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. 2023 Dec 1;102(48):e36137. doi: 10.1097/MD.0000000000036137

Oral glucose gel in the prevention of neonatal hypoglycemia: A systematic review and meta-analysis

Meng-Qin Wang a, Ya-Ning Zheng b, Ying Zhuang a,*
PMCID: PMC10695523  PMID: 38050311

Abstract

Background:

Neonatal hypoglycemia (NH) is the most prevalent metabolic disorder in neonates and glucose gel in oral solution is a relatively new treatment option for NH. We aimed to determine whether oral glucose gel can prevent NH.

Methods:

We conducted an open literature search using PubMed, Embase, Cochrane Library, and Web of Science. We used relative risk as the statistical data, expressed each outcome effect as a 95% confidence interval, and conducted a heterogeneity test. If heterogeneity statistics indicated that I2 was ≥ 50%, the random effects model analysis was used; otherwise, the fixed effects model analysis was conducted, and sensitivity analyses were conducted for all outcomes.

Results:

In this review, we included a total of 10 studies involving 4801 neonates. Meta-analysis revealed that there were no significant differences between the preventive oral glucose gel group and the control group in terms of blood glucose concentration, glucose concentration 30 minutes after the first breastfeeding, length of stay, Bayley-III composite score, subsequent need for intravenous injection of glucose, 24-hour glucose > 50 mg/dL, separation from mother for treatment of hypoglycemia/admitted to neonatal intensive care unit for hypoglycemia, normoglycemia after 1 to 2 treatments, or normoglycemia after more than 2 treatments, breastfeeding at discharge, delayed feeding, neurosensory impairment, parental satisfaction, developmental delay, and seizure. The subsequent intake was significantly lower in the glucose gel group compared to the control group.

Interpretation:

The use of oral glucose gel as a preventative measure may not reduce the incidence of NH. In order to assess the efficacy of glucose gel in preventing NH, a more high-quality, large-sample, and rigorously designed randomized controlled trial is required.

Keywords: Meta-analysis, neonatal hypoglycemia, oral glucose gel, systematic review

Strengths and limitations of this study:

  1. First, this is a meta-analysis, and we determined that oral glucose gel is safe for neonates.

  2. The outcomes of this meta-analysis can serve as an important resource for the prevention of hypoglycemia in neonates.

  3. In order to examine the efficacy of oral glucose gel in preventing neonatal hypoglycemia, data were collected from numerous comprehensive databases and additional studies were included in this review.

  4. Small sample size restricted the scope of this research.

1. Introduction

Neonatal hypoglycemia (NH) is the most prevalent metabolic disorder in neonates, with a prevalence ranging from 5% to 15%.[1,2] The primary source of energy for the brain is glucose, and NH can cause brain damage and death.[3–5] Infants born with a risk for NH may have an increased risk of developmental retardation as they grow older. Although the impact or duration of hypoglycemia prior to morbidity is unknown, it is well-known that even asymptomatic infants can develop negative outcomes.[6–8] Consequently, it is essential to take necessary steps to reduce the incidence of NH.

Currently, hypoglycemia can be treated with complementary feeding (expressed breast milk or infant formula), but intravenous glucose injection cannot be administered.[1,9] Options for treatment depend on birth weight and gestational age. For late preterm and full-term infants, attention should be paid to feeding and heightened monitoring, and require repeated, painful blood tests.[10] If the blood glucose level of the infant remains low, the infant must be transferred to the neonatal intensive care unit (NICU) for intravenous glucose administration.[10,11] However, both strategies may have a negative impact on breastfeeding initiation.[12] Glucose gel in oral solution is a relatively new treatment option for NH, with the potential advantage of keeping the mother and baby together during treatment; it is also simple to administer and inexpensive.[10,13] Based on studies, glucose gel is effective in controlling NH during postpartum ward management, thereby reducing admissions to the NICU.[1,10] Glucose gel has been widely used in clinical practice for preventative purposes. In a randomized controlled trial (RCT),[14] 20 infants were randomly assigned to the breastfeeding group or the breastfeeding + 400 mg/kg glucose gel group on the first day after birth, however, the results demonstrated that there was no difference in blood glucose concentration between 15 and 30 minutes of treatment.

