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

Objectives: To identify the probability of survival and severe neurodevelopmental impairment (sNDI) at which perinatal physicians would or would not offer or recommend resuscitation at birth for extremely preterm infants. Methods: A Delphi process consisting of five rounds was implemented to seek consensus (>80% agreement) amongst British Columbia perinatal physicians. The first-round consisted of neonatal and maternal-fetal-medicine Focus Groups. Rounds two to five surveyed perinatal physicians, building upon previous rounds. Draft guidelines were developed and agreement sought. Results: Based on 401 responses across all rounds, consensus was obtained that resuscitation should not be offered if survival probability <5%, not recommended if survival probability 5 to <10%, resuscitation recommended if survival without sNDI probability >70 to 90% and resuscitation standard care if survival without sNDI >90%. Conclusions: This physician consensus-based, objective framework for the management of an anticipated extremely preterm infant is a transparent alternative to existing guidelines, minimizing gestational-ageism and allowing for individualized management utilizing up-to-date data. Further input from other key stakeholders will be required prior to guideline implementation. [ABSTRACT FROM AUTHOR]

Objectives: Preeclampsia is characterized by maternal systemic inflammation and coagulation activation, akin to the sepsis syndrome. Recombinant human activated protein C (rhAPC; drotrecogin alfa [activated]) may modify disease progression to safely prolong pregnancies and improve perinatal outcomes. Both maternal and perinatal risks are highest remote from term.Study Design: Open-label, single arm safety and efficacy trial of rhAPC in consenting pregnant women with severe early-onset preeclampsia. Disease severity-matched rhAPC-naïve controls were identified from an existing database. An additional six women were recruited as biomarker controls.Main Outcome Measures: Primary safety outcome: incidence of peripartum bleeding; primary efficacy outcome: duration of pregnancy after enrolment.Results: Twelve (31.6%) of 38 eligible women consented; 3 did not receive the infusion due to staffing. Therefore, 9 women received rhAPC (24 μg/kg/hr for ≤96 h antenatally). No safety issues were identified. There was a marginal prolongation in eligibility-to-delivery intervals for women receiving rhAPC (Mantel-Cox p = 0.052; Gehan-Breslow-Wilcoxon p = 0.049). Compared with both the pre-infusion phase in the rhAPC-treated women themselves and with fullPIERS rhAPC-naïve women, rhAPC was associated with increased urine output during the infusion (6/9 vs 1/9 had urine output >100 mL/h during the infusion, Fisher's exact p = 0.003).Conclusions: These data support further investigation of APC in women with severe early-onset preeclampsia; recombinant and purified human APC is available. In addition, these data will inform the design and implementation of randomized controlled trials aiming to modify and/or moderate the proinflammatory and proacoagulant state of preeclampsia. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Intensive resuscitation at birth has been linked to intraventricular haemorrhage (IVH) in the preterm neonate. However, the impact of less intensive resuscitation on more subtle alterations in brain metabolic development is largely unknown. Our objective was to determine the relationship between the intensity of neonatal resuscitation following preterm birth on brain metabolic development. Methods: One hundred thirty-three very preterm-born neonates (median gestational age [GA] 27 ± 2 weeks) underwent MR spectroscopic imaging early in life (median postmenstrual age 32 weeks) and again at term-equivalent age (median 40 weeks). Severity of white matter injury, IVH and cerebellar haemorrhage on magnetic resonance imaging were scored. Ratios of N-acetylaspartate (NAA) and lactate to choline (Cho) were calculated in eight regions of interest and were assessed in relation to intensiveness of resuscitation strategy (bag and mask, continuous positive airway pressure [CPAP], intubation, cardiopulmonary resuscitation [CPR]). Results: Within the first hour of life, 14 newborns had no intervention, 3 received bag and mask, 30 had CPAP, 79 were intubated and 7 had CPR. Resuscitated infants were more likely to have IVH ( p = 0.02). More intensive resuscitation was associated with decreased NAA/Cho maturation ( p < 0.001, adjusting for birth GA). Metabolic development was similar in neonates requiring CPAP in comparison to those receiving no intervention. The change in lactate/Cho did not differ across resuscitation categories ( p = 0.8). Conclusions: Intensity of resuscitation at birth is related to changes in metabolic brain development from early in life to term-equivalent age. Results suggest that preventing the need for intensive neonatal resuscitation may provide an opportunity to improve brain development in preterm neonates. [ABSTRACT FROM AUTHOR]

