Abstract
Background:
Neonatal hypoglycaemia is associated with an increased risk of neurosensory impairment. Prophylactic dextrose gel reduces the risk of neonatal hypoglycaemia. The aim of this study was to determine longer term safety of prophylactic dextrose gel for prevention of neonatal hypoglycaemia.
Methods:
We followed-up participants from the pre-hPOD trial (randomized to one of four dose regimes of buccal 40% dextrose gel, or equivolume placebo) at two years’ corrected age. Co-primary 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%). There were no differences between dextrose gel dose groups, single or multiple dose groups, or between 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% confidence interval [CI] 0.50, 1.19 p=0.23; low executive function RR 0.50, 95% CI 0.24, 1.06, p=0.07). There were also no differences between groups in any secondary outcomes. There was no difference between children who developed neonatal hypoglycaemia or did not in the risk of neurosensory impairment (RR 1.05, 95% CI 0.68, 1.64, p=0.81) or low executive function (RR 0.73, 95% CI 0.34, 1.59, p=0.43).
Conclusion:
Prophylactic dextrose gel appears safe to two years’ corrected age, but this study was underpowered to detect potentially clinically important effects on neurosensory outcomes. These results should be interpreted with caution and no change should be made to current clinical practice.
Table of contents summary:
This prospective follow-up study found that prophylactic oral dextrose gel in infants at risk of neonatal hypoglycaemia is safe up to two years of age.
Background
Neonatal hypoglycemia is common 1,2. Approximately 50% of neonates born at risk of hypoglycemia have at least one episode, and 20% have a severe episode 2. Hypoglycemia is associated with brain injury, seizures and poor neurodevelopmental outcomes 3–5. Even transient and treated neonatal hypoglycemia has been associated with adverse outcomes, particularly executive and visual-motor dysfunction 5 and poorer school performance 1.
Buccal administration of 40% dextrose gel is an effective treatment for neonatal hypoglycemia 6 with no adverse effects reported up to 2 years of age 7, and its potential use for hypoglycemia prophylaxis is currently being trialled 8. We previously have reported the findings of the pre-hPOD randomized trial, designed to determine the optimal dose of 40% dextrose to prevent neonatal hypoglycemia 9. We found that any of the trialled doses of dextrose gel given to infants at risk reduced the incidence of hypoglycemia (RR 0.79, 95% confidence interval [CI] 0.64, 0.98, p = 0.03, number needed to treat 10), and that 200 mg/kg at one hour after birth was most effective with fewest limitations (RR 0.68, 95% CI 0.47, 0.99, p=0.04, number needed to treat 7) 9. In order to assess longer term safety of this approach, we now report outcomes at two years’ corrected age of participants in the pre-hPOD trial.
Methods
Study design
Details of the pre-hPOD trial have been published previously 9. In brief, 416 infants at risk of hypoglycemia (infant of a diabetic mother, small [birthweight <2.5 kg or <10th centile], large [birthweight >4.5 kg or >90th centile] or late preterm [35 or 36 weeks]) were randomized 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 followed by 0.5 ml/kg for a further three doses [total 1,000 mg/kg]) or four dosage arms of equivolume placebo gel. The primary outcome was neonatal hypoglycemia (blood glucose concentration < 47 mg/dl (2.6 mmol/l)).
Two Year Follow-up
All families who participated in the pre-hPOD dosage trial and who had consented at the time of initial recruitment to further contact were invited to participate in this follow-up study. Follow-up took place between August 2015 and February 2017 in New Zealand. Ethics approval was obtained from the Health and Disability Ethics Committees of New Zealand (13/NTA/8) and caregivers gave written informed consent at the time of assessment.
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 randomization group. Assessment included Bayley Scales of Infant Development 3rd edition 10, neurological examination, executive function (clinical assessment of inhibitory control and attentional flexibility 11) and Behavior Rating Inventory of Executive Function—Preschool Version (BRIEF-P ) 12.
Height, weight, head circumference and abdominal circumference were measured to the nearest 0.1 cm. Triceps and subscapular skin-fold thicknesses were measured using a Harpenden caliper to the nearest 0.2 cm, and the mean of two measurements recorded. Total body fat mass and fat free mass were estimated using multifrequency bioimpedance analysis (ImpediMed Imp SFB7).
Home and health information were collected using a questionnaire. Asthma was defined as any of: diagnosis by doctor, medicine or inhaler use for wheeze or asthma in the preceding 12 months, or hospitalized for wheeze or asthma 13. Eczema was defined as itchy rash coming and going for ≥6 months 13 or diagnosis and treatment by doctor for eczema. Visits to a doctor for infectious illnesses were recorded.
The two pre-specified co-primary outcomes were neurosensory impairment (any of: legal blindness; sensorineural deafness requiring hearing aids; cerebral palsy; Bayley Scales of Infant Development 3rd edition [BSID-III] cognitive, language or motor score more than one standard deviation below the mean) and executive function composite z-score <−1.5, derived from standardization within the whole pre-hPOD 2-year cohort. Children unable to complete the cognitive, language or motor scales of the BSID-III because of severe delay in any of these domains were assigned scores of 49. Secondary outcomes were the components of the primary outcomes, neurology, anthropometry, and health measures. The WHO Child Growth Standards were used for calculation of z-scores, based on corrected age 14.
Statistical analysis
Analyses were performed using SAS version 9.4 (SAS Institute Inc. Cary NC). Relative risks (RR) or mean difference (MD) with 95% CI were estimated using generalized linear models, adjusted for recruitment center, socioeconomic status at birth (NZ Deprivation Index 2013 15), gestational age and sex. These potential confounders were pre-specified with knowledge of their association with neurodevelopmental outcomes. We planned to combine placebo groups in the analyses if there were no differences between them in the primary outcomes. We pre-specified that the primary outcomes would be compared between different dextrose gel dosage groups, between single and multiple dose groups, and between any dextrose gel dose and any placebo dose groups. Secondary analyses were pre-specified to examine any interactions between the effect of any dextrose gel versus placebo on primary outcomes and their components and the risk factor for hypoglycemia (diabetic mother versus other) and gestational age (preterm versus term), and also to determine the effect of hypoglycemia on the primary outcomes and their components and the effect of dextrose versus placebo on the primary outcomes and components in those who became hypoglycaemic. In this last subgroup, models to calculate relative risk for low motor or executive function failed to converge when fully adjusted, so the relative risks shown for these two outcomes are only adjusted for socioeconomic status, gestational age and sex.
We used two-sided statistical tests and the p value for the co-primary outcomes was divided evenly, giving a p value of 0.025 for each and maintaining the alpha error at 5%. 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. Data are presented as number (%), mean (SD), median (range), MD (95% CI), or RR (95% CI).
