Neonatal Glycemia and Neurodevelopmental Outcomes at 2 Years

Abstract

Background: Neonatal hypoglycemia is common and can cause neurologic impairment, but evidence supporting thresholds for intervention is limited.

Methods: We performed a prospective cohort study involving 528 neonates with a gestational age of at least 35 weeks who were considered to be at risk for hypoglycemia; all were treated to maintain a blood glucose concentration of at least 47 mg per deciliter (2.6 mmol per liter). We intermittently measured blood glucose for up to 7 days. We continuously monitored interstitial glucose concentrations, which were masked to clinical staff. Assessment at 2 years included Bayley Scales of Infant Development III and tests of executive and visual function.

Results: Of 614 children, 528 were eligible, and 404 (77% of eligible children) were assessed; 216 children (53%) had neonatal hypoglycemia (blood glucose concentration, <47 mg per deciliter). Hypoglycemia, when treated to maintain a blood glucose concentration of at least 47 mg per deciliter, was not associated with an increased risk of the primary outcomes of neurosensory impairment (risk ratio, 0.95; 95% confidence interval [CI], 0.75 to 1.20; P=0.67) and processing difficulty, defined as an executive-function score or motion coherence threshold that was more than 1.5 SD from the mean (risk ratio, 0.92; 95% CI, 0.56 to 1.51; P=0.74). Risks were not increased among children with unrecognized hypoglycemia (a low interstitial glucose concentration only). The lowest blood glucose concentration, number of hypoglycemic episodes and events, and negative interstitial increment (area above the interstitial glucose concentration curve and below 47 mg per deciliter) also did not predict the outcome.

Conclusions: In this cohort, neonatal hypoglycemia was not associated with an adverse neurologic outcome when treatment was provided to maintain a blood glucose concentration of at least 47 mg per deciliter. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.).

Figure 1. Cohort of Children Followed up at 2 Years

BABIES denotes Babies and Blood Sugar's Influence on EEG Study, BRIEF-P Behavior Rating Inventory of Executive Function–preschool version, and BSID-III Bayley Scales of Infant Development III. Pediatric assessment included history taking and physical examination (including neurologic examination) by a pediatrician.

Figure 2. Effect of Hypoglycemia on the Primary Outcome and Relation between Continuous Glycemic Exposure and the Primary Outcome

Panel A shows the effect of hypoglycemia on the risk of the primary outcome. A hypoglycemic episode was defined as a blood glucose concentration of less than 47 mg per deciliter (2.6 mmol per liter) on a single measurement or consecutive measurements; severe hypoglycemia was defined as a blood glucose concentration of less than 36 mg per deciliter (2.0 mmol per liter). Results were adjusted for socioeconomic decile, sex, and primary risk factor for neonatal hypoglycemia. Panel B shows the relationship between continuous glycemic exposure and the primary outcome. Logistic regression was used to compare the risk of an adverse outcome according to the quintile of the continuous glycemic variable in the first 48 hours. Results were adjusted for socioeconomic decile, sex, and primary risk factor for neonatal hypoglycemia. Diamonds denote quintile 1, upward-pointing triangles quintile 2, circles quintile 3 (reference), squares quintile 4, and downward-pointing triangles quintile 5. Values for quintiles 1 through 5 (Q1–5) represent the lowest value for each quintile. The central band was defined as a blood glucose or an interstitial glucose concentration of 54 to 72 mg per deciliter. To convert the values for glucose to millimoles per liter, multiply by 0.05551.

Figure 3. Results of Interstitial Glucose Monitoring in Children with and Those without Neurosensory Disability at 2 Years

Data are means and 95% confidence intervals and represent the per-child 0.5-hour average of continuous interstitial glucose concentrations. ΔIG denotes the mean difference in the first 12 hours or first 48 hours, as determined from repeated-measures analysis, and IG*t the group–time interaction. Panel A shows data for all 302 children who underwent interstitial monitoring in the first 48 hours after birth, Panel B shows data for the 162 children with neonatal hypoglycemia, Panel C shows data for the 104 children with neonatal hypoglycemia who were treated with dextrose (buccal dextrose gel, intravenous dextrose, or both), Panel D shows data for the 58 children with neonatal hypoglycemia who were not treated with dextrose, Panel E shows interstitial glucose values after the first hypoglycemic episode in the 104 children treated with dextrose, and Panel F shows data for the 140 children without neonatal hypoglycemia.