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.

Preterm Neurodevelopmental Trajectories from 18 Months to 4.5 Years.

OBJECTIVE: To assess the longitudinal trajectory of cognitive, language, and motor outcomes from 18 months to 4.5 years of age in children born very preterm. STUDY DESIGN: This was a prospective cohort study of 163 infants born very preterm (born 24-32 weeks of gestation) followed longitudinally and assessed with neurodevelopmental scales and magnetic resonance imaging of the brain. Outcomes at 18 months and 3 years were assessed with the Bayley Scales of Infant and Toddler Development, 3rd Edition, and at 4.5 years with the Wechsler Preschool and Primary Scale of Intelligence-III and the Movement Assessment Battery for Children. Cognitive, language, and motor outcomes were categorized as below-average, average, and above-average, and compared across time. Clinical data were analyzed using ANOVA, χ2 tests, and linear regression. RESULTS: Cognitive and language trajectories were stable from 18 months to 4.5 years for all outcome groups. Motor impairment increased over time, with a greater proportion of children having motor deficits at 4.5 years. Children with below-average cognitive and language outcomes at 4.5 years had more clinical risk factors, greater white matter injury, and lower maternal education. Children with severe motor impairment at 4.5 years were born earlier, had more clinical risk factors, and demonstrated greater white matter injury. CONCLUSIONS: Children born preterm have stable cognitive and language trajectories, while motor impairment increased at 4.5 years. These results highlight the importance of continued developmental surveillance for children born preterm into preschool age.

Guilt and Regret Experienced by Parents of Children Born Extremely Preterm.

OBJECTIVES: To explore decisional regret of parents of babies born extremely preterm and analyze neonatal, pediatric, and parental factors associated with regret. STUDY DESIGN: Parents of infants born <29 weeks of gestational age, aged between 18 months and 7 years, attending neonatal follow-up were enrolled. Hospital records were reviewed to examine morbidities and conversations with parents about levels of care. Parents were asked the following question: "Knowing what you know now, is there anything you would have done differently?" Mixed methods were used to analyze responses. RESULTS: In total, 248 parents (98% participation) answered, and 54% reported they did not have regret. Of those who reported regret (n = 113), 3 themes were most frequently invoked: 35% experienced guilt, thinking they were responsible for the preterm birth; 28% experienced regret about self-care decisions; and 20% regretted decisions related to their parental role, generally wishing they knew sooner how to get involved. None reported regret about life-and-death decisions made at birth or in the neonatal intensive care unit. Impairment at follow-up, gestational age, and decisions about levels/reorientation of care were not associated with regret. More mothers reported feeling guilt about the preterm birth (compared with fathers); parents of children with severe lesions on ultrasonography of the head were less likely to report regret. CONCLUSIONS: Approximately one-half of the parents of infants born extremely preterm had regrets regarding their neonatal intensive care unit stay. Causes of regret and guilt should be addressed and minimized.

Does Growth Velocity Affect Associations between Birth Weight and Neurodevelopment for Infants Born Very Preterm?

OBJECTIVE: To determine how neonatal growth velocity affects the association between birth weight and neurodevelopmental outcomes in infants born preterm. STUDY DESIGN: This study is a secondary analysis of the Maternal Omega-3 Supplementation to Reduce Bronchopulmonary Dysplasia in Very Preterm Infants (MOBYDIck) randomized multicenter trial conducted in breastfed infants born at <29 weeks of gestation, whose mothers were supplemented with docosahexaenoic acid or placebo during the neonatal period. Neurodevelopmental outcomes were assessed at 18-22 months of corrected age using the Bayley-III cognitive and language composite scores. The role of neonatal growth velocity was assessed with causal mediation and linear regression models. Subgroup analyses were stratified by birth weight z-score categories (<25th, ≥25th-≤75th, and >75th percentiles). RESULTS: Neurodevelopmental outcomes were available for 379 children (mean gestational age, 26.7 ± 1.5 weeks). Growth velocity partially mediated the relationships between birth weight and cognitive (ß = -1.1; 95% CI, -2.2 to -0.02; P = .05) and language scores (ß = -2.1; 95% CI, -3.3 to -0.8; P = .002). An increase by 1 g/kg/day in growth velocity was associated with an increase by 1.1 point in the cognitive score (95% CI, -0.03 to 2.1; P = .06) and 1.9 point in the language score (95% CI, 0.7 to 3.1; P = .001), after adjustment for birth weight z-score. For children with birth weight <25th percentile, a 1 g/kg/day increase in growth velocity was associated with an increase by 3.3 points in the cognitive score (95% CI, 0.5 to 6.0; P = .02) and 4.1 points in the language score (95% CI, 1.3 to 7.0; P = .004). CONCLUSIONS: Postnatal growth velocity mediated the relationship between birth weight and neurodevelopmental performance, with larger effects for children with lower birth weight. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02371460.

