The newborn emerges from a uterine environment in which glucose, calcium, and magnesium have been continuously provided and fetal plasma levels are closely regulated, in part by maternal metabolic homeostasis and placental exchange, as well as by fetal regulatory mechanisms. Abrupt termination of nutrient supply at birth requires profound changes in energy and mineral metabolism, depending on the provision of exogenous nutrients and the mobilization of endogenous fuel and mineral stores. The result is the potential for rapid changes in plasma glucose and calcium levels during the first days of life. The infant who is premature, growth restricted, stressed, or born to a diabetic mother is at increased risk for problems with homeostasis, and hypoglycemia or hypocalcemia can develop.
Broad surveys using modern analytic methods demonstrated that glucose and calcium problems are common, are frequently asymptomatic, and thus often go unrecognized in high-risk infants. Since that time, changing routines of care to include prevention, early identification, and metabolic support of the sick newborn has made severe hypoglycemia and hypocalcemia infrequent problems.
Fetal and Neonatal Energy Metabolism
A composite picture of fetal and neonatal fuel metabolism has emerged from studies in animals and humans. Fetal energy consumption is high, deriving from growth needs and energy storage as well as metabolic maintenance. Maternal glucose crosses the placenta via facilitated diffusion (primarily by the glucose transporters GLUT1 and GLUT3) and serves as the principal energy source for the fetus. There is a linear relationship between maternal and fetal glucose concentrations, with fetal concentrations 60% to 80% of maternal concentrations. This linear relationship is present even during episodes of maternal hyperglycemia secondary to maternal diabetes or glucose infusions.
Under normal circumstances, fetal gluconeogenesis is negligible; however, fetal gluconeogenesis may occur during episodes of prolonged maternal hypoglycemia or starvation. Glucose alone cannot account for the total oxygen consumption of the fetus. Other substrates such as lactate, free fatty acids, ketones, and amino acids cross the placenta and are potential energy sources for the fetus.
Energy is stored rapidly near term. Fat storage exceeds 100 kcal/day in the ninth month and accounts for 14% of total body weight at term. Glycogen stores, a vital source of energy in the first hours of life, increase toward term to reach about 5% by weight in liver and muscle and up to 4% in heart muscle. These energy stores are compromised by prematurity and by intrauterine growth restriction. Acute perinatal distress or chronic fetal hypoxia can particularly diminish glycogen stores and predispose the infant to hypoglycemia after birth.
Insulin and glucagon do not cross the placenta and are present in the fetus by 12 and 15 weeks, respectively. The fetal insulin response to glucose infusion is poor very early in gestation. At the end of gestation, the insulin response is improved but remains blunted. Fetal blood insulin levels gradually rise toward term, whereas fetal glucagon levels remain low. The resulting high insulin-to-glucagon ratio promotes the accumulation of hepatic glycogen stores and suppresses gluconeogenesis.
Insulin is an important hormone for fetal growth. The presence of maternal hyperglycemia and fetal hyperinsulinemia as seen in the infant of a diabetic mother is associated with macrosomia with elevated liver glycogen and total body fat stores. Macrosomia in the presence of fetal hyperinsulinemia without maternal hyperglycemia is seen in infants with Beckwith-Wiedemann syndrome and in the rare infant with hyperinsulinemic hypoglycemia, which suggests that fetal insulin and not maternal hyperglycemia may be the important growth-promoting factor. Furthermore, infants born with pancreatic aplasia and those with transient neonatal diabetes mellitus have little or no insulin present and demonstrate severe intrauterine growth restriction.
At birth, cold stress, work of respiration, and muscle activity cause increased energy demands. Because of the interrupted supply of maternal glucose, the newborn must call on stored fuels to maintain blood glucose levels. This transition at birth is facilitated by increased catecholamine and glucagon levels, which promote lipolysis and glycogenolysis. Decreased insulin levels and increased cortisol levels also facilitate glucose homeostasis at birth. Rapid glycogenolysis causes hepatic glycogen to fall to low levels within 24 hours in a fasted neonate. Because the newborn has a twofold greater basal fasting glucose utilization than the adult, gluconeogenesis must supplement glycogenolysis. Lipolysis begins at birth, with the respiratory quotient decreasing from 1.0 in the fetus to less than 0.8 during the first day as most tissues switch to burning fat. Metabolism of free fatty acids and ketones stabilizes blood glucose levels by (1) sparing glucose utilization in heart, liver, muscle, and brain (ketones) and (2) supporting hepatic gluconeogenesis by producing the reduced form of nicotinamide adenine dinucleotide (NADH).
