Cumulative sucrose exposure for repeated procedural pain in preterm neonates and neurodevelopment at 18 months of corrected age: a prospective observational longitudinal study.

INTRODUCTION: Oral sucrose is repeatedly administered to neonates in the neonatal intensive care unit (NICU) to treat pain from commonly performed procedures; however, there is limited evidence on its long-term cumulative effect on neurodevelopment. We examined the association between total sucrose volumes administered to preterm neonates for pain mitigation in the NICU and their neurodevelopment at 18 months of corrected age (CA). METHODS: A prospective longitudinal single-arm observational study that enrolled hospitalised preterm neonates <32 weeks of gestational age at birth and <10 days of life was conducted in four level III NICUs in Canada. Neonates received 0.1 mL of 24% sucrose 2 min prior to all commonly performed painful procedures during their NICU stay. Neurodevelopment was assessed at 18 months of CA using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). Multiple neonatal and maternal factors known to affect development were adjusted for in the generalised linear model analysis. RESULTS: 172 preterm neonates were enrolled and 118 were included in the analysis at 18 months of CA. The total mean sucrose volume administered/neonate/NICU stay was 5.96 (±5.6) mL, and the mean Bayley-III composite scores were: cognitive 91 (±17), language 86 (±18) and motor 88 (±18). There was no association between Bayley-III scores and the total sucrose volume: cognitive (p=0.57), language (p=0.42) and motor (p=0.70). CONCLUSION: Cumulative sucrose exposure for repeated procedural pain in preterm neonates was neither associated with a delay in neurodevelopment nor neuroprotective effects at 18 months of CA. If sucrose is used, we suggest the minimally effective dose combined with other non-pharmacological interventions with demonstrated effectiveness such as skin-to-skin contact, non-nutritive sucking, facilitated tucking and swaddling. TRIAL REGISTRATION NUMBER: NCT02725814.

Change in Volumes and Location of Preterm White Matter Injury over a Period of 15 Years.

OBJECTIVE: To evaluate whether white matter injury (WMI) volumes and spatial distribution, which are important predictors of neurodevelopmental outcomes in preterm infants, have changed over a period of 15 years. STUDY DESIGN: Five hundred and twenty-eight infants born <32 weeks' gestational age from 2 sequential prospective cohorts (cohort 1: 2006 through 2012; cohort 2: 2014 through 2019) underwent early-life (median 32.7 weeks postmenstrual age) and/or term-equivalent-age MRI (median 40.7 weeks postmenstrual age). WMI were manually segmented for quantification of volumes. There were 152 infants with WMI with 74 infants in cohort 1 and 78 in cohort 2. Multivariable linear regression models examined change in WMI volume across cohorts while adjusting for clinical confounders. Lesion maps assessed change in WMI location across cohorts. RESULTS: There was a decrease in WMI volume in cohort 2 compared with cohort 1 (ß = -0.6, 95% CI [-0.8, -0.3], P < .001) with a shift from more central to posterior location of WMI. There was a decrease in clinical illness severity of infants across cohorts. CONCLUSIONS: We found a decrease in WMI volume and shift to more posterior location in very preterm infants over a period of 15 years. This may potentially reflect more advanced maturation of white matter at the time of injury which may be related to changes in clinical practice over time.

Relationships between cortisol levels across early childhood and processing speed at age 4.5 years in children born very preterm.

Children born very low gestational age (VLGA, 29-32 weeks gestational age [GA]) display slower processing speed and altered hypothalamic pituitary adrenal (HPA) axis function, with greater effects in those born extremely low gestational age (ELGA; 24-28 weeks GA). We investigated trajectories of HPA axis activity as indexed by cortisol output and patterns across cognitive assessment at ages 1.5, 3 and 4.5 years, comparing children born ELGA and VLGA and associations with 4.5-year processing speed. In a prospective longitudinal cohort study, infants born very preterm (<33 weeks gestation) returned for developmental assessment at ages 1.5, 3, and 4.5 years. At each age, children completed standardized cognitive testing and saliva samples collected before (Pretest), during (During) and after (End) challenging cognitive tasks were assayed for cortisol. For the total group (n = 188), cortisol area under the curve with respect to ground (AUCg) decreased, while cortisol reactivity to challenge (Pre-test to During) increased from 1.5 to 3 years, remaining stable to 4.5 years. This longitudinal pattern was related to higher Processing Speed (WPPSI-IV) scores at 4.5 years. Children born ELGA displayed higher AUCg than VLGA, particularly at age 3, driven by higher Pre-test cortisol levels. Overall, relative to those born VLGA, children born ELGA displayed greater cortisol responsivity to cognitive challenge. A higher setpoint of cortisol levels at age 3-years in children born ELGA may reflect altered HPA axis regulation more broadly and may contribute to difficulties with information processing in this population, critical for academic and social success.

