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Neonatal hyperglycemia
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Neonatal hyperglycemia
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2016. | This topic last updated: Oct 20, 2016.

INTRODUCTION — Glucose supply and metabolism are of central importance for growth and normal brain development in the fetus and newborn. Disorders in glucose availability or utilization can result in hypoglycemia or hyperglycemia.

The causes and management of neonatal hyperglycemia are reviewed here. Neonatal hypoglycemia is discussed separately. (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia".)


Hyperglycemia — 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). However, these levels are frequently observed during glucose infusions in newborns, especially in extremely preterm infants, and may not require intervention [1].

Most neonatologists become concerned about hyperglycemia when plasma glucose concentration (the standard laboratory test) exceeds 180 to 200 mg/dL (10 to 11.1 mmol/L). However, higher levels of hyperglycemia are required to produce the hyperosmolality and osmotic diuresis that may be clinically important. 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.

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 capacities for glucose, which may be particularly reduced in those who are ill or preterm.

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 born at 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 such as extreme prematurity or sepsis.

In both term and preterm infants, the following observations of glucose metabolism are seen [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 (IV) lipid infusion.

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

However, hyperglycemia is more common in preterm infants compared with term infants. Although the mechanism(s) for the increased risk of hyperglycemia in preterm infants is uncertain, the following may be contributory factors:

Poor insulin response – Insulin responses may be inappropriate in extremely low birth weight (ELBW) infants. In one study, 23 of 56 ELBW infants became hyperglycemic during IV 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 with normoglycemic infants [6].

Incomplete suppression of glucose production – 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.

Proteolysis due to negative nitrogen balance, which occurs more commonly in the preterm infant, may also be a stimulus for inappropriate glucose production. For example, in ELBW infants, insufficient protein intake results in endogenous protein loss (proteolysis) in an effort to meet the basal metabolic needs of the infant.

Increased secretion of counterregulatory hormones associated with stress – Secretion of epinephrine and cortisol in stressed infants may contribute to hyperglycemia. 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 with the euglycemic newborns. (See "Physiologic response to hypoglycemia in normal subjects and patients with diabetes mellitus", section on 'Counterregulatory hormones'.)

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 (IV; parenteral) glucose infusions. A rare cause of hyperglycemia is neonatal diabetes mellitus.

Parenteral administration of glucose — Parenteral glucose is administered to most preterm or ill neonates because adequate enteral feeding is delayed. Neonatal hyperglycemia often occurs in this setting because glucose metabolism and needs change, requiring readjustment of glucose infusion rates. In neonates receiving parenteral administration of glucose, sepsis, prematurity, and stress are all factors that affect glucose metabolism and increase the risk of hyperglycemia.

Immediately after birth, glucose is typically provided at a rate of 5 to 8 mg/kg per minute to avoid hypoglycemia. In most settings, sufficient glucose at a rate of 7 mg/kg per minute is provided by the administration of 10 percent dextrose solution at 100 mL/kg per day. 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 [5]. (See "Parenteral nutrition in premature infants", section on 'Glucose'.)

Prematurity — Hyperglycemia during glucose infusion is common in preterm infants, especially very low birth weight (VLBW) infants (BW <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 one-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 (GA) [10-12].

Extremely low birth weight (ELBW) infants (BW <1000 g) 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. (See 'Pathogenesis' above.)

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 [14]. In the VLBW preterm infant, fungal rather than bacterial sepsis appears to be more commonly associated with hyperglycemia. This was illustrated in a study of preterm infants with BWs less than 1250 g that reported 21 of the 45 infants with fungal infection developed hyperglycemia compared with 11 of 46 infants with late-onset sepsis [15].

Stress — The stress response to critical illness with the release of counter regulatory hormones (eg, epinephrine and cortisol) may result in hyperglycemia, especially in preterm infants who require mechanical ventilation. There is limited evidence that increased severity of respiratory distress and metabolic acidosis requiring medical intervention (eg, administration of bicarbonate) is linked to an increased risk of hyperglycemia [1]. The stress response also may be responsible for hyperglycemia occurring after surgery. In this setting, increased rates of fluid administration containing dextrose may also be a contributory factor.

