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It has been conclusively established that folic acid supplementation prior to and during early pregnancy (up to 12 weeks of gestation) can prevent neural tube defects (NTDs). We hypothesized that folate effects may extend from neuro-structural defects to alterations in neuro-behavioural and emotional skills including autism spectrum disorders (ASDs) and other developmental disorders. The objective of this review was to comprehensively evaluate evidence on the impact of folic acid on neurodevelopment other than NTDs. We conducted an online search of relevant literature compiled by the National Library of Medicine from Medline and EMBASE (searched on Dec 31, 2014: http://www.ncbi.nlm.nih.gov/entrez/query/fcgi and http://www.elsevier.com/online-tools/embase). We first created 3 files (search restricted to English literature) using the following key words: 1) folate or folic acid (171322 papers identified by this search); 2) maternal or pregnancy or pregnant or gestation or gestational or prenatal or antenatal or periconception or periconceptional (1349219 papers identified by this search); and 3) autism or autism spectrum disorders or developmental delay or development or neurodevelopment or mental or cognitive or language or personal-social or gross motor or fine motor or behaviour or intellectual or intelligence or Bayley Scale (8268145 papers identified by this search). We then merged the 3 files and reviewed the papers that addressed these three issues simultaneously. A total of 22 original papers that examined the association between folic acid supplementation in human pregnancy and neurodevelopment/autism were identified after the screening, with 15 studies showing a beneficial effect of folic acid supplementation on neurodevelopment/autism, 6 studies showed no statistically significant difference, while one study showed a harmful effect in > 5 mg folic acid supplementation/day during pregnancy. Folic acid supplementation in pregnancy may have beneficial effects on the neurodevelopment of children beyond its proven effect on NTDs.

ObjectivesIdentify determinants of neurodevelopmental outcome in preterm children.MethodsProspective national cohort study of children born between 2009 and 2011 at <29 weeks gestational age, admitted to one of 28 Canadian neonatal intensive care units and assessed at a Canadian Neonatal Follow-up Network site at 21 months corrected age for cerebral palsy (CP), visual, hearing and developmental status using the Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III). Stepwise regression analyses evaluated the effect of (1) prenatal and neonatal characteristics, (2) admission severity of illness, (3) major neonatal morbidities, (4) neonatal neuroimaging abnormalities, and (5) site on neurodevelopmental impairment (NDI) (Bayley-III score < 85, any CP, visual or hearing impairment), significant neurodevelopmental impairment (sNDI) (Bayley-III < 70, severe CP, blind or hearing aided and sNDI or death.ResultsOf the 3700 admissions without severe congenital anomalies, 84% survived to discharge and of the 2340 admissions, 46% (IQR site variation 38%–51%) had a NDI, 17% (11%–23%) had a sNDI, 6.4% (3.1%–8.6%) had CP, 2.6% (2.5%–13.3%) had hearing aids or cochlear implants and 1.6% (0%–3.1%) had a bilateral visual impairment. Bayley-III composite scores of <70 for cognitive, language and motor domains were 3.3%, 10.9% and 6.7%, respectively. Gestational age, sex, outborn, illness severity, bronchopulmonary dysplasia, necrotising enterocolitis, late-onset sepsis, retinopathy of prematurity, abnormal neuroimaging and site were significantly associated with NDI or sNDI. Site variation ORs for NDI, sNDI and sNDI/death ranged from 0.3–4.3, 0.04–3.5 and 0.12–1.96, respectively.ConclusionMost preterm survivors are free of sNDI. The risk factors, including site, associated with neurodevelopmental status suggest opportunities for improving outcomes.

