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15/9/2015

Pathogenesis, screening, and diagnosis of neonatal hypoglycemia

Official reprint from UpToDate ® www.uptodate.com ©2015 UpToDate ®

Pathogenesis, screening, and diagnosis of neonatal hypoglycemia Author Paul J Rozance, MD

Section Editors Joseph A Garcia-Prats, MD Joseph I Wolfsdorf, MB, BCh

Deputy Editor Melanie S Kim, MD

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Aug 2015. | This topic last updated: Aug 04, 2015. INTRODUCTION — During the normal transition to extrauterine life, blood glucose concentration in the healthy term newborn falls during the first two hours after delivery, reaching a nadir that usually is no lower than 40 mg/dL. It is important to differentiate this normal physiologic transitional response from disorders that result in persistent or recurrent hypoglycemia, which may lead to neurologic sequelae. This topic will discuss the normal transient neonatal low glucose levels, causes of persistent or pathologic neonatal hypoglycemia, and the clinical manifestations and diagnosis of neonatal hypoglycemia. The management of neonatal hypoglycemia, including evaluation of persistent hypoglycemia and outcome of neonatal hypoglycemia, is discussed separately. (See "Management and outcome of neonatal hypoglycemia".) CHALLENGE OF DEFINING NEONATAL HYPOGLYCEMIA — Clinically significant neonatal hypoglycemia requiring intervention cannot be defined by a precise numerical blood glucose concentration because of the following: ● Normal low neonatal blood glucose levels − Low blood glucose concentrations normally occur in the first hours after birth and may persist for up to several days. Although most newborns remain asymptomatic despite very low blood glucose concentrations, some newborns become symptomatic at the same or even higher blood glucose concentrations than are observed in asymptomatic infants. This variability in the clinical response in neonates to low blood glucose concentrations is due to a number of factors that include the infant's gestational age and postnatal age, the presence of other sources of energy (eg, lactate and ketone bodies), and circumstances that affect glucose metabolism and cerebral glucose uptake and utilization. ● Lack of outcome data − Ideally, clinically significant neonatal hypoglycemia would be defined as the blood glucose concentration at which intervention should be initiated to avoid significant morbidity, especially neurologic sequelae. However, this definition remains elusive because the blood glucose concentration and duration of hypoglycemia associated with poor neurodevelopmental outcome has not been established [1,2]. Nevertheless, most guidelines used in clinical practice provide arbitrary treatment thresholds of blood glucose concentrations to initiate intervention and bypass the controversies surrounding the definition of hypoglycemia [1,3]. This approach tries to reduce the harm due to hypoglycemia, identify newborns with a serious underlying hypoglycemia disorder, and at the same time, minimize overtreatment of newborns with normal transitional low glucose concentrations that resolve without intervention. This has resulted in guidelines that favor simplicity and ease of use over an emphasis on the physiology of normal neonatal glucose homeostasis, the normal age-related increase in glucose concentrations over the first few days of life, and the varying pathophysiological conditions that may lead to clinical hypoglycemia. (See "Management and outcome of neonatal hypoglycemia".) When using guidelines based on low glucose concentrations, it is important to recognize that glucose concentrations measured in whole blood are approximately 15 percent lower than those in plasma and may be further reduced if the hematocrit is high. In addition, when reviewing the literature and guidelines one must be careful to note whether the normal values are mean glucose values (used in this topic review), as opposed to using a threshold range of glucose values (below the 5th percentile used in the American Academy of Pediatrics [AAP] guidelines). (See 'How glucose testing is performed' below.) http://www.uptodate.com/contents/pathogenesis-screening-and-diagnosis-of-neonatal-hypoglycemia?topicKey=PEDS%2F5053&elapsedTimeMs=6&source=s…

