Diazoxide for Severe or Recurrent Neonatal Hypoglycemia: A Randomized Clinical Trial.

Importance: Neonatal hypoglycemia is an important preventable cause of neurodevelopmental impairment, but there is a paucity of evidence to guide treatment. Objective: To evaluate whether early, low-dose oral diazoxide for severe or recurrent neonatal hypoglycemia reduces time to resolution of hypoglycemia. Design, Setting, and Participants: This 2-arm, placebo-controlled randomized clinical trial was conducted from May 2020 to February 2023 in tertiary neonatal units at 2 New Zealand hospitals. Participants were neonates born at 35 or more weeks' gestation and less than 1 week of age with severe hypoglycemia (blood glucose concentration <22 mg/dL or <36 mg/dL despite 2 doses of dextrose gel) or recurrent hypoglycemia (≥3 episodes of a blood glucose concentration <47 mg/dL within 48 hours). Interventions: Newborns were randomized 1:1 to receive diazoxide suspension (loading dose, 5 mg/kg; maintenance, 1.5 mg/kg every 12 hours) or placebo, titrated per protocol. Main Outcome and Measures: The primary outcome was time to resolution of hypoglycemia, defined as enteral bolus feeding without intravenous fluids and normoglycemia (blood glucose concentration of 47-98 mg/dL) for at least 24 hours, compared between groups using adjusted Cox proportional hazards regression. Hazard ratios adjusted for stratification variables and gestation length are reported. Prespecified secondary outcomes, including number of blood glucose tests and episodes of hypoglycemia, duration of hypoglycemia, and time to enteral bolus feeding and weaning from intravenous fluids, were compared by generalized linear models. Newborns were followed up for at least 2 weeks. Results: Of 154 newborns screened, 75 were randomized and 74 with evaluable data were included in the analysis (mean [SD] gestational age for the full cohort, 37.6 [1.6] weeks), 36 in the diazoxide group and 38 in the placebo group. Baseline characteristics were similar: in the diazoxide group, mean (SD) gestational age was 37.9 (1.6) weeks and 26 (72%) were male; in the placebo group, mean (SD) gestational age was 37.4 (1.5) weeks and 27 (71%) were male. There was no significant difference in time to resolution of hypoglycemia (adjusted hazard ratio [AHR], 1.39; 95% CI, 0.84-2.23), possibly due to increased episodes of elevated blood glucose concentration and longer time to normoglycemia in the diazoxide group. Resolution of hypoglycemia, when redefined post hoc as enteral bolus feeding without intravenous fluids for at least 24 hours with no further hypoglycemia, was reached by more newborns in the diazoxide group (AHR, 2.60; 95% CI, 1.53-4.46). Newborns in the diazoxide group had fewer blood glucose tests (adjusted count ratio [ACR], 0.63; 95% CI, 0.56-0.71) and episodes of hypoglycemia (ACR, 0.32; 95% CI, 0.17-0.63), reduced duration of hypoglycemia (adjusted ratio of geometric means [ARGM], 0.18; 95% CI, 0.06-0.53), and reduced time to enteral bolus feeding (ARGM, 0.74; 95% CI, 0.58-0.95) and weaning from intravenous fluids (ARGM, 0.72; 95% CI, 0.60-0.87). Only 2 newborns (6%) treated with diazoxide had hypoglycemia after the loading dose compared with 20 (53%) with placebo. Conclusions and Relevance: In this randomized clinical trial, early treatment of severe or recurrent neonatal hypoglycemia with low-dose oral diazoxide did not reduce time to resolution of hypoglycemia but reduced time to enteral bolus feeding and weaning from intravenous fluids, duration of hypoglycemia, and frequency of blood glucose testing compared with placebo. Trial Registration: ANZCTR.org.au Identifier: ACTRN12620000129987.

Neonatal Hypoglycemia and Neurocognitive Function at School Age: A Prospective Cohort Study.

OBJECTIVE: To determine the relationship between transient neonatal hypoglycemia in at-risk infants and neurocognitive function at 6-7 years of corrected age. STUDY DESIGN: The pre-hPOD Study involved children born with at least 1 risk factor for neonatal hypoglycemia. Hypoglycemia was defined as ≥1 consecutive blood glucose concentrations <47 mg/dl (2.6 mmol/L), severe as <36 mg/dl (2.0 mmol/L), mild as 36 to <47 mg/dL (2.0 to <2.6 mmol/L), brief as 1-2 episodes, and recurrent as ≥3 episodes. At 6-7 years children were assessed for cognitive and motor function (NIH-Toolbox), learning, visual perception and behavior. The primary outcome was neurocognitive impairment, defined as >1 SD below the normative mean in ≥1 Toolbox tests. The 8 secondary outcomes covered children's cognitive, motor, language, emotional-behavioral, and visual perceptual development. Primary and secondary outcomes were compared between children who did and did not experience neonatal hypoglycemia, adjusting for potential confounding by gestation, birthweight, sex and receipt of prophylactic dextrose gel (pre-hPOD intervention). Secondary analysis included assessment by severity and frequency of hypoglycemia. RESULTS: Of 392 eligible children, 315 (80%) were assessed at school age (primary outcome, n = 308); 47% experienced hypoglycemia. Neurocognitive impairment was similar between exposure groups (hypoglycemia 51% vs 50% no hypoglycemia; aRD -4%, 95% CI -15%, 7%). Children with severe or recurrent hypoglycemia had worse visual motion perception and increased risk of emotional-behavioral difficulty. CONCLUSION: Exposure to neonatal hypoglycemia was not associated with risk of neurocognitive impairment at school-age in at-risk infants, but severe and recurrent episodes may have adverse impacts. TRIAL REGISTRATION: Hypoglycemia Prevention in Newborns with Oral Dextrose: the Dosage Trial (pre-hPOD Study): ACTRN12613000322730.

