The aim of this trial was to determine if midwives or doctor leaders are more effective at implementing a clinical practice guideline for oral dextrose gel to treat neonatal hypoglycaemia. This was a ...cluster-randomised, controlled, trial. New Zealand maternity hospitals were randomised to guideline implementation by a midwife or doctor implementation leader. The primary outcome was the change in the proportion of hypoglycaemic babies (blood glucose concentration <2.6 mmol/L in the first 48 hours after birth), treated with dextrose gel from before, to three months after, implementation. Twenty-one maternity hospitals that cared for babies at risk of hypoglycaemia consented to participate, of which 15 treated babies with hypoglycaemia at both time points (7 randomised to midwifery led, 8 randomised to doctor led implementation). The primary outcome included 463 hypoglycaemic babies (292 midwifery led, 171 doctor led implementation). There was no difference in the primary outcome between hospitals randomised to midwifery or doctor led implementation (proportion treated with gel, mean(SD); midwifery led: before 71 (38)%, 3 months after 87 (12)%; doctor led: before 63 (43)%, 3 months after 86 (16)%; adjusted mean change in proportion (95%CI); 19.3% (-4.5–43.1), p = 0.11). There was an increase in the proportion of eligible babies treated with oral dextrose gel from before to 3 months after implementation of the guideline (122/153 (80%) v 144/163 (88%), OR (95%CI); 3.42 (1.67–6.98), p<0.001). Implementation of a clinical practice guideline improved uptake of oral dextrose gel. There was no evidence of a difference between midwife and doctor implementation leaders for implementing this guideline for treatment of hypoglycaemic babies. The trial was prospectively registered on the ISRCTN registry on the 20/05/2015 (ISRCTN61154098).
To determine postnatal changes in plasma and interstitial glucose concentrations of healthy infants receiving current recommended care and to compare the incidence of low concentrations with ...recommended thresholds for treatment of at-risk infants.
A prospective masked observational study in Hamilton, New Zealand. Healthy, term, appropriately grown singletons had continuous glucose monitoring and repeated heel-prick plasma glucose measurements (4 in the first 24 hours then twice daily using the glucose oxidase method) from birth to 120 hours.
The 67 infants had a mean birth weight of 3584 ± 349 g, and gestational age of 40.1 ± 1.2 weeks. The mean glucose concentrations increased over the first 18 hours, remained stable to 48 hours (59 ± 11 mg/dL; 3.3 ± 0.6 mmol/L) before increasing to a new plateau by the fourth day (89 ± 13 mg/dL; 4.6 ± 0.7 mmol/L). Plasma glucose concentrations of 47 mg/dL (2.6 mmol/L) approximated the 10th percentile in the first 48 hours, and 39% of infants had ≥1 episode below this threshold. Early term infants had lower mean glucose concentrations than those born at later gestational ages and were more likely to have episodes <47 mg/dL (<2.6 mmol/L) (19/32 59% vs 7/35 20%; relative risk, 3.0; 95% CI, 1.4-6.1; P = .001).
Healthy infants seem to complete their metabolic transition by day 4. Many have glucose concentrations below the accepted thresholds for treatment of hypoglycemia.
ACTRN: 12615000986572.
Extremely preterm babies are at increased risk of less than optimal neurodevelopment compared with their term-born counterparts. Optimising nutrition is a promising avenue to mitigate the adverse ...neurodevelopmental consequences of preterm birth. In this narrative review, we summarize current knowledge on how nutrition, and in particular, protein intake, affects neurodevelopment in extremely preterm babies. Observational studies consistently report that higher intravenous and enteral protein intakes are associated with improved growth and possibly neurodevelopment, but differences in methodologies and combinations of intravenous and enteral nutrition strategies make it difficult to determine the effects of each intervention. Unfortunately, there are few randomized controlled trials of nutrition in this population conducted to determine neurodevelopmental outcomes. Substantial variation in reporting of trials, both of nutritional intakes and of outcomes, limits conclusions from meta-analyses. Future studies to determine the effects of nutritional intakes in extremely preterm babies need to be adequately powered to assess neurodevelopmental outcomes separately in boys and girls, and designed to address the many potential confounders which may have clouded research findings to date. The development of minimal reporting sets and core outcome sets for nutrition research will aid future meta-analyses.
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.