Parent-reported health outcomes at preschool age in preterm survivors: a population-based cohort study.

OBJECTIVE: Literature on health status (HS) and health-related quality of life of preterm survivors at preschool age is sparse. Further, little is known about the relationship between parent-reported HS outcomes and standardised neurodevelopmental outcomes measured in preterm survivors at preschool age. Our objective was to evaluate parent-reported child HS outcomes and their relationship to neurodevelopmental outcomes at 36 months of age in very preterm survivors. DESIGN: Prospective population-based cohort study. SETTING: Perinatal follow-up programme. PATIENTS: Infants <31 weeks' gestational age born from 2014 to 2016. OUTCOME MEASURES: Parents completed the Health Status Classification System for Pre-School Children questionnaire at 36 months. At the same age, neurodevelopmental assessments were completed to determine neurodevelopmental impairment (NDI). NDI was categorised as none, 'mild' or 'significant' (moderate or severe cerebral palsy, Bayley Scales of Infant and Toddler Development - Third Edition <70, blind or required hearing aid). RESULTS: Of 118 children, 87 (73.7%) parents reported their child had an HS concern (mild: 61 (51%); moderate: 16 (13.6%); and severe: 10 (8.5%)). Mild and significant NDIs were observed in 17 (14.4%) and 14 (11.9%) children, respectively. For the 14 (12%) children with significant NDI, 7 (50.0%) parents reported severe and 4 (28.6%) reported moderate concerns. Conversely, for 26 (22%) children with parent-reported moderate to severe concerns, 11 (42.3%) met the criteria for significant NDI. There was a moderate positive correlation between parental concern and NDI status (Spearman correlation=0.46, p<0.0001). CONCLUSIONS: Parental HS concerns only moderately correlated with the NDI status. Of the 12% of children with significant NDI, only half of the parents reported severe HS concerns.

Cortisol levels are related to neonatal pain exposure in children born very preterm at age 18 months in two independent cohorts.

Exposure to pain-related stress from frequent invasive procedures in the neonatal intensive care unit (NICU) has been associated with altered physiological stress regulation, neurodevelopment, and behavior in children born very preterm (≤32 weeks gestation). Previously, in a cohort born 2003-2006 (Cohort 1), we found that, at 18 months corrected age (CA), children born extremely low gestational age (ELGA; 24-28 weeks) and very low gestational age (VLGA; 29-32 weeks), had higher pre-test cortisol levels and a different pattern of cortisol output across a developmental assessment involving cognitive challenge compared to children born full-term (FT; 39-41 weeks). Also, greater neonatal pain-related stress exposure among the preterm children was related to higher pre-test cortisol levels. Given the adverse long-term effects of neonatal pain in preterm infants and the ensuing rise in clinical concerns to appropriately manage pain in the NICU in recent years, we aimed to examine whether our findings from Cohort 1 would still be evident in an independent cohort (Cohort 2) born 2006-2011 and recruited from the same tertiary NICU in Vancouver, Canada. We also compared the cortisol patterns, clinical and socio-demographic factors, and their interrelationships between the two cohorts. In Cohort 2, our findings using multi-level modeling support and extend our earlier findings in Cohort 1, demonstrating that children born ELGA display higher pre-test cortisol levels than FT. As well, greater cortisol output across assessment was related to more anxiety/depressive behaviors in children born VLGA. Importantly, children born ELGA were exposed to less neonatal pain/stress, mechanical ventilation, and morphine in Cohort 2 than Cohort 1. In both cohorts, however, cortisol levels and patterns were related to neonatal pain/stress and clinical factors (days on mechanical ventilation, overall morphine exposure). Despite less exposure to pain/stress and adverse clinical factors in Cohort 2 compared to Cohort 1, cortisol levels and patterns across cognitive challenge in preterm children at 18-month CA were consistent across the two independent cohorts. These findings highlight that, despite improvements to neonatal care, children born extremely preterm continue to display altered HPA axis activity, which is associated with their poorer neurodevelopmental and behavioral outcomes.

Fragility and resilience: parental and family perspectives on the impacts of extreme prematurity.