Drugs — Hyperglycemia is a common complication of glucocorticoid therapy, especially in ELBW infants [16]. Hyperglycemia can also occur following administration of methylxanthines [17] and phenytoin (the mechanism may be suppression of insulin release or insulin insensitivity) [18].

Neonatal diabetes mellitus — Neonatal diabetes is a rare cause of hyperglycemia, with an estimated incidence of 1 in 500,000 births [19]. 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 (SGA), 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 cells such as proteins that are subunits in the adenosine triphosphate (ATP)-sensitive potassium channel [20,21]. 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 7 and 20 years of age in 13, and permanent in 26 [22].

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 [23-27]. Mutations of the imprinting gene ZAC/PLAGL1, a transcriptional regulator of the type 1 receptor for pituitary adenylate cyclase-activating polypeptide (an important regulator of insulin secretion), at chromosome 6q24 have been shown to be the major cause of neonatal transient diabetes mellitus [24-27].

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 [28].

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 [29]. (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. Oral sulfonylurea is efficacious for patients with neonatal diabetes dues to mutations that affect the KATP channel and can be safely used before genetic testing results are available [30].

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 [31-33]. The diagnosis is made within the first two months of life [31]. Infants are SGA, but exhibit postnatal catch-up growth with insulin therapy [34]. Affected patients can also have neurologic abnormalities including severe developmental delay, epilepsy, muscle weakness, and dysmorphic features [31]. These findings are also known as the DEND syndrome (developmental delay, epilepsy, neonatal diabetes) [35].

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 [30,36,37]. In a study of 49 patients with neonatal diabetes due to activating mutations of the KCNJ11 gene, 44 were able to discontinue insulin therapy after starting oral sulfonylurea therapy [36]. In patients switched to sulfonylurea therapy, insulin secretion and glycated hemoglobin improved (8.1 to 6.4 percent).

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 [38]. 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 GATA6, RfX6, IPF-1, EIF2AK3, GCK, FOXP3, PTF1A, GLIS3, and the Ins2 genes [39-56]. 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 [45,46]. 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".)

Preterm infants — Neonatal diabetes due to a monogenic etiology may also present in preterm infants. In a large case series, 146 of 750 infants with diabetes diagnosed before six months of age were born preterm (gestational age <37 weeks) [57]. A genetic etiology was identified in 97/146 (66 percent) preterm infants compared with 501/604 (83 percent) term infants. Chromosome 6q24 imprinting abnormalities and GATA6 mutations were more frequent in patients born preterm compared to term infants, whereas KCNJ11 gene mutations were less common.


Reduction of glucose infusion rate — 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 parenteral 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 the metabolism of glycerol and amino acids [58].

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, including the authors, 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 decreased glucose administration resulting in 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 (IV) therapy with glucose and total parenteral nutrition with or without a continuous insulin infusion [59]. 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 with controls. There were no differences between groups in mortality or morbidity (eg, hypoglycemia, electrolyte abnormalities, or bronchopulmonary dysplasia).

Benefit from insulin therapy was also demonstrated in a trial of 23 ELBW infants who became hyperglycemic while receiving glucose at a rate of 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 in the group who received 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 [60].

Routine early insulin therapy — The routine use of early insulin therapy in preterm 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 of hypoglycemia.

This was illustrated in a multicenter, open-label trial of 389 very low birth weight (VLBW) infants (BW <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 [61]. The following findings were noted:

The early insulin group had lower mean glucose levels compared with the standard care group (112 versus 121 mg/dL [6.2 versus 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 "Management and outcome of 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.

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 [62]. 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 [63]. 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 [63]. (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia".)

Dose and target glucose levels — In neonates who receive insulin therapy, regular insulin (100 units/mL) is used and 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 of 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 [64].

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/hour was greater at one, two, four, and eight hours compared with unprimed tubing (42, 85, 91, and 95 versus 22, 38, 67, and 75 percent, respectively) [65].

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.

Amino acid infusion — Insulin infusion during euglycemia reduces proteolysis and protein synthesis in preterm infants who are not also given amino acids. This is in contrast to adults and children, in whom insulin increases protein synthesis.