Summary Background Neonatal hypoglycaemia is common, and a preventable cause of brain damage. Dextrose gel is used to reverse hypoglycaemia in individuals with diabetes; however, little evidence ...exists for its use in babies. We aimed to assess whether treatment with dextrose gel was more effective than feeding alone for reversal of neonatal hypoglycaemia in at-risk babies. Methods We undertook a randomised, double-blind, placebo-controlled trial at a tertiary centre in New Zealand between Dec 1, 2008, and Nov 31, 2010. Babies aged 35–42 weeks' gestation, younger than 48-h-old, and at risk of hypoglycaemia were randomly assigned (1:1), via computer-generated blocked randomisation, to 40% dextrose gel 200 mg/kg or placebo gel. Randomisation was stratified by maternal diabetes and birthweight. Group allocation was concealed from clinicians, families, and all study investigators. The primary outcome was treatment failure, defined as a blood glucose concentration of less than 2·6 mmol/L after two treatment attempts. Analysis was by intention to treat. The trial is registered with Australian New Zealand Clinical Trials Registry, number ACTRN12608000623392. Findings Of 514 enrolled babies, 242 (47%) became hypoglycaemic and were randomised. Five babies were randomised in error, leaving 237 for analysis: 118 (50%) in the dextrose group and 119 (50%) in the placebo group. Dextrose gel reduced the frequency of treatment failure compared with placebo (16 14% vs 29 24%; relative risk 0·57, 95% CI 0·33–0·98; p=0·04). We noted no serious adverse events. Three (3%) babies in the placebo group each had one blood glucose concentration of 0·9 mmol/L. No other adverse events took place. Interpretation Treatment with dextrose gel is inexpensive and simple to administer. Dextrose gel should be considered for first-line treatment to manage hypoglycaemia in late preterm and term babies in the first 48 h after birth. Funding Waikato Medical Research Foundation, the Auckland Medical Research Foundation, the Maurice and Phyllis Paykel Trust, the Health Research Council of New Zealand, and the Rebecca Roberts Scholarship.
Background
Neonatal hypoglycaemia is a common condition that can be associated with brain injury. Current practice usually includes early identification of at‐risk infants (e.g. infants of diabetic ...mothers; preterm, small‐ or large‐for‐gestational‐age infants), and prophylactic measures are advised. However, these measures often involve use of formula milk or admission to the neonatal unit. Dextrose gel is non‐invasive, inexpensive and effective for treatment of neonatal hypoglycaemia. Prophylactic dextrose gel can reduce the incidence of neonatal hypoglycaemia, thus potentially reducing separation of mother and baby and supporting breastfeeding, as well as preventing brain injury.
This is an update of a previous Cochrane Review published in 2021.
Objectives
To assess the effectiveness and safety of oral dextrose gel in preventing hypoglycaemia before first hospital discharge and reducing long‐term neurodevelopmental impairment in newborn infants at risk of hypoglycaemia.
Search methods
We searched CENTRAL, MEDLINE, Embase and Epistemonikos in April 2023. We also searched clinical trials databases and the reference lists of retrieved articles.
Selection criteria
We included randomised controlled trials (RCTs) and quasi‐RCTs comparing oral dextrose gel versus placebo, no intervention, or other therapies for the prevention of neonatal hypoglycaemia. We included newborn infants at risk of hypoglycaemia, including infants of mothers with diabetes (all types), high or low birthweight, and born preterm (< 37 weeks), age from birth to 24 hours, who had not yet been diagnosed with hypoglycaemia.
Data collection and analysis
Two review authors independently extracted data and assessed the risk of bias. We contacted investigators to obtain additional information. We used fixed‐effect meta‐analyses. We used the GRADE approach to assess the certainty of evidence.
Main results
We included two studies conducted in high‐income countries comparing oral dextrose gel versus placebo in 2548 infants at risk of neonatal hypoglycaemia. Both of these studies were included in the previous version of this review, but new follow‐up data were available for both. We judged these two studies to be at low risk of bias in 13/14 domains, and that the evidence for most outcomes was of moderate certainty.
Meta‐analysis of the two studies showed that oral dextrose gel reduces the risk of hypoglycaemia (risk ratio (RR) 0.87, 95% confidence interval (CI) 0.79 to 0.95; risk difference (RD) ‐0.06, 95% CI ‐0.10 to ‐0.02; 2548 infants; high‐certainty evidence). Evidence from two studies showed that there may be little to no difference in the risk of major neurological disability at two years of age after oral dextrose gel (RR 1.00, 95% CI 0.59 to 1.68; 1554 children; low‐certainty evidence).
