Article Text

Two-year outcomes after dextrose gel prophylaxis for neonatal hypoglycaemia
  1. Rebecca Griffith1,
  2. Joanne Elizabeth Hegarty2,
  3. Jane M Alsweiler1,2,
  4. Greg D Gamble3,
  5. Robyn May3,
  6. Christopher Joel Dorman McKinlay3,4,
  7. Benjamin Thompson5,6,
  8. Trecia Ann Wouldes7,
  9. Jane E Harding3
  1. 1 Department of Paediatrics: Child and Youth Health, The University of Auckland, Auckland, New Zealand
  2. 2 Newborn Services, Auckland City Hospital, Auckland, New Zealand
  3. 3 Liggins Institute, University of Auckland, Auckland, New Zealand
  4. 4 Kids First Neonatal Care, Counties District Health Board, Auckland, New Zealand
  5. 5 Optometry and Vision Science, University of Waterloo, Waterloo, Ontario, Canada
  6. 6 Optometry and Vision Science, University of Auckland, Auckland, New Zealand
  7. 7 Psychological Medicine, University of Auckland, Auckland, New Zealand
  1. Correspondence to Professor Jane E Harding, Liggins Institute, University of Auckland, Auckland 1142, New Zealand; j.harding{at}auckland.ac.nz

Abstract

Objective To determine the effect of prophylactic dextrose gel for prevention of neonatal hypoglycaemia on neurodevelopment and executive function at 2 years’ corrected age.

Design Prospective follow-up of a randomised trial.

Setting New Zealand.

Patients Participants from the pre-hypoglycaemia Prevention with Oral Dextrose (pre-hPOD) trial randomised to one of four dose regimes of buccal 40% dextrose gel or equivolume placebo.

Main outcome measures Coprimary outcomes were neurosensory impairment and executive function. Secondary outcomes were components of the primary outcomes, neurology, anthropometry and health measures.

Results We assessed 360 of 401 eligible children (90%) at 2 years’ corrected age. There were no differences between dextrose gel dose groups, single or multiple dose groups, or any dextrose and any placebo groups in the risk of neurosensory impairment or low executive function (any dextrose vs any placebo neurosensory impairment: relative risk (RR) 0.77, 95% CI 0.50 to 1.19, p=0.23; low executive function: RR 0.50, 95% CI 0.24 to 1.06, p=0.07). There were also no differences between groups in any secondary outcomes. There was no difference between children who did or did not develop neonatal hypoglycaemia in the risk of neurosensory impairment (RR 1.05, 95% CI 0.68 to 1.64, p=0.81) or low executive function (RR 0.73, 95% CI 0.34 to 1.59, p=0.43).

Conclusion Prophylactic dextrose gel did not alter neurodevelopment or executive function and had no adverse effects to 2 years’ corrected age, but this study was underpowered to detect potentially clinically important effects on neurosensory outcomes.

  • neonatology
  • neurology

Data availability statement

Data are available upon reasonable request. Published data are available to approved researchers under the data sharing arrangements provided by the Maternal and Perinatal Central Coordinating Research Hub (CCRH), based at the Liggins Institute, University of Auckland (https://wiki.auckland.ac.nz/researchhub). Metadata, along with instructions for data access, are available at the University of Auckland’s research data repository, Figshare (https://auckland.figshare.com). Data access requests are to be submitted to Data Access Committee via researchhub@auckland.ac.nz. De-identified published data will be shared with researchers who provide a methodologically sound proposal and have appropriate ethical and institutional approval. Researchers must sign and adhere to the Data Access Agreement that includes a commitment to using the data only for the specified proposal, to refrain from any attempt to identify individual participants, to store data securely and to destroy or return the data after completion of the project. The CCRH reserves the right to charge a fee to cover the costs of making data available, if required.

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What is already known on this topic?

  • Neonatal hypoglycaemia is common and associated with adverse neurodevelopmental outcomes, even if transient and treated.

  • Oral dextrose gel for the treatment of neonatal hypoglycaemia is safe and effective and is now widely used in clinical practice.

  • The prehypoglycaemia prevention with oral dextrose trial found that prophylactic oral dextrose gel reduced the risk of neonatal hypoglycaemia, but longer-term effects are unknown.

What this study adds?