Results
In the pre-hPOD trial, 416 infants were randomized. One was incorrectly randomized after the trial had finished, 13 withdrew and 1 child died prior to 2 years, leaving 401 children eligible for follow-up, of whom 360 were assessed at two years (90% of those eligible, 87% of those randomized) (Figure 1). The mean age of mothers of children followed up was 33 years compared to 30 years in those not followed up, and the gestational age at birth of those followed up was 0.40 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 amongst all randomization groups. Mean corrected age at follow up was ~25 months and similar in all groups.
Figure 1:
Profile of participants: recruitment to two years
Table 1.
Characteristics of mothers and infants who were and were not followed up at 2 years
| Not followed up | Followed up | |||||||
|---|---|---|---|---|---|---|---|---|
| Single dose | Multiple dose | |||||||
| Total | Total | Single placebo | Dextrose 0.5 ml/kg | Dextrose 1 ml/kg | Multiple placebo | Dextrose 0.5 ml/kg × 4 | Dextrose 1 ml/kg × 1, 0.5 ml/kg × 3 | |
| Mothers (N=403)a | 55 | 358 | 63 | 62 | 62 | 54 | 54 | 63 |
| Age, years | 30 (5) | 33 (5)b | 33 (6) | 33 (5) | 34 (5) | 32 (6) | 32 (5) | 32 (5) |
| Booking BMI kg/m2 c | 29 (9) | 29 (8) | 29 (8) | 29 (7) | 29 (8) | 29 (7) | 29 (7) | 28.1 (9.2) |
| Caesarean section | 23 (42) | 176 (49) | 34 (54) | 33 (53) | 30 (47) | 31 (57) | 21 (39) | 27 (43) |
| Parityd | 1 (0–5) | 1 (0–8) | 1 (0–8) | 1 (0–6) | 0 (0–4) | 1 (0–4) | 1 (0–7) | 1 (0–7) |
| Diabetice | 41 (75) | 260 (73) | 45 (71) | 47 (76) | 44 (72) | 38 (70) | 42 (78) | 44 (70) |
| Highest level of educationf | ||||||||
| High School | NA | 65 (20) | 13 (24) | 11 (19) | 11 (20) | 13 (28) | 9 (18) | 8 (14) |
| Tertiary | NA | 253 (80) | 42 (76) | 47 (81) | 43 (79) | 33 (72) | 40 (82) | 48 (86) |
| Infants (N=415) | 55 | 360 | 63 | 62 | 64 | 54 | 54 | 63 |
| Female | 28 (51) | 174 (48) | 27 (43) | 33 (53) | 35 (55) | 26 (48) | 28 (52) | 25 (40) |
| Gestation, weeks | 38.7 (1.1) | 38.3 (1.1)a | 38.2 (0.9) | 38.3 (1.2) | 38.2 (1.2) | 38.4 (1.2) | 38.4 (1.2) | 38.4 (1.2) |
| Birthweight, grams | 3217 (616) | 3249 (616) | 3189 (650) | 3276 (618) | 3261 (650) | 3326 (650) | 3268 (550) | 3191 (578) |
| Birthweight z-score | −0.07 (1.30) | 0.17 (1.29) | 0.05 (1.34) | 0.29 (1.30) | 0.24 (1.38) | 0.32 (1.34) | 0.17 (1.25) | −0.04 (1.12) |
| Twins | 1 (2) | 30 (8) | 6 (10) | 4 (6) | 8 (13) | 5 (9) | 2 (4) | 5 (8) |
| NZDPI | 6 (1–10) | 6 (1–10) | 6 (1–10) | 7 (1–10) | 5 (1–10) | 7 (1–10) | 6.5 (1–10) | 7 (1–10) |
| Prioritized ethnicity | ||||||||
| Māori | 7 (12.7) | 35 (9.7) | 9 (14.3) | 5 (8.1) | 3 (4.7) | 9 (16.7) | 5 (9.3) | 4 (6.4) |
| Pacific | 11 (20.0) | 57 (15.8) | 9 (14.3) | 12 (19.4) | 11 (17.2) | 9 (16.7) | 7 (13.0) | 9 (14.3) |
| Asian | 15 (27.3) | 91 (25.3) | 15 (23.8) | 13 (21.0) | 16 (25.0) | 18 (33.3) | 17 (31.5) | 12 (19.1) |
| NZ European | 14 (25.5) | 100 (27.8) | 16 (25.4) | 14 (22.6) | 23 (35.9) | 7 (13.0) | 15 (27.8) | 25 (39.7) |
| Other | 8 (14.6) | 77 (21.4) | 14 (22.2) | 18 (29.0) | 11 (17.2) | 11 (20.4) | 10 (18.5) | 13 (20.6) |
| Primary risk factorg | ||||||||
| Infant of diabetic | 41 (75) | 260 (72) | 45 (71) | 47 (76) | 44 (69) | 38 (70) | 42 (78) | 44 (70) |
| Preterm | 3 (5) | 24 (7) | 3 (5) | 4 (6) | 6 (9) | 3 (6) | 2 (4) | 6 (10) |
| Small | 6 (11) | 43 (12) | 10 (16) | 6 (10) | 7 (11) | 6 (11) | 5 (9) | 9 (14) |
| Large | 5 (9) | 33 (9) | 5 (8) | 5 (8) | 7 (11) | 7 (13) | 5 (9) | 4 (6) |
| Hypoglycemia | 22 (40) | 164 (46) | 35 (56) | 23 (37) | 31 (48) | 28 (52) | 23 (43) | 24 (38) |
Data are n (%), mean (SD), or median (range)
There are 12 mothers of twins, of whom 10 appear in more than one column because each twin was assigned to a different treatment group
p<0.05 for comparison between those who were and were not followed up
Data missing for 12 not followed up, 10 single placebo, 7 dextrose 0.5ml/kg, 7 dextrose 1ml/kg, 6 multiple placebo, 6 dextrose 0.5ml/kg multiple, 9 dextrose 1ml/kg multiple
Data missing for 12 not followed up, 10 single placebo, 7 dextrose 0.5ml/kg, 7 dextrose 1ml/kg, 6 multiple placebo, 6 dextrose 0.5ml/kg multiple, 9 dextrose 1ml/kg multiple
Data missing for 1 dextrose 1ml/kg
Data missing for 8 single placebo, 4 dextrose 0.5ml/kg, 10 dextrose 1ml/kg, 8 multiple placebo, 5 dextrose 0.5ml/kg multiple, 7 dextrose 1ml/kg multiple
NA not available
NZDPI: New Zealand Deprivation Index: a measure of socioeconomic status (1 is least deprived)
Risk factors prioritized in order: infant of diabetic mother, preterm, small, large
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 (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 co-primary outcome. 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 co-ordination or tone (p=0.05). There were no differences in any other secondary outcomes with increasing dose of dextrose gel.
