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Pathogenesis, screening, and diagnosis of neonatal hypoglycemia

Pathogenesis, screening, and diagnosis of neonatal hypoglycemia
Author:
Paul J Rozance, MD
Section Editors:
Joseph A Garcia-Prats, MD
Joseph I Wolfsdorf, MD, BCh
Deputy Editor:
Laurie Wilkie, MD, MS
Literature review current through: Apr 2022. | This topic last updated: Dec 20, 2021.

INTRODUCTION — During the normal transition to extrauterine life, blood glucose concentration in the healthy term newborn falls during the first one to two hours after delivery, reaching a nadir (median concentration of approximately 55 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:

Variability of neonatal blood glucose levels and response − Low blood glucose concentrations normally occur in the first hours after birth and may persist for up to several days [1]. 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 [2,3].

This was illustrated in a large prospective study of newborns (gestational age ≥35 weeks) at risk for hypoglycemia (ie, maternal diabetes, large for gestational age, fetal growth restriction, and prematurity [gestational age <37 weeks]) in whom ongoing monitoring of blood glucose concentrations were performed for the first 48 hours of life and treatment was provided to maintain blood glucose concentrations greater than 47 mg/dL (2.61 mmol/L) regardless of postnatal age [4]. Neurodevelopmental outcome at two years of age was similar between infants in whom intervention was provided for hypoglycemia compared with those without evidence of hypoglycemia. However, at 4.5 years of age follow-up assessment demonstrated that children with treated neonatal hypoglycemia had poorer executive and visual motor functions [5]. Of note, despite intensive capillary blood glucose monitoring, 25 percent of the infants had glucose concentrations below the targeted level for at least five hours as detected by continuous interstitial glucose monitoring (which was masked to the clinical providers). These results do not provide a definitive threshold for treating neonatal hypoglycemia in all newborns.

Nevertheless, most guidelines used in clinical practice provide arbitrary treatment thresholds of blood glucose concentrations to initiate intervention despite the controversies surrounding the definition of hypoglycemia [2,6]. The goal of these guidelines is 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".)

Most guidelines are based on plasma glucose concentrations, therefore it is important to recognize that glucose concentrations measured in whole blood (often used at the point-of-care) 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, as opposed to using a threshold range of glucose values (eg, below the 5th percentile used in the American Academy of Pediatrics [AAP] guidelines). (See 'How glucose testing is performed' below.)

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 [7]. 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 with a median concentration of approximately 55 mg/dL, and 95 percent values in this nadir above 25 mg/dL [2,3,8-10]. Glucose concentrations increase over the first 18 hours and stabilize between 45 and 80 mg/dL (2.5 and 4.4 mmol/L) for the first 48 hours of life [1-3,8]. Mean glucose concentrations then rise more slowly to levels similar to the mean concentrations seen in older children and adults by day 4 [1]. However, blood glucose levels vary widely even in individual infants. In a prospective study, low glucose concentrations (defined as <47 mg/dL [2.6 mmol/L) were observed in about 40 percent of healthy term infants undergoing continuous glucose monitoring and frequent plasma glucose testing over the first 120 hours after birth [1].

Immediately after birth, the newborn infant breaks down hepatic glycogen (glycogenolysis) to produce glucose in response to increased plasma epinephrine and glucagon concentrations, and falling insulin levels. As a result, glycogen stores are depleted during the first 8 to 12 hours of life. At that point, the newborn needs to produce glucose (gluconeogenesis) by synthesizing glucose from lactate, glycerol, and amino acids. 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) [11,12].

PATHOGENESIS OF NEONATAL HYPOGLYCEMIA — Hypoglycemia is caused by a lower rate of glucose production than glucose utilization due to either inadequate glucose supply or increased glucose utilization.

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 [8,13]. (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 "Inborn errors of metabolism: Classification", section on 'Congenital disorders of glycosylation' and "Causes of hypoglycemia in infants and children".)

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 disorders of glucose and glycogen metabolism" and "Causes of hypoglycemia in infants and children", section on 'Disorders of glycogen metabolism'.)