Lethal respiratory course and additional features expand the phenotypic spectrum of PIEZO2-related distal arthrogryposis type 5.

Distal arthrogryposes (DA) are a group of conditions presenting with multiple congenital contractures in the distal joints. The 10 types of DA are distinguished by different extra-articular manifestations. Heterozygous gain-of-function variants in PIEZO2 are known to cause a spectrum of DA conditions including DA type 3, DA type 5, and possibly Marden Walker syndrome, which are usually distinguished by the presence of cleft palate (DA3), ptosis and restriction in eye movements (DA5), and specific facial abnormalities and central nervous system involvement, respectively. We report on a boy with a recurrent de novo heterozygous PIEZO2 variant in exon 20 (NM_022068.3: c.2994G > A, p.(Met998Ile); NM_001378183.1: c.3069G > A, p.(Met1023Ile)), who presented at birth with DA and later developed respiratory insufficiency. His phenotype broadly fits the PIEZO2 phenotypic spectrum and potentially extends it with novel phenotypic features of pretibial linear vertical crease, immobile skin, immobile tongue, and lipid myopathy.

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.

Parental perspectives of outcomes following very preterm birth: Seeing the good, not just the bad.

AIM: To describe parental perspective on health and developmental outcomes of their preterm child in relation to level of neurodevelopmental impairment (NDI). METHODS: A parental survey about their children aged 15-36 months corrected age born ˂29 weeks' gestation investigated parental concerns and positive attributes. Parental responses in relation to their child's level of NDI were examined using Kruskal-Wallis and chi-square for trend tests. RESULTS: One hundred ninety-nine parental responses were obtained for 163 children, including 44% with NDI. Vast majority of parents reported their children were developing well with good physical health. All parents, irrespective of NDI, reported their children were happy and had a positive personality. Appreciation of social interactions was higher for parents of children without versus with NDI (96% vs. 87%, p = 0.039). Parents of children with NDI were more likely to express concerns than those without NDI. Overall, development was the most common area of concern (45%), followed by the child's future (40%) and physical health (35%). CONCLUSION: Parents of preterm children report many positive points and concerns, some of which are not examined in neonatal follow-up data. These parental perspectives could be used to inform parents of preterm infants, both antenatally and in the neonatal unit.

Neurodevelopmental Outcomes of Infants at <29 Weeks of Gestation Born in Canada Between 2009 and 2016.

