Different Approaches to requesting Consent for Routine data linkage in Neonatal follow-up (ACORN): protocol for a 2×2 factorial randomised trial.

INTRODUCTION: Routinely collected data can be linked to research data to create a rich dataset and inform practice. However, consent is normally required to link identifiable data. Reported rates of consent to data linkage for children ranged from 21% to 96%, but no studies have investigated different approaches to seeking consent for data linkage for school-age children. METHODS AND ANALYSIS: The Approaches to Consent for Routine Data Linkage in Neonatal Follow-up (ACORN) trial is a 2×2 factorial randomised trial to assess whether, for children who participated in neonatal randomised trials (pre-hypoglycaemia Prevention with Oral Dextrose Gel (hPOD), hPOD and The Impact of Protein Intravenous Nutrition on Development in Extremely Low Birth Weight Babies (ProVIDe)) and are approached to participate in an in-person assessment at 6-7 years of age, parental consent to data linkage is higher if consent is sought (1) after the in-person assessment (delayed) or concurrently and (2) for health and education data combined or separately. The primary outcomes will be rates of consent to linkage of (1) either health or education data and (2) both health and education data. A pilot study indicates the potentially available cohort size of 2110 (80% follow-up of the neonatal trial cohorts) would be adequate to detect an absolute difference of 6%-5%-4% from a baseline consent rate of 70%-85%-90%, respectively (2-tailed alpha 0.05, 90% power). With at least 1136 participants, the ACORN trial would have 90% power to detect an absolute difference of 5% in the primary outcome for each factor, assuming a consent rate of 90% in the control groups and alpha 0.05. Data are categorical and will be presented as number and per cent. The effects of factors will be tested using generalised linear models and presented as ORs and 95% CIs. ETHICS AND DISSEMINATION: Ethics approval by the New Zealand Health and Disability Ethics Committee (19/STH/202). Dissemination will be via peer-reviewed publications, scientific meetings, educational sessions and public fora. TRIAL REGISTRATION NUMBER: ACTRN12621000571875 (Australian New Zealand Clinical Trials Registry).

(Rad 8)Caffeine prophylaxis to improve intermittent hypoxaemia in infants born late preterm: a randomised controlled dosage trial (Latte Dosage Trial).

INTRODUCTION: Infants born late preterm (34+0 to 36+6 weeks' gestational age) have frequent episodes of intermittent hypoxaemia compared with term infants. Caffeine citrate reduces apnoea and intermittent hypoxaemia and improves long-term neurodevelopmental outcomes in infants born very preterm and may have similar effects in late preterm infants. Clearance of caffeine citrate increases with gestational age and late preterm infants are likely to need a higher dose than very preterm infants. Our aim is to determine the most effective and best-tolerated dose of caffeine citrate to reduce transient intermittent hypoxaemia events in late preterm infants. METHODS AND ANALYSIS: A phase IIB, double-blind, five-arm, parallel, randomised controlled trial to compare the effect of four doses of oral caffeine citrate versus placebo on the frequency of intermittent hypoxaemia. Late preterm infants will be enrolled within 72 hours of birth and randomised to receive 5, 10, 15 or 20 mg/kg/day caffeine citrate or matching placebo daily until term corrected age. The frequency of intermittent hypoxaemia (events/hour where oxygen saturation concentration is ≥10% below baseline for ≤2 min) will be assessed with overnight oximetry at baseline, 2 weeks after randomisation (primary outcome) and at term corrected age. Growth will be measured at these timepoints, and effects on feeding and sleeping will be assessed by parental report. Data will be analysed using generalised linear mixed models. ETHICS AND DISSEMINATION: This trial has been approved by the Health and Disability Ethics Committees of New Zealand (reference 18/NTA/129) and the local institutional research review committees. Findings will be disseminated to peer-reviewed journals to clinicians and researchers at local and international conferences and to the public. The findings of the trial will inform the design of a large multicentre trial of prophylactic caffeine in late preterm infants, by indicating the most appropriate dose to use and providing information on feasibility. TRIAL REGISTRATION NUMBER: ACTRN12618001745235; Pre-results.

