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 one 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 to 2 episodes, and recurrent as ≥3 episodes. At 6-7 y 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 eight 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.

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.

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.).

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.

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.

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.

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).

Low dose or very low dose phenylephrine and cyclopentolate microdrops for retinopathy of prematurity eye examinations (The Little Eye Drop Study): a randomised controlled non-inferiority trial.

OBJECTIVE: To determine if very low dose (VLD, 0.5% phenylephrine, 0.1% cyclopentolate) mydriatic microdrop (approximately 7 µL) administration (up to three doses) is non-inferior to low dose (LD, 1% phenylephrine, 0.2% cyclopentolate) mydriatic microdrop administration for ophthalmologist-determined successful retinopathy of prematurity eye examination (ROPEE). DESIGN: Multicentre, prospective, randomised controlled, non-inferiority clinical trial. SETTING: Four neonatal intensive care units in Aotearoa, New Zealand from October 2019 to September 2021. PATIENTS: Infants with a birth weight less than 1250 g or gestational age less than 30+6 weeks and who required a ROPEE. INTERVENTIONS: The intervention: microdrop (approximately 7 µL) of VLD (0.5% phenylephrine and 0.1% cyclopentolate) to both eyes, or the comparison: microdrop of LD (1% phenylephrine and 0.2% cyclopentolate) to both eyes. Up to three doses could be administered. MAIN OUTCOME MEASURES: The primary outcome measure was an ophthalmologist-determined successful ROPEE. RESULTS: One hundred and fifty preterm infants (LD mean GA=27.4±1.8 weeks, mean birth weight=1011±290 g, VLD mean GA=27.5±1.9 weeks, mean birth weight=1049±281 g,) were randomised. Non-inferiority for successful ROPEE was demonstrated for the VLD group compared with the LD group (VLD successful ROPEE=100%, LD successful ROPEE=100%, 95% CI no continuity correction -0.05 to 0.05) and for Maori (95% CI no continuity correction -0.02 to 0.19). CONCLUSION: VLD microdrops enable safe and effective screening for ROPEE in both Maori and non-Maori preterm infants. TRIAL REGISTRATION NUMBER: ACTRN12619000795190.

Caffeine to prevent intermittent hypoxaemia in late preterm infants: randomised controlled dosage trial.

OBJECTIVE: To establish the most effective and best tolerated dose of caffeine citrate for the prevention of intermittent hypoxaemia (IH) in late preterm infants. DESIGN: Phase IIB, double-blind, five-arm, parallel, randomised controlled trial. SETTING: Neonatal units and postnatal wards of two tertiary maternity hospitals in New Zealand. PARTICIPANTS: Late preterm infants born at 34+0-36+6 weeks' gestation, recruited within 72 hours of birth. INTERVENTION: Infants were randomly assigned to receive a loading dose (10, 20, 30 or 40 mg/kg) followed by 5, 10, 15 or 20 mg/kg/day equivolume enteral caffeine citrate or placebo daily until term corrected age. PRIMARY OUTCOME: IH (events/hour with oxygen saturation concentration ≥10% below baseline for ≤2 min), 2 weeks postrandomisation. RESULTS: 132 infants with mean (SD) birth weight 2561 (481) g and gestational age 35.7 (0.8) weeks were randomised (24-28 per group). Caffeine reduced the rate of IH at 2 weeks postrandomisation (geometric mean (GM): 4.6, 4.6, 2.0, 3.8 and 1.7 events/hour for placebo, 5, 10, 15 and 20 mg/kg/day, respectively), with differences statistically significant for 10 mg/kg/day (GM ratio (95% CI] 0.39 (0.20 to 0.76]; p=0.006) and 20 mg/kg/day (GM ratio (95% CI] 0.33 (0.17 to 0.68]; p=0.003) compared with placebo. The 20 mg/kg/day dose increased mean (SD) pulse oximetry oxygen saturation (SpO2) (97.2 (1.0) vs placebo 96.0 (0.8); p<0.001), and reduced median (IQR) percentage of time SpO2 <90% (0.5 (0.2-0.8) vs 1.1 (0.6-2.4); p<0.001) at 2 weeks, without significant adverse effects on growth velocity or sleeping. CONCLUSION: Caffeine reduces IH in late preterm infants at 2 weeks of age, with 20 mg/kg/day being the most effective dose. TRIAL REGISTRATION NUMBER: ACTRN12618001745235.

