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 Exposures Neonatal hypoglycemic episode, defined as at least 1 consecutive blood glucose concentration less than 47 mg/dL, a severe episode ( 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.

/pdf/association-of-neonatal-glycemia-with-neurodevelopmental-3brbh2nn2g.pdf

Association of Neonatal Glycemia with Neurodevelopmental Outcomes at 4.5 Years

Background Hypoglycaemia is the most common metabolic problem in neonates but there is no universally accepted threshold for safe blood glucose concentrations due to uncertainty regarding effects on neurodevelopment. Objective To systematically assess the association between neonatal hypoglycaemia on neurodevelopment outcomes in childhood and adolescence. Methods We searched MEDLINE, EMBASE, CINAHL, and PsycINFO from inception until February 2018. We included studies that reported one or more prespecified outcomes and compared children exposed to neonatal hypoglycaemia with children not exposed. Studies of neonates with congenital malformations, inherited metabolic disorders and congenital hyperinsulinism were excluded. Two authors independently extracted data using a customized form. We used ROBINS-I to assess risk of bias, GRADE for quality of evidence, and REVMAN for meta-analysis (inverse variance, fixed effects). Results 1,665 studies were screened, 61 reviewed in full, and 11 included (12 publications). In early childhood, exposure to neonatal hypoglycaemia was not associated with neurodevelopmental impairment (n = 1,657 infants; OR = 1.16, 95% CI = 0.86-1.57) but was associated with visual-motor impairment (n = 508; OR = 3.46, 95% CI = 1.13-10.57) and executive dysfunction (n = 463; OR = 2.50, 95% CI = 1.20-5.22). In mid-childhood, neonatal hypoglycaemia was associated with neurodevelopmental impairment (n = 54; OR = 3.62, 95% CI = 1.05-12.42) and low literacy (n = 1,395; OR = 2.04, 95% CI = 1.20-3.47) and numeracy (n = 1,395; OR = 2.04, 95% CI = 1.21-3.44). No data were available for adolescents. Conclusions Neonatal hypoglycaemia may have important long-lasting adverse effects on neurodevelopment that may become apparent at later ages. Carefully designed randomized trials are required to determine the optimal management of neonates at risk of hypoglycaemia with long-term follow-up at least to school age.

/pdf/neonatal-glycaemia-and-neurodevelopmental-outcomes-a-105iy6zy84.pdf

Neonatal Glycaemia and Neurodevelopmental Outcomes: A Systematic Review and Meta-Analysis

Background
Neonatal hypoglycaemia, a common condition, can be associated with brain injury. It is frequently managed by providing infants with an alternative source of glucose, given enterally with formula or intravenously with dextrose solution. This often requires that mother and baby are cared for in separate environments and may inhibit breast feeding. Dextrose gel is simple and inexpensive and can be administered directly to the buccal mucosa for rapid correction of hypoglycaemia, in association with continued breast feeding and maternal care.

Objectives
To assess the effectiveness of dextrose gel in correcting hypoglycaemia and in reducing long-term neurodevelopmental impairment.

Search methods
We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Web of Science from inception of the database to February 2016. We also searched international clinical trials networks and handsearched proceedings of specific scientific meetings.

Selection criteria
Randomised and quasi-randomised studies comparing dextrose gel versus placebo, no treatment or other therapies for treatment of neonatal hypoglycaemia.

Data collection and analysis
Two review authors independently assessed trial quality and extracted data and did not assess publications for which they themselves were study authors.