In the newborn, basal glucose production and utilization is 4 to 6 mg/kg/min. This high glucose utilization compared with the adult is primarily due to the higher ratio of brain weight to body weight in the newborn infant. During euglycemic conditions most of the brain’s metabolic needs are met by oxidation of glucose. When the availability of glucose is limited, alternative cerebral fuels such as lactate and ketone bodies may by used. Although these alternative fuels provide some protection to reduce the risk of hypoglycemia-induced brain injury in the newborn, the brain requires a continuous glucose supply; thus, these alternative substrates are unable to completely replace glucose as a fuel for brain metabolism.
Blood glucose level at birth is 60% to 80% of the simultaneous maternal plasma concentrations. Glucose concentrations normally decrease over 1 to 2 hours, stabilize at a minimum of 40 to 45 mg/dL, and then increase by 6 hours to 50 to 60 mg/dL in healthy unstressed newborns ( Fig. 12-1 ). The current practice of early oral or intravenous alimentation avoids the many instances of neonatal hypoglycemia previously reported when neonates fasted for 24 hours ( Fig. 12-2 ).
Several factors need to be considered when interpreting glucose concentrations. First, blood glucose concentrations are 10% to 15% lower than simultaneous plasma concentrations. This is particularly pronounced when the hematocrit is very high. Second, use of capillary samples from unwarmed heels may lead to an underestimation of venous glucose concentration because of stasis. Finally, glucose concentrations decline as much as 18 mg/dL/hr at room temperature while analysis is awaited. Thus, all samples should be analyzed immediately or placed on ice.
Although plasma glucose determination in the laboratory using the glucose oxidase reaction is the optimum method, point-of-care (POC) testing using reflectance glucometers offers the advantage of speed. The sensitivity for detecting hypoglycemia ranges from 80% to 100% and the negative predictive values ranges from 80% to 96% depending on the device and parameters used. Therefore, confirmatory plasma glucose concentrations should be measured if hypoglycemia is detected using a POC device or if the infant has symptoms consistent with hypoglycemia even if the POC test value shows a normal blood glucose concentration.
Accurate measurement of blood glucose levels in the newborn is important, but although POC glucose testing provides rapid results with small sample volumes and permits quick clinical responses, the common thresholds for the diagnosis of hypoglycemia in the newborn (blood glucose concentration of <2.0 mmol/L or <2.6 mmol/L, 35 to 45 mg/dL) and hyperglycemia (blood glucose concentration of >10 mmol/L, 170 mg/dL) are at the limits of accuracy for many POC glucose analyzers. Therefore, although useful for screening, such devices cannot be relied upon for accurate diagnosis of hypoglycemia. Also, with intermittent blood sampling there may be many hours between measurements when both hypoglycemia and hyperglycemia may be undetected clinically. Continuous glucose monitoring has the potential to help improve glucose assessment and management in the high-risk neonate. Harris et al used a continuous glucose monitoring system (CGMS) in 102 infants of 32 weeks’ gestation or less who were at risk for hypoglycemia. The babies received routine treatment, including intermittent blood glucose measurement using the glucose oxidase method, and blinded continuous interstitial glucose monitoring. The investigators documented 265 episodes of low interstitial glucose concentrations, 215 (81%) of which were not detected with blood glucose measurement. One hundred seven episodes in 34 babies lasted longer than 30 minutes, and 78 (73%) of these were not detected with blood glucose measurement. Platas et al also studied continuous glucose monitoring. Hyperglycemia was detected in 22 of 38 patients (58%) and lasted a mean of 20 ± 30 hours. Hypoglycemia was detected in 14 (37%) and lasted a mean of 2.45 ± 2.3 hours. However, the CGMS was not able to provide real-time glucose concentration data. Continuous glucose monitoring via a subcutaneous sensor gives a safe and useful estimate of glucose levels in very low-birth-weight infants, revealing abnormal glucose levels at a much higher rate than expected by usual sampling. The physiologic significance of these previously undetected episodes is unknown. A CGMS may be very useful in providing information on the influence of hyperglycemia and hypoglycemia on short- and long-term outcomes in very low-birth-weight infants.