Nutritional Support for Moderate-to-Late-Preterm Infants - A Randomized Trial.

BACKGROUND: Most moderate-to-late-preterm infants need nutritional support until they are feeding exclusively on their mother's breast milk. Evidence to guide nutrition strategies for these infants is lacking. METHODS: We conducted a multicenter, factorial, randomized trial involving infants born at 32 weeks 0 days' to 35 weeks 6 days' gestation who had intravenous access and whose mothers intended to breast-feed. Each infant was assigned to three interventions or their comparators: intravenous amino acid solution (parenteral nutrition) or dextrose solution until full feeding with milk was established; milk supplement given when maternal milk was insufficient or mother's breast milk exclusively with no supplementation; and taste and smell exposure before gastric-tube feeding or no taste and smell exposure. The primary outcome for the parenteral nutrition and the milk supplement interventions was the body-fat percentage at 4 months of corrected gestational age, and the primary outcome for the taste and smell intervention was the time to full enteral feeding (150 ml per kilogram of body weight per day or exclusive breast-feeding). RESULTS: A total of 532 infants (291 boys [55%]) were included in the trial. The mean (±SD) body-fat percentage at 4 months was similar among the infants who received parenteral nutrition and those who received dextrose solution (26.0±5.4% vs. 26.2±5.2%; adjusted mean difference, -0.20; 95% confidence interval [CI], -1.32 to 0.92; P = 0.72) and among the infants who received milk supplement and those who received mother's breast milk exclusively (26.3±5.3% vs. 25.8±5.4%; adjusted mean difference, 0.65; 95% CI, -0.45 to 1.74; P = 0.25). The time to full enteral feeding was similar among the infants who were exposed to taste and smell and those who were not (5.8±1.5 vs. 5.7±1.9 days; P = 0.59). Secondary outcomes were similar across interventions. Serious adverse events occurred in one infant. CONCLUSIONS: This trial of routine nutrition interventions to support moderate-to-late-preterm infants until full nutrition with mother's breast milk was possible did not show any effects on the time to full enteral feeding or on body composition at 4 months of corrected gestational age. (Funded by the Health Research Council of New Zealand and others; DIAMOND Australian New Zealand Clinical Trials Registry number, ACTRN12616001199404.).

Neonatal hypoglycaemia.

Low blood concentrations of glucose (hypoglycaemia) soon after birth are common because of the delayed metabolic transition from maternal to endogenous neonatal sources of glucose. Because glucose is the main energy source for the brain, severe hypoglycaemia can cause neuroglycopenia (inadequate supply of glucose to the brain) and, if severe, permanent brain injury. Routine screening of infants at risk and treatment when hypoglycaemia is detected are therefore widely recommended. Robust evidence to support most aspects of management is lacking, however, including the appropriate threshold for diagnosis and optimal monitoring. Treatment is usually initially more feeding, with buccal dextrose gel, followed by intravenous dextrose. In infants at risk, developmental outcomes after mild hypoglycaemia seem to be worse than in those who do not develop hypoglycaemia, but the reasons for these observations are uncertain. Here, the current understanding of the pathophysiology of neonatal hypoglycaemia and recent evidence regarding its diagnosis, management, and outcomes are reviewed. Recommendations are made for further research priorities.

Caffeine for apnea and prevention of neurodevelopmental impairment in preterm infants: systematic review and meta-analysis.

This systematic review and meta-analysis evaluated the evidence for dose and effectiveness of caffeine in preterm infants. MEDLINE, EMBASE, CINHAL Plus, CENTRAL, and trial databases were searched to July 2022 for trials randomizing preterm infants to caffeine vs. placebo/no treatment, or low (≤10 mg·kg-1) vs. high dose (>10 mg·kg-1 caffeine citrate equivalent). Two researchers extracted data and assessed risk of bias using RoB; GRADE evaluation was completed by all authors. Meta-analysis of 15 studies (3530 infants) was performed in REVMAN across four epochs: neonatal/infant (birth-1 year), early childhood (1-5 years), middle childhood (6-11 years) and adolescence (12-19 years). Caffeine reduced apnea (RR 0.59; 95%CI 0.46,0.75; very low certainty) and bronchopulmonary dysplasia (0.77; 0.69,0.86; moderate certainty), with higher doses more effective. Caffeine had no effect on neurocognitive impairment in early childhood but possible benefit on motor function in middle childhood (0.72; 0.57,0.91; moderate certainty). The optimal dose remains unknown; further long-term studies, are needed.

