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Neonatal hyperglycemia
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Neonatal hyperglycemia

Disclosures: See Wai Chan, MD, MPH Nothing to disclose. Ann R Stark, MD Nothing to disclose. Steven A Abrams, MD Grant/Research/Clinical Trial Support: Mead-Johnson [Nutrition (Infant formulas)]. Joseph I Wolfsdorf, MB, BCh Nothing to disclose. Melanie S Kim, MD Nothing to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.

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All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2015. | This topic last updated: Aug 07, 2013.

INTRODUCTION — Glucose supply and metabolism are of central importance for growth and normal brain development in the fetus and newborn. Disorders in glucose supply or metabolism can result in hypoglycemia or hyperglycemia. Hyperglycemia in the neonatal period is reviewed here. Neonatal hypoglycemia is discussed separately. (See "Neonatal hypoglycemia".)

PARENTERAL GLUCOSE — Most infants who are preterm or ill require parenteral administration of glucose because adequate enteral feeding is delayed. Neonatal hyperglycemia often occurs in this setting.

Immediately after birth, sufficient glucose is provided to avoid hypoglycemia, typically at a rate of 5 to 8 mg/kg per minute. As an example, administration of 10 percent dextrose solution at 100 mL/kg per day provides glucose at a rate of 7 mg/kg per minute. Although dextrose is a hydrated form of glucose and is 91 percent glucose, the correction usually is not applied in clinical practice.

The glucose infusion rate is increased to approximately 11 to 12 mg/kg per minute in the first two to three days after birth to provide calories for growth. In general, glucose infusion rates >15 mg/kg per minute are avoided, as this exceeds the ability of most infants to oxidize glucose and may promote excessive lipogenesis. (See "Parenteral nutrition in premature infants", section on 'Glucose'.)

DEFINITION — The definition of hyperglycemia is uncertain. It is often defined as blood glucose >125 mg/dL (6.9 mmol/L) or plasma glucose >150 mg/dL (8.3 mmol/L). These glucose levels are frequently observed during glucose infusions in newborns, especially in extremely preterm infants, and may not require intervention [1].

Plasma osmolality increases by 1 mosmol/L for each 18 mg/dL increase in plasma glucose concentration. Thus, a rise in glucose concentration from 110 to 200 mg/dL (6.1 to 11.1 mmol/L) only increases osmolality by 5 mosmol/L, which is a relatively small change. More marked hyperglycemia is required to produce the osmotic diuresis and hyperosmolality that may be clinically important. Most neonatologists become concerned about hyperglycemia when the blood glucose concentration exceeds approximately 180 to 200 mg/dL (10 to 11.1 mmol/L).

Glucosuria — Glucose excretion in the urine in hyperglycemic neonates is determined by the degree of hyperglycemia and renal tubular reabsorptive capacity for glucose. Newborns have variable reabsorptive capacity for glucose, which may be particularly reduced in those who are ill or premature.

The net effect is that glucosuria alone is not a good marker for hyperglycemia since it can occur at normal blood glucose concentrations. In one study of sick preterm infants 25 to 33 weeks gestation, for example, fractional glucose excretion varied widely and glucosuria was often seen at normal blood glucose concentrations [2]. These variations presumably are related to immaturity of the proximal tubule.

On the other hand, mild hyperglycemia may be associated with little or no glucosuria in infants with mature proximal tubules. This was illustrated in a study of newborns who were given glucose infusions; at a mean blood glucose concentration of 197 mg/dL (11 mmol/L), there was little glucosuria and no significant osmotic diuresis [3].

PATHOGENESIS — Hyperglycemia typically occurs when a newborn cannot adapt to parenteral glucose infusion by decreasing endogenous glucose production or increasing peripheral glucose uptake [4]. This is usually related to an associated clinical condition.

Hyperglycemia is more common in preterm than in term infants, although the mechanism is uncertain. Glucose production rate and regulation are comparable in moderately preterm and term infants. In both [4]:

Hepatic glucose production is suppressed by infusion of glucose (with or without amino acids), hyperglycemia, and insulin.