Intermittent Hypoxemia in Infants Born Late Preterm: A Prospective Cohort Observational Study.

OBJECTIVE: To determine if late preterm infants are at increased risk of intermittent hypoxemic events compared with term infants. STUDY DESIGN: Prospective, cohort, observational study of late preterm infants (340/7-366/7 weeks gestational age) and term infants (390/7-416/7 weeks gestational age). Overnight pulse oximetry recordings were performed on days 2-3 after birth, at term equivalent age, and at 45 weeks postmenstrual age. The primary outcome was the frequency of intermittent hypoxemic events per hour (desaturation ≥10% below the preceding baseline SpO2) on the oximetry recording on days 2-3 after birth. Data were analyzed by the Student t test and general linear mixed model. RESULTS: Eighty-five infants were enrolled (late preterm n = 43; term infants n = 42). On days 2-3 after birth, late preterm infants had more intermittent hypoxemic events than term infants (events per hour, mean ± standard error of the mean, 2.5 ± 1.2 vs 1.0 ± 1.2; P < .0001). On mixed model analysis, late preterm infants had a higher frequency of intermittent hypoxemic events at term equivalent age, which decreased to a similar frequency as in term infants by 45 weeks postmenstrual age (events per hour; term equivalent age, late preterm: least squares mean, 3.7 [95% CI, 2.7-5.1] vs term: least squares mean, 1.7 [95% CI, 1.2-2.3]; 45 weeks postmenstrual age, late preterm: least squares mean, 1.5 [95% CI, 1.1-2.1] vs term: least squares mean, 1.9 [95% CI, 1.4-2.6]; P < .0005). CONCLUSIONS: Late preterm infants are at greater risk of intermittent hypoxemia than term infants soon after birth. We speculate that preventing intermittent hypoxemia in late preterm infants may improve neurodevelopmental outcomes.

Early-Stage Translational Research in Perinatal Medicine.

BACKGROUND: Pre-clinical research, which encompasses studies in animals and in the laboratory, has made significant contributions to the improvement of neonatal outcomes. METHODS: Here, we describe examples of how pre-clinical research can be the starting point on the journey to the development of new interventions to improve neonatal care and outcomes and discuss recent progress in ensuring methodological and ethical rigour in pre-clinical research involving animal models. RESULTS: Studies in pregnant sheep led to the serendipitous discovery that preterm lambs born after exogenous corticosteroid exposure were able to aerate their lungs. Subsequent clinical trials confirmed that antenatal corticosteroids given to women at risk of preterm delivery substantially reduce mortality and morbidity in babies born preterm. Animal research also contributed to discoveries in the mechanism of brain injury after hypoxic ischaemic encephalopathy, leading to the use of therapeutic hypothermia as an effective treatment. However, animals are sentient creatures and there are significant ethical concerns with their use in studies to benefit human health. Mandated institutional animal research ethics committees ensure adherence to ethical requirements. To provide high-quality data which can be translated into clinical research, pre-clinical research needs to follow rigorous standards of study design and reporting. The ARRIVE guidelines provide guidance for pre-clinical research similar to that provided in the CONSORT guidelines for clinical trials and are gaining acceptance among researchers and journal editors. CONCLUSION: Improved scientific rigour in the use of animal research will increase the likelihood that pre-clinical research will continue to translate into improved neonatal outcomes.

Long-Term Outcomes of Hyperglycemic Preterm Infants Randomized to Tight Glycemic Control.