  • Prophylactic dextrose gel did not alter the risk of neurosensory impairment at 2 years of age.

  • Dextrose gel was associated with trends towards improved language, motor and executive function, but these results were not statistically significant and should be interpreted with caution.

  • Oral dextrose gel when used in infants at risk to prevent hypoglycaemia reduces the risk of hypoglycaemia and has no adverse effects to 2 years of age.

Introduction

Neonatal hypoglycaemia is common1 2 and is associated with brain injury, seizures and poor neurodevelopmental outcomes.3–5 Even transient and treated neonatal hypoglycaemia has been associated with adverse outcomes, particularly executive and visual–motor dysfunction5 and poorer school performance.1

Buccal 40% dextrose gel is an effective treatment for neonatal hypoglycaemia6 with no adverse effects up to 2 years of age,7 and its potential use for hypoglycaemia prophylaxis is currently being trialled.8 The pre-hypoglycaemia Prevention with Oral Dextrose (pre-hPOD) randomised trial, designed to determine the optimal dose of 40% dextrose to prevent neonatal hypoglycaemia in infants at risk,9 found that any of the trialled doses of dextrose gel reduced the incidence of hypoglycaemia (relative risk (RR) 0.79, 95% CI 0.64 to 0.98, p=0.03, number needed to treat 10). Two hundred milligrams per kilogram at 1 hour after birth was most effective with fewest limitations (RR 0.68, 95% CI 0.47 to 0.99, p=0.04, number needed to treat 7).9 In order to assess longer-term effects of this approach on neurodevelopment, growth and health, we assessed outcomes at 2 years of participants in the pre-hPOD trial.

Methods

Study design

Details of the pre-hPOD trial have been published.9 In brief, 416 infants at risk of hypoglycaemia (infant of a diabetic mother, small (birth weight<2.5 kg or <10th centile), large (birth weight>4.5 kg or >90th centile) or late preterm (35 or 36 weeks)) were randomised to one of four dosage arms of 40% dextrose gel (0.5 mL/kg (200 mg/kg) once, 1 mL/kg (400 mg/kg) once, 0.5 mL/kg for four doses (total 800 mg/kg) or 1 mL/kg once then 0.5 mL/kg for a further three doses (total 1000 mg/kg)) or equivolume placebo gel. The primary outcome was neonatal hypoglycaemia (blood glucose concentration<2.6 mmol/L).

Two-year follow-up

All families who participated in the pre-hPOD dosage trial and who had consented at initial recruitment to further contact were invited to participate.

At 24 months’ corrected age, children underwent a comprehensive assessment of neurodevelopment, growth and general health by trained research doctors who were unaware of the child’s randomisation group. Assessment included Bayley Scales of Infant Development, Third Edition (BSID-III),10 neurological examination, executive function (clinical assessment of inhibitory control and attentional flexibility11) and Behaviour Rating Inventory of Executive Function—Preschool Version (BRIEF-P).12

Height, weight, and head and abdominal circumferences were measured to the nearest 0.1 cm. Triceps and subscapular skinfold thicknesses were measured using a Harpenden calliper to the nearest 0.2 cm. Total body fat mass and fat free mass were estimated using multifrequency bioimpedance analysis (ImpediMed Imp SFB7).

Home and health information were collected by questionnaire. Asthma was defined as any of diagnosis by doctor, medicine or inhaler use for wheeze or asthma in the preceding 12 months, or hospitalisation for wheeze or asthma.13 Eczema was defined as itchy rash coming and going for ≥6 months13 or diagnosis and treatment by doctor for eczema. Visits to a doctor for suspected infections were recorded.

The two prespecified coprimary outcomes were neurosensory impairment (any of legal blindness; sensorineural deafness requiring hearing aids; cerebral palsy; BSID-III cognitive, language or motor score more than 1 SD below the mean) and executive function composite z-score of <−1.5, derived from standardisation within the whole pre-hPOD 2-year cohort. Children unable to complete any domain of the BSID-III because of severe delay were assigned a score of 49. Secondary outcomes were the components of the primary outcomes, neurology, anthropometry and health measures. The WHO Child Growth Standards were used to calculate z-scores using corrected age.14 The sample size was limited by the number of participants in the original trial, but we estimated that this study would have 80% power to detect a reduction in neurosensory impairment from 39% (based on a similar cohort assessed at 2 years’ corrected15) to 24% (two-tailed alpha 0.05).