Neurocognitive Outcomes at Age 2 Years After Neonatal Hypoglycemia in a Cohort of Participants From the hPOD Randomized Trial.

Importance: Neonatal hypoglycemia is common, but its association with later neurodevelopment is uncertain. Objective: To examine associations between neonatal hypoglycemia and neurocognitive outcomes at corrected age 2 years. Design, Setting, and Participants: Exploratory cohort analysis of the Hypoglycaemia Prevention With Oral Dextrose (hPOD) randomized clinical trial was conducted. The trial recruited participants from January 9, 2015, to May 5, 2019, with follow-up between January 26, 2017, and July 31, 2021. Infants were recruited from 9 maternity hospitals in New Zealand and assessed at home or in a research clinic. Children born late preterm and at term at risk of neonatal hypoglycemia but without evidence of acute or imminent illness in the first hour after birth were screened and treated to maintain blood glucose concentrations greater than or equal to 47 mg/dL. Exposures: Hypoglycemia was defined as any blood glucose concentration less than 47 mg/dL, recurrent as 3 or more episodes, and severe as less than 36 mg/dL. Main Outcomes and Measures: Neurologic examination and tests of development (Bayley III) and executive function. The primary outcome was neurosensory impairment (any of the following: blindness, deafness, cerebral palsy, developmental delay, or executive function total score worse than 1.5 SD below the mean). Results: A total of 1197 of 1321 (91%) eligible children were assessed at a mean of corrected age 24 months; 616 (52%) were male. Compared with the normoglycemia group, children who experienced hypoglycemia were more likely to have neurosensory impairment (111 [23%] vs 125 [18%]; adjusted risk ratio [aRR], 1.28; 95% CI, 1.01-1.60), particularly if they experienced severe episodes (30 [28%] vs 125 [18%]; aRR, 1.68; 95% CI, 1.20-2.36), but not recurrent episodes (12 [19%] vs 125 [18%]; aRR, 1.06; 95% CI, 0.63-1.80). The risk of cognitive, language, or motor delay was similar between groups, but children who experienced hypoglycemia had lower Bayley-III composite cognitive (adjusted mean difference [aMD], -1.48; 95% CI, -2.79 to -0.18) and motor scores (aMD, -2.05; 95% CI, -3.30 to -0.79). Conclusions and Relevance: In children born at risk of hypoglycemia but otherwise well, those who experienced neonatal hypoglycemia were more likely to have neurosensory impairment at corrected age 2 years, with higher risks after severe episodes. Further research is required to determine causality.

Tighter or less tight glycaemic targets for women with gestational diabetes mellitus for reducing maternal and perinatal morbidity: A stepped-wedge, cluster-randomised trial.

BACKGROUND: Treatment for gestational diabetes mellitus (GDM) aims to reduce maternal hyperglycaemia. The TARGET Trial assessed whether tighter compared with less tight glycaemic control reduced maternal and perinatal morbidity. METHODS AND FINDINGS: In this stepped-wedge, cluster-randomised trial, identification number ACTRN12615000282583, 10 hospitals in New Zealand were randomised to 1 of 5 implementation dates. The trial was registered before the first participant was enrolled. All hospitals initially used less tight targets (fasting plasma glucose (FPG) <5.5 mmol/L (<99 mg/dL), 1-hour <8.0 mmol/L (<144 mg/dL), 2 hour postprandial <7.0 mmol/L (<126 mg/dL)) and every 4 months, 2 hospitals moved to use tighter targets (FPG ≤5.0 mmol/L (≤90 mg/dL), 1-hour ≤7.4 mmol/L (≤133 mg/dL), 2 hour postprandial ≤6.7 mmol/L) (≤121 mg/dL). Women with GDM, blinded to the targets in use, were eligible. The primary outcome was large for gestational age. Secondary outcomes assessed maternal and infant health. Analyses were by intention to treat. Between May 2015 and November 2017, data were collected from 1,100 women with GDM (1,108 infants); 598 women (602 infants) used the tighter targets and 502 women (506 infants) used the less tight targets. The rate of large for gestational age was similar between the treatment target groups (88/599, 14.7% versus 76/502, 15.1%; adjusted relative risk [adjRR] 0.96, 95% confidence interval [CI] 0.66 to 1.40, P = 0.839). The composite serious health outcome for the infant of perinatal death, birth trauma, or shoulder dystocia was apparently reduced in the tighter group when adjusted for gestational age at diagnosis of GDM, BMI, ethnicity, and history of GDM compared with the less tight group (8/599, 1.3% versus 13/505, 2.6%, adjRR 0.23, 95% CI 0.06 to 0.88, P = 0.032). No differences were seen for the other infant secondary outcomes apart from a shorter stay in intensive care (P = 0.041). Secondary outcomes for the woman showed an apparent increase for the composite serious health outcome that included major haemorrhage, coagulopathy, embolism, and obstetric complications in the tighter group (35/595, 5.9% versus 15/501, 3.0%, adjRR 2.29, 95% CI 1.14 to 4.59, P = 0.020). There were no differences between the target groups in the risk for pre-eclampsia, induction of labour, or cesarean birth, but more women using tighter targets required pharmacological treatment (404/595, 67.9% versus 293/501, 58.5%, adjRR 1.20, 95% CI 1.00 to 1.44, P = 0.047). The main study limitation is that the treatment targets used may vary to those in use in some countries. CONCLUSIONS: Tighter glycaemic targets in women with GDM compared to less tight targets did not reduce the risk of a large for gestational age infant, but did reduce serious infant morbidity, although serious maternal morbidity was increased. These findings can be used to aid decisions on the glycaemic targets women with GDM should use. TRIAL REGISTRATION: The Australian New Zealand Clinical Trials Registry (ANZCTR). ACTRN12615000282583.

