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Official reprint from UpToDatewww.uptodate.com ©2015 UpToDate

Author 

Paul J Rozance, MD

Section Editors

Joseph A Garcia-Prats, MD

Joseph I Wolfsdorf, MB,

BCh

Deputy Editor 

Melanie S Kim, MD

Management and outcome of neonatal hypoglycemia

 All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Aug 2015. | This topic last updated: Aug 04, 2015.

INTRODUCTION — During the normal transition to extrauterine life, blood glucose concentration in the healthy

term newborn falls during the first two hours after delivery, reaching a nadir that usually is no lower than 40 mg/dL. It

is important to differentiate this normal physiologic transitional response from disorders that result in persistent or 

recurrent hypoglycemia, which if left untreated may lead to significant neurologic and developmental sequelae.

This topic will discuss the outcome and management of neonatal hypoglycemia, including evaluation of persistent

hypoglycemia. The physiology of normal transient neonatal low blood glucose levels, causes of persistent or 

pathologic neonatal hypoglycemia, and the clinical manifestations and diagnosis of neonatal hypoglycemia are

discussed separately. (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia".)

GOALS AND CHALLENGES — The goals of managing neonatal hypoglycemia are:

The long-term goal is to prevent neurologic sequelae of neonatal hypoglycemia. However, a specific blood glucoseconcentration and/or duration of hypoglycemia have not been established that accurately predict poor 

neurodevelopmental outcome. As a result, significant neonatal hypoglycemia requiring intervention cannot be

defined by a precise numerical blood glucose concentration and there are no data that have demonstrated that any

management strategy is superior in reducing long-term neurologic adverse outcome. (See "Pathogenesis,

screening, and diagnosis of neonatal hypoglycemia", section on 'Challenge of defining neonatal hypoglycemia'.)

Nevertheless, clinical guidelines have been developed by the American Academy of Pediatrics (AAP) and the

Pediatric Endocrine Society (PES) because of the observed association between symptomatic neonatal

hypoglycemia and neurodevelopmental impairment [1,2] (see 'Neurodevelopmental outcome' below). The goals of 

these recommendations from the AAP and PES are to reduce neurologic impairment due to neonatal

hypoglycemia, but also to minimize overtreatment of neonates with normal transitional low glucose concentrations,which resolve without intervention and are not associated with any long-term sequelae. In addition, the PES

guidelines provide guidance on how and when to identify infants with a serious underlying persistent hypoglycemic

disorder.

Target blood glucose levels — The threshold goals for intervention that we use at our center are consistent with

the guidelines developed by the AAP and the PES, which are based on limited available data [1,2]. The following

target plasma glucose levels are used to provide a margin of safety for infants who are at risk for neonatal

hypoglycemia (see "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia", section on 'Who should be

evaluated?'). They are dependent on the presence or absence of symptoms, age of the infant to reflect the normal

physiologic increase of low blood glucose levels after delivery, and whether or not there is a genetic underlying

®

®

To correct blood glucose levels in symptomatic patients (see "Pathogenesis, screening, and diagnosis of 

neonatal hypoglycemia", section on 'Clinical manifestations')

●

To prevent symptomatic hypoglycemia in at-risk patients●

To avoid unnecessary treatment of infants with transitional low blood glucose, which will self-resolve without

intervention

●

To identify newborns with a serious underlying hypoglycemia disorder ●

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etiology.

MANAGEMENT APPROACH — The treatment of hypoglycemia is a stepwise process depending on the presence

or absence of symptoms and signs, and the response of the infant at each step. The following approach is

consistent with guidelines published by the American Academy of Pediatrics (AAP) and the Pediatric Endocrine

Society (PES) [1,2,5].

Symptomatic patients — Outcome data have shown that symptomatic neonatal hypoglycemia may result in brain

injury (see 'Neurodevelopmental outcome' below). As a result, aggressive therapy that includes the use of parenteralglucose (dextrose) is used to increase blood glucose levels in symptomatic patients [ 1,2].

Therapy should be initiated while awaiting laboratory confirmation of low blood glucose levels. Although most

symptomatic patients will have plasma glucose levels less than 25 mg/dL (2.2 mmol/L), there is great variability in

the clinical response in neonates to low blood glucose concentrations [6]; some newborns become symptomatic at

the same or even higher blood glucose concentrations than those observed in asymptomatic infants. As a result,

there is not a precise numerical blood glucose level that accurately predicts when and if a neonate will present with

symptoms. (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia", section on 'Challenge of 

defining neonatal hypoglycemia'.)

Parenteral glucose (dextrose) infusion — For symptomatic patients, an intravenous (IV) bolus of dextrose,

the D-isomer of glucose (200 mg/kg), is given over 5 minutes (2 mL/kg of 10 percent dextrose in water [D ]). This

is followed by the continuous administration of parenteral dextrose infusion at a rate of 6 to 8 mg/kg of dextrose per 

minute. If hypoglycemia is persistent, infusion rates should be increased as needed to restore and maintain

normoglycemia (see 'Target blood glucose levels' above). The maximum rate of glucose infusion for treatment is

limited by the maximum amount of fluids that can be administered to a patient (this is variable for each patient, but

we have used rates as high as 200 mL/kg per day while monitoring for evidence of hyponatremia and fluid overload)

and the maximum concentration of dextrose for the type of vascular access (see 'Target blood glucose levels'

above). In general, if the glucose infusion rate approaches 12 mg/kg per minute, other interventions should be

considered.