The definition of hypoglycemia is controversial. Several factors contribute to this controversy, including the poor correlation between glucose concentrations and symptoms; the nonspecific nature of the symptoms of hypoglycemia; the performance of epidemiologic studies under differing conditions (i.e., fed versus fasted states, formula feeding versus breast feeding); and the poor correlation between low glucose values and adverse long-term outcome. Rather than making the diagnosis of hypoglycemia when the plasma glucose concentration is below a specific value, a consensus statement recommends the use of an “operational threshold” that defines the glucose concentration below which clinical intervention to raise the plasma glucose should be considered. These threshold values are pragmatic rather than diagnostic and recognize the uniqueness of each individual’s physiologic characteristics while providing an adequate safety margin to prevent long-term sequelae. The recommended thresholds for asymptomatic and symptomatic infants are plasma glucose concentrations of less than 36 mg/dL (2.0 mmol/L) and less than 45 mg/dL (2.5 mmol/L), respectively. The diagnosis of hypoglycemia can be made when all components of the Whipple triad have been observed: (1) low plasma glucose concentration, (2) signs and symptoms consistent with hypoglycemia, and (3) resolution of these signs and symptoms when the glucose concentration is normalized. As a practical matter, most nurseries use a screening blood glucose level of 40 mg/dL or less or the presence of signs and symptoms consistent with hypoglycemia as a threshold for obtaining a plasma glucose measurement and evaluating the need for further intervention. Because blood glucose values are 10% to 15% below plasma glucose values, this allows for a safety margin when using POC test devices.
In 2011, a position statement issued by the Committee of the Fetus and Newborn (COFN) of the American Academy of Pediatrics (AAP) discussed the challenge of defining clinically significant hypoglycemia based on blood glucose concentrations. “This report provides a practical guide and algorithm for the screening and subsequent management of neonatal hypoglycemia. Current evidence does not support a specific concentration of glucose that can discriminate normal from abnormal or can potentially result in acute or chronic irreversible neurologic damage. Early identification of the at-risk infant and institution of prophylactic measures to prevent neonatal hypoglycemia are recommended as a pragmatic approach despite the absence of a consistent definition of hypoglycemia in the literature.” This report noted that the generally adopted level used to define neonatal hypoglycemia is less than 47 mg/dL (2.6 mmol/L) and proposed an operational threshold of 45 mg/dL (2.5 mmol/L) as a target glucose level before routine feeds.
Hypoglycemia in newborns is often asymptomatic. The most frequent symptoms are jitteriness and cyanosis. Other symptoms include convulsions, hypotonia, coma, poor feeding, apnea, congestive heart failure, high-pitched cry, abnormal eye movements, and temperature instability with hypothermia. In small sick infants, symptoms may easily be missed. When symptoms are present, the age of onset is most commonly between 24 and 72 hours.
Because these symptoms are nonspecific, they often occur in newborns who are normoglycemic and have other problems. For example, jitteriness, the most common symptom, is found in up to 44% of normal newborns as well as in infants with a variety of other conditions ( Box 12-1 ). Hypoglycemia must therefore always be confirmed by chemical analysis and by response to treatment.
Neonatal drug withdrawal
Selective serotonin reuptake inhibitors (SSRIs)
Central nervous system disorders
Transient Neonatal Hypoglycemia
Transient neonatal hypoglycemia is the most common type of hypoglycemia in a well-baby nursery and an intensive care nursery. It may occur within 1 to 2 hours of birth and resolves within hours to days. Asymptomatic patients exceed those with symptoms by about 10 to 1. Transient hypoglycemia typically occurs in “high-risk” infants in association with either alterations in maternal metabolism or other neonatal problems ( Box 12-2 ).
Infant of diabetic mother (IDM)
Intrapartum glucose administration
Maternal use of β-sympathomimetics
Maternal use of oral hypoglycemic agents
Large for gestational age (non-IDM)
Small for gestational age
Intrauterine growth restriction
Severe illness, respiratory distress syndrome
The pathogenesis involves multiple factors affecting glucose supply and demand, including hyperinsulinism; inadequate total body energy reserves; high energy requirement—particularly a large, glucose-requiring brain; and inordinate energy demands imposed by disease. There is an association with central nervous system (CNS) injury or anomaly, which may reflect a subtle control problem.
