MANUSCRIPT CITATION

Wei X, Franke N, Alsweiler JM, Brown GTL, Gamble GD, McNeill A, Rogers J, Thompson B, Turuwhenua J, Wouldes TA, Harding JE, McKinlay CJD; pre-hPOD Early School-age Outcomes Study Group. Dextrose gel prophylaxis for neonatal hypoglycaemia and neurocognitive function at early school age: a randomised dosage trial. Arch Dis Child Fetal Neonatal Ed. 2024 Jun 19;109(4):421-427. doi: 10.1136/archdischild-2023-326452. PMID: 38307710; PMCID: PMC11186727.

REVIEWED BY

Ashlee Smith-Patel, M.D.

Neonatal-Perinatal Medicine Fellow

Baylor College of Medicine, Houston, TX, United States

Email: ashlee.smith-patel@bcm.edu

 

Daniela Dinu, M.D.

Associate Professor

Baylor College of Medicine, Houston, TX, United States

Email: daniela.dinu@bcm.edu

 

Elena Itriago, M.D.

Assistant Professor

Baylor College of Medicine, Houston, TX, United States

Email: earaujo@bcm.edu

TYPE OF INVESTIGATION

Treatment

 

QUESTION

In children born at ≥35 weeks gestational age with at least one risk factor for hypoglycemia, such as maternal diabetes, small or large gestational age, or late preterm gestation (P), does prophylactic buccal dextrose gel at 1 hour of age (I), compared with placebo gel (C), affect neurocognitive function and health (O) at 6-7 years of age (T)?

 

METHODS

• Design: early school-age follow-up study of the participants of the pre-hPOD (hypoglycemia Prevention with Oral Dextrose) study, which was a dose-finding randomized controlled trial
• Allocation: Infants were randomized in a 2:1 ratio of dextrose (one of four dosages) to placebo, and were stratified by center and primary risk factor
• Blinding: yes
• Follow-up period: 6-7 years corrected age
• Setting: two hospitals in New Zealand with randomization occurring between August 2013 to November 2014
• Patients: 415 infants randomized
  • Inclusion criteria:
    • GA ≥35 weeks
    • ≥1 risk factor for hypoglycemia:
      • Maternal diabetes
      • Small for gestational age (birth weight <2.5 kg or <10^th percentile)
      • Large for gestational age (birth weight >4.5 kg or >90^th percentile)
      • Late preterm (35-36 weeks gestation)
    • Unlikely to require NICU admission
    • Birth weight ≥ 2.2kg
    • Less than 1 hour of age
    • Mother intending to breastfeed
    • Parental written informed consent and child written assent
  • Exclusion criteria:
    • Major congenital abnormality
    • Previous formula feed or intravenous fluids
    • Previous diagnosis of hypoglycemia
    • Admitted to NICU or imminent admission to NICU
  • Intervention: One of four treatment groups: buccal dextrose gel (40%) 200 mg/kg at 1 hour of age, 400 mg/kg at 1 hour of age, 200 mg/kg at 1 hour, and then before three subsequent feeds (total 800 mg/kg), or 400 mg/kg at 1 hour and 200 mg/kg before three subsequent feeds (total 1000 mg/kg)
  • Placebo: four corresponding placebo groups with equivolume 2% hydroxymethyl cellulose
  • Outcomes:
    • Primary outcome: neurocognitive impairment, defined as a standard score of <85 in one or more of the seven National Institutes of Health Toolbox tests, which provides age-adjusted scale scores with normative mean (SD) of 100.
    • Secondary outcomes:
      • Executive dysfunction (Flanker or Dimensional Change Card Sort Tests (DCCS standard score <85)
      • Motor impairment (Pegboard Dexterity Test or Standing Balance Test standard score <85)
      • Language impairment (Picture Vocabulary Test or Oral Reading Recognition Test standard score <85)
      • Episodic memory impairment (Picture Sequence Memory Test standard score <85)
      • Composite cognitive score (Early Childhood Composite Cognitive Score, or if this was unavailable, the mean of the scores for Picture Vocabulary Test, Flanker Test, DCCS, and Picture Sequence Memory Test)
      • Low numeracy
      • Motion coherence threshold (%)
      • Emotional–behavioral difficulty (SDQ total difficulties score ≥14)
      • Low physical functioning (CHQ physical functioning summary score <40)
      • Low psychosocial functioning (CHQ psychosocial summary scale score <40)
      • Overweight or obese (body mass index (BMI) z-score >1)
    • Analysis and Sample Size: for the primary analysis, authors estimated that with a follow-up rate of 80% and a primary outcome rate of 43% in the control group, the study would have 80% power to detect a reduction to 26% in one or more of the dextrose gel groups. Of the 415 randomized infants, 392 were eligible for school-age follow-up (22 withdrew, one died), and 315 were assessed (80% follow-up).

