Hegarty 2016a.

Study characteristics
Methods	2 centre randomised, double‐blind, placebo‐controlled trial
Participants	416 infants were randomised (1 infant randomised in error). Of 401 children eligible for follow‐up at two years' corrected age (13 withdrawals, one death, one incorrectly randomised), 360 (90%) were assessed (12 declined, 26 overseas, 3 lost to follow‐up). At six to seven years' corrected age, 392 of the 415 correctly randomised children were eligible for follow‐up (22 withdrawals, one death) and 315 (80%) were assessed (40 declined, 37 lost to follow‐up). Inclusion criteria: infants born to mothers with diabetes, late preterm (35 to 36 weeks' gestation) or small (< 2.5 kg or < 10th percentile) or large birthweight (> 4.5 kg or > 90th percentile), or other risk factors for hypoglycaemia; ≥ 35 weeks gestation; birthweight ≥ 2.2 kg; < 1 hour old; no apparent indication for admission to NICU, unlikely to require admission to NICU for other reasons; mother intended to breastfeed Exclusion criteria: major congenital abnormality, previously fed by formula or received intravenous fluid, previous diagnosis of hypoglycaemia, admission to NICU or imminent admission to NICU Setting: 2 hospitals providing maternity and neonatal services (Auckland City Hospital and Waitakere Hospital) in Auckland, New Zealand Timing: Recruitment: August 2013 to November 2014 Follow‐up: August 2015 to February 2017 Follow‐up: dates not stated
Interventions	40% dextrose gel massaged into the buccal mucosa as a single dose (0.5 mL/kg or 1 mL/kg at 1 hour) or multiple doses (additional 0.5 mL/kg 3 times pre‐feed in first 12 hours) (n = 277) vs Placebo gel massaged into the buccal mucosa using the same protocol and volume as the intervention (n = 138) In both groups, babies were breastfed after the intervention and their blood glucose concentration was measured using the glucose oxidase method at 2 hours after birth. Subsequent blood glucose measurements were performed according to local hospital protocol. Babies who developed hypoglycaemia were managed according to the standard clinical practice at each hospital.
Outcomes	Primary outcome Hypoglycaemia, defined as any blood glucose concentration < 2.6 mmol/L in the first 48 hours after birth ‐ significantly lower incidence in dextrose gel group Neurosensory impairment (any of: legal blindness; sensorineural deafness requiring hearing aids; cerebral palsy; Bayley‐III cognitive, language or motor score > 1 SD below the mean) at 2 years follow‐up ‐ adjusted model shows a nonsignificant decrease in dextrose gel group. Neurocognitive impairment (standard score > 1 SD below the normative mean on ≥ 1 of 7 Toolbox tests) at 6‐7 years follow‐up ‐ the most adjusted model shows a significant reduction in risk in the dextrose gel group. No difference between dextrose and placebo in subgroups (dose volume, risk factor, number of doses) except significant reduction in risk when a single dose applied (adjusted model). Secondary outcomes at neonatal stage Admission to NICU after birth (defined as admission for > 4 hours) ‐ no significant difference between dextrose and placebo groups Adverse events such as choking or vomiting at the time of gel administration ‐ no significant difference between dextrose and placebo groups Receipt of treatment for hypoglycaemia (includes intravenous, oral dextrose gel, or any medications) ‐ no significant difference between dextrose and placebo groups Separation of infant from mother for treatment of hypoglycaemia (admission to NICU) ‐ significantly reduced admission in dextrose group Neonatal seizures ‐ only 1 case in dextrose gel group, no statistical analysis available Hyperglycaemia (blood glucose concentration > 10 mmol/L) ‐ no cases Receipt of any formula before discharge from hospital ‐ no significant difference between dextrose and placebo groups Breastfeeding at discharge from hospital (full or exclusive) ‐ no significant difference between dextrose and placebo groups Formula feeding at 6 weeks of age ‐ no significant difference between dextrose and placebo groups Number of episodes of hypoglycaemia per infant ‐ no significant difference between dextrose and placebo groups Duration of initial hospital stay (days) ‐ no significant difference between dextrose and placebo groups Cost of care until discharge home (to be reported separately) Maternal satisfaction at 6 weeks ‐ no significant difference between dextrose and placebo groups Secondary outcomes at two years of age Neurosensory impairment (any of: legal blindness; sensorineural deafness requiring hearing aids; cerebral palsy; Bayley‐III cognitive, language or motor score more than one standard deviation below the mean) at 2 years follow‐up ‐ adjusted model shows a nonsignificant decrease in risk in dextrose gel group. Deafness defined as requiring hearing aids, measured at 2 years corrected age ‐ not estimable as only one case in placebo group Legal blindness defined as visual acuity < 3/60 or > 1.3 logMAR measured at 2 years corrected age ‐ no cases Cerebral palsy measured at 2 years corrected age ‐ no cases Executive dysfunction (composite z‐score < ‐1.5 within the cohort) measured at 2 years