Healthy term infants do not require routine screening for hypoglycemia if they do not have clinical manifestations. “At-risk” infants (see Box 12-2 ), including all infants admitted to the intensive care nursery or those with clinical manifestations, should undergo screening blood glucose determination. Providing caloric support with early feeding or intravenous glucose by 1 to 2 hours of age and maintaining a continuous energy supply throughout the neonatal period dramatically reduce the incidence of hypoglycemia. High-risk infants should be screened for hypoglycemia as soon as possible after birth at intervals of 1 to 2 hours initially and then every 2 to 4 hours until their condition is definitely stabilized.
Infants of Diabetic Mothers
Hypoglycemia occurs in infants of diabetic mothers soon after birth, with a nadir at 1 to 2 hours of age that may be as low as 10 mg/dL (see Fig. 12-1 ). A spontaneous increase in glucose concentration usually follows, with acceptable levels reached by 4 to 6 hours of age. Few infants of diabetic mothers become symptomatic. Infants of mothers with gestational diabetes have a less dramatic decline in glucose level.
Fluctuating maternal hyperglycemia results in fetal hyperglycemia, pancreatic beta cell hyperplasia, and hyperinsulinism. After birth, hyperinsulinemia persists, as evidenced by accelerated use of exogenous glucose and diminished endogenous glucose production. Furthermore, levels of free fatty acids and ketones are low (see Fig. 12-1 ). In addition to having increased insulin levels, infants of diabetic mothers have increased concentrations of leptin, insulin-like growth factor I, and insulin propeptides. Infants of diabetic mothers have multiple problems in addition to hypoglycemia ( Box 12-3 ). Congenital anomalies occur in 4.2% to 12.1% of infants of mothers with type 1 diabetes. The rate of anomalies decreases with improved preconceptual glycemic control. Infants of mothers with gestational diabetes do not have an increased risk of congenital anomalies but continue to have a high rate of the other morbidities (see Box 12-3 ). Achieving tight metabolic control in pregnant diabetic women during pregnancy and preventing hyperglycemia in labor ameliorates excess fetal weight and helps prevent perinatal deaths and reduces the incidence of neonatal hypoglycemia and hypocalcemia. Early oral feeding is both prophylactic and therapeutic. Poor feeding, respiratory distress, or additional problems (congenital anomalies) may require intravenous glucose administration.
Respiratory distress syndrome
Thrombosis (renal vein)
Cardiac malformations and abnormalities
Intraventricular septal hypertrophy
Ventricular septal defect
Transposition of the great arteries
Pulmonary valve abnormalities
Renal agenesis or dysgenesis
Central nervous system malformations
Small left colon syndrome
Maternal Drugs (e.g., β-Sympathomimetics, β-Blockers, Oral Antidiabetic Agents)
β-Sympathomimetics (e.g., terbutaline, ritodrine) are used as tocolytic agents and may cause maternal hyperglycemia and fetal hyperinsulinism leading to neonatal hypoglycemia. Use of β-blockers may lead to hypoglycemia by blocking catecholamine release at birth, which results in decreased lipolysis and glycogenolysis.
First-generation sulfonylurea oral antidiabetic agents (e.g., chlorpropamide, tolbutamide) cross the placenta and have a long half-life in the newborn. These agents cause increased insulin release and may cause prolonged hypoglycemia. Newer oral antidiabetic agents do not lead to significant neonatal hypoglycemia, either because they do not cross the placenta in significant concentrations (second-generation sulfonylureas such as glipizide and glyburide) or because they do not enhance insulin production (biguanides and α-glucosidase inhibitors).
Intrauterine Growth Restriction, Small Size for Gestational Age, Prematurity
Infants with intrauterine growth restriction, small size for gestational age, and prematurity have inadequate glycogen stores, which leads to decreased glucose production after birth. Glucose homeostasis is further complicated in these infants by reduced fat stores, increased brain-to-body weight ratios, immature hepatic enzymes, and an inadequate cortisol response. Infants who are small for gestational age or experienced intrauterine growth restriction have inadequate stores due to fetal malnutrition, which is often associated with placental insufficiency, maternal preeclampsia, maternal hypertension, and severe maternal diabetes with vascular disease. Premature infants fail to undergo the normal deposition of glycogen and fat that occurs during the third trimester of pregnancy.
A subset of infants with intrauterine growth restriction and small size for gestational age have prolonged hypoglycemia associated with hyperinsulinism. These infants are most often male, are born by cesarean section, and have a history of perinatal stress.