For the primary outcome, a hypothesis test (two-tailed) was undertaken to test for differences between the dextrose and control groups. Because of the small sizes of the four placebo groups, they were merged into one comparator group.

Adjustments were made for stratification variables and potential confounding by socioeconomic decile and gestation length.

 MAIN RESULTS

There were several differences in baseline characteristics between the children assessed at 6-7 years and those lost to follow-up. Compared to children who were lost to follow-up (n=100), the children who were assessed were born slightly earlier, with mothers who were older, and more likely to have received tertiary education. Between dextrose gel dosage treatment groups in children who were assessed, there were also several differences including lower maternal BMI, nulliparity, and fewer female children in the 1000 mg/kg group, and fewer children of Māori and Pacific ethnicity in the 400 mg/kg and 1000 mg/kg groups.

Table 1: Baseline characteristics of children randomized to dextrose gel (combined) or placebo (combined) and their mothers

Characteristics	Combined placebo gel group	Combined dextrose gel group
Maternal	n=100	n=204
Age (years), mean (SD)	32.6 (5.6)	32.8 (5.4)
BMI at booking (kg/m2), mean (SD)	29.1 (7.9)	28.8 (8.1)
Nulliparous, n (%)	41 (41)	99 (49)
Highest education level, n (%)
High school	18 (22)	29 (16)
Polytechnic	23 (28)	33 (18)
University	41 (50)	119 (66)
Diabetes, n (%)	70 (70)	153 (75)
Pre-eclampsia, n (%)	5 (5)	6 (3)
Infants	n=100	n=212
Female, n (%)	48 (47)	108 (51)
Gestation (weeks), mean (SD)	38.3 (1.1)	38.2 (1.1)
Preterm, n (%)	10 (10)	25 (12)
Birth weight (g), mean (SD)	3266 (643)	3222 (573)
Multiple pregnancy, n (%)	10 (10)	18 (8)
High deprivation, n (%)	32 (31)	82 (39)
Ethnicity, n (%)
Māori	18 (17)	16 (8)
Pacific	13 (13)	33 (16)
Other	51 (50)	90 (42)
European	21 (20)	73 (34)
Primary risk factor for hypoglycemia, n (%)
Maternal diabetes	71 (69)	155 (73)
Preterm	5 (5)	18 (8)
Small	15 (15)	25 (12)
Large	12 (12)	14 (7)
Neonatal hypoglycemia, n (%)
Any <2.6 mmol/L	56 (54)	91 (43)
Severe <2.0 mmol/L	14 (14)	21 (10)

Among 308 children with primary outcome data, there were no significant differences in the rate of neurocognitive impairment between those randomized to placebo and different dosages of dextrose gel.

However, when the dextrose groups were combined, thereby increasing sample size, dextrose gel prophylaxis was associated with a lower risk of motor impairment (3% vs 14%, aRD=-11%, 95% CI -19% to -3%) and higher mean (SD) cognitive scores (106.0 (15.3) vs 101.1 (15.7), adjusted mean difference=5.4, 95% CI 1.8 to 8.9) (Table 2).