Symptomatic patients (eg, jitteriness/tremors, hypotonia, changes in level of consciousness,

apnea/bradycardia, cyanosis, tachypnea, poor suck or feeding, hypothermia, and/or seizures) (see

"Pathogenesis, screening, and diagnosis of neonatal hypoglycemia", section on 'Clinical manifestations'):

●

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

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

 Asymptomatic patients at risk for hypoglycemia (eg, preterm infant or an infant with fetal growth restriction)(see "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia", section on 'Who should be

evaluated?') or in patients in whom a low glucose concentration was identified as an incidental laboratory

finding:

●

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

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

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

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

In newborns with a suspected or confirmed genetic hypoglycemia disorder (such as a family history of a

hypoglycemia disorder or physical exam features consistent with Beckwith-Wiedemann syndrome), the goal

is to maintain plasma glucose concentrations >70 mg/dL (3.9 mmol/L). This treatment goal is higher because

the risks of harm from repetitive low glucose concentrations in this population are significant [3,4]. In addition,

consultation with a specialist should be considered for further diagnostic testing to diagnose the underlying

disorder [2].

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In addition, parenteral administration is used for asymptomatic infants with severe hypoglycemia (plasma glucose

less than 25 mg/dL [1.4 mmol/L]), especially after 4 hours of age, who are unable to be fed enterally or who

experience persistent hypoglycemia despite oral feedings. (See 'Asymptomatic term or late preterm infants' below.)

The maximum dextrose concentrations for fluid administered through a peripheral IV catheter or a low lying

umbilical venous catheter is 12.5 percent, and through a central venous catheter (including a centrally positioned

umbilical venous catheter) is 25 percent. If no IV access has been established, dextrose at a concentration of 12.5

percent or less can be infused through an umbilical arterial catheter. In severe cases, rates of fluid administration

required to deliver sufficient glucose to treat hypoglycemia may be greater than the rate of maintenance fluids. In

these cases, the patient's fluid and clinical status should be monitored closely for volume overload, looking for 

evidence of pulmonary edema, heart failure, and hyponatremia. Infants who depend upon high infusion rates or a

dextrose concentration greater than 12.5 percent require placement of a central venous catheter. In some cases

diuretics may be indicated.

Plasma glucose concentration should be determined 20 minutes after the bolus infusion, and the infusion rate or 

dextrose concentration adjusted as needed to maintain plasma glucose concentration >50 mg/dL (2.8 mmol/L) in

the first 48 hours of life and >60 mg/dL (3.3 mmol/L) after 48 hours of age [2]. (See 'Target blood glucose levels'

above.)

Glucagon — Administration of glucagon should be considered in the rare patients with persistent plasma

glucose <50 mg/dL (2.8 mmol/L) despite continuous maximum parenteral dextrose infusion. Glucagon can be givenintravenously or subcutaneously to symptomatic infants without IV access.

 Although a wide range of glucagon doses (20 to 200 mcg/kg, maximum dose of 1 mg) have been described in

treating neonates and infants with acute severe hypoglycemia [7-10], we suggest that glucagon be administered at

an initial dose of 20 to 30 mcg/kg to infants with persistent hypoglycemia despite parenteral glucose infusion [9].

Glucagon is typically given as a temporizing measure administered as a slow IV push over one minute, or by

intramuscular or subcutaneous injection. A rise in plasma glucose of approximately 30 to 50 mg/dL should occur 

within 15 to 30 minutes of administration and should last approximately two hours, though a more rapid decrease in

the glucose concentration may occur. Due to the short duration of action of glucagon, glucose concentrations

should be checked frequently and repeat doses of glucagon administered as needed. If the plasma glucose does

not rise within 20 minutes of glucagon administration, then a repeat dose of glucagon is given. A failure to respond

to glucagon raises the possibility of a glycogen storage disorder or defect in glycogen synthesis. In these patients,

further evaluation is warranted. (See 'Persistent hypoglycemia' below and "Overview of inherited disorders of glucose

and glycogen metabolism".)

One case series of newborns (n = 55) used a continuous IV infusion of 1 mg glucagon total for 24 hours (average

dose 10 to 20 mcg/kg per hour) [9]. This was effective in the treatment of persistent significant hypoglycemia. In

this cohort, cared for at a tertiary Canadian center, causes of hypoglycemia included asphyxia, fetal (intrauterine)

growth restriction, prematurity, and neonatal hyperinsulinism due to maternal diabetes (ie, infant of a diabetic

mother). Further confirmation is needed before continuous infusion of glucagon can be recommended for routine

use. However, continuous infusion may be a reasonable option if repetitive dosing of glucagon were being used to

maintain glucose.

