McMaster Children's Hospital

In the interest of more systematically documenting the early signs of autism, and of testing specific hypotheses regarding their underlying neurodevelopmental substrates, we have initiated a longitudinal study of high-risk infants, all of whom have an older sibling diagnosed with an autistic spectrum disorder. Our sample currently includes 150 infant siblings, including 65 who have been followed to age 24 months, who are the focus of this paper. We have also followed a comparison group of low-risk infants. Our measures include a novel observational scale (the first, to our knowledge, that is designed to assess autism-specific behavior in infants), a computerized visual orienting task, and standardized measures of temperament, cognitive and language development. Our preliminary results indicate that by 12 months of age, siblings who are later diagnosed with autism may be distinguished from other siblings and low-risk controls on the basis of: (1) several specific behavioral markers, including atypicalities in eye contact, visual tracking, disengagement of visual attention, orienting to name, imitation, social smiling, reactivity, social interest and affect, and sensory-oriented behaviors; (2) prolonged latency to disengage visual attention; (3) a characteristic pattern of early temperament, with marked passivity and decreased activity level at 6 months, followed by extreme distress reactions, a tendency to fixate on particular objects in the environment, and decreased expression of positive affect by 12 months; and (4) delayed expressive and receptive language. We discuss these findings in the context of various neural networks thought to underlie neurodevelopmental abnormalities in autism, including poor visual orienting. Over time, as we are able to prospectively study larger numbers and to examine interrelationships among both early-developing behaviors and biological indices of interest, we hope this work will advance current understanding of the neurodevelopmental origins of autism.

Deep vein thrombosis (DVT) and pulmonary embolism (PE) occur in pediatric patients; however, the incidence, associated morbidity, and mortality are unknown. A Canadian registry of DVT and PE in children (ages 1 month to 18 years) was established July 1, 1990 in 15 tertiary-care pediatric centers. One-hundred thirty-seven patients were identified prospectively and are the subject of this report. The incidence of DVT/PE was 5.3/10,000 hospital admissions or 0.07/10,000 children in Canada. Infants under 1 year old and teenagers predominated with equal numbers of both sexes. DVT were located in the upper (n = 50) and lower (n = 79) venous system, or as PE alone (n = 8). Central venous lines (CVLs) were present in approximately 33% of children with DVT (n = 45). Associated conditions were present in 96% of children and 90% of children had two or more associated conditions for DVT. DVT was diagnosed by venography (n = 83), duplex ultrasound (n = 37), and other combinations (n = 17). Twenty-two of the 31 ventilation/perfusion scans performed were interpreted as high-probability scans for PE. Therapy consisted of heparin (n = 115), thrombolysis (n = 15), surgical removal of a CVL or thrombus (n = 22), and oral anticoagulant therapy (n = 103). Significant bleeding complications did not occur. However, three (2.2%) children died as a direct consequence of their thromboembolic disease; DVT reoccurred in 23 children and postphlebitic syndrome (PPS) occurred in 26. In conclusion, DVTs occur in a significant number of hospitalized children with a mortality of 2.2%. Complications are not hemorrhagic, but thrombotic, and characterized by PE, recurrent disease, and PPS. In contrast to adults, the upper venous system is frequently affected because of the use of CVLs. The frequency of DVT/PE justifies controlled trials of primary prophylaxis in high-risk groups, and therapeutic trials to determine optimal treatment.

The most common indications for warfarin therapy are atrial fibrillation, the presence of a mechanical heart valve, and venous thromboembolism.1,2 Treatment with warfarin presents a problem if patients with these indications need surgery, because the interruption of anticoagulant therapy increases the risk of thromboembolism. After warfarin therapy is discontinued, it takes several days for its antithrombotic effect to recede, and when it is resumed, several days are needed to reestablish therapeutic anticoagulation.There is no consensus on the appropriate perioperative management of anticoagulation for patients who have been receiving long-term warfarin therapy. Rational decisions about the treatment of such . . .

