Persistence of the hyperinsulinemic state after birth in many IDMs who develop elevated insulin secretion in utero in response to maternal hyperglycemia causes self-limited hypoglycemia that can be severe but relatively asymptomatic (see Chapter 63, Infant of the Diabetic Mother). Infants with intrauterine growth restriction (IUGR) are at risk for neonatal hypoglycemia; 65% of premature and 25% of full-term IUGR babies become hypoglycemic. Factors contributing to their low plasma glucose levels include decreased glycogen and fat stores, large brain–to–body weight ratio, failure to mobilize alternative fuels adequately, and in some instances, a relative hyperinsulinemia. Premature neonates (less than 37 weeks’ gestation) also are at risk for the development of hypoglycemia. They have multiple contributing factors, such as lower total body energy stores, impaired ability to mobilize alternative fuels due to functional immaturity of the metabolic enzymes, and inadequate dietary intake. They also have an increased likelihood of having neonatal distress with sepsis, hypoxia, or perinatal depression, that can further compromise glucose homeostasis. ELBW babies must rely on gluconeogenesis and exogenous glucose infusion for glucose balance, because they have minimal glycogen available for glycogenolysis.

Hypoglycemia may develop in neonates with polycythemia-hyperviscosity with hematocrits greater than 65%. The greater red cell mass has increased glucose utilization, whereas less glucose is carried in a given volume of blood as a result of the diminished plasma fraction. The increased viscosity leads to sludging, which may leave tissues poorly oxygenated and, thus, more dependent on glucose for anaerobic metabolism. The hypoglycemia in these instances resolves with partial-exchange transfusion to reduce the hematocrit. Severe perinatal stress also predisposes to hypoglycemia; contributing features include excessive glucose utilization and exhaustion of stored substrates. Certain maternal therapies that suppress counter-regulatory mechanisms, such as treatment with propranolol, may contribute to inducing a hypoglycemic state in newborns.

Although rare, congenital hyperinsulinism is the most common cause of persistent hypoglycemia in infancy. Multiple genetic mutations have been identified thus far. Autosomal recessive mutations of the sulfonylurea receptors (SUR1) or associated potassium channels (Kir6.2) of pancreatic beta cells constitute the most severe forms of congenital hyperinsulinism with diffuse beta-cell disease. Mutations of either of these two adjacent genes on chromosome 11 affect the subunits of the K_ATP channel such that insulin secretion is constitutively active and unresponsive to ambient glucose. A sporadic form, due to loss of heterozygosity for the maternal allele and inheritance of an abnormal paternal allele for SUR1, causes focal beta-cell hyperplasia and is clinically indistinguishable from diffuse disease. These mutations of the ATP-dependent potassium channel are the most common cause of severe neonatal hyperinsulinism with the classic clinical picture of macrosomia, increased insulin/glucose ratios, and a requirement for high glucose infusion rates. Autosomal dominant hyperinsulinism appears to be a milder disease. Although the majority of cases have not been associated with particular mutations, a gain-of-function mutation of the glucokinase gene can cause a mild form of congenital hyperinsulinism that is responsive to diazoxide. Congenital hyperinsulinism with associated hyperammonemia is caused by an activating mutation in the glutamate dehydrogenase gene. These infants typically present later in infancy and have leucine-sensitive hypoglycemia with mild fasting defects.

Neonates with the Beckwith-Wiedemann syndrome (Fig. 62.2) have macroglossia, characteristic ear creases or pits, visceromegaly, omphalocele, and are large for gestational age (LGA). Nearly 50% of reported cases exhibit hyperinsulinemic hypoglycemia caused by diffuse islet cell hyperplasia. Hypoglycemia in such infants may be severe and long-lasting, necessitating pharmacologic management of their hyperinsulinism in addition to glucose supplementation.