A digital Acceptance and Commitment Therapy and education intervention targeting stress of parents and caregivers with preterm babies in the neonatal intensive care unit: A randomised controlled cluster trial protocol.

BACKGROUND: Parents with babies in the neonatal intensive care unit (NICU) experience high levels of stress, anxiety, and depression. The NICU experience may also lead to impaired parenting and early childhood socio-emotional problems. Psychosocial interventions can reduce NICU parent distress. Yet many are time-intensive and costly to deliver. Acceptance and Commitment Therapy (ACT), an evidence-based psychological therapy, may address these needs. ACT has been shown to be effective in reducing distress of parents of children with chronic illnesses, particularly when combined with parent education. Therefore, the primary aim of this study is to determine if a digital intervention that uses a brief form of ACT plus parent education will reduce the stress of primary caregivers with preterm babies in the NICU more than a digital education-only intervention or standard care control group. METHODS: In a randomised controlled cluster trial design, participants will be randomly assigned to one of three groups: ACT plus education; education-only; or standard care control. The primary outcome will be parental/caregiver stress levels, measured on the Parental Stress Scale: Neonatal Intensive Care Unit. Secondary outcomes include overall stress, anxiety, and depression. Outcome measures will be evaluated at baseline, two weeks after enrolment, discharge to home, and 3-months post-discharge. CONCLUSION: This study will explore the efficacy of a digital ACT plus education intervention on parental stress levels. While position papers have advocated for the use of ACT with NICU parents, this study will be the first to test ACT as a stand-alone intervention with this population. TRIAL REGISTRATION: This trial was prospectively registered with the Australian New Zealand Clinical Trials Registry on 14 June 2023 (ACTRN12623000641695p).

Dextrose gel prophylaxis for neonatal hypoglycaemia and neurocognitive function at early school age: a randomised dosage trial.

OBJECTIVE: To investigate the effect of different doses of prophylactic dextrose gel on neurocognitive function and health at 6-7 years. DESIGN: Early school-age follow-up of the pre-hPOD (hypoglycaemia Prevention with Oral Dextrose) study. SETTING: Schools and communities. PATIENTS: Children born at ≥35 weeks with ≥1 risk factor for neonatal hypoglycaemia: maternal diabetes, small or large for gestational age, or late preterm. INTERVENTIONS: Four interventions commencing at 1 hour of age: dextrose gel (40%) 200 mg/kg; 400 mg/kg; 200 mg/kg and 200 mg/kg repeated before three feeds (800 mg/kg); 400 mg/kg and 200 mg/kg before three feeds (1000 mg/kg); compared with equivolume placebo (combined for analysis). MAIN OUTCOMES MEASURES: Toolbox cognitive and motor batteries, as well as tests of motion perception, numeracy and cardiometabolic health, were used. The primary outcome was neurocognitive impairment, defined as a standard score of more than 1 SD below the age-corrected mean on one or more Toolbox tests. FINDINGS: Of 392 eligible children, 309 were assessed for the primary outcome. There were no significant differences in the rate of neurocognitive impairment between those randomised to placebo (56%) and dextrose gel (200 mg/kg 46%: adjusted risk difference (aRD)=-14%, 95% CI -35%, 7%; 400 mg/kg 48%: aRD=-7%, 95% CI -27%, 12%; 800 mg/kg 45%: aRD=-14%, 95% CI -36%, 9%; 1000 mg/kg 50%: aRD=-8%, 95% CI -29%, 13%). Children exposed to any dose of dextrose gel (combined), compared with placebo, had a lower risk of motor impairment (3% vs 14%, aRD=-11%, 95% CI -19%, -3%) and higher mean (SD) cognitive scores (106.0 (15.3) vs 101.1 (15.7), adjusted mean difference=5.4, 95% CI 1.8, 8.9). CONCLUSIONS: Prophylactic neonatal dextrose gel did not alter neurocognitive impairment at early school age but may have motor and cognitive benefits. Further school-age follow-up studies are needed.

Maternal and neonatal morbidity associated with Fetal Pillow® use at full dilatation caesarean: A retrospective cohort.

