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.

Pathophysiology from preconception, during pregnancy, and beyond.

Gestational diabetes is the most common medical complication in pregnancy. Historically, gestational diabetes was considered a pregnancy complication involving treatment of rising glycaemia late in the second trimester. However, recent evidence challenges this view. Pre-pregnancy and pregnancy-specific factors influence gestational glycaemia, with open questions regarding roles of non-glycaemic factors in the aetiology and consequences of gestational diabetes. Varying patterns of insulin secretion and resistance in early and late pregnancy underlie a heterogeneity of gestational diabetes in the timing and pathophysiological subtypes with clinical implications: early gestational diabetes and insulin resistant gestational diabetes subtypes are associated with a higher risk of pregnancy complications. Metabolic perturbations of early gestational diabetes can affect early placental development, affecting maternal metabolism and fetal development. Fetal hyperinsulinaemia can affect the development of multiple fetal tissues, with short-term and long-term consequences. Pregnancy complications are prevented by managing glycaemia in early and late pregnancy in some, but not all women with gestational diabetes. A better understanding of the pathophysiology and heterogeneity of gestational diabetes will help to develop novel management approaches with focus on improved prevention of maternal and offspring short-term and long-term complications, from pre-conception, throughout pregnancy, and beyond.

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.

The impact of CREBRF rs373863828 Pacific-variant on infant body composition.

In Maori and Pacific adults, the CREBRF rs373863828 minor (A) allele is associated with increased body mass index (BMI) but reduced incidence of type-2 and gestational diabetes mellitus. In this prospective cohort study of Maori and Pacific infants, nested within a nutritional intervention trial for pregnant women with obesity and without pregestational diabetes, we investigated whether the rs373863828 A allele is associated with differences in growth and body composition from birth to 12-18 months' corrected age. Infants with and without the variant allele were compared using generalised linear models adjusted for potential confounding by gestation length, sex, ethnicity and parity, and in a secondary analysis, additionally adjusted for gestational diabetes. Carriage of the rs373863828 A allele was not associated with altered growth and body composition from birth to 6 months. At 12-18 months, infants with the rs373863828 A allele had lower whole-body fat mass [FM 1.4 (0.7) vs. 1.7 (0.7) kg, aMD -0.4, 95% CI -0.7, 0.0, P = 0.05; FM index 2.2 (1.1) vs. 2.6 (1.0) kg/m2 aMD -0.6, 95% CI -1.2,0.0, P = 0.04]. However, this association was not significant after adjustment for gestational diabetes, suggesting that it may be mediated, at least in part, by the beneficial effect of CREBRF rs373863828 A allele on maternal glycemic status.

Cardiovascular outcomes 50 years after antenatal exposure to betamethasone: Follow-up of a randomised double-blind, placebo-controlled trial.

BACKGROUND: Antenatal corticosteroids for women at risk of preterm birth reduce neonatal morbidity and mortality, but there is limited evidence regarding their effects on long-term health. This study assessed cardiovascular outcomes at 50 years after antenatal exposure to corticosteroids. METHODS AND FINDINGS: We assessed the adult offspring of women who participated in the first randomised, double-blind, placebo-controlled trial of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome (RDS) (1969 to 1974). The first 717 mothers received 2 intramuscular injections of 12 mg betamethasone or placebo 24 h apart and the subsequent 398 received 2 injections of 24 mg betamethasone or equivalent volume of placebo. Follow-up included a health questionnaire and consent to access administrative data sources. The co-primary outcomes were the prevalence of cardiovascular risk factors (any of hypertension, hyperlipidaemia, diabetes mellitus, gestational diabetes mellitus, or prediabetes) and age at first major adverse cardiovascular event (MACE) (cardiovascular death, myocardial infarction, coronary revascularisation, stroke, admission for peripheral vascular disease, and admission for heart failure). Analyses were adjusted for gestational age at entry, sex, and clustering. Of 1,218 infants born to 1,115 mothers, we followed up 424 (46% of survivors; 212 [50%] female) at mean (standard deviation) age 49.3 (1.0) years. There were no differences between those exposed to betamethasone or placebo for cardiovascular risk factors (159/229 [69.4%] versus 131/195 [67.2%]; adjusted relative risk 1.02, 95% confidence interval [CI] [0.89, 1.18;]; p = 0.735) or age at first MACE (adjusted hazard ratio 0.58, 95% CI [0.23, 1.49]; p = 0.261). There were also no differences in the components of these composite outcomes or in any of the other secondary outcomes. Key limitations were follow-up rate and lack of in-person assessments. CONCLUSIONS: There is no evidence that antenatal corticosteroids increase the prevalence of cardiovascular risk factors or incidence of cardiovascular events up to 50 years of age. Established benefits of antenatal corticosteroids are not outweighed by an increase in adult cardiovascular disease.