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) [14]. (See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Hypoglycemia' and "Organic acidemias: An overview and specific defects" and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Hypoglycemia' and "Causes of hypoglycemia in infants and children", section on 'Disorders of gluconeogenesis' and "Causes of hypoglycemia in infants and children", section on 'Fatty acid oxidation disorders' and "Causes of hypoglycemia in infants and children".)

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 "Causes of hypoglycemia in infants and children", section on 'Hormone deficiencies'.)

Other causes — Other reported causes of impaired glucose production resulting in neonatal hypoglycemia include:

Maternal treatment with beta-sympathomimetic agents (eg, terbutaline and beta-blockers), which interrupts glycogenolysis by blocking epinephrine's effect [15]. In addition, hypoglycemia has been associated with antenatal administration of betamethasone in late preterm infants [16].

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 "Infants of women with diabetes", 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 [8,17]. (See "Infants with fetal (intrauterine) growth restriction".)

Beckwith-Wiedemann syndrome (BWS) − Approximately one-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 [8,18,19]. (See "Perinatal asphyxia in term and late preterm infants", section on 'Glucose metabolism'.)

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 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 ATP-dependent potassium channel in the beta cell membrane. Persistent hyperinsulinemic hypoglycemia of infancy is discussed separately. (See "Pathogenesis, clinical presentation, and diagnosis of congenital hyperinsulinism".)

Excess exogenous insulin given to newborns with hyperglycemia [20]. (See "Neonatal hyperglycemia", section on 'Risk of hypoglycemia'.)

Other 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 "Meconium aspiration syndrome: Pathophysiology, clinical manifestations, and diagnosis".),

Polycythemia [8]. (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. (See "Infants with fetal (intrauterine) growth restriction", section on 'Fetal growth restriction'.)

Conditions associated with anaerobic glycolysis due to decreased tissue perfusion, poor oxygenation, or biochemical defects that interfere with aerobic glucose metabolism [21]. The energy (ATP) per molecule of glucose produced by anaerobic glycolysis is only approximately 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 [18].

Hypothermic infants who have increased rates of glucose utilization in an attempt to maintain normal temperatures.

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.

CLINICAL PRESENTATION

Asymptomatic infants — 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. (See 'Who should be screened?' below.)

Symptomatic infants — 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 [9]:

Neurogenic (autonomic) symptoms result from changes due to neural sympathetic discharge triggered by hypoglycemia.

Jitteriness/tremors

Sweating

Irritability

Tachypnea

Pallor

Neuroglycopenic symptoms are caused by brain dysfunction from impaired brain energy metabolism due to a deficient glucose supply.

Pathological poor feeding

Weak or high-pitched cry

Change in level of consciousness (lethargy, coma)

Seizures

Pathological hypotonia for gestational age

In newborns, additional nonspecific signs of hypoglycemia include apnea, bradycardia, cyanosis, and hypothermia.

Because these signs 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.)

SCREENING

Who should be screened? — Blood glucose concentration should be measured in infants who exhibit signs consistent with hypoglycemia [9]. Blood glucose concentrations should not be measured in healthy asymptomatic term infants born after an uncomplicated pregnancy and delivery [8,9]. (See 'Clinical presentation' above.)

Blood glucose concentration should be measured in infants at risk for hypoglycemia. The most agreed upon risk factors mandating screening are:

Large for gestational age

Intrauterine growth impairment

Pregnancy complicated by diabetes

Preterm birth.

Blood glucose concentrations should not be measured in healthy asymptomatic term infants born after an uncomplicated pregnancy and delivery [8,9]. (See 'Clinical presentation' above.)

Blood glucose concentration should be measured in infants at risk for hypoglycemia including the following (table 2):

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 of diabetic mothers (see "Infants of women with diabetes", section on 'Hypoglycemia')

Infants with fetal growth restriction (FGR) or small for gestational age (see "Infants with fetal (intrauterine) growth restriction", section on 'Hypoglycemia' and "Infants with fetal (intrauterine) growth restriction", section on 'FGR versus SGA')

Infants who have experienced perinatal stress due to:

Birth asphyxia/ischemia; this includes infants delivered by Cesarean birth for fetal distress (see "Perinatal asphyxia in term and late preterm infants", section on 'Glucose metabolism' and "Perinatal asphyxia in term and late preterm infants")

Maternal preeclampsia/eclampsia or hypertension

Meconium aspiration syndrome (see "Meconium aspiration syndrome: Pathophysiology, clinical manifestations, and diagnosis", section on 'Clinical manifestations')

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

Congenital syndromes (eg, Beckwith-Wiedemann, Kabuki syndrome) associated with hypoglycemia (See "Beckwith-Wiedemann syndrome", section on 'Metabolic abnormalities' and "Pathogenesis, clinical presentation, and diagnosis of congenital hyperinsulinism", section on 'Differential diagnosis'.)

