The Auckland group has been studying the treatment and implications of neonatal hypoglycaemia for many years now, with unique high quality studies. Two of their recent publications have addressed the safety of glucose gel for hypoglycaemia, the first (St Clair SL, et al. Effect of prophylactic dextrose gel on the neonatal gut microbiome. Arch Dis Child Fetal Neonatal Ed. 2022;107(5):501-7) was a substudy of the hPOD trial of prophylactic glucose gel in at-risk babies. If you remember, the original trial enrolled late preterm babies and term babies who were Infants of Diabetic Mothers, or small or large for GA. The trial showed a reduction in the number of babies with hypoglycaemia (<2.6 mmol/L) from 42 to 37%, but no difference in NICU admission (which was the primary outcome). Long term follow up of the hPOD trial, which I already blogged about, showed no major difference in neurosensory outcomes, except for an increase in motor delay in the active treatment group. This substudy examined the impact of glucose gel on the development of the intestinal microbiome, and showed no real difference in bacterial diversity between gel-treated, placebo-treated, and untreated non-randomized controls over the first 4 weeks of life. They did show the expected differences between vaginally delivered and cesarean delivered babies, and despite the tiny numbers of mothers not breast feeding, they showed impacts of milk source on the microbiome also. This is reassuring data that the intervention does not impact gut colonization.
The longer term outcomes of the “Sugar Babies”, randomized treatment trial at 4.5 years have also just been published (Harris DL, et al. Outcome at 4.5 years after dextrose gel treatment of hypoglycaemia: follow-up of the Sugar Babies randomised trial. Arch Dis Child Fetal Neonatal Ed. 2022:fetalneonatal-2022-324148). A very high proportion were evaluated, 78%, and there were very minor differences in background characteristics between groups. Overall there were no real differences in the primary outcome between groups, that is “neurosensory impairment” defined as : one or more of cerebral palsy; visual or hearing impairment; full-scale intelligence quotient (IQ) or Visual Motor Integration score >1 SD below the test mean; Movement Assessment Battery for Children-2 total score <15th centile; motion coherence threshold or executive function score worse than 1.5 SDs from the CHYLD (Children with Hypoglycaemia and their Later Development) cohort means.
The primary outcome occurred in about 38% of each group. Which seems like a lot! There are in particular many infants with MABC scores below the 15th centile, 25% vs 34% in the gel and placebo groups respectively. There are also many actively treated babies with VMI scores below 85, which is a standard deviation beneath the standardized mean, 24% glucose vs 15% placebo. There were a very large number of comparisons, so to find one that was “statistically significant” is hardly a surprise, but it does suggest that there is a need for further studies and further evaluation to see if the difference between groups in VMI scores is reproducible. The high rate of “neurosensory impairment” warrants evaluation, is that similar to other New Zealand infants at this age? I would have expected about 15% below -1 SD for each test, with a lot of overlap, so it is hard to guess how many in the general population would satisfy that definition of “NSI”. It makes me think that infants eligible for the study, and at risk for neonatal hypoglycaemia, are also at increased risk for these outcomes, regardless of how they are treated; which is consistent with other data I have discussed before.
Being maximally critical you could say that there are some minor indications of a possible adverse effect of oral dextrose gel, with a hint of a possible adverse effect on visual motor integration. Could this possibly be related to the effect that the same group reported a few years ago, infants with hypoglycaemia who had glucose therapy and had a more rapid rise in their glucose levels appeared to have an increase in risk of neurosensory impairment (RR 1.8)? This certainly isn’t an argument against glucose therapy, nor against glucose gel therapy, which I think is an advance that can spare many babies from intravenous infusions, but perhaps the first approach should be feeding with breast milk rather than glucose, at least for the majority of babies who have lowish blood sugars, above the threshold that HypoEXIT suggests is safe (2.0 mmol/L). It looks possible that a too rapid increase in blood sugar might have some minor adverse effects. Trying to balance this against the adverse effects of severe hypoglycaemia, and the apparent association of hypoglycaemia risk factors with poorer outcomes is a hugely complex undertaking.