OBJECTIVES: Extremely preterm babies have a significant risk of neurodevelopmental impairment (NDI). There has been little investigation regarding the impact of prematurity on families. The objective of this study was to explore parental perspectives regarding the impact of prematurity on themselves/their family. METHODS: Over 1 year, parents of children born <29 weeks' gestational age (GA) who were between 18 months old and 7 years old and came for their follow-up visit were invited to participate. They were asked to categorise the impacts of prematurity on their life and their family as positive, negative or both and to describe those impacts in their own words. Thematic analysis was performed by a multidisciplinary group, including parents. Logistic regression was performed to compare parental responses. RESULTS: Among parents (n=248, 98% participation rate), most (74%) reported that their child's prematurity had both positive and negative impacts on their life or their family's life, while 18% reported only positive impacts and 8% only negative impacts. These proportions were not correlated with GA, brain injury, nor level of NDI. The positive impacts reported included: an improved outlook on life, such as gratitude and perspective (48%), stronger family relationships (31%) and the gift of the child (28%). The negative themes were stress and fear (42%), loss of equilibrium due to medical fragility (35%) and concerns about developmental outcomes including the child's future (18%). CONCLUSION: Parents report both positive and negative impacts after an extremely preterm birth, independent of disability. These balanced perspectives should be included in neonatal research, clinical care and provider education.

Early-life exposure to analgesia and 18-month neurodevelopmental outcomes in very preterm infants.

BACKGROUND: We assessed variability of analgesic use across three tertiary neonatal intensive care units (NICUs) accounting for early-life pain, quantified as number of invasive procedures. We also determined whether analgesia exposure modifies associations between early-life pain and neurodevelopment. METHODS: Multicenter prospective study of 276 very preterm infants (born <24-32 weeks' gestational age [GA]). Detailed data of number of invasive procedures and duration of analgesia exposure were collected in initial weeks after birth. Eighteen-month neurodevelopmental assessments were completed in 215 children with Bayley Scales for Infant Development-Third edition. RESULTS: Multivariable linear regressions revealed significant differences in morphine use across sites, for a given exposure to early-life pain (interaction p < 0.001). Associations between early-life pain and motor scores differed by duration of morphine exposure (interaction p = 0.01); greater early-life pain was associated with poorer motor scores in infants with no or long (>7 days) exposure, but not short exposure (≤7 days). CONCLUSIONS: Striking cross-site differences in morphine exposure in very preterm infants are observed even when accounting for early-life pain. Negative associations between greater early-life pain and adverse motor outcomes were attenuated in infants with short morphine exposure. These findings emphasize the need for further studies of optimal analgesic approaches in preterm infants. IMPACT: In very preterm neonates, both early-life exposure to pain and analgesia are associated with adverse neurodevelopment and altered brain maturation, with no clear guidelines for neonatal pain management in this population. We found significant cross-site variability in morphine use across three tertiary neonatal intensive care units in Canada. Morphine use modified associations between early-life pain and motor outcomes. In infants with no or long durations of morphine exposure, greater early-life pain was associated with lower motor scores, this relationship was attenuated in those with short morphine exposure. Further trials of optimal treatment approaches with morphine in preterm infants are warranted.

Head circumference, total cerebral volume and neurodevelopment in preterm neonates.

OBJECTIVES: To assess the association of head circumference (HC) <10th percentile at birth and discharge from the neonatal intensive care unit (NICU) with neurodevelopment in very preterm (24-32 weeks' gestational age) neonates, and to compare the association of HC and total cerebral volume (TCV) with neurodevelopmental outcomes. DESIGN: In a prospective cohort, semiautomatically segmented TCV and manually segmented white matter injury (WMI) volumes were obtained. Multivariable regressions were used to study the association of HC and TCV with neurodevelopmental outcomes, accounting for birth gestational age, WMI and postnatal illness. SETTING: Participants born in 2006-2013 at British Columbia Women's Hospital were recruited. PATIENTS: 168 neonates had HC measurements at birth and discharge and MRI at term-equivalent age (TEA). 143 children were assessed at 4.5 years. MAIN OUTCOME MEASURES: Motor, cognitive and language outcomes at 4.5 years were assessed using the Movement Assessment Battery for Children Second Edition (M-ABC) and Wechsler Preschool and Primary Scale of Intelligence Third Edition Full Scale IQ (FSIQ) and Verbal IQ (VIQ). RESULTS: Small birth HC was associated with lower M-ABC and FSIQ scores. In children with small birth HC, small discharge HC was associated with lower M-ABC, FSIQ and VIQ scores, while normal HC at discharge was no longer associated with adverse outcomes. HC strongly correlated with TCV at TEA. TCV did not correlate with outcomes. CONCLUSIONS: Small birth HC is associated with poorer neurodevelopment, independent of postnatal illness and WMI. Normalisation of HC during NICU care appears to moderate this risk.