Table 2.
Primary and secondary outcomes at 2 years in children exposed to placebo or increasing cumulative doses of prophylactic dextrose gel after birth
| Outcome | Placebo (N=117) | Dextrose 200 mg (N=62) | Dextrose 400 mg (N=64) | Dextrose 800 mg (N=54) | Dextrose 1 g (N=63) | P Linear trenda | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| N | n (%) or mean (SD) | N | n (%) or mean (SD) | RR or MD (95%CI) | Adjusted RR or MD (95%CI), p | N | n (%) or mean (SD) | RR or MD (95%CI) | Adjusted RR or MD (95%CI), p | N | n (%) or mean (SD) | RR or MD (95%CI) | Adjusted RR or MD (95%CI), p | N | n (%) or mean (SD) | RR or MD (95%CI) | Adjusted RR or MD (95%CI), p | ||
| Neurosensory impairment | 116 | 26 (22) | 62 | 10 (16) | 0.72 (0.37–1.39) | 0.74 (0.32–1.68), 0.81 | 64 | 14 (22) | 0.98 (0.55–1.73) | 1.04 (0.51–2.13), 1.00 | 54 | 6 (11) | 0.50 (0.22–1.13) | 0.51 (0.18–1.43), 0.33 | 63 | 11 (17) | 0.78 (0.41–1.47) | 0.76 (0.35–1.69), 0.85 | 0.25 |
| Bayley-III cognitive score <85 | 116 | 15 (13) | 62 | 3 (5) | 0.37 (0.11–1.24) | 0.39 (0.08–1.78), 0.39 | 64 | 9 (14) | 1.09 (0.50–2.34) | 1.17 (0.44–3.11), 0.99 | 54 | 4 (7) | 0.57 (0.20–1.64) | 0.60 (0.16–2.28), 0.80 | 63 | 6 (10) | 0.74 (0.30–1.80) | 0.73 (0.24–2.25), 0.92 | 0.86 |
| Bayley-III language score <85 | 116 | 20 (17) | 62 | 9 (15) | 0.84 (0.41–1.74) | 0.87 (0.36–2.13), 0.99 | 64 | 10 (16) | 0.91 (0.45–1.82) | 0.96 (0.41–2.25), 1.00 | 54 | 3 (6) | 0.32 (0.10–1.04) | 0.34 (0.08–1.46), 0.22 | 63 | 7 (11) | 0.64 (0.29–1.44) | 0.62 (0.23–1.68), 0.63 | 0.06 |
| Bayley-III motor score <85 | 116 | 5 (4) | 62 | 1 (2) | 0.37 (0.04–3.13) | 0.48 (0.04–5.21), 0.74 | 64 | 1 (2) | 0.36 (0.04–3.04) | 0.49 (0.04–5.46), 0.75 | 54 | 0 | 63 | 0 | |||||
| Deaf | 116 | 1 (1) | 62 | 0 | 64 | 0 | 54 | 0 | 63 | 0 | |||||||||
| Executive function score <−1.5 SD | 115 | 13 (11) | 61 | 5 (8) | 0.73 (0.27–1.94) | 0.77 (0.22–2.65), 0.97b | 64 | 5 (8) | 0.69 (0.26–1.85) | 0.82 (0.24–2.85), 0.99 b | 54 | 2 (4) | 0.33 (0.08–1.40) | 0.37 (0.06–2.30), 0.52b | 63 | 1 (2) | 0.14 (0.02–1.05) | 0.13 (0.01–1.75), 0.19* | 0.03 |
| Bayley-III cognitive score | 116 | 99.6 (14.9) | 62 | 100.1 (14.8) | 0.47 (−3.96 to 4.90) | 0.82 (−4.62 to 6.26), 0.99 | 64 | 100.1 (15.8) | 0.47 (−3.92 to 4.85) | −0.20 (−5.59 to 5.18), 1.00 | 54 | 99.4 (11.7) | −0.26 (−4.90 to 4.38) | −0.63 (−6.32 to 5.06), 1.00 | 63 | 101.5 (14.1) | 1.90 (−2.51 to 6.30) | 2.23 (−3.17 to 7.62), 0.74 | 0.55 |
| Bayley-III language score | 116 | 99.7 (18.1) | 62 | 100.8 (14.6) | 1.10 (−3.99 to 6.20) | 1.28 (−4.85 to 7.42), 0.97 | 64 | 104.7 (17.8) | 5.00 (−0.04 to 10.04) | 3.85 (−2.23 to 9.92), 0.36 | 54 | 103.8 (14.4) | 4.12 (−1.21 to 9.46) | 3.60 (−2.81 to 10.01), 0.48 | 63 | 103.6 (16.2) | 3.90 (−1.17 to 8.97) | 4.51 (−1.58 to 10.59), 0.22 | 0.05 |
| Bayley-III motor score | 116 | 102.7 (13.4) | 62 | 104.2 (10.7) | 1.55 (−2.15 to 5.26) | 1.42 (−3.21 to 6.04), 0.89 | 64 | 105.6 (12.8) | 2.89 (−0.78 to 6.56) | 2.36 (−2.22 to 6.93), 0.56 | 54 | 106.6 (11.8) | 3.94 (0.06 to 7.82) | 3.60 (−1.24 to 8.43), 0.22 | 63 | 105.3 (10.2) | 2.58 (−1.11 to 6.27) | 2.81 (−1.77 to 7.40), 0.39 | 0.07 |
| Bayley III social emotional score | 75 | 103.4 (13.4) | 42 | 106.8 (16.1) | 3.28 (−4.73 to 11.5) | 3.30 (−3.87 to 12.42), 0.54 | 35 | 111.3 (18.5) | 3.49 (−0.73 to 16.5) | 7.74 (−0.81 to 16.30),0.09 | 32 | 103.6 (18.9) | 0.19 (−8.70 to 9.08) | 0.32 (−8.48 to 9.13), 0.99 | 43 | 106.3 (15.1) | 3.23 (−4.83 to 11.28) | 3.51 (−4.46, 11.48),0.28 | 0.69 |
| Bayley III adaptive score | 75 | 100.7 (16.2) | 42 | (98.3 (12.6) | −2.34 (−9.13 to 4.44) | −2.16 (−8.87 to 4.55), 0.88 | 35 | 105.3 (15.1) | 4.69 (−2.51 to 11.89) | 3.99 (−3.06 to 11.04), 0.47 | 32 | 101.4 (12.9) | 0.72 (−6.71 to 8.15) | 0.45 (−6.80 to 7.70), 0.88 | 43 | 102.0 (13.1) | 1.39 (−5.34 to 8.13) | 1.41 (−5.15 to 7.80), 0.97 | 0.38 |
| Executive function score | 115 | 9.9 (4.5) | 61 | 10.4 (4.1) | 0.56 (−0.71 to 1.82) | 0.66 (−0.89 to 2.22), 0.71 | 64 | 10.5 (4.1) | 0.66 (−0.58 to 1.91) | 0.47 (−1.06 to 2.00), 0.89 | 54 | 11.1 (4.1) | 1.30 (−0.02 to 2.62) | 1.19 (−0.43 to 2.81), 0.23 | 63 | 10.5 (3.4) | 0.67 (−0.58 to 1.93) | 0.77 (−0.77 to 2.30), 0.58 | 0.15 |