OBJECTIVE: To evaluate changes in mortality or significant neurodevelopmental impairment (NDI) in children born at <29 weeks of gestation in association with national quality improvement initiatives. STUDY DESIGN: This longitudinal cohort study included children born at 220/7 to 286/7 weeks of gestation who were admitted to Canadian neonatal intensive care units between 2009 and 2016. The primary outcome was a composite rate of death or significant NDI (Bayley Scales of Infant and Toddler Development, Third Edition score <70, severe cerebral palsy, blindness, or deafness requiring amplification) at 18-24 months corrected age. To evaluate temporal changes, outcomes were compared between epoch 1 (2009-2012) and epoch 2 (2013-2016). aORs were calculated for differences between the 2 epochs accounting for differences in patient characteristics. RESULTS: The 4426 children included 1895 (43%) born in epoch 1 and 2531 (57%) born in epoch 2. Compared with epoch 1, in epoch 2 more mothers received magnesium sulfate (56% vs 28%), antibiotics (69% vs 65%), and delayed cord clamping (37% vs 31%) and fewer infants had a Score for Neonatal Acute Physiology, version II >20 (31% vs 35%) and late-onset sepsis (23% vs 27%). Death or significant NDI occurred in 30% of children in epoch 2 versus 32% of children in epoch 1 (aOR, 0.86; 95% CI, 0.75-0.99). In epoch 2, there were reductions in the need for hearing aids or cochlear implants (1.4% vs 2.6%; aOR, 0.50; 95% CI, 0.31-0.82) and in blindness (0.6% vs.1.4%; aOR, 0.38; 95% CI, 0.18-0.80). CONCLUSIONS: Among preterm infants born at <29 weeks of gestation, composite rates of death or significant NDI and rates of visual and hearing impairment were significantly lower in 2013-2016 compared with 2009-2012.

Ventricular Volume in Infants Born Very Preterm: Relationship with Brain Maturation and Neurodevelopment at Age 4.5 Years.

OBJECTIVE: To evaluate the relationship of quantitative ventricular volume with brain maturation and neurodevelopmental outcomes at age 4.5 years in children born very preterm. STUDY DESIGN: T1-weighted imaging, diffusion tensor imaging, and magnetic resonance spectroscopy were performed shortly after birth (n = 212) and at term-equivalent age (TEA) (n = 194). Intraventricular hemorrhage (IVH) grade and white matter injury (WMI) volume were measured on early T1-weighted magnetic resonance imaging (MRI) scans. Total cerebral volume and ventricular volume were quantified using the Multiple Automatically Generated Templates-Brain pipeline. At age 4.5 years, 178 children (84%) underwent cognitive and motor assessments. Multivariable linear regression was used to examine the relationships between ventricular volume and neurodevelopmental outcomes. Generalized estimating equations were used to account for repeated measures when analyzing neonatal MRI data. All models accounted for sex, postmenstrual age at scan, WMI volume, IVH grade, and total cerebral volume and were corrected for multiple comparisons. RESULTS: On early MRI, 97 infants had IVH (grade 1, n = 22; grade 2, n = 66; grade 3, n = 9), and 68 had WMI (median, 44 mm3; IQR, 21-296 mm3). IQ at 4.5 years was associated with MRI ventricular volume at the early (ß = -0.64; P < .001) and TEA (ß = -0.44, P < .001) time points. Motor outcomes were associated with ventricular volume at TEA (ß = -0.84, P = .01). Greater ventricular volume independently predicted lower fractional anisotropy in corpus callosum (genu: ß = -0.0008, P = .002; splenium: ß = -0.003, P < .001) and optic radiations (ß = -0.001, P = .004); ventricular volume did not predict the N-acetylaspartate/choline ratio. CONCLUSIONS: In children born very preterm, neonatal ventricular size was associated with 4.5-year neurodevelopmental outcomes. Our findings suggest that white matter maturation may be abnormal in the setting of enlarged ventricular size beyond that expected from concurrent brain injuries.

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.

Interaction between Preterm White Matter Injury and Childhood Thalamic Growth.