Hypopituitarism and isolated growth hormone (GH) deficiency are other endocrine causes of persistent hypoglycemia in infancy. Although growth may remain normal during infancy, associated physical features, such as midline defects or microphallus, are helpful diagnostically. Very infrequently, neonatal hypoglycemia is caused by one of the inborn errors of metabolism in the gluconeogenic or glycogenolysis pathways, such as galactosemia or type I glycogen storage disease (see Chapter 387, Disorders of Carbohydrate Metabolism). Genetic defects of the glucose transporter 1, which transfers glucose across the blood–brain barrier, have been recognized as a cause of central nervous system hypoglycemia and seizures despite normal blood glucose levels.

Clinicians must have a low threshold for suspecting hypoglycemia in neonates, because the symptoms are subtle.
Affected infants may be jittery or manifest such nonspecific symptoms as apnea, seizures, poor feeding, or lethargy, but they may be also essentially asymptomatic. The neurocognitive sequelae of asymptomatic neonatal hypoglycemia are unknown. A careful pregnancy history and physical examination may reveal evidence of growth restriction, visceromegaly, or other clues to the etiology of the hypoglycemia. A plasma glucose level should be obtained; if capillary sampling is used, care must be taken to warm the heel adequately. If the glucose concentration is 40 mg/dL or less in asymptomatic infants or less than 45 mg/dL in infants with symptoms, assessment and possibly treatment should be instituted. Initial screening can be carried out using glucose oxidase strips (e.g., Dextrostix, Chemstrips) or with a bedside glucose analyzer, but laboratory confirmation of low values is required. The strips should be fresh or packaged individually, because strips from open bottles may be inaccurate and give erroneously low values.

Stable and relatively mature babies may be treated safely with early enteral feedings and careful monitoring of subsequent plasma glucose values. If blood glucose is greater than 45 mg/dL, normal feeding may be started as soon as the infant’s condition permits, with capillary glucose monitoring every 1 to 2 hours until blood sugars stabilize in the normal range. If the glucose value is between 25 and 45 mg/dL, a repeat sample is obtained while the baby is given 10 to 15 mL of formula (orally or by gavage feeding) with frequent monitoring of the blood glucose until it is stable (greater than 40 to 45 mg/dL). If the blood glucose is less than 25 mg/dL, parenteral glucose supplementation is required, first administering a “mini-bolus” of 10% glucose, 2 to 3 mL/kg intravenously, followed by a constant infusion of 10% glucose delivered at a rate of 4 to 6 mg/kg/minute, which approximates the basal glucose production rate of the healthy neonate. Glucose values must be monitored closely, with titration of the infusate to maintain normoglycemia.

Infants with transient hypoglycemia or hypoglycemia attributable to one of the self-limited disorders described require supportive therapy to maintain glucose levels in the normal range, but minimal diagnostic evaluation is necessary. Infants with prolonged hypoglycemia, those requiring high glucose infusions (more than 10 to 15 mg/kg/minute), and those with a clinical course suspicious for a pathologic disorder of glucose regulation need further workup. Inappropriately high serum insulin levels (relative to simultaneously obtained plasma glucose levels) without evidence of Beckwith-Wiedemann syndrome or maternal diabetes mellitus suggest hyperinsulinism. Insulin secretion should be suppressed completely during a hypoglycemic episode; thus, the finding of measurable concentrations of insulin and absent ketone production is suspicious for hyperinsulinism. A glucagon stimulation test can help identify a hyperinsulinemic state. In a hypoglycemic infant, the administration of 0.5 mg of glucagon will not raise significantly the plasma glucose, unless glycogen breakdown is being suppressed by insulin (hyperinsulinism) or decreased counter-regulatory hormones (panhypopituitarism). An increase in glucose of more than 30 mg/dL is indicative of glycogen reserve. Therefore, obtaining a blood sample for ketones, free fatty acids, cortisol, and GH, in addition to the insulin level, during hypoglycemia is essential. Evaluation of the gluconeogenic or glycogenolytic pathway may be necessary in rare cases suspicious for these disorders. Fasting studies are at times necessary to assess fasting tolerance and to make a definitive diagnosis.