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) [66]. 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.

Our approach — Blood glucose concentration should be monitored in all infants receiving intravenous glucose infusions. For infants with stable glucose concentration, daily monitoring is adequate. For ELBW, stressed, or septic infants who may not have a stable glucose concentration, or 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 decreased glucose infusion rates resulting in 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. (See 'Dose and target glucose levels' above.)

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 and 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 and 200 mg/dL. In the very preterm ill neonate, insulin may be given safely as long as the glucose concentration is monitored frequently because of the relatively wide heterogeneous response that occurs with IV administration. (See 'Insulin therapy' above.)

Enteral feedings should be initiated as soon as possible in order to wean and discontinue parenteral nutrition. An enhanced gastrointestinal incretin-mediated insulin release in response to orogastric administration of a glucose load may occur when a threshold of glucose concentration has exceeded 105 mg/dL.

OUTCOME — It is unclear if neonatal hyperglycemia is a clinically significant factor in neonatal outcome.

Several studies reported that hyperglycemia in extremely preterm infants (gestational age [GA] less than 27 weeks) was associated with an increased risk of mortality [10,11,67,68].

In addition, early hyperglycemia during the first few days of life was reported to be associated with severe grade III and IV intraventricular hemorrhage in preterm infants [67,69]. In extremely preterm survivors, hyperglycemia occurring on the first day of life was associated with white matter reduction detected by magnetic resonance imaging performed at term-equivalent age [10]. However, sepsis was a concomitant condition in a large percentage of these infants and it remains unclear whether hyperglycemia is a significant independent factor for mortality and major morbidity.

In contrast, two studies have not found an association between hyperglycemia and mortality or major morbidity.

A study from a single United States neonatal intensive care unit (NICU) reported that hyperglycemia (defined as a glucose level >150 mg/dL [8.3 mmol/L] on two separate occasions) after adjusting for confounding factors was not associated with death, or an increased risk of bronchopulmonary dysplasia or intraventricular hemorrhage [12]. However, there was a statistical increase in retinopathy of prematurity.

A study of 260 Korean extremely low birth weight (ELBW) infants (BW <1000 g) showed that hyperglycemia up to 300 mg/dL without insulin treatment, during the first 14 days of life was not associated with osmotic diuresis or increased mortality or morbidity [70]. Differences in study results may be due to lack of consensus in defining hyperglycemia and the number of episodes and duration of hyperglycemia [71].

Of note, a large prospective study that focused on the outcome of infants at risk for hypoglycemia reported that rapid correction of hypoglycemia resulting in glucose concentrations greater than 72 mg/dL in the first 48 hours of life was associated with neurodevelopmental impairment [72]. This finding was unexpected and must be interpreted with caution, since the study was observational and unknown confounders cannot be excluded in such studies. (See "Management and outcome of neonatal hypoglycemia", section on 'Asymptomatic term or late preterm infants'.)

Further research is needed to provide a better understanding of the consequences of hyperglycemia and determine which infants require intervention.

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. (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 secretion 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 (VLBW) infants (BW <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 synthesis or release from the pancreatic beta cells. (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 (ELBW) infants (BW <1000 g), stressed or septic infants, or those receiving insulin infusion. (See 'Management' above.)

In our practice, we suggest using the following stepwise management approach for neonates whose blood glucose exceeds 180 to 200 mg/dL (10 to 11.1 mmol/L) (Grade 2C). (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 the dextrose concentration does not go below 5 percent. (See 'Reduction of glucose infusion rate' above.)

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. (See 'Routine early insulin therapy' above.)

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 levels between 150 and 200 mg/dL (8.3 to 11.1 mmol/L).

Initiate enteral feeds as soon as possible.

