screening guidelines for newborns at risk for low blood ... statement_lo… · 12 the hospital....

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Screening guidelines for newborns at risk for low blood glucose 1 Michael Narvey, Seth Marks; Canadian Paediatric Society, Fetus and Newborn Committee 2

Abstract 3

Hypoglycemia in the first hours to days after birth remains one of the most common conditions facing 4 practitioners across Canada who care for newborns. This statement addresses a number of areas 5 pertaining to hypoglycemia including the topics; How should screening for neonatal hypoglycemia be 6 performed? How is neonatal hypoglycemia defined? Who is at risk for neonatal hypoglycemia? When 7 should at-risk infants be screened? What levels of blood glucose require intervention? What interventions 8 should be offered when neonatal hypoglycemia is diagnosed? How frequently should asymptomatic, at-9 risk infants be screened? Additional advice is provided regarding the use of dextrose gels and how to 10 ensure safe discharge of these affected infants to reduce the risk of hypoglycemia recurring after leaving 11 the hospital. This version differentiates the approach to hypoglycemia during the transitional phase in the 12 first 72 hours of life to persistent hypoglycemia that occurs beyond this time point. 13

Keywords: hypoglycemia, dextrose gel, point of care, newborn 14

This statement provides an update to the previous version from 2004. Despite the passage of many years 15 the questions remain largely the same. [1]. Compared to the previous versions of this statement, 16 transitional hypoglycemia in the first 72 hours after birth is now explicitly defined as < 2.6 mmol/L. This 17 change allows for an emphasis that persistent hypoglycemia beyond the first 72 hours after birth is 18 defined by levels below <3.3 mmol/L. 19

An algorithm has been included providing direction in managing infants at risk for neonatal 20 hypoglycemia in the first 72 hours after birth, see Figure 1. 21

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22

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Search strategy 23

A MEDLINE search was performed for studies up to March 2017 using the key words “Hypoglycemia”, 24 “Blood Glucose” and “All Infant: birth-23 months”, limited to “Human”, “English” and “French”, and 25 including all trials, reviews, clinical practice guidelines, follow-up studies and meta-analyses. The 26 Cochrane Database was searched for reviews and articles relating to glucose and infant feeding. No 27 randomized clinical trials relating to strategies for screening for neonatal hypoglycemia in at-risk infants 28 were identified. All case-control and cohort studies were reviewed. Levels of evidence and grades of 29 recommendations were assigned according to the Oxford Centre for Evidence-Based Medicine guideline 30 [2]. 31

How should screening for neonatal hypoglycemia be performed? 32

Traditionally, blood glucose has been conveniently measured on capillary samples using chemical strips 33 or portable, bedside glucose meters as a substitute for formal laboratory analysis. Unfortunately, many of 34 these ‘pointof-care’ methods are not reliable at low glucose levels, and are prone to sample or user error 35 [3][4] (Level 3b). In addition, variations between capillary and venous blood [5], blood and plasma, and 36 immediate and stored samples may confound results (Level 3b). In particular, delays in processing may 37 result in artefactually lower levels. Capillary and venous whole blood and plasma glucose levels (Level 38 3b) may differ in the range of 10% variation, with whole blood being lower than plasma [6]. While acute 39 management may be initiated based on bedside point of care capillary whole blood sampling to prevent 40 delay, any diagnosis or “label” of persistent hypoglycemia should be confirmed by laboratory assays of 41 serum samples. It is likely that more accurate ‘pointof-care’ technologies will be developed and improve 42 the quality and ease of screening, as well as provide opportunities for research into the utility and cost 43 effectiveness of screening. 44

Continuous glucose monitors have looked promising and may prove to be beneficial in monitoring 45 neonates. Barriers to this technology include decreased accuracy at lower glucose levels, delays in the 46 immediacy of the glucose measures, need for ongoing calibration, limited surface area for placement on 47 small neonates for the sensors, and lack of treatment protocols [7][8]. 48

How is neonatal hypoglycemia defined? 49

It is difficult to define neonatal hypoglycemia by a single value of glucose applicable to all clinical 50 situations and to all infants and this has been the case since glucose levels were first measured in neonates 51 [9]. At least in the 48 – 72 hours after birth, infants may develop signs suggestive of hypoglycemia over a 52 range of blood glucose levels that are substantially lower than normal adult levels. In adults or older 53 children, Whipple’s triad (signs and symptoms of hypoglycemia, low serum glucose level, and the 54 resolution of signs and symptoms with the provision of glucose) can be used, but this is often impractical 55 in the neonate yet the principles should be adhered to if possible. Neonatal signs of hypoglycemia in 56 approximate order of frequency are jitteriness or tremors, episodes of cyanosis, convulsions, intermittent 57 apneic spells or tachypnea, weak or high- pitched cry, limpness or lethargy, difficulty in feeding, and eye 58 rolling. Episodes of sweating, sudden pallor, hypothermia, and cardiac arrest and failure also occur. Since 59

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other conditions may share these clinical manifestations it is critical to document hypoglycemia and 60 confirm whether they disappear with the administration of sufficient glucose to raise the blood sugar to 61 normal levels [10]. 62

Signs and Symptoms of Neonatal Hypoglycemia

jitteriness

tremors

cyanosis

convulsions

apnea

tachypnea

weak or high- pitched cry

limpness

lethargy

difficulty in feeding

eye rolling

sweating

pallor

hypothermia

cardiac arrest

cardiac failure

So-called “normal ranges” are presumably dependent on the infant’s size, gestation, the presence of 63 previous hypoglycemia, and the clinical condition, as well as the availability of energy sources and 64 ongoing energy demands. Definitions of hypoglycemia should be flexible enough to encompass all of 65 these factors. 66

There are four approaches to defining a safe range for blood glucose, all with limitations. [11][12] 67