OBJECTIVE: To determine whether tight glycemic control of neonatal hyperglycemia changes neurodevelopment, growth, and metabolism at school age. STUDY DESIGN: Children born very low birth weight and randomized as hyperglycemic neonates to a trial of tight vs standard glycemic control were assessed at 7 years corrected age, including Wechsler Intelligence Scale for Children Fourth Edition, Movement Assessment Battery for Children 2, visual and neurologic examinations, growth measures, dual X-ray absorptiometry, and frequently sampled intravenous glucose tolerance test. The primary outcome was survival without neurodevelopmental impairment at age 7 years. Outcomes were compared using linear regression, adjusted for sex, small for gestational age, birth plurality, and the clustering of twins. Data are reported as number (%) or mean (SD). RESULTS: Of the 88 infants randomized, 11 (13%) had died and 57 (74% of eligible children) were assessed at corrected age 7 years. Survival without neurodevelopmental impairment occurred in 25 of 68 children (37%), with no significant difference between tight (14 of 35; 40%) and standard (11 of 33; 33%) glycemic control groups (P = .60). Children in the tight group were shorter than those in the standard group (121.3 [6.3] cm vs 125.1 [5.4] cm; P < .05), but had similar weight and head circumference. Children in the tight group had greater height-adjusted lean mass (18.7 [0.3] vs 17.6 [0.2] kg; P < .01) and lower fasting glucose concentrations (84.6 [6.30] vs 90.0 [5.6] mg⋅dL-1; P < .05), but no other differences in measures of body composition or insulin-glucose metabolism. CONCLUSION: Tight glycemic control for neonatal hyperglycemia does not change survival without neurodevelopmental impairment, but reduces height, increases height-adjusted lean mass, and reduces fasting blood glucose concentrations at school age. TRIAL REGISTRATION: ACTRN: 12606000270516.

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

INTRODUCTION: Neonatal hypoglycaemia is a common condition that can cause developmental delay. Treatment of neonatal hypoglycaemia with oral dextrose gel has been shown to reverse hypoglycaemia and reduce admissions to neonatal intensive care for hypoglycaemia. An evidence-based clinical practice guideline was written to guide the use of dextrose gel to treat neonatal hypoglycaemia in New Zealand. However, it is unclear what clinical discipline might most effectively lead the implementation of the guideline recommendations. OBJECTIVE: To determine if midwife or doctor local opinion leaders are more effective in implementing a clinical practice guideline for use of oral dextrose gel to treat hypoglycaemia in babies on postnatal wards. METHODS AND ANALYSIS: A cluster-randomised, blinded, controlled trial. New Zealand maternity hospitals that care for babies born at risk of neonatal hypoglycaemia will be randomised to having either a local midwife or doctor lead the guideline implementation at that hospital. The primary outcome will be the change in the proportion of hypoglycaemic babies treated with dextrose gel from before implementation of the guideline to 3 months after implementation. ETHICS AND DISSEMINATION: Approved by Health and Disability Ethics Committee: 15/NTA/31. Findings will be disseminated to peer-reviewed journals, guideline developers and the public. TRIAL REGISTRATION NUMBER: ISRCTN61154098.

Relationship between Measures of Neonatal Glycemia, Neonatal Illness, and 2-Year Outcomes in Very Preterm Infants.

OBJECTIVES: To investigate relationships between early neonatal glycemia, neonatal characteristics, neonatal illness, and developmental outcomes in very preterm infants. STUDY DESIGN: A retrospective, observational cohort study of 443 infants born weighing <1500 g or <30 weeks of gestation, and admitted within 24 hours to National Women's Hospital, Auckland, New Zealand. Glucose variability was defined as the standard deviation around the mean after log transformation of all blood glucose concentrations. Absolute glycemic excursions in the first week were used to divide the infants into 4 groups: normoglycemic; hypoglycemic; hyperglycemic, and unstable. RESULTS: Compared with normoglycemic infants, hypoglycemic and unstable infants had lower birth weight z-scores, and hyperglycemic and unstable infants were of lower birth weight. Hypoglycemic infants had similar outcomes to normoglycemic infants. Hyperglycemic and unstable infants were less likely to survive without neonatal morbidity and less likely to survive without neurodevelopmental impairment at 2 years of age. Higher mean blood glucose concentration was seen in the hyperglycemic and unstable groups, and was associated with worse neonatal and 2-year outcomes. Greater glucose variability was seen in the hypoglycemic and unstable groups, and was associated with worse neonatal illness but not outcome at 2 years. No associations between measures of neonatal glycemia and neonatal or 2-year outcomes remained after correction for gestation, birth weight z-score, and socioeconomic status. CONCLUSIONS: In very preterm infants, measures of neonatal glycemia are markers of gestational age and intrauterine growth, and are not independent predictors of neonatal illness or outcomes at 2 years of age.