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

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  1. Louik C, Mitchell AA, Epstein MF, Shapiro S. Risk factors for neonatal hyperglycemia associated with 10% dextrose infusion. Am J Dis Child 1985; 139:783.
  2. Wilkins BH. Renal function in sick very low birthweight infants: 4. Glucose excretion. Arch Dis Child 1992; 67:1162.
  3. Cowett RM, Oh W, Schwartz R. Persistent glucose production during glucose infusion in the neonate. J Clin Invest 1983; 71:467.
  4. Kalhan SC, Devaskar SU. Disorders of carbohydrate metabolism. In: Neonatal-Perinatal Medicine: Diseases of the Fetus and Infant, 9th ed, Martin RJ, Fanaroff AA, Walsh MC (Eds), Elsevier Mosby, St. Louis 2011. Vol 2, p.1497.
  5. Meetze W, Bowsher R, Compton J, Moorehead H. Hyperglycemia in extremely- low-birth-weight infants. Biol Neonate 1998; 74:214.
  6. Mitanchez-Mokhtari D, Lahlou N, Kieffer F, et al. Both relative insulin resistance and defective islet beta-cell processing of proinsulin are responsible for transient hyperglycemia in extremely preterm infants. Pediatrics 2004; 113:537.
  7. Sunehag A, Gustafsson J, Ewald U. Very immature infants (< or = 30 Wk) respond to glucose infusion with incomplete suppression of glucose production. Pediatr Res 1994; 36:550.
  8. Lilien LD, Rosenfield RL, Baccaro MM, Pildes RS. Hyperglycemia in stressed small premature neonates. J Pediatr 1979; 94:454.
  9. Beardsall K, Vanhaesebrouck S, Ogilvy-Stuart AL, et al. Prevalence and determinants of hyperglycemia in very low birth weight infants: cohort analyses of the NIRTURE study. J Pediatr 2010; 157:715.
  10. Alexandrou G, Skiöld B, Karlén J, et al. Early hyperglycemia is a risk factor for death and white matter reduction in preterm infants. Pediatrics 2010; 125:e584.
  11. Kao LS, Morris BH, Lally KP, et al. Hyperglycemia and morbidity and mortality in extremely low birth weight infants. J Perinatol 2006; 26:730.
  12. Blanco CL, Baillargeon JG, Morrison RL, Gong AK. Hyperglycemia in extremely low birth weight infants in a predominantly Hispanic population and related morbidities. J Perinatol 2006; 26:737.
  13. Farrag HM, Cowett RM. Glucose homeostasis in the micropremie. Clin Perinatol 2000; 27:1.
  14. White RH, Frayn KN, Little RA, et al. Hormonal and metabolic responses to glucose infusion in sepsis studied by the hyperglycemic glucose clamp technique. JPEN J Parenter Enteral Nutr 1987; 11:345.
  15. Manzoni P, Castagnola E, Mostert M, et al. Hyperglycaemia as a possible marker of invasive fungal infection in preterm neonates. Acta Paediatr 2006; 95:486.
  16. Doyle LW, Ehrenkranz RA, Halliday HL. Early (< 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev 2014; :CD001146.
  17. Srinivasan G, Singh J, Cattamanchi G, et al. Plasma glucose changes in preterm infants during oral theophylline therapy. J Pediatr 1983; 103:473.
  18. al-Rubeaan K, Ryan EA. Phenytoin-induced insulin insensitivity. Diabet Med 1991; 8:968.
  19. Rubio-Cabezas O, Ellard S. Diabetes mellitus in neonates and infants: genetic heterogeneity, clinical approach to diagnosis, and therapeutic options. Horm Res Paediatr 2013; 80:137.
  20. Støy J, Steiner DF, Park SY, et al. Clinical and molecular genetics of neonatal diabetes due to mutations in the insulin gene. Rev Endocr Metab Disord 2010; 11:205.
  21. De Franco E, Flanagan SE, Houghton JA, et al. The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study. Lancet 2015; 386:957.
  22. von Mühlendahl KE, Herkenhoff H. Long-term course of neonatal diabetes. N Engl J Med 1995; 333:704.
  23. Hermann R, Laine AP, Johansson C, et al. Transient but not permanent neonatal diabetes mellitus is associated with paternal uniparental isodisomy of chromosome 6. Pediatrics 2000; 105:49.