Using the presence of clinical manifestations 68

Using normative ranges: Studies of exclusively breastfed, appropriate for gestational age (AGA), term 69 babies, show that blood glucose levels fall immediately after birth from two-thirds of maternal levels to as 70 low as the 5th percentile or approximately 1.8 mmol/L at 1 h of age (Level 2b) [13][14] and subsequently 71 rise to levels > 2.0 mmol/L that is maintained for 72 h [14]. Approximately 12% to 14% of normal, AGA 72 breastfed newborns have a blood glucose level of < 2.6 mmol/L in the first 72 hours after birth [15] after 73 which babies generally maintain a glucose level > 3.3 mmol/L [12]. Preterm infants may take longer to 74 reach this threshold. 75

Using the presence or absence of acute normal physiologic metabolic and endocrine changes: In 76 response to hypoglycemia there are normal physiological responses such as a rise in ketones, growth 77 hormone, cortisol, and catecholamines and the suppression of insulin. 78

Using the presence or absence of sequelae: A number of studies in at-risk term, preterm and small-for-79 gestational-age (SGA; weight < 10th %tile) infants have suggested an association of blood glucose levels 80 of < 2.6 mmol/L with abnormal short (Level 4) and long-term neurological (Level 2a) or neuroimaging 81 changes (Level 4) [10][16][17]-[19] Other studies have indicated that a lower glucose level within the 82 first 72 hours after birth, is required for long-term sequelae [20] Yet some studies have shown no harm 83 from transient hypoglycemia [21][22] but rather an increased risk of long term sequelae with recurrent 84 episodes of hypoglycemia. [19] 85

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Unfortunately, given the wide range of suggested normal blood glucose levels, the presence of significant 86 comorbidities in the population, and the myriad causes of low blood glucose, cohort and case-control 87 studies cannot determine causation between low blood glucose and adverse outcome. Evidence exploring 88 hypoglycemia outside of the initial transitional period is less abundant. There are suggestions that 89 therapeutic goals for glucose levels in infants with persistent hypoglycemia outside of the transitional 90 period, should be ≥ 3.3 mmol/L. [23][24][25] 91

Who is at risk for neonatal hypoglycemia? 92

Impairment of gluconeogenesis [26] is the most common cause in infants with hypoglcyemia [27]. 93 Specific etiologies include, excess insulin production, altered counter-regulatory hormone production or 94 inadequate substrate supply. Classically these states can occur transiently in small for gestational age 95 infants (weight <10th percentile) (Table 1) [28], large for gestational age (LGA; weight > 90th percentile) 96 infants, infants of diabetic mothers (IDMs) and preterm infants (Level 3/4) [29]-[32]. Questions exist as 97 to whether non-syndromic LGA non-IDM infants are truly at risk although other infants with conditions 98 such as Beckwith-Wiedemann syndrome need to be followed closely [33]. A number of additional 99 maternal and fetal conditions, including maternal use of labetalol or late preterm administration of 100 antenatal steroids [34][35] as well as intrauterine growth restriction and perinatal asphyxia, can also result 101 in hypoglycemia. More rarely, metabolic and endocrine disorders may lead to persistent neonatal 102 hypoglycemia [27] however their disease specific investigations and management are beyond the scope of 103 this statement [36]. Thresholds for treatment may differ depending on the etiology of hypoglycemia. 104 While <2.6 mmol/L has generally been adopted as a threshold for treatment in otherwise healthy infants 105 in the transitional period, those with documented hyperinsulinism may be deserving of a higher target of ³ 106 3.3 mmol/L. The higher threshold may be warranted due to the absence of alternative fuels in this non-107 ketotic state. [37] 108

Table 1

10th and 90th percentile cut-offs for birthweight at term in Canadian infants

Gestation

(completed weeks)

Birthweight (g)

10th percentile 90th percentile

Male Female Male Female

37 2552 2452 3665 3543

38 2766 2658 3877 3738

39 2942 2825 4049 3895

40 3079 2955 4200 4034

41 3179 3051 4328 4154

42 3233 3114 4433 4251

Adapted with permission from reference [18]

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When and how frequently should at-risk infants be screened? 109

No study evaluating the optimal timing and intervals for glucose screening was identified. There is 110 insufficient evidence to support screening asymptomatic infants without risk factors for hypoglycemia. 111

Given the paucity of evidence on the adverse effect of glucose levels between 1.8 mmol/L and 2.5 112 mmol/L in asymptomatic infants at several hours of age, a staged approach to screening and intervention 113 is suggested. Because feeding raises blood glucose [38] and stimulates ketosis [39], it seems rational to 114 feed at-risk infants at regular intervals, while screening before feeds. 115

Holtrop [32] showed that IDMs (and, by inference, LGA infants) were most likely to develop 116 hypoglycemia in the first few hours after birth. As a consequence, screening is not required in this 117 population after 12 h of age if levels remain at 2.6 mmol/L or greater. SGA and preterm infants may 118 become hypoglycemic as late as the second day (although this may be prevented by establishing intake). 119 If there are no feeding concerns and the infant is well, screening may be discontinued at 24 h of age 120 (Level 2b). It would be reasonable to screen once or twice on the second day after birth, if there have been 121 more than one glucose reading below 2.6 mmol/L in the first 24 hours to ensure levels remain at or above 122 this level after this period. 123

‘Symptomatic infants’ should have a blood glucose assessment without delay as part of the workup for 124 diagnostic and therapeutic purposes. 125

How should caregivers be educated or counselled regarding screening for neonatal hypoglycemia? 126

Both parents and health care providers require education regarding screening. Parents should be aware 127 that their child is symptomatic or at risk, and therefore, requires blood testing at regular intervals. An 128 informed explanation, possibly with the aid of a parent handout (“Checking blood glucose in newborn 129 babies”), will help ensure appropriate parental participation in monitoring and allay fears if further 130 interventions are required. An algorithm (Figure 1) is provided to assist health care providers in the use of 131 this statement. 132

What levels of blood glucose require intervention? 133

First 72 hours 134

Symptomatic hypoglycemia 135

Symptomatic hypoglycemia results in neuronal injury [40], making urgent intervention desirable in sick 136 infants. Based on the available data, maintaining glucose levels ≥ 2.6 mmol/L in an at-risk infant is 137 recommended. 138