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NORMAL TRANSITIONAL LOW GLUCOSE LEVELS — Transient low blood glucose concentrations in neonates are normal, as the source of glucose at delivery changes from a continuous supply from the mother to an intermittent supply from milk feeds [4]. With loss of the continuous transplacental supply of glucose, plasma glucose concentration in the healthy term newborn falls during the first two hours after delivery, reaching a nadir that usually is no lower than 40 mg/dL (2.2 mmol/L), and then stabilizes by four to six hours of age in the range of 45 to 80 mg/dL (2.5 to 4.4 mmol/L) [1,2,5,6]. Mean concentrations then rise more slowly in the next few days to concentrations similar to those seen in older children and adults. Immediately after birth, the plasma glucose concentration is maintained by the breakdown of hepatic glycogen (glycogenolysis) in response to increased plasma epinephrine and glucagon concentrations, and falling insulin levels. Glycogen stores are depleted during the first 8 to 12 hours of life. Thereafter, plasma glucose levels are maintained by the synthesis of glucose from lactate, glycerol, and amino acids (gluconeogenesis). As feeds with adequate carbohydrate are established, maintenance of plasma glucose concentrations is no longer solely dependent on gluconeogenesis. However, if the first feeding is delayed for three to six hours after birth, approximately 10 percent of normal term newborns cannot maintain a plasma glucose concentration above 30 mg/dL (1.7 mmol/L) [7,8]. PATHOLOGIC AND/OR PERSISTENT HYPOGLYCEMIA — Hypoglycemia is caused by a lower rate of glucose production than glucose utilization. The underlying mechanisms of neonatal hypoglycemia in at-risk neonates that usually require intervention (pathologic or persistent) include the following (see "Etiology of hypoglycemia in infants and children"): ● Inadequate glucose supply • Inadequate glycogen stores • Impaired glucose production (ie, glycogenolysis or gluconeogenesis) ● Increased glucose utilization • Excessive insulin secretion • Other causes Diminished glucose supply Inadequate glycogen stores — Inadequate glycogen stores can lead to a diminished supply of glucose and present in the following settings: ● Prematurity – Because glycogen is deposited during the third trimester of pregnancy, infants born prematurely have diminished glycogen reserves. ● Fetal growth restriction (FGR) – Infants with FGR, also referred to as intrauterine growth restriction (IUGR), may have reduced glycogen stores or may rapidly deplete their glycogen stores if the transition to extrauterine life is difficult, which increases their metabolic needs (ie, increased glucose utilization). After delivery, there may also be impaired glucose production due to a poorly coordinated response to hypoglycemia by counter regulatory hormones (epinephrine and glucagon) and increased insulin sensitivity [5,9]. (See "Infants with fetal (intrauterine) growth restriction", section on 'Hypoglycemia'.) Impaired glucose production — Impaired glucose production is due to the disruption of either glycogenolysis or gluconeogenesis. (See "Etiology of hypoglycemia in infants and children", section on 'Disorders of glycogenolysis' and "Etiology of hypoglycemia in infants and children", section on 'Disorders of glycosylation' and "Etiology of hypoglycemia in infants and children", section on 'Disorders of gluconeogenesis'.) Inborn errors of metabolism — Inborn errors of metabolism that may cause neonatal hypoglycemia include (table 1): ● Disorders of glycogen metabolism (glycogenolysis) resulting from mutations in genes that encode proteins involved in glycogen synthesis, degradation, or regulation of these processes. (See "Overview of inherited http://www.uptodate.com/contents/pathogenesis-screening-and-diagnosis-of-neonatal-hypoglycemia?topicKey=PEDS%2F5053&elapsedTimeMs=6&source=s…