OBJECTIVE: The purpose of this study was to determine how preterm white matter injury (WMI) and long-term thalamic growth interact to predict 8-year neurodevelopmental outcomes. METHODS: A prospective cohort of 114 children born at 24 to 32 weeks' gestational age (GA) underwent structural and diffusion tensor magnetic resonance imaging early in life (median 32 weeks), at term-equivalent age and at 8 years. Manual segmentation of neonatal WMI was performed on T1-weighted images and thalamic volumes were obtained using the MAGeT brain segmentation pipeline. Cognitive, motor, and visual-motor outcomes were evaluated at 8 years of age. Multivariable regression was used to examine the relationship among neonatal WMI volume, school-age thalamic volume, and neurodevelopmental outcomes. RESULTS: School-age thalamic volumes were predicted by neonatal thalamic growth rate, GA, sex, and neonatal WMI volume (p < 0.0001). After accounting for total cerebral volume, WMI volume remained associated with school-age thalamic volume (ß = -0.31, p = 0.005). In thalamocortical tracts, fractional anisotropy (FA) at term-equivalent age interacted with early WMI volume to predict school-age thalamic volumes (all p < 0.02). School-age thalamic volumes and neonatal WMI interacted to predict full-scale IQ (p = 0.002) and adverse motor scores among those with significant WMI (p = 0.01). Visual-motor scores were predicted by thalamic volumes (p = 0.04). INTERPRETATION: In very preterm-born children, neonatal thalamic growth and WMI volume predict school-age thalamic volumes. The emergence at term of an interaction between FA and WMI to impact school-age thalamic volume indicates dysmaturation as a mechanism of thalamic growth failure. Cognition is predicted by the interaction of WMI and thalamic growth, highlighting the need to consider multiple dimensions of brain injury in these children. ANN NEUROL 2021;90:584-594.

Location and Size of Preterm Cerebellar Hemorrhage and Childhood Development.

OBJECTIVE: To examine the association between cerebellar hemorrhage (CBH) size and location and preschool-age neurodevelopment in very preterm neonates. METHODS: Preterm magnetic resonance images of 221 very preterm neonates (median gestational age = 27.9 weeks) were manually segmented for CBH quantification and location. Neurodevelopmental assessments at chronological age 4.5 years included motor (Movement Assessment Battery for Children, 2nd Edition [MABC-2]), visuomotor integration (Beery-Buktenica Developmental Test of Visual-Motor Integration, 6th Edition), cognitive (Wechsler Primary and Preschool Scale of Intelligence, 3rd Edition), and behavioral (Child Behavior Checklist) outcomes. Multivariable linear regression models examined the association between CBH size and 4.5-year outcomes accounting for sex, gestational age, and supratentorial injury. Probabilistic maps assessed CBH location and likelihood of a lesion to predict adverse outcome. RESULTS: Thirty-six neonates had CBH: 14 (6%) with only punctate CBH and 22 (10%) with ≥1 larger CBH. CBH occurred mostly in the inferior aspect of the posterior lobes. CBH total volume was independently associated with MABC-2 motor scores at 4.5 years (ß = -0.095, 95% confidence interval = -0.184 to -0.005), with a standardized ß coefficient (-0.16) that was similar to that of white matter injury volume (standardized ß = -0.22). CBH size was similarly associated with visuomotor integration and externalizing behavior but not cognition. Voxelwise odds ratio and lesion-symptom maps demonstrated that CBH extending more deeply into the cerebellum predicted adverse motor, visuomotor, and behavioral outcomes. INTERPRETATION: CBH size and location on preterm magnetic resonance imaging were associated with reduced preschool motor and visuomotor function and more externalizing behavior independent of supratentorial brain injury in a dose-dependent fashion. The volumetric quantification and localization of CBH, even when punctate, may allow opportunity to improve motor and behavioral outcomes by providing targeted intervention. ANN NEUROL 2020;88:1095-1108.

Neurodevelopmental outcomes of preterm infants conceived by assisted reproductive technology.