Glucose production is not changed by intravenous lipid infusion.

Circulating insulin concentrations increase appropriately with hyperglycemia and increase hepatic and peripheral glucose uptake.

However, insulin responses may be inappropriate in extremely low birth weight (ELBW) infants. In one study, 23 of 56 ELBW infants became hyperglycemic during intravenous glucose infusions that were incrementally increased to a maximum rate of 12 mg/kg per minute between days two and six of age [5]. Baseline insulin levels were similar in hyperglycemic and euglycemic infants, but only 15 of 23 hyperglycemic infants had a normal insulin response.

The inappropriate insulin response in hyperglycemic ELBW infants may be related to defective islet beta cell processing of proinsulin. In a study comparing 15 hyperglycemic to 12 normoglycemic ELBW infants during the first week of life, proinsulin levels were significantly higher in the hyperglycemic ELBW infants, who also needed higher insulin levels to reach euglycemia compared to normoglycemic infants [6].

Suppression of hepatic glucose production in response to glucose infusion also varies in very immature infants and may be incomplete. In a series of 10 infants born at 25 to 30 weeks gestation, glucose production rates decreased from 4.3 to 1.4 mg/kg per minute as glucose infusion was increased from 1.7 to 6.5 mg/kg per minute [7]. Plasma concentrations of glucose and insulin also increased.

What remains unclear is why the same degree of glucose infusion produces variable elevations in blood glucose in newborns. A possible contributing factor is increased secretion of counterregulatory hormones associated with stress (particularly epinephrine and cortisol). (See "Physiologic response to hypoglycemia in normal subjects and patients with diabetes mellitus", section on 'Response to hypoglycemia in normal subjects'.)

The role of stress was demonstrated in a report of metabolic responses to glucose infusion in preterm infants (weight 700 to 1550 g) [8]. Measurements were made before and after infusion in controls and in infants who required assisted ventilation and were considered stressed. Stressed infants had higher levels of glucose and of cortisol compared with controls and were more likely to have hyperglycemia (13 of 18 versus 1 of 12 infants). This difference was not due to decreased insulin or increased cortisol levels, because, among the stressed infants, insulin levels were higher and cortisol levels lower in the hyperglycemic compared to euglycemic newborns.

CAUSES — In general, neonatal hyperglycemia is associated with a clinical condition, rather than a specific disorder of glucose metabolism, and occurs in infants receiving intravenous glucose infusions. A rare cause of hyperglycemia is neonatal diabetes mellitus.

High rates of glucose infusion — Administration of 10 percent dextrose solution to meet maintenance fluid requirements in the first few days after birth typically results in glucose infusion rates of approximately 5 to 8 mg/kg per minute. Rates that exceed 10 to 12 mg/kg per minute (in infants who do not have hyperinsulinemic hypoglycemia) may result in hyperglycemia, particularly in extremely low birth weight (ELBW) infants [5].

Prematurity — Hyperglycemia during glucose infusion is common in premature infants, especially very low birth weight (VLBW) infants (birth weights below 1500 g). In a prospective study of continuous glucose monitoring of 188 VLBW infants during the first week of life, 80 percent of patients had glucose levels greater than 8 mmol/L (144 mg/dL), and a third had glucose levels greater than 10 mmol/L (180 mg/dL) for more than 10 percent of the time [9]. Risk factors associated with hyperglycemia included increasing prematurity, small for gestational age, use of inotropic agents, lipid infusions, and sepsis. Other studies also demonstrate an increased risk of hyperglycemia with decreasing gestational age [10-12].

ELBW infants frequently develop hyperglycemia in the absence of high rates of glucose infusion [13]. Proposed underlying mechanisms include reduced insulin secretion, incomplete suppression of hepatic glucose production, and stress response resulting in counter hormone regulation.

