OVERVIEW: What every practitioner needs to know about Neonatal Hypoglycemia
Are you sure your patient has Neonatal Hypoglycemia? What are the typical findings for this disease?
The classic definition of hypoglycemia (Whipple triad) requires the following:
Reliable measurement of low glucose level
Signs and symptoms consistent with hypoglycemia
Resolution of signs and symptoms within minutes to hours after establishment of normoglycemia
However, today most practitioners use a statistically derived definition to avoid the occurrence of symptomatic hypoglycemia. Although low glucose concentrations and hypoglycemia can often be asymptomatic, the clinical signs and symptoms of hypoglycemia are the following:
General: hypothermia, abnormal cry, poor feeding
Neurologic: jitteriness/tremors, hypotonia, irritability, lethargy, seizures
Cardiorespiratory: cyanosis/pallor, tachypnea, apnea
Guidelines for Screening of Neonatal Hypoglycemia
Because plasma glucose homeostasis requires glucogenesis and ketogenesis to maintain normal rates of fuel use, neonatal hypoglycemia should be suspected in infants who may have defects in these processes. Infants at higher risk for neonatal hypoglycemia include those with excessive insulin production, increased insulin sensitivity and glucose utilization, impaired counterregulatory hormone production, an inadequate substrate supply, or a disorder of fatty acid oxidation. Neonatal hypoglycemia is more common in preterm infants, small for gestational age (SGA) infants, infants of diabetic mothers (IDM), and large for gestational age infants (LGA).
Maternal history: When evaluating a neonate for risk of hypoglycemia, one should take a detailed maternal and family history. This should include any history of family members with atypical diabetes or other abnormalities of glucose homeostasis, metabolic disease, unexplained stillbirths, or infant deaths. It is also important to determine any maternal risk factors such as the following:
Diabetes or abnormal glucose tolerance test result
Preeclampsia or gestational hypertension
Previous macrosomic infants
Treatment with beta-agonist tocolytic agents
Treatment with oral hypoglycemic agents
Late antepartum or intrapartum administration of intravenous (IV) glucose
Neonatal history: Often this is the most important information and should include gestational age, Apgar scores, and details of the delivery room events. Neonatal risk factors that place an infant at high risk for problems with glucose homeostasis include the following:
Intrauterine growth restriction (IUGR)
Iatrogenic administration of insulin
Congenital cardiac malformations
Inborn errors of metabolism
Routine screening and monitoring of blood glucose concentration is not recommended in healthy term newborn infants after a normal pregnancy and delivery. The American Academy of Pediatrics (AAP) published a clinical report in which they recommended the following thresholds for the consideration of hypoglycemia and further evaluation and/or treatment in high-risk infants (late preterm, SGA, IDM, and LGA):
Less than 40 mg/dL if symptomatic
Birth to 4 hours of age: less than 40 mg/dL before feeding
4 hours to 24 hours of age: less than 45 mg/dL before feeding
Although the AAP report is specific to late preterm, IDM, SGA, and LGA infants, it is reasonable to apply the same guidelines to all the at-risk groups listed above, though higher glucose concentrations should be considered if there is a family history or strong suspicion of inborn errors of metabolism, persistent congenital hyperinsulinemia, or other endocrine disorders.
What other disease/condition shares some of these symptoms?
Features of neonatal hypoglycemia also occur in other conditions such as sepsis, intraventricular hemorrhage, asphyxia, hypocalcemia, congenital heart disease, and structural central nervous system lesions.
What caused this disease to develop at this time?
At birth, the newborn infant is removed abruptly from its glucose supply, and blood glucose concentration falls, which makes low glucose concentrations common in healthy neonates by 1 to 2 hours after birth.