Table 2: Primary and secondary outcomes for children randomized to any dose of dextrose gel or to any dose of placebo gel, adjusted and after adjustment for additional variables:

	Placebo	N	Dextrose	N	Model 1 aRD, aMD (95% CI) aRR (95% CI)	Model 4 aRD, aMD (95% CI) aRR (95% CI)
Neurocognitive impairment	57 (56%)	102	98 (48%)	206	-11% (-22,1) 0.76 (0.61, 0.96)	-8% (-20, 4) 0.85 (0.68, 1.07)
Executive dysfunction	16 (16%)	102	21 (10%)	206	-5% (15, 5) 0.63 (0.34, 1.14)	5% (14, 3) 0.65 (0.35, 1.19)
Motor impairment	14 (14%)	102	7 (3%)	206	-11% (-19, -3) 0.25 (0.11, 0.61)	-12% (-20, 5) 0.23 (0.10, 0.55)
Language impairment	20 (20%)	102	28 (14%)	206	-7% (-17, 3) 0.66 (0.40, 1.10)	-6% (-15, 3) 0.69 (0.41, 1.17)
Episodic memory impairment	12 (12%)	102	16 (8%)	205	-7% (16, 3) 0.65 (0.32, 1.32)	-4% (-11, 3) 0.66 (0.33, 1.35)
Composite cognitive score	101.1 (15.7)	102	106.0 (15.3)	206	5.4 (1.8, 8.9)	4.9 (1.2, 8.6)
Low numeracy	15 (15%)	102	22 (11%)	206	-5% (-15, 5) 0.67 (0.37, 1.23)	-4% (12, 4) 0.73 (0.39, 1.34)
Motion Coherence Threshold	25.2 (25.4)	98	24.3 (22.4)	203	-1.2 (-6.9, 4.5)	-0.9 (-6.5, 4.8)
Emotional-behavioral difficulty	13 (19%)	68	19 (12%)	160	-5% (-17, 7) 0.61 (0.32, 1.15)	-7% (-18, 3) 0.62 (0.32, 1.19)
Low physical functioning	6 (9%)	67	11 (7%)	162	0% (-12, 12) 0.71 (0.28, 1.83)	-2% (-10, 6) 0.76 (0.29, 1.98)
Low psychosocial functioning	9 (13%)	67	15 (9%)	162	-4% (14, 6) 0.69 (0.31, 1.53)	-4% (-14, 5) 0.69 (0.32, 1.50)
Overweight or obese	44 (44%)	100	84 (41%)	206	-3% (-14, 9) 0.86 (0.65, 1.13)	-3% (-15, 9) 0.93 (0.70, 1.22)

Model 1 = adjusted for stratification variables (site, primary risk factor for neonatal hypoglycemia)

Model 4= unadjusted

aRD: adjusted risk difference

aMD: adjusted mean difference

aRR: adjusted risk ratio

CONCLUSION

The authors conclude that different doses of prophylactic dextrose gel administered at 1 hour of age in neonates at risk of hypoglycemia did not impact the primary outcome of neurocognitive impairment at 6-7 years of age. However, composite data on secondary outcomes suggested that prophylactic dextrose gel may reduce motor impairment and increase cognitive function.

 

COMMENTARY

Neonatal hypoglycemia is a common condition. Symptomatic neonatal hypoglycemia has been associated with white matter injury on brain magnetic resonance imaging, and even transient or undetected hypoglycemia may be associated with impaired executive functioning in early childhood.(3,4) This has led to studies evaluating prophylactic use of dextrose gel to decrease the incidence of hypoglycemia and, potentially, the incidence of neurodevelopmental impairment (NDI) later in life.(5,6)

 

In this study, the authors were able to follow up and assess 80% of the initial cohort from the pre-hPOD trial (6), which compared various dextrose gel dosages (200 mg/kg, 400 mg/kg, 800 mg/kg, 1000 mg/kg) administered prophylactically at one hour of life with placebo. A previous analysis of the same cohort at two years of age found no difference in the composite neurosensory impairment outcome between placebo and dextrose gel (7), consistent with another trial (the hPOD trial) which also compared the neurodevelopmental outcome at two years for infants born at risk and found no significant difference between 200 mg/kg 40% dextrose gel and placebo, but was underpowered to detect small but potentially clinically relevant differences in neurosensory impairment.(8)

 

