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.

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.

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.

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.

Timing of delivery in a high-risk obstetric population: a clinical prediction model.

BACKGROUND: The efficacy of antenatal corticosteroid treatment for women with threatened preterm birth depends on timely administration within 7 days before delivery. We modelled the probability of delivery within 7 days of admission to hospital among women presenting with threatened preterm birth, using routinely collected clinical characteristics. METHODS: Data from the Canadian Perinatal Network (CPN) were used, 2005-11, including women admitted to hospital with preterm labour, preterm pre-labour rupture of membranes, short cervix without contractions, or dilated cervix or prolapsed membranes without contractions at preterm gestation. Women with fetal anomaly, intrauterine fetal demise, twin-to-twin transfusion syndrome, and quadruplets were excluded. Logistic regression was undertaken to create a predictive model that was assessed for its calibration capacity, stratification ability, and classification accuracy (ROC curve). RESULTS: We included 3012 women admitted at 24-28 weeks gestation, or readmitted at up to 34 weeks gestation, to 16 tertiary-care CPN hospitals. Of these, 1473 (48.9%) delivered within 7 days of admission. Significant predictors of early delivery included maternal age, parity, gestational age at admission, smoking, preterm labour, prolapsed membranes, preterm pre-labour rupture of membranes, and antepartum haemorrhage. The area under the ROC curve was 0.724 (95% CI 0.706-0.742). CONCLUSION: We propose a useful tool to improve prediction of delivery within 7 days after admission among women with threatened preterm birth. This information is important for optimal corticosteroid treatment.

STEAM - Statistical Template Estimation for Abnormality Mapping: A personalized DTI analysis technique with applications to the screening of preterm infants.

We introduce the STEAM DTI analysis engine: a whole brain voxel-based analysis technique for the examination of diffusion tensor images (DTIs). Our STEAM analysis technique consists of two parts. First, we introduce a collection of statistical templates that represent the distribution of DTIs for a normative population. These templates include various diffusion measures from the full tensor, to fractional anisotropy, to 12 other tensor features. Second, we propose a voxel-based analysis (VBA) pipeline that is reliable enough to identify areas in individual DTI scans that differ significantly from the normative group represented in the STEAM statistical templates. We identify and justify choices in the VBA pipeline relating to multiple comparison correction, image smoothing, and dealing with non-normally distributed data. Finally, we provide a proof of concept for the utility of STEAM on a cohort of 134 very preterm infants. We generated templates from scans of 55 very preterm infants whose T1 MRI scans show no abnormalities and who have normal neurodevelopmental outcome. The remaining 79 infants were then compared to the templates using our VBA technique. We show: (a) that our statistical templates display the white matter development expected over the modeled time period, and (b) that our VBA results detect abnormalities in the diffusion measurements that relate significantly with both the presence of white matter lesions and with neurodevelopmental outcomes at 18months. Most notably, we show that STEAM produces personalized results while also being able to highlight abnormalities across the whole brain and at the scale of individual voxels. While we show the value of STEAM on DTI scans from a preterm infant cohort, STEAM can be equally applied to other cohorts as well. To facilitate this whole-brain personalized DTI analysis, we made STEAM publicly available at http://www.sfu.ca/bgb2/steam.

Early postnatal docosahexaenoic acid levels and improved preterm brain development.