Maintenance of glucose homeostasis depends on the balance between hepatic glucose output and glucose use by the brain and peripheral tissues. The hepatic glucose output is a function of the rates of glycogenolysis (breakdown of hepatic glycogen) and gluconeogenesis (synthesis of glucose from lactate, glycerol, and amino acids). Many hormonal and metabolic changes occur at birth that facilitate the adaptation necessary to prevent hypoglycemia. Some of these mechanisms include the following:
Increased catecholamine levels:Activate brown fat triglyceride turnover, which produces heat necessary for postnatal thermoregulation, in addition to increasing glycogenolysis and gluconeogenesis
Increased glucagon concentrations: Reverse the high insulin-glucagon ratio characteristic of fetal life; increased glucagon activates hepatic glycogenolysis and gluconeogenesis
Increased cortisol levels: Decrease peripheral insulin sensitivity and increase hepatic gluconeogenesis as well as inhibiting insulin release
Stimulation of lipolysis: Caused by increased catecholamines, breaks down triglycerides to provide precursors for gluconeogenesis as well as energy through direct oxidation and ketone body production
If rates of glycogenolysis and gluconeogenesis do not match the rate of glucose use because of failure of hormonal control mechanisms or reduced alternative substrate supply, disturbances of glucose homeostasis develop, including hypoglycemia.
Increased glucose use: Peripheral glucose use varies with the metabolic demands placed on the neonate. In term neonates, steady state glucose use rates are 4-6 mg/kg/min. Peripheral glucose use may increase with the following:
Hypoxia: Peripheral glucose use may increase during hypoxia because of inefficiency of anaerobic glycolysis.
Hyperinsulinemia: Glucose uptake is increased by insulin-sensitive tissues.
Cold stress: Metabolic rate increases through sympathetic nervous system activity and thyroid hormone secretion.
Infants who are hypotensive or hypoxemic or those who are hypoventilated, in septic shock, or asphyxiated rely on anaerobic metabolism for energy, which is less efficient and metabolizes more glucose than do aerobic conditions. Infants with sepsis may have increased stimulation of glucose use because of circulating endotoxins that increase the rate of glycolysis.
Asphyxiated infants may have impaired synthesis of gluconeogenic enzymes because of liver damage and elevated insulin concentrations, providing additional causes for hypoglycemia. Hypothermia, most often seen in infants born at home, may result in hypoglycemia by depletion of brown fat stores and exhaustion of glycogen stores.
Most often, an inadequate substrate supply is caused by subnormal fat and glycogen stores that do not provide sufficient energy to maintain glucose homeostasis until gluconeogenesis reaches adequate levels. Because most hepatic glycogen is accumulated during the third trimester of pregnancy, infants born prematurely have diminished glycogen stores.
Infants with IUGR caused by placental insufficiency may also be at risk for decreased glycogen accumulation, likely due to diminished transfer of glycogen precursors across the placenta, and their exposure to hypoxemia may increase catecholamine levels, leading to increased intrapartum glycogen breakdown and further compromising the postnatal substrate supply.
Postnatally, depleted glycogen supplies, impaired gluconeogenesis due to low levels of phosphoenolpyruvate carboxykinase, low levels of hepatic microsomal glucose-6-phosphatase activity contributing to diminished glucose production, inadequate cortisol secretion have all been cited as causes for hypoglycemia, and transient hyperinsulinism.
Once normal feedings are established, glycerol and amino acids continue to fuel gluconeogenesis. Galactose derived from hydrolysis of milk sugar (lactose) in the gut increases hepatic glycogen production and allows for sustained between-feeding hepatic glucose release from glycogen breakdown. Feedings also induce production of intestinal peptides, or incretins, that promote insulin secretion. Insulin decreases hepatic glucose production and increases glucose use for energy production and storage as glycogen.
Specific Disorders Associated with Neonatal Hypoglycemia
Hyperinsulinemia is the most common endocrinologic disturbance producing neonatal hypoglycemia and may also be the most common cause of persistent hypoglycemia in infants. Excessive insulin secretion increases glucose use in newborn tissues such as muscle; however brain glucose uptake does not appear to be significantly altered until glucose concentrations decrease.
High insulin concentrations also promote glycogen synthesis and inhibit glycogenolysis and gluconeogenesis, which impairs the infant’s response to increased glucose demand. In addition, suppression of ketone body production by insulin may also limit the availability of alternative fuels for cerebral metabolism, putting this population at higher risk for adverse neurologic outcomes. Causes of hyperinsulinemia include the following:
IDM: The most common presentation of hyperinsulinemia is IDM. In utero, the fetus becomes hyperglycemic in response to maternal hyperglycemia, which results in increased transfer of glucose across the placenta. The fetal pancreatic beta cells are stimulated by the increased fetal glucose and produce increased quantities of insulin. After delivery, the source of glucose is abruptly removed and high insulin concentrations persist, causing hypoglycemia.