In this study, a systematic review and meta-analysis were conducted to evaluate the efficacy of glucose gel in preventing NH.

2. Methods

2.1. Retrieval strategy

PubMed, Embase, Cochrane Library, and Web of Science were queried from the date of database establishment to December 26, 2020, to retrieve published articles. “Glucose gel” or “glucose” or “d-glucose” or “d glucose” or “glucose” or “glucose (alpha-d)-isomer” or “anhydrous glucose” or “glucose, ‘glucose’ isomer” or “L-glucose” or “glucose” or “glucose” (isomer); “infants” or “newborns” or “neonate”; “hypoglycemia” or “postprandial hypoglycemia” or “reactive hypoglycemia” or “hypoglycemia, reactive” or “fasting hypoglycemia” or “hypoglycemia, fasting” or “hypoglycemia after absorption” or “hypoglycemia, after absorption.”

2.2. Inclusion and exclusion criteria

Inclusion criteria: NH; neonates who received oral glucose gel for preventive therapy were included in the experimental group, while those not administered oral glucose gel or who received delayed treatment were included in the control group; RCTs, quasi-experimental studies, or cohort studies; English literature.

Exclusion criteria: Animal experiments; materials unrelated to the topic; reviews, meta-analyses, protocols, case reports, and conference abstracts; studies from which it was impossible to extract valid data.

2.3. Quality assessment and data extraction

For RCTs and quasi-experimental studies, the literature quality was evaluated using a modified Jadad scale (total score: 7 points; low quality: 1–3 points; high quality: 4–7 points). The modified Newcastle-Ottawa Scale (total score: 10 points, low quality: < 5 points, high quality: ≥ 5 points) was used to evaluate the quality of the cohort study literature.[15]

The following information was compiled for each study: author, year, country, design, patient, group, intervention, pregnancy, gender, birth weight, quality, and outcome.

3. Results

The prevention of NH with oral glucose gel was evaluated based on changes in neonatal blood glucose concentration, the next intake, glucose concentration 30 minutes after the first feeding, length of stay, Bayley-III composite score, the need for intravenous injection of glucose, blood glucose > 50 mg/dL for 24 hours, separation from mother for treatment of hypoglycemia/admission to NICU for hypoglycemia, normoglycemia after 1 or 2 treatment attempts, and normoglycemia after more than 2 treatments, breastfeeding at discharge, delayed feeding, neurosensory impairment, parental satisfaction, developmental delay, and seizure.

3.1. Statistical analysis

For statistical analysis, Stata 15.1 software (Stata Company, College Station, TX, USA) was utilized. Counting data were analyzed using relative risk (RR), each outcome effect was expressed as a 95% CI, and the heterogeneity test was conducted. If I2 was ≥ 50%, the random effects model analysis was conducted based on heterogeneity statistics; otherwise, the fixed effects model analysis was conducted. Sensitivity analyses were conducted for all outcomes. P < .05 indicated a statistically significant difference.

3.2. Ethics approval and consent to participate

There were no participants in this study. Ethical approval and consent were not required as this study was based on publicly available data.

4. Results

A total of 3349 articles were initially retrieved using the retrieval strategy. After removing duplicates, 2100 articles remained; 68 articles were initially screened based on titles and abstracts, and 10 were finalized and selected for this study.[1,10,14,16–22] The flowchart is depicted in Figure 1. This study included 4801 neonates, of which 2551 were assigned to the experimental group and 2250 were assigned to the control group. Table 1 displays the baseline characteristics of the included studies.

Figure 1.

Figure 1.

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The flow diagram of the search strategy.