Hypoglycemia occurs in approximately 13% to 40% of infants with polycythemia. An increased rate of glucose disposal without hyperinsulinemia is part of the syndrome of hyperviscosity; it responds to exchange transfusion to reduce the hematocrit.
Infants with erythroblastosis show islet cell hyperplasia, increased cord blood insulin levels, and hypoglycemia both shortly after birth and reactively following exchange transfusion. It is speculated that glutathione release from severe hemolysis stimulates insulin production. The severity of the problem relates inversely to cord hemoglobin level and is decreased by intrauterine transfusion.
Other Causes of Transient Hypoglycemia
Excess intrapartum glucose administration leads to acute maternal and fetal hyperglycemia. The subsequent transient hyperinsulinemia can lead to rebound neonatal hypoglycemia.
Hypoglycemia is also associated with infection, asphyxia, and hypothermia. The cause of hypoglycemia in these conditions is multifactorial but is most often due to increased glucose utilization. Perinatal asphyxia may occasionally be associated with hyperinsulinism requiring high glucose infusion rates.
Infusion of glucose through an umbilical artery catheter located above the celiac axis may lead to hyperinsulinemic hypoglycemia from direct infusion of glucose into the pancreatic artery with resulting beta cell overstimulation.
Persistent or Recurrent Hypoglycemia
Persistent or recurrent hypoglycemia refers to conditions in which the hypoglycemia persists for more than several days. Many of these conditions require prolonged therapy and may continue beyond the neonatal period ( Box 12-4 ). In contrast with infants with transient hypoglycemia, the majority of these infants are symptomatic.
Persistent hyperinsulinemic hypoglycemia of infancy
Focal beta-cell adenoma
Growth hormone deficiency
Adrenocorticotropic hormone deficiency
Glycogen storage disease (GSD)
Glucose-6-phosphatase deficiency (GSD type I)
Debrancher deficiency (GSD type III)
Disorders of gluconeogenesis
Fructose 1,6-diphosphatase deficiency
Phosphoenol pyruvate-carboxykinase deficiency
Disorders of fatty acid oxidation
Carnitine-acylcarnitine translocase deficiency
Very long-chain acyl-CoA dehydrogenase deficiency
Long-chain acyl-CoA dehydrogenase deficiency
Medium-chain acyl-CoA dehydrogenase deficiency
Multiple acyl-CoA dehydrogenase deficiency
Disorders of amino acid and organic acid metabolism
Maple syrup urine disease
Multiple carboxylase deficiency
3-Hydroxy-3-methylglutaryl CoA lyase deficiency
Congestive heart failure
CoA, Coenzyme A.
Persistent Hyperinsulinemic Hypoglycemia of Infancy
Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is caused by abnormalities in the regulation of insulin secretion. This condition was previously known as nesidioblastosis, in reference to a histopathologic finding that implied abnormal islet formation; however, this histologic pattern has been found to be common in the developing pancreas of infants without hypoglycemia in the first year of life.
PHHI occurs in both sporadic and familial patterns. The majority of cases involve mutations on chromosome band 11p14-15.1, leading to abnormalities in one of the two components of the islet beta cell adenosine triphosphate–sensitive potassium channel (K ATP channel), either the sulfonylurea receptor (SUR1) or the inward rectifier K + channel (Kir6.2). The inability to open the islet beta cell K ATP channel causes membrane depolarization and calcium influx resulting in inappropriate insulin release. Usually these mutations are autosomal recessive and associated with diffuse beta cell hyperplasia.
Milder autosomal dominant forms of the disease are caused by mutations in the glutamate dehydrogenase gene or the glucokinase gene. These mutations cause an increase in the ratio of ATP to adenosine diphosphate (ADP) in the beta cell, which inappropriately closes the structurally normal K ATP channels. These forms of PHHI are also usually associated with diffuse beta cell hyperplasia.
Focal beta cell hyperplasia is found when abnormalities of the beta cell K ATP channel are associated with unbalanced expression of one or more growth suppression genes due to focal loss of the maternal DNA on chromosome band 11p15. Other genetic mutations associated with PHHI have been described but occur less frequently.