Objective:To examine whether early inflammation is related to cortisol levels at 18 months corrected age (CA) in children born very preterm.Study Design:Infants born 32 weeks of gestational age were recruited in the neonatal intensive care unit (NICU), and placental histopathology, magnetic resonance imaging (MRI) and chart review were obtained. At 18 months CA, developmental assessment and collection of three salivary cortisol samples were carried out. Generalized least squares was used to analyze data from 85 infants providing 222 cortisol samples.Result:Infants exposed to chorioamnionitis with funisitis had a significantly different pattern of cortisol across the samples compared with infants with chorioamnionitis alone or no prenatal inflammation (F(4, 139)=7.3996, P<0.0001). Postnatal infections, necrotizing enterocolitis and chronic lung disease were not significantly associated with the cortisol pattern at 18 months CA.Conclusion:In children born very preterm, prenatal inflammatory stress may contribute to altered programming of the hypothalamic-pituitary-adrenal (HPA) axis. [ABSTRACT FROM AUTHOR]

BACKGROUND: Very preterm infants (born 24-32 weeks' gestation) undergo numerous invasive procedures during neonatal care. Repeated skin-breaking procedures in rodents cause neuronal cell death, and in human preterm neonates higher numbers of invasive procedures from birth to term-equivalent age are associated with abnormal brain development, even after controlling for other clinical risk factors. It is unknown whether higher numbers of invasive procedures are associated with long-term alterations in brain microstructure and cognitive outcome at school age in children born very preterm. METHODS: Fifty children born very preterm underwent MRI and cognitive testing at median age 7.6 years (interquartile range, 7.5-7.7). T1- and T2- weighted images were assessed for the severity of brain injury. Magnetic resonance diffusion tensor sequences were used to measure fractional anisotropy (FA), an index of white matter (WM) maturation, from 7 anatomically defined WM regions. Child cognition was assessed using the Wechsler Intelligence Scale for Children-IV. Multivariate modeling was used to examine relationships between invasive procedures, brain microstructure, and cognition, adjusting for clinical confounders (eg, infection, ventilation, brain injury). RESULTS: Greater numbers of invasive procedures were associated with lower FA values of the WM at age 7 years (P = .01). The interaction between the number of procedures and FA was associated with IQ (P = .02), such that greater numbers of invasive procedures and lower FA of the superior WM were related to lower IQ. CONCLUSIONS: Invasive procedures during neonatal care contribute to long-term abnormalities in WM microstructure and lower IQ. [ABSTRACT FROM AUTHOR]

Competing Interests: Conflict of Interest: None.

Objective: The aim of this study was to determine the incidence of births fathered by men with multiple sclerosis (MS) exposed to a disease-modifying drug (DMD) around the time of conception, and investigate the association between DMD exposure and birth outcomes in newborns of exposed and unexposed MS fathers., Methods: Population-based databases in British Columbia (BC), Canada, (the BCMS database, Vital Statistics Birth Registry, Population Data BC Consolidation File/Census GeoData, BC PharmaNet and the BC Perinatal Database Registry) were linked in this retrospective cohort study (1996 to 2010). Multivariate models were used to examine the association between interferon-beta (IFNβ) or glatiramer acetate (GA) exposure (within 64 days prior to or at conception; i.e., the duration of spermatogenesis) with birth weight and gestational age of newborns., Results: Of 195 births fathered by men with relapsing-onset MS, 80 births (41%) were to fathers treated with a DMD before their child was born, with 53/195 (27%) exposed within 64 days prior to or at the time of conception. Of the 53 exposed births, 37 were to IFNβ and 16 to GA. Mean birth weight of IFNβ-exposed and GA-exposed newborns was similar to that of unexposed newborns (adjusted difference: -107 g for both, p>0.3). IFNβ-exposed and GA-exposed newborns also had comparable mean gestational ages relative to unexposed newborns (adjusted difference: -0.5 and -0.3 weeks, respectively, p>0.2)., Conclusions: About one in three would-be fathers with MS were exposed to IFNβ or GA around the time of conception; there was no compelling evidence to suggest that exposure was associated with either lower birth weight or gestational age.