Idiopathic hyperinsulinism: This is a condition in which there is increased and persistent insulin secretion without a known predisposing factor possibly resulting from altered regulation of insulin secretion in pancreatic beta cells.
Prolonged idiopathic neonatal hyperinsulinism affects infants with some evidence of stress before or during delivery (IUGR, SGA, birth asphyxia, maternal preeclampsia). It usually manifests in the first days after birth and may be severe, requiring high glucose infusion rates. This condition may resolve quickly or may last weeks, occasionally requiring treatment with diazoxide. This condition also may be seen in erythroblastosis fetalis, conditions associated with chronic fetal hypoxia and polycythemia, or in utero exposure to drugs such as beta-agonist tocolytic agents.
Focal pancreatic beta-cell adenoma: This condition requires localization of the adenomatous region to guide surgical resection.
Beckwith-Wiedemann syndrome: Infants with this syndrome are macrosomic and hyperinsulinemic and have other associated anomalies, including macroglossia and omphalocele.
Growth hormone/cortisol deficiencies: These hormones oppose the actions of insulin and increase glucose concentrations by reducing glucose uptake in muscle and stimulating gluconeogenesis. Hormone replacement is the treatment of choice.
Hereditary disorders associated with deficiencies of specific enzymes that are rare but are frequently associated with hypoglycemia. These disorders are almost always inherited in an autosomal recessive pattern.
Defects of Carbohydrate Metabolism
Glycogen storage diseases are caused by an enzyme deficiency that prevents glycogenolysis and release of glucose into the circulation. These infants often present with hypoglycemia, failure to thrive, hepatomegaly, and lactic acidosis.
Fructose 1,6-diphosphatase deficiency
Pyruvate carboxylase/phosphoenolpyruvate carboxykinase deficiency
Galactose-1-phosphate uridylyl transferase deficiency (classic galactosemia): Infants with this condition are intolerant of products containing galactose.
They often present with hypoglycemia, failure to thrive, sepsis, diarrhea, and vomiting after ingesting products with galactose. Postprandial hypoglycemia is caused by sudden inhibition of glycogenolysis. Most infants with this condition are identified by routine newborn screening.
Defects of Amino Acid Metabolism
Inborn errors of metabolism (propionic acidemia, methylmalonic acidemia, glutaric aciduria) may present with hypoglycemia in the first week of life; maple syrup urine disease presents with hypoglycemia and hypoalaninemia and often markedly elevated branched-chain amino acids and alpha-keto acids.
Defects of Fatty Acid Metabolism
Associated with abnormalities in fatty acid oxidation and ketone body formation, these rare metabolic disorders present with hypoglycemia and hypoketonemia. Hypoglycemia in these children may be due to decreased hepatic glucose production or accelerated rates of glucose use.
Congenital persistent hyperinsulinism: This is associated with either diffuse or focal pancreatic abnormalities, depending on the genetic mutation. Most often infants present with severe recurrent hypoglycemia within the first few days of life. Infants are typically LGA and require high rates of glucose infusion (10-30 mg/kg/min). Because of disruption of the potassium–adenosine triphosphate complex, these infants usually do not respond to diazoxide. Octreotide may be helpful as a short-term therapy, but pancreatectomy is usually necessary as are continuous feedings.
What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
It should be noted that laboratory measurement of glucose levels is affected by the type of sample. Glucose concentration measured in whole blood is approximately 15% lower than that measured in plasma and may be even lower with polycythemia. Blood glucose values may also decrease by 15-20 mg/dL/h in samples at room temperature, so prompt analysis is important for accurate results. Rapid bedside measurement of plasma glucose concentration in high-risk or symptomatic neonates is essential. Confirmation of bedside measurements with a specimen sent right away to the chemistry laboratory is indicated, although treatment should not be postponed.