  24. Shield JP. Neonatal diabetes: new insights into aetiology and implications. Horm Res 2000; 53 Suppl 1:7.
  25. Kamiya M, Judson H, Okazaki Y, et al. The cell cycle control gene ZAC/PLAGL1 is imprinted--a strong candidate gene for transient neonatal diabetes. Hum Mol Genet 2000; 9:453.
  26. Temple IK, Shield JP. Transient neonatal diabetes, a disorder of imprinting. J Med Genet 2002; 39:872.
  27. Mackay DJ, Callaway JL, Marks SM, et al. Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57. Nat Genet 2008; 40:949.
  28. Chen R, Hussain K, Al-Ali M, et al. Neonatal and late-onset diabetes mellitus caused by failure of pancreatic development: report of 4 more cases and a review of the literature. Pediatrics 2008; 121:e1541.
  29. Thomas P, Ye Y, Lightner E. Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy. Hum Mol Genet 1996; 5:1809.
  30. Carmody D, Bell CD, Hwang JL, et al. Sulfonylurea treatment before genetic testing in neonatal diabetes: pros and cons. J Clin Endocrinol Metab 2014; 99:E2709.
  31. Gloyn AL, Pearson ER, Antcliff JF, et al. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med 2004; 350:1838.
  32. Gloyn AL, Cummings EA, Edghill EL, et al. Permanent neonatal diabetes due to paternal germline mosaicism for an activating mutation of the KCNJ11 Gene encoding the Kir6.2 subunit of the beta-cell potassium adenosine triphosphate channel. J Clin Endocrinol Metab 2004; 89:3932.
  33. Vaxillaire M, Populaire C, Busiah K, et al. Kir6.2 mutations are a common cause of permanent neonatal diabetes in a large cohort of French patients. Diabetes 2004; 53:2719.
  34. Slingerland AS, Hattersley AT. Activating mutations in the gene encoding Kir6.2 alter fetal and postnatal growth and also cause neonatal diabetes. J Clin Endocrinol Metab 2006; 91:2782.
  35. Hattersley AT, Ashcroft FM. Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy. Diabetes 2005; 54:2503.
  36. Pearson ER, Flechtner I, Njølstad PR, et al. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med 2006; 355:467.
  37. Landau Z, Wainstein J, Hanukoglu A, et al. Sulfonylurea-responsive diabetes in childhood. J Pediatr 2007; 150:553.
  38. Babenko AP, Polak M, Cavé H, et al. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med 2006; 355:456.
  39. Smith SB, Qu HQ, Taleb N, et al. Rfx6 directs islet formation and insulin production in mice and humans. Nature 2010; 463:775.
  40. Scharfmann R, Polak M. Transcribing neonatal diabetes mellitus. N Engl J Med 2010; 362:1538.
  41. Stoffers DA, Zinkin NT, Stanojevic V, et al. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet 1997; 15:106.
  42. Dodge JA, Laurence KM. Congenital absence of islets of Langerhans. Arch Dis Child 1977; 52:411.
  43. Blum D, Dorchy H, Mouraux T, et al. Congenital absence of insulin cells in a neonate with diabetes mellitus and mutase-deficient methylmalonic acidaemia. Diabetologia 1993; 36:352.
  44. Winter WE, Maclaren NK, Riley WJ, et al. Congenital pancreatic hypoplasia: a syndrome of exocrine and endocrine pancreatic insufficiency. J Pediatr 1986; 109:465.
  45. Baumeister FA, Engelsberger I, Schulze A. Pancreatic agenesis as cause for neonatal diabetes mellitus. Klin Padiatr 2005; 217:76.
  46. Delépine M, Nicolino M, Barrett T, et al. EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nat Genet 2000; 25:406.
  47. Thornton CM, Carson DJ, Stewart FJ. Autopsy findings in the Wolcott-Rallison syndrome. Pediatr Pathol Lab Med 1997; 17:487.
  48. Stoffers DA, Stanojevic V, Habener JF. Insulin promoter factor-1 gene mutation linked to early-onset type 2 diabetes mellitus directs expression of a dominant negative isoprotein. J Clin Invest 1998; 102:232.
  49. Bennett CL, Christie J, Ramsdell F, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 2001; 27:20.