139

https://www.caringforkids.cps.ca/handouts/blood_glucose_in_newborn_babies

https://www.caringforkids.cps.ca/handouts/blood_glucose_in_newborn_babies

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Asymptomatic hypoglycemia 140

Population data suggest that blood glucose levels as low as 2.0 mmol/L (or even 1.8 mmol/L at 1 h of 141 age) are not uncommon in healthy newborns (Level 2a). In at-risk infants, however, outcome data support 142 raising the intervention threshold. Lucas et al [41] suggest that persistent glucose levels of < 2.6 mmol/L 143 in preterm infants may have adverse long-term effects (Level 2b). More recently, Duvanel et al [42] 144 studied neurodevelopmental outcomes in a cohort of 85 SGA preterm infants in relation to episodes of 145 hypoglycemia (defined as < 2.6 mmol/L) (Level 2b). Compared to non-hypoglycemic control subjects, 6 146 or more episodes of hypoglycemia was associated with lower head circumference at 12 and 18 months as 147 well as at 5 years of age. Furthermore, psychometric testing using the McCarthy’s test at 3.5 years of age 148 demonstrated impairments compared to controls without exposure to neonatal hypoglycemia. It must be 149 noted that 58% of this cohort had severe hypoglycemia between 0.6 to 1.6 mmol/l so it is uncertain 150 whether these results would be reflective in a modern cohort of more aggressive management of glucose. 151 Stenninger et al [43] followed-up 28 IDMs (13 with hypoglycemia <1.5 mmol/L and 15 without) at eight 152 years of age and matched, healthy control subjects and discovered minimal evidence of neurological 153 dysfunction whether hypoglycemic or not using the Griffith’s developmental and Movement ABC tests 154 (Level 2b). It is worth noting that most of these babies had asymptomatic hypoglycemia. 155

Williams [44] supports the cut-off of < 2.6 mmol/ L in at-risk infants at 4 h to 6 h of age. Cornblath et al 156 [24] proposed the concept of operational thresholds, the range of blood glucose concentrations at which 157 clinicians should consider intervention. They distinguished between the threshold glucose value that 158 requires action (2.0 mmol/L) and the target glucose level that interventions are aimed at (2.6 mmol/L or 159 greater) (Level 5). Recently, the 4.5 year follow up of a large cohort by McKinlay et al [19] indicated an 160 increased risk in some measures of neurological impairment, such as executive functioning and visual 161 motor function, with recurrent (3 or more episodes <2.6 mmol/L) or severe (<2 0 mmol/L) hypoglycemia. 162

It seems that, in at-risk infants, blood glucose levels < 2.6 mmol/L, particularly if persistent or repeated, 163 may be associated with adverse outcomes. There is a strong case for randomized clinical trials comparing 164 interventions, intervention thresholds and their long-term outcomes. 165

Recommendations for management of hypoglycemia are outlined in the algorithm, see Figure 1. 166

Beyond 72 hours: 167

Recent guidelines have suggested a raised threshold and/or treatment goal for infants beyond the 168 transitional period, defined as 48 hours by some or 3 days after birth by others [23][25]. Much of the 169 evidence to recommend such levels is based on the follow up of children with hyperinsulinism, a major 170 cause of persistent hypoglycemia, who are at increased risk of neurological sequelae due to lack of 171 alternate fuel source of ketones for the brain. Additional motivating factors include the development of 172 neuroglycopenic and neuroendocrine responses in adults and older children at glucose levels as low as 173 2.7-2.8 mmol/L [45][46]. 174

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While glucose values increase perhaps very slightly with age, normal glucose ranges do not differ much 175 in children versus adults. For example, one study showed that the mean glucose in children after a 176 prolonged 24 hour fast was 3.6 (2.7 - 4.5) mmol/L in children 1-12 months old, 3.3 mmol/l (2.8-3.8) in 177 children 1-7 years old, and 3.8 mmol/L (3.0-4.3) in children 7-15 years old. [47][48] 178

Although difficult to define hypoglycemia by a specific cut off, taking into account safety, limiting 179 morbidity, and over investigation and treatment, after the transitional period, a laboratory confirmed 180 glucose value of < 3.3 mmol/L should be defined as persistent hypoglycemia warranting further 181 assessment. Those requiring ongoing treatment for persistent hypoglycemia should have therapeutic 182 targets of ≥ 3.3 mmol/L, above the cut off for neurogenic and neuroglycopenic symptoms. A critical 183 sample to aid in the diagnosis of an underlying etiology for persistent hypoglycemia at ≥ 72 hours should 184 be collected when a point of care glucose is < 2.8 mmol/L. The distinction between the two values for 185 investigation and therapeutic target reflects the need to ensure the potential normally expected 186 biochemical physiological responses needed to make a diagnosis of etiology. As by the point of a glucose 187 level <2.8 mmol/L one should normally see a suppressed insulin, elevated ketones, and increased counter 188 regulatory hormones (GH, cortisol). In addition, there is a possible 20 % error in measurement that may 189 exist between point of care and laboratory glucose values. Given the volume of blood required for a 190 critical sample it seems prudent to restrict collection of such bloodwork to situations in which the point of 191 care sample has a reading of < 2.8 mmol/L to try and ensure a useful critical sample. This will avoid the 192 situation of being unable to interpret the critical sample results when the laboratory glucose is ≥ 3.3 193 mmol/L. The thresholds for defining hypoglycemia and when to obtain critical samples are provided in 194 Table 2. 195

Table 2: Thresholds For Investigation and Treatment of Hypoglycemia

Birth to 72 hours of age ≥ 72 hours of age

Therapeutic goal 2.6 3.3

Confirmatory lab glucose 2.6 2.8*

* Critical sample should be sent to determine etiology in addition to lab glucose. Critical samples may

be sent earlier than this time point if strong suspicion of an endocrine or metabolic etiology.