OBJECTIVE: To investigate associations of the Fetal Pillow® with maternal and neonatal morbidity. DESIGN: Retrospective cohort. SETTING: Two tertiary maternity units, New Zealand. POPULATION OR SAMPLE: Full dilatation singleton, term, cephalic caesarean section, with three comparisons: at Unit A (1) before versus after introduction of the Fetal Pillow® (1 Jaunary 2016-31 October 2021); (2) with versus without the Fetal Pillow® after introduction (27 July 2017-31 October 2021); and (3) between Unit A and Unit B during the same time period (1 January 2019-31 October 2021). The Fetal Pillow® is unavailable at Unit B. METHODS: Cases were ascertained and clinical data were extracted from electronic clinical databases and records. Outcome data were adjusted and presented as adjusted odds ratios (aOR) with 95% CI. MAIN OUTCOME MEASURES: Primary outcome "any" uterine incision extension; secondary outcomes included major extension (into adjacent structures), and a composite neonatal outcome. RESULTS: In all, 1703 caesareans were included; 375 with the device and 1328 without. Uterine incision extension rates were: at Unit A before versus after introduction: 26.8% versus 24.8% (aOR 0.88, 95% CI 0.65-1.19); at Unit A with the Fetal Pillow® versus without: 26.1% versus 23.8% (aOR 1.14, 95% CI 0.83-1.57); and at Unit A versus Unit B: 24.2% versus 29.2% (aOR 0.73, 95% CI 0.54-0.99). No differences were found in major extensions, or neonatal composite outcome. CONCLUSIONS: Despite the relatively large size of this study, it could not rule out either a positive or a negative association between use of the Fetal Pillow® and uterine extensions, major uterine incision extensions, and neonatal morbidity. Randomised controlled trial evidence is required to assess efficacy.

Neonatal and maternal outcomes at early vs. full term following induction of labor; A secondary analysis of the OBLIGE randomized trial.

INTRODUCTION: Birth at early term (37+0-38+6 completed gestational weeks [GW] and additional days) is associated with adverse neonatal outcomes compared with waiting to ≥39 GW. Most studies report outcomes after elective cesarean section or a mix of all modes of births; it is unclear whether these adverse outcomes apply to early-term babies born after induction of labor (IOL). We aimed to determine, in women with a non-urgent induction indication (elective/planned >48 h in advance), if IOL at early and late term was associated with adverse neonatal and maternal outcomes compared with IOL at full term. MATERIAL AND METHODS: An observational cohort study as a secondary analysis of a multicenter randomized controlled trial of 1087 New Zealand women with a planned IOL ≥37+0 GW. Multivariable logistic regression was used to analyze neonatal and maternal outcomes in relation to gestational age; 37+0-38+6 (early term), 39+0-40+6 (full term) and ≥41+0 (late term) GW. Neonatal outcome analyses were adjusted for sex, birthweight, mode of birth and induction indication, and maternal outcome analyses for parity, age, body mass index and induction method. The primary neonatal outcome was admission to neonatal intensive care unit (NICU) for >4 hours; the primary maternal outcome was cesarean section. RESULTS: Among the 1087 participants, 266 had IOL at early term, 480 at full term, and 341 at late term. Babies born following IOL at early term had increased odds for NICU admission for >4 hours (adjusted odds ratio [aOR] 2.16, 95% confidence intervals (CI) 1.16-4.05), compared with full term. Women having IOL at early term had no difference in emergency cesarean rates but had an increased need for a second induction method (aOR 1.70, 95% CI 1.15-2.51) and spent 4 h longer from start of IOL to birth (Hodges-Lehmann estimator 4.10, 95% CI 1.33-6.95) compared with those with IOL at full term. CONCLUSIONS: IOL for a non-urgent indication at early term was associated with adverse neonatal and maternal outcomes and no benefits compared with IOL at full term. These findings support international guidelines to avoid IOL before 39 GW unless there is an evidence-based indication for earlier planned birth and will help inform women and clinicians in their decision-making about timing of IOL.

Impact of Gestational Diabetes Detection Thresholds on Infant Growth and Body Composition: A Prospective Cohort Study Within a Randomized Trial.

OBJECTIVE: Gestational diabetes mellitus (GDM) is associated with offspring metabolic disease, including childhood obesity, but causal mediators remain to be established. We assessed the impact of lower versus higher thresholds for detection and treatment of GDM on infant risk factors for obesity, including body composition, growth, nutrition, and appetite. RESEARCH DESIGN AND METHODS: In this prospective cohort study within the Gestational Diabetes Mellitus Trial of Diagnostic Detection Thresholds (GEMS), pregnant women were randomly allocated to detection of GDM using the lower criteria of the International Association of Diabetes and Pregnancy Study Groups or higher New Zealand criteria (ACTRN12615000290594). Randomly selected control infants of women without GDM were compared with infants exposed to A) GDM by lower but not higher criteria, with usual treatment for diabetes in pregnancy; B) GDM by lower but not higher criteria, untreated; or C) GDM by higher criteria, treated. The primary outcome was whole-body fat mass at 5-6 months. RESULTS: There were 760 infants enrolled, and 432 were assessed for the primary outcome. Fat mass was not significantly different between control infants (2.05 kg) and exposure groups: A) GDM by lower but not higher criteria, treated (1.96 kg), adjusted mean difference (aMD) -0.09 (95% CI -0.29, 0.10); B) GDM by lower but not higher criteria, untreated (1.94 kg), aMD -0.15 (95% CI -0.35, 0.06); and C) GDM detected and treated using higher thresholds (1.87 kg), aMD -0.17 (95% CI -0.37, 0.03). CONCLUSIONS: GDM detected using lower but not higher criteria, was not associated with increased infant fat mass at 5-6 months, regardless of maternal treatment. GDM detected and treated using higher thresholds was also not associated with increased fat mass at 5-6 months.