Oral diazoxide versus placebo for severe or recurrent neonatal hypoglycaemia: Neonatal Glucose Care Optimisation (NeoGluCO) study - a randomised controlled trial.

INTRODUCTION: Infants with severe or recurrent transitional hypoglycaemia continue to have high rates of adverse neurological outcomes and new treatment approaches are needed that target the underlying pathophysiology. Diazoxide is one such treatment that acts on the pancreatic ß-cell in a dose-dependent manner to decrease insulin secretion. METHODS AND ANALYSIS: Phase IIB, double-blind, two-arm, parallel, randomised trial of diazoxide versus placebo in neonates ≥35 weeks' gestation for treatment of severe (blood glucose concentration (BGC)<1.2 mmol/L or BGC 1.2 to <2.0 mmol/L despite two doses of buccal dextrose gel and feeding in a single episode) or recurrent (≥3 episodes <2.6 mmol/L in 48 hours) transitional hypoglycaemia. Infants are loaded with diazoxide 5 mg/kg orally and then commenced on a maintenance dose of 1.5 mg/kg every 12 hours, or an equal volume of placebo. The intervention is titrated from the third maintenance dose by protocol to target BGC in the range of 2.6-5.4 mmol/L. The primary outcome is time to resolution of hypoglycaemia, defined as the first point at which the following criteria are met concurrently for ≥24 hours: no intravenous fluids, enteral bolus feeding and normoglycaemia. Groups will be compared for the primary outcome using Cox's proportional hazard regression analysis, expressed as adjusted HR with a 95% CI. ETHICS AND DISSEMINATION: This trial has been approved by the Health and Disability Ethics Committees of New Zealand (19CEN189). Findings will be disseminated in peer-reviewed journals, to clinicians and researchers at local and international conferences and to the public. TRIAL REGISTRATION NUMBER: ACTRN12620000129987.

Prioritising long-term outcomes for preterm babies: A survey of consumers and clinicians.

AIM: To determine if consumers and clinicians believe intelligence or health outcomes are more important long-term outcomes for babies born preterm. METHODS: Prospective, online survey of six outcomes ranked using a hierarchy ladder, Likert scale and a hypothetical scenario: education (complete secondary school); longevity (70 years of age or more); money (sufficient for rent and food); normal weight; good health and intelligence. Participants were clinicians taking care of preterm babies, parents of preterm babies, ex-preterm adults and adult controls. RESULTS: The survey was completed by 145 participants (35 controls, 36 clinicians, 39 parents and 35 ex-preterm adults). Health was the most frequently top-ranked variable on the hierarchy ladder (health; 99/145 (68.3%), money; 17/145 (11.7%), longevity; 10/145 (6.9%), education; 8/145 (5.5%), normal weight; 6/145 (4.1%), intelligence; 5/145 (3.4%), P < 0.0001), with no statistical difference between the groups. On a 5-point Likert scale, participants were most likely to agree that sufficient money, health and finishing secondary school were important for preterm babies to have a good life (mean (SD): money 4.43 (0.81); health 4.39 (0.72); education 4.37 (0.81); normal weight 4.10 (0.81); intelligence 4.03 (0.94); longevity 4.01 (1.07), P < 0.0001). In the scenario, the option of an ex-preterm adult having a healthy life with low socio-economic status (SES), was preferred over high SES with an unhealthy life (p < 0.0001). CONCLUSIONS: Health was perceived as the most important long-term outcome for preterm babies. Future research should prioritise good health outcomes for babies born preterm.