Neonates being monitored for persistent hypoglycemia should have a 5 to 6 hours fast prior to discharge 196 to ensure their safety at home if time between feeds is prolonged. Additionally, the underlying diagnosis 197 should be ascertained and specific medical management (eg. Diazoxide in hyperinsulinism) initiated in 198 hospital with parental education completed with respect to recommended frequency of feeding., home 199 blood glucose monitoring, medication delivery as applicable, and treatment of hypoglycemia. 200

Our recommendations are similar to those in the recent PES recommendations [25]. While the PES 201 statement used a cutoff of 48 hours, the transition point likely lies somewhere between 48-72 hours. Due 202 to concerns over increased admission rates for hypoglycemia and given the uncertainty around the 48-203 hour time point we believe 72 hours allows a balance between safety and minimizing negative impacts to 204 families and care providers. Importantly a distinction between the transition period and the period beyond 205

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is recognized with a high index of suspicion for investigations and intervention suggested after 72 hours 206 of life for hypoglycemia that persists below suggested levels. 207

What interventions should be offered when neonatal hypoglycemia is suspected? 208

There are, essentially, two approaches. The first supports increased energy intake (orally or 209 intravenously), while the second supports increased mobilization of energy stores (using counter-210 regulatory hormones, such as glucagon or corticosteroids) [49][50]. Pragmatically, the urgency and nature 211 of interventions depend on the presence of symptoms and the severity of the hypoglycemia. Additional 212 treatment is disease specific, for example diazoxide or octreotide in hyperinsulinemia and recombinant 213 growth hormone in growth hormone deficiency. 214

Asymptomatic Hypoglycemia 215

Common clinical practices in both the prevention and treatment of asymptomatic hypoglycemia include 216 increased breastfeeding frequency, supplementation with breastmilk or a breastmilk substitute, intrabuccal 217 dextrose gel, or intravenous glucose therapy [51][52]. No clinical trials have been performed to 218 demonstrate the benefit of one supplement over another (or, indeed, over breastfeeding on demand [53]) 219 on long-term outcome. Frequent breastfeeding on demand should be encouraged in at risk babies, and, if 220 formula fed or supplemented, the volume of enteral intake should be adjusted according to the size, age 221 and gestation of the infant [54]. Additionally, delaying the first bath has also been found to reduce 222 incidence of hypoglycemia and this practice may help avoid additional cases. [55] 223

There is some evidence that increased carbohydrate intake prevents low blood glucose levels in healthy 224 term breastfed infants. Randomized clinical trials in SGA [56] and AGA [57] infants found that 225 augmented glucose formulas raise blood glucose and prevent hypoglycemia (Level 1b). 226

When feeding interventions are offered for low blood glucose, levels should be rechecked in 30 min to 227 ensure that there has been a response. 228

If increased enteral caloric intake is not effective, historically the next intervention would be to provide 229 intravenous glucose. More recently dextrose gels have gained traction in the management of 230 hypoglycemia and are discussed in the next section. When using an IV route however, the recommended 231 initial glucose infusion regime is 80 mL/kg/day of 10% dextrose, providing 5.5 mg/kg/min of glucose, in 232 keeping with studies that have measured glucose flux in newborns [58]-[61] (Level 3b). Infants with very 233 low glucose levels, particularly those with levels < 1.8 mmol/L, should be managed with some 234 expedience, confirming response to intervention in a timely fashion (a response to intravenous 235 interventions should occur within 30 min) [62]. A single bolus of 2 mL/kg of 10% dextrose at the start of 236 an infusion more rapidly achieves steady state levels, but the benefit of this practice in asymptomatic 237 babies is uncertain (Level 4). Due to the short duration of action of glucose, after one or two boluses of 238 dextrose the infusion rate or concentration of dextrose should be increased. 239

240

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Symptomatic Hypoglycemia 241

There is both observational evidence and clinical consensus that sick, hypoglycemic infants, particularly 242 those with neurological signs, should be treated immediately with an intravenous infusion of glucose. The 243 effect of intravenous interventions may be rechecked after 30 min. An initial failure to respond to 244 intravenous glucose requires a stepwise increase in glucose supply, with a review of blood glucose 30 min 245 after each increment. The effect of changes in the glucose infusion rate (GIR) from either increasing the 246 total fluid intake (TFI) and/or concentration are shown in Figure 2 below and online calculators exist to 247 aid the practitioner in determining the effects of changes to either dextrose concentration or infusion rates. 248 [63] 249

Figure 2 250

GIR: mg / kg / min

TFI: ml/kg/day (ml/kg/h) D 5 D 7.5 D 10 D 12.5 D 15 D 20

60 (2.5) 2 3.1 4.1 5.2 6.3 8.4

80 (3.3) 2.8 4.1 5.5 6.9 8.3 11.0

100 (4.1) 3.4 5.1 6.6 8.6 10.3 13.1

120 (5.0) 4.2 6.3 8.4 10.4 12.5 16.7

140 (5.8) 4.8 7.3 9.7 12.1 14.5 19.4

160 (6.6) 5.5 8.3 11.0 13.2 16.5 22.0

180 (7.5) 6.3 9.4 12.5 15.7 18.8 25.0

200 (8.3) 6.9 10.4 13.9 17.3 20.8 27.7

With respect to venous access, previous recommendations of placing a central venous line for 251 concentrations ≥15% may not be necessary. Recent evidence has emerged supporting the integrity of 252 peripheral veins using dextrose concentrations as high as 20%. No difference in rate of IV loss was noted 253 in patients randomized to receive dextrose solutions at these higher dextrose concentrations. [64] 254

If infusions fail to keep blood glucose levels at appropriate levels, or high rates (>10 mg/kg/min) are 255 required, further investigation, specialist referral and/or pharmacological intervention (eg, intravenous 256 glucagon) should be considered [65]-[69] (Level 4). Investigations should be aimed at identifying 257 endocrine pathology (particularly hyperinsulinism) and inborn errors of metabolism. Glucagon by 258 intravenous bolus (0.1 mg/kg to 0.3 mg/kg) or infusion (10 µg/kg/h to 30 µg/kg/h) has been observed to 259 raise blood glucose and prevent recurrent episodes of hypoglycemia in both term and preterm infants. 260 Alternative therapies include hydrocortisone, diazoxide and octreotide, but data are limited in their use for 261 the initial management of hypoglycemia. 262