The investigators evaluated multiple domains (neurocognitive function, visual perception, reading, and numeracy, body size and composition, and grip strength) and found no difference in the primary outcome of cognitive impairment at 6-7 years of age for children randomized to various doses of prophylactic dextrose gel compared with control. When sample size was increased by combining all those exposed to intervention there was a lower risk of motor impairment (3% vs. 14%) and higher mean (SD) cognitive scores (106.0 (15.3) vs. 101.1 (15.7). These findings support the hypothesis that certain higher-order cognitive functions may not be fully developed at younger ages, and longer follow-up might be needed to detect poor executive function or visual impairment.(5) The improvement in the motor skills at 6-7 y of age in this study which contrasts with previous reports may be due to the poor predictive value of the neurological exam and Bayley exam performed at 2y of age in predicting motor skills later in childhood.(9) However, it should also be considered that alimitation of this study were differences in baseline characteristics, with the children who were assessed being more likely to be born to older and more educated mothers, compared to those children lost to follow up.

 

The placebo group had a high rate of neurocognitive impairment (56%), compared with the dextrose group (48%). These results supports the hypothesis that the prophylactic gel prevented episodes of hypoglycemia which went undetected with intermittent sampling, as shown by studies using continuous glucose monitoring (4).

 

While there were no identified adverse effects associated with the use of prophylactic dextrose gel, the number needed to treat (NNT) to prevent one case of NDI would likely be high, considering that the initial trial showed an NNT of 21 to prevent one case of hypoglycemia and larger studies.(8)

 

More studies are needed to evaluate benefits, harms, timing, and dosing of prophylactic treatment in infants at risk of developing hypoglycemia.

 

Reference:

1. Roberts L, Lin L, Alsweiler J, Edwards T, Liu G, Harding JE. Oral dextrose gel to prevent hypoglycaemia in at-risk neonates. Cochrane Database Syst Rev. 2023 Nov 28;11(11):CD012152.
2. Harris DL, Weston PJ, Signal M, Chase JG, Harding JE. Dextrose gel for neonatal hypoglycaemia (the Sugar Babies Study): a randomised, double-blind, placebo-controlled trial. Lancet Lond Engl. 2013 Dec 21;382(9910):2077–83.
3. Burns CM, Rutherford MA, Boardman JP, Cowan FM. Patterns of cerebral injury and neurodevelopmental outcomes after symptomatic neonatal hypoglycemia. Pediatrics. 2008 Jul;122(1):65–74.
4. McKinlay CJD, Alsweiler JM, Anstice NS, Burakevych N, Chakraborty A, Chase JG, et al. Association of Neonatal Glycemia With Neurodevelopmental Outcomes at 4.5 Years. JAMA Pediatr. 2017 Oct 1;171(10):972–83.
5. Harding JE, Hegarty JE, Crowther CA, Edlin RP, Gamble GD, Alsweiler JM, et al. Evaluation of oral dextrose gel for prevention of neonatal hypoglycemia (hPOD): A multicenter, double-blind randomized controlled trial. PLoS Med. 2021 Jan;18(1):e1003411.
6. Hegarty JE, Harding JE, Gamble GD, Crowther CA, Edlin R, Alsweiler JM. Prophylactic Oral Dextrose Gel for Newborn Babies at Risk of Neonatal Hypoglycaemia: A Randomised Controlled Dose-Finding Trial (the Pre-hPOD Study). PLoS Med. 2016 Oct;13(10):e1002155.
7. Griffith R, Hegarty JE, Alsweiler JM, Gamble GD, May R, McKinlay CJD, et al. Two-year outcomes after dextrose gel prophylaxis for neonatal hypoglycaemia. Arch Dis Child Fetal Neonatal Ed. 2021 May;106(3):278–85.
8. Edwards T, Alsweiler JM, Crowther CA, Edlin R, Gamble GD, Hegarty JE, et al. Prophylactic Oral Dextrose Gel and Neurosensory Impairment at 2-Year Follow-up of Participants in the hPOD Randomized Trial. JAMA. 2022 Mar 22;327(12):1149–57.
9. Burakevych N, Mckinlay CJD, Alsweiler JM, Wouldes TA, Harding JE, Chyld Study Team. Bayley-III motor scale and neurological examination at 2 years do not predict motor skills at 4.5 years. Dev Med Child Neurol. 2017 Feb;59(2):216–23.