In the following cases, the initial diagnostic evaluation should also include simultaneous determination of glucose, insulin concentration (>2 mU/L is considered a positive test result, especially with negative serum ketone concentrations), serum ketone concentrations, cortisol, and growth hormone levels sampled during an episode of hypoglycemia (<40 mg/dL):
Symptomatic hypoglycemia in a healthy infant
Hypoglycemia with seizures or abnormalities of consciousness
Persistent or recurrent hypoglycemia
Hypoglycemia requiring greater than 8-10 mg/kg/min of intravenous glucose administration
Hypoglycemia in association with midline defects, micropenis, or erratic temperature control
Family history of sudden infant death or developmental delay
After the initial diagnostic evaluation is performed, other tests—such as concentrations of free fatty acids, TSH, T4, adrenocorticotropic hormone, ammonia, lactate, and pyruvate; liver function tests; urinary organic acid and serum amino acid determinations; acylcarnitine profile; enzymatic assays (require fibroblasts/leukocytes for culture); targeted genetic analysis; and transferrin western blot (for congenital disorders of glycosylation)—can further aid in diagnosis.
Would imaging studies be helpful? If so, which ones?
Magnetic resonance imaging (MRI) may be useful diagnostically to demonstrate hypopituitarism and associated defects such as septo-optic dysplasia. A brain MRI performed 2-3 weeks after severe hypoglycemia may demonstrate an abnormal signal in the cortex, often most apparent in the occipital lobes.
More recent neuroradiologic investigations have shown a much wider variety in the pattern of injury involving both white matter and gray matter associated with severe neonatal hypoglycemia. Radiographically defined lesions after severe hypoglycemia in the newborn period can be transient and not associated with long-term neurologic consequences. Therefore, early MRI may be of limited value and follow-up MRI may be indicated.
If you are able to confirm that the patient has Neonatal Hypoglycemia, what treatment should be initiated?
Initiate oral feeding: In asymptomatic infants, management with oral feeding is used widely and is successful.
Dextrose gel: Emerging evidence demonstrates some utility in the use of dextrose gel (200 mg/kg) massaged into the buccal mucosa of asymptomatic hypoglycemic IDM, LGA, IUGF/SGA, and late preterm neonates in conjunction with oral milk feeding.
Parenteral glucose infusion: In infants who are symptomatic, have severe hypoglycemia, remain hypoglycemic after feedings, or are unable to tolerate enteral feedings, glucose infusion should be initiated. Initially this consists of a bolus dose of 200 mg/kg (D10 at 2 mL/kg) given over 5 minutes followed by initiation of a constant dextrose infusion at 5-8 mg/kg/min, which should be adjusted based on frequent glucose measurements. In asymptomatic neonates who remain hypoglycemic after feedings it may be reasonable to start a constant dextrose infusion at 5-8 mg/kg/min and not provide an initial 200 mg/kg bolus of dextrose.
Once therapy for hypoglycemia is initiated, the infant should have additional glucose measurements obtained after feeding, then every 3 hours before feeding for at least two feedings to ensure that normoglycemia is maintained. If the infant remains hypoglycemic, reassessment of glucose should continue while adjusting therapy until normoglycemia is achieved and maintained.
Treatment of Persistent Hypoglycemia
Glucagon causes the release of glycogen from hepatic stores except in the case of glycogen storage defects and therefore may suggest this diagnosis in an infant who does not respond to treatment. Initial doses of 30 µg/kg IV or intramuscularly are standard; however infants with hyperinsulinemia (i.e., IDM) may require much larger doses to produce a response.
Immediately after glucagon administration, there is a risk of increased insulin secretion. Despite the rapid increase in glucose concentration, the underlying cause of hypoglycemia may persist, which is why glucose infusion should be maintained after glucagon is given, and infant glucose levels should be monitored because repeated dosing and even a continuous infusion may be indicated.
Diazoxide: Diazoxide suppresses the release of insulin and can be useful in infants with hyperinsulinemia, islet cell dysplasia, and persistent hypoglycemia after partial pancreatectomy. The infant should be monitored for fluid and electrolyte disturbances which might manifest as pulmonary edema or rarely congestive heart failure.