| BRIEF P GEC T-score >65 | 94 | 15 (16) | 51 | 5 (10) | 0.61 (0.24–1.59) | 0.51 (0.16–1.65), 0.46 | 50 | 7 (14) | 0.88 (0.38–2.01) | 0.81 (0.30–2.24), 0.97 | 46 | 10 (22) | 1.36 (0.66–2.79) | 1.24 (0.52–2.98), 0.95 | 53 | 8 (15) | 0.95 (0.43–2.08) | 0.82 (0.31–2.17), 0.97 | 0.59 |
| BRIEF P GEC T-score | 94 | 51.5 (11.1) | 51 | 51.3 (10.5) | −0.25 (−4.37 to 3.88) | −1.63 (−6.60 to 3.35), 0.86 | 50 | 50.7 (13.5) | −0.86 (−5.02 to 3.29) | −1.48 (6.47 to 3.51), 0.90 | 46 | 52.8 (13.1) | 1.22 (−3.05 to 5.49) | 0.51 (−4.62 to 5.63), 1.00 | 53 | 52.7 (13.4) | 0.14 (−2.94 to 5.21) | 0.69 (−4.18 to 5.56), 0.99 | 0.44 |
| Abnormality of tone or coordination | 115 | 9 (8) | 62 | 7 (11) | 1.44 (0.56–3.69) | 1.61 (0.53–4.91), 0.72b | 64 | 4 (6) | 0.80 (0.26–2.49) | 0.76 (0.18–3.17), 0.98 b | 54 | 2 (4) | 0.47 (0.11–2.12) | 0.48 (0.07–3.21), 0.79* | 63 | 1 (2) | 0.20 (0.03–1.56) | 0.20 (0.01–2.65), 0.39 b | 0.05 |
| Seizures | 116 | 2 (2) | 62 | 1 (2) | 0.94 (0.09–10.11) | NC | 64 | 1 (2) | 0.91 (0.08–9.80) | NC | 54 | 0 | 63 | 1 (2) | 0.92 (0.09–9.96) | NC | |||
| Asthma | 116 | 24 (21) | 62 | 12 (19) | 0.94 (0.50–1.74) | 0.96 (0.44–2.10), 1.00 | 64 | 12 (19) | 0.91 (0.49–1.69) | 0.96 (0.44–2.09), 1.00 | 54 | 9 (17) | 0.81 (0.40–1.61) | 0.83 (0.35–1.97), 0.96 | 63 | 15 (24) | 1.15 (0.65–2.03) | 1.13 (0.56–2.30), 0.98 | 0.89 |
| Eczema | 116 | 42 (36) | 62 | 28 (45) | 1.25 (0.87–1.80) | 1.20 (0.76–1.90), 0.74 | 64 | 27 (42) | 1.17 (0.80–1.70) | 1.15 (0.72–1.84), 0.90 | 54 | 24 (44) | 1.23 (0.84–1.80) | 1.24 (0.77–2.00), 0.67 | 63 | 27 (43) | 1.18 (0.81–1.72) | 1.18 (0.74–1.89), 0.81 | 0.40 |
| Allergy | 116 | 46 (40) | 62 | 27 (44) | 0.10 (0.77–1.58) | 1.08 (0.69–1.71), 0.98 | 64 | 30 (47) | 1.18 (0.84–1.67) | 1.20 (0.78–1.85), 0.72 | 54 | 25 (46) | 1.17 (0.81–1.68) | 1.19 (0.75–1.87), 0.78 | 63 | 33 (52) | 1.32 (0.95–1.83) | 1.32 (0.88–1.99), 0.29 | 0.10 |
| Doctor visits for suspected infectious illnesses | 116 | 19 (16) | 62 | 11 (18) | 1.08 (0.55–2.13) | 1.12 (0.48–2.62), 0.99 | 64 | 9 (14) | 0.86 (0.41–1.79) | 0.87 (0.34–2.20), 0.99 | 54 | 12 (22) | 1.36 (0.71–2.59) | 1.38 (0.61–3.13), 0.75 | 63 | 13 (21) | 1.26 (0.67–2.38) | 1.26 (0.57–2.80), 0.90 | 0.37 |
| Weight z-score | 116 | 0.9 (1.3) | 62 | 0.8 (1.2) | −0.08 (−0.45 to 0.29) | −0.10 (−0.56 to 0.37), 0.97 | 64 | 0.9 (1.1) | −0.03 (−0.40 to 0.34) | −0.02 (−0.48 to 0.44), 1.00 | 54 | 0.7 (1.3) | −0.18 (−0.57 to 0.21) | −0.19 (−0.68 to 0.30), 0.79 | 63 | 0.7 (1.1) | −0.17 (−0.54 to 0.20) | −0.18 (−0.65 to 0.28), 0.77 | 0.30 |
| Height z-score | 115 | 0.3 (1.1) | 62 | 0.2 (1.2) | −0.03 (−0.37 to 0.32) | −0.05 (−0.48 to 0.38), 1.00 | 64 | 0.3 (1.2) | 0.00 (−0.34 to 0.34) | −0.01 (−0.44 to 0.42), 1.00 | 53 | 0.0 (1.0) | −0.24 (−0.60 to 0.13) | −0.26 (−0.71 to 0.20), 0.47 | 63 | 0.0 (1.0) | −0.25 (−0.59 to 0.09) | −0.26 (−0.68 to 0.17), 0.42 | 0.09 |
| Weight for height z-score | 115 | 1.0 (1.3) | 62 | 0.9 (1.2) | −0.08 (−0.45 to 0.29) | −0.08 (−0.55 to 0.39), 0.98 | 64 | 0.9 (1.0) | −0.04 (−0.40 to 0.33) | −0.01 (−0.47 to 0.45), 1.00 | 53 | 0.9 (1.4) | −0.08 (−0.47 to 0.31) | −0.07 (−0.56 to 0.42), 0.99 | 63 | 0.9 (1.1) | −0.05 (−0.42 to 0.32) | −0.06 (−0.53 to 0.40), 0.99 | 0.79 |
| Head circumference z-score | 115 | 0.8 (1.2) | 61 | 0.8 (1.2) | −0.07 (−0.43 to 0.28) | −0.06 (−0.50 to 0.39), 1.00 | 63 | 0.8 (0.9) | −0.03 (−0.39 to 0.32) | 0.01 (−0.43 to 0.45), 1.00 | 53 | 0.7 (1.2) | −0.16 (−0.54 to 0.21) | −0.15 (−0.61 to 0.32), 0.88 | 61 | 0.9 (1.2) | 0.04 (−0.31 to 0.40) | 0.02 (−0.43 to 0.46), 1.00 | 0.91 |
| Triceps skinfold z-score | 84 | 0.4 (1.2) | 39 | 0.4 (1.3) | 0.09 (−0.38 to 0.55), 0.71 | 0.05 (−0.53 to 0.62), 1.00 | 45 | 0.4 (1.3) | 0.08 (−0.36 to 0.52), 0.72 | 0.06 (−0.49 to 0.61), 1.00 | 38 | 0.4 (1.3) | 0.00 (−0.47 to 0.46), 0.99 | −0.03 (−0.62 to 0.55), 1.00 | 41 | 0.2 (1.1) | −0.13 (−0.59 to 0.33), 0.58 | −0.16 (−0.72 to 0.41), 0.92 | 0.46 |