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.

Childhood outcomes after maternal antenatal sildenafil treatment for severe early-onset fetal growth restriction: a randomized trial (STRIDER NZAus).

In this follow-up at 2.5 years of children from the STRIDER NZAus Trial (N = 112), in which women with singleton pregnancies affected by severe early fetal growth restriction were randomized to sildenafil citrate 75 mg daily or placebo until 32 weeks, there was no difference between groups in survival without neurosensory impairment, defined as any of cerebral palsy, deafness, blindness, cognitive delay (Bayley III cognition or language score >1 SD below mean) or motor delay: 30/56[54%] vs. 34/56[61%]; aOR = 0.74, 95%CI: 0.31, 1.77. However, children exposed to sildenafil appeared to be more likely to have cognitive delay (13/45[29%] vs. 4/40[10%]; aOR = 3.71, 95% CI: 1.01, 13.63) but less likely to have emotional-behavioural difficulties (2/43[5%] vs. 8/38[21%]; aOR = 0.19, 95%CI: 0.03, 1.00). Conclusion: maternal sildenafil treatment for severe early-onset FGR was not associated with altered survival free of neurosensory impairment at 2.5 years' corrected age.

Stability of executive function in children born at risk of neonatal hypoglycemia.

Executive function plays an important role in promoting learning and social-emotional development in children. Neonatal hypoglycemia associates with executive function difficulties at 4.5 years, but little is known about the development of executive function over time in children born at risk of neonatal hypoglycemia. We aimed to describe the stability of executive function from early to mid-childhood in children born at risk of neonatal hypoglycemia and its association with neonatal hypoglycemia. Participants in a prospective cohort study of infants born at risk for neonatal hypoglycemia were assessed at ages 2, 4.5, and 9-10 years. We assessed executive function with batteries of performance-based and questionnaire-based measures, and classified children into one of four stability groups (persistent typical, intermittent typical, intermittent difficulty, and persistent difficulty) based on dichotomized scores (typical versus low at each age). Multinomial logistic regression was used to determine the associations between neonatal hypoglycemia and executive function stability groups. Three hundred and nine children, of whom 197 (64%) experienced neonatal hypoglycemia were assessed. The majority of children had stable and typical performance-based (63%) and questionnaire-based (68%) executive function across all three ages. Around one-third (30-36%) of children had transient difficulties, and only a few (0.3-1.9%) showed persistent difficulties in executive function at all ages. There was no consistent evidence of an association between neonatal hypoglycemia and the stability of executive function. Neonatal hypoglycemia does not appear to predict a specific pattern of development of executive function in children born at risk.

Intratracheal budesonide mixed with surfactant to increase survival free of bronchopulmonary dysplasia in extremely preterm infants: statistical analysis plan for the international, multicenter, randomized PLUSS trial.