Other therapeutic options

Glucocorticoids — Administration of glucocorticoid therapy (hydrocortisone 2 to 6 mg/kg per day divided in

2 to 3 doses orally or intravenously) in infants requiring a glucose infusion rate of 12 mg/kg per minute or greater 

has been used. However, due to the potential side effects of steroid administration, its use should be restricted to a

short course (1 to 2 days), unless a patient has documented adrenal insufficiency, in which case lifelong

glucocorticoid replacement will be necessary. The proposed mechanism of action of glucocorticoids is stimulation

of gluconeogenesis and reduction in peripheral glucose utilization. Serum cortisol and insulin concentrations during

an episode of hypoglycemia should be measured before beginning glucocorticoid treatment.

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Persistent hyperinsulinemic hypoglycemia — Other therapeutic options for persistent hyperinsulinemic

hypoglycemia, which is not responsive to parenteral dextrose infusion and glucagon therapy, include drug therapy

(eg, diazoxide and somatostatin), and pancreatectomy in patients with hyperinsulinemia unresponsive to medical

management. (See "Treatment and complications of persistent hyperinsulinemic hypoglycemia of infancy", section

on 'Diazoxide' and "Treatment and complications of persistent hyperinsulinemic hypoglycemia of infancy", section

on 'Somatostatin analogues' and "Treatment and complications of persistent hyperinsulinemic hypoglycemia of 

infancy", section on 'Surgical therapy'.)

Transition to oral feeds — When the glucose concentration is stabilized and maintained at or above the

threshold value, the glucose infusion rate can be tapered slowly as feedings are advanced. The taper typically

occurs over a period of two to four days. While the IV glucose infusion is tapered, the preprandial blood glucose

level should be monitored every three to four hours depending upon the feeding schedule. Blood glucose levels

should be maintained at the target thresholds as discussed above. (See 'Target blood glucose levels' above.)

Need for further evaluation — For infants with severe hypoglycemia that require prolonged and/or high rates

of IV dextrose infusion to maintain glucose threshold levels, further laboratory evaluation is warranted, especially if 

no underlying cause has been identified by either history or physical examination. In these uncommon situations,

consultation with a pediatric endocrinologist or a clinician with expertise in managing neonatal hypoglycemia is

recommended. (See 'Laboratory testing' below.)

Asymptomatic term or late preterm infants — Asymptomatic patients are typically identified because they areat risk for hypoglycemia. The management of these patients is focused on normalizing their blood glucose levels

and preventing them from becoming symptomatic. The first intervention for these patients is usually oral feeding.

(See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia", section on 'Who should be evaluated?'.)

Oral feeds — Healthy infants are fed as soon as possible after birth. Infants who are at risk for hypoglycemia

should be fed within the first hour of life [1]. Blood glucose concentrations should be measured frequently starting

20 to 30 minutes after the initial and subsequent feedings. Feedings should be offered at two- to three-hour intervals

and the newborn monitored for symptoms consistent with hypoglycemia.

 Although, as noted above, there is not a precise numerical blood glucose level that accurately predicts when and if 

a neonate will present with symptoms, guidelines from the AAP and the PES recommend that additional oral

feeding should be given as quickly as possible for the following patients, based on the age of the neonate and

plasma glucose level.

The following is our management approach regarding when an additional oral feeding is given and the need for 

further intervention based on the infant's response, which is consistent with these guidelines. Additional feeds are

given to:

While breast milk is strongly preferred, formula feeding may be provided for infants when breast milk is not

Infants less than 4 hours of age with plasma glucose <25 mg/dL (1.4 mmol/L). If plasma glucose fails to

increase, parenteral glucose is administered. If the plasma glucose increases to above 25 mg/dL (1.4

mmol/L), oral feedings should continue every two to three hours with preprandial measurements of 

plasma glucose.

•

Infants between 4 and 24 hours of age and with plasma glucose <35 mg/dL (1.9 mmol/L). If plasma

glucose fails to increase, parenteral glucose is administered. If the plasma glucose increases to above

35 mg/dL (1.9 mmol/L), oral feedings should continue every two to three hours with preprandial

measurements of plasma glucose. If a patient becomes symptomatic or if plasma glucose fails to

increase above 45 mg/dL (2.5 mmol/L) after three oral feedings, then parenteral glucose should be given

(2 mL/kg of 10 percent dextrose in water followed by a continuous infusion of 4 to 6 mg/kg/min with

repeat determinations of plasma glucose as noted above). (See 'Parenteral glucose (dextrose) infusion'

above.)

•

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available. Buccal dextrose gel is emerging as an effective and safe therapy when used in conjunction with milk

feeding for at-risk infants [11]. However, further trials, including larger multicenter trials, are required before this

intervention can be recommended for use in routine clinical practice.

Prior to discharge, infants should be able to maintain plasma glucose above the threshold blood glucose goal even

if a feeding is skipped [5]. (See 'Discharge criteria' below.)

Preterm infants — Preterm infants, especially those ≤34 weeks gestation, are at risk for low blood glucose

concentrations, likely due to immaturity of counter regulatory hormone systems and poor nutrient reserves [ 12]. In

addition, some patients are at particular risk of having low glucose concentrations as they transition from parenteralnutrition to bolus enteral feeds [13]. Even on full bolus enteral feeds, preterm infants have episodes of both low and

high glucose concentrations [14,15]. It appears that infants who are at risk for growth failure are also at risk for 

recurrent and persistent episodes of low glucose concentrations [12].