| Subscapular skinfold z-score | 84 | 0.1 (1.3) | 39 | 0.2 (1.3) | 0.16 (−0.30 to 0.63) | 0.14 (−0.45 to 0.72), 0.95 | 46 | −0.1 (1.2) | −0.19 (−0.62 to 0.25) | −0.20 (−0.75 to 0.35), 0.82 | 37 | −0.1 (1.2) | −0.13 (−0.60 to 0.34) | −0.15 (−0.75 to 0.44), 0.94 | 40 | −0.2 (1.1) | −0.28 (−0.74 to 0.18) | −0.28 (−0.86 to 0.30), 0.61 | 0.12 |
| Fat mass kg | 88 | 2.8 (1.0) | 44 | 2.7 (1.0) | −0.06 (−0.42 to 0.30) | −0.07 (−0.50 to 0.37), 0.99 | 55 | 2.6 (1.1) | −0.20 (−0.53 to 0.13) | −0.17 (−0.57 to 0.24), 0.74 | 42 | 2.7 (1.0) | −0.08 (−0.44 to 0.28) | −0.00 (−0.44 to 0.45), 1.00** | 45 | 2.5 (0.9) | −0.24 (−0.59 to 0.12) | −0.16 (−0.59 to 0.27), 0.81** | 0.55 |
| Fat free mass kg | 88 | 10.8 (1.8) | 44 | 10.8 (1.9) | −0.01 (−0.65 to 0.63) | −0.03 (−0.59 to 0.53), 1.00 | 55 | 10.8 (1.9) | 0.06 (−0.54 to 0.6) | 0.14 (−0.38 to 0.66), 0.92 | 42 | 10.6 (2.0) | −0.18 (−0.83 to 0.47) | 0.11 (−0.45 to 0.69), 0.97** | 45 | 10.4 (1.4) | −0.34 (−0.98 to 0.30) | −0.03 (−0.59 to 0.53), 1.00** | 0.87 |
| Abdominal circumference (cm) | 107 | 49.6 (3.9) | 53 | 49.5 (4.1) | −0.15 (−1.40 to 1.10) | −0.23 (−1.81 to 1.35), 0.99 | 58 | 49.4 (3.5) | −0.17 (−1.39 to 1.04) | −0.14 (−1.68 to 1.39), 1.00 | 46 | 48.5 (4.1) | −1.07 (−2.39 to 0.24) | −1.09 (−2.74 to 0.56), 0.32 | 58 | 49.3 (3.5) | −0.37 (−1.58 to 0.85) | −0.43 (−1.95 to 1.10), 0.92 | 0.24 |
No children had cerebral palsy or were blind.
Data are n (%); RR (95% CI), p or MD (95% CI), p
Adjusted values were adjusted for recruitment center, socioeconomic status, gestation, sex and for multiple comparisons using Dunnett test.
Fat mass and fat free mass were additionally adjusted for height
Adjusted for recruitment center, socioeconomic status, gestation, sex
Log binomial model did not converge, modified Poisson used
NC = Not calculable, model did not converge
When combined single and combined multiple doses of dextrose gel were compared with the combined placebo group, the risk of neurosensory impairment was similar amongst groups (Table 3). The multiple dextrose doses group had fewer low executive function scores compared to single or placebo groups, but this was not statistically significant (p=0.04) using the split p value of 0.025 for each co-primary outcome. There were no other differences in secondary outcomes between single, multiple and placebo groups.
Table 3.
Primary and secondary outcomes at 2 years in children exposed to placebo or any dextrose dose, any single dose of dextrose, or any multiple doses of dextrose
| Outcome | Placebo (N=117) | Any dextrose (N=243) | Any single dose dextrose (N=126) | Any multiple dose dextrose (N=117) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| n | n (%) or mean, SD | n | n (%) or mean, SD | RR or MD (95%CI) | Adjusted RR or MD (95%CI), p1 | n | n (%) or mean, SD | RR or MD (95%CI) | Adjusted RR or MD (95%CI), p2 | n | n (%) or mean, SD | RR or MD (95%CI) | Adjusted RR or MD (95%CI), p2 | |
| Neurosensory impairment | 116 | 26 (22.4) | 243 | 41 (16.9) | 0.75 (0.49–1.17) | 0.77 (0.50–1.19), 0.23 | 126 | 24 (19.1) | 0.85 (0.52–1.39) | 0.89 (0.51–1.55), 0.86 | 117 | 17 (14.5) | 0.65 (0.37–1.13) | 0.65 (0.35–1.21), 0.21 |
| Bayley-III cognitive score <85 | 116 | 15 (12.9) | 243 | 22 (9.1) | 0.70 (0.38–1.30) | 0.73 (0.39–1.35), 0.31 | 126 | 12 (9.5) | 0.74 (0.36–1.51) | 0.78 (0.35–1.76), 0.73 | 117 | 10 (8.6) | 0.66 (0.31–1.41) | 0.67 (0.29–1.58), 0.49 |
| Bayley-III language score <85 | 116 | 20 (17.2) | 243 | 29 (11.9) | 0.69 (0.41–1.17) | 0.71 (0.42–1.18), 0.19 | 126 | 19 (15.1) | 0.87 (0.49–1.55) | 0.92 (0.49–1.73), 0.94 | 117 | 10 (8.6) | 0.50 (0.24–1.01) | 0.49 (0.22–1.10), 0.09 |
| Bayley-III motor score <85 | 116 | 5 (4.3) | 243 | 2 (0.8) | 0.19 (0.04–0.97) | 0.22 (0.04–1.12), 0.07 | 126 | 2 (1.6) | 0.38 (0.07–1.86) | 0.49 (0.10–2.42), 0.38 | 117 | 0 | ||
| Deaf | 116 | 1 (0.9) | 243 | 0 | 126 | 0 | 117 | 0 | ||||||
| Executive function score <−1.5 SD | 115 | 13 (11.3) | 242 | 13 (5.4) | 0.48 (0.23–0.99) | 0.50 (0.24–1.06), 0.07a | 125 | 10 (8.0) | 0.71 (0.32–1.55) | 0.79 (0.32–1.93), 0.80a | 117 | 3 (2.6) | 0.23 (0.07–0.78) | 0.23 (0.06–0.94), 0.04a |
