Are there alternatives to over-the-counter diabetes-care glucose-gels for transitional neonatal hypoglycemia?

Abstract

Transitional neonatal hypoglycemia is common in at-risk well newborns, requires immediate attention, interferes with breastfeeding, and frequently results in separation of mothers from their babies. Breastfeeding shortly after birth and screening at-risk newborns at 2 hours of age is standard practice in Canada. In the Sugar Babies Trial, a custom-made 40% glucose-gel massaged to the buccal mucosa in at-risk infants decreased intravenous glucose treatment, but not neonatal intensive care unit admission. It increased the rate of full breastfeeding after discharge but experts suggest that additional evidence is needed. Further, commercially available neonatal glucose-gels do not exist, so practitioners around the world have started using diabetes-care products, which do not meet standards for use in newborns. Here, we provide a condensed summary of the topic and of management alternatives.

Transitional neonatal hypoglycemia (TNH) affects up to 47% of well orally feeding newborns with risk factors (1). Maximizing skin-to-skin contact, initiating breastfeeding at birth, and screening at-risk newborns at 2 hours of age decrease maternal-infant separation and over-diagnosis of TNH (2,3). Breastfeeding supplementation in TNH with human-milk or formula has long been standard (2,3) but has not been systematically studied. Intravenous dextrose is administered to newborns that remain hypoglycemic despite supplementation (1–3).

In the 2013 Sugar Babies Trial (SBT) (1), 0.2 g/kg (0·5 mL/kg) of buccal glucose was given to at-risk newborns with hypoglycemia, using a custom-made 40% glucose-gel, in addition to supplemental feeding. This was well tolerated and decreased the need for intravenous glucose treatment but not for neonatal intensive care unit admissions, and improved the rate of full breastfeeding after discharge. However, the quality of this evidence has been considered moderate to very low (4). Also, glucose-gel for prevention of TNH did not decrease maternal-infant separation for hypoglycemia or improve breastfeeding (5). Thus, some reviewers concluded that additional evidence is needed to assess the overall efficacy and safety of this treatment (4–7).

After the SBT and subsequent nonrandomized studies, many started re-purposing diabetes-care products, such as Insta-Glucose^R and Dex4^R gels, which are not formulated for and may be considered unsuitable for newborns (8). Further, Dex4^R contains xantham-gum, a thickener that has been associated with necrotizing enterocolitis in premature infants (9).

While more detailed reviews are available on this subject (4,6,7), this review is intended to facilitate teaching and deliberations regarding supplementation strategies for newborns with TNH in support of upcoming versions of Acute Care of At-Risk Newborns (ACoRN) and Canadian Paediatric Society (CPS) guidelines, and outreach education. Specifically, we consider it timely and necessary to consider if there are alternatives to diabetes-care gels.

METHODS

We reviewed the early management of newborns at-risk for and/or with TNH, as recommended in ACoRN-2012 and the 2004 CPS guidelines (reaffirmed in 2018) (2,3), the glucose-gel randomized trials (1,5,14), the Cochrane Database of Systematic Reviews (4,6), the Canadian Agency for Drugs and Technologies in Health (CADTH) rapid response report (7), and BC Women’s Hospital’s internal protocol (13).

We investigated the state of commercial development of glucose-gel preparations for newborns and if a 40% glucose-gel could be made in-house.

We reviewed literature on the clinical response to oral glucose supplementation in newborns (14) and in diabetic children and adults (10,11), and compared supplementation strategies including types and doses of carbohydrate administered (1–3).

RESULTS

Prevention guidelines for TNH in babies at-risk remain simple; skin-to-skin contact, breastfeeding shortly after birth and screening for TNH are uniformly recommended (1–3,12,13).

In terms of oral supplementation, Table 1 compares the dose and type of carbohydrate provided by different strategies (1–3,13).

Table 1.

Carbohydrate (CHO) supplementation recommended or administered by referenced sources, and modelling of alternative supplementation options

		Feed volume (mL/kg)	Supplemental carbohydrate (g/kg)	Supplemental carbohydrate ("gel units")
A	With ACoRN 2012 supplemental volume of 8 mL/kg (2)	8.0	0.56	2.80
	With CPS Guidelines (2004, reaffirmed in 2018) (5)	5.0–10.0	0.35–0.70	1.75–3.50
	With BC Women's Hospital 2019 (8)	5.0	0.35	1.75
B	SBT buccal 0.2 g/kg using 40% gel (1)	0.5	0.20	1.00
	SBT milk/formula-supplementation given to 59% (1)	5.9	0.41	2.05
	SBS-supplemented milk/formula plus 0.2 g/kg using 40% gel	6.4	0.61	3.05
C	If ACoRN 2020 supplemented with 5 mL/kg feed	5.0	0.35	1.75
	then, supplemented 5 mL/kg volume plus 40% gel	5.5	0.55	2.75
	If ACoRN 2020 supplemented with 6 mL/kg	6.0	0.42	2.10
	then, supplemented 6 mL/kg volume plus 40% gel	6.5	0.62	3.10
D	Oral dextrose modelling: 0.2 g/kg using D50%	0.4	0.20	1.00

ACoRN = Acute Care of At-Risk Newborn guidelines; CPS = Canadian Paediatric Society guidelines; SBT = Sugar Babies Trial.