Outcome — Several studies have found that hyperglycemia in extremely premature infants (gestational age less than 27 weeks) is associated with an increased risk of mortality [10,11,14]. However, one study from a single NICU reported that hyperglycemia (defined as a glucose level >150 mg/dL [8.3 mmol/L] on two separate occasions) was not associated with death. Differences in study results may be due to lack of consensus in defining hyperglycemia and the number of episodes and duration of hyperglycemia [15].

Two studies have also reported an association between hyperglycemia in the first few days of life and severe grade III and IV intraventricular hemorrhage in preterm infants [14,16].

Further research is needed to provide a better understanding of the consequences of hyperglycemia and determine which infants require therapy. (See 'Definition' above and 'Insulin therapy' below.)

Stress — The stress response to critical illness (epinephrine and cortisol) may result in hyperglycemia, especially in preterm infants who require mechanical ventilation. The stress response also may be responsible for hyperglycemia occurring after surgery. In this setting, increased rates of fluid administration may also contribute.

Sepsis — Hyperglycemia may be a presenting sign of sepsis in an infant with previously normal blood glucose concentrations and no change in glucose infusion rate. Potential mechanisms include the stress response, decreased insulin release, and reduced peripheral utilization of glucose [17].

Drugs — Administration of certain drugs can result in hyperglycemia. Hyperglycemia is a common complication of glucocorticoid therapy, especially in ELBW infants [18]. It also has been noted following phenytoin administration; the mechanism may be suppression of insulin release or insulin insensitivity [19].

Neonatal diabetes mellitus — Neonatal diabetes is a rare cause of hyperglycemia, with an estimated incidence of one in 500,000 births [20]. It is defined as persistent hyperglycemia occurring in the first months of life that lasts more than two weeks and requires insulin for management. The majority of infants are small for gestational age, which may be related to decreased insulin secretion in the fetus [4]. They present with weight loss, volume depletion, hyperglycemia, and glucosuria with or without ketonuria and ketoacidosis.

Neonatal diabetes is caused by mutations in a number of genes that encode proteins that play a critical role in the normal function of the pancreatic beta-cell such as proteins that are subunits in the ATP-sensitive potassium channel [21]. The course of neonatal diabetes is variable depending on the affected gene. Genetic mutations of the KIR6.2 subunit of the ATP-sensitive potassium channel can result in permanent neonatal diabetes mellitus, whereas mutations of the SUR1 subunit can result in either permanent or transient neonatal disease. In a series of 57 infants presenting before one month of age with hyperglycemia requiring insulin therapy for more than two weeks, the disorder was transient in 18, transient with recurrence between seven and 20 years of age in 13, and permanent in 26 [20].

Transient — Either paternal uniparental disomy of chromosome 6 or an unbalanced duplication of paternal chromosome 6 is present in the majority of cases of transient neonatal diabetes [22-26]. Mutations of the imprinting gene ZAC/PLAG1, a transcriptional regulator of the type 1 receptor for pituitary adenylate cyclase-activating polypeptide, (an important regulator of insulin secretion), at chromosome 6q24 has been shown to be the major cause of neonatal transient DM [23-26].

Activating mutations of the ABCC8 gene that encodes SUR1, the type 1 subunit of the sulfonylurea receptor, can cause either transient or permanent neonatal diabetes as discussed in the next section.

Permanent — About one-half of patients with neonatal diabetes mellitus have a permanent form that is primarily due to gene mutations related to the ATP-sensitive potassium channel. In rare cases, permanent neonatal diabetes mellitus is due to pancreatic agenesis or hypoplasia. In one case series of four patients with developmental failure of the pancreas, who were products of a consanguineous kinship, a specific gene defect was not identified [27].

Most patients with permanent neonatal diabetes mellitus have mutations that affect the ATP-sensitive potassium channel (KATP channel), which regulates the release of insulin from pancreatic beta cells. Activating mutations increase the number of open KATP channels at the plasma membrane, hyperpolarizing the beta cells, and preventing the release of insulin.