OBJECTIVES: The American College of Critical Care Medicine provided 2002 and 2007 guidelines for hemodynamic support of newborn and pediatric septic shock. Provide the 2014 update of the 2007 American College of Critical Care Medicine "Clinical Guidelines for Hemodynamic Support of Neonates and Children with Septic Shock." DESIGN: Society of Critical Care Medicine members were identified from general solicitation at Society of Critical Care Medicine Educational and Scientific Symposia (2006-2014). The PubMed/Medline/Embase literature (2006-14) was searched by the Society of Critical Care Medicine librarian using the keywords: sepsis, septicemia, septic shock, endotoxemia, persistent pulmonary hypertension, nitric oxide, extracorporeal membrane oxygenation, and American College of Critical Care Medicine guidelines in the newborn and pediatric age groups. MEASUREMENTS AND MAIN RESULTS: The 2002 and 2007 guidelines were widely disseminated, translated into Spanish and Portuguese, and incorporated into Society of Critical Care Medicine and American Heart Association/Pediatric Advanced Life Support sanctioned recommendations. The review of new literature highlights two tertiary pediatric centers that implemented quality improvement initiatives to improve early septic shock recognition and first-hour compliance to these guidelines. Improved compliance reduced hospital mortality from 4% to 2%. Analysis of Global Sepsis Initiative data in resource rich developed and developing nations further showed improved hospital mortality with compliance to first-hour and stabilization guideline recommendations. CONCLUSIONS: The major new recommendation in the 2014 update is consideration of institution-specific use of 1) a "recognition bundle" containing a trigger tool for rapid identification of patients with septic shock, 2) a "resuscitation and stabilization bundle" to help adherence to best practice principles, and 3) a "performance bundle" to identify and overcome perceived barriers to the pursuit of best practice principles.

In 1995, a consensus statement was published for the purpose of summarizing the salient clinical features of Angelman syndrome (AS) to assist the clinician in making a timely and accurate diagnosis. Considering the scientific advances made in the last 10 years, it is necessary now to review the validity of the original consensus criteria. As in the original consensus project, the methodology used for this review was to convene a group of scientists and clinicians, with experience in AS, to develop a concise consensus statement, supported by scientific publications where appropriate. It is hoped that this revised consensus document will facilitate further clinical study of individuals with proven AS, and assist in the evaluation of those who appear to have clinical features of AS but have normal laboratory diagnostic testing.

Ischemic stroke during infancy and childhood has the potential for life-long morbidity. Information on the neurologic outcome of children who survive ischemic stroke is lacking. Children surviving ischemic stroke between January 1, 1995 and July 1, 1999 were prospectively followed. Neurologic deficit severity was based on the Pediatric Stroke Outcome Measure (PSOM) developed in this study and parental response to two recovery questions. Predictor variables for poor outcome were tested. One-hundred twenty-three children with arterial ischemic stroke and 38 with sinovenous thrombosis were followed for a mean of 2.1 years (range, 0.8 to 6.6 years). The primary outcome based on PSOM assessment was: normal, 37%; mild deficit, 20%; moderate deficit, 26%; and severe deficit, 16%. The secondary outcome was full recovery in 45% of patients, based on parental response. The primary and secondary outcome measures were moderately correlated (P < .001; K = 0.5). In bivariate analysis, arterial stroke type, male gender, age of at least 28 days, presence of associated neurologic disorders, and need for rehabilitation therapy after stroke were predictors of poor outcome (P < .05). Multivariate analysis showed that only arterial ischemic stroke, associated neurologic disorders, and presence of rehabilitation therapy were independent predictors of poor outcome (P < .02). Poor outcome in children after ischemic stroke is therefore frequent and more likely in the presence of arterial stroke, rehabilitation therapy, and associated neurologic disorders, which justifies clinical trials of treatment strategies in childhood ischemic stroke.

Aicardi-Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi-Goutières syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials.

Our understanding of the coagulation and fibrinolytic systems (the hemostatic system) in the adult has progressed rapidly in recent years. However, a more complete understanding of the physiology of the hemostatic system in the neonate has lagged behind that of the adult for many reasons. First, the hemostatic system in the newborn exists in a dynamic state and is rapidly evolving toward the adult system. This situation necessitates the generation of not one, but several, reference ranges (or ranges of normal values) in the postnatal period for the various tests and components of the hemostatic system. Also, microtechniques must be used to perform the required assays, both because of the small size of blood samples available and because of the difficulty of obtaining blood from infants. Recently, many of these problems have been resolved, which resulted in a better appreciation of the development of the hemostatic system in the infant. This article reviews our current understanding of the protein components of the coagulation and fibrinolytic systems in the neonate. Reference ranges for normal values of the various tests and components of the hemostatic system have been provided for the premature and full-term infant at birth and during the first 6 months of life.