Breastfeeding may be continued without risk of overhydration in the transitional period because the 263 volume of colostrum is small. To avoid overhydration and hyponatremia in supplemented infants, oral 264

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and intravenous intake should not exceed 100 mL/kg/day without careful monitoring for dilutional 265 hyponatremia. Blood glucose levels should be checked frequently until interventions result in stable 266 glucose levels and failure to achieve this level requires re-evaluation and consultation. Intravenous 267 dextrose can be weaned when levels have been stable for 12 h. 268

Dextrose gel 269

Recently, intrabuccal 0.5 mL/kg of 40% dextrose gel has become available for management of 270 hypoglycemia. [52] This amount of dextrose gel provides 200 mg/kg of glucose equivalent to an 271 intravenous bolus of 2 mL/kg of D10W solution. The Sugar Babies trial [70] compared administration of 272 dextrose gel versus placebo for treatment of hypoglycemia, with the primary outcome being achievement 273 of blood glucose above 2.6 mmol/l after up to two doses. Dextrose gel reduced the frequency of treatment 274 failure compared with placebo (14% vs 24%; relative risk 0·57, 95% CI 0·33–0·98; p=0·04). Additional 275 important outcomes were reduction in admission to NICU for hypoglycemia 14% vs 25%; RR 0.54 (CI 276 0.31 – 0.93; p=0.03) and a greater number of babies receiving no supplementation with formula (7% vs 277 10%; p=0.04). 278

Outcomes 279

The cohort from the Sugar Babies trial and a second trial of 102 patients who received dextrose gel with 280 admission to NICU for monitoring with amplitude integrated EEG were evaluated together at 2 years of 281 age. [22] In both, the goal was to maintain blood glucose ³ 2.6 mmol/L. For the Sugar Babies cohort 282 alone, no difference in developmental outcomes were noted between control and dextrose gel groups. Of 283 concern though, was the finding of sixty-six children (36%) with neurosensory impairment overall for all 284 patients enrolled (1 severe, 6 moderate, 59 mild) with similar rates in both groups (dextrose 38% vs 285 placebo 34%, relative risk 1.11, 95% CI 0.75-1.63). When combined with the patients from the smaller 286 trial and the Sugar Babies group, again no difference in neurosensory impairment was found (risk ratio, 287 0.95; 95% confidence interval (CI), 0.75 to 1.20; P = 0.67). 288

The reasons for such a high rate of neurosensory impairment overall are unclear. Whether it is the 289 underlying conditions leading to hypoglycemia or the detrimental effect of hypoglycemia itself is 290 unknown. Supporting the former, is previous work showing that late preterms and those with intrauterine 291 growth restriction have independent risk for neurosensory impairment even with normoglycemia. [71]. 292 Finally, an interesting finding was that infants who tended to spend more time with blood glucose levels > 293 4.0 mmol/L in the first 48 hours had worse neurodevelopmental outcome. While this did not reach 294 statistical significance, it raises the question of whether overcorrection of low blood glucose may itself 295 lead to harm. 296

Investigations for causes of persistent hypoglycemia: 297

Generally, infants with hypoglycemia in the first 72 hours after birth do not require investigations unless 298 there is a strong clinical suspicion at that time of the neonate having a persistent hypoglycemic disorder, 299 such as recurrent severe hypoglycemia. Infants with hypoglycemia that persists beyond this transitional 300

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period, should be evaluated further for possible etiologies. If possible, with the presence of hypoglycemia 301 (glucose < 2.8 mmol/l) a critical sample should be obtained including a confirmatory plasma glucose, 302 beta-hydroxy-butyrate, bicarbonate, lactate, free fatty acids, insulin, growth hormone, cortisol and 303 carnitine. Further workup for possible etiologies should be done with collaboration with specialists in 304 endocrinology, and/or inborn errors of metabolism. 305

Summary 306

Although transient blood glucose levels as low as 1.8 mmol/L may be considered normal in healthy 307 babies in the first few hours after birth, adverse short and long-term outcomes may result from levels 308 lower than 2.6 mmol/L in those who are at-risk, particularly if the hypoglycemia is persistent or 309 symptomatic. Higher thresholds of 2.8 mmol/L for triggering investigation investigations and 3.3 mmol/L 310 for therapeutic targets are recommended after the initial transitional period that occurs in the first few 311 days after birth. Screening and intervention is therefore aimed at the detection and treatment of infants 312 who are at risk. 313

Recommendations 314

Routine screening of AGA infants at term is not recommended (Grade of Recommendation C). It 315 is recommended that IDMs (gestational or otherwise), preterm infants (< 37 weeks) and SGA 316 infants (weight < 10th %tile) be routinely screened for neonatal hypoglycemia (Grade of 317 Recommendation C). Until further data are available, LGA infants (weight > 90th %tile) should 318 be considered at risk (Grade of Recommendation D). 319

Blood glucose screening of asymptomatic, at-risk infants may be performed at 2 h of age and 320 every 3 h to 6 h after this, in keeping with breastfeeding practices. Testing may be discontinued 321 after 12 h in LGA infants and IDMs if blood glucose levels re main > 2.6 mmol/L, and after 24 h 322 in SGA and preterm infants if feeding has been established and blood glucose levels remain 323 at > 2.6 mmol/L. Symptomatic and unwell babies require immediate glucose testing (Grade of 324 Recommendation C). 325

It is recommended that, methods should be instituted to measure blood glucose that are quality-326 controlled, accurate and reliable in the range of 1 mmol/L to 3 mmol/L (Grade of 327 Recommendation D). 328

At-risk infants in the first 72 hours after birth with glucose levels < 1.8 mmol/L on one occasion 329 (assuming one effective feed), or repeatedly < 2.6 mmol/L, require intervention (Grade of 330 Recommendation C). Symptomatic infants should be treated immediately for blood glucose levels 331 < 2.6 mmol/L; there should be concurrent investigation and management of the underlying cause. 332

Enteral supplementation may be used in asymptomatic infants with blood glucose levels of 1.8 333 mmol/ L to 2.5 mmol/L to augment caloric intake, rechecking levels in 30 min to identify 334 persistent hypoglycemia (Grade of Recommendation D). 335