In contrast, inactivating mutations, described in children with persistent hyperinsulinemic hypoglycemia of infancy, reduce the number of open KATP channels, resulting in depolarization of the beta cells and persistent hypersecretion of insulin [28]. (See "Pathogenesis, clinical features, and diagnosis of persistent hyperinsulinemic hypoglycemia of infancy".)

The KATP channel is composed of a small subunit Kir6.2 that surrounds a central pore and four regulatory SUR1 subunits. Activating gene mutations that affect these subunits can prevent insulin release, resulting in hyperglycemia.

KCNJ11 gene encoding Kir6.2 – The most common cause of permanent neonatal diabetes is due to activating mutations in the KCNJ11 gene, which encodes Kir6.2 [29-31]. The diagnosis is made within the first two months of life [29]. Infants are small for gestational age but exhibit postnatal catch-up growth with insulin therapy [32]. Affected patients can also have neurologic abnormalities including severe developmental delay, epilepsy, muscle weakness, and dysmorphic features [29]. These findings are also known as the DEND syndrome (developmental delay, epilepsy, neonatal diabetes) [33].

Subcutaneous insulin was routinely used in the past to treat patients with this disorder. However, oral sulfonylurea therapy appears to be more effective in controlling hyperglycemia [34,35]. In a study of 49 patients with neonatal diabetes due to activating mutations of KCNJ11 gene, 44 were able to discontinue insulin therapy after starting oral sulfonylurea therapy [34]. In patients switched to sulfonylurea therapy, insulin secretion and glycated hemoglobin (8.1 to 6.4 percent) improved.

SUR1 – Activating mutations of the ABCC8 gene, which encodes SUR1 (the type 1 subunit of the sulfonylurea receptor), can cause both transient and permanent forms of neonatal diabetes. In a series of 73 patients with neonatal diabetes, nine had activating mutations of the ABCC8 gene [36]. Two had permanent diabetes and the others had transient diabetes. The patients were diagnosed at a median of 32 days (range 3 to 125 days). Oral sulfonylurea therapy normalized glycemic control in patients with genetic mutations of SUR1.

Neonatal diabetes mellitus has also been associated with mutations in other genes including RfX6, IPF-1, EIF2AK3, GCK, FOXP3, PTF1A, GLIS3, and the Ins2 genes [37-54]. In some cases, these mutations result in pancreatic agenesis or hypoplasia, or absent beta cells. As an example, patients with permanent neonatal diabetes mellitus due to Wolcott-Rallison syndrome (diabetes mellitus, exocrine pancreatic insufficiency, and multiple epiphyseal dysplasia) have been shown to have hypoplastic pancreatic islets and a mutation in the EIF2AK3 gene that encodes translation initiation factor 2-alpha kinase 3 [43,44]. FOXP3 mutations cause a rare, x-linked disorder that presents in infancy with autoimmune endocrinopathy, enteropathy, and eczema. (See "IPEX: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked".)

MANAGEMENT — Interventions to reduce the blood glucose concentration are initiated at values above 180 to 200 mg/dL (10 to 11.1 mmol/L). The first step in management is to decrease the glucose infusion rate. Reducing the rate to 4 to 6 mg/kg per minute usually lowers the blood glucose concentration. In most cases, this is accomplished by reducing the concentration of the dextrose solution from 10 to 5 percent. If provided with parenteral nutrition solution and lipid emulsion, infants can maintain normoglycemia with the reduced glucose supply by gluconeogenesis from glycerol and amino acids [55].

However, reducing the glucose infusion rate is a short-term solution because it results in decreased caloric intake and compromises growth. Glucose tolerance typically improves when enteral feedings are established. (See "Nutritional composition of human milk and preterm formula for the premature infant".)

