Cross-cultural validity and reliability of the BRIEF-P at age 2 and 4.5 years in children born at risk of neonatal hypoglycemia.

Executive function (EF) encompasses several neurocognitive processes that are important in self-regulation of behavior and the attainment of social and cognitive competencies. While much progress has been made in developing valid measures for adult and adolescent EF, there is a dearth of valid measures for preschool children. Given the steep trajectory of neuropsychological development among this age group and the importance of EF, a valid measure for clinical assessment and research is needed that can capture EF in the everyday context of early childhood. The Behavior Rating Inventory of Executive Function Preschool Version (BRIEF-P) measures parent and teacher observations of children's everyday self-regulatory behaviors. The BRIEF-P has been validated in a range of normative and non-normative samples, but further validation is needed across cultures. This study aimed to evaluate the cross-cultural validity and reliability of the BRIEF-P when used by New Zealand Maori (n = 131) and European (n = 193) parents of children born with risk factors of neonatal hypoglycemia. Parents of children who participated in the prospective, longitudinal Children with Hypoglycemia and their Later Development (CHYLD) study completed the BRIEF-P when the child was 2 years ±4 weeks and 4.5 years ±8 weeks old. Results showed that the BRIEF-P is a highly reliable and valid instrument. Comparisons between Maori and New Zealand European samples revealed biases, which could be a source of further work to improve the construct validity of this measure, such as the development of norms and item validation for non-European and non-Western samples.

Cortical Oxygenation Changes during Gastric Tube Feeding in Moderate- and Late-Preterm Babies: A NIRS Study.

Smell and taste of food can trigger physiological responses facilitating digestion and metabolism of nutrients. Controlled experimental studies in preterm babies have demonstrated that smell activates the orbitofrontal cortex (OFC) but none have investigated the effect of taste stimulation. Using cotside Near-Infrared Spectroscopy (NIRS), we measured changes in OFC cerebral oxygenation in response to gastric tube feeds five and 10 days after birth in 53 assessments of 35 moderate- to late-preterm babies enrolled in a randomized trial. Babies were randomly assigned to receive smell and taste of milk before gastric tube feeds (intervention group, n = 16) or no exposure (control group, n = 19). The majority of babies were born at 33 weeks of gestation (range 32-34) and 69% were boys. No differences in OFC cerebral oxygenation were observed between control and intervention groups. Gastric tube feeds induced activation of the OFC (p < 0.05), but sensory stimulation alone with smell and taste did not. Boys, but not girls, showed activation of the OFC following exposure to smell of milk (p = 0.01). The clinical impact of sensory stimulation prior to tube feeds on nutrition of preterm babies, as well as the impact of environmental inputs on cortical activation, remains to be determined.

Effects of intrauterine insulin-like growth factor-1 therapy for fetal growth restriction on adult metabolism and body composition are sex specific.

Fetal growth restriction (FGR) is associated with compromised growth and metabolic function throughout life. Intrauterine therapy of FGR with intra-amniotic insulin-like growth factor-1 (IGF1) enhances fetal growth and alters perinatal metabolism and growth in a sex-specific manner, but the adult effects are unknown. We investigated the effects of intra-amniotic IGF1 treatment of FGR on adult growth and body composition, adrenergic sensitivity, and glucose-insulin axis regulation. Placental embolization-induced FGR was treated with four weekly doses of 360 µg intra-amniotic IGF1 (FGRI) or saline (FGRS). Offspring were raised to adulthood (18 mo: FGRI, n = 12 females, 12 males; FGRS, n = 13 females, 10 males) alongside offspring from unembolized and untreated sheep (CON; n = 12 females, 21 males). FGRI females had increased relative lean mass compared with CON but not FGRS (P < 0.05; 70.6 ± 8.2% vs. 61.4 ± 8.2% vs. 67.6 ± 8.2%), decreased abdominal adipose compared with CON and FGRS (P < 0.05; 43.7 ± 1.2% vs. 49.3 ± 0.9% vs. 48.5 ± 1.0%), increased glucose utilization compared with FGRS but not CON (P < 0.05; 9.6 ± 1.0 vs. 6.0 ± 0.9 vs. 7.6 ± 0.9 mg·kg-1·min-1), and increased ß-hydroxybutyric acid:nonesterified fatty acid ratio in response to adrenaline compared with CON and FGRS (P < 0.05; 3.9 ± 1.4 vs. 1.1 ± 1.4 vs. 1.8 ± 1.4). FGRS males were smaller and lighter compared with CON but not FGRI (P < 0.05; 86.8 ± 6.3 vs. 93.5 ± 6.1 vs. 90.7 ± 6.3 kg), with increased peak glucose concentration (10%) in response to a glucose load but few other differences. These effects of intra-amniotic IGF1 therapy on adult body composition, glucose-insulin axis function, and adrenergic sensitivity could indicate improved metabolic regulation during young adulthood in female FGR sheep.

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.

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.