Statistical analysis

All analyses were prespecified and performed using SAS V.9.4. RRs or mean difference (MD) with 95% CI were estimated using generalised linear models, adjusted for recruitment centre, socioeconomic status at birth (NZ Deprivation Index 201316), gestational age and sex. We planned to combine placebo groups if there were no differences between them in the primary outcomes. Primary outcomes were compared between different dextrose gel dosage groups, between single and multiple dose groups, and between any dextrose gel and any placebo groups. Secondary analyses included examining any interactions between the effect of any dextrose gel versus placebo on primary outcomes and their components and the risk factor for hypoglycaemia (diabetic mother vs other) and gestational age (preterm vs term), and also determining the effect of hypoglycaemia on the primary outcomes and their components, including in the subgroup of those who became hypoglycaemic (only adjusted for socioeconomic status, gestational age and sex because the fully adjusted model failed to converge).

We used two-sided statistical tests and the alpha error of 5% for the coprimary outcomes was divided evenly, giving a p value of 0.025 for each. All analyses were performed on an intention-to-treat basis. A significance level of 5% was used for each secondary outcome. Dunnett’s test was used for multiple comparisons. Linear trends were tested using orthogonal contrasts.

Results

In the pre-hPOD trial, 416 infants were randomised. One was incorrectly randomised after the trial had closed, 13 withdrew and 1 died prior to 2 years, leaving 401 children eligible for follow-up, of whom 360 were assessed at 2 years (90% of those eligible, 87% of those randomised) (figure 1). The mean age of mothers of children followed up was 3 years older than those not followed up, and the gestational age at birth of those followed up was 0.4 weeks less than of those not followed up (table 1). Other maternal and infant characteristics were similar in those followed up and not followed up, and also among all randomisation groups. Mean corrected age at follow-up was 25 months and similar in all groups.

Figure 1

Profile of participants: recruitment to 2 years.

Table 1

Characteristics of mothers and infants who were and were not followed up at 2 years

There were no differences in outcomes between placebo groups so these were combined into one placebo group for further comparisons. The overall incidence of neurosensory impairment was 19% (69/360). There were no children with cerebral palsy or blindness. The overall incidence of executive function composite z-score <−1.5 was 7% (26/357).

Increasing cumulative dextrose dose did not alter the risk of neurosensory impairment or low executive function scores (table 2). Although there was a trend towards an improvement in executive function with increasing cumulative dextrose dose (p=0.03), this did not reach statistical significance with the split p value of 0.025 for each coprimary outcome. There were no differences in secondary outcomes with increasing dose of dextrose gel (table 2 and online supplemental table S1). However, there was a trend for increasing cumulative dextrose dose to be associated with improved composite language scores (p=0.05) and fewer abnormalities of coordination or tone (p=0.05).

Table 2

Primary and secondary neurodevelopmental outcomes at 2 years in children exposed to placebo or increasing cumulative doses of prophylactic dextrose gel after birth

When combined single and combined multiple doses of dextrose gel were compared with the combined placebo group, the risk of neurosensory impairment was similar among groups (table 3). The multiple dextrose doses group had fewer low executive function scores compared with single or placebo groups, but this was not statistically significant (p=0.04). There were no other differences in secondary outcomes between single, multiple and placebo groups (table 3 and online supplemental table S2).

Table 3

Primary and secondary neurodevelopmental outcomes at 2 years in children exposed to placebo, a single dose of dextrose, or multiple doses of dextrose

When children who had received any dextrose dose were compared with those who received any placebo, the risk of neurosensory impairment was similar (table 4). Although low executive function scores were less likely in the dextrose group (RR 0.48, 95% CI 0.23 to 0.99), after adjustment this difference was no longer significant (p=0.07). Similarly, motor scores were higher in the dextrose group (MD 2.70, 95% CI 0.04 to 5.37), but this difference was no longer significant after adjustment (p=0.06). There were no differences in other secondary outcomes between any dextrose and any placebo groups (table 4 and online supplemental table S3).