BACKGROUND: Bronchopulmonary dysplasia (BPD), an inflammatory-mediated chronic lung disease, is common in extremely preterm infants born before 28 weeks' gestation and is associated with an increased risk of adverse neurodevelopmental and respiratory outcomes in childhood. Effective and safe prophylactic therapies for BPD are urgently required. Systemic corticosteroids reduce rates of BPD in the short term but are associated with poorer neurodevelopmental outcomes if given to ventilated infants in the first week after birth. Intratracheal administration of corticosteroid admixed with exogenous surfactant could overcome these concerns by minimizing systemic sequelae. Several small, randomized trials have found intratracheal budesonide in a surfactant vehicle to be a promising therapy to increase survival free of BPD. The primary objective of the PLUSS trial is to determine whether intratracheal budesonide mixed with surfactant increases survival free of bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age (PMA) in extremely preterm infants born before 28 weeks' gestation. METHODS: An international, multicenter, double-blinded, randomized trial of intratracheal budesonide (a corticosteroid) mixed with surfactant for extremely preterm infants to increase survival free of BPD at 36 weeks' postmenstrual age (PMA; primary outcome). Extremely preterm infants aged < 48 h after birth are eligible if (1) they are mechanically ventilated, or (2) they are receiving non-invasive respiratory support and there is a clinical decision to treat with surfactant. The intervention is budesonide (0.25 mg/kg) mixed with poractant alfa (200 mg/kg first intervention, 100 mg/kg if second intervention), administered intratracheally via an endotracheal tube or thin catheter. The comparator is poractant alfa alone (at the same doses). Secondary outcomes include the components of the primary outcome (death, BPD prior to or at 36 weeks' PMA), and potential systemic side effects of corticosteroids. Longer-term outcomes will be published separately, and include cost-effectiveness, early childhood health until 2 years of age, and neurodevelopmental outcomes at 2 years of age (corrected for prematurity). STATISTICAL ANALYSIS PLAN: A sample size of 1038 infants (519 in each group) is required to provide 90% power to detect a relative increase in survival free of BPD of 20% (an absolute increase of 10%), from the anticipated event rate of 50% in the control arm to 60% in the intervention (budesonide) arm, alpha error 0.05. To allow for up to 2% of study withdrawals or losses to follow-up, PLUSS aimed to enroll a total of 1060 infants (530 in each arm). The binary primary outcome will be reported as the number and percentage of infants who were alive without BPD at 36 weeks' PMA for each randomization group. To estimate the difference in risk (with 95% CI), between the treatment and control arms, binary regression (a generalized linear multivariable model with an identity link function and binomial distribution) will be used. Along with the primary outcome, the individual components of the primary outcome (death, and physiological BPD at 36 weeks' PMA), will be reported by randomization group and, again, binary regression will be used to estimate the risk difference between the two treatment groups for survival and physiological BPD at 36 weeks' PMA.

Associations Between Autism Spectrum Quotient and Integration of Visual Stimuli in 9-year-old Children: Preliminary Evidence of Sex Differences.

PURPOSE: The dorsal stream vulnerability hypothesis posits that the dorsal stream, responsible for visual motion and visuo-motor processing, may be particularly vulnerable during neurodevelopment. Consistent with this, autism spectrum disorder (ASD) has been associated with deficits in global motion integration, though deficits in ventral stream tasks, such as form identification, have also been reported. In the current study, we examined whether a similar pattern of results is found in a cohort of 381 children born with neurodevelopmental risk factors and exhibiting a wide spectrum of caregiver-reported autistic traits. METHODS: We examined the associations between global motion perception, global form perception, fine motor function, visual-motor integration, and autistic traits (autism spectrum quotient, AQ) using linear regression, accounting for possible interactions with sex and other factors relevant to neurodevelopment. RESULTS: All assessments of dorsal stream function were significantly associated with AQ such that worse performance predicted higher AQ scores. We also observed a significant sex interaction, with worse global form perception associated with higher AQ in boys (n = 202) but not girls (n = 179). CONCLUSION: We found widespread associations between dorsal stream functions and autistic traits. These associations were observed in a large group of children with a range of AQ scores, demonstrating a range of visual function across the full spectrum of autistic traits. In addition, ventral function was associated with AQ in boys but not girls. Sex differences in the associations between visual processing and neurodevelopment should be considered in the designs of future studies.

Intratracheal budesonide mixed with surfactant to increase survival free of bronchopulmonary dysplasia in extremely preterm infants: study protocol for the international, multicenter, randomized PLUSS trial.