| Bayley-III cognitive score | 116 | 99.6 (14.9) | 243 | 100.3 (14.2) | 0.68 (−2.50 to 3.86) | 0.60 (−2.49 to 3.70), 0.70 | 126 | 100.1 (15.2) | 0.47 (−3.16 to 4.09) | 0.31 (−3.68 to 4.30), 0.98 | 117 | 100.5 (13.0) | 0.90 (−2.79 to 4.59) | 0.91 (−3.14 to 4.96), 0.84 |
| Bayley-III language score | 116 | 99.7 (18.1) | 243 | 103.2 (15.9) | 3.53 (−0.14 to 7.19) | 3.32 (−0.17 to 6.81), 0.06 | 126 | 102.8 (16.4) | 3.08 (−1.10 to 7.26) | 2.59 (−1.91 to 7.08), 0.34 | 117 | 103.7 (15.4) | 4.00 (−0.25 to 8.26) | 4.09 (−0.47 to 8.66), 0.09 |
| Bayley-III motor score | 116 | 102.7 (13.4) | 243 | 105.4 (114) | 2.70 (0.04 to 5.37) | 2.51 (−0.12 to 5.14), 0.06 | 126 | 104.9 (11.8) | 2.23 (−0.80 to 5.27) | 1.89 (−1.50 to 5.28), 0.36 | 117 | 105.9 (10.9) | 3.21 (0.12 to 6.30) | 3.18 (−0.26 to 6.62), 0.08 |
| Bayley III social emotional score | 75 | 103.4 (17.7) | 152 | 107.1 (17.0) | 3.71 (−1.04 to 8.45) | 4.02 (−0.70 to 8.73), 0.10 | 77 | 108.8 (17.2) | 5.43 (−0.01 to 10.9) | 5.89 (−0.24 to 12.02), 0.06 | 75 | 105.3 (16.8) | 1.93 (−3.54 to 7.41) | 2.16 (−3.96 to 8.27), 0.65 |
| Bayley III adaptive score | 75 | 100.7 (16.2) | 152 | 101.6 (3.5) | 0.98 (−3.00 to 4.96) | 0.85 (−3.04 to 4.74), 0.67 | 77 | 101.5 (14.2) | 0.85 (−3.72 to 5.43) | 0.69 (−4.39 to 5.76), 0.94 | 75 | 101.8 (13.0) | 1.11 (−3.50 to 5.72) | 1.01 (−4.05 to 6.07), 0.87 |
| Executive function score | 115 | 9.9 (4.5) | 242 | 10.6 (3.9) | 0.78 (−0.13 to 1.69) | 0.76 (−0.12 to 1.64), 0.09 | 125 | 10.5 (4.1) | 0.61 (−0.42 to 1.65) | 0.56 (−0.57 to 1.70), 0.44 | 117 | 10.8 (3.7) | 0.96 (−0.09 to 2.01) | 0.96 (−0.19 to 2.11), 0.12 |
| BRIEF P GEC T-score >65 | 94 | 15 (16.0) | 200 | 30 (15.0) | 0.94 (0.53–1.66) | 0.84 (0.48–1.44), 0.52 | 101 | 12 (119) | 0.74 (0.37–1.51) | 0.65 (0.30–1.41), 0.36 | 99 | 18 (18.2) | 1.14 (0.61–2.13) | 1.01 (0.51–2.00), 1.00 |
| BRIEF P GEC T-score | 94 | 51.5 (11.1) | 200 | 51.8 (12.6) | 0.30 (−2.67 to 3.27) | −0.47 (−3.31 to 2.37), 0.75 | 101 | 51.0 (12.0) | −0.55 (−3.95 to 2.85) | −1.55 (−5.23 to 2.12), 0.54 | 99 | 52.7 (13.2) | 1.17 (−2.24 to 4.59) | 0.60 (−3.06 to 4.27), 0.91 |
| Abnormalities of tone and coordination | 115 | 9 (7.8) | 243 | 14 (5.8) | 0.74 (0.33–1.65) | 0.74 (0.33–1.65), 0.46a | 126 | 11 (8.7) | 1.12 (0.48–2.59) | 1.14 (0.45–2.93), 0.93a | 117 | 3 (2.6) | 0.33 (0.09–1.18) | 0.33 (0.08–1.39), 0.16a |
| Seizures | 116 | 2 (1.7) | 243 | 3 (1.2) | 0.72 (0.12–4.23) | NC | 126 | 2 (1.6) | 0.92 (0.13–6.43) | NC | 117 | 1 (0.9) | 0.50 (0.05–5.39) | NC |
| Asthma | 116 | 24 (20.7) | 243 | 48 (19.8) | 0.95 (0.62–1.48) | 0.98 (0.63–1.51), 0.92 | 126 | 24 (19.1) | 0.92 (0.55–1.53) | 0.96 (0.54–1.70), 0.98 | 117 | 24 (20.5) | 0.99 (0.60–1.64) | 1.00 (0.57–1.75), 1.00 |
| Eczema | 116 | 42 (36.2) | 243 | 106 (43.6) | 1.20 (0.91–1.60) | 1.19 (0.90–1.58), 0.22 | 126 | 55 (43.7) | 1.21 (0.88–1.65) | 1.18 (0.83–1.67), 0.48 | 117 | 51 (43.6) | 1.20 (0.88–1.65) | 1.21 (0.85–1.72), 0.39 |
| Allergy | 116 | 46 (39.7) | 243 | 115 (47.3) | 1.19 (0.92–1.55) | 1.20 (0.92–1.55), 0.17 | 126 | 57 (45.2) | 1.14 (0.85–1.53) | 1.14 (0.82–1.59), 0.57 | 117 | 58 (50.0) | 1.25 (0.94–1.67) | 1.26 (0.91–1.74), 0.20 |
| Doctor visits for suspected infectious illnesses | 116 | 19 (16.4) | 243 | 45 (18.5) | 1.13 (0.69–1.84) | 1.15 (0.71–1.88), 0.57 | 126 | 20 (15.9) | 0.97 (0.55–1.72) | 0.99 (0.52–1.90), 1.00 | 117 | 25 (21.4) | 1.30 (0.76–2.24) | 0.32 (0.72–2.24), 0.49 |
| Weight for age and sex z-score | 116 | 0.9 (1.3) | 243 | 0.8 (1.2) | −0.11 (−0.38 to 0.15) | −0.12 (−0.39 to 0.15), 0.38 | 126 | 0.8 (1.2) | −0.05 (−0.36 to 0.25) | −0.06 (−0.40 to 0.29), 0.91 | 117 | 0.7 (1.2) | −0.18 (−0.49 to 0.12) | −0.18 (−0.53 to 0.16), 0.39 |
| Height for age and sex z-score | 115 | 0.3 (1.1) | 242 | 0.1 (1.1) | −0.12 (−0.37 to 0.12) | −0.14 (−0.39 to 0.11), 0.27 | 126 | 0.3 (1.2) | −0.01 (0.29 to 0.27) | −0.03 (−0.35 to 0.29), 0.97 | 116 | 0.0 (1.0) | −0.24 (−0.53 to 0.04) | −0.26 (−0.58 to 0.06), 0.14 |
| Weight for height and sex z-score | 115 | 1.0 (1.3) | 242 | 0.9 (1.2) | −0.06 (−0.33 to 0.21) | −0.06 (−0.32 to 0.21), 0.68 | 126 | 0.9 (1.1) | −0.06 (−0.36 to 0.25) | −0.04 (−0.39 to 0.30), 0.94 | 116 | 0.9 (1.2) | −0.06 (−0.37 to 0.25) | −0.07 (−0.41 to 0.28), 0.88 |