Bayley-III motor scale and neurological examination at 2 years do not predict motor skills at 4.5 years.

AIM: To determine whether Bayley Scales of Infant and Toddler Development (3rd edition) (Bayley-III) motor scores and neurological examination at 2 years corrected age predict motor difficulties at 4.5 years corrected age. METHOD: A prospective cohort study of children born at risk of neonatal hypoglycaemia in Waikato Hospital, Hamilton, New Zealand. Assessment at 2 years was performed using the Bayley-III motor scale and neurological examination, and at 4.5 years using the Movement Assessment Battery for Children (2nd edition) (MABC-2). RESULTS: Of 333 children, 8 (2%) had Bayley-III motor scores below 85, and 50 (15%) had minor deficits on neurological assessment at 2 years; 89 (27%) scored less than or equal to the 15th centile, and 54 (16%) less than or equal to the 5th centile on MABC-2 at 4.5 years. Motor score, fine and gross motor subtest scores, and neurological assessments at 2 years were poorly predictive of motor difficulties at 4.5 years, explaining 0 to 7% of variance in MABC-2 scores. A Bayley-III motor score below 85 predicted MABC-2 scores less than or equal to the 15th centile with a positive predictive value of 30% and a negative predictive value of 74% (7% sensitivity and 94% specificity). INTERPRETATION: Bayley-III motor scale and neurological examination at 2 years were poorly predictive of motor difficulties at 4.5 years.

Prophylactic Oral Dextrose Gel for Newborn Babies at Risk of Neonatal Hypoglycaemia: A Randomised Controlled Dose-Finding Trial (the Pre-hPOD Study).

BACKGROUND: Neonatal hypoglycaemia is common, affecting up to 15% of newborns, and can cause brain damage. Currently, there are no strategies, beyond early feeding, to prevent neonatal hypoglycaemia. Our aim was to determine a dose of 40% oral dextrose gel that will prevent neonatal hypoglycaemia in newborn babies at risk. METHODS AND FINDINGS: We conducted a randomised, double-blind, placebo-controlled dose-finding trial of buccal dextrose gel to prevent neonatal hypoglycaemia at two hospitals in New Zealand. Babies at risk of hypoglycaemia (infant of a mother with diabetes, late preterm delivery, small or large birthweight, or other risk factors) but without indication for admission to a neonatal intensive care unit (NICU) were randomly allocated either to one of four treatment groups: 40% dextrose at one of two doses (0.5 ml/kg = 200 mg/kg, or 1 ml/kg = 400 mg/kg), either once at 1 h of age or followed by three additional doses of dextrose (0.5 ml/kg before feeds in the first 12 h); or to one of four corresponding placebo groups. Treatments were administered by massaging gel into the buccal mucosa. The primary outcome was hypoglycaemia (<2.6 mM) in the first 48 h. Secondary outcomes included admission to a NICU, admission for hypoglycaemia, and breastfeeding at discharge and at 6 wk. Prespecified potential dose limitations were tolerance of gel, time taken to administer, messiness, and acceptability to parents. From August 2013 to November 2014, 416 babies were randomised. Compared to babies randomised to placebo, the risk of hypoglycaemia was lowest in babies randomised to a single dose of 200 mg/kg dextrose gel (relative risk [RR] 0.68; 95% confidence interval [CI] 0.47-0.99, p = 0.04) but was not significantly different between dose groups (p = 0.21). Compared to multiple doses, single doses of gel were better tolerated, quicker to administer, and less messy, but these limitations were not different between dextrose and placebo gel groups. Babies who received any dose of dextrose gel were less likely to develop hypoglycaemia than those who received placebo (RR 0.79; 95% CI 0.64-0.98, p = 0.03; number needed to treat = 10, 95% CI 5-115). Rates of NICU admission were similar (RR 0.64; 95% CI 0.33-1.25, p = 0.19), but admission for hypoglycaemia was less common in babies randomised to dextrose gel (RR 0.46; 95% CI 0.21-1.01, p = 0.05). Rates of breastfeeding were similar in both groups. Adverse effects were uncommon and not different between groups. A limitation of this study was that most of the babies in the trial were infants of mothers with diabetes (73%), which may reduce the applicability of the results to babies from other risk groups. CONCLUSIONS: The incidence of neonatal hypoglycaemia can be reduced with a single dose of buccal 40% dextrose gel 200 mg/kg. A large randomised trial (Hypoglycaemia Prevention with Oral Dextrose [hPOD]) is under way to determine the effects on NICU admission and later outcomes. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12613000322730.