Parental perspective on important health outcomes of extremely preterm infants.

BACKGROUND AND OBJECTIVE: Neonatal outcome research and clinical follow-up principally focus on neurodevelopmental impairment (NDI) after extremely preterm birth, as defined by the scientific community, without parental input. This survey aimed to investigate parental perspectives about the health and development of their preterm children. METHODS: Parents of children aged 18 months to 7 years born <29 weeks' gestational age presenting at a neonatal follow-up clinic over a 1-year period were asked to evaluate their children's health and development. They were also asked the following question: 'if you could improve two things about your child, what would they be?' Responses were analysed using mixed methods. Logistic regressions were done to compare parental responses. RESULTS: 248 parents of 213 children (mean gestational age 26.6±1.6 weeks, 20% with severe NDI) were recruited. Parents evaluated their children's health at a median of 9/10. Parental priorities for health improvements were (1) development, mainly behaviour, emotional health and language/communication (55%); (2) respiratory heath and overall medical fragility (25%); and (3) feeding/growth issues (14%). Nineteen per cent explicitly mentioned 'no improvements'. Parents were more likely to state 'no improvements' if child had no versus severe NDI OR 4.33 (95% CI 1.47 to 12.75)) or if parents had no versus at least a high school diploma (OR 4.01 (95% 1.99 to 8.10)). CONCLUSIONS: Parents evaluate the health of their preterm children as being very good, with positive perspectives. Parental concerns outside the developmental sphere should also be addressed both in clinical follow-up and research.

Parent-reported health status of preterm survivors in a Canadian cohort.

OBJECTIVES: Health status (HS)/ health-related quality of life measures, completed by self or proxy, are important outcome indicators. Most HS literature on children born preterm includes adolescents and adults with limited data at preschool age. This study aimed to describe parent-reported HS in a large national cohort of extreme preterm children at preschool age and to identify clinical and sociodemographic variables associated with HS. METHODS: Infants born before 29 weeks' gestation between 2009 and 2011 were enrolled in a prospective longitudinal national cohort study through the Canadian Neonatal Network (CNN) and the Canadian Neonatal Follow-Up Network (CNFUN). HS, at 36 months' corrected age (CA), was measured with the Health Status Classification System for Pre-School Children tool completed by parents. Information about HS predictors was extracted from the CNN and CNFUN databases. RESULTS: Of 811 children included, there were 79, 309 and 423 participants in 23-24, 25-26 and 27-28 weeks' gestational age groups, respectively. At 36 months' CA, 78% had a parent-reported health concern, mild in >50% and severe in 7%. Most affected HS attributes were speech (52.1%) and self-care (41.4%). Independent predictors of HS included substance use during pregnancy, infant male sex, Score for Neonatal Acute Physiology-II, bronchopulmonary dysplasia, severe retinopathy of prematurity, caregiver employment and single caregiver. CONCLUSION: Most parents expressed no or mild health concerns for their children at 36 months' CA. Factors associated with health concerns included initial severity of illness, complications of prematurity and social factors.

Family integrated care: very preterm neurodevelopmental outcomes at 18 months.

OBJECTIVE: To examine whether the family integrated care (FICare) programme, a multifaceted approach which enables parents to be engaged as primary caregivers in the neonatal intensive care unit, impacts infant neurodevelopment and growth at 18 months' corrected age. DESIGN/METHODS: Prospective cohort study of infants born <29 weeks' gestational age (GA) who participated in the FICare cluster randomised control trial (cRCT) and were assessed in the Canadian Neonatal Follow-Up Network (CNFUN). The primary outcome measure, Cognitive or Language composite score <85 on the Bayley-III, was compared between FICare exposed and routine care children using logistic regression, adjusted for potential confounders and employing generalised estimation equations to account for clustering of infants within sites. RESULTS: Of 756 infants <29 weeks' GA in the FICare cRCT, 505 were enrolled in CNFUN and 455 were assessed (238 FICare, 217 control). Compared with controls, FICare infants had significantly higher incidence of intraventricular haemorrhage (IVH) (19.5% vs 11.7%, p=0.024) and higher proportion of employed mothers (76.6% vs 73.6%, p=0.043). There was no significant difference in the odds of the primary outcome (adjusted OR: 0.92 (0.59 to 1.42) FiCare vs Control) on multivariable analyses adjusted for GA, IVH and maternal employment. However, Bayley-III Motor scores (adjusted difference in mean (95% CI) 3.87 (1.22 to 6.53) and body mass index 0.67 (0.36 to 0.99) were higher in the FICare group. CONCLUSIONS: Very preterm infants exposed to FICare had no significant difference in incidence of cognitive or language delay but had better motor development. TRIAL REGISTRATION NUMBER: Participants in this cohort study were previously enrolled in a registered trial: NCT01852695.