Table 4

Primary and secondary neurodevelopmental outcomes at 2 years in children exposed to placebo or any dextrose dose

Secondary analyses revealed no difference in risk of neurosensory impairment between infants of diabetic mothers versus infants with other risk factors (adjusted p value for interaction=0.47), nor between preterm and term infants (adjusted p value for interaction=0.87). There was no difference between children who did or did not develop neonatal hypoglycaemia in the risk of neurosensory impairment (RR 1.05, 95% CI 0.68 to 1.64, p=0.81) or its components: Bayley-III cognitive score of <85 (RR 0.90, 95% CI 0.47 to 1.70, p=0.74); language score of <85 (RR 1.04, 95% CI 0.62 to 1.75, p=0.89); motor score of <85 (RR 0.18, 95% CI 0.02 to 1.48, p=0.11); deafness (not calculable, 0/164 dextrose, 1/196 placebo); low executive function (RR=0.77, 95% CI 0.35 to 1.68, p=0.51). In the subgroup of children who developed neonatal hypoglycaemia, there was also no effect of dextrose versus placebo on neurosensory impairment (RR 0.77, 95% CI 0.50 to 1.19, p=0.23) or its components: Bayley-III cognitive score of <85 (RR 0.73, 95% CI 0.39 to 1.35, p=0.31); language score of <85 (RR 0.71, 95% CI 0.42 to 1.18), p=0.19); motor score of <85 (RR=0.21 95% CI 0.04 to 1.04, p=0.06); and low executive function (RR 0.49, 95% CI 0.24 to 1.02, p=0.06).

Discussion

In children born at risk of neonatal hypoglycaemia, prophylactic dextrose gel did not alter the risk of neurosensory impairment or low executive function scores at 2 years’ corrected age, regardless of the dose used. The secondary outcomes were also similar in dextrose and placebo groups, with no adverse effects, providing reassurance about use of oral dextrose gel prophylaxis in neonates at risk of hypoglycaemia. Our results are in keeping with a previous study demonstrating similar rates of neurosensory impairment between dextrose and placebo gel groups and no adverse effects when used for treatment of neonatal hypoglycaemia.17

The primary aim of this follow-up study was to assess neurodevelopment, health and growth in children treated with prophylactic dextrose gel. As the pre-hPOD trial was powered to detect differences in the rates of hypoglycaemia rather than later neurodevelopment, the study was underpowered to detect small but clinically important differences in the primary and secondary outcomes. However, since this was the first follow-up study of prophylactic oral dextrose gel, it was important to assess a wide range of outcomes, including growth and health, to detect possible adverse effects. Further studies are needed with sufficient power to detect small but potentially clinically important long-term effects of prophylactic oral dextrose gel on neurodevelopmental outcomes.

Executive function is the ability to learn using working memory, problem solving, reasoning and cognitive flexibility. Thus, subtle detrimental effects on executive function seen at 2 years of age may later translate into poorer academic performance. Adverse effects on later executive function have been reported in infants born moderate to late preterm,18 19 those born to diabetic mothers20 and those who experienced neonatal hypoglycaemia.5 We found no statistically significant relationship between prophylactic dextrose gel and performance either on assessed executive function tasks specifically developed for this age group11 or on the parent-reported BRIEF-P. However, there was a trend towards a decreased risk of low executive function with increasing cumulative doses of prophylactic oral dextrose gel, with multiple doses, or with any dextrose dose compared with placebo, and in the subgroup of infants who became hypoglycaemic. At 2 years of age, executive function is still developing, and it is possible that further testing once the children are older may clarify the clinical significance of these observations.

There were no relationships between any outcomes and the presence or absence of recorded hypoglycaemia. It is possible that prophylactic dextrose gel prevented periods of hypoglycaemia not detected on intermittent blood glucose monitoring. Continuous glucose monitoring has shown that up to 80% of episodes of neonatal hypoglycaemia may be unrecognised using intermittent blood glucose monitoring.21 Further, in a prospective cohort study, exposure to neonatal hypoglycaemia was not associated with neurosensory impairment at 2 years,15 but at 4.5 years of age was associated with impaired executive and visual motor development in a dose-dependent manner,5 suggesting that the effects of hypoglycaemia may not be evident at 2 years of age. It is also possible that the threshold we used to define hypoglycaemia is not optimal for prediction of later outcomes. The threshold for defining hypoglycaemia remains a topic of debate,22 but we used the widely used cut-off based on studies showing an association between glucose concentrations below 2.6 mmol/L and altered brain function3 4 and have not found a more discriminatory threshold to date.5 15