Abstract Objective There are many challenges in ensuring medical students learn paediatrics. Medical educators must develop and maintain curricula that meet learners’ needs and accreditation requirements. Paediatricians and family physicians, practicing and teaching in busy clinical environments, require Canadian-relevant curricular guidance and resources to teach and assess learners. Students struggle with curricular cohesion, clear expectations, and resources. Recognizing these challenges and acknowledging the need to address them, the Paediatric Undergraduate Program Directors of Canada (PUPDOC) created canuc-paeds, a comprehensive competency-based undergraduate curriculum that teachers and students would actually use. Methods Curriculum development included the following: utilization of best practices in curriculum development, an environmental scan, development of guiding principles, Delphi surveys, in-person meetings, and quality improvement. All Canadian paediatric undergraduate educator leaders and other stakeholders were invited to participate. Results The curriculum, based on the RCPSC CanMEDS Framework, includes 29 clinical presentations, each with key conditions, foundational knowledge objectives, and learning resources. Essential paediatric-specific physical examination and procedural skills that graduating medical students are expected to perform are identified. Objectives specific to Intrinsic Roles of Collaborator, Communicator, Professional, Leader, Health Advocate and Scholar that can be assessed in the field of paediatrics at the undergraduate level are articulated. The national curriculum has been implemented widely at Canadian medical schools. Online, open-access clinical resources have been developed and are being used world-wide. Conclusion This curriculum provides overarching Canadian-specific curricular guidance and resources for students and for the paediatricians and family physicians who are responsible for teaching and assessing undergraduate learners.

There were no differences in the rate of survival or neurosensory impairment at 18 months. The prophylactic administration of indomethacin reduces the incidence of patent ductus arteriosus and severe intraventricular hemorrhage in very-low-birth-weight infants (those with birth weights below 1500 g). 1 Our current understanding of the mechanisms by which indomethacin prevents intraventricular hemorrhage is speculative 2 and indicates that a decrease in cerebral perfusion may be involved. 3 , 4 Although such a decrease may provide protection against intraventricular hemorrhage, 4 it may also increase the risk of brain ischemia. 3 Knowledge about the effects of indomethacin prophylaxis on neurologic development is therefore crucial, but few data are available on its longer-term motor, sensory, and cognitive effects. 1 We undertook this . . .

Neurodevelopmental challenges in children born very preterm are common and not improving. This study tested the feasibility of using Evidence-based Practice to Improve Quality (EPIQ), a proven quality improvement technique that incorporates scientific evidence to target improving language abilities in very preterm populations in 10 Canadian neonatal follow-up programs. Feasibility was defined as at least 70% of sites completing four intervention cycles and 75% of cycles meeting targeted aims. Systematic reviews were reviewed and performed, an online quality improvement educational tool was developed, multidisciplinary teams that included parents were created and trained, and sites provided virtual support to implement and audit locally at least four intervention cycles of approximately 6 months in duration. Eight of ten sites implemented at least four intervention cycles. Of the 48 cycles completed, audits showed 41 (85%) met their aim. Though COVID-19 was a barrier, parent involvement, champions, and institutional support facilitated success. EPIQ is a feasible quality improvement methodology to implement family-integrated evidence-informed interventions to support language interventions in neonatal follow-up programs. Further studies are required to identify potential benefits of service outcomes, patients, and families and to evaluate sustainability.

