Hypoglycemia in the Newborn

               Mark A. Sperling and Ram Menon

INTRODUCTION

This chapter outlines the epidemiology, etiology, pathophysiology, differential diagnosis, and management approach to the neonate with hypoglycemia, here defined as 40 mg/dL or less (≤2.2 mmol, the fifth percentile for age) during the first 2 days of life and 50 mg/dL or less (≤2.8 mmol) of whole blood glucose thereafter, with or without suggestive symptoms. Note that plasma glucose concentration is about 10%–15% greater than whole blood glucose concentration, so criteria for hypoglycemia based on plasma glucose measurements must be appropriately adjusted to be greater. Recent advances in our understanding of the biochemistry, physiology, and molecular biology regulating prenatal and postnatal glucose homeostasis combine to provide a rational basis for defining, identifying, diagnosing, and treating hypoglycemia in the newborn to enable normal neurodevelopment.^1,2 These considerations provide a systematic approach to the problem of neonatal hypoglycemia and argue for glucose measurements to become part of routine care in all neonates prior to discharge from the newborn nursery and in all sick neonates even after discharge from the newborn nursery.

EPIDEMIOLOGY

Hypoglycemia is a relatively common and highly important problem in the newborn.^3–5 Precise data on incidence are unavailable and depend in part on the definition of hypoglycemia, an area of ongoing discussion, as well as the degree of gestational maturity and condition of the newborn.^1–3 Based on a meta-analysis,⁵ it has been proposed that, in full-term normal newborns, blood glucose of 40 mg/dL or less in the first 48 hours and 48 mg/dL or less between 48 and 72 hours represents less than the fifth percentile for age. A minor modification to these data permits defining hypoglycemia as 40 mg/dL or less in the first 2 days of life and 50 mg/dL or less thereafter. By the fourth day of life, normal infants usually maintain average blood glucose values greater than 60 mg/dL, approaching values of healthy children and adults. Using these criteria, the reported incidence of hypoglycemia in the first days of life varies from approximately 70% in infants who are small for gestational age (SGA),⁶ 20%–50% in those large for gestational age (LGA) but otherwise-normal newborn infants born to nondiabetic mothers, and greater than 50% in those born to infants of diabetic mothers⁷; only about 2% of term infants born to nondiabetic mothers after normal pregnancy develop hypoglycemia.⁸

The importance of neonatal hypoglycemia lies in its association with potential impairment of neurocognitive development⁶ because glucose is the preferential energy substrate of the newborn’s brain, which normally utilizes greater than 90% of normal basal glucose turnover and has been shown to be about 4–8 mg/kg/min.⁹ Although the brain of a neonate can use other energy substrates, such as lactate and β-hydroxybutyrate, in hypoglycemia secondary to hyperinsulinism (HI), the production of glucose (by glycogenolysis or gluconeogenesis) is suppressed, as is lipolysis and ketogenesis, while glucose utilization and storage are increased. Hence, in HI, the brain is effectively deprived of all sources of nutrients. The consequences of such hyperinsulinemic hypoglycemia, the most common form of persistent hypoglycemia of the newborn, include high rates of seizures, mental retardation, neuromuscular spasticity, and other disturbances in psychomotor development.^10–12

In SGA and preterm infants, hypoglycemia that is recurrent or repetitive is a more predictable factor for long-term neurodevelopmental deficits than the severity of a single hypoglycemia episode.⁶ Thus, the degree and duration of hypoglycemia, as well as associated conditions such as hypoxia and seizures, add to the risk of neural and intellectual impairment. Moreover, the younger the infant, the earlier and more persistent the hypoglycemia, and the greater the difficulty to control seizures by medical means alone, the more likely it is that long-term neural and intellectual development will be adversely affected.^10–12 There is some evidence that the neonatal brain may be more resistant than the adult brain to hypoglycemia, especially because of its ability to better use lactate and β-hydroxybutyrate as alternate fuels.¹³ Precisely for these reasons, HI is the most concerning of the syndromes of hypoglycemia of the newborn because generation of alternate fuels also is diminished or abolished by the HI.

