Deborah L. Harris

Incidence of Neonatal Hypoglycemia in Babies Identified as at Risk

OBJECTIVES Routine blood glucose screening is recommended for babies at risk of neonatal hypoglycemia. However, the incidence of hypoglycemia in those screened is not well described. We sought to determine the incidence of hypoglycemia in babies identified as being at risk, and also to determine differences in incidence between at risk groups. STUDY DESIGN Infants (n = 514) were recruited who were born in a tertiary hospital, ≥35 weeks gestation and identified as at risk of hypoglycemia (small, large, infant of a diabetic, late-preterm, and other). Blood glucose screening used a standard protocol and a glucose oxidase method of glucose measurement in the first 48 hours after birth. RESULTS One-half of the babies (260/514, 51%) became hypoglycemic (<2.6 mM), 97 (19%) had severe hypoglycemia (≤2.0 mM), and 98 (19%) had more than 1 episode. The mean duration of an episode was 1.4 hours. Most episodes (315/390, 81%) occurred in the first 24 hours. The median number of blood glucose measurements for each baby was 9 (range 1-22). The incidence and timing of hypoglycemia was similar in all at risk groups, but babies with a total of 3 risk factors were more likely to have severe hypoglycemia. CONCLUSIONS Hypoglycemia is common amongst babies recommended for routine blood glucose screening. We found no evidence that screening protocols should differ in different at risk groups, but multiple risk factors may increase severity. The significance of these hypoglycemic episodes for long-term outcome remains undetermined.

Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children

Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children Paul S. Thornton, MB, BCh, Charles A. Stanley, MD, Diva D. De Leon, MD, MSCE, Deborah Harris, PhD, Morey W. Haymond, MD, Khalid Hussain, MD, MPH, Lynne L. Levitsky, MD, Mohammad H. Murad, MD, MPH, Paul J. Rozance, MD, Rebecca A. Simmons, MD, Mark A. Sperling, MBBS, David A. Weinstein, MD, MMSc, Neil H. White, MD, and Joseph I. Wolfsdorf, MB, BCh

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.).

Continuous glucose monitoring in newborn babies at risk of hypoglycemia

OBJECTIVE To determine the usefulness of continuous glucose monitoring in babies at risk of neonatal hypoglycemia. STUDY DESIGN Babies >/=32 weeks old who were at risk of hypoglycemia and admitted to newborn intensive care received routine treatment, including intermittent blood glucose measurement using the glucose oxidase method, and blinded continuous interstitial glucose monitoring. RESULTS Continuous glucose monitoring was well tolerated in 102 infants. There was good agreement between blood and interstitial glucose concentrations (mean difference, 0.0 mmol/L; 95% CI, -1.1-1.1). Low glucose concentrations (<2.6 mmol/L) were detected in 32 babies (32%) with blood sampling and in 45 babies (44%) with continuous monitoring. There were 265 episodes of low interstitial glucose concentrations, 215 (81%) of which were not detected with blood glucose measurement. One hundred seven episodes in 34 babies lasted >30 minutes, 78 (73%) of which were not detected with blood glucose measurement. CONCLUSION Continuous interstitial glucose monitoring detects many more episodes of low glucose concentrations than blood glucose measurement. The physiological significance of these previously undetected episodes is unknown.

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.

A survey of the management of neonatal hypoglycaemia within the Australian and New Zealand Neonatal Network.

Background:  Neonatal hypoglycaemia is a common problem linked to both brain damage and death. There is controversy regarding both the definition of and best treatment for neonatal hypoglycaemia.

Variable interpretation of ultrasonograms may contribute to variation in the reported incidence of white matter damage between newborn intensive care units in New Zealand

Background: The incidence of cerebral white matter damage reported to the Australian and New Zealand Neonatal Network (ANZNN) varies between neonatal intensive care units (NICUs). Hypothesis: Differences in the capture, storage, and interpretation of the cerebral ultrasound scans could account for some of this variation. Methods: A total of 255 infants of birth weight <1500 g and gestation <32 weeks born between 1997 and 2002 and drawn equally from each of the six NICUs in New Zealand were randomly selected from the ANZNN database. Half had early cerebral ultrasound scans previously reported to ANZNN as normal, and half had scans reported as abnormal. The original scans were copied, anonymised, and independently read by a panel of three experts using a standardised method of reviewing and reporting. Results: There was considerable variation between NICUs in methods of image capture, quality, and completeness of the scans. There was only moderate agreement between the reviewers’ reports and the original reports to the ANZNN (κ 0.45–0.51) and between the reviewers (κ 0.54–0.64). The reviewers reported three to six times more white matter damage than had been reported to the ANZNN. Conclusion: Some of the reported variation in white matter damage between NICUs may be due to differences in capture and interpretation of cerebral ultrasound scans.