Lower Maternal Chronic Physiological Stress and Better Child Behavior at 18 Months: Follow-Up of a Cluster Randomized Trial of Neonatal Intensive Care Unit Family Integrated Care.

OBJECTIVE: To assess whether Family Integrated Care (FICare) in the neonatal intensive care unit improves maternal chronic physiological stress and child behavior at 18 months of corrected age for infants born preterm. STUDY DESIGN: Follow-up of a multicenter, prospective cluster-randomized controlled trial comparing FICare and standard care of children born at <33 weeks of gestation and parents, stratified by tertiary neonatal intensive care units, across Canada. Primary outcomes at 18 months of corrected age were maternal stress hormones (cortisol, ie, hair cumulative cortisol [HCC], dehydroepiandrosterone [DHEA]) assayed from hair samples. Secondary outcomes included maternal reports of parenting stress, child behaviors (Internalizing, Externalizing, Dysregulation), and observer-rated caregiving behaviors. Outcomes were analyzed using multilevel modeling. RESULTS: We included 126 mother-child dyads from 12 sites (6 FICare sites, n = 83; 6 standard care sites, n = 43). FICare intervention significantly lowered maternal physiological stress as indicated by HCC (B = -0.22 [-0.41, -0.04]) and cortisol/DHEA ratio (B = -0.25 [-0.48, -0.02]), but not DHEA (B = 0.01 [-0.11, 0.14]). Enrollment in FICare led to lower child Internalizing (B = -0.93 [-2.33, 0.02]) and Externalizing behavior T scores (B = -0.91 [-2.25, -0.01]) via improvements to maternal HCC (mediation). FICare buffered the negative effects of high maternal HCC on child Dysregulation T scores (B = -11.40 [-23.01, 0.21]; moderation). For mothers reporting high parenting stress at 18 months, FICare was related to lower Dysregulation T scores via maternal HCC; moderated mediation = -0.17 (-0.41, -0.01). CONCLUSIONS: FICare has long-term beneficial effects for mother and child, attenuating maternal chronic physiological stress, and improving child behavior in toddlerhood. CLINICAL TRIAL REGISTRATION: NCT01852695.

Mortality and significant neurosensory impairment in preterm infants: an international comparison.

OBJECTIVE: To compare mortality and rates of significant neurosensory impairment (sNSI) at 18-36 months' corrected age in infants born extremely preterm across three international cohorts. DESIGN: Retrospective analysis of prospectively collected neonatal and follow-up data. SETTING: Three population-based observational cohort studies: the Australian and New Zealand Neonatal Network (ANZNN), the Canadian Neonatal and Follow-up Networks (CNN/CNFUN) and the French cohort Etude (Epidémiologique sur les Petits Ages Gestationnels: EPIPAGE-2). PATIENTS: Extremely preterm neonates of <28 weeks' gestation in year 2011. MAIN OUTCOME MEASURES: Primary outcome was composite of mortality or sNSI defined by cerebral palsy with no independent walking, disabling hearing loss and bilateral blindness. RESULTS: Overall, 3055 infants (ANZNN n=960, CNN/CNFUN n=1019, EPIPAGE-2 n=1076) were included in the study. Primary composite outcome rates were 21.3%, 20.6% and 28.4%; mortality rates were 18.7%, 17.4% and 26.3%; and rates of sNSI among survivors were 4.3%, 5.3% and 3.3% for ANZNN, CNN/CNFUN and EPIPAGE-2, respectively. Adjusted for gestational age and multiple births, EPIPAGE-2 had higher odds of composite outcome compared with ANZNN (OR 1.71, 95% CI 1.38 to 2.13) and CNN/CNFUN (OR 1.72, 95% CI 1.39 to 2.12). EPIPAGE-2 did have a trend of lower odds of sNDI but far short of compensating for the significant increase in mortality odds. These differences may be related to variations in perinatal approach and practices (and not to differences in infants' baseline characteristics). CONCLUSIONS: Composite outcome of mortality or sNSI for extremely preterm infants differed across high-income countries with similar baseline characteristics and access to healthcare.