Meta‐analysis of the two studies showed that oral dextrose gel probably reduces the risk of receipt of treatment for hypoglycaemia during initial hospital stay (RR 0.89, 95% CI 0.79 to 1.00; 2548 infants; moderate‐certainty evidence) but probably makes little or no difference to the risk of receipt of intravenous treatment for hypoglycaemia (RR 1.01, 0.68 to 1.49; 2548 infants; moderate‐certainty evidence). Oral dextrose gel may have little or no effect on the risk of separation from the mother for treatment of hypoglycaemia (RR 1.12, 95% CI 0.81 to 1.55; two studies, 2548 infants; low‐certainty evidence).
There is probably little or no difference in the risk of adverse effects in infants who receive oral dextrose gel compared to placebo gel (RR 1.22, 95% CI 0.64 to 2.33; two studies, 2510 infants; moderate‐certainty evidence), but there are no studies comparing oral dextrose with other comparators such as no intervention or other therapies.
No data were available on exclusive breastfeeding after discharge.
Authors' conclusions
Prophylactic oral dextrose gel reduces the risk of neonatal hypoglycaemia in at‐risk infants and probably reduces the risk of treatment for hypoglycaemia without adverse effects. It may make little to no difference to the risk of major neurological disability at two years, but the confidence intervals include the possibility of substantial benefit or harm. Evidence at six to seven years is limited to a single small study.
In view of its limited short‐term benefits, prophylactic oral dextrose gel should not be incorporated into routine practice until additional information is available about the balance of risks and harms for later neurological disability. Additional large follow‐up studies at two years of age or older are required. Future research should also be undertaken in other high‐income countries, low‐ and middle‐income countries, preterm infants, using other dextrose gel preparations, and using comparators other than placebo gel. There are three studies awaiting classification and one ongoing study which may alter the conclusions of the review when published.
Background
Exclusively breast milk‐fed preterm infants may accumulate nutrient deficits leading to extrauterine growth restriction. Feeding preterm infants with multi‐nutrient fortified human breast ...milk rather than unfortified breast milk may increase nutrient accretion and growth rates and may improve neurodevelopmental outcomes.
Objectives
To determine whether multi‐nutrient fortified human breast milk improves important outcomes (including growth and development) over unfortified breast milk for preterm infants without increasing the risk of adverse effects (such as feed intolerance and necrotising enterocolitis).
Search methods
We used the standard search strategy of the Cochrane Neonatal Review Group. This included electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 2), MEDLINE, EMBASE and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (until February 2016), as well as conference proceedings and previous reviews.
Selection criteria
Randomised and quasi‐randomised controlled trials that compared feeding preterm infants with multi‐nutrient (protein and energy plus minerals, vitamins or other nutrients) fortified human breast milk versus unfortified (no added protein or energy) breast milk.
Data collection and analysis
We extracted data using the standard methods of the Cochrane Neonatal Review Group. We separately evaluated trial quality, data extracted by two review authors and data synthesised using risk ratios (RRs), risk differences and mean differences (MDs). We assessed the quality of evidence at the outcome level using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
Main results
We identified 14 trials in which a total of 1071 infants participated. The trials were generally small and weak methodologically. Meta‐analyses provided low‐quality evidence that multi‐nutrient fortification of breast milk increases in‐hospital rates of growth (MD 1.81 g/kg/d, 95% confidence interval (CI) 1.23 to 2.40); length (MD 0.12 cm/wk, 95% CI 0.07 to 0.17); and head circumference (MD 0.08 cm/wk, 95% CI 0.04 to 0.12). Only very limited data are available for growth and developmental outcomes assessed beyond infancy, and these show no effects of fortification. The data did not indicate other potential benefits or harms and provided low‐quality evidence that fortification does not increase the risk of necrotising enterocolitis in preterm infants (typical RR 1.57, 95% CI 0.76 to 3.23; 11 studies, 882 infants).
Authors' conclusions
Limited available data do not provide strong evidence that feeding preterm infants with multi‐nutrient fortified breast milk compared with unfortified breast milk affects important outcomes, except that it leads to slightly increased in‐hospital growth rates.
Background
Preterm infants require high protein intake to achieve adequate growth and development. Although breast milk feeding has many benefits for this population, the protein content is highly ...variable, and inadequate to support rapid infant growth. This is a 2020 update of a Cochrane Review first published in 1999.
Objectives
To determine whether protein‐supplemented human milk compared with unsupplemented human milk, fed to preterm infants, improves growth, body composition, cardio‐metabolic, and neurodevelopmental outcomes, without significant adverse effects.
Search methods
We used the standard search strategy of Cochrane Neonatal to search Cochrane Central Register of Controlled Trials (CENTRAL 2019, Issue 8) in the Cochrane Library and MEDLINE via PubMed on 23 August 2019. We also searched clinical trials databases and the reference lists of retrieved articles for randomised controlled trials and quasi‐randomised trials.