BACKGROUND: Preterm birth has a dramatic impact on polyunsaturated fatty acid exposures for the developing brain. This study examined the association between postnatal fatty acid levels and measures of brain injury and development, as well as outcomes. METHODS: A cohort of 60 preterm newborns (24-32 wk gestational age) was assessed using early and near-term magnetic resonance imaging (MRI) studies. Red blood cell fatty acid composition was analyzed coordinated with each scan. Outcome at a mean of 33 mo corrected age was assessed using the Bayley Scales of Infant Development, 3rd edition. RESULTS: Adjusting for confounders, a 1% increase in postnatal docosahexaenoic acid (DHA) levels at early MRI was associated with 4.3-fold decreased odds of intraventricular hemorrhage, but was not associated with white matter injury or cerebellar haemorrhage. Higher DHA and lower linoleic acid (LA) levels at early MRI were associated with lower diffusivity in white matter tracts and corresponding improved developmental scores in follow-up. CONCLUSION: Higher DHA and lower LA levels in the first few weeks of life are associated with decreased intraventricular haemorrhage, improved microstructural brain development, and improved outcomes in preterm born children. Early and possibly antenatal interventions in high-risk pregnancies need to be studied for potential benefits in preterm developmental outcomes.

Maternal morbidity and perinatal outcomes among women in rural versus urban areas.

BACKGROUND: Most studies examining geographic barriers to maternity care in industrialized countries have focused solely on fetal and neonatal outcomes. We examined the association between rural residence and severe maternal morbidity, in addition to perinatal mortality and morbidity. METHODS: We conducted a retrospective population-based cohort study of all women who gave birth in British Columbia, Canada, between Jan. 1, 2005, and Dec. 31, 2010. We compared maternal mortality and severe morbidity (e.g., eclampsia) and adverse perinatal outcomes (e.g., perinatal death) between women residing in areas with moderate to no metropolitan influence (rural) and those living in metropolitan areas or areas with a strong metropolitan influence (urban). We used logistic regression analysis to obtain adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: We found a significant association between death or severe maternal morbidity and rural residence (adjusted OR 1.15, 95% CI 1.03-1.28). In particular, women in rural areas had significantly higher rates of eclampsia (adjusted OR 2.70, 95% CI 1.79-4.08), obstetric embolism (adjusted OR 2.16, 95% CI 1.14-4.07) and uterine rupture or dehiscence (adjusted OR 1.96, 95% CI 1.42-2.72) than women in urban areas. Perinatal mortality did not differ significantly between the study groups. Infants in rural areas were more likely than those in urban areas to have a severe neonatal morbidity (adjusted OR 1.14, 95% CI 1.02-1.29), to be born preterm (adjusted OR 1.06, 95% CI 1.01-1.11), to have an Apgar score of less than 7 at 5 minutes (adjusted OR 1.24, 95% CI 1.13-1.31) and to be large for gestational age (adjusted OR 1.14, 95% CI 1.10-1.19). They were less likely to be small for gestational age (adjusted OR 0.90, 95% CI 0.85-0.95) and to be admitted to an neonatal intensive care unit (NICU) (adjusted OR 0.36, 95% CI 0.33-0.38) compared with infants in urban areas. INTERPRETATION: Compared with women in urban areas, those in rural areas had higher rates of severe maternal morbidity and severe neonatal morbidity, and a lower rate of NICU admission. Maternity care providers in rural regions need to be aware of potentially life-threatening maternal and perinatal complications requiring advanced obstetric and neonatal care.

Sensory Processing Patterns in Children Born Very Preterm.

OBJECTIVE: We describe the prevalence and type of sensory processing differences in children born very preterm and determine associations with neonatal risk factors. METHOD: We assessed sensory processing patterns using the Short Sensory Profile in a retrospective cohort of 160 children age 4 yr born very preterm (≤ 32 wk gestational age). Data analyses included descriptive statistics to describe the prevalence of sensory processing patterns and logistic regression to examine associations with neonatal risk factors. RESULTS: Almost half of our cohort (46%) exhibited atypical sensory processing patterns. Lower Apgar scores (p = .03) and longer length of stay in the neonatal intensive care unit (NICU; p = .02) independently predicted atypical sensory processing patterns. CONCLUSION: Children born very preterm are at increased risk for sensory processing differences, which are associated with perinatal risk factors and length of stay in the NICU. Routine evaluation for sensory processing differences of children born preterm is recommended.