Hippocampus, Amygdala, and Thalamus Volumes in Very Preterm Children at 8 Years: Neonatal Pain and Genetic Variation.

Altered hippocampal morphology and reduced volumes have been found in children born preterm compared to full-term. Stress inhibits neurogenesis in the hippocampus, and neonatal stress/noxious stimulation in rodent pups are associated with long-term alterations in hippocampal volumes. We have previously shown reduced cortical thickness and cerebellar volumes in relation to more exposure to pain-related stress of neonatal invasive procedures in children born very preterm. We have reported targeted gene-by-pain environment interactions that contribute to long-term brain development and outcomes in this population. We now aim to determine whether exposure to pain-related stress (adjusted for clinical factors and genotype) differentially impacts regional structures within the limbic system and thalamus, and investigate relationships with outcomes in very preterm children. Our study included 57 children born very preterm (<32 weeks GA) followed longitudinally from birth who underwent 3-D T1 MRI neuroimaging at ∼8 years. Hippocampal subfields and white matter tracts, thalamus and amygdala were automatically segmented using the MAGeT Brain algorithm. The relationship between those subcortical brain volumes (adjusted for total brain volume) and neonatal invasive procedures, gestational age (GA), illness severity, postnatal infection, days of mechanical ventilation, number of surgeries, morphine exposure, and genotype (COMT, SLC6A4, and BDNF) was examined using constrained principal component analysis. We found that neonatal clinical factors and genotypes accounted for 46% of the overall variance in volumes of hippocampal subregions, tracts, basal ganglia, thalamus and amygdala. After controlling for clinical risk factors and total brain volume, greater neonatal invasive procedures was associated with lower volumes in the amygdala and thalamus (p = 0.0001) and an interaction with COMT genotype predicted smaller hippocampal subregional volume (p = 0.0001). More surgeries, days of ventilation, and lower GA were also related to smaller volumes in various subcortical regions (p < 0.002). These reduced volumes were in turn differentially related to poorer cognitive, visual-motor and behavioral outcomes. Our findings highlight the complexity that interplays when examining how exposure to early-life stress may impact brain development both at the structural and functional level, and provide new insight on possible novel avenues of research to discover brain-protective treatments to improve the care of children born preterm.

Morphine biotransformation genes and neonatal clinical factors predicted behaviour problems in very preterm children at 18 months.

BACKGROUND: Behaviour problems are prevalent among children born very preterm (≤ 32 weeks gestation), and have been associated with morphine exposure. Morphine accumulation in the brain is determined by genetic variations related to morphine biotransformation. The objective of the study was to investigate whether morphine-biotransformation genotypes contribute to individual differences in long-term effects of morphine on behaviour at 18 months corrected age (CA). METHODS: 198 children born very preterm (24-32 weeks gestation) were followed from birth and seen at 18 months CA. Relationships between child behavior (Internalizing, Externalizing on the Child Behavior Checklist), morphine exposure, neonatal clinical variables, and morphine biotransformation gene variants in ABCB1, UGT1A9, UGT 2B7*2, ABCC2, ABCC3, SLCO1B1, CYP3A4, COMT were examined. FINDINGS: Neonatal clinical predictors and genotypes accounted for 39% of the overall variance in behaviour. In children with the minor allele of UGT1A9 rs17863783 (marker of UGT1A6*4, UDP-glucuronosyltransferase), greater morphine exposure (p = ·0011) was associated with more Internalizing behaviour. More Externalizing behaviour was predicted by greater morphine exposure in children with the COMT rs4680 Met/Met genotype (p = ·0006). INTERPRETATION: Genetic variations that affect relative accumulation of morphine in the brain, together with neonatal clinical factors, are differentially related to anxiety and depressive symptoms (internalizing) and to acting out (externalizing) behaviours at 18 months CA in children born very preterm. FUND: NIH/NICHD HD039783 (REG); CIHR MOP86489 (REG), MOP68898 (SPM), MOP79262 (SPM, REG).

Predictive connectome subnetwork extraction with anatomical and connectivity priors.