Somatostatin and octreotide: These agents also suppress insulin release and can be useful in infants with diazoxide unresponsive hyperinsulinemia.
Glucocorticoids: These agents reduce peripheral glucose use and increase gluconeogenesis and are often used in infants requiring very high glucose infusion rates (12-15 µg/kg/min) to maintain normal glucose concentrations, especially if serum cortisol levels are low.
Surgery: This mode of treatment is often necessary for congenital hyperinsulinism if other therapies such as octreotide are not successful. If disease is focal, partial pancreatectomy is usually curative, whereas diffuse disease requires near total pancreatectomy and subsequent treatment of the exocrine and endocrine deficiencies that result.
Weaning IV dextrose: Once enteral feeding is established and glucose concentrations have normalized, IV dextrose may be weaned gradually, with frequent glucose measurements.
Consultation with an endocrinologist and/or a neonatologist: At any point in the evaluation of an infant with persistent hypoglycemia, it is reasonable to enlist the help of specialists to aid in the diagnosis and treatment.
Follow-up: For infants with persistent hypoglycemia, observation for several days (1-3) is indicated to ensure that normoglycemia is maintained. Before hospital discharge, one should consider a fasting challenge for 6-8 hours to ensure that the infant is not in danger at home if a feeding is missed, especially for infants with a history suspicious for hyperinsulinism.
What are the possible outcomes of Neonatal Hypoglycemia?
In almost all infants with transient neonatal hypoglycemia, the prognosis is good, with no associated morbidities.
Infants with symptomatic hypoglycemia, primarily those with severe (0-18 mg/dL) and protracted (several hours or more) low glucose concentrations associated with neurologic conditions such as seizures and coma may have a poor prognosis, especially in the case of congenital hyperinsulinemia or a metabolic defect.
The abnormalities in these infants range from learning disabilities to cerebral palsy and persistent or recurrent seizure disorders as well as mental retardation of varying degrees. In order to ascribe long-term impairment to neonatal hypoglycemia, the following conditions should be present:
Blood or plasma glucose concentrations less than 18 mg/dL. Such values are well below normal, although if only transient there is no current evidence confirming that they lead to permanent neurologic injury.
Persistence of such severely low glucose concentrations for prolonged periods (>2-3 hours)
Early mild to moderate clinical signs, such as alternating central nervous system signs of jitteriness/tremors versus stupor/lethargy or convulsions that diminish or disappear with effective treatment, which promptly restores glucose concentration to a normal range (>45 mg/dL)
More serious clinical signs that are prolonged (many hours or more), including coma, seizures, respiratory depression, apnea, hypotonia, high-pitched cry, hypothermia, and poor feeding after feeding well initially
Concurrence of associated conditions, especially persistent excessive insulin secretion and hyperinsulinemia with repeated episodes of acute, severe hypoglycemia with seizures and/or coma
Diagnosis of a metabolic or genetic defect associated with hypoglycemia
Prognosis and outcome of neonates with hypoglycemia are also dependent on comorbidities such as prematurity, sepsis, and hypoxic-ischemic organ damage. Each of these conditions may make independent contributions to an adverse neurologic outcome. The paucity of reliable follow-up data on infants with neonatal hypoglycemia per se and the inconsistency of the definition of neonatal hypoglycemia makes it difficult to compare studies.
In cases of hyperinsulinism requiring near-total pancreatectomy, approximately one third of patients will effectively be cured, another one third will go on to have further surgery for total pancreatectomy, and the last third will require long-term insulin therapy for the treatment of diabetes. In the case of focal beta-cell pancreatic adenoma, partial pancreatectomy is curative. Neurologic outcomes in these patients is dependent on the degree and duration of hypoglycemia present before surgery.
What causes this disease and how frequent is it?
Using the most commonly used standard definitions of hypoglycemia, the incidence has been estimated at 1.3-4.4/1000 live births. Differences in incidence figures reflect variable inclusion of symptomatic versus asymptomatic infants. The incidence of low glucose concentrations is increased in preterm infants and ranges from 1.5%-5.5%. The incidence in term infants with IUGR may be as high as 25% and even higher in preterm SGA infants. The incidence in IDM ranges from 15%-75%.