Infants with PHHI are large for gestational age with profound, symptomatic hypoglycemia. Plasma insulin and C-peptide concentrations are inappropriately elevated during episodes of hypoglycemia. Plasma free fatty acid and ketone concentrations are low. Ketonuria is absent. Glucagon infusion results in a glycemic response in the presence of hypoglycemia. Mutation in the glutamate dehydrogenase gene also causes elevated ammonia concentrations. Hyperinsulinemia may be temporarily managed with diazoxide (which opens the K ATP channel) or the long-acting somatostatin analog octreotide (which opens rectifier K channels). These therapies are most effective when the K ATP channel is intact but is closed due to altered ATP/ADP concentrations. Other potential therapies include nifedipine, which inhibits insulin release, and glucagon, which increases gluconeogenesis.
The majority of neonates do not respond to medical management and require either a partial pancreatectomy (for focal lesions) or a 95% pancreatectomy (for diffuse disease). Previously, selective pancreatic arterial calcium stimulation with hepatic venous and portal venous insulin sampling using interventional radiology was used to identify focal or diffuse disease preoperatively. Positron emission tomography, a less invasive technique, has now been shown to be more accurate in diagnosing whether the disease is focal or diffuse. Neurodevelopmental impairment secondary to frequent and severe episodes of hypoglycemia is common in PHHI. Complications of pancreatectomy include diabetes mellitus and pancreatic exocrine insufficiency.
Beckwith-Wiedemann Syndrome (Hyperplastic Fetal Visceromegaly)
Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome associated with macrosomia (88% of cases), macroglossia (97% of cases), abdominal wall defects (80% of cases), usually an omphalocele, hypoglycemia in the neonatal period, and embryonal cancers of infancy and early childhood (4% of cases). Other clinical features of BWS are listed in Box 12-5 . The frequency of hypoglycemia in BWS is between 30% and 63%, and the hypoglycemia is caused by hyperinsulinism. The hypoglycemia may be asymptomatic and usually resolves within the first 3 days of life. Fewer than 5% of infants will have hypoglycemia beyond the neonatal period requiring either continuous feeding or, in rare cases, partial pancreatectomy. The genetics of BWS is complex and involves defects in imprinted gene expression in the 11p15 region. The majority of cases are sporadic but 10% to 15% occur in an autosomal dominant pattern, with maternal transmission associated with increased penetrance. The risk of BWS is higher after the use of assisted reproductive therapies. Seventy percent of cases can be detected by DNA methylation analysis at the differentially methylated regions 1 (regulating insulin-like growth factor II) and 2. The similarity of affected gene regions in BWS and PHHI may provide a molecular basis for hypoglycemia in BWS, particularly for the occasional patient with hypoglycemia requiring a partial pancreatectomy.
Abdominal wall defects
Ear lobe creases
Posterior helical pits
Congenital heart defects
Hypopituitarism with deficiencies in growth hormone and adrenocorticotropic hormone (ACTH) is often associated with facial and genital abnormalities (microphallus). Cortisol deficiency secondary to congenital adrenal hyperplasia or adrenal hemorrhage is associated with hypoglycemia. These disorders may cause electrolyte abnormalities and cardiovascular collapse. Congenital adrenal hyperplasia causes virilization in female infants.
Metabolic disorders associated with persistent neonatal hypoglycemia are all very rare. Box 12-4 lists the disorders that manifest in the neonatal period. Many other metabolic syndromes are associated with hypoglycemia but present later in infancy or childhood. Clues to the diagnosis include lactic acidosis, excessive or reduced ketonuria, persistent emesis and coma despite correction of hypoglycemia, hepatomegaly, family history, and elevated values on liver function tests (e.g., ammonia, direct bilirubin).
Glycogen storage diseases result in impaired ability of hepatic glucose release. Neonatal presentation is most common with glycogen storage disease type I (glucose-6-phosphatase deficiency). Glycogen storage disease type III (Debrancher deficiency) may be detected after prolonged fasting. These diseases also are associated with lactic acidosis, ketosis, and hepatomegaly.
Disorders of fatty acid oxidation, particularly disorders of very long-chain and long-chain fatty acid metabolism, may occur in the neonatal period. These disorders are often accompanied by hyperammonemia, liver disease, and cardiac disease. Usually ketosis is absent. Medium-chain acyl–coenzyme A (CoA) dehydrogenase deficiency is the most common disorder of fatty acid oxidation but only rarely presents in the neonatal period.
Amino acid and organic acid disorders are also associated with hypoglycemia but often ketosis, lactic acidosis, and hyperammonemia are present.