Associations between neonatal nutrition and visual outcomes in 7-year-old children born very preterm.

PURPOSE: There is uncertainty about the effect of increased neonatal protein intake on neurodevelopmental outcomes following preterm birth. The aim of this study was to assess the effect of a change in neonatal nutrition protocol at a major tertiary neonatal intensive care unit intended to increase protein intake on ophthalmic and visual development in school-age children born very preterm. METHODS: The study cohort comprised children (n = 128) with birthweight <1500 g or gestational age < 30 weeks born at Auckland City Hospital before (OldPro group, n = 55) and after (NewPro group, n = 73) a reformulation of parenteral nutrition that resulted in increased total protein intake during the first postnatal week and decreased carbohydrate, total parenteral fluid and sodium intake. Clinical and psychophysical vision assessments were completed at 7 years' corrected age, including visual acuity, global motion perception (a measure of dorsal stream function), stereoacuity, ocular motility and ocular health. Composite measures of favourable overall visual, binocular and functional visual outcomes along with individual vision measures were compared between the groups using logistic and linear regression models. RESULTS: Favourable overall visual outcome did not differ between the two groups. However, global motion perception was better in the NewPro group (p = 0.04), whereas the OldPro group were more likely to have favourable binocular visual outcomes (60% vs. 36%, p = 0.02) and passing stereoacuity (p = 0.02). CONCLUSIONS: These results indicate subtle but complex associations between early neonatal nutrition after very preterm birth and visual development at school age.

Oral dextrose gel to prevent hypoglycaemia in at-risk neonates.

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.

Different intensities of glycaemic control for women with gestational diabetes mellitus.