We present a new method to identify anatomical subnetworks of the human connectome that are optimally predictive of targeted clinical variables, developmental outcomes or disease states. Given a training set of structural or functional brain networks, derived from diffusion MRI (dMRI) or functional MRI (fMRI) scans respectively, our sparse linear regression model extracts a weighted subnetwork. By enforcing novel backbone network and connectivity based priors along with a non-negativity constraint, the discovered subnetworks are simultaneously anatomically plausible, well connected, positively weighted and reasonably sparse. We apply our method to (1) predicting the cognitive and neuromotor developmental outcomes of a dataset of 168 structural connectomes of preterm neonates, and (2) predicting the autism spectrum category of a dataset of 1013 resting-state functional connectomes from the Autism Brain Imaging Data Exchange (ABIDE) database. We find that the addition of each of our novel priors improves prediction accuracy and together outperform other state-of-the-art prediction techniques. We then examine the structure of the learned subnetworks in terms of topological features and with respect to established function and physiology of different regions of the brain.

CHIPS-Child: Testing the developmental programming hypothesis in the offspring of the CHIPS trial.

OBJECTIVES: As a follow-up to the CHIPS trial (Control of Hypertension In Pregnancy Study) of 'less tight' (versus 'tight') control of maternal blood pressure in pregnancy, CHIPS-Child investigated potential developmental programming of maternal blood pressure control in pregnancy, by examining measures of postnatal growth rate and hypothalamic-pituitary adrenal (HPA) axis activation. METHODS: CHIPS follow-up was extended to 12 ±â€¯2 months corrected post-gestational age for anthropometry (weight, length, head/waist circumference). For eligible children with consent for a study visit, we collected biological samples (hair/buccal samples) to evaluate HPA axis function (hair cortisol levels) and epigenetic change (DNA methylation analysis of buccal cells). The primary outcome was 'change in z-score for weight' between birth and 12 ±â€¯2 mos. Secondary outcomes were hair cortisol and genome-wide DNA methylation status. RESULTS: Of 683 eligible babies, 183 (26.8%) were lost to follow-up, 83 (12.2%) declined, 3 (0.4%) agreed only to ongoing contact, and 414 (60.6%) consented. 372/414 (89.9%) had weight measured at 12mos. In 'less tight' (vs. 'tight') control, the primary outcome was similar [-0.26 (-0.53, +0.01); p = 0.14, padjusted = 0.06]; median (95% confidence interval) hair cortisol (N = 35 samples) was lower [-496 (-892, -100) ng/g; p = 0.02], and buccal swab DNA methylation (N = 16 samples) was similar. No differences in growth rate could be demonstrated up to 5 years. CONCLUSIONS: Results demonstrate no compelling evidence for developmental programming of growth or the HPA axis. Clinicians should look to the clinical findings of CHIPS to guide practice. Researchers should seek to replicate these findings and extend outcomes to paediatric blood pressure and neurodevelopment.

Intrapartum magnesium sulfate is associated with neuroprotection in growth-restricted fetuses.

BACKGROUND: Intrapartum magnesium sulfate administration is recommended for fetal neuroprotection in women with imminent very preterm birth. However, previous studies have not included or separately analyzed the outcomes of pregnancies with fetal growth restriction that were treated with intrapartum magnesium sulfate. OBJECTIVE: We sought to evaluate the neonatal and neurodevelopmental outcomes of growth-restricted fetuses born <29 weeks' gestation and exposed to maternal intrapartum magnesium sulfate. STUDY DESIGN: We conducted a retrospective cohort study of infants born <29 weeks' gestation from 2010 through 2011, admitted to participating Canadian Neonatal Network units, and followed by the Canadian Neonatal Follow-up Network centers. Growth restriction was defined either as estimated fetal or actual neonatal birthweight <10th percentile according to fetal or neonatal growth standards for gestational age and sex, respectively. Infants exposed to intrapartum magnesium sulfate were compared with unexposed infants. The primary outcome was composite of death or significant neurodevelopmental impairment at 18-36 months' corrected age. Secondary outcomes were death or any neurodevelopmental impairment at 18-36 months' corrected age. Neonatal morbidities were also compared. RESULTS: Of the 336 growth-restricted fetuses, 112 (33%) received magnesium sulfate and of the 177 growth-restricted infants, 61 (34%) received magnesium sulfate. Administration of magnesium sulfate was at the discretion of the treating physician. Intrapartum magnesium sulfate was associated with reduced odds of composite of death or significant neurodevelopmental impairment for infants classified according to both fetal standards (adjusted odds ratio, 0.42; 95% confidence interval, 0.22-0.80) and neonatal standards (adjusted odds ratio, 0.44; 95% confidence interval, 0.20-0.98). CONCLUSION: Intrapartum administration of magnesium sulfate to women with growth-restricted fetuses born <29 weeks' gestation was associated with reduced odds of composite of death or significant neurodevelopmental impairment.