BACKGROUND: Bronchopulmonary dysplasia (BPD), an inflammatory-mediated chronic lung disease, is common in extremely preterm infants born before 28 weeks' gestation and is associated with an increased risk of adverse neurodevelopmental and respiratory outcomes in childhood. Effective and safe prophylactic therapies for BPD are urgently required. Systemic corticosteroids reduce rates of BPD in the short-term but are associated with poorer neurodevelopmental outcomes if given to ventilated infants in the first week after birth. Intratracheal administration of corticosteroid admixed with exogenous surfactant could overcome these concerns by minimizing systemic sequelae. Several small, randomized trials have found intratracheal budesonide in a surfactant vehicle to be a promising therapy to increase survival free of BPD. METHODS: An international, multicenter, double-blinded, randomized trial of intratracheal budesonide (a corticosteroid) mixed with surfactant for extremely preterm infants to increase survival free of BPD at 36 weeks' postmenstrual age (PMA; primary outcome). Extremely preterm infants aged < 48 h after birth are eligible if: (1) they are mechanically ventilated, or (2) they are receiving non-invasive respiratory support and there is a clinical decision to treat with surfactant. The intervention is budesonide (0.25 mg/kg) mixed with poractant alfa (200 mg/kg first intervention, 100 mg/kg if second intervention), administered intratracheally via an endotracheal tube or thin catheter. The comparator is poractant alfa alone (at the same doses). Secondary outcomes include the components of the primary outcome (death, BPD prior to or at 36 weeks' PMA), potential systemic side effects of corticosteroids, cost-effectiveness, early childhood health until 2 years of age, and neurodevelopmental outcomes at 2 years of age (corrected for prematurity). DISCUSSION: Combining budesonide with surfactant for intratracheal administration is a simple intervention that may reduce BPD in extremely preterm infants and translate into health benefits in later childhood. The PLUSS trial is powered for the primary outcome and will address gaps in the evidence due to its pragmatic and inclusive design, targeting all extremely preterm infants regardless of their initial mode of respiratory support. Should intratracheal budesonide mixed with surfactant increase survival free of BPD, without severe adverse effects, this readily available intervention could be introduced immediately into clinical practice. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ( https://www.anzctr.org.au ), ACTRN12617000322336. First registered on 28th February 2017.

Executive function and behaviour problems in school-age children born at risk of neonatal hypoglycaemia.

AIM: To examine the relationship between neonatal hypoglycaemia and specific areas of executive function and behaviour in mid-childhood. METHOD: Participants in a prospective cohort study of infants born late preterm or at term at risk of neonatal hypoglycaemia were assessed at 9 to 10 years. We assessed executive function using performance-based (Cambridge Neuropsychological Tests Automated Battery) and questionnaire-based (Behavior Rating Inventory of Executive Function) measures and behaviour problems with the Strengths and Difficulties Questionnaire. Data are reported as adjusted odds ratio (aOR) with 95% confidence intervals, and standardized regression coefficients. RESULTS: We assessed 480 (230 females, 250 males; mean age 9 years 5 months [SD 4 months, range 8 years 8 months-11 years 0 months]) of 587 eligible children (82%). There were no differences in performance-based executive function between children who did and did not experience neonatal hypoglycaemia (blood glucose <2.6 mmoL/L). However, children who experienced hypoglycaemia, especially if severe or recurrent, were at greater risk of parent-reported metacognition difficulties (aOR 2.37-3.71), parent-reported peer (aOR 1.62-1.89) and teacher-reported conduct (aOR 2.14 for severe hypoglycaemia) problems. Both performance- and questionnaire-based executive functions were associated with behaviour problems. INTERPRETATION: Neonatal hypoglycaemia may be associated with difficulties in specific aspects of parent-reported executive functions and behaviour problems in mid-childhood.

Mid-Childhood Outcomes after Dextrose Gel Treatment of Neonatal Hypoglycaemia: Follow-Up of the Sugar Babies Randomized Trial.

INTRODUCTION: Dextrose gel is widely used as first-line treatment for neonatal hypoglycaemia given its cost-effectiveness and ease of use. The Sugar Babies randomized trial first showed that 40% dextrose gel was more effective in reversing hypoglycaemia than feeding alone. Follow-up of the Sugar Babies Trial cohort at 2 and 4.5 years of age reported that dextrose gel appeared safe, with similar rates of neurosensory impairment in babies randomized to dextrose or placebo gel. However, some effects of neonatal hypoglycaemia may not become apparent until school age. METHODS: Follow-up of the Sugar Babies Trial cohort at 9-10 years of age was reported. The primary outcome was low educational achievement in reading or mathematics. Secondary outcomes included other aspects of educational achievement, executive function, visual-motor function, and psychosocial adaptation. RESULTS: Of 227 eligible children, 184 (81%) were assessed at a mean (SD) age of 9.3 (0.2) years. Low educational achievement was similar in dextrose and placebo groups (36/86 [42%] vs. 42/94 [45%]; RR 1.04, 95% CI 0.76, 1.44; p = 0.79). Children allocated to dextrose gel had lower visual perception standard scores (95.2 vs. 100.6; MD -5.68, 95% CI -9.79, -1.57; p = 0.006) and a greater proportion had low (<85) visual perception scores (20/88 [23%] vs. 10/95 [11%]; RR 2.23, 95% CI 1.13, 4.37; p = 0.02). Other secondary outcomes, including other aspects of visual-motor function, were similar in both groups. CONCLUSION: Treatment dextrose gel does not appear to result in any clinically significant differences in educational achievement or other neurodevelopmental outcomes at mid-childhood.