  50. Sellick GS, Barker KT, Stolte-Dijkstra I, et al. Mutations in PTF1A cause pancreatic and cerebellar agenesis. Nat Genet 2004; 36:1301.
  51. Senée V, Chelala C, Duchatelet S, et al. Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism. Nat Genet 2006; 38:682.
  52. Senée V, Vattem KM, Delépine M, et al. Wolcott-Rallison Syndrome: clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity. Diabetes 2004; 53:1876.
  53. Njølstad PR, Søvik O, Cuesta-Muñoz A, et al. Neonatal diabetes mellitus due to complete glucokinase deficiency. N Engl J Med 2001; 344:1588.
  54. Colombo C, Porzio O, Liu M, et al. Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus. J Clin Invest 2008; 118:2148.
  55. Støy J, Edghill EL, Flanagan SE, et al. Insulin gene mutations as a cause of permanent neonatal diabetes. Proc Natl Acad Sci U S A 2007; 104:15040.
  56. Edghill EL, Flanagan SE, Patch AM, et al. Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood. Diabetes 2008; 57:1034.
  57. Besser RE, Flanagan SE, Mackay DG, et al. Prematurity and Genetic Testing for Neonatal Diabetes. Pediatrics 2016; 138.
  58. Sunehag AL, Haymond MW, Schanler RJ, et al. Gluconeogenesis in very low birth weight infants receiving total parenteral nutrition. Diabetes 1999; 48:791.
  59. Collins JW Jr, Hoppe M, Brown K, et al. A controlled trial of insulin infusion and parenteral nutrition in extremely low birth weight infants with glucose intolerance. J Pediatr 1991; 118:921.
  60. Kanarek KS, Santeiro ML, Malone JI. Continuous infusion of insulin in hyperglycemic low-birth weight infants receiving parenteral nutrition with and without lipid emulsion. JPEN J Parenter Enteral Nutr 1991; 15:417.
  61. Beardsall K, Vanhaesebrouck S, Ogilvy-Stuart AL, et al. Early insulin therapy in very-low-birth-weight infants. N Engl J Med 2008; 359:1873.
  62. Binder ND, Raschko PK, Benda GI, Reynolds JW. Insulin infusion with parenteral nutrition in extremely low birth weight infants with hyperglycemia. J Pediatr 1989; 114:273.
  63. Vaucher YE, Walson PD, Morrow G 3rd. Continuous insulin infusion in hyperglycemic, very low birth weight infants. J Pediatr Gastroenterol Nutr 1982; 1:211.
  64. Alsweiler JM, Harding JE, Bloomfield FH. Tight glycemic control with insulin in hyperglycemic preterm babies: a randomized controlled trial. Pediatrics 2012; 129:639.
  65. Fuloria M, Friedberg MA, DuRant RH, Aschner JL. Effect of flow rate and insulin priming on the recovery of insulin from microbore infusion tubing. Pediatrics 1998; 102:1401.
  66. Poindexter BB, Karn CA, Denne SC. Exogenous insulin reduces proteolysis and protein synthesis in extremely low birth weight infants. J Pediatr 1998; 132:948.
  67. Hays SP, Smith EO, Sunehag AL. Hyperglycemia is a risk factor for early death and morbidity in extremely low birth-weight infants. Pediatrics 2006; 118:1811.
  68. Stensvold HJ, Strommen K, Lang AM, et al. Early Enhanced Parenteral Nutrition, Hyperglycemia, and Death Among Extremely Low-Birth-Weight Infants. JAMA Pediatr 2015; 169:1003.
  69. Auerbach A, Eventov-Friedman S, Arad I, et al. Long duration of hyperglycemia in the first 96 hours of life is associated with severe intraventricular hemorrhage in preterm infants. J Pediatr 2013; 163:388.
  70. Yoo HS, Ahn SY, Lee MS, et al. Permissive hyperglycemia in extremely low birth weight infants. J Korean Med Sci 2013; 28:450.
  71. Soghier LM, Brion LP. Multivariate analysis of hyperglycemia in extremely low birth weight infants. J Perinatol 2006; 26:723.
  72. McKinlay CJ, Alsweiler JM, Ansell JM, et al. Neonatal Glycemia and Neurodevelopmental Outcomes at 2 Years. N Engl J Med 2015; 373:1507.
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