Neonatal Pain and Infection Relate to Smaller Cerebellum in Very Preterm Children at School Age.

OBJECTIVE: To examine whether specific neonatal factors differentially influence cerebellar subregional volumes and to investigate relationships between subregional volumes and outcomes in very preterm children at 7 years of age. STUDY DESIGN: Fifty-six children born very preterm (24-32 weeks gestational age) followed longitudinally from birth underwent 3-dimensional T(1)-weighted neuroimaging at median age 7.6 years. Children with severe brain injury were excluded. Cerebellar subregions were automatically segmented using the multiple automatically generated templates algorithm. The relation between cerebellum subregional volumes (adjusted for total brain volume and sex) and neonatal clinical factors were examined using constrained principal component analysis. Cognitive and visual-motor integration functions in relation to cerebellar volumes were also investigated. RESULTS: Higher neonatal procedural pain and infection, as well as other clinical factors, were differentially associated with reduced cerebellar volumes in specific subregions. After adjusting for clinical risk factors, neonatal procedural pain was distinctively associated with smaller volumes bilaterally in the posterior VIIIA and VIIIB lobules. Specific smaller cerebellar subregional volumes were related to poorer cognition and motor/visual integration. CONCLUSIONS: In very preterm children, exposure to painful procedures, as well as additional neonatal risk factors such as infection, were associated with reduced cerebellar volumes in specific subregions and poorer outcomes at school age.

Magnesium sulphate for fetal neuroprotection: benefits and challenges of a systematic knowledge translation project in Canada.

BACKGROUND: Administration of magnesium sulphate (MgSO4) to women with imminent preterm birth at <34 weeks is an evidence-based antenatal neuroprotective strategy to prevent cerebral palsy. Although a Society of Obstetricians and Gynaecologists of Canada (SOGC) national guideline with practice recommendations based on relevant clinical evidence exists, ongoing controversies about aspects of this treatment remain. Given this, we anticipated managed knowledge translation (KT) would be needed to facilitate uptake of the guidelines into practice. As part of the Canadian Institutes of Health Research (CIHR)-funded MAG-CP (MAGnesium sulphate to prevent Cerebral Palsy) project, we aimed to compare three KT methods designed to impact both individual health care providers and the organizational systems in which they work. METHODS: The KT methods undertaken were an interactive online e-learning module available to all SOGC members, and at MAG-CP participating sites, on-site educational rounds and focus group discussions, and circulation of an anonymous 'Barriers and Facilitators' survey for the systematic identification of facilitators and barriers for uptake of practice change. We compared these strategies according to: (i) breadth of respondents reached; (ii) rates and richness of identified barriers, facilitators, and knowledge needed; and (iii) cost. RESULTS: No individual KT method was superior to the others by all criteria, and in combination, they provided richer information than any individual method. The e-learning module reached the most diverse audience of health care providers, the site visits provided opportunity for iterative dialogue, and the survey was the least expensive. Although the site visits provided the most detailed information around individual and organizational barriers, the 'Barriers and Facilitators' survey provided more detail regarding social-level barriers. The facilitators identified varied by KT method. The type of knowledge needed was further defined by the e-learning module and surveys. CONCLUSIONS: Our findings suggest that a multifaceted approach to KT is optimal for translating national obstetric guidelines into clinical practice. As audit and feedback are essential parts of the process by which evidence to practice gaps are closed, MAG-CP is continuing the iterative KT process described in this paper concurrent with tracking of MgSO4 use for fetal neuroprotection and maternal and child outcomes until September 2015; results are anticipated in 2016.

Magnesium Sulphate for Eclampsia and Fetal Neuroprotection: A Comparative Analysis of Protocols Across Canadian Tertiary Perinatal Centres.