OBJECTIVE: To report the clinical, radiological, and immunological association of demyelinating disorders with anti–Nmethyl- D-aspartate receptor (NMDAR) encephalitis. METHODS: Clinical and radiological analysis was done of a cohort of 691 patients with anti-NMDAR encephalitis. Determination of antibodies to NMDAR, aquaporin-4 (AQP4), and myelin oligodendrocyte glycoprotein (MOG) was performed using brain immunohistochemistry and cell-based assays. RESULTS: Twenty-three of 691 patients with anti-NMDAR encephalitis had prominent magnetic resonance imaging (MRI) and/or clinical features of demyelination. Group 1 included 12 patients in whom anti-NMDAR encephalitis was preceded or followed by independent episodes of neuromyelitis optica (NMO) spectrum disorder (5 cases, 4 anti-AQP4 positive) or brainstem or multifocal demyelinating syndromes (7 cases, all anti-MOG positive). Group 2 included 11 patients in whom anti-NMDAR encephalitis occurred simultaneously with MRI and symptoms compatible with demyelination (5 AQ4 positive, 2 MOG positive). Group 3 (136 controls) included 50 randomly selected patients with typical anti-NMDAR encephalitis, 56 with NMO, and 30 with multiple sclerosis; NMDAR antibodies were detected only in the 50 anti-NMDAR patients, MOG antibodies in 3 of 50 anti-NMDAR and 1 of 56 NMO patients, and AQP4 antibodies in 48 of 56 NMO and 1 of 50 anti-NMDAR patients (p<0.0001 for all comparisons with Groups 1 and 2). Most patients improved with immunotherapy, but compared with anti-NMDAR encephalitis the demyelinating episodes required more intensive therapy and resulted in more residual deficits. Only 1 of 23 NMDAR patients with signs of demyelination had ovarian teratoma compared with 18 of 50 anti-NMDAR controls (p50.011). INTERPRETATION: Patients with anti-NMDAR encephalitis may develop concurrent or separate episodes of demyelinating disorders, and conversely patients with NMO or demyelinating disorders with atypical symptoms (eg, dyskinesias, psychosis) may have anti-NMDAR encephalitis.

Growth retardation as well as the development of Cushingoid features in adrenally insufficient patients treated with the currently accepted replacement dose of cortisol (33-41 mumol/day.m2; 12-15 mg/m2.day) prompted us to reevaluate the cortisol production rate (FPR) in normal subjects and patients with Cushing's syndrome, using a recently developed thermospray liquid chromatography-mass spectrometry method. The stable isotope [9,12,12-2H3]cortisol was infused continuously for 31 h at about 5% of the anticipated FPR. Blood samples were obtained at 20-min intervals for 24 h, spun, and pooled in 4-h groups. Tracer dilution in plasma was determined by liquid chromatography/mass spectrometry. The method was validated with controlled infusions in 6 patients with adrenal insufficiency. Results from 12 normal volunteers revealed a FPR of 27.3 +/- 7.5 mumol/day (9.9 +/- 2.7 mg/day) or 15.7 mumol/day.m2; 5.7 mg/m2. day). A previously unreported circadian variation in FPR was observed. Patients with Cushing's syndrome demonstrated unequivocal elevation of FPR and cortisol concentration correlated during each sample period in normal volunteers, indicating that cortisol secretion, rather than metabolism, is mainly responsible for changes in plasma cortisol. Our data suggest that the FPR in normal subjects may be lower than previously believed.

BACKGROUND: Despite an increasing incidence of venous thromboembolism (VTE) in pediatric patients in tertiary care settings, relatively few pediatric physicians have experience with antithrombotic interventions. OBJECTIVE: These guidelines of the American Society of Hematology (ASH), based on the best available evidence, are intended to support patients, clinicians, and other health care professionals in their decisions about management of pediatric VTE. METHODS: ASH formed a multidisciplinary guideline panel that included 2 patient representatives and was balanced to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline-development process, including updating or performing systematic evidence reviews (up to April of 2017). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. RESULTS: The panel agreed on 30 recommendations, covering symptomatic and asymptomatic deep vein thrombosis, with specific focus on management of central venous access device-associated VTE. The panel also addressed renal and portal vein thrombosis, cerebral sino venous thrombosis, and homozygous protein C deficiency. CONCLUSIONS: Although the panel offered many recommendations, additional research is required. Priorities include understanding the natural history of asymptomatic thrombosis, determining subgroup boundaries that enable risk stratification of children for escalation of treatment, and appropriate study of newer anticoagulant agents in children.