Selection criteria
Published and unpublished RCTs were eligible if they used random or quasi‐random methods to allocate hospitalised preterm infants who were being fed human milk, to additional protein supplementation or no supplementation.
Data collection and analysis
Two review authors independently ed data, assessed risk of bias and the quality of evidence at the outcome level, using GRADE methodology. We performed meta‐analyses, using risk ratio (RR) for dichotomous data, and mean difference (MD) for continuous data, with their respective 95% confidence intervals (CIs). We used a fixed‐effect model and had planned to explore potential causes of heterogeneity via subgroup or sensitivity analyses.
Main results
We included six RCTs, involving 204 preterm infants. The risk of bias for most methodological domains was unclear as there was insufficient detail reported. Low‐quality evidence showed that protein supplementation of human milk may increase in‐hospital rates of growth in weight (MD 3.82 g/kg/day, 95% CI 2.94 to 4.7; five RCTs, 101 infants; I² = 73%), length (MD 0.12 cm/wk, 95% CI 0.07 to 0.17; four RCTs, 68 infants; I² = 89%), and head circumference (MD 0.06 cm/wk, 95% CI 0.01 to 0.12; four RCTs, 68 infants; I² = 84%). Protein supplementation may lead to longer hospital stays (MD 18.5 days, 95% CI 4.39 to 32.61; one RCT, 20 infants; very low‐quality evidence). Very low quality evidence means that the effect of protein supplementation on the risk of feeding intolerance (RR 2.70, 95% CI 0.13 to 58.24; one RCT, 17 infants), or necrotizing enterocolitis (RR 1.11, 95% CI 0.07 to 17.12; one RCT, 76 infants) remains uncertain. No data were available about the effects of protein supplementation on neurodevelopmental outcomes.
Authors' conclusions
Low‐quality evidence showed that protein supplementation of human milk, fed to preterm infants, increased short‐term growth. However, the small sample sizes, low precision, and very low‐quality evidence regarding duration of hospital stay, feeding intolerance, and necrotising enterocolitis precluded any conclusions about these outcomes. There were no data on outcomes after hospital discharge. Our findings may not be generalisable to low‐resource settings, as none of the included studies were conducted in these settings.
Since protein supplementation of human milk is now usually done as a component of multi‐nutrient fortifiers, future studies should compare different amounts of protein in multi‐component fortifiers, and be designed to determine the effects on duration of hospital stay and safety, as well as on long‐term growth, body composition, cardio‐metabolic, and neurodevelopmental outcomes.
Hypoglycemia is common during neonatal transition and may cause permanent neurological impairment, but optimal intervention thresholds are unknown.
To test the hypothesis that neurodevelopment at 4.5 ...years is related to the severity and frequency of neonatal hypoglycemia.
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.
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.
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.
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.
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.
Clinical practice guidelines recommend administering antenatal corticosteroids (ACS), either betamethasone or dexamethasone, to women at risk of preterm birth at less than 35 weeks' gestation. If ...women remain at risk of preterm birth seven or more days after an initial course of ACS, most guidelines recommend administration of a repeat dose(s). No randomised trials have assessed the efficacy of dexamethasone as a repeat steroid compared to betamethasone.
We aimed to determine if there were differences between the use of dexamethasone or betamethasone as repeat ACS, for women who remain at risk of preterm birth after an initial course, on maternal, infant, and childhood health outcomes.
We performed a secondary analysis of data from the ASTEROID randomised trial, where women at risk of preterm birth were allocated to either betamethasone or dexamethasone. Infant, childhood, and maternal outcomes were compared according to whether women received a repeat dose(s) of dexamethasone or betamethasone. The primary outcome was a composite outcome of death or any neurosensory disability at age two years (corrected for prematurity). The ASTEROID trial is registered with ANZCTR, ACTRN12608000631303.
168 women and their infants were included, with 86 women receiving dexamethasone and 82 women receiving betamethasone as a repeat dose. Women in the two ACS groups had similar baseline characteristics. We observed little to no difference in the incidence of death or any neurosensory disability at age two years (OR 0.89, 95% CI 0.39 to 2.06, p = 0.79) or in the incidence of other infant, childhood, and maternal adverse health outcomes between women who received dexamethasone and those who received betamethasone.
Use of dexamethasone for a repeat dose(s) compared to betamethasone did not result in any differences in infant, childhood, and maternal health outcomes. These results can be used to support clinical practice guideline recommendations.
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