BACKGROUND: Magnesium sulphate (MgSO4) has been recommended for fetal neuroprotection to prevent cerebral palsy, with national societies adopting new guidelines for its use. A knowledge translation project to implement Canadian guidelines is ongoing. Discussion about MgSO4 for fetal neuroprotection could not occur distinct from MgSO4 for eclampsia prophylaxis and treatment. Thus, in order to explore standardization of MgSO4 use in Canada, we sought to compare local protocols for eclampsia and fetal neuroprotection across tertiary perinatal centres. METHODS: Twenty-five Canadian tertiary perinatal centres were asked to submit their protocols for use of MgSO4 for eclampsia prophylaxis/treatment and fetal neuroprotection. Information abstracted included date of protocol, definitions of indications for treatment, details of MgSO4 administration, maternal and fetal monitoring, antidote for toxicity, and abnormal signs requiring physician attention. Descriptive analyses were used to compare site protocols with known definitions of preeclampsia. Data from the Canadian Perinatal Network (CPN) were used to verify what was done in clinical practice. RESULTS: Twenty-two of the 25 centres submitted protocols for eclampsia prevention/treatment. Eleven of these provided a definition of preeclampsia that warranted treatment; five of the 22 advised treatment of severe preeclampsia only. Criteria for treatment and monitoring procedures varied across centres. Sixteen of the 22 sites with protocols had data from the CPN. Of 635 women with pre-eclampsia, 422 (66.5%) received MgSO4. Twenty of 25 centres provided protocols for fetal neuroprotection. Definitions of indications were consistent across sites, except for gestational age cut-off. CONCLUSION: This study suggests that local protocols are often inconsistent with published evidence. While this may be related to local institutional practices, relevant processes must be put in place to maximize uniformity of practice and improve patient care.

Contexte : L'utilisation de sulfate de magnésium (MgSO4) a été recommandée à des fins de neuroprotection fœtale dans le but de prévenir l'infirmité motrice cérébrale; des sociétés nationales adoptent d'ailleurs de nouvelles lignes directrices quant à son utilisation. Un projet de transfert des connaissances visant la mise en œuvre des lignes directrices canadiennes est en cours. Le rôle du MgSO4 en ce qui concerne la neuroprotection fœtale ne peut être abordé sans que l'on mentionne son utilisation dans le cadre de la prophylaxie et de la prise en charge de l'éclampsie. Ainsi, pour explorer la standardisation de l'utilisation de MgSO4 au Canada, nous avons cherché à comparer les protocoles locaux qui en régissent l'utilisation en matière d'éclampsie et de neuroprotection fœtale dans les centres périnataux tertiaires. Méthodes : Nous avons demandé à 25 centres périnataux tertiaires canadiens de nous soumettre leurs protocoles quant à l'utilisation du MgSO4 aux fins de la neuroprotection fœtale et de la prophylaxie / prise en charge de l'éclampsie. Les renseignements que nous avons tirés de ces protocoles comprenaient la date du protocole, les définitions des indications de traitement, les détails de l'administration du MgSO4, le monitorage maternel et fœtal, l'antidote pour contrer la toxicité et les symptômes anormaux nécessitant l'offre de soins médicaux. Des analyses descriptives ont été utilisées pour comparer les protocoles de ces centres aux définitions connues de la prééclampsie. Des données issues du Réseau périnatal canadien (RPC) ont été utilisées pour vérifier ce qui se faisait dans le cadre de la pratique clinique. Résultats : Vingt-deux des 25 centres nous ont soumis leurs protocoles de prévention / prise en charge de l'éclampsie. Onze de ces centres nous ont fourni une définition de ce qui était considéré comme une prééclampsie justifiant une prise en charge; cinq des 22 centres ne préconisaient que la prise en charge de la prééclampsie grave. Les critères des interventions de traitement et de monitorage variaient d'un centre à l'autre. Seize des 22 sites comptant des protocoles présentaient des données issues du RPC. Au sein d'un groupe de 635 femmes connaissant une prééclampsie, 422 (66,5 %) ont reçu du MgSO4. Vingt des 25 centres nous ont fourni leurs protocoles de neuroprotection fœtale. Les définitions des indications étaient uniformes d'un site à l'autre, sauf en ce qui concerne le seuil en matière d'âge gestationnel. Conclusion : Cette étude avance que les protocoles locaux ne concordent souvent pas avec les données probantes publiées. Bien que cela puisse être attribuable aux pratiques institutionnelles locales, des processus pertinents doivent être mis en place pour maximiser l'uniformité de la pratique et améliorer les soins offerts aux patientes.