 Although a safe glucose concentration for these infants has not been established, experts in the field, including the

author, suggest maintaining plasma glucose levels greater than 50 to 60 mg/dL (2.8 to 3.3 mmol/L). This is likely to

be a safe strategy to avoid long-term neurologic sequelae [2,16,17]. However, the setting of the targeted threshold

levels must also take into account the patient's overall clinical and nutritional status. (See 'Asymptomatic

hypoglycemia and preterm infants' below.)

The management approach is similar for asymptomatic preterm infants who are able to receive sufficient nutrition

through enteral feeds with initiation of early feeds and monitoring of plasma blood glucose levels [16]. For those who

are not expected to be able to receive enough enteral nutrition due to prematurity, parenteral nutrition, which

includes glucose, should be started quickly. (See "Approach to enteral nutrition in the premature infant" and

"Parenteral nutrition in premature infants", section on 'Glucose'.)

Persistent hypoglycemia

Definition and timing of evaluation — Persistent hypoglycemia is defined as persistent low glucose

concentrations beyond the first 48 hours of life or the requirement of parenteral glucose infusion to treat

hypoglycemia beyond 48 hours of life [2]. This waiting period of at least 48 hours is necessary because it is difficult

to distinguish newborns with a pathological hypoglycemia disorder (transient or permanent) from normal newborns

with low transitional glucose concentrations since the biochemical features (mild hyperinsulinism) are similar. (See"Pathogenesis, screening, and diagnosis of neonatal hypoglycemia", section on 'Normal transitional low glucose

levels'.)

For example, the constellation of findings consistent with hyperinsulinemic hypoglycemia in an older child (ie,

inappropriately elevated serum insulin levels, low ketone body [beta-hydroxybutyrate] and free fatty acid

concentrations, and a brisk rise in glucose concentrations following glucagon administration) is also seen in an

asymptomatic and otherwise healthy term infant less than 48 hours old with normal low blood glucose levels. It

remains uncertain exactly when this group of biochemical findings changes from normal physiology to representing

a pathological hypoglycemic condition. However, for most healthy term newborns this transition is believed to take

place by 48 to 96 hours of age [2,18].

 As a result, the evaluation for a persistent hypoglycemic disorder should be performed when the infant is ≥48

hours of age so that the transitional period of adjusting the source of glucose from a continuous supply provided

by the mother through the placenta to an intermittent supply from oral feeds has passed.

Evaluation — Once persistent hypoglycemia is established, further evaluation is warranted to determine the

underlying cause. Most cases of persistent hypoglycemia in term infants will have biochemical features of 

hyperinsulinism, which are usually caused by perinatal stress and typically resolve in the first few weeks of life.

However, some cases may persist and require ongoing medical management. This is true even in the absence of a

suspected or defined genetic hypoglycemia disorder [19,20]. Therefore, the clinician needs to determine the

appropriate and safe point at which glucose monitoring can be discontinued and when hospital discharge should

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occur, versus when it is likely that a permanent or ongoing hypoglycemic disorder exists, which requires further 

intervention and/or evaluation [5]. In cases with prolonged persistent hypoglycemia, consultation with a pediatric

endocrinologist is recommended to help in the evaluation and management of these patients.

The evaluation consists of a thorough history, physical examination, and, in some cases, laboratory evaluation.

(See 'Laboratory testing' below.)

History — A thorough history can help determine the underlying cause of hypoglycemia (see

"Pathogenesis, screening, and diagnosis of neonatal hypoglycemia", section on 'Pathologic and/or persistent

hypoglycemia'). The following are historical etiologic clues:

Physical findings — The physical examination may provide clues to an underlying cause of neonatal

hypoglycemia as follows [2]:

Laboratory testing

Who should be tested? — Laboratory testing is warranted in patients who:

Prematurity – Preterm infants, as noted above, have poor nutrient reserves and immature counter regulatory

hormone systems, which increase their risk of hypoglycemia.

●

Fetal growth restriction (FGR) – Infants with FGR are at risk for hypoglycemia due to poor nutrient reserves

and hyperinsulinism.

●

History of perinatal asphyxia or stress – Hyperinsulinism and increased metabolism in neonates with perinatal

asphyxia or stress can contribute to hypoglycemia.

●

History of maternal diabetes – Neonatal hyperinsulinism results in hypoglycemia. (See "Infant of a diabetic

mother", section on 'Hypoglycemia'.)

●

Positive family history of an infant with neonatal hypoglycemia may be indicative of an underlying genetic

disorder, including inborn errors of metabolism.