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disorders of glucose and glycogen metabolism" and "Etiology of hypoglycemia in infants and children", section on 'Disorders of glycogenolysis'.) ● Disorders of gluconeogenesis (eg, fructose-1,6-bisphosphatase deficiency, pyruvate carboxylase deficiency), defects in amino acid metabolism (eg, maple syrup urine disease, propionic acidemia, and methylmalonic academia), disorders of carbohydrate metabolism (eg, hereditary fructose intolerance, galactosemia), and fatty acid metabolism (eg, medium or long-chain acyl-CoA dehydrogenase deficiency) [10]. (See "Etiology of hypoglycemia in infants and children", section on 'Disorders of gluconeogenesis' and "Etiology of hypoglycemia in infants and children", section on 'Disorders of amino acid metabolism' and "Etiology of hypoglycemia in infants and children", section on 'Disorders of fatty acid metabolism' and "Inborn errors of metabolism: Metabolic emergencies", section on 'Hypoglycemia' and "Organic acidemias" and "Inborn errors of metabolism: Metabolic emergencies", section on 'Hypoglycemia'.) Endocrine disorders — Deficiency of the hormones (eg, cortisol and growth hormone) that regulate glucose homeostasis result in hypoglycemia. The hormonal deficiency can be isolated or associated with other pituitary hormone deficiencies, or primary adrenocortical insufficiency. (See "Etiology of hypoglycemia in infants and children", section on 'Hormone deficiencies'.) Other causes — Other causes of impaired glucose production resulting in neonatal hypoglycemia include: ● Maternal treatment with beta-sympathomimetic agents (eg, terbutaline), which interrupts glycogenolysis by blocking epinephrine's effect ● Hypothermic infants who have diminished availability of glucose and increased rates of glucose utilization ● Severe hepatic dysfunction due to impairment of both glycogenolysis and gluconeogenesis Increased glucose utilization Hyperinsulinism — Increased glucose utilization primarily results from hyperinsulinism. Excess insulin also suppresses hepatic glucose production. The infant of a diabetic mother is the most common neonatal clinical situation in which hyperinsulinism causes hyperinsulinemic hypoglycemia. In this setting, it is postulated that intermittent maternal hyperglycemia causes fetal hyperglycemia, which leads to hypertrophied and hyperfunctioning beta cells resulting in fetal and neonatal hyperinsulinemia. After termination of the maternal glucose supply at delivery, hypoglycemia from persistent hyperinsulinism in the newborn usually is transient and typically resolves two to four days after birth. (See "Infant of a diabetic mother", section on 'Hypoglycemia'.) Other conditions associated with hyperinsulinism and transient hypoglycemia include: ● Fetal growth restriction (FGR) − In addition to a decrease in glucose/glycogen stores (as noted above), hyperinsulinism may contribute to hypoglycemia in newborns with FGR [5,11]. (See "Infants with fetal (intrauterine) growth restriction".) ● Beckwith-Wiedemann syndrome (BWS) − About half of all neonates with BWS have transient or prolonged hypoglycemia caused by hyperinsulinism. (See "Beckwith-Wiedemann syndrome", section on 'Metabolic abnormalities'.) ● Perinatal asphyxia or stress [5,12,13]. (See "Systemic effects of perinatal asphyxia".) ● Maternal intrapartum treatment with glucose or with antihyperglycemic agents such as sulfonylureas. ● Abrupt interruption of an infusion of a solution with a high glucose concentration. Rarely, glucose infusion through an umbilical artery catheter with its tip near the celiac or superior mesenteric arteries will stimulate excessive insulin release. ● Persistent hyperinsulinemic hypoglycemia of infancy − Infants with persistent hyperinsulinemia typically develop severe hypoglycemia that requires high rates of glucose infusion to maintain normal blood glucose http://www.uptodate.com/contents/pathogenesis-screening-and-diagnosis-of-neonatal-hypoglycemia?topicKey=PEDS%2F5053&elapsedTimeMs=6&source=s…

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levels in the first postnatal days. Mutations in genes encoding enzymes that control intracellular metabolic pathways of the pancreatic beta cell or transport of cations across the beta cell membrane have been identified in as many as 50 percent of patients. The genes most often affected control the sulfonylurea receptor (SUR1) and the inward rectifier potassium channel (Kir6.2); these proteins form the functional ATPdependent potassium channel in the beta cell membrane. Persistent hyperinsulinemic hypoglycemia of infancy is discussed separately. (See "Pathogenesis, clinical features, and diagnosis of persistent hyperinsulinemic hypoglycemia of infancy".) ● Excess exogenous insulin given to newborns with hyperglycemia may result in hypoglycemia [14]. (See "Neonatal hyperglycemia", section on 'Risk of hypoglycemia'.) ● Neonatal conditions associated with excess insulin secretion include alloimmune hemolytic disease of the newborn (see "Postnatal diagnosis and management of hemolytic disease of the fetus and newborn"), meconium aspiration syndrome (see "Clinical features and diagnosis of meconium aspiration syndrome"), hypothermia, and polycythemia [5]. (See "Neonatal polycythemia", section on 'Hypoglycemia'.) Without hyperinsulinism — Conditions associated with glucose utilization that exceeds production without hyperinsulinism include the following: ● Asymmetric neonates with FGR have relatively large (spared) head and brain size compared with their birth weight. Because the neonatal brain accounts for a large proportion of total glucose utilization, many of these infants become hypoglycemic if provided a glucose supply that seems appropriate relative to body weight (4 to 6 mg/kg/min) rather than the higher appropriate glucose supply required to prevent hypoglycemia relative to the larger head size. ● Conditions associated with anaerobic glycolysis due to decreased tissue perfusion, poor oxygenation, or biochemical defects that interfere with aerobic glucose metabolism [15]. The energy (ATP) per molecule of glucose produced by anaerobic glycolysis is only about 5 percent of that produced by aerobic glucose metabolism. ● Hypoglycemia associated with polycythemia may result from greater glucose utilization by the increased mass of red blood cells. (See "Neonatal polycythemia", section on 'Hypoglycemia'.) ● Increased glucose consumption can occur with heart failure or perinatal asphyxia; hyperinsulinism has also been documented in infants who experience perinatal asphyxia [12]. ● Although the mechanism is not known, sepsis is sometimes associated with hypoglycemia. Proposed contributing factors include increased glucose utilization, depleted glycogen stores, or impaired gluconeogenesis. Neuroglycopenia — The transport protein GLUT1 facilitates glucose diffusion across blood vessels into the brain and cerebrospinal fluid (CSF). Although blood glucose concentrations are normal, deficiency of GLUT1, a rare condition, results in low CSF glucose concentrations and neurologic symptoms associated with hypoglycemia [16]. CLINICAL MANIFESTATIONS — Infants with low blood glucose concentrations frequently are asymptomatic; hypoglycemia in these cases is usually detected by screening of blood glucose in at-risk infants or as an incidental laboratory finding. In the symptomatic infant, signs are nonspecific and reflect responses of the nervous system to glucose deprivation. These can be categorized as neurogenic or neuroglycopenic findings [6]: ● Neurogenic (autonomic) symptoms result from changes due to neural sympathetic discharge triggered by hypoglycemia. • Jitteriness/tremors • Sweating http://www.uptodate.com/contents/pathogenesis-screening-and-diagnosis-of-neonatal-hypoglycemia?topicKey=PEDS%2F5053&elapsedTimeMs=6&source=s…