Table 1.

Baseline characteristics of included studies.

Author Yr Country Study design Patients Groups Intervention N Gestation (wk) Male/female Birthweight (g) Quality Outcomes
Troughton 2000 Ireland A randomized controlled trial Neonates admitted to the neonatal intensive care with hypoglycemia T Receiving 1 mL/kg of 40% dextrose gel massaged into the buccal mucosa plus a feed 39 ≥36 NA NA 3 The change in blood glucose concentration, subsequent requirement for intravenous dextrose, volume of the next feed taken
C A feed alone 36
Harris 2013 New Zealand A randomized, double-blind, placebo-controlled trial Babies at risk of neonatal hypoglycemia T 200 mg/kg (0.5 mL/kg) gel into the buccal mucosa 118 37.4 ± 1.6 48/70 3091 ± 824 6 Receipt of intravenous treatment for hypoglycemia, Admitted to NICU for treatment of hypoglycemia
C 2% carboxymethyl cellulose placebo gel 119 37.2 ± 1.6 65/54 3031 ± 782
Harris 2015 New Zealand A randomized, double-blind, placebo-controlled trial Babies at risk of neonatal hypoglycemia T 200 mg/kg (0.5 mL/kg) gel into the buccal mucosa 90 37.7 ± 1.6 36/54 3139 ± 804 6 Neurosensory impairment, Developmental delay, Bayley-III Composite scores, Seizures
C 2% carboxymethyl cellulose placebo gel 94 37.7 ± 1.6 48/46 3049 ± 803
Hegarty 2016 New Zealand A randomized, double-blind, placebo-controlled dose-finding trial Babies at risk of hypoglycemia T 40% dextrose gel 277 38 ± 1 139/138 3244 ± 607 4 Admission to NICU for Hypoglycaemia, Breastfeeding at Discharge, Delayed Feeding, Parental Satisfaction
C Placebo gel 138 38 ± 1 63/75 3248 ± 633
Ter 2016 Australia Prospective cohort study Neonates treated for hypoglycemia T After the implementation of 40% dextrose gel 100 38.3 ± 1.5 62/38 3113.2 ± 726.6 3 Admissions to NICU, Normoglycaemia after 1 or 2 treatment attempts, Normoglycaemia after more than 2 treatment attempts, Length of hospital stay
C Before the implementation of 40% dextrose gel 100 37.8 ± 1.4 43/57 3178.7 ± 823.0
Harris 2017 New Zealand A randomized controlled trial Infants with hypoglycemia T Dextrose gel plus feeding with formula 147 37.6 (35.0–42.3) 143/152 2890 (1590–5550) 5 The change in blood glucose concentration, Episodes Treated with 2 Doses of Gel
C Placebo gel plus feeding with formula 148
Scheans 2017 America Prospective cohort study Infants at risk of hypoglycemia T Receiving 40% glucose gel 1084 NA NA NA 4 Infants admitted to NICU for hypoglycemia
C Not receiving 40% glucose gel 870 NA NA NA
Coors 2018 America A quasi-experimental pilot study Infants presumed to be late preterm T 0.5 mL/kg was rubbed into the buccal mucosa after finishing the first feeding 72 37.9 ± 1.5 43/29 3233 ± 620 5 Glucose concentration 30 min after the first milk feeding, The rate of NICU admission for IV dextrose
C A feed alone 164 38.5 ± 1.7 82/82 3487 ± 761
Makker 2018 America A retrospective study Infants at risk for NH admitted to the newborn nursery T Admitted to the newborn nursery in yr 1 421 37.4 ± 1.8 224/197 2984 ± 670 6 Transfer to NICU for treatment with a continuous infusion of dextrose
C Admitted to the newborn nursery in yr 2 383 37.7 ± 1.7 184/199 2996 ± 657
Stanzo 2019 America Quasi-experimental, pre- and postintervention Healthy newborns born at 35 wk gestation or later who were at risk for NH T After the implementation of dextrose gel 203 38.6 ± 1.4 102/101 3380.4 ± 709.4 4 Blood glucose > 50 mg/dL at 24 h, Exclusive breastfeeding at discharge, NICU admission, Seizures
C Before the implementation of dextrose gel 198 38.4 ± 1.5 91/107 3326.8 ± 709.7
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40% dextrose given according to usual clinical guidelines after the baby had failed treatment; T = Test; C = Control; NICU = neonatal intensive-care unit; Bayley-III = Bayley Scales of Infant and Toddler Development, Third Edition; NH = Neonatal hypoglycemia; NA = Represents missing data.