Insulin therapy — Insulin improves glucose tolerance, allows provision of more calories, and promotes growth in infants who remain hyperglycemic at reduced glucose infusion rates. The exact indications for insulin therapy are not well defined. Most neonatologists would begin an insulin infusion in infants with persistent hyperglycemia (>200 to 250 mg/dL [11.1 to 13.9 mmol/L]) despite reductions in glucose infusion rate, and in infants who fail to thrive because of reduced caloric intake.

The efficacy of insulin therapy was illustrated by a study of 24 extremely low birth weight (ELBW) infants with glucose intolerance who were randomly assigned to receive standard intravenous therapy with glucose and total parenteral nutrition with or without a continuous insulin infusion [56]. Over a mean duration of 15 days, insulin therapy resulted in significantly higher glucose infusion rates (20.1 versus 13.2 mg/kg per min), greater nonprotein energy intake (124 versus 86 kcal/kg per day), and greater weight gain (20.1 versus 7.8 g/kg per day) compared to control. There were no differences between groups in hypoglycemia, electrolyte abnormalities, chronic lung disease, or mortality.

Benefit from insulin therapy was also demonstrated in a trial of 23 ELBW infants who became hyperglycemic while receiving glucose at a rate up to 12 mg/kg per min [5]. The infants were randomly assigned to reduced glucose intake or to insulin infusion. The duration of caloric intake less than 60 kcal/kg per day was significantly shorter with the insulin infusion (4.1 versus 8.6 days). There were no differences in morbidity or mortality between the two groups.

In infants receiving parenteral nutrition, improvement in glucose tolerance by continuous insulin infusion appears to be comparable with and without the addition of lipid emulsion [57].

Routine early insulin therapy — The routine use of early insulin therapy in premature infants has been proposed to prevent catabolism, improve glucose control, and increase energy intake, which might improve growth. However, early insulin therapy does not appear to improve growth and may be associated with an increased risk of mortality at 28 days of age and hypoglycemia.

This was illustrated in a multicenter, open-label trial of 389 very low birth weight (VLBW) infants (birth weights <1500 g) who were randomly selected to receive either standard care for glycemic control or a parenteral infusion of 20 percent dextrose with early insulin therapy (0.05 units/kg per hour) starting within 24 hours of birth until seven days of age [58]. The following findings were noted:

The early insulin group had lower mean glucose levels compared to the standard care group (112 vs 121 mg/dL [6.2 vs 6.7 mmol/L]), were less likely to be hyperglycemic (defined as serum glucose greater than 180 mg/dL [10 mmol/L]) for more than 10 percent of the first week of life (21 versus 33 percent), were able to receive greater amounts of glucose infusion (51 versus 43 kcal/kg per day), and had less weight loss during the first week of life.

More patients who received early insulin had episodes of hypoglycemia (29 versus 17 percent), which was defined as serum glucose levels less than 47 mg/dL (2.6 mmol/L) for more than one hour.

There were no differences between the groups in the primary end point of mortality at the expected date of delivery or in the secondary end points of sepsis, necrotizing enterocolitis, retinopathy of prematurity, and growth parameters (ie, weight, length, and head circumference) at 28 days of age. However, the early insulin group had a higher mortality rate at 28 days of life.

This trial was ended early because of concerns of futility with regard to outcomes and concern for potential harm from insulin therapy. Follow-up is ongoing to determine whether the increased incidence of hypoglycemia in the early insulin group had a detrimental effect on neurodevelopmental outcomes. (See "Neonatal hypoglycemia", section on 'Neurodevelopmental outcome'.)

Based upon these data, routine insulin therapy should NOT be used in VLBW infants. Insulin should, however, be used to treat hyperglycemia when reducing the glucose infusion rate to approximately 6 mg/kg per minute is ineffective or not possible.