●

Large for gestational age●

Hemihypertrophy, macroglossia, and omphalocele are findings consistent with a diagnosis of Beckwith-

Wiedemann syndrome (BWS) (see "Beckwith-Wiedemann syndrome", section on 'Clinical manifestations')

●

 Ambiguous genitalia, hypertension, hyponatremia, and hyperkalemia are features that may be seen incongenital adrenal insufficiency, which also is associated with hypoglycemia (see "Causes and clinical

manifestations of primary adrenal insufficiency in children", section on 'Congenital adrenal hyperplasia')

●

Hepatomegaly is seen in some glycogen storage and other hereditary metabolic diseases that can present

with hypoglycemia, and with BWS

●

Midline facial defects and ambiguous genitalia may be seen in cases of hypopituitarism●

Present with severe symptomatic hypoglycemia that requires prolonged and/or high rates of intravenousdextrose infusion for treatment.

●

Have persistent hypoglycemia.●

Have neurologic symptoms.●

Have historical or physical findings suggestive of an underlying etiology. In these patients, regardless of 

whether hypoglycemia has been documented or not, consideration should be given to performing specific

tests to rule out a hypoglycemia disorder if there is a family history of a genetic hypoglycemia disorder or if 

physical exam features suggest a syndromic hypoglycemia disorder (eg, BWS or congenital adrenal

hyperplasia).

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Consultation with a clinician with expertise in managing neonatal hypoglycemia (ie, pediatric endocrinologist)

should be considered in these cases, as the specific tests required to rule out a hypoglycemia disorder will vary

based on the clinical setting (eg, family history and physical exam) [2].

When should testing be performed ("critical" blood test sampling)? — Because tests performed when the

blood glucose levels are normal are not helpful in determining the underlying cause of hypoglycemia, laboratory

testing is based on "critical samples" obtained when the plasma glucose level is <50 mg/dL (2.8 mmol/L). In

asymptomatic patients, when a bedside glucometer is used, samples should be obtained when the glucose

concentration is <40 mg/dL (2.2 mmol/L). This difference in suggested blood glucose threshold is due to the

inaccuracy of a bedside glucometer for diagnosing hypoglycemia. (See "Pathogenesis, screening, and diagnosis of 

neonatal hypoglycemia", section on 'How glucose testing is performed'.)

For infants who are on enteral feeds, sampling may need to be obtained after a 6- to 8-hour fast (one skipped feed)

that results in an appropriately low glucose concentration. During the fast, frequent monitoring of vital signs, and

plasma glucose levels (every hour) should be performed. If the plasma glucose concentration drops to less than 50

mg/dL (2.8 mmol/L) prior to 6 to 8 hours, the critical labs should be obtained and the fast terminated.

For patients who are receiving parenteral glucose infusion, sampling can still occur as long as the plasma glucose

is <50 mg/dL (2.8 mmol/L). Interventions to normalize blood glucose levels (ie, feeding or an increase in the

dextrose infusion rate) are delayed until after the samples are obtained [2].

What tests to obtain? — In our practice, while the patient has a plasma glucose <50 mg/dL, we obtain blood

samples to confirm hypoglycemia (<50 mg/dL) and measure plasma insulin, beta-hydroxybutyrate, blood pH,

bicarbonate, and free fatty acids. These initial tests are used to distinguish diagnostic categories for neonatal

hypoglycemia and help determine if other blood tests should be obtained including plasma C-peptide, growth

hormone, cortisol, acylcarnitine profile, plasma free and total carnitine levels, serum amino acids, urine organic

acids, or specific genetic tests (algorithm 1). These specific blood tests should be performed in consultation with a

pediatric endocrinologist or other appropriate specialist. Many of these blood tests are rapidly altered by changes in

blood glucose levels including serum insulin, C-peptide, beta-hydroxybutyrate, cortisol, growth hormone, and free

fatty acids [2].

Discharge criteria — It is important to ensure that neonates are able to maintain plasma glucose concentrations

in a normal range through cycles of feeding and fasting prior to discharge. In our practice, for infants who are at risk

for hypoglycemia, preprandial glucose concentrations through three feed-fast cycles should be >50 mg/dL (2.8

mmol/L) in infants less than 48 hours of age, and >60 mg/dL (3.3 mmol/L) in those who are ≥48 hours of life [2,5].

In general, if a neonate can maintain a plasma glucose concentration >60 mg/dL (3.3 mmol/L) after a 6- to 8-hour 

fast, it is likely that the infant is safe for discharge [2].

NEURODEVELOPMENTAL OUTCOME

Symptomatic hypoglycemia — Symptomatic hypoglycemia can result in brain injury that can be detected by

magnetic resonance imaging (MRI). However, there are no available data that clearly define the glucose

concentration or the duration of hypoglycemia associated with brain damage detected by MRI or other long-term

neurologic sequelae.

 A systematic review of the literature published in 2006 reported inconclusive evidence on the effect of neonatal

hypoglycemia on neurodevelopment [21]. Two subsequent studies using brain MRI suggest an association between

hypoglycemia and brain injury in term infants [22,23]. Although it remains uncertain whether timely treatment of 

hypoglycemia will prevent brain injury and poor developmental outcome, experts in the field, including the author,

recommend symptomatic neonatal hypoglycemia should be aggressively treated given the potential significant

adverse effects based on the available data [1,2,5].