Background We aimed to determine predictors of, and outcomes after, veno-arterial extracorporeal membrane oxygenation instituted within 48 h after cardiac surgery (early ECMO) in young infants. Methods Patients ≤ 6 weeks old having cardiac surgery from 2003 to 2012 were enrolled prospectively. Patients cannulated pre-operatively, intra-operatively, or ≥ 48 h post-operatively were excluded. Variables at p  ≤ 0.1 on univariate regression were entered into multiple logistic regression to predict early ECMO. Early-ECMO cases were matched 1:2 for six demographic variables, and death by age 2 years old (determined using conditional logistic regression; presented as odds ratio (OR), 95% confidence interval (CI)) and General Adaptive Composite scores at age 2 years (determined using Wilcoxon rank sum) were compared; p  ≤ 0.05 was considered statistically significant. Results Of 565 eligible patients over the 10-year period, 20 had early ECMO instituted at a mean (standard deviation) of 12.4 (11.4) h post-operatively, 10 of whom had extracorporeal cardiopulmonary resuscitation. Of early-ECMO patients, 8 (40%) were found to have residual anatomic defects requiring intervention with catheterization ( n  = 1) and/or surgery ( n  = 7). On multiple regression, the post-operative day 1 highest vasoactive-inotrope score (OR 1.02; 95%CI 1.06,1.08; p  < 0.001), highest lactate (OR 1.2; 95%CI 1.06,1.35; p  = 0.003), and lowest base deficit (OR 0.82; 95%CI 0.71,0.94; p  = 0.004), CPB time (OR 1.01; 95%CI 1.00,1.02; p  = 0.002), and single-ventricle anatomy (OR 5.35; 95%CI 1.66,17.31; p  = 0.005) were associated with early ECMO. Outcomes at 2 years old compared between early-ECMO and matched patients were mortality 11/20 (55%) vs 11/40 (28%) (OR 3.22, 95%CI 0.98,10.63; p  = 0.054) and General Adaptive Composite median 65 [interquartile range (IQR) 58, 81.5] in 9 survivors vs 93 [IQR 86.5, 102.5] in 29 survivors ( p  = 0.02). Conclusions The identified risk factors for, and outcomes after, having early ECMO may aid decision making in the acute period and confirm that neurodevelopmental follow-up for these children is necessary. The hypothesis that earlier institution of ECMO may improve long-term outcomes requires further study.

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

Importance Data on the middle school outcomes of preterm children are limited and have methodologic issues. Objective To study the association between preterm birth and grade 7 school performance. Methods A retrospective population-based cohort study of children born in Manitoba, Canada between 1994 and 2006 using their grade 7 school performance data. A secondary sibling cohort was created comprising children born preterm and their full-term siblings. Primary exposure was preterm birth categorized as <28, 28–33 and 34–36 weeks gestation. The two co-primary grade 7 outcome measures were: not meeting the mathematics competencies, and not meeting the student engagement competencies. Multivariable logistic regression models tested the association between preterm birth and both co-primary outcomes; adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated. Results 7653 preterm (gestational age median [IQR]: 35 weeks [34,36]) and 110,313 term (40 [39,40]) were included. 43% of < 28 weeks, 18% of 28–33 weeks and 17% of 34–36 weeks had the mathematics co-primary outcome compared to 13% of term children. The corresponding % for the student engagement outcome were 42%, 24%, 24% and 24% respectively. Preterm birth was associated with the mathematics (<28 weeks: 5.48, 3.89–7.70; 28–33 weeks: 1.47, 1.27–1.70; 34–36 weeks: 1.26, 1.16–1.35) and student engagement outcomes (<28 weeks: 2.49, 1.76–3.51; 28–33 weeks: 1.21, 1.06–1.39; 34–36 weeks: 1.09, 1.01–1.16). However, there was no difference in outcomes among the sibling cohort. Conclusions and relevance Children born preterm had lower grade 7 performance compared to children born term in this population-based cohort. Screening and supports for them in their middle school years are warranted.