Infants with hyperinsulinemic hypoglycemia and infants with IUGR may require especially high glucose infusions (15 mg/kg/minute or higher), which usually are delivered via a central venous catheter. Intravenous therapy should be maintained until the glucose level has stabilized. Rebound hypoglycemia in IDMs can be avoided by a slow tapering of the intravenous glucose being administered and the maintenance of the blood glucose in the normal range, avoiding both hypoglycemia and hyperglycemia. If intravenous access is difficult in IDMs, glucagon (0.3 mg/kg to a maximum dose of 1 mg) can be given to override the inhibitory effect of insulin on glycogenolysis and raise an affected infant’s blood glucose level within 10 to 15 minutes of the injection. It must be emphasized that glucagon benefits only infants with a large glucose reservoir in the form of glycogen; it is ineffective in low-birth-weight or perinatally depressed infants who have depleted their glycogen stores.

Infants who require very high glucose infusions may need pharmacologic therapy to aid in the treatment of hypoglycemia. Diazoxide suppresses insulin secretion and is the initial choice for hyperinsulinism; the usual dosage is 10 to 15 mg/kg/day. Patients with SUR1 or Kir6.2 mutations, however, are unlikely to respond adequately to diazoxide and generally require a subtotal 95% to 99% pancreatectomy. Octreotide, a somatostatin analogue, suppresses insulin release and has been useful in conjunction with diazoxide in certain patients for the long-term management of hyperinsulinemia. Glucagon infusions (5 to10 μg/kg/hour) can be helpful as a temporizing measure, particularly preoperatively, but the action of these infusions are not sustained for chronic use. At some centers, focal lesions can be localized intraoperatively and successfully resected. Postoperatively, pharmacologic intervention still may be necessary for optimal glucose control.

ELBW infants have a relative insulin insensitivity and delayed processing of proinsulin during hyperglycemia. Other conditions associated with transient hyperglycemia in the newborn period include sepsis, surgical stress, hypoxia, central nervous system insults (including intracranial hemorrhage), and treatment with methylxanthines. Stress-related hyperglycemia results, in part, from elevated catecholamine and cortisol levels. Pancreatic agenesis is a rare cause of neonatal glucose intolerance and is caused by insulin promoter factor 1 mutations; these babies also exhibit significant IUGR. Neonatal diabetes, estimated to occur once in 500,000 births, has a highly variable course. Affected babies may have transient diabetes, with or without periods of remission, or permanent diabetes, and most are small for gestational age. A complete deficiency of glucokinase has been found to cause permanent neonatal diabetes. The small size of these neonates, in contrast to the macrosomia of IDMs, is believed to reflect insulin’s important role as an intrauterine growth hormone.

In a hyperglycemic neonate (greater than 150 mg/dL), the first measure is to calculate the glucose infusion rate in mg/kg/minute and gradually decrease the rate by 1 to 2 mg/kg/minute every 3 to 4 hours, monitoring glucose levels 30 to 60 minutes after changing the rate. Hypotonic infusates must be avoided. Insulin therapy should be considered if hyperglycemia persists despite the administration of glucose at basal production rates (approximately 4 to 6 mg/kg/minute). Fluid
balance, glycosuria, blood pressure, oxygenation, and perfusion should be checked carefully and, if sepsis is suspected, appropriate cultures should be obtained and antibiotics given. In very low-birth-weight infants (of less than 1.5 kg), consider measures to minimize insensible fluid losses, such as transfer from radiant warmers to isolettes. If hyperglycemia persists (greater than 200 mg/dL), therapy may be required using a continuous infusion of regular insulin, starting at 0.01 to 0.02 units/kg/hour, with the aim of maintaining plasma glucose at 100 to 150 mg/dL and taking care to avoid hypoglycemia. ELBW infants often require insulin infused continuously, along with intravenous glucose containing hyperalimentation, to permit the delivery of adequate nutritional substrates for growth. A larger and persistent requirement for insulin generally distinguishes the rare neonate with diabetes mellitus from the infant mounting a vigorous stress response who has transient hyperglycemia that resolves within a few days.