Asymptomatic hypoglycemia and preterm infants — In preterm infants, controversy exists as to whether 

asymptomatic hypoglycemia causes neurologic injury and whether glucose concentrations requiring intervention

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should be lower in premature than in term infants. However, several studies report neurodevelopmental sequelae

due to repeated or prolonged asymptomatic episodes of neonatal hypoglycemia in preterm patients. As a result,

experts in the field, including the author, use a lower blood glucose level for intervention in preterm infants. (See

'Preterm infants' above.)

Supporting data for this approach include the following studies:

In contrast, a study of premature infants (gestational age <32 weeks) with daily measurements of blood glucose

obtained at a fixed time each morning for the first 10 days of life reported no differences in developmental status or 

physical disability based on psychometric assessment between 47 patients who had neonatal blood glucose

concentration ≤45 mg/dL (2.5 mmol/L) on ≥3 days compared with matched control patients during follow-up at 2

and 15 years of age [27].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and

"Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5 to 6 grade

reading level, and they answer the four or five key questions a patient might have about a given condition. Thesearticles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the

Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the

10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with

some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these

topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on

"patient info" and the keyword(s) of interest.)

SUMMARY AND RECOMMENDATIONS

Retrospective data analysis of a multicenter trial in premature infants showed a correlation between prolonged

hypoglycemia (plasma glucose concentrations less than 47 mg/dL [2.6 mmol/L] on five different days during

the first two months of age) and lower Bayley mental and psychomotor scores at 18 months corrected age[24]. Developmental delay or cerebral palsy was 3.5 times greater (95% CI 1.3-9.4) in the hypoglycemic

infants. However, the frequency of glucose testing was variable and occurred more often in sicker infants.

Furthermore, only arithmetic and motor scores were lower in hypoglycemic infants at 7.5 to 8 years of age [ 6].

●

In a study of preschool-age children who were born moderately premature (gestational age 32 to less than 36

weeks), multivariate analysis showed that hypoglycemia was associated with increased incidence of parent-

reported developmental delay when the children were 43 to 49 months old (odds ratio: 2.19, 95% CI 1.08-4.46)

[25].

●

The long-term impairment of neurodevelopment may be greater in preterm infants with repeated hypoglycemic

episodes who are also small for gestational age (SGA). In a prospective study of 85 SGA preterm infants,

repeated episodes of hypoglycemia were associated with a smaller head circumference at 18 months

corrected age and lower psychometric testing scores at 3.5 and 5 years of age [ 26].

●

th th

th th

Basics topic (see "Patient information: Newborn hypoglycemia (The Basics)")●

Transient low blood glucose concentrations are common in healthy term infants after birth as the glucose

supply changes from a continuous transplacental supply from the mother to an intermittent supply from feeds.

It is important to differentiate this normal physiologic transitional response from disorders that result in

persistent or recurrent hypoglycemia, which if left untreated may lead to significant neurologic and

developmental sequelae. (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia", section

on 'Normal transitional low glucose levels' and "Pathogenesis, screening, and diagnosis of neonatal

hypoglycemia", section on 'Pathologic and/or persistent hypoglycemia' and 'Neurodevelopmental outcome'

above.)

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The goals of managing neonatal hypoglycemia are to correct blood glucose levels in symptomatic patients,

prevent symptomatic hypoglycemia in at-risk patients, and identify newborns with a serious underlying

hypoglycemic disorder, while avoiding unnecessary treatment of infants with normal transitional low blood

glucose, which will resolve without intervention. The long-term goal is to prevent long-term neurologic

complications. (See 'Goals and challenges' above and "Pathogenesis, screening, and diagnosis of neonatal

hypoglycemia", section on 'Challenge of defining neonatal hypoglycemia'.)

●

In our practice, target plasma glucose levels consistent with the American Academy of Pediatrics (AAP) and

Pediatric Endocrine Society (PES) guidelines are used to provide a margin of safety for infants who are at risk

for neonatal hypoglycemia. (See 'Target blood glucose levels' above.)

●

For at-risk neonates without a suspected or confirmed genetic hypoglycemia disorder, the goal is to

maintain plasma glucose concentrations >50 mg/dL (2.8 mmol/L) in the first 48 hours of life, and >60

mg/dL (3.3 mmol/L) after 48 hours of life.

•

In neonates with a suspected or confirmed genetic hypoglycemia disorder, the goal is to maintain

plasma glucose concentrations >70 mg/dL (3.9 mmol/L).

•

Treatment of neonatal hypoglycemia is a stepwise process depending on the presence or absence of 

symptoms and signs, and the response of the infant at each step. The following approach is consistent with

guidelines published by the AAP and the PES. (See 'Management approach' above.)

●

For symptomatic infants, we recommend administering parenteral glucose (Grade 1C). Therapy should

be started while awaiting laboratory confirmation. We begin with an intravenous (IV) bolus of dextrose

(200 mg/kg) given over 5 minutes (2 mL/kg of 10 percent dextrose in water). This is followed by the

continuous administration of parenteral glucose infusion at an initial rate of 6 to 8 mg/kg per minute. If 

hypoglycemia is persistent, glucose infusion rates should be increased as needed. In the rare patients

who fail to maintain target blood glucose levels despite maximal glucose infusion rates, we suggest the

administration of glucagon at an initial dose of 20 to 30 mcg/kg (Grade 2C). (See 'Symptomatic

patients' above.)