Based on these findings, we suggest that an operational threshold of whole blood glucose of 50 mg/dL or less should be viewed with concern for monitoring and intervention. In making this recommendation, we recognize that we are “raising the bar” from previous standards. However, it is now established that persistent hypoglycemia is harmful, even if a precise glucose concentration below which harm ensues cannot be individually determined.^10–12 Hence, we urge earlier investigation and intervention as a precautionary measure. When symptoms of hypoglycemia, especially seizures, accompany the low glucose measurements, adverse neurodevelopmental outcomes should be anticipated.

PATHOPHYSIOLOGY

Hypoglycemia

Neonatal hypoglycemia has its origins in utero and in the dramatic transition to independent existence following separation from the placenta. In utero, the fetus receives all of its nutrients from the mother via the umbilical vein, and gluconeogenesis is absent or minimal until birth.^1,2 During the third trimester, weight doubles from approximately 1700 g at 32 weeks’ gestation to approximately 3500 g at term, representing in large part accretion and deposition of glycogen, fat, and muscle tissue. The degree of fetal insulin secretion, though modest, is sufficient to stimulate cognate insulin receptors and permit partitioning of nutrients for immediate energy use and for tissue growth. Excessive nutrient transfer, as occurs to a variable degree in all diabetic pregnancies, promotes secretion of insulin, a growth-promoting hormone, which leads to macrosomia in utero.^14,15 Transient neonatal hypoglycemia, lasting 1-3 days, occurs after umbilical cord cutting, when glucose supply is interrupted, whereas excessive insulin continues for some time. Similar considerations determine macrosomia resulting from genetic defects causing HI in utero, but in these cases, postnatal hypoglycemia persists.^16,17 The severity of the hypoglycemia depends on the degree of HI and the duration between feedings, that is, “fasting.”

The term hyperinsulinism denotes excessive insulin action relative to the prevailing blood glucose concentration. This is reflected in the metabolic profile of HI-associated hypoglycemia caused by suppressed glucose production concurrent with increased glucose utilization, exceeding the usual range of 4–8 mg/kg/min,⁹ suppressed lipolysis leading to low circulating free fatty acids (FFAs), and suppressed ketogenesis leading to low circulating concentrations of β-hydroxybutyrate. The degree of HI may not be reflected in the circulating concentration of insulin, in part because insulin is secreted into the portal vein, and hepatic extraction may exceed the theoretical 50% reported in normal adults, and in part because activating mutations in elements of the insulin-signaling pathway will produce an identical clinical and biochemical phenotype (macrosomia, hypoglycemia, low FFA, low β-hydroxybutyrate) but with insulin levels that are low (<2 mIU/mL) or even below the limits of assay detection.¹⁸ Thus, the key to differentiating and managing the causes of neonatal hypoglycemia is the metabolic profiles of glucose, FFAs, and β-hydroxybutyrate, which are more readily available in most laboratories than accurate ultrasensitive assays for measurement of hormones such as insulin, cortisol, and growth hormone (GH).

Umbilical cord cutting at birth triggers a series of coordinated hormonal and enzymatic changes that mobilize the fuel stores deposited in utero to sustain energy needs until feeding is established.¹⁹ Epinephrine and glucagon concentrations increase 3- to 5-fold within minutes and can act quickly via cyclic adenosine monophosphate (cAMP) to mobilize glucose by glycogenolysis. GH and cortisol concentrations in blood also are high in the initial hours after birth. Cortisol promotes gluconeogenesis, which takes several hours to be initiated and several days before it is fully established, whereas GH in concert with epinephrine acts to induce lipolysis with provision of fatty acids for oxidation, and the high concentrations of glucagon induce ketogenesis in mitochondria. A key enzyme for gluconeogenesis, phosphoenol pyruvate carboxykinase (PEPCK) is not expressed at birth and, under the influence of glucocorticoids, matures by about 24 hours.^19,20 Likewise, a key enzyme for ketogenesis, carnitine palmitoyl transferase 1 (CPT-1) is not expressed initially, and transcription is activated in part by long-chain fatty acids that are contained in colostrum, so that expression is evident by about 24 hours.^20,21

Thus, immediately after birth, all infants initially must rely on glucose derived from glycogen and calories received from feedings of colostrum or milk. Moreover, whereas the four energy-mobilizing hormones are increased, insulin concentrations initially decline in the first few hours after delivery, and insulin secretion responds only sluggishly to glucose stimulation. As a result, the pattern in a normal full-term infant is for glucose to decrease to approximately 50 mg/dL in the first few hours after delivery and to return to average concentrations of 60 mg/dL or higher by day 2 and certainly by day 3 of life.⁵ Thus, conditions that diminish nutrient reserves for mobilization, such as intrauterine growth retardation or premature birth, will impair the ability to maintain glucose concentration that is appropriate for a normal newborn and hence predispose to hypoglycemia.