| Head circumference for age and sex z-score | 115 | 0.8 (1.2) | 238 | 0.8 (1.1) | −0.05 (−0.31 to 0.20) | −0.04 (−0.29 to 0.21), 0.76 | 124 | 0.8 (1.1) | −0.05 (−0.35 to 0.24) | −0.02 (−0.35 to 0.30), 0.98 | 114 | 0.8 (1.2) | −0.05 (−0.35 to 0.25) | −0.06 (−0.39 to 0.28), 0.90 |
| Triceps skinfold z-score | 84 | 0.4 (1.2) | 163 | 0.4 (1.2) | 0.01 (−0.31 to 0.33) | −0.02 (−0.34 to 0.30), 0.91 | 84 | 0.4 (1.3) | 0.08 (−0.29 to 0.45) | 0.06 (−0.36 to 0.47), 0.94 | 79 | 0.3 (1.2) | −0.07 (−0.44 to 0.31) | −0.09 (−0.52 to 0.32), 0.82 |
| Subscapular skinfold z-score | 84 | 0.1 (1.3) | 162 | 0 (1.2) | −0.11 (−0.43 to 0.21) | −0.13 (−0.45 to 0.19), 0.43 | 85 | 0.0 (1.2) | −0.03 (−0.39 to 0.34) | −0.05 (−0.46 to 0.37), 0.96 | 77 | −0.1 (1.1) | −0.21 (−0.58 to 0.17) | −0.22 (−0.65 to 0.21), 0.41 |
| Fat mass kg | 88 | 2.8 (1.0) | 186 | 2.6 (1.0) | −0.15 (−0.40 to 0.10) | −0.10 (−0.34 to 0.14), 0.40 | 99 | 2.6 (1.1) | −0.14 (−0.42 to 0.15) | −0.12 (−0.43 to 0.19), 0.58 | 87 | 2.6 (0.9) | −0.16 (−0.45 to 0.13) | −0.08 (−0.40 to 0.24), 0.80 |
| Fat free mass kg | 88 | 10.8 (1.8) | 186 | 10.7 (1.8) | −0.11 (−0.56 to 0.34) | 0.06 (−0.26 to 0.37), 0.73 | 99 | 10.8 (1.8) | 0.03 (−0.48 to 0.54) | 0.07 (−0.33 to 0.46), 0.91 | 87 | 10.5 (1.7) | −0.26 (−0.79 to 0.26) | 0.04 (−0.37 to 0.45), 0.96 |
| Abdominal circumference (cm) | 107 | 49.6 (3.9) | 215 | 49.2 (3.8) | −0.41 (−1.30 to 0.47) | −0.45 (−1.33 to 0.43), 0.32 | 111 | 49.5 (3.8) | −0.16 (−1.18 to 0.85) | −0.18 (−1.33 to 0.96), 0.91 | 104 | 48.9 (3.8) | −0.68 (−1.71 to 0.35) | −0.72 (−1.87 to 0.43), 0.28 |
No children had cerebral palsy or were blind.
Data are n (%); RR (95% CI), p or MD (95% CI), p1 value for comparison with placebo group; or p2 value for comparison between placebo, single and multiple groups
Adjusted values were adjusted for recruitment center, socioeconomic status, gestation, sex and for multiple comparisons using Dunnett test.
Fat mass and fat free mass were additionally adjusted for height
Log binomial model did not converge, modified Poisson used
NC= Not calculable
When children who had received any dextrose dose were compared with those who received any placebo, the risk of neurosensory impairment was similar (Table 3). Although low executive function scores were less likely in the dextrose group (RR 0.48, 95% CI 0.23, 0.99), after adjustment this difference was no longer significant (p=0.07). Similarly, motor scores were higher in the dextrose group (mean difference 2.70, 95% CI 0.04, 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.
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 hypoglycemia in the risk of neurosensory impairment (RR 1.05, 95% CI 0.68, 1.64, p=0.81) or its components: Bayley-III cognitive score <85 (RR 0.90, 95% CI 0.47, 1.70, p=0.74), Bayley-III language score <85 (RR 1.04, 95% CI 0.62, 1.75, p=0.89), Bayley-III motor score <85 (RR 0.18, 95% CI 0.02, 1.48, p=0.11), deafness (not calculable as 0/164 dextrose, 1/196 placebo), nor in low executive function (RR=0.77, 95% CI 0.35, 1.68, p=0.51). In the subgroup of children who had developed neonatal hypoglycemia there was also no effect of dextrose versus placebo on neurosensory impairment (RR 0.77, 95% CI 0.50, 1.19, p=0.23) or its components: Bayley-III cognitive score <85 (RR 0.73, 95% CI 0.39, 1.35, p=0.31), Bayley-III language score <85 (RR 0.71, 95% CI 0.42, 1.18), p=0.19), Bayley-III motor score <85 (RR=0.21 (0.04, 1.04), P=0.06), nor on low executive function (RR 0.49, 95% CI 0.24, 1.02, p=0.06).
Discussion
In children born at risk of neonatal hypoglycemia, prophylactic dextrose gel does 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 including neurology, growth, eczema, asthma and infectious illness rates were also similar in dextrose and placebo groups, providing reassurance about the safety of using oral dextrose gel prophylaxis in neonates at risk of hypoglycemia. 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 hypoglycemia 7.