The term carbohydrate is used irrespective of whether it is lactose or glucose. For simplicity, the carbohydrate content of breast milk and formula has all been estimated at 7 g/dL, in this table. However, the carbohydrate content of colostrum approximates 3.2 g/dL on day 1, of mature breast milk 6.9 to 7.2 g/dL, of donor milk 6.4 to 7.6 g/dL, and of Enfamil A+ 68 kcal/100 mL + Fe (RTF) (used as an example) is 7.6 g/dL. Also, note that the volume of colostrum in the first 6 h is unlikely to exceed 0.5 mL/kg.

‘Gel units’ indicates the total carbohydrate supplemented divided by the 0.2 g/kg dextrose supplemented in the Sugar Babies Trial.

While the administration of glucose versus lactose is different metabolically, it should be noted that in the SBT oral glucose gel did not correct documented hypoglycaemia more rapidly than did feeding alone, and that neither breastfeeding nor expressed breast milk increased the blood glucose concentration (13).

Whether administering oral glucose or milk or both, it is critical to check the blood glucose level 30 minutes after completing the treatment.

ACoRN-2012 recommends supplementing breastfeeding using 8 mL/kg q2h of human-milk or formula, and checking blood glucose 1 hour later (3); this supplements 0.56 g/kg of carbohydrate as lactose.

In the SBT (1,14), 95% of babies who had hypoglycemia on screening were breastfed, 83% received expressed breast milk, and 59% received formula in addition to the buccal glucose or placebo. The median number of expressed-milk feeds was 5 and the median volume was 0.5 mL/kg. The median number of formula feeds was 9 and median volume was 4.5 mL/kg. Therefore, most infants supplemented with formula alone would have received 0.32 g/kg of carbohydrate as lactose; those in the buccal glucose group would have received this plus 0.2 g/kg as glucose.

While the administration of glucose versus lactose is different metabolically, in the SBT oral glucose-gel did not correct documented hypoglycemia more rapidly than did formula feeding alone (14), and neither did breastfeeding nor expressed breast milk increase the blood glucose concentration (14); however, there was an unexplained reduction in the need for a second treatment associated with breastfeeding, independent of the initial blood glucose concentration (14).

Forty percent glucose-gels formulated for newborns are not yet commercially available. Sandbox Medical LLC of Massachusetts abandoned the development of a 40% glucose-gel in 2019 due to the inability to make stable batches (Reid McCarty, personal communication, January 24, 2019). At BC Women’s Hospital, compounding gel-formulations in larger quantities has been considered impractical and at-risk of microbial contamination (Dr Roxane Carr, Clinical Coordinator, Pharmacy Department, personal communication, January 22, 2019).

Oral glucose in water produces the fastest rise in blood glucose in hypoglycemic diabetics, compared to milk and orange juice which “are slower to increase blood glucose levels and provide symptom relief” (10,11).

We did not find literature describing a differential response to buccal versus gastric glucose supplementation in any population, or supporting that the glucose in gels is absorbed buccally in newborns, as is frequently affirmed in the glucose-gel literature. We did find, however, that glucose-gels have the slowest absorption and “must be swallowed to have a significant effect” (10,11).

DISCUSSION

If a 0.2 g/kg oral glucose-boost was included in the ACoRN 2020 guideline, this would theoretically allow decreasing milk/formula supplementation from 8 to 5 mL/kg, and still match its currently recommended carbohydrate supplementation; indeed, this would slightly exceed the estimated carbohydrate supplementation used in the SBT.

With no 40% glucose-gel commercially formulated for newborns (8), three possible alternatives exist to provide an oral glucose-boost:

• 1) Implement protocols similar to the SBT using diabetes-care glucose-gels. Some hospitals and regional/national organizations have done so, before or despite concerns over use of diabetes-care glucose-gels in newborns, and others have published supportive nonrandomized data (12).

• 2) Until there is a commercial glucose gel for newborns, continue using only milk/formula to supplement breastfeeding, as has been standard in ours and other centres, reflecting ACoRN-2012 and CPS guidelines (2,3,13). The focus would then be on maximizing compliance, and tracking effectiveness and outcomes (13).

• 3) Consider a protocol where the 0.2 g/kg glucose supplementary-boost is administered orally using 0.4 mL/kg of D50%W USP. D50%W is available in every hospital, is pharmacologically pure, and has reliable dextrose content allowing accurate and low volume dosing similar to the SBT. Dextrose solutions, including D50%W, have been investigated as substitutes for 25% sucrose for newborn procedural pain control (15). No references exist for D50%W use as a replacement of 40% glucose gel for hypoglycemia.

Whether administering oral glucose or milk or both, it is critical to check the blood glucose level 30 minutes after completing the treatment.

Whichever the institutional choice, management protocols and checklists should be used to decrease practice variation in how TNH stabilization guidelines are actually followed. Specifically, checklists are auditable, improve outcomes, and reduce patient harm by improving standardization and communication, and facilitating the measurement of compliance and outcomes (16–18).

Funding: There are no funders to report for this submission.

Potential Conflicts of Interest: All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Author contributions: AS had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: AS, HO, EK, DM, RE. Analysis and interpretation of data: AS, HO, EK, DM, RE. Drafting of the manuscript: AS, HO. Critical revision of the manuscript for important intellectual content: AS, HO, EK, DM, RE. Administrative, technical, or material support: AS.

Internal review and feedback: Dr Pascal Lavoie, Neonatologist, BC Women’s Hospital; Division of Neonatology, Department of Pediatrics, University of British Columbia, Vancouver.

External review and feedback: Dr Michael Narvey, Head of Neonatology, Health Sciences Centre & St Boniface Hospital, University of Manitoba.

The terms glucose and dextrose are used indistinctly in this manuscript, attempting to follow usual terminology.