Association of Neonatal Glycemia With Neurodevelopmental Outcomes at 4.5 Years

Abstract

Importance: Hypoglycemia is common during neonatal transition and may cause permanent neurological impairment, but optimal intervention thresholds are unknown.

Objective: To test the hypothesis that neurodevelopment at 4.5 years is related to the severity and frequency of neonatal hypoglycemia.

Design, setting, and participants: The Children With Hypoglycemia and Their Later Development (CHYLD) Study is a prospective cohort investigation of moderate to late preterm and term infants born at risk of hypoglycemia. Clinicians were masked to neonatal interstitial glucose concentrations; outcome assessors were masked to neonatal glycemic status. The setting was a regional perinatal center in Hamilton, New Zealand. The study was conducted from December 2006 to November 2010. The dates of the follow-up were September 2011 to June 2015. Participants were 614 neonates born from 32 weeks' gestation with at least 1 risk factor for hypoglycemia, including diabetic mother, preterm, small, large, or acute illness. Blood and masked interstitial glucose concentrations were measured for up to 7 days after birth. Infants with hypoglycemia (whole-blood glucose concentration <47 mg/dL) were treated to maintain blood glucose concentration of at least 47 mg/dL.

Exposures: Neonatal hypoglycemic episode, defined as at least 1 consecutive blood glucose concentration less than 47 mg/dL, a severe episode (<36 mg/dL), or recurrent (≥3 episodes). An interstitial episode was defined as an interstitial glucose concentration less than 47 mg/dL for at least 10 minutes.

Main outcomes and measures: Cognitive function, executive function, visual function, and motor function were assessed at 4.5 years. The primary outcome was neurosensory impairment, defined as poor performance in one or more domains.

Results: In total, 477 of 604 eligible children (79.0%) were assessed. Their mean (SD) age at the time of assessment was 4.5 (0.1) years, and 228 (47.8%) were female. Those exposed to neonatal hypoglycemia (280 [58.7%]) did not have increased risk of neurosensory impairment (risk difference [RD], 0.01; 95% CI, -0.07 to 0.10 and risk ratio [RR], 0.96; 95% CI, 0.77 to 1.21). However, hypoglycemia was associated with increased risk of low executive function (RD, 0.05; 95% CI, 0.01 to 0.10 and RR, 2.32; 95% CI, 1.17 to 4.59) and visual motor function (RD, 0.03; 95% CI, 0.01 to 0.06 and RR, 3.67; 95% CI, 1.15 to 11.69), with highest risk in children exposed to severe, recurrent, or clinically undetected (interstitial episodes only) hypoglycemia.

Conclusions and relevance: Neonatal hypoglycemia was not associated with increased risk of combined neurosensory impairment at 4.5 years but was associated with a dose-dependent increased risk of poor executive function and visual motor function, even if not detected clinically, and may thus influence later learning. Randomized trials are needed to determine optimal screening and intervention thresholds based on assessment of neurodevelopment at least to school age.

Figure 1.. Profile of the Children With Hypoglycemia and Their Later Development (CHYLD) Study Participants at 4.5 Years

BABIES indicates Babies and Blood Sugar’s Influence on EEG Study.

Figure 2.. Neonatal Hypoglycemia and Neurosensory Function at 4.5 Years

Secondary analyses of the severity (A) and frequency (B) of hypoglycemic episodes are shown. P values represent comparison across all groups. Children who were not exposed to neonatal hypoglycemia are the referent. Data on the y-axis are outcome rates or mean (SD) for each group.

Figure 3.. Blood and Interstitial Glucose Concentrations in the First 48 Hours After Birth and Neurosensory Function at 4.5 Years

P values represent comparison across all groups. Quintile 3 for neurosensory impairment is the referent. BGC indicates blood glucose concentration; IG, interstitial concentration. The central band is 54 to 72 mg/dL. To convert BGC to millimoles per liter, multiply by 0.0555.