Effect of magnesium sulphate on fetal heart rate parameters: a systematic review.

OBJECTIVE: To examine the potential effects of intravenous magnesium sulphate (MgSO4) administration on antepartum and intrapartum fetal heart rate (FHR) parameters measured by cardiotocography (CTG) or electronic fetal monitoring (EFM). METHODS: We undertook a systematic review of randomized controlled trials, observational studies, and case series. Studies were reviewed independently by two reviewers and qualitatively analyzed with regard to CTG/EFM parameters (baseline FHR, variability and acceleration-deceleration patterns), types of participants, interventions offered, and outcomes reported. RESULTS: Of 18 included studies, two were RCTs (72 women); 12 were prospective observational studies (269 women), 10 of which were of a pre- and post-intervention design; one was a prospective cohort study (36 women) and three were retrospective cohort studies (555 women). Lower baseline FHR was associated with MgSO4 exposure in seven of nine relevant studies. Decreased FHR variability was reported in nine of 12 relevant studies. Reductions in reactivity or acceleration pattern were seen in four of six relevant studies without an increase in decelerative patterns. All changes were small and not associated with adverse clinical outcomes. CONCLUSION: Maternal administration of MgSO4 for eclampsia prophylaxis/treatment, tocolysis or fetal neuroprotection appears to have a small negative effect on FHR, variability, and accelerative pattern, but is not sufficient clinically to warrant medical intervention.

Objectif : Examiner les effets potentiels de l'administration de sulfate de magnésium (MgSO4) par voie intraveineuse sur les paramètres de la fréquence cardiaque fœtale (FCF) antepartum et intrapartum mesurés par cardiotocographie (CTG) ou monitorage fœtal électronique (MFÉ). Méthodes : Nous avons mené une analyse systématique ayant porté sur des essais comparatifs randomisés, des études observationnelles et des séries de cas. Ces études ont été analysées de façon indépendante par deux arbitres scientifiques; de plus, elles ont fait l'objet d'une analyse qualitative en fonction des paramètres de la CTG / du MFÉ (FCF initiale, variabilité et profils d'accélération-décélération), des types de participantes, des interventions offertes et des issues signalées. Résultats : Parmi les 18 études admises à l'analyse systématique, on comptait deux ECR (72 femmes); 12 études observationnelles prospectives (269 femmes), dont 10 comptaient un devis préintervention et postintervention; une étude de cohorte prospective (36 femmes); et trois études de cohorte rétrospectives (555 femmes). Une FCF initiale moindre a été associée à l'exposition au MgSO4 dans le cadre de sept des neuf études pertinentes. Une variabilité moindre de la FCF a été signalée dans neuf des 12 études pertinentes. Des baisses des profils de réactivité ou d'accélération ont été constatées dans quatre des six études pertinentes, sans hausse des profils de décélération. Toutes les modifications ont été faibles et n'ont pas été associées à des issues cliniques indésirables. Conclusion : Bien que l'administration de MgSO4 à la mère à des fins de prophylaxie / prise en charge de l'éclampsie, de tocolyse ou de neuroprotection fœtale semble exercer un faible effet négatif sur la FCF, la variabilité et le profil d'accélération, cet effet n'est pas suffisant sur le plan clinique pour justifier la tenue d'une intervention médicale.

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.

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.

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.

Procedural pain and brain development in premature newborns.