4.1. Next feeding and changes in blood glucose concentration

Troughton et al compared the changes in blood glucose concentration before and after treatment in the experimental group and the control group, and found no statistically significant difference between the 2 groups after treatment (P = .2).[14] The results of their study also indicated that the subsequent feeding was significantly lower in the glucose gel group than in the control group (P = .001).

4.2. Glucose concentration 30 minutes after the first feeding

Coors et al measured glucose concentrations 30 minutes after the initial feeding (control group) or after administering glucose gel (preventive participants).[16] The bivariate analysis revealed no difference between the prevention group and the control group in terms of the initial glucose concentration (52.1 ± 17.1 vs 50.5 ± 15.3 mg/dL, P = .69).

4.3. Length of stay

In a study evaluating the use of glucose gel in the control of NH, it was determined that the length of stay in the postnatal ward were comparable for all neonates receiving treatment for hypoglycemia (P = .55).[1]

4.4. Bayley-III composite score and neurosensory impairment and developmental retardation

Mild developmental retardation (Bayley-III cognitive or language score is 1–2 SDs below the mean), moderate (Bayley-III cognitive or language score is 2–3 SDs below the mean), or severe (Bayley-III cognitive or language score is 3–5 SDs below the mean) Harris et al discovered that the mean Bayley-III cognitive or language score among all children was 0.25 to 0.5 SD below the mean, neurosensory impairment was found in 66 children (36%), and impairment rates were comparable (38% in the glucose group and 34% in the placebo group, RR = 1.11, 95% CI: 0.75–1.50, P = .60).[17] In addition, developmental retardation was found in 61 children (33%) (severe: 1, moderate: 6, mild: 54), and incidence rates were comparable in both treatment groups (34% in the glucose group and 32% in the placebo group, RR = 1.07, 95% CI: 0.71–1.61, P = .75).

4.5. Subsequent need for intravenous injection of glucose

Two studies were included on the need for subsequent intravenous glucose administration.[10,14] All of the heterogeneity test results were statistically significant (I2 = 95.9%), so the random effects model was used for analysis. The results of the combined study revealed no statistically significant difference (RR = 0.808, 95% CI: 0.291–2.246, P = .682). After being administered oral glucose gel, there was no difference between the experimental group and the control group regarding the need for intravenous glucose injection (Fig. 2).

Figure 2.

Figure 2.

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Forest plot of subsequent need for intravenous dextrose between the experimental group and control group.

4.6. Blood glucose > 50 mg/dL at 24 hours

In a study evaluating the effect of glucose gel on neonates with the risk of NH in a pediatric hospital,[22] the proportion of neonates with 24-hour blood glucose > 50 mg/dL before and after the intervention did not differ significantly (67.3% vs 70.4%, P = .27).

4.7. Separation from mother for treatment of hypoglycemia/admitted to NICU for hypoglycemia

Seven studies were included to evaluate separation from mother for hypoglycemia treatment/admission to the NICU for hypoglycemia.[1,10,16,19–22] The results of the heterogeneity test indicated that the difference was statistically significant (I2 = 81.9%); thus, the random effects model was utilized for analysis. The combined study results indicated that there was no statistically significant difference (RR = 0.592, 95% CI: 0.334–1.051, P = .073) (Fig. 3).