BACKGROUND: Gestational diabetes mellitus (GDM) has major short- and long-term implications for both the mother and her baby. GDM is defined as a carbohydrate intolerance resulting in hyperglycaemia or any degree of glucose intolerance with onset or first recognition during pregnancy from 24 weeks' gestation onwards and which resolves following the birth of the baby. Rates for GDM can be as high as 25% depending on the population and diagnostic criteria used, and overall rates are increasing globally. There is wide variation internationally in glycaemic treatment target recommendations for women with GDM that are based on consensus rather than high-quality trials. OBJECTIVES: To assess the effect of different intensities of glycaemic control in pregnant women with GDM on maternal and infant health outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (26 September 2022), and reference lists of the retrieved studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs), cluster-RCTs, and quasi-RCTs. Trials were eligible for inclusion if women were diagnosed with GDM during pregnancy and the trial compared tighter and less-tight glycaemic targets during management. We defined tighter glycaemic targets as lower numerical glycaemic concentrations, and less-tight glycaemic targets as higher numerical glycaemic concentrations. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods for carrying out data collection, assessing risk of bias, and analysing results. Two review authors independently assessed trial eligibility for inclusion, evaluated risk of bias, and extracted data for the four included studies. We assessed the certainty of evidence for selected outcomes using the GRADE approach. Primary maternal outcomes included hypertensive disorders of pregnancy and subsequent development of type 2 diabetes. Primary infant outcomes included perinatal mortality, large-for-gestational-age, composite of mortality or serious morbidity, and neurosensory disability. MAIN RESULTS: This was an update of a previous review completed in 2016. We included four RCTs (reporting on 1731 women) that compared a tighter glycaemic control with less-tight glycaemic control in women diagnosed with GDM. Three studies were parallel RCTs, and one study was a stepped-wedged cluster-RCT. The trials took place in Canada, New Zealand, Russia, and the USA. We judged the overall risk of bias to be unclear. Two trials were only published in abstract form. Tight glycaemic targets used in the trials ranged between ≤ 5.0 and 5.1 mmol/L for fasting plasma glucose and ≤ 6.7 and 7.4 mmol/L postprandial. Less-tight targets for glycaemic control used in the included trials ranged between < 5.3 and 5.8 mmol/L for fasting plasma glucose and < 7.8 and 8.0 mmol/L postprandial. For the maternal outcomes, compared with less-tight glycaemic control, the evidence suggests a possible increase in hypertensive disorders of pregnancy with tighter glycaemic control (risk ratio (RR) 1.16, 95% confidence interval (CI) 0.80 to 1.69, 2 trials, 1491 women; low certainty evidence); however, the 95% CI is compatible with a wide range of effects that encompass both benefit and harm. Tighter glycaemic control likely results in little to no difference in caesarean section rates (RR 0.98, 95% CI 0.82 to 1.17, 3 studies, 1662 women; moderate certainty evidence) or induction of labour rates (RR 0.96, 95% CI 0.78 to 1.18, 1 study, 1096 women; moderate certainty evidence) compared with less-tight control. No data were reported for the outcomes of subsequent development of type 2 diabetes, perineal trauma, return to pre-pregnancy weight, and postnatal depression. For the infant outcomes, it was difficult to determine if there was a difference in perinatal mortality (RR not estimable, 2 studies, 1499 infants; low certainty evidence), and there was likely no difference in being large-for-gestational-age (RR 0.96, 95% CI 0.72 to 1.29, 3 studies, 1556 infants; moderate certainty evidence). The evidence suggests a possible reduction in the composite of mortality or serious morbidity with tighter glycaemic control (RR 0.84, 95% CI 0.55 to 1.29, 3 trials, 1559 infants; low certainty evidence); however, the 95% CI is compatible with a wide range of effects that encompass both benefit and harm. There is probably little difference between groups in infant hypoglycaemia (RR 0.92, 95% CI 0.72 to 1.18, 3 studies, 1556 infants; moderate certainty evidence). Tighter glycaemic control may not reduce adiposity in infants of women with GDM compared with less-tight control (mean difference -0.62%, 95% CI -3.23 to 1.99, 1 study, 60 infants; low certainty evidence), but the wide CI suggests significant uncertainty. We found no data for the long-term outcomes of diabetes or neurosensory disability. Women assigned to tighter glycaemic control experienced an increase in the use of pharmacological therapy compared with women assigned to less-tight glycaemic control (RR 1.37, 95% CI 1.17 to 1.59, 4 trials, 1718 women). Tighter glycaemic control reducedadherence with treatment compared with less-tight glycaemic control (RR 0.41, 95% CI 0.32 to 0.51, 1 trial, 395 women). Overall the certainty of evidence assessed using GRADE ranged from low to moderate, downgraded primarily due to risk of bias and imprecision. AUTHORS' CONCLUSIONS: This review is based on four trials (1731 women) with an overall unclear risk of bias. The trials provided data on most primary outcomes and suggest that tighter glycaemic control may increase the risk of hypertensive disorders of pregnancy. The risk of birth of a large-for-gestational-age infant and perinatal mortality may be similar between groups, and tighter glycaemic targets may result in a possible reduction in composite of death or severe infant morbidity. However, the CIs for these outcomes are wide, suggesting both benefit and harm. There remains limited evidence regarding the benefit of different glycaemic targets for women with GDM to minimise adverse effects on maternal and infant health. Glycaemic target recommendations from international professional organisations vary widely and are currently reliant on consensus given the lack of high-certainty evidence. Further high-quality trials are needed, and these should assess both short- and long-term health outcomes for women and their babies; include women's experiences; and assess health services costs in order to confirm the current findings. Two trials are ongoing.

Infants Eligible for Neonatal Hypoglycemia Screening: A Systematic Review.

Importance: Neonatal hypoglycemia is common, occurring in up to 50% of infants at risk for hypoglycemia (infant of diabetic mother [IDM], small for gestational age [SGA], large for gestational age [LGA], and preterm) and is associated with long-term neurodevelopmental impairment. Guidelines recommend screening infants at risk of hypoglycemia. The proportion of infants who require screening for neonatal hypoglycemia is unknown. Objective: To determine the proportion of infants eligible for neonatal hypoglycemia screening using criteria from the highest-scoring critically appraised clinical guideline. Design, Setting, and Participants: This systematic review of the literature was conducted to identify clinical practice guidelines for neonatal hypoglycemia and took place at a tertiary maternity hospital in Auckland, New Zealand. Eligible guidelines were critically appraised using the Appraisal of Guidelines for Research and Evaluation II tool. Using screening criteria extracted from the highest-scoring guideline, the proportion of infants eligible for neonatal hypoglycemia screening was determined in a retrospective observational cohort study of infants born January 1, 2004, to December 31, 2018. Data were analyzed by logistic regression. Infant participants were included if gestational age was 35 weeks or more, birth weight was 2000 g or more, and they were not admitted to a neonatal intensive care unit less than 1 hour after birth. The data were analyzed from November 2022 through February 2023. A total of 101 372 infants met the inclusion criteria. Exposure: Risk factors for neonatal hypoglycemia. Main Outcome: Proportion of infants eligible for neonatal hypoglycemia screening. Results: The study team screened 2366 abstracts and 18 guidelines met inclusion criteria for appraisal. There was variability in the assessed quality of guidelines and a lack of consensus between screening criteria. The highest-scoring guideline defined screening criteria as: IDM, preterm (less than 37 weeks' gestation), SGA (less than 10th percentile), birth weight of less than 2500 g or more than 4500 g, LGA (more than 90th percentile), or gestational age more than 42 weeks. A total of 101 372 infants met criteria for inclusion in the cohort study; median (IQR) gestational age was 39 (38-40) weeks and 51% were male. The overall proportion of infants eligible for screening was 26.3%. There was an increase in the proportion of eligible infants from 25.6% to 28.5% over 15 years, which was not statistically significant after adjustment for maternal age, body mass index, ethnicity, and multiple pregnancy (odds ratio, 0.99; 95% CI, 0.93-1.03; change in proportion per year). Conclusion: A systematic review found that practice guidelines providing recommendations for clinical care of neonatal hypoglycemia were of variable quality with is a lack of consensus regarding definitions for infants at risk for hypoglycemia. In the cohort study, one-quarter of infants were eligible for hypoglycemia screening. Further research is required to identify which infants may benefit from neonatal hypoglycemia screening.