A strength of this study is the high follow-up rate, as participants not followed up in studies are more likely to have worse outcomes than those followed up.23 In addition, this was a prospective follow-up study of participants in a blinded randomised controlled trial with similar sociodemographic characteristics across randomisation groups, minimising the possible effect of unrecognised confounders on the outcomes. Our assessment was comprehensive, including a standard and widely accepted assessment of early development (BSID-III), in which low scores in cognitive and language domains are predictive of later intellectual function at age 4 years,24 25 and also tests of more subtle neurodevelopment, and executive function, skills known to be affected by neonatal hypoglycaemia.20

An important limitation of this study was that the original trial was designed to have sufficient power to compare the incidence of hypoglycaemia between groups, but not small differences in later developmental outcomes. Future follow-up of the 2149 children recruited to the hPOD study8 of dextrose gel prophylaxis should help clarify if this intervention affects neurodevelopment or executive function. We performed multiple comparisons since we wished to maximise the chance of detecting any possible adverse effects, but this leads to increased risk of a type I error. Thus, these findings should be interpreted with caution. In addition, the majority of participants in the pre-hPOD trial were infants of diabetic mothers, so our results primarily reflect the outcomes of this risk group.

The use of dextrose gel for treatment of neonatal hypoglycaemia is expanding.26–28 Although it had no adverse effects on neurodevelopment, growth or health at 2 years of age, as yet, there is insufficient evidence about long-term effects of prophylactic dextrose gel, especially as large numbers of infants would be potentially eligible for such treatment. The follow-up of the larger hPOD trial with will have greater power to detect any effect of prophylactic dextrose gel both on short-term efficacy and on later outcomes.

Conclusions

Prophylactic oral dextrose gel given to infants at risk of neonatal hypoglycaemia did not alter the risk of neurosensory impairment or low executive function scores and had no adverse effects to 2 years of age.

Data availability statement

Data are available upon reasonable request. Published data are available to approved researchers under the data sharing arrangements provided by the Maternal and Perinatal Central Coordinating Research Hub (CCRH), based at the Liggins Institute, University of Auckland (https://wiki.auckland.ac.nz/researchhub). Metadata, along with instructions for data access, are available at the University of Auckland’s research data repository, Figshare (https://auckland.figshare.com). Data access requests are to be submitted to Data Access Committee via researchhub@auckland.ac.nz. De-identified published data will be shared with researchers who provide a methodologically sound proposal and have appropriate ethical and institutional approval. Researchers must sign and adhere to the Data Access Agreement that includes a commitment to using the data only for the specified proposal, to refrain from any attempt to identify individual participants, to store data securely and to destroy or return the data after completion of the project. The CCRH reserves the right to charge a fee to cover the costs of making data available, if required.

Ethics statements

Ethics approval

Ethics approval was obtained from the Health and Disability Ethics Committees of New Zealand (13/NTA/8) and caregivers gave written informed consent.

Acknowledgments

We thank all the people who contributed to this study: Caroline Crowther, Richard Edlin, Kelly Fredell, Jenny Rogers, Mariam Buksh, Alena Vasilenko, Heather Stewart and the Maternal and Perinatal Central Coordinating Research Hub, Liggins Institute, University of Auckland. We are grateful to all the children and their families who participated in this study.

References

Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

Footnotes

  • Contributors Contributed equally to this paper: RG and JoH. Conceptualisation/ design: JoH, JMA, BT and JaneH. Assessments: RG, JoH, CJDMcK and TAW. Data analysis: RG, RM, GDG and JaneH. Contributed analysis tools: GDG and RM. Drafted the initial manuscript: RG.

  • Funding This study was funded by Lottery Health Research (241266), Cure Kids (3561), philanthropic donations to the University of Auckland Foundation (F-ILG-LRSR), Health Research Council of New Zealand (15-216), Gravida, National Centre for Growth and Development (SCH-14-14 Hegarty), Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health (R01HD091075). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. RG received a fellowship in 2016 from the New Zealand Diabetes Foundation.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.