•

For asymptomatic term and late preterm infants at risk for hypoglycemia, an initial oral feeding should

be given within the first hour of life as follows, based on the age of the patient and plasma glucose.Blood glucose concentrations should be measured frequently, starting 20 to 30 minutes after the initial

feed and then before subsequent feedings. (See 'Asymptomatic term or late preterm infants' above.)

•

Infants less than 4 hours of age and with plasma glucose <25 mg/dL (1.4 mmol/L). If plasma

glucose fails to increase, parenteral glucose is administered. If the plasma glucose increases to

above 25 (1.4 mmol/L), oral feedings should continue every two to three hours with preprandial

measurement of plasma glucose.

-

Infants between 4 and 24 hours of age and with plasma glucose <35 mg/dL (1.9 mmol/L). If plasma

glucose fails to increase, parenteral glucose is administered. If the plasma glucose increases to

above 35 to mg/dL (1.9 mmol/L), oral feedings should continue every two to three hours withpreprandial measurement of plasma glucose. If a patient becomes symptomatic or if plasma

glucose fails to increase above 45 mg/dL (2.5 mmol/L) after three oral feedings, then parenteral

glucose should be given.

-

For more premature infants (gestational age <35 weeks) who are able to maintain adequate nutrition by

enteral feeds, the management is the same as that used in term infants, with initial oral feeding within

the first hour of life and ongoing monitoring of blood glucose levels. For those who are not expected to be

able to receive enough enteral nutrition due to prematurity, parenteral nutrition, which includes glucose,

should be started quickly. (See 'Preterm infants' above.)

•

Further diagnostic testing is usually reserved for infants with persistent hypoglycemia (who are not able to●

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REFERENCES

1. Committee on Fetus and Newborn, Adamkin DH. Postnatal glucose homeostasis in late-preterm and term

infants. Pediatrics 2011; 127:575.2. Stanley CA, Rozance PJ, Thornton PS, et al. Re-evaluating "transitional neonatal hypoglycemia": mechanism

and implications for management. J Pediatr 2015; 166:1520.

3. Menni F, de Lonlay P, Sevin C, et al. Neurologic outcomes of 90 neonates and infants with persistent

hyperinsulinemic hypoglycemia. Pediatrics 2001; 107:476.

4.  Avatapalle HB, Banerjee I, Shah S, et al. Abnormal Neurodevelopmental Outcomes are Common in Children

with Transient Congenital Hyperinsulinism. Front Endocrinol (Lausanne) 2013; 4:60.

5. Thornton PS, Stanley CA, De Leon DD, et al. Recommendations from the Pediatric Endocrine Society for 

Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children. J Pediatr 2015;

167:238.

6. Cornblath M, Schwartz R. Outcome of neonatal hypoglycaemia. Complete data are needed. BMJ 1999;318:194.

7. Haymond MW, Schreiner B. Mini-dose glucagon rescue for hypoglycemia in children with type 1 diabetes.

Diabetes Care 2001; 24:643.

8. Hartley M, Thomsett MJ, Cotterill AM. Mini-dose glucagon rescue for mild hypoglycaemia in children with

type 1 diabetes: the Brisbane experience. J Paediatr Child Health 2006; 42:108.

9. Miralles RE, Lodha A, Perlman M, Moore AM. Experience with intravenous glucagon infusions as a treatment

for resistant neonatal hypoglycemia. Arch Pediatr Adolesc Med 2002; 156:999.

10. Hawdon JM, Aynsley-Green A, Ward Platt MP. Neonatal blood glucose concentrations: metabolic effects of 

intravenous glucagon and intragastric medium chain triglyceride. Arch Dis Child 1993; 68:255.

maintain preprandial plasma glucose concentrations >60 mg/dL [3.3 mmol/L] after 48 hours of age without IV

dextrose, have severe hypoglycemia requiring prolonged and/or high rates of IV dextrose infusion after 48

hours of life to treat hypoglycemia, have a family history of a genetic hypoglycemia disorder, or have physical

exam features suggestive of a syndromic hypoglycemia disorder). A waiting period beyond the first 48 hours

of life is necessary because it is difficult to distinguish newborns with a pathological hypoglycemia disorder 

(transient or permanent) from normal newborns with low transitional glucose concentrations because the

biochemical features (mild hyperinsulinism) are similar. (See 'Laboratory testing' above and 'Persistent

hypoglycemia' above.)

Laboratory testing is based on "critical samples" obtained when the plasma glucose level is <50 mg/dL (2.8

mmol/L). Initial tests that are used to distinguish diagnostic categories for neonatal hypoglycemia are plasma

insulin, beta-hydroxy butyrate, bicarbonate, lactate, and free fatty acids. The results of these tests help

determine if other blood tests should be obtained to determine the underlying cause of persistent

hypoglycemia (algorithm 1). (See 'Laboratory testing' above.)