The primary aim of this study was to assess the safety of prophylactic dextrose gel; it was underpowered to detect small but clinically important differences in the primary and secondary outcomes. Nevertheless, we found several consistent trends in the data that, although not statistically significant, would be of potential importance if confirmed in a larger study. 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 to placebo, and in the subgroup of infants who became hypoglycaemic. 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 two 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 16,17 and those born to diabetic mothers 18. We observed a relationship between prophylactic dextrose gel and performance on assessed executive function tasks specifically developed for this age group 11, but not on the parent-reported BRIEF-P. The assessment tasks address specific components of executive function and are complementary to the manifestations of executive function in everyday behaviour assessed in the BRIEF-P. Thus, our findings may reflect improvement in specific components of executive function rather than observable effects in the child’s usual environment. 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.
We also found a trend towards fewer abnormalities of tone and co-ordination with increasing cumulative dose of dextrose and a trend towards improved motor function with any dextrose dose compared to placebo. Infants of diabetic mothers 19,20, moderate and late preterm infants 21 or small for gestational term infants 22 have previously been shown to have poorer motor scores compared to control infants, and poorer motor skills have been associated with neonatal hypoglycemia in infants of diabetic mothers 23 and preterm infants 4.
There was also a trend towards higher language scores with increasing cumulative dose of dextrose and with any dextrose dose compared to placebo. The largest risk group in our study was infants of diabetic mothers. Poorer language skills have previously been documented in children of diabetic mothers 24 and associated with maternal glycaemic control 25 and in term SGA infants 26.
Interestingly, these possible relationships between dextrose gel prophylaxis and executive function, language, motor performance were not associated with the presence or absence of recorded hypoglycemia. The reason for this is unclear, especially as there was no dose-response observed for the effect of dextrose gel prophylaxis on the incidence or severity of neonatal hypoglycemia in the pre-hPOD trial 9. It is possible that prophylactic dextrose gel prevented periods of hypoglycemia not detected on intermittent blood glucose monitoring. Continuous glucose monitoring has shown that up to 80% of episodes of neonatal hypoglycemia may be unrecognized using intermittent blood glucose monitoring 27. Further, in the CHYLD study of a cohort of children born at risk, exposure to neonatal hypoglycemia was not associated with neurosensory impairment or its components at 2 years 28, 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 hypoglycemia may not be evident at 2 years of age. It is also possible that the threshold we used to define hypoglycemia is not optimal for prediction of later outcomes. The threshold for defining hypoglycemia remains a topic of debate 29, but we used the widely used cut-off based on studies showing a detrimental effect below 47 mg/dL (2.6 mmol/L) 3,4, and have not found a more discriminatory threshold to date 5,28.
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 5,30. In addition, this was a prospective follow-up study of participants in a blinded randomized controlled trial with similar sociodemographic characteristics across randomization groups, which should have minimized the possible effect of unrecognized 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 31,32, and also tests of more subtle neurodevelopment, and executive function; skills known to be affected by neonatal hypoglycemia 18.
An important limitation of this study was that the original trial was designed to have sufficient power to compare the incidence of hypoglycemia in at-risk infants treated with prophylactic dextrose or placebo, but not differences in later developmental outcomes. Future follow-up of the 2,149 children who have now been recruited to the hPOD study 8 of oral dextrose gel prophylaxis should help clarify if this intervention does indeed result in improvements in executive function, language and motor performance function, as suggested by the trends observed in this study. We performed multiple comparisons, since this was primarily a safety study and we wished to maximize the chance of detecting any possible adverse effects, but this leads to increased risk of a type 1 error. Thus, these findings should be interpreted with caution, pending the results of follow-up of the larger hPOD trial cohort 8. 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 hypoglycemia is expanding 33–35. Although it appears to be safe, as yet there is insufficient evidence for use of prophylactic dextrose gel in clinical practice, especially as large numbers of infants would be potentially eligible for such treatment. The follow-up of the 2,149 participants in the recently completed hPOD trial with will have much 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 hypoglycemia appears to be safe to 2 years of age. It does not alter the risk of neurosensory impairment or executive function, although we observed trends in improved executive function, language and motor performance across several analyses. These results should be interpreted with caution and no change should be made to current clinical practice.
Supplementary Material
What’s Known on This Subject:
Neonatal hypoglycaemia is common, with 30% of infants identified as at risk, and is associated with neurosensory impairment. Prophylactic oral dextrose gel reduces the incidence of neonatal hypoglycaemia in infants born at risk.
What This Study Adds:
In this prospective follow-up study of the pre-hPOD randomized, controlled, dosage trial of prophylactic oral dextrose gel in at risk infants, there was no difference in neurodevelopment at two years between children randomized to prophylactic dextrose or placebo.
Acknowledgements
Group information: The pre-hPOD (Hypoglycaemia Prevention with Oral Dextrose) study group: Caroline Crowther, Richard Edlin, Kelly Fredell, Jenny Rogers, Mariam Buksh, Alena Vasilenko, Heather Stewart and the Maternal and Perinatal Central Coordinating Research Hub.
We would like to thank: The Data Monitoring Committee: Professor Frank Bloomfield (Chair), Mr Greg Gamble and Associate Professor Katie Groom. The pre-hPOD Steering Group: Professor Jane Harding (Chair), Professor Caroline Crowther, Dr Jane Alsweiler, Dr Joanne Hegarty, Dr Richard Edlin, Mr Greg Gamble. The pre-hPOD@2YR Steering Group: Professor Jane Harding (Chair), Associate Professor Trecia Wouldes, Dr Jane Alsweiler, Dr Christopher McKinlay, Associate Professor Ben Thompson, Dr Joanne Hegarty, Dr Richard Edlin, Mr Greg Gamble.
We are grateful to all the children and their families who participated in this study.
Funding Sources: 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 (NIH). Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number R01HD091075. Rebecca Griffith received a fellowship during 2016 from the New Zealand Diabetes Foundation. Funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Abbreviations:
- RR
relative risk
- CI
confidence interval
- BSID-III
Bayley Scales of Infant Development, 3rd edition
- WHO
World Health Organization
- SD
standard deviation
- MD
mean difference
- BRIEF-P
Behavior Rating Inventory of Executive Function—Preschool Version
Footnotes
Conflict of interest: The authors have indicated they have no potential conflicts of interest to disclose.
Financial disclosure: The authors have indicated they have no financial relationships relevant to this article to disclose.
Data Collection: Jenny Rogers, MSc, Heather Stewart, Mariam Buksh, MSc, Alena Vasilenko
Study Coordination: Jenny Rogers, MSc and Kelly Fredell, BNurs
Data Management: Maternal and Perinatal Central Coordinating Research Hub, Liggins Institute, University of Auckland.
Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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