Reports from an ongoing prospective study have shown that half of the infants who present with hypoglycemia (defined in this study as blood glucose concentration ≤47 mg/dL [2.6 mmol/L]) are in one of the most common at-risk categories (ie, large or small for gestational age, infant of diabetic mother, late preterm infants) [4,22]. In addition, 20 percent of these at-risk infants had a blood glucose concentration ≤36 mg/dL (2 mmol/L), and 20 percent had more than one episode of a documented low blood glucose level [22]. 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).

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 [23,24]. For preterm infants, many experts in the field, including the author, would suggest maintaining blood glucose concentrations above 50 to 60 mg/dL (2.8 to 3.3 mmol/L) [2,25]. In all neonatal cases, glucose concentrations should be considered in the context of the patient's overall clinical and nutritional status.

Timing 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. If the first feed is delayed, testing is recommended by 90 to 120 minutes of age. 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 [22]. A retrospective study suggests that in some at-risk infants (eg, late preterm infants) the period of monitoring can be shorter [26]. In asymptomatic at-risk newborns in a well-baby nursery, we monitor prefeed glucose concentrations every 3 to 6 hours until we have at least three plasma glucose concentrations greater than 50 mg/dL in the first 48 hours of life.

Blood glucose concentration should be monitored at least weekly in infants receiving total parenteral nutrition (TPN), and in infants transitioning from parenteral to enteral nutrition.

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 [27,28]. Thus, the plasma glucose concentration in an infant with a low glucose value determined by a glucose meter should be confirmed by laboratory measurement [9]. 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. More accurate point-of-care glucose measurement devices are becoming increasingly available [29].

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 of these samples 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 [8].

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 in neonates including very preterm infants [30-33]. 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 screening and management of neonatal hypoglycemia [34].

Parental/caregiver refusal — Hypoglycemia screening in the at-risk asymptomatic newborn is typically conducted with implied consent from the parental/legal caretaker. When parents refuse, clinicians should prioritize efforts to educate them about the potential dangers of hypoglycemia and the benefits and risks of screening [35]. However, if the parents'/caregivers' position remains unchanged, their informed refusal in most cases should be accepted. The exception is for infants who are at great risk for severe hypoglycemia such as those with a previous sibling with congenital hyperinsulinism, or those who have signs consistent with hypoglycemia or have with Beckwith-Wiedemann syndrome.

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 [8,9] (see "Management and outcome of neonatal hypoglycemia"):

Symptomatic patients (eg, jitteriness/tremors, pathological hypotonia, changes in level of consciousness, apnea/bradycardia, cyanosis, tachypnea, pathological poor feeding, sustained hypothermia, and/or seizures) (see 'Clinical presentation' above):

Who are less than 48 hours of life with plasma glucose levels <50 mg/dL (2.8 mmol/L)

Who are greater than 48 hours of life with plasma glucose levels <60 mg/dL (3.3 mmol/L)

Asymptomatic patients at risk for hypoglycemia (eg, preterm infant, an infant of a diabetic mother, or an infant who is large or small for gestational age) or patients in whom low glucose was identified as an incidental laboratory finding (see 'Who should be screened?' above):

Who are less than 4 hours of life with plasma glucose levels <25 mg/dL (1.4 mmol/L)

Who are between 4 and 24 hours of life with plasma glucose <35 mg/dL (1.9 mmol/L)

Who are between 24 and 48 hours of life with plasma glucose levels <50 mg/dL (2.8 mmol/L)

Who are greater than 48 hours of life with plasma glucose levels <60 mg/dL (3.3 mmol/L)

FOLLOW-UP MONITORING AND EVALUATION

Asymptomatic patients — Asymptomatic patients are typically identified because they are at risk for hypoglycemia. Management is focused on normalizing their blood glucose levels and preventing them from becoming symptomatic. The first intervention for these patients is usually oral feeding. (See "Management and outcome of neonatal hypoglycemia", section on 'Asymptomatic and mildly symptomatic infants'.)