It has long been known that, in the first 8 hours after birth, almost one-third of term infants who are adequate for gestational age (AGA) and almost one-half of preterm or immature infants will have blood glucose concentrations less than 50 mg/dL.²² These are the normal adaptations in the transition from intrauterine life and dependence on maternal glucose supply to extrauterine existence with integration of glucose homeostasis during feeding and fasting that may be associated with “transitional” forms of hypoglycemia during adaptation. However, by day 3 of life, virtually no term AGA infant and less than 1% of all those in other categories have a plasma glucose concentration below 50 mg/dL.^5,22

Hypoglycemia, as we have defined it, represents a mismatch between the ability to provide glucose either entirely by endogenous production or supplemented by feeding and factors that enhance its utilization. Hence, the ability to maintain glucose concentration may be impaired if feeding is delayed; if enzymatic pathways are not established fully, as occurs in the premature infant; or if there is transient persistence of excessive insulin secretion, as occurs in infants born to mothers with diabetes during pregnancy.²³ Hypoglycemia will persist if there are defects in the ability to metabolize glycogen to glucose, to initiate gluconeogenesis, or to convert fatty acids to ketones as a source of energy. Higher-than-normal glucose utilization rates can be anticipated with conditions such as sepsis, fever, or seizures, all of which also prevent normal feeding, or if hypoxia or other intrauterine stress has depleted glycogen stores. However, a glucose utilization rate in excess of 10 mg/kg/min, as reflected in the glucose infusion rate needed to maintain blood glucose above 60 mg/dL, almost invariably indicates a state of HI.^1,2,16–18 In an otherwise-healthy full-term AGA infant, delay in initiating feeding via breast or bottle does not in itself cause hypoglycemia, but it hastens the unmasking of an underlying defect, such as HI, deficiency of cortisol or GH, or even more rarely, severe defects in gluconeogenesis or fatty acid oxidation.^23–25 Less-severe disorders of glycogen breakdown and gluconeogenesis are not likely to manifest while the baby is being fed at 2- to 4-hour intervals, and with rare exceptions the same holds for disorders of fatty acid oxidation. These tend to be manifested later when the interval between feedings is lengthened (eg, at weaning), and the increased period of fasting unmasks an inborn error of metabolism. GH deficiency and cortisol deficiency, either as isolated defects or as part of hypopituitarism,²⁶ also may be masked by frequent feedings and unmasked by fasting.^24–26 The same holds true for transient or permanent HI, the most important and frequent cause of persistent hypoglycemia in a newborn child.^1,2 The more severe the defect, the sooner the clinical manifestations will appear in an otherwise-normal full-term newborn even with a normal feeding schedule.

In the absence of predisposing factors such as diabetes mellitus in the mother, premature birth, or intrauterine growth retardation, hypoglycemia in the first hours or days of life is almost always caused by deficiencies of GH or cortisol,^24,25 HI associated with perinatal asphyxia/hypoxia,^27,28 or HI due to genetic defects in the regulation of insulin secretion, manifesting as “fasting hypoglycemia” when the baby cannot feed or the interval between feedings is lengthened.^29–31

Mechanisms of Central Nervous System Damage

Neuroglycopenia of short duration may be reversible. However, prolonged severe hypoglycemia, when glucose concentration is 1 mM (18 mg/dL) or less, results in neuronal death from cellular energy failure and the release of the excitatory amino acid aspartate into the extracellular space. Interaction of aspartate with its receptor on central nervous system (CNS) cells leads to membrane disruption, influx of calcium, activation of enzymes such as phospholipase, changes in cellular redox state, and cell death primarily affecting the posterior cerebral cortex but sparing the cerebellum and brainstem.³² In addition, hypoglycemia is reported to activate A1 adenosine receptors, permitting influx of calcium and activation of the proapoptotic enzyme caspase-3; blockade of adenosine A1 receptors ameliorated neuronal damage in the mouse model used.^33,34 These findings suggest the possible future use of adenosine A1 receptor antagonists to mitigate neuronal damage in newborns with severe hypoglycemia.^33,34 They also may explain the patterns of injury in severe hypoglycemia reported in magnetic resonance imaging (MRI) studies.