It is recommended that symptomatic, hypoglycemic infants (and asymptomatic infants who have 336 failed to respond to enteral supplementation) be treated with intravenous dextrose solution. 337 Consider investigation, consultation and pharmacological intervention if target blood glucose 338 levels are not achieved by intravenous dextrose (Grade of Recommendation C). 339

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Dextrose gel may be used as an alternative to intravenous therapy in asymptomatic infants with a 340

blood glucose < 2.6 mmol/L in addition to enteral supplementation. In symptomatic infants, 341 dextrose gel may also be used as a temporizing measure to raise blood glucose while awaiting the 342 establishment of an intravenous dextrose bolus and infusion (Grade of Recommendation B) 343

Infants with hypoglycemia persisting beyond the first 72 hours should be investigated further if 344 glucose levels <2.8 mmol. A critical sample should be collected in the presence of hypoglycemia. 345

Infants with persistent hypoglycemia beyond the initial 72 hours after birth should have 346 therapeutic glucose targets of > 3.3 mmol/L. 347

Infants with persistent hypoglycemia beyond the initial 72 hours after birth should have a 5-6 348 hour fast with maintenance of glucose > 3.3 mmol/L prior to discharge to ensure safety at home. 349

References 350

1. K Aziz, P Dancey; Canadian Paediatric Society, Fetus and Newborn Committee Paediatr Child 351 Health 2004;9(10):723-9.] 352

2. Oxford Centre for Evidence-Based Medicine. Levels of evidence and grades of recommendation. 353 Cornblath M and Reisner SH. New Engl J Med 1965;273:378 354

3. Hume R, McGeechan A, Burchell A. Failure to detect preterm infants at risk of hypoglycemia before 355 discharge. J Pediatr 1999;134:499-502. 356

4. Marcus C. How to measure and interpret glucose in neonates. Acta Paediatr 2001;90:963-4. 357 5. Hussain K, Sharief N. The inaccuracy of venous and capillary blood glucose measurement using 358

reagent strips in the newborn period and the effect of haemat ocrit. Early Hum Dev 2000;57:111-21. 359 6. Kuwa K, Nakayama T, Hoshino T, Tominaga M. Relationships of glucose concentrations in capillary 360

whole blood, venous whole blood and venous plasma. Clin Chim Acta 2001;307:187-92. 361 7. Beardsall K, Vanhaesebrouck S, Ogilvy-Stuart AL, Vanhole C, VanWeissenbruch M, Midgley P, 362

Thio M, Cornette L, Ossuetta I, Palmer CR, Iglesias I, de Jong M, Gill B, de Zegher F, Dunger DB. 363 Validation of the continuous glucose monitoring sensor in preterm infants. Arch Dis Child Fetal 364 Neonatal Ed. 2013 Mar;98(2):F136-40. 365

8. McKinlay CJD, Chase JG, Dickson J, Harris DL, Alsweiler JM, Harding JE. Continuous glucose 366 monitoring in neonates: a review. Maternal Health, Neonatology, and Perinatology 2017; 3(18): 367

9. Cornblath M, Reisner SH. Blood glucose in the neonate and its clinical significance. N Engl J Med. 368 1965 Aug 12;273(7):378-81. 369

10. Behrman RE, Kliegman R, Jenson HB. Nelson Textbook of Pediatrics, 16th edn. Philadelphia: WB 370 Saunders Company, 2000:533-4. 371

11. Sinclair JC. Approaches to the definition of neonatal hypoglycemia. Acta Paediatr Jpn 1997;39(Suppl 372 1):S17-20. 373

12. Cornblath M, Hawdon JM, Williams AF, et al. Controversies regarding definition of neonatal 374 hypoglycemia: Suggested operational thresholds. Pediatrics 2000;105:1141-5. 375

13. Hoseth E, Joergensen A, Ebbesen F, Moeller M. Blood glucose levels in a population of healthy, 376 breast fed, term infants of appropriate size for gestational age. Arch Dis Child Fetal Neonatal Ed 377 2000;83:F117-9. 378

14. Diwakar KK, Sasidhar MV. Plasma glucose levels in term infants who are appropriate size for 379 gestation and exclusively breast fed. Arch Dis Child Fetal Neonatal Ed 2002;87:F46-8. 380

-EMBARGO-


-EMBARGO-

15. Nicholl R. What is the normal range of blood glucose concentrations in healthy term newborns? Arch 381

Dis Child 2003;88:238-9. 382 16. Koivisto M, Blanco-Sequeiros M, Krause U. Neonatal symptomatic and asymptomatic hypoglycemia: 383

A fol low-up study of 151 children. Dev Med Child Neurol 1972;14:603-14. 384 17. Kinnala A, Rikalainen H, Lapinleimu H, Parkkola R, Kormano M, Kero P. Cerebral magnetic 385

resonance imaging and ultrasonography findings after neonatal hypoglycemia. Pediatrics 386 1999;103:724-9. 387

18. Cornblath M, Schwartz R. Outcome of neonatal hypoglycaemia. Complete data are needed.BMJ. 388 1999 Jan 16;318(7177):194-5. 389

19. McKinlay CJD(1)(2), Alsweiler JM(1)(2), Anstice NS(3), Burakevych N(1), Chakraborty A(1)(4), 390 Chase JG(5), Gamble GD(1), Harris DL(1)(6), Jacobs RJ(3), Jiang Y(1), Paudel N(3), San Diego 391 RJ(7), Thompson B(3)(4), Wouldes TA(7), Harding JE(1)Association of Neonatal Glycemia With 392 Neurodevelopmental Outcomes at 4.5 Years. JAMA Pediatr. 2017 Oct 1;171(10):972-983 393

20. Kerstjens JM(1), Bocca-Tjeertes IF, de Winter AF, Reijneveld SA, Bos AF. Neonatal morbidities and 394 developmental delay in moderately preterm-born children. Pediatrics. 2012 Aug;130(2):e265-72 395