To examine obstetrical epidural and spinal anesthesia use in women with multiple sclerosis (MS) and the relationship with MS clinical factors. This was a retrospective cohort study, linking clinical data from women with MS in the British Columbia (BC) MS database to obstetrical data (1998-2009) from the BC Perinatal Database Registry. We compared epidural use in 431 deliveries to women with MS and 2,959 deliveries from the general population, as well as spinal use in cesarean deliveries (128 to women with MS and 846 in the general population), considering parity and using multivariate models. We also examined the association between epidural or spinal anesthesia and MS clinical factors-disease duration and disability [Expanded Disability Status Scale (EDSS) score]. Of 431 deliveries to women with MS, 116 were exposed to epidural anesthesia and of 128 cesarean deliveries, 82 were exposed to spinal anesthesia. The use of epidural anesthesia was similar in nullipara (adjusted OR = 0.86, 95 % CI = 0.63-1.18, p = 0.36), but more likely in multipara with MS (adjusted OR = 1.75, 95 % CI = 1.20-2.54, p = 0.004). Spinal anesthesia use in cesarean deliveries was comparable between the MS and general population cohorts (adjusted OR = 0.84, 95 % CI = 0.55-1.31, p = 0.45). Women who delivered 5 to <10 years after MS onset were less likely to have an epidural (adjusted OR = 0.57, 95 % CI = 0.34-0.95, p = 0.03) vs. those delivering within 5 years. EDSS was not associated with use of either type of anesthesia (adjusted p > 0.1). Contrary to previous studies, epidural anesthesia use differed between women with MS and the general population and was influenced by parity and MS disease duration; these findings warrant further investigation.

Objective: To compare the duration of birth hospitalization in mothers with multiple sclerosis (MS) and their newborns relative to the general population and to investigate the impact of MS-related clinical factors on the length of birth hospitalization stays., Methods: Data from the British Columbia Perinatal Database Registry and the British Columbia MS database were linked in this retrospective cohort study. The duration of birth hospitalization in mothers with MS and their newborns (n = 432) were compared with a frequency-matched sample of the general population (n = 2,975) from 1998 to 2009. Clinical factors investigated included disease duration and disability, as measured by the Expanded Disability Status Scale. A multivariable model (generalized estimating equations) was used to analyze the association between MS and duration of birth hospitalization, adjusting for factors such as maternal age, diabetes, hypertension, and consecutive births to the same mother. Additional analyses included propensity score matching to further balance cohort characteristics., Results: Compared with the general population, the duration of birth hospitalization was not statistically or clinically different for mothers with MS or their newborns (median differences = +1.5 and +2.1 hours, respectively; adjusted p > 0.4). Lengths of birth hospitalization were not significantly associated with disease duration (adjusted p > 0.7) or level of disability (adjusted p > 0.5). Findings remained virtually unchanged after propensity score matching., Conclusions: Birth hospitalization has been understudied in women with MS. Contrary to existing studies, we found that MS was not associated with a longer birth hospitalization. This study provides assurance to expectant mothers with MS, their families, and health care providers.

Objective: To describe the incidence trend and long-term visual outcomes of infants diagnosed with stages 3 to 4 retinopathy of prematurity (ROP) or laser-treated ROP born in British Columbia (Canada)., Study Design: Data from all (n=1384) neonates with birth weight (BW) <1250 g, admitted to British Columbia Children's Hospital between period 1 (January 1992 to December 1996) and period 2 (January 1997 to December 2001) were analyzed. Ophthalmologic records of infants with stages 3 to 4 ROP or laser-treated ROP were abstracted. chi(2)- and t-test were used to compare neonatal characteristics between periods. Logistic regression was used to identify risk factors associated with visual impairment (defined as visual acuity

Objective: Long-term outcomes of preterm infants have been extensively studied, but few studies have examined long-term outcomes of term infants who require neonatal intensive care unit (NICU). Our objectives were to assess perinatal characteristics and health status of preschool age term babies using data from a population-based study of NICU graduates., Study Design: Retrospective cross-sectional survey. All babies were born in 1996 to 1997 in BC (Canada). The Health Status Classification System Preschool (HSCS-PS) questionnaire was completed by parents at 42 months of age. HSCS-PS was grouped in four categories (neurosensory, learning, motor and quality of life). Logistic regression was used to identify perinatal risk factors associated with moderate/severe problems at 42 months of age., Result: Completed surveys were received for 261 term NICU survivors and 393 control children. Term infants represent 32% of all NICU admissions. Mean birth weight of NICU graduates was 3458 g (s.d.=600 g). Median length-of-stay in NICU was 5 days. At 42 months, the NICU group had significantly more problems on the HSCS-PS as compared to the full-term healthy infants in neurosensory, motor and learning/remembering. Moderate/severe health status problems were associated with congenital anomalies (odds ratio (OR), 3.2; confidence interval (CI): 1.3 to 7.8); smoking status (OR, 2.7, CI: 1.1 to 6.6) and SNAP score (OR, 1.04; CI: 1.0 to 1.1)., Conclusion: Term babies admitted to NICUs may have significant health issues in childhood. Greater attention needs to be paid to long-term outcomes of term NICU graduates. Further study is warranted to address which NICU term survivors warrant secondary and/or tertiary-level neurodevelopmental follow-up.