Jane M. Alsweiler

Neonatal Glycemia and Neurodevelopmental Outcomes at 2 Years

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.).

Tight Glycemic Control With Insulin in Hyperglycemic Preterm Babies: A Randomized Controlled Trial

OBJECTIVE: The optimal treatment of neonatal hyperglycemia is unclear. The aim of this trial was to determine whether tight glycemic control with insulin improves growth in hyperglycemic preterm infants, without increasing the incidence of hypoglycemia. METHODS: Randomized, controlled, nonblinded trial of 88 infants born at <30 weeks’ gestation or <1500 g who developed hyperglycemia (2 consecutive blood glucose concentrations (BGC) >8.5 mmol/L, 4 hours apart) and were randomly assigned to tight glycemic control with insulin (target BGC 4–6 mmol/L, “tight” group) or standard practice (restrictive guidelines for starting insulin, target BGC 8–10 mmol/L, “control” group). The primary outcome was linear growth rate to 36 weeks’ postmenstrual age. RESULTS: Eighty-eight infants were randomly assigned (tight group n = 43; control group n = 45). Infants in the tight group had a lesser lower leg growth rate (P < .05), but greater head circumference growth (P < .0005) and greater weight gain (P < .001) to 36 weeks’ postmenstrual age than control infants. Tight group infants had lower daily BGC (median [interquartile range] 5.7 [4.8–6.7] vs 6.5 [5.1–8.2] mmol/L, P < .001) and greater incidence of hypoglycemia (BGC <2.6 mmol/L) (25/43 vs 12/45, P < .01) than controls. There were no significant differences in nutritional intake, or in the incidences of mortality or morbidity. CONCLUSIONS: Tight glycemic control with insulin in hyperglycemic preterm infants increases weight gain and head growth, but at the expense of reduced linear growth and increased risk of hypoglycemia. The balance of risks and benefits of insulin treatment in hyperglycemic preterm neonates remains uncertain.

Survey of the management of neonatal hyperglycaemia in Australasia.

Aim:  Hyperglycaemia is a common problem in very low birthweight (VLBW) preterm neonates and has been associated with an increase in intraventricular haemorrhage and mortality. There are few data to guide clinicians on the best range of blood glucose levels to aim for when treating hyperglycaemic preterm babies with insulin. The aim of this study was to survey all Australasian tertiary neonatal intensive care units for their current practice in the definition and management of neonatal hyperglycaemia to aid in the design of a randomised controlled trial of the effect of tight glycaemic control on long‐term outcome in VLBW babies.

Association of Neonatal Glycemia With Neurodevelopmental Outcomes at 4.5 Years

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.

Advances in nutrition of the newborn infant

Nutrition of newborn infants, particularly of those born preterm, has advanced substantially in recent years. Extremely preterm infants have high nutrient demands that are challenging to meet, such that growth faltering is common. Inadequate growth is associated with poor neurodevelopmental outcomes, and although improved early growth is associated with better cognitive outcomes, there might be a trade-off in terms of worse metabolic outcomes, although the contribution of early nutrition to these associations is not established. New developments include recommendations to increase protein supply, improve formulations of parenteral lipids, and provide mineral supplements while encouraging human milk feeding. However, high quality evidence of the risks and benefits of these developments is lacking. Clinical trials are also needed to assess the effect on preterm infants of experiencing the smell and taste of milk, to determine whether boys and girls should be fed differently, and to test effects of insulin and IGF-1 supplements on growth and developmental outcomes. Moderate-to-late preterm infants have neonatal nutritional challenges that are similar to those infants born at earlier gestations, but even less high quality evidence exists upon which to base clinical decisions. The focus of research in nutrition of infants born at term is largely directed at new formula products that will improve cognitive and metabolic outcomes. Providing the most effective nutrition to preterm infants should be prioritised as an important focus of neonatal care research to improve long-term metabolic and developmental outcomes.