21. Brand PLP, Molenaar NLD, Kaaijk C, Wierenga WS. Neurodevelopmental outcome of 396 hypoglycaemia in healthy, large for gestational age, term newborns. Arch Dis Child 2005;90:78–81 397

22. McKinlay CJ(1), Alsweiler JM, Ansell JM, Anstice NS, Chase JG, Gamble GD, Harris DL, Jacobs 398 RJ, Jiang Y, Paudel N, Signal M, Thompson B, Wouldes TA, Yu TY, Harding JE Neonatal Glycemia 399 and Neurodevelopmental Outcomes at 2 Years.N Engl J Med. 2015 Oct 15;373(16):1507-18. 400

23. Stanley CA, Baker L. The causes of neonatal hypoglycemia.N Engl J Med. 1999 Apr 401 15;340(15):1200-1. 402

24. Cornblath M, Hawdon JM, Williams AF, et al. Controversies regarding definition of neonatal 403 hypoglycemia: Suggested operational thresholds. Pediatrics 2000;105:1141-5. 404

25. Thornton PS, Stanley CA, De Leon DD, Harris D, Haymond MW, Hussain K, Levitsky LL, Murad 405 MH, Rozance PJ, Simmons RA, Sperling MA Weinstein DA(11), White NH(12), Wolfsdorf JI; 406 Pediatric Endocrine Society. Recommendations from the Pediatric Endocrine Society for Evaluation 407 and Management of Persistent Hypoglycemia in Neonates, Infants, and Children.J Pediatr. 2015 408 Aug;167(2):238-45 409

26. Kalhan S, Parimi P. Gluconeogenesis in the fetus and neonate. Semin Perinatol 2000;24:94-106. 410 27. Cornblath M, Ichord R. Hypoglycemia in the neonate. Semin Perinatol 2000;24:136-49. 411 28. Kramer MS, Platt RW, Wen SW, et al, and the Fetal/Infant Health Study Group of the Canadian 412

Perinatal Sur veillance System. A new and improved population- based Canadian reference for birth 413 weight for gestation al age. Pediatrics 2001;108:E35. 414

29. Lubchenco LO, Bard H. Incidence of hypoglycemia in newborn infants classified by birth weight and 415 gestation al age. Pediatrics 1971;47:831-8. 416

30. Hawdon JM, Ward Platt MP. Metabolic adaptation in small for gestational age infants. Arch Dis 417 Child 1993;68:262-8. 418

31. Stenninger E, Schollin J, Aman J. Early postnatal hypoglycemia in newborn infants of diabetic 419 mothers. Acta Paediatr 1997;86:1374-6. 420

32. Holtrop PC. The frequency of hypoglycemia in full-term large and small for gestational age 421 newborns. Am J Perinatol 1993;10:150-4. 422

33. de Rooy L, Hawdon J. Nutritional factors that affect the postnatal metabolic adaptation of full-term 423 small- and large-for-gestational-age infants. Pediatrics 2002;109:E42. 424

-EMBARGO-


-EMBARGO-

34. Bateman BT, Patorno E, Desai RJ, Seely EW, Mogun H, Maeda A, Fischer MA, Hernandez-Diaz S, 425

Huybrechts KF. Late Pregnancy ? Blocker Exposure and Risks of Neonatal Hypoglycemia and 426 Bradycardia.Pediatrics. 2016 Sep;138(3) 427

35. Gyamfi-Bannerman C, Thom EA, Blackwell SC, Tita AT, Reddy UM, Saade GR, Rouse DJ, 428 McKenna DS, Clark EA, Thorp JM Jr, Chien EK, Peaceman AM, Gibbs RS, Swamy GK, Norton 429 ME, Casey BM, Caritis SN, Tolosa JE, Sorokin Y, VanDorsten JP, Jain L. Antenatal Betamethasone 430 for Women at Risk for Late Preterm Delivery. N Engl J Med. 2016 Apr 7;374(14):1311-20 431

36. Burton BK. Inborn errors of metabolism in infancy: A guide to diagnosis. Pediatrics 1998;102:E69. 432 37. Hussain K, Blankenstein O, De Lonlay P, Christesen HT. Hyperinsulinaemic hypoglycaemia: 433

biochemical basis and the importance of maintaining normoglycaemia during management. Arch Dis 434 Child. 2007 Jul;92(7):568-70. 435

38. Beard AG, Panos TC, Marasigan BV, Eminians J, Kennedy HF, Lamb J. Perinatal stress and the 436 prema ture neonate. II. Effect of fluid and calorie deprivation on blood glucose. J Pediatr 437 1966;68:329-43 438

39. Hawdon JM, Ward Platt MP, Aynsley-Green A. Patterns of metabolic adaptation for preterm and 439 term infants in the first neonatal week. Arch Dis Child 1992;67:357-65. 440

40. Auer RN, Siesjö BK. Hypoglycemia: Brain neurochemistry and neuropathology. Baillieres Clin 441 Endocrinol Metab 1993;7:611-25. 442

41. Lucas A, Morley R, Cole TJ. Adverse neurodevelopmental outcome of moderate neonatal 443 hypoglycemia. BMJ 1988;297:1304-8. 444

42. Duvanel CB, Fawer CL, Cotting J, Hohlfeld P, Matthieu JM. Long-term effects of neonatal 445 hypoglycemia on brain growth and psychomotor development in small-for- gestational-age preterm 446 infants. J Pediatr. 1999;134:492-8. 447

43. Stenninger E, Flink R, Eriksson B, Sahlen C. Long term neurological dysfunction and neonatal 448 hypoglycemia af ter diabetic pregnancy. Arch Dis Child Fetal Neonatal Ed 1998;79:F174-9. 449

44. Williams AF. Hypoglycemia of the newborn: A review. Bull World Health Organ 1997;75:261-90. 450 45. Steinkrauss L, Lipman TH, Hendell CD, Gerdes M, Thornton PS, Stanley CA. Effects of 451

hypoglycemia on developmental outcome in children with congenital hyperinsulinism. J Pediatr Nurs. 452 2005 Apr;20(2):109-18. 453