Association of admission temperature and death or adverse neurodevelopmental outcomes in extremely low-gestational age neonates.

OBJECTIVE: Preterm infants are at higher risk of developing hypothermia and complications from cold stress, resulting in high mortality and short-term morbidity. Our objective is to evaluate the association between admission temperatures of extremely low-gestational age neonates (ELGAN) (<29 weeks') and adverse short-term neurodevelopmental outcomes. STUDY DESIGN: In this retrospective study, we included ELGAN admitted to NICUs across Canada between April 2009 and September 2011, who underwent neurodevelopmental assessment at 18-21 months' corrected age. RESULTS: Of 2739 infants with a complete data set identified during the study period, 968 (35.3%) had admission temperatures ≤36.4 °C (hypothermia group), 1489 (54.5%) had temperature of 36.5-37.2 °C (normothermia group), and 282 (10.3%) had hyperthermia (≥37.3 °C). Their mean birth weight was 823 ± 230 g, 944 ± 227 g and 927 ± 223 g, respectively (p < 0.01). More than 50% of infants born at 23-24 weeks were in the hypothermic group compared to 28.5-36.1% at higher gestational ages. We found 39.5% of infants in the hypothermic group had primary composite outcome of death or severe neurodevelopmental impairment (sNDI). Multivariate logistic regression revealed an increased adjusted odd of primary composite outcome (OR = 1.32; 95% CI = [1.05, 1.66]) in the hypothermic group, compared to infants with normothermia on admission. CONCLUSIONS: In our cohort of ELGAN, hypothermia on admission was associated with increased risk of death or sNDI.

MAGnesium sulphate for fetal neuroprotection to prevent Cerebral Palsy (MAG-CP)-implementation of a national guideline in Canada.

BACKGROUND: Evidence supports magnesium sulphate (MgSO4) for women at risk of imminent birth at < 32-34 weeks to reduce the likelihood of cerebral palsy in the child. MAGnesium sulphate for fetal neuroprotection to prevent Cerebral Palsy (MAG-CP) was a multifaceted knowledge translation (KT) strategy for this practice. METHODS: The KT strategy included national clinical practice guidelines, a national online e-learning module and, at MAG-CP sites, educational rounds, focus group discussions and surveys of barriers and facilitators. Participating sites contributed data on pregnancies with threatened very preterm birth. In an interrupted time-series study design, MgSO4 use for fetal neuroprotection (NP) was tracked prior to (Aug 2005-May 2011) and during (Jun 2011-Sept 2015) the KT intervention. Effectiveness of the strategy was measured by optimal MgSO4 use (i.e. administration when and only when indicated) over time, evaluated by a segmented generalised estimating equations logistic regression (p < 0.05 significant). Secondary outcomes included maternal effects and, using the Canadian Neonatal Network (CNN) database, national trends in MgSO4 use for fetal NP and associated neonatal resuscitation. With an anticipated recruitment of 3752 mothers over 4 years at Canadian Perinatal Network sites, we anticipated > 95% power to detect an increase in optimal MgSO4 use for fetal NP from < 5 to 80% (2-sided, alpha 0.05) and at least 80% power to detect any increases observed in maternal side effects from RCTs. RESULTS: Seven thousand eight hundred eighty-eight women with imminent preterm birth were eligible for MgSO4 for fetal NP: 4745 pre-KT (18 centres) and 3143 during KT (11 centres). The KT intervention was associated with an 84% increase in the odds of optimal use (OR 1.00 to 1.84, p < 0.001), a reduction in the odds of underuse (OR 1.00 to 0.47, p < 0.001) and an increase in suboptimal use (too early or at ≥ 32 weeks; OR 1.18 to 2.18, p < 0.001) of MgSO4 for fetal NP. Maternal hypotension was uncommon (7/1512, 0.5%). Nationally, intensive neonatal resuscitation decreased (p = 0.024) despite rising MgSO4 use for fetal NP (p < 0.001). CONCLUSION: Multifaceted KT was associated with significant increases in use of MgSO4 for fetal NP, with neither important maternal nor neonatal risks.