Prophylactic Oral Dextrose Gel for Newborn Babies at Risk of Neonatal Hypoglycaemia: A Randomised Controlled Dose-Finding Trial (the Pre-hPOD Study)

<div><p>Background</p><p>Neonatal hypoglycaemia is common, affecting up to 15% of newborns, and can cause brain damage. Currently, there are no strategies, beyond early feeding, to prevent neonatal hypoglycaemia. Our aim was to determine a dose of 40% oral dextrose gel that will prevent neonatal hypoglycaemia in newborn babies at risk.</p><p>Methods and Findings</p><p>We conducted a randomised, double-blind, placebo-controlled dose-finding trial of buccal dextrose gel to prevent neonatal hypoglycaemia at two hospitals in New Zealand. Babies at risk of hypoglycaemia (infant of a mother with diabetes, late preterm delivery, small or large birthweight, or other risk factors) but without indication for admission to a neonatal intensive care unit (NICU) were randomly allocated either to one of four treatment groups: 40% dextrose at one of two doses (0.5 ml/kg = 200 mg/kg, or 1 ml/kg = 400 mg/kg), either once at 1 h of age or followed by three additional doses of dextrose (0.5 ml/kg before feeds in the first 12 h); or to one of four corresponding placebo groups. Treatments were administered by massaging gel into the buccal mucosa. The primary outcome was hypoglycaemia (<2.6 mM) in the first 48 h. Secondary outcomes included admission to a NICU, admission for hypoglycaemia, and breastfeeding at discharge and at 6 wk. Prespecified potential dose limitations were tolerance of gel, time taken to administer, messiness, and acceptability to parents. From August 2013 to November 2014, 416 babies were randomised. Compared to babies randomised to placebo, the risk of hypoglycaemia was lowest in babies randomised to a single dose of 200 mg/kg dextrose gel (relative risk [RR] 0.68; 95% confidence interval [CI] 0.47–0.99, <i>p</i> = 0.04) but was not significantly different between dose groups (<i>p</i> = 0.21). Compared to multiple doses, single doses of gel were better tolerated, quicker to administer, and less messy, but these limitations were not different between dextrose and placebo gel groups. Babies who received any dose of dextrose gel were less likely to develop hypoglycaemia than those who received placebo (RR 0.79; 95% CI 0.64–0.98, <i>p</i> = 0.03; number needed to treat = 10, 95% CI 5–115). Rates of NICU admission were similar (RR 0.64; 95% CI 0.33–1.25, <i>p</i> = 0.19), but admission for hypoglycaemia was less common in babies randomised to dextrose gel (RR 0.46; 95% CI 0.21–1.01, <i>p</i> = 0.05). Rates of breastfeeding were similar in both groups. Adverse effects were uncommon and not different between groups. A limitation of this study was that most of the babies in the trial were infants of mothers with diabetes (73%), which may reduce the applicability of the results to babies from other risk groups.</p><p>Conclusions</p><p>The incidence of neonatal hypoglycaemia can be reduced with a single dose of buccal 40% dextrose gel 200 mg/kg. A large randomised trial (Hypoglycaemia Prevention with Oral Dextrose [hPOD]) is under way to determine the effects on NICU admission and later outcomes.</p><p>Trial Registration</p><p>Australian New Zealand Clinical Trials Registry <a href="https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12613000322730" target="_blank">ACTRN12613000322730</a></p></div

Details of study gel and supplementary dextrose administration for each dosage group.

<p>Details of study gel and supplementary dextrose administration for each dosage group.</p

Median blood glucose concentration at four time intervals for each dose regime of dextrose gel.

<p>Boxplots for blood glucose concentration (mM) at time = 2, 4, 8, and 12 h ± 30 min, for each cumulative dose of prophylactic dextrose gel, where 0 mg/kg is placebo, 200 mg/kg is 0.5 ml/kg dextrose once, 400 mg/kg is 1 ml/kg once, 800 mg/kg is 0.5 ml/kg for four doses, and 1,000 mg/kg is 1 ml/kg once followed by 0.5 ml/kg for a further three doses. The box represents 25th to 75th percentiles. The horizontal bar within the box is the median, and the solid dot within the box is the mean. The whiskers are 1.5 (interquartile range [IQR]) above and below the 25th and 75th percentile. Solid dots beyond the whiskers represent outliers.</p

Primary and secondary outcomes for each dosage group.

<p>Primary and secondary outcomes for each dosage group.</p

Different Approaches to requesting Consent for Routine data linkage in Neonatal follow-up (ACORN): protocol for a 2×2 factorial randomised trial

Introduction Routinely collected data can be linked to research data to create a rich dataset and inform practice. However, consent is normally required to link identifiable data. Reported rates of consent to data linkage for children ranged from 21% to 96%, but no studies have investigated different approaches to seeking consent for data linkage for school-age children.Methods and analysis The Approaches to Consent for Routine Data Linkage in Neonatal Follow-up (ACORN) trial is a 2×2 factorial randomised trial to assess whether, for children who participated in neonatal randomised trials (pre-hypoglycaemia Prevention with Oral Dextrose Gel (hPOD), hPOD and The Impact of Protein Intravenous Nutrition on Development in Extremely Low Birth Weight Babies (ProVIDe)) and are approached to participate in an in-person assessment at 6–7 years of age, parental consent to data linkage is higher if consent is sought (1) after the in-person assessment (delayed) or concurrently and (2) for health and education data combined or separately. The primary outcomes will be rates of consent to linkage of (1) either health or education data and (2) both health and education data. A pilot study indicates the potentially available cohort size of 2110 (80% follow-up of the neonatal trial cohorts) would be adequate to detect an absolute difference of 6%–5%–4% from a baseline consent rate of 70%–85%–90%, respectively (2-tailed alpha 0.05, 90% power). With at least 1136 participants, the ACORN trial would have 90% power to detect an absolute difference of 5% in the primary outcome for each factor, assuming a consent rate of 90% in the control groups and alpha 0.05. Data are categorical and will be presented as number and per cent. The effects of factors will be tested using generalised linear models and presented as ORs and 95% CIs.Ethics and dissemination Ethics approval by the New Zealand Health and Disability Ethics Committee (19/STH/202). Dissemination will be via peer-reviewed publications, scientific meetings, educational sessions and public fora.Trial registration number ACTRN12621000571875 (Australian New Zealand Clinical Trials Registry)

Limitation scores.

<p>Limitation scores.</p

Odds of hypoglycaemia for each cumulative dose of prophylactic dextrose gel.

<p>Odds ratios of blood glucose concentration < 2.6 mM for each cumulative dose of prophylactic dextrose gel, where 0 mg/kg is placebo, 200 mg/kg is 0.5 ml/kg dextrose once, 400 mg/kg is 1 ml/kg once, 800 mg/kg is 0.5 ml/kg for four doses, and 1,000 mg/kg is 1 ml/kg once followed by 0.5 ml/kg for a further three doses. Data are odds ratios +/− 95% CI adjusted for prespecified potential confounders (sex, gestational age, and delivery mode), and the numerals above the figure are the number (%) of babies who experienced hypoglycaemia (blood glucose concentration < 2.6 mM) in each group.</p

Consolidated Standards of Reporting Trials (CONSORT) diagram.

<p>One baby was randomised in error following closure of the trial after randomisation of 415 babies and was excluded from the analysis. All other babies had primary outcome data available and were included in the intention-to-treat analysis.</p