How do these pathogens/genes/exposures cause the disease?
Congenital hyperinsulinism: The overall incidence is low (1/50,000 births), but the incidence of inherited forms may be as high as 1/2500 infants in genetically homogeneous populations. At least five different genes have been associated with congenital hyperinsulinism. Mutations in several regions on the short arm of chromosome 11 have been found in approximately 50% of infants with this disorder, and these mutations are most commonly inherited in an autosomal recessive pattern. Other mutations, including mutations in genes that code for glucokinase (GCKHI), missense mutations of SUR1, and mutations of glutamate dehydrogenase (GDH), have also been identified.
Focal beta-cell pancreatic adenoma: This condition is caused by a localized clone of beta cells that expresses a paternally derived mutation in the gene for either SUR1 or Kir6.2 due to loss of heterozygosity for the maternal allele.
Beckwith-Wiedemann syndrome: Some infants with this condition have been found to have mutations in the short arm of chromosome 11.
Are additional laboratory studies available; even some that are not widely available?
Pancreatic imaging to differentiate diffuse versus focal cell defects is being performed in some centers. Localization of focal adenomatous regions of the pancreas can be performed through catheterization of the pancreatic circulation and localized sampling of insulin production. The use of positron emission tomography with 18F-fluoro-L-DOPA has allowed definition of the abnormal region of the pancreas, thus guiding limited resection and avoiding more extensive pancreatectomies.
What is the evidence?
Cornblath, M,, Hawdon, JM,, Williams, AF. “Controversies regarding definition of neonatal hypoglycemia: suggested operational thresholds.”. Pediatrics. vol. 105. 2000. pp. 1141-45. (Pragmatic recommendations for operational thresholds—that is, blood glucose levels at which clinical interventions should be considered—are offered in light of current knowledge to aid health care providers in neonatal medicine.)
Adamkin, DH. “Committee on Fetus and Newborn. Postnatal glucose homeostasis in late-preterm and term Infants.”. Pediatrics. vol. 127. 2011. pp. 575-79. (Provides a practical guide and algorithm for the screening and subsequent management of neonatal hypoglycemia.)
Thornton, PS,, Stanley, CA,, De Leon, DD. “Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children.”. Journal of Pediatrics. vol. 167. 2015. pp. 238-45. (Provides a practical guide for the management of neonatal hypoglycemia with a focus on hypoglycemic neonates beyond 48 hours of age.)
McKinlay, CJ,, Alsweiler, JM,, Ansell, JM. “Neonatal Glycemia and Neurodevelopmental Outcomes at 2 Years.”. New England Journal of Medicine.. vol. 373. 2015. pp. 1507-18. (A large study demonstrating that hypoglycemic at-risk newborns managed to target a glucose concentrations greater than 47 mg/dL have equivalent outcomes to at-risk newborns that were not hypoglycemic. An association between rapid correction of hypoglcyemia and worse outcomes was noted.)
Harris, DL,, Alsweiler, JM,, Ansell, JM. “Outcome at 2 Years after Dextrose Gel Treatment for Neonatal Hypoglycemia: Follow-Up of a Randomized Trial.”. Journal of Pediatrics. vol. 170. 2016. pp. 54-9. (Two year outcomes of a placebo controlled randomized trial of buccal dextrose gel in the management of asymptomatic neonatal hypoglycemia are reported.)
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- OVERVIEW: What every practitioner needs to know about Neonatal Hypoglycemia
- Are you sure your patient has Neonatal Hypoglycemia? What are the typical findings for this disease?
- What other disease/condition shares some of these symptoms?
- What caused this disease to develop at this time?
- Would imaging studies be helpful? If so, which ones?
- If you are able to confirm that the patient has Neonatal Hypoglycemia, what treatment should be initiated?
- What are the possible outcomes of Neonatal Hypoglycemia?
- What causes this disease and how frequent is it?
- How do these pathogens/genes/exposures cause the disease?
- Are additional laboratory studies available; even some that are not widely available?