●

It is important that neonates are able to maintain plasma blood glucose in a normal range through cycles of 

feeding and fasting prior to discharge. In our practice, discharge criterion for infants who are at risk for 

hypoglycemia is a preprandial glucose concentration through three feed-fast cycles >50 mg/dL (2.8 mmol/L)

in infants less than 48 hours of age, and >60 mg/dL (3.3 mmol/L) in those who are ≥48 hours of age.

●

Symptomatic neonatal hypoglycemia has been associated with brain damage, demonstrated on magneticresonance imaging, and poorer developmental outcome. However, there are no available data that clearly

define the glucose concentration or the duration of hypoglycemia that correlate with long-term neurologic

sequelae.

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11. Harris DL, Weston PJ, Signal M, et al. Dextrose gel for neonatal hypoglycaemia (the Sugar Babies Study): a

randomised, double-blind, placebo-controlled trial. Lancet 2013; 382:2077.

12. Hume R, McGeechan A, Burchell A. Failure to detect preterm infants at risk of hypoglycemia before

discharge. J Pediatr 1999; 134:499.

13. Staffler A, Klemme M, Mola-Schenzle E, et al. Very low birth weight preterm infants are at risk for 

hypoglycemia once on total enteral nutrition. J Matern Fetal Neonatal Med 2013; 26:1337.

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15. Mizumoto H, Honda Y, Ueda K, et al. Glycemic variability in preterm infants receiving intermittent gastric tube

feeding: report of three cases. Pediatr Int 2013; 55:e25.

16. Cornblath M, Hawdon JM, Williams AF, et al. Controversies regarding definition of neonatal hypoglycemia:

suggested operational thresholds. Pediatrics 2000; 105:1141.

17. Rozance PJ, Hay WW. Hypoglycemia in newborn infants: Features associated with adverse outcomes. Biol

Neonate 2006; 90:74.

18. Srinivasan G, Pildes RS, Cattamanchi G, et al. Plasma glucose values in normal neonates: a new look. J

Pediatr 1986; 109:114.

19. Hoe FM, Thornton PS, Wanner LA, et al. Clinical features and insulin regulation in infants with a syndrome of 

prolonged neonatal hyperinsulinism. J Pediatr 2006; 148:207.

20.  Arya VB, Flanagan SE, Kumaran A, et al. Clinical and molecular characterisation of hyperinsulinaemic

hypoglycaemia in infants born small-for-gestational age. Arch Dis Child Fetal Neonatal Ed 2013; 98:F356.

21. Boluyt N, van Kempen A, Offringa M. Neurodevelopment after neonatal hypoglycemia: a systematic review

and design of an optimal future study. Pediatrics 2006; 117:2231.

22. Burns CM, Rutherford MA, Boardman JP, Cowan FM. Patterns of cerebral injury and neurodevelopmental

outcomes after symptomatic neonatal hypoglycemia. Pediatrics 2008; 122:65.

23. Tam EW, Widjaja E, Blaser SI, et al. Occipital lobe injury and cortical visual outcomes after neonatal

hypoglycemia. Pediatrics 2008; 122:507.

24. Lucas A, Morley R, Cole TJ. Adverse neurodevelopmental outcome of moderate neonatal hypoglycaemia.

BMJ 1988; 297:1304.

25. Kerstjens JM, Bocca-Tjeertes IF, de Winter AF, et al. Neonatal morbidities and developmental delay in

moderately preterm-born children. Pediatrics 2012; 130:e265.

26. Duvanel CB, Fawer CL, Cotting J, et al. Long-term effects of neonatal hypoglycemia on brain growth and

psychomotor development in small-for-gestational-age preterm infants. J Pediatr 1999; 134:492.

27. Tin W, Brunskill G, Kelly T, Fritz S. 15-year follow-up of recurrent "hypoglycemia" in preterm infants.

Pediatrics 2012; 130:e1497.

Topic 101425 Version 2.0

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GRAPHICS

Diagnostic testing for persistent neonatal hypoglycemia

Initial diagnostic testing for persistent neonatal hypoglycemia (low glucose concentrations that pe

beyond 48 hours of life) differentiates major etiologic categories of hypoglycemia based on labora

testing (bicarbonate, beta-hydroxybutyrate, and free fatty acid) from a critical sample (obtained

plasma glucose level is <50 mg/dL [2.8 mmol/L]). Additional specific testing (eg, plasma insulin, C-

and carnitine and acyl-carnitine levels) using a critical sample is used to confirm the diagnosis of

underlying cause of hypoglycemia.

HCO : bicarbonate; BOHB: beta-hydroxybutyrate; FFA: free fatty acid; GH: growth hormone.

Original figure modified for this publication. Thornton PS, Stanley CA, De Leon DD, et al. Recommendations f

Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants

Children. J Pediatr 2015. Illustration used with the permission of Elsevier Inc. All rights reserved.

Graphic 101681 Version 1.0

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Disclosures: Paul J Rozance, MD Nothing to disclose. Joseph A Garcia-Prats, MD Nothing to

disclose. Joseph I Wolfsdorf, MB, BCh Nothing to disc lose. Melanie S Kim, MD Nothing to disclose.

Contributor disclosures are review ed for conflicts of interest by the editorial group. When found, theseare 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

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Disclosures