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• Irritability • Tachypnea • Pallor ● Neuroglycopenic symptoms are caused by brain dysfunction from impaired brain energy metabolism due to a deficient glucose supply. • • • • •

Poor suck or poor feeding Weak or high-pitched cry Change in level of consciousness (lethargy, coma) Seizures Hypotonia

In newborns, additional signs of hypoglycemia include apnea, bradycardia, cyanosis, and hypothermia. Because these findings are nonspecific, further evaluation for other possible causes (eg, sepsis) should be conducted if symptoms do not resolve after normalization of the blood glucose concentration. (See 'Differential diagnosis' below.) EVALUATION Who should be evaluated? — Blood glucose concentrations should not be measured in healthy asymptomatic term infants born after an uncomplicated pregnancy and delivery [5,6]. Blood glucose concentration should be measured in infants at risk for hypoglycemia and in infants who exhibit signs or symptoms consistent with hypoglycemia [6]. (See 'Clinical manifestations' above.) Infants at risk for hypoglycemia include: ● Preterm infants including late preterm infants with gestational age less than 37 weeks (see "Late preterm infants", section on 'Hypoglycemia') ● Infants who are large for gestational age (see "Large for gestational age newborn", section on 'Hypoglycemia') ● Infants with fetal growth restriction (FGR) (see "Infants with fetal (intrauterine) growth restriction", section on 'Hypoglycemia') ● Infants of diabetic mothers (see "Infant of a diabetic mother", section on 'Hypoglycemia') ● Infants who have experienced perinatal stress due to: • Birth asphyxia/ischemia; this includes infants delivered by Cesarean birth for fetal distress (see "Systemic effects of perinatal asphyxia", section on 'Organ involvement') • Maternal preeclampsia/eclampsia or hypertension • Meconium aspiration syndrome (see "Clinical features and diagnosis of meconium aspiration syndrome", section on 'Clinical features') • Erythroblastosis fetalis (see "Postnatal care of hydrops fetalis") • Polycythemia (see "Neonatal polycythemia") ● Postmature infants, as these infants are at risk for placental insufficiency due to either the infant "outgrowing the placenta" or due to decreasing placental function as a result of aging (see "Postterm infant") ● Infants who require intensive care ● Infants whose mothers were treated with beta adrenergic or oral hypoglycemic agents ● Family history of a genetic form of hypoglycemia http://www.uptodate.com/contents/pathogenesis-screening-and-diagnosis-of-neonatal-hypoglycemia?topicKey=PEDS%2F5053&elapsedTimeMs=6&source=s…