Background Few studies examine differences in neurodevelopmental outcomes between spontaneous preterm birth (sPTB) and those additionally complicated by preterm prelabour rupture of membranes (PPROM). Objectives This prospective cohort study from the Canadian Neonatal Follow-Up Network compared mortality and neurodevelopmental outcomes (Bayley-III scores <70 and <85, hearing/vision loss and cerebral palsy) at 18-24 months corrected age following PPROM versus sPTB among infants <29 weeks of gestation born between 2010-2018. Secondarily, this study compared neurodevelopmental outcomes between those with PPROM lasting 1-7 days, >7days, and sPTB. Design/Methods Differences in maternal-infant characteristics and neonatal morbidities were assessed by Chi-square and Student t-tests. Raw and adjusted odds ratios (OR) with 95% CIs were calculated to compare outcomes. Results Study population included 4271 children, 1503 (35%) PPROM, 2768 (65%) sPTB. The sPTB group had younger mothers, and a higher proportion of maternal nulliparity, maternal hypertension, and outborn infants. In the neonatal period, PPROM neonates had lower rates of ROP and severe neurologic injury. Raw OR comparing PPROM vs. sPTB showed decreased mortality (OR: 0.75[0.65, 0.87]), and decreased total cerebral palsy rates (OR: 0.57 [0.41, 0.80]) (Table 1). Conclusion Among Canadian infants born at <29 weeks of gestation, PPROM lasting 1-7 days associated with decreased mortality and decreased rates of non-ambulatory cerebral palsy at 18-24 months corrected age when compared to sPTB. Such findings may be explained by heightened maternal/fetal care in PPROM cases. RESULTS Table1 Comparisons of the neurodevelopmental outcomes between exposure groups. Characteristics AOR *(95%CI) PPPROM (1-7 days vs >7 days) AOR (95%CI) PPPROM (>1-7 days) vs sPTB AOR (95%CI) PPPROM (1-7 days) vs sPTB Mortality 0.69(0.55,0.85) 1.14(0.94,1.37) 0.78(0.66,0.93) Cerebral palsy (CP) 0.69(0.41,1.14) 0.83(0.47,1.47) 0.57(0.33,0.99) Bayley cognitive score <70 0.8(0.4,1.61) 1.03(0.52,2.03) 0.83(0.47,1.45) Bayley language score <70 1.09(0.84,1.41) 1.03(0.68,1.56) 1.12(0.86,1.47) Bayley motor score <70 0.6(0.37,0.95) 1.28(0.82,2) 0.76(0.49,1.2) Bayley cognitive score <85 1.39(1.03,1.87) 0.77(0.62,0.96) 1.07(0.76,1.49) Bayley language score <85 1.05(0.84,1.32) 1.17(0.92,1.48) 1.23(1.02,1.5) Bayley motor score <85 0.78(0.52,1.16) 1.07(0.77,1.49) 0.83(0.65,1.06) Visual impairment 1.56(0.57,4.26) 0.96(0.46,2.02) 1.5(0.65,3.46) Hearing loss 0.72(0.47,1.11) 1.54(1.15,2.05) 1.11(0.78,1.58) CP (GMFCS**>3) 0.4(0.12,1.34) 0.9(0.28,2.95) 0.36(0.14,0.95) Notes: * Adjusted odds ratio AOR: Adjusted for potential confounders identified in univariate analysis: primipara, diabetics, hypertension, steroid use and maternal age, and GA, SGA and Sex. **Gross m=Motor Function Classification System.

ObjectiveTo study the association between prematurity and grade 3 school performance in a contemporary cohort of children.MethodsPopulation-based retrospective cohort study in Manitoba, Canada. Children born between 1999 and 2011 who had their grade 3 school performance data available were eligible. Preterm birth (<37 weeks) was the exposure of interest assessed using multivariable logistic regression models. Our primary outcomes were ‘needs ongoing help’ or ‘outside the range’ in at least two of each of the (1) four numeracy and (2) three reading competencies.ResultsOf the 186 956 eligible children, 101 436 children (7187 preterm (gestational age, median (IQR) 35 weeks (34, 36)) and 94 249 term (40 weeks (39,40)) were included. Overall, 19% of preterm and 14% of term children had the numeracy outcome (adjusted OR (aOR) 1.38; 95% CI 1.29 to 1.47, p<0.001), while 19% and 13% had the reading outcome (aOR 1.38; 1.29 to 1.48, p<0.001). These differences showed a gestational age gradient. Gestational age (for numeracy, <28 weeks aOR 4.93 (3.45 to 7.03), 28–33 weeks 1.72 (1.50 to 1.98), 34–36 weeks 1.24 (1.15 to 1.34); for reading, <28 weeks 3.51 (2.40 to 5.14), 28–33 weeks 1.72 (1.49 to 1.98), 34–36 weeks 1.24 (1.17–1.37)), male sex, small for gestational age and maternal medical and sociodemographic factors were associated with the numeracy and reading outcomes in this cohort.Conclusions and relevanceChildren born preterm had poorer performance in grade 3 numeracy and reading proficiencies than children born full term. All children born preterm, not just those born extremely preterm, should be screened for reading and numeracy performance in school and strategies implemented to address any deficits.