corrected age ‐ adjusted model shows a nonsignificant decrease in risk in dextrose gel group. Developmental delay (defined as Bayley‐III cognitive, language or motor composite score > 1 SD below the mean) measured at 2 years corrected age ‐ additional data received from the study authors showed no difference between any dextrose and placebo groups. Secondary outcomes at six to seven years of age Neurocognitive impairment ‐ standard score < 85 in one or more of the seven Toolbox tests (> 1 SD below the normative mean). Adjusted model shows a significant decrease in risk in the dextrose gel group. In the adjusted model and dextrose gel group, children of mothers with diabetes had lower risk compared to children with another risk group. Also, children that received a single dose had a lower risk than those that received multiple doses. Executive dysfunction (Flanker or DCCS standard score < 85) ‐ Adjusted model shows a nonsignificant decrease in risk in the dextrose gel group. No difference between dextrose and placebo in subgroups (dose volume, risk factor, number of doses) except significant reduction in risk when a single dose applied (adjusted model). Emotional‐behavioural difficulty (and whether it was ≥ 14) An adjusted model shows a nonsignificant decrease in risk in the dextrose gel group. No difference between dextrose and placebo in subgroups (dose volume, risk factor, number of doses)
Notes	Funding This trial was funded by the A+ Trust (www.adhb.govt.nz; A+5696); Auckland Medical Research Foundation (www.medicalresearch.org.nz; 1113012); Cure Kids (www.curekids.org.nz; 3537); and Lottery Health Research (http://www.communitymatters.govt.nz; 326844), and by philanthropic donations to the University of Auckland Foundation (www.auckland.ac.nz). The two‐year follow‐up studies were also funded by grants from the Health Research Council of New Zealand (13/131. 15/216), Lottery Health Research (241266), Cure Kids (3561), Gravida, National Centre for Growth and Development (SCH‐14‐14 Hegarty) and the Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health (R01HD091075). The six to seven year follow‐up study was funded by the Health Research Council of New Zealand (19/960) and the Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health (R01HD091075). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Declarations of interest Jane Harding received an unrestricted research grant from Biomed Auckland, who manufacture dextrose gel. That sponsor was said to have no involvement in the study. No other disclosures were reported. Other primary authors reported no competing interests. Australian New Zealand Clinical Trials Registry ACTRN12613000322730
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote from Hegarty 2016: "We used computer‐generated blocked randomisation with variable block sizes to assign babies to one of eight treatment arms".
Allocation concealment (selection bias)	Low risk	Centralised allocation. Quote from Hegarty 2016: "Research staff entered demographic and entry criteria data into an online randomisation website that provided a number corresponding to a numbered trial pack".
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote from Hegarty 2016: "Clinicians, families, and all study investigators were masked to treatment group allocation throughout the study and remain so for planned follow‐up".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote from Hegarty 2016: "At 24 months’ corrected age, children underwent a comprehensive assessment of neurodevelopment, growth and general health by doctors trained in all assessments who were unaware of the child’s randomisation group". Quote from Wei: “Assessors were blinded to trial allocation and the neonatal glycemic history of the child.”
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote from Hegarty 2016: “All other babies had primary outcome data available and were included in the intention‐to‐treat analysis”.
Selective reporting (reporting bias)	Low risk	All prespecified outcomes were reported except for cost of care which was reported separately.
Other bias	Unclear risk	The study was not terminated early. Co‐interventions were similar across arms. Quote from Hegarty 2016: “There was no difference between placebo and dextrose gel groups in timing of gel administration or in volume of gel administered”. Quote from Wei: “Of those assessed [at six‐to‐seven years follow‐up], there was potential imbalance in several baseline prognostic variables between treatment groups, including lower maternal BMI and nulliparity and fewer females among those allocated to dextrose gel 1000 mg/kg, and fewer children of Māori and Pacific ethnicity among those allocated to dextrose gel 400 mg/kg and dextrose gel 1000 mg/kg (Table 1).” Intervention delivery was compliant with protocol. Follow‐up assessments were conducted at the same time points across arms. The authors concluded that the study was not at risk of other bias.

aRR: adjusted risk ratio
BMI: body mass index
DCCS: Dimensional Change Card Sort
logMAR: Logarithm of the Minimum Angle of Resolution
NICU: neonatal intensive care unit
SCBU: special care baby unit
SD: standard deviation
vs: versus