In neonates identified with low 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 <48 hours old and >60 mg/dL (3.3 mmol/L) in newborns >48 hours old [8].

If an infant is unable to maintain plasma glucose concentrations >60 mg/dL after 48 hours of age, a hypoglycemia disorder should be considered and further evaluation is warranted [8]. (See "Management and outcome of neonatal hypoglycemia", section on 'Evaluation of infants with persistent hypoglycemia'.)

Symptomatic patients — Patients who have severe neuroglycopenic signs (eg, lethargy, coma, seizures) and are hypoglycemic should be treated promptly with intravenous dextrose. Treatment should be initiated as soon as the confirmatory blood sample is drawn, and without waiting for results.

We manage less severely symptomatic patients with dextrose gel followed by feeds.

Management of neonatal hypoglycemia is discussed elsewhere. (See "Management and outcome of neonatal hypoglycemia", section on 'Severely symptomatic patients'.)

DIFFERENTIAL DIAGNOSIS — Because the clinical manifestations are nonspecific, the following disorders can present with similar symptoms to those seen in neonatal hypoglycemia. In general, neonatal hypoglycemia is differentiated from these conditions by the resolution of symptoms as blood glucose levels normalize. However, in some cases, it is still challenging to confirm the underlying diagnosis, as interventions that address these other disorders may be administered during the same time period.

Sepsis – In neonates, nonspecific signs of sepsis are often similar to those of hypoglycemia, such as irritability, lethargy, and tachypnea. Because of the serious consequences, empiric antibiotic therapy should be provided (after cultures are obtained) to infants with suspected sepsis pending definitive culture-based diagnosis, in addition to administrating interventions directed towards hypoglycemia. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants" and "Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation".)

Neonatal abstinence syndrome (NAS) – The timing and clinical manifestations of NAS can mimic neonatal hypoglycemia. Overlapping signs include sleepiness, poor feeding, sweating, tachypnea, jitteriness, tremors, irritability, and seizures. The presentation of NAS is variable and depends on the type and timing of maternal substance exposures. (See "Neonatal abstinence syndrome", section on 'Clinical findings'.)

Inborn errors of metabolism – Metabolic diseases that often present between 12 and 72 hours of age after the initiation of oral feeding include nonketotic hyperglycinemia, urea cycle disorders, and branched-chain organic acidemias. Hypoglycemia may also be an associated finding in patients with some metabolic diseases (table 1) and will persist despite measures to increase blood glucose levels. The diagnosis of inborn errors of metabolism and specific disorders is discussed separately. (See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Initial evaluation' and "Inborn errors of metabolism: Identifying the specific disorder", section on 'Laboratory evaluation'.)

Hyponatremia – Patients typically are not symptomatic until serum or plasma sodium falls below 125 mEq/L, and present with neurologic manifestations including lethargy, obtundation, and, eventually, seizures. The diagnosis of hyponatremia is made by obtaining serum electrolyte levels. (See "Hyponatremia in children: Etiology and clinical manifestations", section on 'Clinical manifestations'.)

Neonatal encephalopathy due to perinatal asphyxia – Neonatal encephalopathy can present with lethargy and irritability, but symptoms fail to improve with an increase in blood glucose levels. Evidence by magnetic resonance imaging of acute brain injury confirms the diagnosis of encephalopathy. (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy".)

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 [36].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypoglycemia in the neonate".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Newborn hypoglycemia (The Basics)")

SUMMARY AND RECOMMENDATIONS

Normal transitional low blood glucose ‒ Low blood glucose concentrations are common in healthy term infants after birth as the glucose supply changes from a continuous transplacental supply from the mother to an intermittent supply from feeds. With loss of the continuous transplacental supply of glucose, glucose concentration in the healthy term newborn falls during the first two hours after delivery, reaching a nadir with a median concentration of approximately 55 mg/dL. Glucose concentrations increase over the first 18 hours and stabilize between 45 and 80 mg/dL. (See 'Normal transitional low glucose levels' above.)