Magnetic Resonance Imaging in Neonatal Hypoglycemia

Some investigators reported specific patterns of MRI changes in newborns with severe hypoglycemia that differed from findings reported in hypoxic-ischemic brain injury. Diffuse cortical and subcortical white matter damage affecting primarily the parietal and occipital lobes is typically seen with severe hypoglycemia of less than 20 mg/dL and may be associated with bilateral occipital lobe cortical atrophy, a possible distinguishing feature not seen in hypoxic-ischemic brain injury. These changes may later manifest as cortical blindness. In some reports, changes observed initially seemed to resolve over time.^35–38

Diagnostic Approach

The symptoms and signs of hypoglycemia in a newborn are predominantly neurological, due to neuroglycopenia, as listed in Table 45-1. Most are nonspecific and could be caused by other conditions, such as sepsis in the newborn. Hence, eternal vigilance and consideration for the possibility of hypoglycemia as the cause of the symptom are keys to early diagnosis and favorable outcome. Therefore, we recommend that hypoglycemia be considered in any newborn with the symptoms listed. A blood glucose concentration of less than 40 mg/dL on days 1–2 of life, less than 50 mg/dL on day 3, and less than 60 mg/dL thereafter should be followed at a minimum by a formal blood glucose measurement in a laboratory together with the concentration of FFAs and β-hydroxybutyrate. If all 3 are suppressed, HI is the most likely diagnosis. If glucose is low but β-hydroxybutyrate and FFAs are normal or elevated, a defect in the ability to produce glucose is most likely. If the concentrations of both glucose and β-hydroxybutyrate are low but that of FFA is elevated, then a defect in fatty acid oxidation should be suspected. Sufficient blood should be made available to measure insulin, GH, and cortisol; a more detailed analysis of the “critical sample” taken at the time of hypoglycemia is discussed in the section on the diagnostic approach and treatment.

Table 45-1 Symptoms and Signs of Hypoglycemia in the Neonate

CLASSIFICATION OF NEONATAL HYPOGLYCEMIA

A classification of neonatal hypoglycemia is presented in Table 45-2. Routine screening of blood glucose concentration is not indicated in a healthy term infant after a normal pregnancy and delivery and with no hint of perinatal asphyxia. Blood glucose measurements and monitoring are promptly indicated in any infant who manifests the signs and symptoms listed in Table 45-1. Such infants also require measurements of FFAs and β-hydroxybutyrate and determination of insulin, GH, and cortisol.

Table 45-2 Classification of Neonatal Hypoglycemia

Table 45-3 Classification of Hyperinsulinemic Hypoglycemia of Newborns

Transitional Hypoglycemia (Days)

Transitional hypoglycemia that resolves within days occurs in newborn infants who are SGA or born prematurely. Such newborns should be monitored for hypoglycemia (<40 mg/dL) within 4 hours of birth and treated by feeding and intravenous glucose as needed to maintain plasma glucose concentrations equal to or greater than 45 mg/dL before each feeding. The target glucose should be greater than 45 mg/dL before routine feedings during the first 4 to 48 hours of life and greater than 50–60 mg/dL thereafter. Late preterm infants, defined as infants at 34 to 37 weeks’ gestation, are likely to resolve their hypoglycemia within days as they have transitional hypoglycemia due to delay in enzyme maturation and diminished nutrient reserves.

