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.

How to measure patient and family important outcomes in extremely preterm infants: A scoping review.

AIM: Parents of children born preterm have identified outcomes to be measured for audit and research at 18-24 months of age: child well-being, quality of life/function, socio-emotional/behavioural outcomes, respiratory, feeding, sleeping, and caregiver mental health. The aim was to identify the best tools to measure these seven domains. METHODS: Seven working groups completed literature reviews and evaluated potential tools to measure these outcomes in children aged 18-24 months. A group of experts and parents voted on the preferred tools in a workshop and by questionnaire. Consensus was 80% agreement. RESULTS: Consensus was obtained for seven brief, inexpensive, parent friendly valid measures available in English or French for use in a minimum dataset and potential alternative measures for use in funded research. CONCLUSION: Valid questionnaires and tools to measure parent-identified outcomes in young preterm children exist. This study will facilitate research and collection of data important to families.

Size and Location of Preterm Brain Injury and Associations With Neurodevelopmental Outcomes.

BACKGROUND AND OBJECTIVES: We examined associations of white matter injury (WMI) and periventricular hemorrhagic infarction (PVHI) volume and location with 18-month neurodevelopment in very preterm infants. METHODS: A total of 254 infants born <32 weeks' gestational age were prospectively recruited across 3 tertiary neonatal intensive care units (NICUs). Infants underwent early-life (median 33.1 weeks) and/or term-equivalent-age (median 41.9 weeks) MRI. WMI and PVHI were manually segmented for quantification in 92 infants. Highest maternal education level was included as a marker of socioeconomic status and was defined as group 1 = primary/secondary school; group 2 = undergraduate degree; and group 3 = postgraduate degree. Eighteen-month neurodevelopmental assessments were completed with Bayley Scales of Infant and Toddler Development, Third Edition. Adverse outcomes were defined as a score of less than 85 points. Multivariable linear regression models were used to examine associations of brain injury (WMI and PVHI) volume with neurodevelopmental outcomes. Voxel-wise lesion symptom maps were developed to assess relationships between brain injury location and neurodevelopmental outcomes. RESULTS: Greater brain injury volume was associated with lower 18-month Motor scores (ß = -5.7, 95% CI -9.2 to -2.2, p = 0.002) while higher maternal education level was significantly associated with higher Cognitive scores (group 3 compared 1: ß = 14.5, 95% CI -2.1 to 26.9, p = 0.03). In voxel-wise lesion symptom maps, brain injury involving the central and parietal white matter was associated with an increased risk of poorer motor outcomes. DISCUSSION: We found that brain injury volume and location were significant predictors of motor, but not cognitive outcomes, suggesting that different pathways may mediate outcomes across domains of neurodevelopment in preterm infants. Specifically, assessing lesion size and location may allow for more accurate identification of infants with brain injury at highest risk of poorer motor outcomes. These data also highlight the importance of socioeconomic status in cognitive outcomes, even in preterm infants with brain injury.

A longitudinal observational study on the epidemiology of painful procedures and sucrose administration in hospitalized preterm neonates.

Although sucrose is widely administered to hospitalized infants for single painful procedures, total sucrose volume during the entire neonatal intensive care unit (NICU) stay and associated adverse events are unknown. In a longitudinal observation study, we aimed to quantify and contextualize sucrose administration during the NICU stay. Specifically, we investigated the frequency, nature, and severity of painful procedures; proportion of procedures where neonates received sucrose; total volume of sucrose administered for painful procedures; and incidence and type of adverse events. Neonates <32 weeks gestational age at birth and <10 days of life were recruited from four Canadian tertiary NICUs. Daily chart reviews of documented painful procedures, sucrose administration, and any associated adverse events were undertaken. One hundred sixty-eight neonates underwent a total of 9093 skin-breaking procedures (mean 54.1 [±65.2] procedures/neonate or 1.1 [±0.9] procedures/day/neonate) during an average NICU stay of 45.9 (±31.4) days. Pain severity was recorded for 5399/9093 (59.4%) of the painful procedures; the majority (5051 [93.5%]) were heel lances of moderate pain intensity. Sucrose was administered for 7839/9093 (86.2%) of painful procedures. The total average sucrose volume was 5.5 (±5.4) mL/neonate or 0.11 (±0.08) mL/neonate/day. Infants experienced an average of 7.9 (±12.7) minor adverse events associated with pain and/or sucrose administration that resolved without intervention. The total number of painful procedures, sucrose volume, and incidence of adverse events throughout the NICU stay were described addressing an important knowledge gap in neonatal pain. These data provide a baseline for examining the association between total sucrose volume during NICU stay and research on longer-term behavioral and neurodevelopmental outcomes.

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.