Figure 3.

Figure 3.

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Forest plot of separation from mother for treatment of hypoglycemia/admitted to NICU for hypoglycemia between the experimental group and control group. NICU = neonatal intensive care unit.

4.8. Normoglycemia after 1 to 2 treatments, or normoglycemia after more than 2 attempts

Ter et al found no difference in the proportion of neonates achieving normoglycemia after 1 or 2 treatments in the postnatal ward; the majority of neonates received only 1 dose of glucose gel (75%).[1] To achieve normoglycemia, the remaining 11 infants in the post-implementation group received more than 2 treatments with glucose gel and supplement feed.

4.9. Breastfeeding at discharge

Two studies were included for analysis of breastfeeding at discharge.[19,22] The heterogeneity test yielded no statistically significant results (I2 = 0.0%), so the fixed effects model was utilized for analysis. There was no difference between the experimental and control groups in terms of breastfeeding at discharge (RR = 1.018, 95% CI: 0.913–1.134, P = .751) (Fig. 4).

Figure 4.

Figure 4.

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Forest plot of breastfeeding at discharge between the experimental group and control group.

4.10. Delayed feeding and parental satisfaction

Hegarty et al conducted a randomized, double-blind, placebo-controlled study in 2 New Zealand hospitals to determine the effectiveness of glucose gel in preventing NH.[19] In terms of the incidence of delayed feeding, there was no statistical difference between the experimental group and the control group (P > .05). In addition, there was no difference in parental satisfaction between infants receiving a single dose or multiple doses of glucose gel (RR = 1.06, 95% CI: 1.00–1.13, P = .06). In terms of infant satisfaction, there was no difference between infants receiving glucose gel or placebo gel (RR = 0.95, 95% CI: 0.90–1.01, P = .12).

4.11. Seizure

Two studies evaluating the efficacy of glucose gel involved seizures.[17,22] According to the fixed effects model, there was no difference in the incidence of seizures between the experimental group and the control group [RR = 0.809, 95% CI: (0.224–2.915), P = .746] (Fig. 5).

Figure 5.

Figure 5.

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Forest plot of seizures between the experimental group and control group.

5. Discussion

Glucose gel is increasingly used to treat NH.[2] To investigate the efficacy of oral glucose gel in the treatment of NH, a systematic review and meta-analysis were conducted utilizing an integrated search of multiple databases. A total of 10 studies involving 4801 patients were included (2551 in the experimental group, and 2250 in the control group). Results suggested that oral glucose gel may not be effective in preventing NH. In contrast, the subsequent intake in the glucose gel group was significantly lower than that in the control group. Consequently, glucose gel should not be employed to prevent NH. Preventive therapy should be conducted based on the view that the identification and treatment of hypoglycemia after the first feeding may not be sufficient to prevent adverse sequelae. In addition, the preventive use of glucose gel may reduce the need for laboratory tests and other interventions that would separate mothers from neonates and reduce the next feeding.

Previous trials included a multi-center randomized trial regarding the prevention of NH in high-risk infants with oral glucose gel, involving 2149 cases with NH (maternal diabetes, large or small gestational age, late preterm birth), and a trial involving 416 high-risk newborns.[19,23] In the meta-analysis of both trials, early preventive administration of oral glucose gel (within 1 hour of birth) reduced the incidence of hypoglycemia (38% vs 43%, RR 0.87, 95% CI 0.79–0.95).[24] However, the rates of intravenous glucose administration were the same in both groups (37%), as were the percentages of neonates who were separated from their parents or caregivers due to hypoglycemia (5.6% vs 5%).

As demonstrated in a previous study, glucose gel may improve the blood glucose level in neonates with asymptomatic hypoglycemia in comparison to breastfeeding.[25] Similar conclusions were reached in other studies regarding the effect of glucose gel on blood glucose levels. The results of this study found that glucose gel could be used to treat infant hypoglycemia and improve blood glucose levels.[18] However, the sample sizes of these studies were still inadequate, and additional research is required.