Amino acid infusion — Insulin infusion during euglycemia reduces proteolysis and protein synthesis in preterm infants who are not also given amino acids. In a report of four ELBW infants at two to five days of age, whole body proteolysis and protein synthesis decreased by 20 percent during a continuous infusion of insulin (0.05 units/kg per hour) and glucose (without amino acids) [59]. Glucose utilization doubled (8 to 16.7 mg/kg per min) but there was no net anabolic effect. In addition, plasma lactate concentration tripled (2.1 to 5.7 mmol/L), possibly because the high rate of glucose infusion exceeded the maximal capacity for glucose oxidation. Whether administration of amino acids during insulin infusion would further reduce proteolysis or increase protein synthesis and improve protein balance is uncertain.

Based upon the limited current data, we suggest amino acid solution and lipid emulsion also should be administered to infants receiving glucose infusion to provide substrate for gluconeogenesis, spare glucose utilization, and stimulate insulin release.

Risk of hypoglycemia — The blood glucose concentration should be monitored frequently during insulin infusion, although the risk of hypoglycemia appears to be small. This was documented in a retrospective review of 34 ELBW infants who developed hyperglycemia and glucosuria while receiving parenteral nutrition and were treated with insulin [60]. Before therapy, mean blood glucose concentration was 195 mg/dL (11.1 mmol/L) while receiving glucose at a mean rate of 7.9 mg/kg per min. During insulin infusion, given for 1 to 58 days, blood glucose values of 25 to 40 mg/dL (1.4 to 2.2 mmol/L) were detected in fewer than 0.5 percent of samples (26 episodes of hypoglycemia in 7368 samples) and no values <25 mg/dL were seen.

Similar findings were noted in another study of 10 ELBW infants treated with insulin [61]. Glucose measurements were normal (46 to 130 mg/dL [2.6 to 7.2 mmol/L]) in 78 percent of samples and less than 24 mg/dL (1.3 mmol/L) in less than 1 percent [61]. (See "Neonatal hypoglycemia".)

Dose and target glucose levels — Regular insulin (100 units/mL) is usually diluted in normal saline to a concentration of 0.1 units/mL. In some centers, concentration of 0.5 units/mL is used.

The initial step in management of a persistently elevated glucose level is administering a bolus insulin infusion via a syringe pump over 15 minutes at a dose between 0.05 and 0.1 units/kg. The blood glucose level is monitored every 30 to 60 minutes, and if it remains elevated, the insulin dose is repeated as a bolus every four to six hours. If the glucose level remains elevated after three bolus doses, a continuous infusion is considered at an initial rate of between 0.01 and 0.05 units/kg per hour and is adjusted in small increments up to a maximum rate 0.1 units/kg per hour to maintain glucose levels of 150 to 200 mg/dL (8.3 to 11 mmol/L). Tighter glycemic control aiming for glucose values substantially below 150 mg/dL (8.3 mmol/L) increases the risk of hypoglycemia [62].

As glucose tolerance improves, the insulin infusion should be tapered and discontinued to avoid hypoglycemia. In general, reductions in the insulin infusion rate can be made more rapidly than can increases.

Adherence of insulin to plastic tubing — Plastic tubing used for infusion should be primed with insulin for at least 20 minutes before treatment because insulin nonspecifically binds to the tubing, resulting in decreased availability to the patient. In one report, recovery of insulin from effluent of primed polyvinyl chloride tubing at a flow rate of 0.2 mL/h was greater at one, two, four, and eight hours (42, 85, 91, and 95 versus 22, 38, 67, and 75 percent, respectively) compared to unprimed tubing [63].

Monitoring — The blood glucose concentration should be monitored within 30 minutes to one hour of the start of the infusion and after any change in the rate of glucose or insulin infusion. Glucose concentration should be monitored hourly until stable, and then less frequently.

Our approach — Blood glucose concentration should be monitored in all infants receiving intravenous glucose infusions. For most infants, daily monitoring is recommended until blood glucose concentration is stable. For ELBW, for stressed or septic infants, or for those receiving insulin infusion, more frequent monitoring is needed.

In infants with blood glucose concentration greater than 180 to 200 mg/dL (10 to 11.1 mmol/L), the glucose infusion rate should be decreased; this should be done by decreasing the concentration of infused glucose, as long as it does not go below 5 percent.