Pathogenesis ‒ Hypoglycemia is caused by a rate of glucose production that is lower than that of glucose utilization. (See 'Pathogenesis of neonatal hypoglycemia' above and "Causes of hypoglycemia in infants and children".)

In neonates, diminished glucose supply is due to inadequate energy stores or impaired glucose production (ie, glycogenolysis or gluconeogenesis). (See 'Inadequate glycogen stores' above.)

Increased glucose utilization is primarily due to various causes of hyperinsulinism (eg, infant of a diabetic mother) or conditions associated with increased metabolic needs or anaerobic glycolysis. (See 'Increased glucose utilization' above and 'Without hyperinsulinism' above.)

Who should be screened for neonatal hypoglycemia

In our center, screening is not performed for healthy asymptomatic term infants without risk factors. (See 'Who should be screened?' above.)

In our center, screening for hypoglycemia is performed for:

-Infants with symptoms consistent with hypoglycemia – Symptoms are nonspecific and include jitteriness/tremors, hypotonia, changes in level of consciousness, apnea/bradycardia, cyanosis, tachypnea, poor suck or feeding, hypothermia, and/or seizures. Blood glucose should be measured as quickly as possible. (See 'Who should be screened?' above and 'Symptomatic infants' above.)

-Asymptomatic infants who are at-risk for hypoglycemia ‒ Risk factors include prematurity (gestational age <37 weeks), infants who are large or small for gestational age, and infants of mothers with diabetes(table 2). (See 'Who should be screened?' above.)

Timing of screening ‒ Blood glucose measurement is performed after the first feed (which should occur within one hour after birth) or by 90 to 120 minutes of age, whichever occurs first. (See 'Timing of glucose screening' above.)

Glucose testing ‒ Most nurseries perform point of care capillary blood glucose measurements using a glucose meter as a rapid screening method. A low screening glucose value should always be confirmed by laboratory measurement unless a highly accurate point-of-care testing device is used. However, treatment (feeding, dextrose gel, intravenous dextrose depending on the situation) is initiated after the blood sample is obtained while awaiting confirmatory results. (See 'How glucose testing is performed' above.)

Diagnosis ‒ Although it is not possible to establish a single numerical blood glucose concentration that accurately predicts significant neonatal hypoglycemia at which intervention should be initiated to prevent morbidity, 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. (See 'Challenge of defining neonatal hypoglycemia' above and 'Diagnosis' above.)

We make a clinical diagnosis of neonatal hypoglycemia based on the presence or absence of signs, the age of the newborn, and the plasma glucose level as follows:

Symptomatic patients:

-Who are less than 48 hours of life with plasma glucose levels <50 mg/dL (2.8 mmol/L)

-Who are greater than 48 hours of life with plasma glucose levels <60 mg/dL (3.3 mmol/L)

Asymptomatic patients at risk for hypoglycemia (table 2) or in patients in whom low glucose was identified as an incidental laboratory finding:

-Who are less than 4 hours of life with plasma glucose levels <25 mg/dL (1.4 mmol/L)

-Who are between 4 and 24 hours of life with plasma glucose <35 mg/dL (1.9 mmol/L)

-Who are between 24 and 48 hours of life with plasma glucose levels <50 mg/dL (2.8 mmol/L)

-Who are greater than 48 hours of life with plasma glucose levels <60 mg/dL (3.3 mmol/L)

Initial management ‒ For infants who are diagnosed with hypoglycemia, initial management includes administration of glucose by feeds, buccal dextrose gel, or intravenously, with continued testing of glucose concentrations to monitor response. (See 'Follow-up monitoring and evaluation' above and "Management and outcome of neonatal hypoglycemia", section on 'Management approach'.)

Differential diagnosis ‒ The differential diagnosis for neonatal hypoglycemia is broad because of the overlap of nonspecific findings (eg, lethargy and irritability). Neonatal hypoglycemia is differentiated from these other disorders (eg, sepsis) with signs of clinical improvement as the blood glucose level normalizes. (See 'Differential diagnosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges See Wai Chan, MD, MPH, who contributed to an earlier version of this topic review.

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