The blood glucose levels of some neonates could not be restored through individual feeding; therefore, intravenous glucose injection must be administered; as a result, the corresponding neonates must be transferred from the newborn baby-caring nursery (NBN) to the NICU. The neonates would need to be separated from their mothers, which would have a negative impact on intimacy, cause excessive anxiety about breastfeeding, and raise hospitalization expenses.[25] Few infants receiving glucose gel would need to be separated from their mothers, and they would be more likely to be exclusively breastfed after discharge, according to a review study.[12] The results of a quality improvement project and a retrospective study revealed that glucose gel decreased NICU admissions, increased breastfeeding, and decreased the need for intravenous glucose injections.[25,26] The reduced NICU admission rate was a consistent result of reversing NH with glucose gel (the NICU admission rate could be reduced by 73% in the first year). Also, the rate of exclusive breastfeeding could be increased to 49%.[21] Similar findings demonstrated that the use of 200 mg/kg glucose gel in infants with NH did not inhibit subsequent feeding, but rather enhanced the quality of breastfeeding.[27]

Given that the primary objective of NH treatment is to prevent cerebral injury, it is crucial to determine whether glucose gel can have positive or negative effects on later development.[17] In a region birth cohort, transient NH was associated with school performance at age 10, and there was a graded relationship between the severity of hypoglycemia and the rate of literacy and numeracy.[28] However, Harris et al failed to find evidence that glucose gel improved brain injury in infants.[17] To solve this issue, randomized treatment comparison trials need to be conducted.

In this systematic review and meta-analysis, we collected data from various comprehensive databases and included additional studies evaluating the efficacy of oral glucose gel. The main limitation of this study is the small sample size. Large, well-designed trials need to be conducted in future.

6. Conclusion

Based on the integrated retrieval from multiple databases, a systematic review and meta-analysis were conducted to examine the efficacy of oral glucose gel in the prevention of NH. The outcomes suggest that preventative oral glucose gel may not be effective in reducing the incidence of NH. However, due to the benefits of simple administration and low cost, physicians should place greater emphasis on the clinical efficacy of oral glucose gel. This study may offer some insights and recommendations for the prevention and reduction of NH.

Author contributions

Conceptualization: Meng-Qin Wang.

Data curation: Meng-Qin Wang, Ya-Ning Zheng, Ying Zhuang.

Formal analysis: Meng-Qin Wang, Ya-Ning Zheng.

Funding acquisition: Ying Zhuang.

Investigation: Ya-Ning Zheng.

Project administration: Meng-Qin Wang.

Resources: Ya-Ning Zheng.

Software: Meng-Qin Wang.

Validation: Ying Zhuang.

Visualization: Ying Zhuang.

Writing – original draft: Meng-Qin Wang, Ying Zhuang.

Writing – review & editing: Meng-Qin Wang, Ya-Ning Zheng, Ying Zhuang.

Abbreviations:

NH
neonatal hypoglycemia
NICU
neonatal intensive care unit
RCT
randomized controlled trial
RR
relative risk

YNZ and MQW contributed equally to this work.

We are particularly grateful to all the people who have given us help on our article.

The authors have no conflicts of interest to disclose.

This study was funded by the Project of Chinese Hospital Reform and Development Institute, Nanjing University and Aid project of Nanjing Drum Tower hospital health, Education & Research Foundation (No:NDYG2022066).

The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.

How to cite this article: Wang M-Q, Zheng Y-N, Zhuang Y. Oral glucose gel in the prevention of neonatal hypoglycemia: A systematic review and meta-analysis. Medicine 2023;102:48(e36137).

Contributor Information

Meng-Qin Wang, Email: wang82266@outlook.com.

Ya-Ning Zheng, Email: zhengyaningzyn8@126.com.

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