Treatment of Hypoglycemia
Prevention is key and consists of early oral or enteral tube feeding of breast milk or formula if appropriate. For those infants who are not able to be fed enterally, early initiation of intravenous fluids with 10% dextrose at a glucose infusion rate of 4 to 8 mg/kg/min is indicated. Glucose infusion should be continuous and steady, by pump, and should be continued until replaced calorically by enteral feeding.
Treatment is indicated for all hypoglycemic infants (plasma glucose level of <36 mg/dL if asymptomatic, <45 mg/dL or higher if symptomatic). Asymptomatic infants with transient hypoglycemia and no other medical illness may be given enteric formula or breast milk. Blood glucose concentration should be monitored every 30 minutes to determine adequacy of response. If glucose concentrations do not increase or if enteric alimentation is contraindicated, intravenous glucose, 4 to 8 mg/kg/min, should begin. If hypoglycemia is severe (plasma glucose level of <20 to 25 mg/dL) or if symptoms are present, intravenous glucose should be initiated starting with a bolus of 200 mg/kg glucose (2 mL/kg of 10% dextrose in water) followed by a continuous infusion of 6 to 8 mg/kg/min of glucose ( Fig. 12-3 ). The bolus of glucose should be no greater than 200 mg/kg to prevent excessive hyperglycemia and rebound hypoglycemia. Blood glucose concentrations should be monitored every 30 to 60 minutes until stable. This bolus and infusion is adequate for most infants; however, if plasma glucose concentrations remain low the glucose infusion should be increased in increments of 2 mg/kg/min. On rare occasions, refractory hypoglycemia may require as much as 20 mg/kg/min.
For those infants with persistent hypoglycemia requiring high glucose infusion rates (>12 to 14 mg/kg/min), additional laboratory studies should be considered. These studies should be performed during episodes of hypoglycemia and include plasma insulin, cortisol, and growth hormone concentrations. For severe persistent hypoglycemia additional therapies may be required, including hydrocortisone, diazoxide, octreotide, or glucagon.
Symptomatic, prolonged, or recurrent hypoglycemia may cause neurologic impairment. Although the degree of neurologic injury correlates with the severity and duration of hypoglycemia, scientific analysis does not allow one to define a specific level or duration of hypoglycemia at which harm occurs. Infants with asymptomatic, transient hypoglycemia do well. Infants with hypoglycemic seizures have the poorest outcome. Neurologic impairment is also more likely when other risk factors such as asphyxia and intrauterine growth restriction are present. Infants with hyperinsulinemic hypoglycemia or with inborn metabolic errors have a prognosis related to their primary illness.
In infants of diabetic mothers, long-term neurologic outcome is also related to maternal metabolic factors independent of postnatal glucose concentrations.
To define the relationship between magnetic resonance imaging (MRI) findings and hypoglycemia, Burns et al studied 35 term infants who underwent early brain MRI scanning after symptomatic neonatal hypoglycemia (median glucose level: 1 mmol/L) without evidence of hypoxic-ischemic encephalopathy and assessed neurodevelopmental outcome at a minimum of 18 months. White matter abnormalities occurred in 94% of infants with hypoglycemia and was severe in 43%, with a predominantly posterior pattern in 29% of cases. Cortical abnormalities occurred in 51% of infants; 30% had white matter hemorrhage; 40% had basal ganglia/thalamic lesions; and 11% had an abnormal posterior limb of the internal capsule. Three infants had middle cerebral artery territory infarctions. At 18 months, 23 infants (65%) demonstrated impairments, which were related to the severity of white matter injury and involvement of the posterior limb of the internal capsule.
Patterns of injury associated with symptomatic neonatal hypoglycemia were more varied than described previously. White matter injury was not confined to the posterior regions; hemorrhage, middle cerebral artery infarction, and basal ganglia/thalamic abnormalities were seen, and cortical involvement was common. Surprisingly, early MRI findings were more instructive than the severity or duration of hypoglycemia for predicting neurodevelopmental outcomes.
Boluyt et al attempted to assess the effect of episodes of neonatal hypoglycemia on subsequent neurodevelopment. A comprehensive search revealed 18 eligible studies. The overall methodological quality of the included studies was considered poor in 16 studies and high in 2 studies. None of the studies provided a valid estimate of the effect of neonatal hypoglycemia on neurodevelopment. Boluyt et al concluded, “Recommendations for clinical practice cannot be based on valid scientific evidence in this field. To assess the effect of neonatal hypoglycemia on subsequent neurodevelopment, a well-designed prospective study should be undertaken.”