BACKGROUND: There have been concerns about the development of children conceived through assisted reproductive technology. Despite multiple studies investigating the outcomes of assisted conception, data focusing specifically on the neurodevelopmental outcomes of infants conceived through assisted reproductive technology and born preterm are limited. OBJECTIVE: This study aimed to evaluate and compare the neurodevelopmental outcomes of preterm infants born at <29 weeks' gestation at 18 to 24 months' corrected age who were conceived through assisted reproductive technology and those who were conceived naturally. STUDY DESIGN: This retrospective cohort study included inborn, nonanomalous infants, born at <29 weeks' gestation between January 1, 2010, and December 31, 2016, who had a neurodevelopmental assessment at 18 to 24 months' corrected age at any of the 10 Canadian Neonatal Follow-Up Network clinics. The primary outcome was neurodevelopmental impairment at 18 to 24 months, defined as the presence of any of the following: cerebral palsy; Bayley-III cognitive, motor, or language composite score of <85; sensorineural or mixed hearing loss; and unilateral or bilateral visual impairment. Secondary outcomes included mortality, composite of mortality or neurodevelopmental impairment, significant neurodevelopmental impairment, and each component of the primary outcome. We compared outcomes between infants conceived through assisted reproductive technology and those conceived naturally, using bivariate and multivariable analyses after adjustment. RESULTS: Of the 4863 eligible neonates, 651 (13.4%) were conceived using assisted reproductive technology. Maternal age; education level; and rates of diabetes mellitus, receipt of antenatal corticosteroids, and cesarean delivery were higher in the assisted reproduction group than the natural conception group. Neonatal morbidity and death rates were similar except for intraventricular hemorrhage, which was lower in the assisted reproduction group (33% [181 of 546] vs 39% [1284 of 3318]; P=.01). Of the 4176 surviving infants, 3386 (81%) had a follow-up outcome at 18 to 24 months' corrected age. Multivariable logistic regression adjusting for gestational age, antenatal steroids, sex, small for gestational age, multiple gestations, mode of delivery, maternal age, maternal education, pregnancy-induced hypertension, maternal diabetes mellitus, and smoking showed that infants conceived through assisted reproduction was associated with lower odds of neurodevelopmental impairment (adjusted odds ratio, 0.67; 95% confidence interval, 0.52-0.86) and the composite of death or neurodevelopmental impairment (adjusted odds ratio, 0.67; 95% confidence interval, 0.54-0.84). Conception through assisted reproductive technology was associated with decreased odds of a Bayley-III composite cognitive score of <85 (adjusted odds ratio, 0.68; 95% confidence interval, 0.48-0.99) and composite language score of <85 (adjusted odds ratio, 0.67; 95% confidence interval, 0.50-0.88). CONCLUSION: Compared with natural conception, assisted conception was associated with lower odds of adverse neurodevelopmental outcomes, especially cognitive and language outcomes, at 18 to 24 months' corrected age among preterm infants born at <29 weeks' gestation. Long-term follow-up studies are required to assess the risks of learning disabilities and development of complex visual-spatial and processing skills in these children as they reach school age.

Longitudinal neurodevelopmental outcomes in preterm twins.

BACKGROUND: Several factors contribute to neurodevelopmental outcomes in preterm infants. The aim of this study was to examine the genetic and environmental influences on long-term outcomes in preterm twins. METHODS: From a prospective cohort of 225 preterm neonates studied with MRI, 24 monozygotic and 52 dizygotic twins were included. Neurodevelopmental outcomes at 1.5 and 3 years were assessed with the Bayley-III and at 4.5 years with The Movement Assessment Battery for Children and The Wechsler Preschool and Primary Scale of Intelligence-III. RESULTS: Preterm monozygotic and dizygotic twin pairs (N = 76 neonates) had similar neurodevelopmental outcomes at all time points. Monozygotic twins (N = 24) did not show greater agreement for outcomes relative to dizygotic twins (N = 52). Twin pairs who were discordant in development (N = 12) were born at a lower gestational age and had a higher incidence of bronchopulmonary dysplasia and retinopathy of prematurity. Discordant twins become more similar in cognitive and language outcomes over time. CONCLUSIONS: Neurodevelopmental outcomes in preterm twins may relate more strongly to environmental factors than genetics. Discordant twins were born earlier and had more perinatal morbidities. Despite the initial discordance, these twin pairs become similar in outcomes over time, which may reflect the positive impact of home environment or early intervention programs. IMPACT: Neurodevelopmental outcomes in preterm twins relate more strongly to environmental factors than genetics. Monozygotic twins did not show greater agreement in outcomes relative to dizygotic twins suggesting a stronger environmental, rather than genetic, influence on development. Twin pairs who were discordant in development were born at a lower gestational age and had a higher incidence of perinatal morbidities. Despite the initial discordance, these twin pairs become more similar in cognitive and language outcomes over time, which may reflect the positive impact of early intervention programs or home environment. Neurodevelopmental outcomes in preterm twins are influenced by exposure to early-life insults or environmental stressors. The initial variability in outcomes among preterm infants is not fixed, and efforts made post-discharge from the neonatal intensive care unit can have a substantial impact on long-term outcomes.