Nutritional Management of Moderate- and Late-Preterm Infants Commenced on Intravenous Fluids Pending Mother's Own Milk: Cohort Analysis From the DIAMOND Trial.

Background: Exclusive breastmilk is the desired enteral nutrition for babies born moderate- and late-preterm between 32+0 and 36+6 weeks' gestation; however, this goal is often difficult to achieve. Methods: A prospective cohort of babies 32+0 -35+6 weeks' gestation enrolled in the DIAMOND trial were randomized to a condition specifying that babies should receive mother's own milk (MOM) as the only enteral feed. Factors associated with the successful transition to MOM, defined as MOM being the sole enteral feeding at the time of the first cessation of intravenous (IV) fluids, were investigated by logistic regression. Time to commencement of a milk other than MOM was analyzed by Kaplan-Meier survival curves. Results: A total of 151 eligible babies (60% boys) were included, 93 (63%) of whom successfully transitioned from IV fluids onto MOM only. Alternative sources of milk, mostly formula, were used to transition from IV fluids onto enteral feeds more often in multiples and Maori, and was commenced earlier in Maori than other ethnicities (p = 0.007) and in late-preterm compared with moderate-preterm babies (p=0.01). Receiving exclusively breastmilk at discharge was more likely for babies who successfully transitioned from IV fluids onto MOM only [OR (95% confidence intervals) 4.9 (2.3-10.6)] and who received only MOM in the first week after birth [4.8 (2.2-10.4)], both p < 0.0001. Receiving breastmilk exclusively at discharge was less likely for Maori than Caucasian babies [0.2 (0.1-0.6), p < 0.0006]. There was no difference in the use of alternative sources of milk in babies who received parenteral nutrition or dextrose or between small-for-gestational-age and appropriate-for-gestational-age babies. Conclusions: Despite an intention to provide only MOM, significant numbers of moderate- and late-preterm babies received formula to transition from IV fluids, and this differed by ethnicity. The drivers underlying these decisions require further investigation. These data highlight an urgent need for quality initiatives to support and encourage mothers of moderate- and late-preterm babies in their lactation.

Glucagon for Neonatal Hypoglycaemia: Systematic Review and Meta-Analysis.

INTRODUCTION: Glucagon is often used in neonatal hypoglycaemia, but its effects have not been systematically assessed. We undertook a systematic review to determine the efficacy and safety of glucagon treatment for neonatal hypoglycaemia. METHODS: We searched MEDLINE, CINAHL, EMBASE, and CENTRAL from inception until May 2021. We included studies that reported one or more prespecified outcomes and compared glucagon with placebo or no glucagon. Studies were excluded if the majority (>70%) of participants were >1 month of age. Two authors independently extracted data. We used ROB-2/modified ROBINS-I to assess risk of bias, GRADE for certainty of evidence, and RevMan for meta-analysis. RESULTS: 100 studies were screened, 37 reviewed in full, and seven single-arm non-randomised intervention studies, involving 348 infants, were included (no trials). Data were insufficient to undertake meta-analysis of the critical outcomes (time to blood glucose normalization, recurrent hypoglycaemia, neurocognitive impairment). In 3 studies, ≥80% of neonates achieved normoglycaemia within 4 h of glucagon administration. However, recurrent hypoglycaemia was common (up to 55%). Glucagon increased blood glucose concentration at 1-2 h by 2.3 mmol/L (95% CI 2.1, 2.5) (low certainty evidence, 6 studies, N = 323). There were few data for other important clinical outcomes. CONCLUSION: There is a paucity of evidence about the efficacy and safety of glucagon for treatment of neonatal hypoglycaemia. Low certainty evidence suggests that glucagon may increase blood glucose by ∼2.3 mmol/L but recurrent hypoglycaemia appears common. High-quality, randomized controlled trials are required to determine the role of glucagon in managing neonatal hypoglycaemia.