OBJECTIVES: To compare measures of psychometric assessment and school difficulties in a cohort of extremely low birth weight (ELBW) teenagers and term controls, and to determine whether there is stability in psychometric measures between age 8 and the teen years. STUDY DESIGN: Longitudinal follow-up; geographically defined region. PARTICIPANTS: 150 of 169 (89%) ELBW survivors born between 1977 and 1982 and 124 of 145 (86%) sociodemographically matched term controls between 12 and 16 years of age. Psychometric measures: Wechsler Intelligence Scale for Children-Revised, Wide Range Achievement Test-Revised, and a validated parent questionnaire. RESULTS: Neurosensory impairments were present in 28% of ELBW and 1% of controls. The mean Wechsler Intelligence Scale for Children-Revised scores were ELBW: 89 +/- 19 and controls: 102 +/- 13. ELBW children did less well on Wide Range Achievement Test-Revised Reading, Spelling, and Arithmetic measures with mean scores in the range from 75 to 85. ELBW children <750 g were more disadvantaged, compared with those >/=750 g. A significantly higher proportion of ELBW children were receiving special educational assistance and/or had repeated a grade (ELBW: 58%; controls: 13%; odds ratio: 9.0). Paired analysis of within-cohort data at age 8 and teen years showed that for both cohorts Arithmetic scores declined, but there were small improvements in other measures, predominantly in the term children. CONCLUSIONS: Differences of 13 to 18 points in psychometric measures in ELBW teens compared with controls are both statistically significant and clinically relevant. Decreasing birth weight was associated with increased risk on all measures. The high utilization of special educational resources has economic implications, and the incremental cost attributable to being extremely premature needs to be determined.

OBJECTIVE: Health administrative databases can be used to track chronic diseases. The aim of this study was to validate a case ascertainment definition of paediatric-onset inflammatory bowel disease (IBD) using administrative data and describe its epidemiology in Ontario, Canada. METHODS: A population-based clinical database of patients with IBD aged <15 years was used to define cases, and patient information was linked to health administrative data to compare the accuracy of various patterns of healthcare use. The most accurate algorithm was validated with chart data of children aged <18 years from 12 medical practices. Administrative data from the period 1991-2008 were used to describe the incidence and prevalence of IBD in Ontario children. Changes in incidence were tested using Poisson regression. RESULTS: Accurate identification of children with IBD required four physician contacts or two hospitalisations (with International Classification of Disease (ICD) codes for IBD) within 3 years if they underwent colonoscopy and seven contacts or three hospitalisations within 3 years in those without colonoscopy (children <12 years old, sensitivity 90.5%, specificity >99.9%; children <15 years old, sensitivity 89.6%, specificity >99.9%; children <18 years old, sensitivity 91.1%, specificity 99.5%). Age- and sex-standardised prevalence per 100 000 population of paediatric IBD has increased from 42.1 (in 1994) to 56.3 (in 2005). Incidence per 100 000 has increased from 9.5 (in 1994) to 11.4 (in 2005). Statistically significant increases in incidence were noted in 0-4 year olds (5.0%/year, p = 0.03) and 5-9 year olds (7.6%/year, p<0.0001), but not in 10-14 or 15-17 year olds. CONCLUSION: Ontario has one of the highest rates of childhood-onset IBD in the world, and there is an accelerated increase in incidence in younger children.