Infants born to mothers with diabetes pre-dating pregnancy or developing during pregnancy also should be monitored as they are likely to need frequent feeding or continuous intravenous glucose infusion at rates of 5 to 7 mg/kg/min. These infants typically are LGA and have a surfeit of nutrients that they cannot mobilize due to hyperinsulinemia and diminished glucagon. Also glycogen may have been depleted if there was prolonged labor resulting in stress-activated epinephrine secretion. Meticulous glycemic control during pregnancy minimizes macrosomia, hypoglycemia, and other perinatal problems.^39,40 During labor and delivery of a pregnant woman with diabetes mellitus, intravenous glucose infusion should be avoided if possible as glucose crosses the placenta to the fetus and will stimulate insulin secretion that predisposes to hypoglycemia after placental separation. Treatment of such newborn infants also should avoid bolus glucose infusions; they stimulate surges of insulin secretion and cause rebound hypoglycemia. Most infants of diabetic mothers are stabilized within 3 to 5 days of birth using frequent feedings supplemented by intravenous glucose.

In the absence of a history of documented maternal diabetes, infants born LGA should be suspected of having HI and monitored accordingly. Such infants, along with infants who are SGA, should not be discharged from the hospital without demonstrating that their blood glucose is maintained at equal to or greater than 60 mg/dL at least 4 hours after a feeding for 3 feeding cycles. Blood glucose should be measured one-half hour before the next scheduled feeding. If feeding cannot be established and intravenous glucose infusion rates exceed 5–7 mg/kg/min to maintain a glucose concentration above 60 mg/dL, HI should be suspected. If glucose infusion rates of 10 to 12 mg/kg/min or greater are necessary to maintain blood glucose greater than 60 mg/dL, the cause is most likely HI.

Transient Hypoglycemia (Days–Weeks)

Transient hypoglycemia due to HI that lasts days to weeks is also reported in newborn infants with a history of perinatal stress, including maternal hypertension, preeclampsia, intrauterine growth retardation (IUGR), hypoxia, and cesarean delivery.^27,28 Onset may be sudden, unanticipated, and severe, with glucose concentrations plunging to levels below 20 mg/dL; these concentrations are associated with subsequent neurological devastation. Onset may occur after discharge from the newborn nursery and may be heralded by the baby having “feeding difficulties.” Insulin concentrations are modestly elevated but inappropriate for the degree of hypoglycemia; FFA and β-hydroxybutyrate concentrations are lower than normal. The majority of affected infants respond to diazoxide at a dose of 5–15 mg/kg/d, with the median effective dose 8 mg/kg/d in 1 reported series.²⁷ Some 20% of such affected newborns require frequent feedings or supplementation with intravenous glucose until hypoglycemia resolves. A variant of this hyperinsulinemic syndrome is associated with lactic acidosis and is thought to be associated with defects in the pyruvate dehydrogenase complex.²⁸ Diazoxide is the treatment of choice, and resolution usually occurs within 3–4 weeks. The mechanism responsible for malfunction of insulin secretion in these syndromes is unknown but likely involves the potassium channel regulated by adenosine triphosphate (K_ATP).

Persistent Hypoglycemia in Infancy

The causes of persistent hypoglycemia in infancy are listed in Tables 45-2 and 45-3. Their onset may be in the newborn period, but unlike the causes described previously, they persist if left untreated and can lead to neurological sequelae. Three separate reviews in the literature all pointed to early onset, prolonged hypoglycemia, and inability to achieve target blood glucose concentrations of greater than 60 mg/dL by medical means alone as poor prognostic signs.^10–12

The persistent forms of hypoglycemia in infancy include deficiency of the counterregulatory hormones GH and cortisol, either alone or in combination, as occurs in hypopituitarism. Clues for the diagnosis of hypopituitarism include midline facial defects such as cleft palate, holoprosencephaly, and nystagmus as a manifestation of the septo-optic dysplasia syndrome.²⁶ Jaundice with both cholestatic and inflammatory features is frequently found in hypopituitarism and is likely due to GH and cortisol deficiency; treatment with GH plus cortisol reverses the hepatic defects.⁴¹ In boys, micropenis and small undescended testes provide important clinical clues that gonadotropin deficiency also exists. In normal full-term boys, testosterone concentrations in the first few days of life are as high as they are in the midteen years, and GH concentrations average 30–40 ng/dL in the first days of life. Therefore, stimulation tests for GH or testosterone are unnecessary; low concentrations in association with hypoglycemia are strong clues to the existence of hypopituitarism. If prolactin is elevated while GH, cortisol, and testosterone are low, the primary defect is in the hypothalamus, which normally restrains prolactin through the secretion of dopamine, previously called prolactin-inhibiting factor (PIF). MRI with contrast may reveal an ectopic posterior pituitary bright spot with interruption or absence of the pituitary stalk.^26,42 The deficiencies of GH and cortisol permit the unopposed action of insulin so that hypoglycemia occurs during fasting, which may represent only brief periods beyond the customary 2 to 3 hours between feedings. Cortisol should be replaced at 10 to 15 mg/m²/d, and GH may be given at a dose of 20–40 μg/kg/d if hypoglycemia persists and GH deficiency is documented.

