Lower versus traditional treatment threshold for neonatal hypoglycaemia: No difference between the groups at 18 months of age, awaiting long-term outcomes.

Abstract

Neonatal hypoglycaemia has long been a medical conundrum. The mere definition and operational threshold with which to offer treatment has long been and continues to be debated. Severe and symptomatic hypoglycaemia negatively impacts long-term neurodevelopment. How to balance treatment without risking adverse consequences and without overutilization of health care resources are discussed often. As a result, this research study sets out to challenge the dogma of the required treatment at glucose <47 mg/dL. One aspect that distinguishes this study from others was its unique clinical design. While most other studies are retrospective, this study was a prospective, randomized, non-inferiority study assessing the current operational threshold for hypoglycaemia treatment with a lower threshold. The study allowed for neurodevelopmental outcomes <0.5 standard deviations below the mean, as a threshold for non-inferiority. Given one standard deviation from the mean is considered normal, this was a reasonable threshold. Additionally, the study was able to achieve its goal of 85% neurodevelopmental follow-up at age 18 months, which is impressive for a condition that is usually short-term and often viewed as benign. There were a few critical aspects of this study. First, it was underpowered to assess infants of diabetic mothers. Second, aside from the treatment threshold, there was no defined protocol for how to treat hypoglycaemia, and it was left to provider discretion despite wide practice variations. Lastly and most importantly, follow-up at 18 months of age is likely too soon to detect differences in neurodevelopmental outcomes; therefore, most follow-up studies focus on 24 months of age or higher. The CHYLD studies by McKinlay et al found no difference in neurodevelopmental outcomes between neonate with hypoglycaemia (defined as glucose <47 mg/dL) and those without at 24 months of age, but did find differences in executive and visual-motor functioning at 4.5 years of age.1, 2 Several additional studies with longer-term follow-up have shown differences between cohorts with and without neonatal hypoglycaemia. For instance, Wickström et al (2018) showed evidence of motor and cognitive delay at 2-6 years of age-associated with moderate hypoglycaemia (defined as glucose <40 mg/dL).3 Kaiser used 4th-grade standardised testing to assess 10-year follow-up and found an association with decreased literacy and mathematics scores with a single incidence of glucose <45 mg/dL and even further disparity at lower thresholds of <40 mg/dL and <35 mg/dL.4 A systematic review by Shah in 2019 concluded neonatal hypoglycaemia is associated visual-motor impairment and executive dysfunction in early-childhood (2-5 years of age) and neurodevelopmental impairment and low literacy in mid-childhood (6-11 years of age).5 Given this evidence, it is reasonable to conclude while this study showed no difference at 18-month follow-up that longer-term follow-up might show differences. As this study completed in 2011, it would be interesting to see whether a 4- to 6-year follow-up is assessed, and if so, what the results show. In conclusion, while it may be too soon to instil practice changes based on the results of this study, there is potential if longer-term follow-up can show similar results. https://ebneo.org/2020/04/threshold-for-neonatal-hypoglycemia/ None.