Docosahexaenoic Acid and Bronchopulmonary Dysplasia in Preterm Infants

BACKGROUND Studies in animals and in humans have suggested that docosahexaenoic acid (DHA), an n‐3 long‐chain polyunsaturated fatty acid, might reduce the risk of bronchopulmonary dysplasia, but appropriately designed trials are lacking. METHODS We randomly assigned 1273 infants born before 29 weeks of gestation (stratified according to sex, gestational age [<27 weeks or 27 to <29 weeks], and center) within 3 days after their first enteral feeding to receive either an enteral emulsion providing DHA at a dose of 60 mg per kilogram of body weight per day or a control (soy) emulsion without DHA until 36 weeks of postmenstrual age. The primary outcome was bronchopulmonary dysplasia, defined on a physiological basis (with the use of oxygen‐saturation monitoring in selected infants), at 36 weeks of postmenstrual age or discharge home, whichever occurred first. RESULTS A total of 1205 infants survived to the primary outcome assessment. Of the 592 infants assigned to the DHA group, 291 (49.1% by multiple imputation) were classified as having physiological bronchopulmonary dysplasia, as compared with 269 (43.9%) of the 613 infants assigned to the control group (relative risk adjusted for randomization strata, 1.13; 95% confidence interval [CI], 1.02 to 1.25; P=0.02). The composite outcome of physiological bronchopulmonary dysplasia or death before 36 weeks of postmenstrual age occurred in 52.3% of the infants in the DHA group and in 46.4% of the infants in the control group (adjusted relative risk, 1.11; 95% CI, 1.00 to 1.23; P=0.045). There were no significant differences between the two groups in the rates of death or any other neonatal illnesses. Bronchopulmonary dysplasia based on a clinical definition occurred in 53.2% of the infants in the DHA group and in 49.7% of the infants in the control group (P=0.06). CONCLUSIONS Enteral DHA supplementation at a dose of 60 mg per kilogram per day did not result in a lower risk of physiological bronchopulmonary dysplasia than a control emulsion among preterm infants born before 29 weeks of gestation and may have resulted in a greater risk. (Funded by the Australian National Health and Medical Research Council and others; Australian New Zealand Clinical Trials Registry number, ACTRN12612000503820.)

Continuous Glucose Monitoring in Newborn Infants: How Do Errors in Calibration Measurements Affect Detected Hypoglycemia?

Background: Neonatal hypoglycemia is common and can cause serious brain injury. Continuous glucose monitoring (CGM) could improve hypoglycemia detection, while reducing blood glucose (BG) measurements. Calibration algorithms use BG measurements to convert sensor signals into CGM data. Thus, inaccuracies in calibration BG measurements directly affect CGM values and any metrics calculated from them. Aim: The aim was to quantify the effect of timing delays and calibration BG measurement errors on hypoglycemia metrics in newborn infants. Methods: Data from 155 babies were used. Two timing and 3 BG meter error models (Abbott Optium Xceed, Roche Accu-Chek Inform II, Nova Statstrip) were created using empirical data. Monte-Carlo methods were employed, and each simulation was run 1000 times. Each set of patient data in each simulation had randomly selected timing and/or measurement error added to BG measurements before CGM data were calibrated. The number of hypoglycemic events, duration of hypoglycemia, and hypoglycemic index were then calculated using the CGM data and compared to baseline values. Results: Timing error alone had little effect on hypoglycemia metrics, but measurement error caused substantial variation. Abbott results underreported the number of hypoglycemic events by up to 8 and Roche overreported by up to 4 where the original number reported was 2. Nova results were closest to baseline. Similar trends were observed in the other hypoglycemia metrics. Conclusions: Errors in blood glucose concentration measurements used for calibration of CGM devices can have a clinically important impact on detection of hypoglycemia. If CGM devices are going to be used for assessing hypoglycemia it is important to understand of the impact of these errors on CGM data.

Cot-Side Electro-Encephalography and Interstitial Glucose Monitoring during Insulin-Induced Hypoglycaemia in Newborn Lambs

Background: The optimal approach to detection and management of neonatal hypoglycaemia remains unclear. Objectives: We sought to demonstrate whether electro-encephalography (EEG) changes could be detected on the amplitude-integrated EEG monitor during induced hypoglycaemia in newborn lambs, and also to determine the accuracy of continuously measured interstitial glucose in this situation. Methods: Needle electrodes were placed in the P3-P4, O1-O2 montages. The interstitial glucose sensor was placed subcutaneously. After 30 min baseline recordings, hypoglycaemia was induced by insulin infusion and blood glucose levels were monitored every 5 min. The infusion was adjusted to reduce blood glucose levels by 0.5 mmol/l every 15 min and then maintain a blood glucose level <1.0 mmol/l for 4 h. EEG parameters analysed included amplitude, continuity and spectral edge frequency. The interstitial and blood glucose levels were compared. Results: All lambs (n = 15, aged 3–11 days) became hypoglycaemic, with median blood glucose levels falling from 6.5 to 1.0 mmol/l, p < 0.0001. There were no detectable changes in any of the measured EEG parameters related to hypoglycaemia, although seizures occurred in 2 lambs. There was moderate agreement between the intermittent blood glucose and continuous interstitial glucose measurements in the baseline, decline, and hypoglycaemia periods (mean difference –0.7 mmol/l, 95% confidence interval, CI, –2.8 to 1.4 mmol/l). However, agreement was poor during reversal of hypoglycaemia (mean difference 4.5 mmol/l, 95% CI –1.1 to 10.7 mmol/l). Conclusions: The cot-side EEG may not be a useful clinical tool in the detection of neurological changes induced by hypoglycaemia. However, continuous interstitial glucose monitoring may be useful in the management of babies at risk of hypoglycaemia.