Prophylactic Oral Dextrose Gel for Newborn Babies at Risk of Neonatal Hypoglycaemia: A Randomised Controlled Dose-Finding Trial (the Pre-hPOD Study)

Background Neonatal hypoglycaemia is common, affecting up to 15% of newborns, and can cause brain damage. Currently, there are no strategies, beyond early feeding, to prevent neonatal hypoglycaemia. Our aim was to determine a dose of 40% oral dextrose gel that will prevent neonatal hypoglycaemia in newborn babies at risk. Methods and Findings We conducted a randomised, double-blind, placebo-controlled dose-finding trial of buccal dextrose gel to prevent neonatal hypoglycaemia at two hospitals in New Zealand. Babies at risk of hypoglycaemia (infant of a mother with diabetes, late preterm delivery, small or large birthweight, or other risk factors) but without indication for admission to a neonatal intensive care unit (NICU) were randomly allocated either to one of four treatment groups: 40% dextrose at one of two doses (0.5 ml/kg = 200 mg/kg, or 1 ml/kg = 400 mg/kg), either once at 1 h of age or followed by three additional doses of dextrose (0.5 ml/kg before feeds in the first 12 h); or to one of four corresponding placebo groups. Treatments were administered by massaging gel into the buccal mucosa. The primary outcome was hypoglycaemia (<2.6 mM) in the first 48 h. Secondary outcomes included admission to a NICU, admission for hypoglycaemia, and breastfeeding at discharge and at 6 wk. Prespecified potential dose limitations were tolerance of gel, time taken to administer, messiness, and acceptability to parents. From August 2013 to November 2014, 416 babies were randomised. Compared to babies randomised to placebo, the risk of hypoglycaemia was lowest in babies randomised to a single dose of 200 mg/kg dextrose gel (relative risk [RR] 0.68; 95% confidence interval [CI] 0.47–0.99, p = 0.04) but was not significantly different between dose groups (p = 0.21). Compared to multiple doses, single doses of gel were better tolerated, quicker to administer, and less messy, but these limitations were not different between dextrose and placebo gel groups. Babies who received any dose of dextrose gel were less likely to develop hypoglycaemia than those who received placebo (RR 0.79; 95% CI 0.64–0.98, p = 0.03; number needed to treat = 10, 95% CI 5–115). Rates of NICU admission were similar (RR 0.64; 95% CI 0.33–1.25, p = 0.19), but admission for hypoglycaemia was less common in babies randomised to dextrose gel (RR 0.46; 95% CI 0.21–1.01, p = 0.05). Rates of breastfeeding were similar in both groups. Adverse effects were uncommon and not different between groups. A limitation of this study was that most of the babies in the trial were infants of mothers with diabetes (73%), which may reduce the applicability of the results to babies from other risk groups. Conclusions The incidence of neonatal hypoglycaemia can be reduced with a single dose of buccal 40% dextrose gel 200 mg/kg. A large randomised trial (Hypoglycaemia Prevention with Oral Dextrose [hPOD]) is under way to determine the effects on NICU admission and later outcomes. Trial Registration Australian New Zealand Clinical Trials Registry ACTRN12613000322730

Neonatal Hyperglycaemia Increases Mortality and Morbidity in Preterm Lambs.

Background: Hyperglycaemic preterm babies suffer increased mortality and morbidity, but it is not known if these associations are causal or if treatment with insulin improves outcome. Objectives: We aimed to investigate the effect of neonatal hyperglycaemia, and its treatment with insulin, on mortality and morbidity in preterm lambs. Methods: Preterm lambs (137 days’ gestation; term = 148 days) were randomised to a 12-day intravenous infusion of saline (PremC; n = 39), 50% dextrose (HYPER; n = 47), or 50% dextrose + insulin (INS; n = 21). Term controls (TermC; n = 19) received saline. Dextrose and insulin infusions were titrated to maintain blood glucose concentrations (BGC) at 10–12 mmol·l–1 (HYPER) or 4–6 mmol·l–1 (INS). Results: HYPER lambs had higher BGC (mean (SEM); TermC: 5.6 (0.1), PremC: 5.5 (0.1), HYPER: 10.8 (0.6), INS: 6.2 (0.3) mmol·l–1; p < 0.0001), higher mortality (n (%); TermC: 0, PremC: 2 (5), HYPER: 11 (23), INS: 0; p < 0.001), higher incidence of fever (n (%); TermC: 3 (16), PremC: 13 (33), HYPER: 26 (55), INS: 6 (29); p = 0.01) and lower weight gain (mean (SEM); TermC: 45.9 (2.9), PremC: 44.2 (2.1), HYPER: 28.4 (1.9), INS: 28.7 (2.8) g·kg–1·day–1; p < 0.0001). Conclusions: Neonatal hyperglycaemia in preterm lambs causes increased mortality and morbidity, and decreases growth. Insulin treatment to restore euglycaemia attenuated the increased mortality and morbidity, but not the decreased growth.