Insulin therapy should be considered in neonates with persistent hyperglycemia (blood glucose >200 to 250 mg/dL [11.1 to 13.9 mmol/L]) despite reductions in glucose infusion rate, and in infants who fail to thrive because of reduced caloric intake. Therapy is initially administered as a bolus of insulin administered via a syringe pump over 15 minutes as a dose between 0.05 and 0.1 units/kg.

Continuous
insulin infusion should be considered in infants with persistent hyperglycemia (blood glucose >200 to 250 mg/dL [11.1 to 13.9 mmol/L]) despite reductions in glucose infusion rate and after administering three insulin boluses. Infusion begins at a rate between 0.01 to 0.05 units/kg per hour and is adjusted in small increments up to a maximum rate of 0.1 units/kg per hour to maintain blood glucose levels between 150 to 200 mg/dL. (See 'Insulin therapy' above.)

Enteral feedings should be initiated as soon as possible in order to wean and discontinue parenteral nutrition.

SUMMARY AND RECOMMENDATIONS — Increased blood glucose levels (>125 mg/dL [6.9 mmol/L) are often seen in neonates, especially in preterm infants who receive glucose infusions as parenteral nutrition. With marked hyperglycemia defined as glucose concentration exceeding 180 mg/dL (10 mmol/L), there is a marked increase in plasma osmolality resulting in osmotic diuresis and potential cellular injury due to significant fluid shifts. (See "Parenteral nutrition in premature infants", section on 'Glucose'.)

Although the mechanisms are uncertain, it is speculated that the increased risk of hyperglycemia in preterm infants compared with term infants is due to poorer insulin response, incomplete suppression of hepatic glucose production, and increased secretions of counterregulatory hormones associated with stress. (See 'Pathogenesis' above.)

In general, neonatal hyperglycemia is caused by the administration of parenteral glucose, especially in very low birth weight infants (birth weight below 1500 g). Other contributing conditions include stress response to critical illness, sepsis, and drugs associated with hyperglycemia, such as phenytoin and glucocorticoids. Rarely is neonatal hyperglycemia due to neonatal diabetes mellitus, which is caused by mutations in genes that encode for proteins that are involved with insulin release from the pancreatic beta-cell. (See 'Causes' above.)

Blood glucose concentration should be monitored in all infants receiving intravenous glucose infusions. For most infants, daily monitoring is recommended until blood glucose concentration is stable. More frequent monitoring is recommended for extremely low birth weight infants (birth weight <1000 g), stressed, or septic infants, or those receiving insulin infusion. (See 'Management' above.)

In our practice, we use the following stepwise management approach for neonates whose blood glucose exceeds 180 to 200 mg/dL (10 to 11.1 mmol/L). (See 'Our approach' above.)

In neonates receiving parenteral glucose infusion, the glucose infusion rate should be reduced by decreasing the concentration of infused glucose, as long as it does not go below 5 percent.

Insulin therapy should be considered in neonates with persistent hyperglycemia (blood glucose >200 to 250 mg/dL [11.1 to 13.9 mmol/L]) despite reductions in glucose infusion rate and in infants who fail to thrive because of reduced caloric intake. Therapy is initially administered as a bolus of insulin administered via a syringe pump over 15 minutes as a dose between 0.05 and 0.1 unit/kg.

Continuous insulin infusion should be considered in infants with persistent hyperglycemia (blood glucose >200 to 250 mg/dL [11.1 to 13.9 mmol/L]) despite reductions in glucose infusion rate and administration of three insulin boluses. Infusion begins at a rate between 0.01 and 0.05 unit/kg per hour and is adjusted in small increments up to a maximum rate of 0.1 units/kg per hour to maintain blood glucose level between 150 and 200 mg/dL (8.3 to 11.1 mmol/L).

Initiate enteral feeds as soon as possible.

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