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● Congenital syndromes (eg, Beckwith-Wiedemann) and abnormal physical features (eg, midline facial malformations, and microphallus) associated with hypoglycemia A prospective study of at-risk neonates (ie, large or small for gestational age, infant of diabetic mother, late preterm infants) with a gestational age of 35 weeks or greater reported that one-half of this cohort had at least one documented blood glucose concentration ≤47 mg/dL (2.6 mmol/L) and 20 percent had a blood glucose concentration ≤36 mg/dL (2 mmol/L) [17]. Twenty percent of patients had more than one episode of a documented low blood glucose level. Most of the low glucose concentrations occurred within the first 24 hours of life and were in asymptomatic infants. However, in some newborns, their first low glucose concentration occurred after 48 hours of age and/or after three glucose concentrations greater than 47 mg/dL (2.6 mmol/L). Blood glucose concentration should also be monitored at least weekly in infants receiving total parenteral nutrition (TPN), and in infants transitioning from parenteral to enteral nutrition. No single concentration has been shown to be "safe" for preterm infants who are enterally fed prior to 40 weeks postconceptual age as there is a significant amount of variability in patients' glucose concentrations (both hyper- and hypoglycemic episodes) throughout the day [18,19]. For preterm infants, many experts in the field, including the author, would suggest a target blood glucose concentration of 50 to 60 mg/dL (2.8 to 3.3 mmol/L) [1,20]. In all neonatal cases, glucose concentrations should be considered in the context of the patient's overall clinical and nutritional status. Timing and frequency of glucose screening — The schedule for glucose screening is dependent on the clinical setting as follows: ● Glucose concentrations should be determined whenever symptoms consistent with hypoglycemia occur. ● In infants who are at risk for hypoglycemia, glucose screening is performed after the first feed, which should occur within one hour after birth. Surveillance should be continued by measuring a prefeeding glucose concentration every three to six hours for the first 24 to 48 hours of life because many at-risk newborns present with their first documented low glucose concentrations during this period [17]. ● In neonates identified with low blood glucose concentrations, monitoring should continue until concentrations can be maintained with regular feedings in a normal range: >50 mg/dL (2.8 mmol/L) in newborns 60 mg/dL (3.3 mmol/L) in newborns >48 hours old [5]. ● If an infant is unable to maintain glucose concentrations >60 mg/dL after 48 hours of age, a hypoglycemia disorder should be considered and further evaluation is warranted [5]. (See "Management and outcome of neonatal hypoglycemia", section on 'Persistent hypoglycemia'.) How glucose testing is performed — Most nurseries perform capillary blood glucose measurements using a point of care glucose meter as a rapid screening method. However, glucose meters show large variations in values compared with laboratory methods, especially at low glucose concentrations, and are of unproven reliability to document hypoglycemia in newborns [21,22]. Thus, the plasma glucose concentration in an infant with a low glucose value determined by a glucose meter should be confirmed by laboratory measurement [6]. Likewise, laboratory confirmation of the plasma glucose concentration should be performed in any infant who shows signs consistent with hypoglycemia. However, treatment should be started immediately after the blood sample is obtained and before confirmatory results are available. Laboratory measurement of glucose concentration is affected by the type of sample. Glucose concentration measured in whole blood is approximately 15 percent lower than that in plasma and may be further reduced if the hematocrit is high. Prompt analysis should be performed because delays in processing and assaying glucose can reduce the glucose concentration by up to 6 mg/dL/hour (0.3 mmol/L/hour) due to red cell glycolysis [5]. Continuous glucose monitoring using a sensor that measures interstitial glucose concentration was reported to be reliable (when compared with blood glucose measurement), safe, and tolerable [23,24]. However, it is unclear how to interpret the clinical significance of low interstitial blood glucose levels and whether treatment should be initiated. Further studies are needed to determine whether continuous interstitial glucose monitoring has a useful role in the http://www.uptodate.com/contents/pathogenesis-screening-and-diagnosis-of-neonatal-hypoglycemia?topicKey=PEDS%2F5053&elapsedTimeMs=6&source=s…

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screening and management of neonatal hypoglycemia [25]. DIAGNOSIS — As discussed previously, pathologic neonatal hypoglycemia cannot be defined by a precise numerical blood glucose concentration because of the lack of outcome data that accurately identify a threshold level of blood glucose at which intervention should be initiated to prevent morbidity (see 'Challenge of defining neonatal hypoglycemia' above). Nevertheless, defining a clinical diagnosis of neonatal hypoglycemia is important to provide guidance for when and if therapy should be initiated to increase blood glucose levels. We use the following parameters outlined by the 2011 American Academy of Pediatrics (AAP) clinical report and guidelines from the Pediatric Endocrine Society to make the diagnosis of neonatal hypoglycemia requiring medical intervention [5,6] (see "Management and outcome of neonatal hypoglycemia"): ● Symptomatic patients (eg, jitteriness/tremors, hypotonia, changes in level of consciousness, apnea/bradycardia, cyanosis, tachypnea, poor suck or feeding, hypothermia, and/or seizures) (see 'Clinical manifestations' above): • Who are less than 48 hours of life with plasma glucose levels