Sensory processing and cortisol at age 4 years: Procedural pain-related stress in children born very preterm.

Children born preterm display altered sensory processing, which may manifest as hyper- and/or hypo-sensitivity to sensory information. In this vulnerable population, exposure to neonatal pain-related stress is associated with altered stress regulation, as indexed by alterations in cortisol levels. It is unknown whether sensory processing behaviors are also affected by early life adversity, and whether dysregulated cortisol is related to sensory processing problems in preterm children. We examined relationships between neonatal pain-related stress, sensory processing profiles and cortisol levels at age 4 years, and whether pathways were sex-specific. In a longitudinal prospective cohort study, N = 146 infants born 24-32 weeks gestational age were recruited from BC Women's Hospital, Vancouver, BC, Canada; neonatal factors were collected from daily chart review. At age 4 years, saliva to assay cortisol was collected three times across cognitive assessment (pre-test, during, end) and parents completed the Short Sensory Profile questionnaire. Using generalized linear modeling, independent of other neonatal factors, higher number of invasive procedures (pain/stress) was associated with more sensory processing problems (total, hypo- and hyper-sensitivity) for girls only. After accounting for neonatal factors, greater cortisol output across the assessment was associated with more total sensory processing problems in girls only, and hypersensitivity to sensory input in both boys and girls. Findings suggest that in children born very preterm, how a child responds to sensory input and cortisol reactivity to stress are related but may have different precursors. Girls may be somewhat more susceptible to neonatal pain-related stress exposure in relation to sensory processing at preschool age.

Neonatal follow-up programs in Canada: A national survey.

BACKGROUND: A 2006 Canadian survey showed a large variability in neonatal follow-up practices. In 2010, all 26 tertiary level Neonatal Follow-Up clinics joined the Canadian Neonatal Follow-Up Network (CNFUN) and agreed to implement a standardized assessment (including the Bayley Scales of Infant and Toddler Development-III (Bayley-III) at 18 months corrected age for children born < 29 weeks' gestation. It is unknown whether the variability in follow-up practices lessened as a result. OBJECTIVES: To describe the current status of neonatal follow-up services in Canada and changes over time. METHODS: A comprehensive online survey was sent to all tertiary level CNFUN Follow-up programs. Questions were based on previous survey results, current literature, and investigator expertise and consensus. RESULTS: Respondents included 23 of 26 (88%) CNFUN programs. All sites provide neurodevelopmental screening and referrals in a multidisciplinary setting with variations in staffing. CNFUN programs vary with most offering five to seven visits. Since 2006, assessments at 18 months CA increased from 84% to 91% of sites, Bayley-III use increased from 21% to 74% (P=0.001) and eligibility for follow-up was expanded for children with stroke, congenital diaphragmatic hernia and select anomalies detected in utero. Audit data is collected by > 80% of tertiary programs. CONCLUSION: Care became more consistent after CNFUN; 18-month assessments and Bayley-III use increased significantly. However, marked variability in follow-up practices persists.

Risk factors for re-hospitalization following neonatal discharge of extremely preterm infants in Canada.

OBJECTIVE: Survivors of extremely preterm birth are at risk of re-hospitalization but risk factors in the Canadian population are unknown. Our objective is to identify neonatal, sociodemographic, and geographic characteristics that predict re-hospitalization in Canadian extremely preterm neonates. METHODS: This is a retrospective analysis of a prospective observational cohort study that included preterm infants born 22 to 28 weeks' gestational age from April 1, 2009 to September 30, 2011 and seen at 18 to 24 months corrected gestational age in a Canadian Neonatal Follow-Up Network clinic. Characteristics of infants re-hospitalized versus not re-hospitalized are compared. The potential neonatal, sociodemographic, and geographic factors with significant association in the univariate analysis are included in a multivariate model. RESULTS: From a total of 2,275 preterm infants born at 22 to 28 weeks gestation included, 838 (36.8%) were re-hospitalized at least once. There were significant disparities between Canadian provincial regions, ranging from 25.9% to 49.4%. In the multivariate logistic regression analysis, factors associated with an increased risk for re-hospitalization were region of residence, male sex, bronchopulmonary dysplasia, necrotizing enterocolitis, prolonged neonatal intensive care unit (NICU) stay, ethnicity, Indigenous ethnicity, and sibling(s) in the home. CONCLUSION: Various neonatal, sociodemographic, and geographic factors predict re-hospitalization of extremely preterm infants born in Canada. The risk factors of re-hospitalization provide insights to help health care leaders explore potential preventative approaches to improve child health and reduce health care system costs.