Late neonatal hypocalcemia occurs toward the end or after the first week of life and may be caused by congenital hypoparathyroidism, hypomagnesemia, and high-phosphate formula consumption (synonymous with late infantile tetany). Congenital hypoparathyroidism is caused usually by agenesis or dysgenesis of the parathyroid glands, and often is associated with the DiGeorge syndrome or chromosome 22q11 microdeletion syndrome. A transient hypoparathyroidism may be present in infants of women with hyperparathyroidism. Rarely, intrauterine nutritional vitamin D deficiency from severe maternal vitamin D deficiency or hereditary vitamin D–resistant rickets can present with late-onset hypocalcemia. Late-onset hypocalcemia associated with hypomagnesemia may occur in small-for-gestational-age neonates, in those with hepatic disease or small-bowel resections and, very rarely, in infants with magnesium malabsorption or disorders of renal magnesium handling. Hypomagnesemia causes late hypocalcemia via several mechanisms: It inhibits parathyroid hormone (PTH) secretion, induces a relative end-organ insensitivity to PTH, and causes decreased calcium absorption and decreased exchange of magnesium for calcium at the bone surface.

The diagnosis of neonatal hypocalcemia begins with an assessment of history, clinical signs, and laboratory data. The majority of babies with early neonatal hypocalcemia are asymptomatic and require no treatment except for close follow-up and monitoring. Hypocalcemic neonates may occasionally exhibit seizure activity, tremors, tetany or lethargy, and poor feeding. Monitoring of serum calcium, phosphorus, and magnesium with a careful assessment of intake is indicated in high-risk infants. Late hypocalcemia is more likely to be associated with a chronic condition and, in addition to the laboratory tests mentioned, PTH and vitamin D levels may be helpful diagnostically.

Although many neonatal units treat at-risk neonates with early calcium supplementation, the indications for this practice are not clear. Symptomatic early hypocalcemia is usually transient and may require temporary therapy with calcium supplementation. Oral and intravenous calcium supplementation for early hypocalcemia can be achieved with elemental calcium, 75 mg/kg/day as an initial oral dose or 24 to 75 mg/kg/day parenterally, usually given for less than 3 days. The subacute and chronic conditions of late hypocalcemia are treated with calcitriol (1,25-dihydroxyvitamin D), starting with a dose of 0.125 μg once or twice daily and calcium supplementation as described (see Chapter 64). Parathyroid agenesis requires lifelong therapy to prevent hypocalcemia. During the initiation of therapy, serum calcium and phosphorus should be monitored daily to maintain their concentrations in the low-normal range.

Seizures associated with hypocalcemia are treated with intravenous 10% calcium gluconate, 1 to 2 mL/kg, given slowly over 5 to 10 minutes to avoid inducing bradycardia. Care must be taken with the intravenous dosing of calcium-containing solutions to avoid extravasation and associated tissue damage.

Neonatal hypercalcemia usually is the result of excessive calcium supplementation, especially in very premature newborns. Babies with Williams syndrome (idiopathic infantile hypercalcemia syndrome with elfin facies and supravalvular aortic stenosis) may have hypercalcemia and nephrocalcinosis, which typically resolves spontaneously by 4 years of age. Primary hyperparathyroidism, although extremely rare, is caused by homozygous mutations of the plasma membrane calcium-sensing receptor (CASR). Heterozygotes for mutations of this receptor have familial hypocalciuric hypercalcemia, which is often asymptomatic, but homozygotes have a severe form of hypercalcemia, which is often lethal.

The treatment of neonatal hypercalcemia should be prompt and includes hydration at one-and one-half to two times maintenance using 5% dextrose with 0.5 normal saline and potassium chloride (3 mEq/dL); furosemide given at 1 mg/kg per dose intravenously twice or three times daily to inhibit renal
tubular calcium resorption; and phosphate supplementation to maintain normal serum phosphorus values. Vitamin D and calcium intake should be limited, and hydrocortisone may help decrease the intestinal absorption of calcium. Primary hyperparathyroidism often requires surgical resection of the parathyroid glands for definitive management.