OBJECTIVE: Preterm infants are exposed to multiple painful procedures in the neonatal intensive care unit (NICU) during a period of rapid brain development. Our aim was to examine relationships between procedural pain in the NICU and early brain development in very preterm infants. METHODS: Infants born very preterm (N=86; 24-32 weeks gestational age) were followed prospectively from birth, and studied with magnetic resonance imaging, 3-dimensional magnetic resonance spectroscopic imaging, and diffusion tensor imaging: scan 1 early in life (median, 32.1 weeks) and scan 2 at term-equivalent age (median, 40 weeks). We calculated N-acetylaspartate to choline ratios (NAA/choline), lactate to choline ratios, average diffusivity, and white matter fractional anisotropy (FA) from up to 7 white and 4 subcortical gray matter regions of interest. Procedural pain was quantified as the number of skin-breaking events from birth to term or scan 2. Data were analyzed using generalized estimating equation modeling adjusting for clinical confounders such as illness severity, morphine exposure, brain injury, and surgery. RESULTS: After comprehensively adjusting for multiple clinical factors, greater neonatal procedural pain was associated with reduced white matter FA (ß=-0.0002, p=0.028) and reduced subcortical gray matter NAA/choline (ß=-0.0006, p=0.004). Reduced FA was predicted by early pain (before scan 1), whereas lower NAA/choline was predicted by pain exposure throughout the neonatal course, suggesting a primary and early effect on subcortical structures with secondary white matter changes. INTERPRETATION: Early procedural pain in very preterm infants may contribute to impaired brain development.

Magnesium sulphate for fetal neuroprotection: a cost-effectiveness analysis.

BACKGROUND: The aim of this study was to assess the cost-effectiveness of administering magnesium sulphate to patients in whom preterm birth at < 32+0 weeks gestation is either imminent or threatened for the purpose of fetal neuroprotection. METHODS: Multiple decision tree models and probabilistic sensitivity analyses were used to compare the administration of magnesium sulphate with the alternative of no treatment. Two separate cost perspectives were utilized in this series of analyses: a health system and a societal perspective. In addition, two separate measures of effectiveness were utilized: cases of cerebral palsy (CP) averted and quality-adjusted life years (QALYs). RESULTS: From a health system and a societal perspective, respectively, a savings of $2,242 and $112,602 is obtained for each QALY gained and a savings of $30,942 and $1,554,198 is obtained for each case of CP averted when magnesium sulphate is administered to patients in whom preterm birth is imminent. From a health system perspective and a societal perspective, respectively, a cost of $2,083 is incurred and a savings of $108,277 is obtained for each QALY gained and a cost of $28,755 is incurred and a savings of $1,494,500 is obtained for each case of CP averted when magnesium sulphate is administered to patients in whom preterm birth is threatened. CONCLUSIONS: Administration of magnesium sulphate to patients in whom preterm birth is imminent is a dominant (i.e. cost-effective) strategy, no matter what cost perspective or measure of effectiveness is used. Administration of magnesium sulphate to patients in whom preterm birth is threatened is a dominant strategy from a societal perspective and is very likely to be cost-effective from a health system perspective.

Limb length shortening associated with femoral arterial lines in the neonatal period.

Two cases involving toddlers who presented with limb length shortening and radiological findings consistent with growth plate arrest are presented. Both cases had been cared for in the neonatal intensive care unit because of extreme prematurity, and both cases had a femoral arterial line inserted on the side of the body with the short limb. This complication has not been previously described in the preterm population.

Les auteurs présentent deux cas de tout-petits qui ont consulté en raison du raccourcissement d'un membre et dont les observations radiologiques concordaient avec un arrêt de croissance du cartilage de conjugaison. Les deux cas ont été soignés à l'unité de soins intensifs néonatals en raison d'une extrême prématurité et se sont fait insérer un cathéter de l'artère fémorale du côté du membre plus court. Cette complication n'a jamais été décrite dans la population de prématurés.

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.