg/dL to 100 mg/dL. For defects in glycogen metabolism and gluconeogenesis, maintaining such a PG concentration prevents metabolic acidosis and growth failure; for hyperinsulinism, it can prevent recurrent hypoglycemia, which raises the risk of subsequent hypoglycemic episodes. For any hypoglycemia disorder, base long-term therapy on the specific disorder's etiology, consulting with a physician experienced in diagnosing and managing pediatric hypoglycemia.

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High-risk neonates without a suspected congenital hypoglycemia disorder: The PES committee's consensus was that during the first 48 hours of life, a safe target for such an infant should be near the mean for healthy newborns on the first day of life, and above the threshold for neuroglycopenic symptoms (>50 mg/dL). After 48 hours of age, the committee raised the glucose target (>60 mg/dL) above the threshold for neurogenic symptoms and near the target for older infants and children because hypoglycemia that persists beyond the first 48 hours (and particularly beyond the first week) increases the concern for an underlying hypoglycemia disorder. Absent evidence regarding short-term or long-term consequences of different treatment targets, the PES committee focused on physiology, etiology, and mechanism, balancing the risks and benefits of interventions in setting these targets.

NEXT: Discussion

Discussion

The apparent conflict between the AAP and PES recommendations stems from philosophical and methodological differences. Experts concur that within an hour or 2 of birth, PG concentrations in normal neonates temporarily drop by up to 30 mg/dL,^1,2 a phenomenon known as transitional neonatal hypoglycemia (TNH).¹² However, questions such as what this natural nadir means, how to respond to PG concentrations during the first 2 days of life, and whether newborn brains are more or less susceptible to hypoglycemic injury have sparked controversy.^13-15

A PES committee reviewed available data regarding metabolic fuel and hormonal responses during this period in normal newborns and determined that TNH most closely resembles known genetic forms of congenital hyperinsulinism, which lower the PG threshold for suppression of insulin secretion.¹² During this mild, transient form of hyperinsulinism, mean PG threshold for insulin suppression is approximately 55 mg/dL to 65 mg/dL shortly after birth and rises to approximately 80 mg/dL to 85 mg/dL - the mean level found in older infants, children, and adults - by age 72 hours, as the glucose-stimulated insulin secretion mechanism matures.^16,17 The difficulty in distinguishing TNH from a suspected persistent hypoglycemic disorder during an infant's first 48 hours supports the PES’ suggestion to delay any diagnostic evaluation until 2 to 3 days after birth.²

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In a recent reexamination of the mechanism and implications of TNH, the PES reviewed the major metabolic fuel and hormonal responses to hypoglycemia in neonates.¹² Considering published data from normal newborns during this phase, Stanley and colleagues reasoned that mean responses most likely reflected the responses of normal newborns.

Additionally, the PES found the PG concentrations of normal newborns during the transitional period to be "remarkably stable and relatively unaffected by the timing of initial feeding or interval between feedings." However, Adamkin believes feeding will affect infants with lower levels of glucose.⁴ Studies published between 1950 and 1992 show mean plasma glucose levels of approximately 57 mg/dL across fasting times that ranged from 8 to 24 hours.^18,19 These data led the PES to conclude that TNH appears to be a regulated process in normal newborns.

Researchers have speculated that this dip in glucose levels might stimulate physiological processes necessary for postnatal survival (such as enhancing oxidative fat metabolism, stimulating appetite).²⁰ An alternate explanation advanced by the PES is that this lower threshold for insulin secretion is essential for in utero fetal nutrition and growth, and that persistence of this lower set point of insulin secretion is caused by peripartum stress. In 126 term-appropriate for gestational age (AGA) neonates, the lowest glucose values (<30 mg/dL) appeared to be especially associated with peripartum stresses (fetal distress, birth asphyxia, low Apgar scores) and low weight-versus-length ratios, consistent with fetal growth restriction. By 72 hours, only 0.5% of these babies will have persistent glucose values <50 mg/dL.²¹

Perinatal stress has been associated with hyperinsulinemic hypoglycemia that may persist until up to 6 months of age.^22,23 These factors explain why the PES considers birth asphyxia, ischemia, and other stressors to put infants at risk of hypoglycemia, although the AAP counters that routinely screening such patients would be burdensome and produce many enigmatic readings in asymptomatic infants.³

In setting its thresholds, the AAP focused instead on the lower ranges of glucose concentrations found in fetuses and asymptomatic infants^17,24 in suggesting a bottom line of <25 mg/dL and actionable levels of 25 mg/dL to 40 mg/dL during an infant's first 4 hours of life. From 4 to 24 hours, the AAP's lower range is <35 mg/dL, with actionable values of 35 mg/dL to 45 mg/dL.

The neurodevelopmental approach that underlies the AAP thresholds is hardly free of controversy. For starters, the 1988 study²⁵ that resulted in widespread adoption of 47 mg/dL as the threshold for NH in all infants had methodological flaws, and focused not on hypoglycemia but on feeding patterns of low-birth-weight babies.¹ Subsequent studies in various newborn populations - including a follow-up study showing less dramatic impact when these infants were aged 7 or 8 years²⁶ - have yielded conflicting results. Recent reviews have revealed a dearth of high-quality data regarding the relationship between early glucose levels and neurodevelopmental outcome, especially in late-preterm and newborn infants with risk factors.²⁷ It should be noted that any study that looks only at glucose levels without examining all the brain fuels including oxygen and blood flow is flawed.

Thus, AAP authors conclude that sticking with this group's recently reratified 2011 recommendations, "along with enhanced vigilance to identify persistent hypoglycemia symptoms after 48 hours, might be the best compromise" to prevent overscreening and overtreatment while still committing to diagnosing persistent hypoglycemia after the transitional period, but before infants are discharged home.³

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Mr Jesitus is a medical writer based in Colorado. He has nothing to disclose in regard to affiliations with or financial interests in any organizations that may have an interest in any part of this article. Dr Thornton and Dr Adamkin also report no conflicts of interest.