CONTEXT: In neonatal intensive care, parents make important clinical management decisions in conjunction with health care professionals. Yet little information is available on whether preferences of health care professionals and parents for the resulting health outcomes differ. OBJECTIVE: To measure and compare preferences for selected health states from the perspectives of health care professionals (ie, neonatologists and neonatal nurses), parents of extremely low-birth-weight (ELBW) or normal birth-weight infants, and adolescents who were either ELBW or normal birth-weight infants. DESIGN: Cross-sectional cohort study. SETTING AND PARTICIPANTS: A total of 742 participants were recruited and interviewed between 1993 and 1995, including 100 neonatologists from hospitals throughout Canada; 103 neonatal nurses from 3 regional neonatal intensive care units; 264 adolescents (aged 12-16 years), including 140 who were ELBW infants and 124 sociodemographically matched term controls; and 275 parents of the recruited adolescents. MAIN OUTCOME MEASURE: Preferences (utilities) for 4 to 5 hypothetical health states of children were obtained by direct interviews using the standard gamble method. RESULTS: Overall, neonatologists and nurses had similar preferences for the 5 health states, and a similar proportion rated some health states as worse than death (59% of neonatologists and 68% of nurses; P=.20). Health care professionals rated the health states lower than did parents of ELBW and term infants (P<.001). Overall, 64% of health care professionals and 45% of parents rated 1 or more health states to be worse than death (P<.001). Differences in mean utility scores between health care professionals and parents and adolescent respondents were most pronounced for the 2 most severely disabled health states (P<.001). CONCLUSIONS: When asked to rate the health-related quality of life for the hypothetical conditions of children, health care professionals tend to provide lower utility scores than do adolescents and their parents. These findings have implications for decision making in the neonatal intensive care unit.

The current interest in undertaking cost-effectiveness analyses alongside clinical trials has lead to the increasing availability of patient-level data on both the costs and effectiveness of intervention. In a recent paper, we show how cost-effectiveness analysis can be undertaken in a regression framework. In the current paper we develop a direct regression approach to cost-effectiveness analysis by proposing the use of a system of seemingly unrelated regression equations to provide a more general method for prognostic factor adjustment with emphasis on sub-group analysis. This more general method can be used in either an incremental cost-effectiveness or an incremental net-benefit approach, and does not require that the set of independent variables for costs and effectiveness be the same. Furthermore, the method can exhibit efficiency gains over unrelated ordinary least squares regression.

The new oral anticoagulants dabigatran, rivaroxaban and apixaban have advantages over warfarin which include no need for laboratory monitoring, less drug-drug interactions and less food-drug interactions. However, there is no established antidote for patients who are bleeding or require emergent surgery and there is a paucity of evidence to guide the clinical care during these situations. Members of thrombosis and anticoagulation groups participating in the Thrombosis and Hemostasis Summit of North America formulated expert opinion guidance for reversing the anticoagulant effect of the new oral anticoagulants and suggest: routine supportive care, activated charcoal if drug ingestion was within a couple of hours, and hemodialysis if feasible for dabigatran. Also, the pros and cons of the possible use of four factor prothrombin complex concentrate are discussed.

BACKGROUND: Based on regional and anecdotal reports, there is concern that vitamin D-deficiency rickets is persistent in Canada despite guidelines for its prevention. We sought to determine the incidence and clinical characteristics of vitamin D-deficiency rickets among children living in Canada. METHODS: A total of 2325 Canadian pediatricians were surveyed monthly from July 1, 2002, to June 30, 2004, through the Canadian Paediatric Surveillance Program to determine the incidence, geographic distribution and clinical profiles of confirmed cases of vitamin D-deficiency rickets. We calculated incidence rates based on the number of confirmed cases over the product of the length of the study period (2 years) and the estimates of the population by age group. RESULTS: There were 104 confirmed cases of vitamin D- deficiency rickets during the study period. The overall annual incidence rate was 2.9 cases per 100,000. The incidence rates were highest among children residing in the the north (Yukon Territory, Northwest Territories and Nunavut). The mean age at diagnosis was 1.4 years (standard deviation [SD] 0.9, min-max 2 weeks-6.3 years). Sixty-eight children (65%) had lived in urban areas most of their lives, and 57 (55%) of the cases were identified in Ontario. Ninety-two (89%) of the children had intermediate or darker skin. Ninety-eight (94%) had been breast-fed, and 3 children (2.9%) had been fed standard infant formula. None of the breast-fed infants had received vitamin D supplementation according to current guidelines (400 IU/d). Maternal risk factors included limited sun exposure and a lack of vitamin D from diet or supplements during pregnancy and lactation. The majority of children showed clinically important morbidity at diagnosis, including hypocalcemic seizures (20 cases, 19%). INTERPRETATION: Vitamin D-deficiency rickets is persistent in Canada, particularly among children who reside in the north and among infants with darker skin who are breast-fed without appropriate vitamin D supplementation. Since there were no reported cases of breast-fed children having received regular vitamin D (400 IU/d) from birth who developed rickets, the current guidelines for rickets prevention can be effective but are not being consistently implemented. The exception appears to be infants, including those fed standard infant formula, born to mothers with a profound vitamin D deficiency, in which case the current guidelines may not be adequate to rescue infants from the vitamin D-deficient state.