Neurodevelopmental correlates of caudate volume in children born at risk of neonatal hypoglycaemia.

BACKGROUND: Neonatal hypoglycaemia can lead to brain damage and neurocognitive impairment. Neonatal hypoglycaemia is associated with smaller caudate volume in the mid-childhood. We investigated the relationship between neurodevelopmental outcomes and caudate volume and whether this relationship was influenced by neonatal hypoglycaemia. METHODS: Children born at risk of neonatal hypoglycaemia ≥36 weeks' gestation who participated in a prospective cohort study underwent neurodevelopmental assessment (executive function, academic achievement, and emotional-behavioural regulation) and MRI at age 9-10 years. Neonatal hypoglycaemia was defined as at least one hypoglycaemic episode (blood glucose concentration <2.6 mmol/L or at least 10 min of interstitial glucose concentrations <2.6 mmol/L). Caudate volume was computed using FreeSurfer. RESULTS: There were 101 children with MRI and neurodevelopmental data available, of whom 70 had experienced neonatal hypoglycaemia. Smaller caudate volume was associated with greater parent-reported emotional and behavioural difficulties, and poorer prosocial behaviour. Caudate volume was significantly associated with visual memory only in children who had not experienced neonatal hypoglycaemia (interaction p = 0.03), but there were no other significant interactions between caudate volume and neonatal hypoglycaemia. CONCLUSION: Smaller caudate volume is associated with emotional behaviour difficulties in the mid-childhood. Although neonatal hypoglycaemia is associated with smaller caudate volume, this appears not to contribute to clinically relevant neurodevelopmental deficits. IMPACT: At 9-10 years of age, caudate volume was inversely associated with emotional-behavioural difficulties and positively associated with prosocial behaviour but was not related to executive function or educational achievement. Previous studies have suggested that neonatal hypoglycaemia may contribute to smaller caudate volume but exposure to neonatal hypoglycaemia did not appear to influence the relationship between caudate volume and behaviour. Among children not exposed to neonatal hypoglycaemia, caudate volume was also positively associated with visual memory, but no such association was detected among those exposed to neonatal hypoglycaemia. Understanding early-life factors that affect caudate development may provide targets for improving behavioural function.

Fetal movements: A framework for antenatal conversations.

BACKGROUND: Presentations for decreased fetal movements comprise a significant proportion of acute antenatal assessments. Decreased fetal movements are associated with increased likelihood of adverse pregnancy outcomes including stillbirth. Consensus-based guidelines recommend pregnant women routinely receive information about fetal movements, but practice is inconsistent, and the information shared is frequently not evidence-based. There are also knowledge gaps about the assessment and management of fetal movement concerns. Women have indicated that they would like more accurate information about what to expect regarding fetal movements. DISCUSSION: Historically, fetal movement information has focussed on movement counts. This is problematic, as the number of fetal movements perceived varies widely between pregnant women, and no set number of movements has been established as a reliable indicator of fetal wellbeing. Of late, maternity care providers have also advised women to observe their baby's movement pattern, and promptly present if they notice a change. However, normal fetal movement patterns are rarely defined. Recently, a body of research has emerged relating to maternal perception of fetal movement features such as strength, presence of hiccups, and diurnal pattern as indicators of fetal wellbeing in addition to frequency. CONCLUSION: Sharing comprehensive and gestation-appropriate information about fetal movements may be more satisfying for women, empowering women to identify for themselves when their baby is doing well, and importantly when additional assessment is needed. We propose a conversational approach to fetal movement information sharing, focusing on fetal movement strength, frequency, circadian pattern, and changes with normal fetal development, tailored to the individual.

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.

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.