Glucocorticoid-Induced Preterm Birth and Neonatal Hyperglycemia Alter Ovine β-Cell Development

Adults born preterm are at increased risk of impaired glucose tolerance and diabetes. Late gestation fetuses exposed to high blood glucose concentration also are at increased risk of impaired glucose tolerance as adults. Preterm babies commonly become hyperglycemic and are thus exposed to high blood glucose concentration at an equivalent stage of pancreatic maturation. It is not known whether preterm birth itself, or complications of prematurity, such as hyperglycemia, alter later pancreatic function. To distinguish these, we made singleton preterm lambs hyperglycemic (HYPER) for 12 days after birth with a dextrose infusion and compared them with vehicle-treated preterm and term controls and with HYPER lambs made normoglycemic with an insulin infusion. Preterm birth reduced β-cell mass, apparent by 4 weeks after term and persisting to adulthood (12 mo), and was associated with reduced insulin secretion at 4 months (juvenile) and reduced insulin mRNA expression in adulthood. Hyperglycemia in preterm lambs further down-regulated key pancreatic gene expression in adulthood. These findings indicate that reduced β-cell mass after preterm birth may be an important factor in increased risk of diabetes after preterm birth and may be exacerbated by postnatal hyperglycemia.

Continuous glucose monitoring in neonates: a review

Continuous glucose monitoring (CGM) is well established in the management of diabetes mellitus, but its role in neonatal glycaemic control is less clear. CGM has provided important insights about neonatal glucose metabolism, and there is increasing interest in its clinical use, particularly in preterm neonates and in those in whom glucose control is difficult. Neonatal glucose instability, including hypoglycaemia and hyperglycaemia, has been associated with poorer neurodevelopment, and CGM offers the possibility of adjusting treatment in real time to account for individual metabolic requirements while reducing the number of blood tests required, potentially improving long-term outcomes. However, current devices are optimised for use at relatively high glucose concentrations, and several technical issues need to be resolved before real-time CGM can be recommended for routine neonatal care. These include: 1) limited point accuracy, especially at low or rapidly changing glucose concentrations; 2) calibration methods that are designed for higher glucose concentrations of children and adults, and not for neonates; 3) sensor drift, which is under-recognised; and 4) the need for dynamic and integrated metrics that can be related to long-term neurodevelopmental outcomes. CGM remains an important tool for retrospective investigation of neonatal glycaemia and the effect of different treatments on glucose metabolism. However, at present CGM should be limited to research studies, and should only be introduced into routine clinical care once benefit is demonstrated in randomised trials.

An emerging evidence base for the management of neonatal hypoglycaemia

Neonatal hypoglycaemia is common, and screening and treatment of babies considered at risk is widespread, despite there being little reliable evidence upon which to base management decisions. Although there is now evidence about which babies are at greatest risk, the threshold for diagnosis, best approach to treatment and later outcomes all remain uncertain. Recent studies suggest that treatment with dextrose gel is safe and effective and may help support breast feeding. Thresholds for intervention require a wide margin of safety in light of information that babies with glycaemic instability and with low glucose concentrations may be associated with a higher risk of later higher order cognitive and learning problems. Randomised trials are urgently needed to inform optimal thresholds for intervention and appropriate treatment strategies.