Development and clinical application of a stability-indicating chromatography technique for the quantification of diazoxide.

Diazoxide is a potential candidate for the treatment of transitional hypoglycaemia in infants. A clinical trial is currently underway to investigate whether low-dose oral diazoxide is beneficial for severe or recurrent transitional neonatal hypoglycaemia (the NeoGluCO Study, registration ANZCTR12620000129987). The present study aimed to develop and validate the parameters for quantifying diazoxide from neonatal plasma samples, and to assess the stability of extemporaneously prepared diazoxide suspensions to support the NeoGluCO Study. To determine the plasma concentration of diazoxide, a protein precipitation mediated extraction protocol was developed, which demonstrated >94% diazoxide extraction recoveries from all samples. The method was linear over the range of 0.2-40 µg/mL (R2 > 0.9994) with a limit of quantification of 0.2 µg/mL. Accuracy of the method was within 97-106% with relative standard deviation < 6% for all samples. Diazoxide-plasma samples were stable for up to three months at -20 °C and up to 48 h when stored in the auto-sampler. Samples were stable for up to two freeze-thaw cycles, with further cycles compromising stability of diazoxide in plasma. The developed method was applied to determine chemical stability of the extemporaneously prepared diazoxide suspensions. These were stable at both 2-8 °C and 25 °C/60% RH, with 98% of diazoxide remaining after 35 days in both storage conditions. Diazoxide was successfully quantified from plasma collected from six neonates enrolled in the NeoGluCO Study, using the developed protocol. Overall, an efficient and reproducible extraction protocol was developed and validated for the estimation of diazoxide from human plasma.

Midwife or doctor leader to implement a national guideline in babies on postnatal wards (DesIGN): A cluster-randomised, controlled, trial.

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).

Barriers and enablers to implementing an induction of labour guideline: A clinician survey.

BACKGROUND: Clinical guidelines improve outcomes, but poor compliance with recommendations is common. Insight into perceived barriers and enablers to the implementation of guidelines can engage maternity care providers and inform strategies for effective implementation. AIM: To identify the perceived barriers and enablers to implementing the 2020 'Induction of Labour [IOL] in Aotearoa New Zealand; a Clinical Practice Guideline.' MATERIALS AND METHODS: Electronic anonymous survey of clinical leaders in midwifery, obstetrics, and neonatology in New Zealand, from August to November 2021. Recruitment of participants was initially through provided lists of national clinical leads, followed by chain sampling. RESULTS: There were 32 of 89 surveys returned (36%). The most frequently identified enablers were implementation tools such as 'standardised IOL request form' and 'peer review process,' and administrative support and dedicated time. Six maternity hospitals already had peer review in place, whereby IOL requests that did not adhere to guidelines were reviewed by a multidisciplinary group of senior colleagues or peers, with individual feedback to the referring clinician. Attitudes in the form of 'existing systems, routines and culture' was the most frequently identified barrier, followed by external barriers such as 'lack of human resources.' CONCLUSIONS: Overall, few barriers were identified to implementing this guideline, and some of the key enablers were already in place. The identified enablers warrant future research to develop and evaluate effectiveness in improving outcomes.

Psychosocial Support Provided to Parents of Infants in Neonatal Intensive Care Units: An International Survey.

OBJECTIVE: To describe current psychosocial support practices and programs for parents with infants in level II nurseries and level III neonatal intensive care units (NICUs) across Australia and New Zealand. STUDY DESIGN: A staff member from each level II and level III hospital completed an online survey about the psychosocial support services available for parents in Australia and New Zealand. Mixed methods (descriptive and statistical analysis; descriptive content analysis) were used to describe current services and practices. RESULTS: Of 66 eligible units, 44 participated in the survey (67%). Hospital-based pediatricians (32%) and clinical directors (32%) were the most common respondents. Level III NICUs reported providing significantly more services for parents than level II nurseries (median [IQR]: level III, 7 [5.25-8.75]; level II, 4.5 [3.25-5]; P < .001), with variability in the type and number of services available (range, 4-13). Less than half of units (43%) reported using standardized screening tools to assess parents for mental health distress, and just 4 units (9%) provided staff-led parent mental health support programs. In qualitative feedback, respondents frequently reported a lack of resources (staffing, funding, and training) to support parents. CONCLUSIONS: Despite the well-documented distress that parents with infants in neonatal units experience and the evidence-based practices known to reduce this distress, this study identifies significant gaps in parent support services in level II and level III NICUs across Australia and New Zealand.