Association between Transport Risk Index of Physiologic Stability in Extremely Premature Infants and Mortality or Neurodevelopmental Impairment at 18 to 24 Months.

OBJECTIVES: To examine the association between mortality or neurodevelopmental impairment at 18-24 months of corrected age and the Transport Risk Index of Physiologic Stability (TRIPS) score on admission to the neonatal intensive care unit (NICU) in extremely premature infants. STUDY DESIGN: Retrospective cohort study of extremely premature infants (inborn and outborn) born at 22-28 weeks of gestational age and admitted to NICUs in the Canadian Neonatal Network between April 2009 and September 2011. TRIPS scores and clinical data were collected from the Canadian Neonatal Network database. Follow-up data at 18-24 months of corrected age were retrieved from the Canadian Neonatal Follow-Up Network database. Neurodevelopment was assessed using the Bayley Scales of Infant and Toddler Development, Edition III. The primary outcome was death or significant neurodevelopmental impairment at 18-24 months of corrected age. The secondary outcomes were individual components of the Bayley Scales of Infant and Toddler Development, Edition III assessment. RESULTS: A total of 1686 eligible infants were included. A TRIPS score of ≥20 on admission to the NICU was significantly associated with mortality (aOR 2.71 [95% CI, 2.02-3.62]) and mortality or significant neurodevelopmental impairment (aOR 1.91 [95% CI, 1.52-2.41]) at 18-24 months of corrected age across all gestational age groups of extremely premature infants. CONCLUSION: The TRIPS score on admission to the NICU can be used as an adjunctive, objective tool for counselling the parents of extremely premature infants early after their admission to the NICU.

Mechanical Ventilation Duration, Brainstem Development, and Neurodevelopment in Children Born Preterm: A Prospective Cohort Study.

OBJECTIVES: To determine, in children born preterm, the association of mechanical ventilation duration with brainstem development, white matter maturation, and neurodevelopmental outcomes at preschool age. STUDY DESIGN: This prospective cohort study included 144 neonates born at <30 weeks of gestation (75 male, mean gestational age 27.1 weeks, SD 1.6) with regional brainstem volumes automatically segmented on magnetic resonance imaging at term-equivalent age (TEA). The white matter maturation was assessed by diffusion tensor imaging and tract-based spatial statistics. Neurodevelopmental outcomes were assessed at 4.5 years of age using the Movement Assessment Battery for Children, 2nd Edition, and the Wechsler Primary and Preschool Scale of Intelligence, 4th Edition, full-scale IQ. The association between the duration of mechanical ventilation and brainstem development was validated in an independent cohort of children born very preterm. RESULTS: Each additional day of mechanical ventilation predicted lower motor scores (0.5-point decrease in the Movement Assessment Battery for Children, 2nd Edition, score by day of mechanical ventilation, 95% CI -0.6 to -0.3, P < .0001). Prolonged exposure to mechanical ventilation was associated with smaller pons and medulla volumes at TEA in 2 independent cohorts, along with widespread abnormalities in white matter maturation. Pons and medulla volumes at TEA predicted motor outcomes at 4.5 years of age. CONCLUSIONS: In neonates born very preterm, prolonged mechanical ventilation is associated with impaired brainstem development, abnormal white matter maturation, and lower motor scores at preschool age. Further research is needed to better understand the neural pathological mechanisms involved.