OBJECTIVE: Autoimmune encephalitis (AE) is an important and treatable cause of acute encephalitis. Diagnosis of AE in a developing child is challenging because of overlap in clinical presentations with other diseases and complexity of normal behavior changes. Existing diagnostic criteria for adult AE require modification to be applied to children, who differ from adults in their clinical presentations, paraclinical findings, autoantibody profiles, treatment response, and long-term outcomes. METHODS: A subcommittee of the Autoimmune Encephalitis International Working Group collaborated through conference calls and email correspondence to consider the pediatric-specific approach to AE. The subcommittee reviewed the literature of relevant AE studies and sought additional input from other expert clinicians and researchers. RESULTS: Existing consensus criteria for adult AE were refined for use in children. Provisional pediatric AE classification criteria and an algorithm to facilitate early diagnosis are proposed. There is also discussion about how to distinguish pediatric AE from conditions within the differential diagnosis. CONCLUSIONS: Diagnosing AE is based on the combination of a clinical history consistent with pediatric AE and supportive diagnostic testing, which includes but is not dependent on antibody testing. The proposed criteria and algorithm require validation in prospective pediatric cohorts.

OBJECTIVE: To present the one-year prevalence of 14 psychiatric disorders in a community sample of Ontarians aged 15 to 64 years. METHOD: Data on psychiatric disorders were collected on 9953 respondents using the University of Michigan revision of the Composite International Diagnostic Interview (UM-CIDI). DSM-III-R criteria were used to define the psychiatric disorders. RESULTS: Almost 1 in 5 Ontarians (18.6%) had one or more of the disorders measured in the survey. Among 15-to 24-year-olds, 1 in 4 was affected. The distribution of individual disorders varied by sex and age. CONCLUSION: Because of the immense burden of suffering associated with psychiatric disorders, clinical and research efforts in this area should receive high priority within the health budget.

CONTEXT: Periventricular/intraventricular hemorrhage (PIVH) is a common short-term morbidity in preterm infants, but its long-term neurodevelopmental impact, particularly with mild PIVH, remains unclear. OBJECTIVE: To systematically review and meta-analyze the neurodevelopmental outcomes of preterm infants ≤34 weeks' gestation with mild and severe PIVH, compared with no PIVH. DATA SOURCES: Medline, Embase, CINAHL, and PsychINFO databases from January 2000 through June 2014. STUDY SELECTION: Studies reporting long-term neurodevelopmental outcomes based on severity of PIVH were included. DATA EXTRACTION: Study characteristics, inclusion/exclusion criteria, exposures, and outcome assessment data extracted independently by 2 coauthors. RESULTS: The pooled unadjusted odds ratios of the primary outcome of death or moderate-severe neurodevelopmental impairment (NDI) were higher with both mild (1.48, 95% CI 1.26-1.73; 2 studies) and severe PIVH (4.72, 4.21-5.31; 3 studies); no studies reported adjusted odds ratios. Among survivors, odds of moderate-severe NDI were higher with mild and severe PIVH in both unadjusted (1.75, 1.40-2.20; 3 studies; 3.36, 3.06-3.68; 5 studies) and adjusted (1.39, 1.09-1.77; 3 studies; 2.44, 1.73-3.42; 2 studies) pooled analyses. Adjusted odds of cerebral palsy and cognitive delay were higher with severe but not mild PIVH. LIMITATIONS: Only observational studies were included. Fifteen of 21 included studies had a moderate-high risk of bias. CONCLUSIONS: Mild and severe PIVH are associated with progressively higher odds of death or moderate-severe NDI compared with no PIVH, but no studies adjusted for confounders. Among survivors, mild PIVH was associated with higher odds of moderate-severe NDI compared with no PIVH.