Main results
We included two trials involving 312 infants. No data were available for correction of hypoglycaemia for each hypoglycaemic event. We found no evidence of a difference between dextrose gel and placebo gel for major neurosensory disability at two-year follow-up (risk ratio (RR) 6.27, 95% confidence interval (CI) 0.77 to 51.03; one trial, n = 184; quality of evidence very low). Dextrose gel compared with placebo gel or no gel did not alter the need for intravenous treatment for hypoglycaemia (typical RR 0.78, 95% CI 0.46 to 1.32; two trials, 312 infants; quality of evidence very low). Infants treated with dextrose gel were less likely to be separated from their mothers for treatment of hypoglycaemia (RR 0.54, 95% CI 0.31 to 0.93; one trial, 237 infants; quality of evidence moderate) and were more likely to be exclusively breast fed after discharge (RR 1.10, 95% CI 1.01 to 1.18; one trial, 237 infants; quality of evidence moderate). Estimated rise in blood glucose concentration following dextrose gel was 0.4 mmol/L (95% CI -0.14 to 0.94; one trial, 75 infants). Investigators in one trial reported no adverse outcomes (n = 237 infants).

Authors' conclusions
Treatment of infants with neonatal hypoglycaemia with 40% dextrose gel reduces the incidence of mother-infant separation for treatment and increases the likelihood of full breast feeding after discharge compared with placebo gel. No evidence suggests occurrence of adverse effects during the neonatal period or at two years' corrected age. Oral dextrose gel should be considered first-line treatment for infants with neonatal hypoglycaemia.

Oral dextrose gel for the treatment of hypoglycaemia in newborn infants

Outcome at 2 Years after Dextrose Gel Treatment for Neonatal Hypoglycemia: Follow-Up of a Randomized Trial.

A central goal of The Academy of Breastfeeding Medicine is the development of clinical protocols for managing common medical problems that may impact breastfeeding success. These protocols serve only as guidelines for the care of breastfeeding mothers and infants and do not delineate an exclusive course of treatment or serve as standards of medical care. Variations in treatment may be appropriate according to the needs of an individual patient.

ABM clinical protocol #1: guidelines for blood glucose monitoring and treatment of hypoglycemia in term and late-preterm neonates, revised 2014.

Importance Prolonged neonatal hypoglycemia is associated with poor long-term neurocognitive function. However, little is known about an association between early transient newborn hypoglycemia and academic achievement. Objective To determine if early (within the first 3 hours of life) transient hypoglycemia (a single initial low glucose concentration, followed by a second value above a cutoff) is associated with subsequent poor academic performance. Design, Setting, and Participants A retrospective population-based cohort study of all infants born between January 1, 1998, and December 31, 1998, at the University of Arkansas for Medical Sciences who had at least 1 recorded glucose concentration (a universal newborn glucose screening policy was in effect) was conducted. Medical record data from newborns with normoglycemia or transient hypoglycemia were matched with their student achievement test scores in 2008 from the Arkansas Department of Education and anonymized. Logistic regression models were developed to evaluate the association between transient hypoglycemia and school-age achievement test proficiency based on perinatal factors. Common hypoglycemia cutoffs of a glucose level less than 35 mg/dL (primary) and less than 40 and 45 mg/dL (secondary) were investigated. All 1943 normoglycemic and transiently hypoglycemic infants (23-42 weeks’ gestation) were eligible for inclusion in the study. Infants with prolonged hypoglycemia, congenital anomalies, or chromosomal abnormalities were excluded from the study. Exposure Hypoglycemia as a newborn. Main Outcomes and Measures The primary outcome was proficiency on fourth-grade literacy and mathematics achievement tests at age 10 years. We hypothesized a priori that newborns with early transient hypoglycemia would be less proficient on fourth-grade achievement tests compared with normoglycemic newborns. Results Perinatal data were matched with fourth-grade achievement test scores in 1395 newborn-student pairs (71.8%). Transient hypoglycemia (glucose level Conclusions and Relevance Early transient newborn hypoglycemia was associated with lower achievement test scores at age 10 years. Given that our findings are serious and contrary to expert opinion, the results need to be validated in other populations before universal newborn glucose screening should be adopted.

https://jamanetwork.com/journals/jamapediatrics/articlepdf/2430217/poi150045.pdf

Jennifer K. Mehl

Papers

Association Between Transient Newborn Hypoglycemia and Fourth-Grade Achievement Test Proficiency: A Population-Based Study