46. Mitrakou A, Ryan C, Veneman T, Mokan M, Jenssen T, Kiss I, Durrant J, Cryer P, Gerich J. 454 Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral 455 dysfunction. Am J Physiol. 1991 Jan;260(1 Pt 1):E67-74. 456

47. Bonnefont JP(1), Specola NB, Vassault A, Lombes A, Ogier H, de Klerk JB, Munnich A, Coude M, 457 Paturneau-Jouas M, Saudubray JM. The fasting test in paediatrics: application to the diagnosis of 458 pathological hypo- and hyperketotic states. Eur J Pediatr. 1990 Dec;150(2):80-5. 459

48. van Veen MR, van Hasselt PM, de Sain-van der Velden MG, Verhoeven N, Hofstede FC, de Koning 460 TJ, Visser G. Metabolic profiles in children during fasting. Pediatrics. 2011 Apr;127(4):e1021-7. 461

49. Mehta A. Prevention and management of neonatal hyopoglycaemia. Arch Dis Child Fetal Neonatal 462 Ed 1994;70:F54-9; discussion F59-60. 463

50. Hawdon JM, Ward Platt MP, Aynsley-Green A. Preven tion and management of neonatal 464 hypoglycemia. Arch Dis Child Fetal Neonatal Ed 1994;70:F60-4; discussion F65. 465

51. Cornblath M. Neonatal hypoglycemia. In: Donn SM, Fisher CW, eds. Risk Management Techniques 466 in Peri natal and Neonatal Practice. Armonk, NY: Futura Pub lishing Company Inc, 1996:437-48. 467

-EMBARGO-


-EMBARGO-

52. Weston PJ, Harris DL, Battin M, Brown J, Hegarty JE, Harding JE. Oral dextrose gel for the 468

treatment of hypoglycaemia in newborn infants. Cochrane Database Syst Rev. 2016 May 4;(5) 469 53. Marchini G, Persson B, Berggren V, Hagenas L. Hunger behaviour contributes to early nutritional 470

homeostasis. Acta Paediatr 1998;87:671-5. 471 54. Nechyba C, Gunn VL, eds. Harriet Lane Handbook: A Manual for Pediatric House Officers, 16th 472

edn. St Louis: Mosby Inc, 2002:385-6. 473 55. McInerney, C. M., & Gupta, A. (2015). Delaying the First Bath Decreases the Incidence of Neonatal 474

Hypoglycemia . Journal of Obstetric, Gynecologic, & Neonatal Nursing,, 44, S73-74. 475 56. Singhal PK, Singh M, Paul VK, et al. Prevention of hypoglycemia: A controlled evaluation of sugar 476

fortified milk feeding in small-for-gestational age infants. Indian Pediatr 1992;29:1365-9. 477 57. Singhal PK, Singh M, Paul VK, Malhotra AK, Deorari AK, Ghorpade MD. A controlled study of 478

sugar-fortified milk feeding for prevention of neonatal hypoglycemia. Indian J Med Res 1991;94:342-479 5. 480

58. Kalhan SC, Savin SM, Adam PA. Measurement of glucose turnover in the human newborn with 481 glucose-1-13C. J Clin Endocrinol Metab 1976;43:704-7. 482

59. Bier DM, Leake RD, Haymond MW, et al. Measurement of “true” glucose production rates in infancy 483 and childhood with 6,6-dideuteroglucose. Diabetes 1977;26:1016-23. 484

60. Sunehag A, Ewald U, Larsson A, Gustafsson J. Glucose production rate in extremely immature 485 neonates ( 28 weeks) studied by use of deuterated glucose. Pediatr Res 1993;33:97-100. 486

61. King KC, Tserng KY, Kalhan SC. Regulation of glucose production in newborn infants of diabetic 487 mothers. Pediatr Res 1982;16:608-12. 488

62. Lilien LD, Pildes RS, Srinivasan G, Voora S, Yeh TF. Treatment of neonatal hypoglycemia with 489 minibolus and intravenous glucose infusion. J Pediatr 1980;97:295-8. 490

63. http://nicutools.org/MediCalcs/Glucose.php3 491 64. Vanhatalo T, Tammela O. Glucose infusions into peripheral veins in the management of neonatal 492

hypoglycemia--20% instead of 15%? Acta Paediatr. 2010 Mar;99(3):350-3. 493 65. Wu PY, Modanlou H, Karelitz M. Effect of glucagon on blood glucose homeostasis in infants of 494

diabetic moth ers. Acta Paediatr Scand 1975;64:441-5. 495 66. Carter PE, Lloyd DJ, Duffty P. Glucagon for hypogly caemia in infants small for gestational age. 496

Arch Dis Child 1988;63:1264-6. 497 67. Hawdon JM, Aynsley-Green A, Ward Platt MP. Neonatal blood glucose concentrations: Metabolic 498

effects of intra venous glucagons and intragastric medium chain triglyc eride. Arch Dis Child 499 1993;68:255-61. 500

68. Charsha DS, McKinley PS, Whitfield JM. Glucagon infu sion for treatment of hypoglycemia: 501 Efficacy and safety in sick, preterm infants. Pediatrics 2003;111:220-1. 502

69. Miralles RE, Lodha A, Perlman M, Moore AM. Experi ence with intravenous glucagon infusions as a 503 treatment for resistant neonatal hypoglycemia. Arch Pediatr Ado lesc Med 2002;156:999-1004. 504

70. Harris DL, Weston PJ, Signal M, Chase JG, Harding JE.Dextrose gel for neonatal hypoglycaemia (the 505 Sugar Babies Study): a randomised, double-blind, placebo-controlled trial. Lancet. 2013 Dec 506 21;382(9910):2077-83. 507

71. Arcangeli T, Thilaganathan B, Hooper R, Khan KS, Bhide A. Neurodevelopmental delay in small 508 babies at term: a systematic review. Ultrasound Obstet Gynecol. 2012 Sep;40(3):267-75. 509

72. Srinivasan G, Pildes RS, Cattamanchi G, Voora S, Lilien LD. Plasma glucose values in normal 510 neonates: A new look. J Pediatr 1986;109:114-7. 511

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