Antenatal dietary supplementation with myo-inositol for preventing gestational diabetes.

BACKGROUND: Gestational diabetes with onset or first recognition during pregnancy is an increasing problem worldwide. Myo-inositol, an isomer of inositol, is a naturally occurring sugar commonly found in cereals, corn, legumes and meat. Myo-inositol is one of the intracellular mediators of the insulin signal and correlates with insulin sensitivity in type 2 diabetes. The potential beneficial effect of improving insulin sensitivity suggests that myo-inositol may be useful for women in preventing gestational diabetes. This is an update of a review first published in 2015. OBJECTIVES: To assess if antenatal dietary supplementation with myo-inositol is safe and effective, for the mother and fetus, in preventing gestational diabetes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, WHO ICTRP (17 March 2022) and the reference lists of retrieved studies. SELECTION CRITERIA: We included published and unpublished randomised controlled trials (RCTs) including cluster-RCTs and conference abstracts, assessing the effects of myo-inositol for the prevention of gestational diabetes in pregnant women. We included studies that compared any dose of myo-inositol, alone or in a combination preparation, with no treatment, placebo or another intervention. Quasi-randomised and cross-over trials were not eligible. We excluded women with pre-existing type 1 or type 2 diabetes. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, assessed risk of bias and extracted the data. We checked the data for accuracy. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included seven RCTs (one conducted in Ireland, six conducted in Italy) reporting on 1319 women who were 10 weeks to 24 weeks pregnant at the start of the studies. The studies had relatively small sample sizes and the overall risk of bias was low. For the primary maternal outcomes, meta-analysis showed that myo-inositol may reduce the incidence of gestational diabetes (risk ratio (RR) 0.53, 95% confidence interval (CI) 0.31 to 0.90; 6 studies, 1140 women) and hypertensive disorders of pregnancy (RR 0.34, 95% CI 0.19 to 0.61; 5 studies, 1052 women). However, the certainty of the evidence was low to very low. For the primary neonatal outcomes, only one study measured the risk of a large-for-gestational-age infant and found myo-inositol was associated with both appreciable benefit and harm (RR 1.40, 95% CI 0.65 to 3.02; 1 study, 234 infants; low-certainty evidence). None of the included studies reported on the other primary neonatal outcomes (perinatal mortality, mortality or morbidity composite). For the secondary maternal outcomes, we are unclear about the effect of myo-inositol on weight gain during pregnancy (mean difference (MD) -0.25 kilogram (kg), 95% CI -1.26 to 0.75 kg; 4 studies, 831 women) and perineal trauma (RR 4.0, 95% CI 0.45 to 35.25; 1 study, 234 women) because the evidence was assessed as being very low-certainty. Further, myo-inositol may result in little to no difference in caesarean section (RR 0.91, 95% CI 0.77 to 1.07; 4 studies, 829 women; low-certainty evidence). None of the included studies reported on the other secondary maternal outcomes (postnatal depression and the development of subsequent type 2 diabetes mellitus). For the secondary neonatal outcomes, meta-analysis showed no neonatal hypoglycaemia (RR 3.07, 95% CI 0.90 to 10.52; 4 studies; 671 infants; very low-certainty evidence). However, myo-inositol may be associated with a reduction in the incidence of preterm birth (RR 0.35, 95% CI 0.17 to 0.70; 4 studies; 829 infants). There were insufficient data for a number of maternal and neonatal secondary outcomes, and no data were reported for any of the long-term childhood or adulthood outcomes, or for health service utilisation outcomes. AUTHORS' CONCLUSIONS: Evidence from seven studies shows that antenatal dietary supplementation with myo-inositol during pregnancy may reduce the incidence of gestational diabetes, hypertensive disorders of pregnancy and preterm birth. Limited data suggest that supplementation with myo-inositol may not reduce the risk of a large-for-gestational-age infant.  The current evidence is based on small studies that were not powered to detect differences in outcomes such as perinatal mortality and serious infant morbidity. Six of the included studies were conducted in Italy and one in Ireland, which raises concerns about the lack of generalisability to other settings. There is evidence of inconsistency among doses of myo-inositol, the timing of administration and study population. As a result, we downgraded the certainty of the evidence for many outcomes to low or very low certainty. Further studies for this promising antenatal intervention for preventing gestational diabetes are encouraged and should include pregnant women of different ethnicities and varying risk factors. Myo-inositol at different doses, frequency and timing of administration, should be compared with placebo, diet and exercise, and pharmacological interventions. Long-term follow-up should be considered and outcomes should include potential harms, including adverse effects.