Pre-school screening for developmental and emotional health: Comparison with neurodevelopmental assessment.

AIM: The study aim was to compare detection of and referral for developmental and emotional problems in a school readiness screening programme (New Zealand Before School Check, B4SC) with that of a comprehensive neurodevelopmental assessment. METHODS: This is a prospective cohort study of children (n = 274) born at risk of neonatal hypoglycaemia and recruited to a follow-up study of neurodevelopmental outcomes at 4.5 years (Children with Hypoglycaemia and their Later Development (CHYLD) Study). Children identified as of significant concern for developmental and emotional problems, and referrals made, were compared in the B4SC and CHYLD Study. Scores of the parent-completed Strengths and Difficulties Questionnaire used in both assessments were compared. RESULTS: Of the 274 children who underwent clinical neurodevelopmental assessment at a mean (standard deviation) age of 53.3 (1.8) months, 237 had the B4SC developmental and emotional health screening. Of these, 44 (19%) children met B4SC referral criteria, and 15 (6%) were referred, but only 21 (9%) children met CHYLD referral criteria, and 10 (4%) were referred. Twelve children (5%) met both the B4SC and CHYLD referral criteria, and two were referred by both. When assessed twice, 39 (17%) children changed parent-completed Strengths and Difficulties Questionnaire category. Children who did not have B4SC screening had higher mean total difficulties score (10.5 vs. 8.2, P = 0.009) and were more likely to have cognitive delay than those who were screened (19% vs. 8%, P = 0.04). CONCLUSION: More children met referral criteria for the B4SC screening programme than for a more comprehensive neurodevelopmental assessment. Children who did not have screening had a higher incidence of cognitive and behaviour problems than those who did.

Accuracy of caregivers' recall of hospital admissions: implications for research.

AIM: To determine the accuracy of caregivers' recall of hospital admissions in early childhood. METHODS: Prospective cohort study of babies born at risk of neonatal hypoglycaemia at Waikato Hospital, New Zealand, a regional public hospital and sole provider of acute inpatient care to over 100,000 children. Caregivers' recall of children's hospital admissions up to 4.5 years was compared with medical records. Accuracy of recall was related to neonatal and socio-demographic characteristics. RESULTS: Of 267 children, 179 (67%) visited hospital and 106 (40%) were admitted at least once. The most frequent reasons for admission were for respiratory (29%) and gastrointestinal (18%) problems. Of 106 children admitted to hospital, 27 (25%) caregivers did not recall the admission and only 37 (35%) accurately recalled the number of admissions. The accuracy of recall was lower for gastrointestinal (38%) and surgical (40%) problems, while recall of respiratory (64%) and ear, nose and throat (60%) admissions was more accurate. Low socio-economic status and multiple admissions were associated with less accurate recall of number of admissions. CONCLUSION: Caregivers do not accurately report hospital admissions. Questionnaire data about use of hospital facilities should be interpreted cautiously and may not be sufficiently accurate for use in research studies.