Clues to the existence of an adrenal disorder causing cortisol deficiency may include ambiguous genitalia, hyponatremia, hyperkalemia, and metabolic acidosis. These findings are secondary to lack of aldosterone, and abnormal patterns of steroid precursors define the site of the biosynthetic block in congenital adrenal hyperplasia, the most common of which is 21-OH deficiency.

Bilateral adrenal hemorrhage should be considered after difficult delivery; in boys, congenital adrenal hypoplasia, a contiguous gene defect on the X chromosome also associated with Duchenne muscular dystrophy, and deficiency of glycerol kinase should be considered. Elevated serum levels of creatine phosphokinase (CPK) and triglycerides rapidly identify this condition. Adrenoleukodystrophy, another X-linked condition, usually does not present in the newborn period. Congenital unresponsiveness to ACTH (corticotropin) and the triple A syndrome (alacrima, achalasia, adrenal insufficiency; also known as Allgrove syndrome) can affect both sexes and should be considered in the differential diagnosis of primary adrenal insufficiency (low cortisol with high ACTH) associated with hypoglycemia, although presentation does not generally occur in the newborn period.⁴³

Inborn errors of metabolism affecting glycogen breakdown or synthesis, gluconeogenesis, and fatty acid oxidation are unlikely to become apparent unless feeding is delayed for periods of much longer than the customary schedule of feedings every 2 to 4 hours. These defects generally become apparent after 3 to 6 months when the feeding schedules are progressively delayed and the child is being weaned so that the interval between feedings becomes 4 to 6 hours rather than the previous 2 to 4 hours.^1,2 Fatty acid oxidation defects, unless severe, do not manifest in the immediate newborn period when feedings are frequent. Difficulties with initiating breast-feeding may unmask any of the aforementioned entities, including severe fatty acid oxidation defects that can result in hypoglycemia.^21,23 Moreover, enhanced neonatal genetic screening now identifies infants with defects in fatty acid oxidation so that the diagnosis is known within days after discharge from the newborn nursery. Note again that all these syndromes are manifestations of the inability to adapt to fasting, and that there is an inverse relationship between the duration of fasting necessary to provoke hypoglycemia and the severity of the defect(s) in counterregulatory hormones, in glycogen breakdown, in gluconeogenesis, in fatty acid oxidation defects, and in HI.

Persistent Hyperinsulinemic Hypoglycemia of Infancy

Persistent hyperinsulinemic hypoglycemia of infancy is now generally known as congenital HI and is the most common form of persistent hypoglycemia of infancy, caused by one of several genetic entities (Table 45-3). Understanding the biochemical and molecular basis has revolutionized the care of the newborn with HI and is essential for appropriate management and optimum outcome in affected newborns.^{1,16,17,29–31} The biochemistry of HI, discussed in the previous material, is summarized in Table 45-4. The glycemic response to glucagon is a rapid means to confirm that the liver contains glycogen, whose breakdown is inhibited by the excess actions of insulin. This restraint can be overcome by the intravenous or intramuscular injection of 0.5–1.0 mg glucagon, resulting in a rise of glucose concentration greater than 30 mg/dL above the baseline 30 minutes after injection. In other fasting forms of hypoglycemia, liver glycogen stores are less responsive or unresponsive to glucagon due to a block in glycogenolysis, as occurs in glycogen storage disease, or because glycogen has been depleted by fasting, as occurs in defects of gluconeogenesis or fatty acid oxidation; hence, these entities respond with an increment in glucose less than 30 mg/dL.

Table 45-4 The Critical Sample: Blood and Urine Tests at Time of Hypoglycemia

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