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      Prenatal, Perinatal and Neonatal Risk Factors for Intellectual Disability: A Systemic Review and Meta-Analysis

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          Abstract

          Background

          The etiology of non-genetic intellectual disability (ID) is not fully known, and we aimed to identify the prenatal, perinatal and neonatal risk factors for ID.

          Method

          PubMed and Embase databases were searched for studies that examined the association between pre-, peri- and neonatal factors and ID risk (keywords “intellectual disability” or “mental retardation” or “ID” or “MR” in combination with “prenatal” or “pregnancy” or “obstetric” or “perinatal” or “neonatal”. The last search was updated on September 15, 2015. Summary effect estimates (pooled odds ratios) were calculated for each risk factor using random effects models, with tests for heterogeneity and publication bias.

          Results

          Seventeen studies with 55,344 patients and 5,723,749 control individuals were eligible for inclusion in our analysis, and 16 potential risk factors were analyzed. Ten prenatal factors (advanced maternal age, maternal black race, low maternal education, third or more parity, maternal alcohol use, maternal tobacco use, maternal diabetes, maternal hypertension, maternal epilepsy and maternal asthma), one perinatal factor (preterm birth) and two neonatal factors (male sex and low birth weight) were significantly associated with increased risk of ID.

          Conclusion

          This systemic review and meta-analysis provides a comprehensive evidence-based assessment of the risk factors for ID. Future studies are encouraged to focus on perinatal and neonatal risk factors and the combined effects of multiple factors.

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          Most cited references26

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          Cognitive and behavioral outcomes of school-aged children who were born preterm: a meta-analysis.

          The cognitive and behavioral outcomes of school-aged children who were born preterm have been reported extensively. Many of these studies have methodological flaws that preclude an accurate estimate of the long-term outcomes of prematurity. To estimate the effect of preterm birth on cognition and behavior in school-aged children. MEDLINE search (1980 to November 2001) for English-language articles, supplemented by a manual search of personal files maintained by 2 of the authors. We included case-control studies reporting cognitive and/or behavioral data of children who were born preterm and who were evaluated after their fifth birthday if the attrition rate was less than 30%. From the 227 reviewed studies, cognitive data from 15 studies and behavioral data from 16 studies were selected. Data on population demographics, study characteristics, and cognitive and behavioral outcomes were extracted from each study, entered in a customized database, and reviewed twice to minimize error. Differences between the mean cognitive scores of cases and controls were pooled. Homogeneity across studies was formally tested using a general variance-based method and graphically using Galbraith plots. Linear meta-analysis regression models were fitted to explore the impact of birth weight and gestational age on cognitive outcomes. Study-specific relative risks (RRs) were calculated for the incidence of attention-deficit/hyperactivity disorder (ADHD) and pooled. Quality assessment of the studies was performed based on a 10-point scale. Publication bias was examined using Begg modified funnel plots and formally tested using the Egger weighted-linear regression method. Among 1556 cases and 1720 controls, controls had significantly higher cognitive scores compared with children who were born preterm (weighted mean difference, 10.9; 95% confidence interval [CI], 9.2-12.5). The mean cognitive scores of preterm-born cases and term-born controls were directly proportional to their birth weight (R(2) = 0.51; P<.001) and gestational age (R(2) = 0.49; P<.001). Age at evaluation had no significant correlation with mean difference in cognitive scores (R(2) = 0.12; P =.20). Preterm-born children showed increases in externalizing and internalizing behaviors in 81% of studies and had more than twice the RR for developing ADHD (pooled RR, 2.64; 95% CI, 1.85-3.78). No differences were noted in cognition and behaviors based on the quality of the study. Children who were born preterm are at risk for reduced cognitive test scores and their immaturity at birth is directly proportional to the mean cognitive scores at school age. Preterm-born children also show an increased incidence of ADHD and other behaviors.
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            Inflammation during fetal and neonatal life: implications for neurologic and neuropsychiatric disease in children and adults.

            Inflammation is increasingly recognized as being of both physiological and pathological importance in the immature brain. The rationale of this review is to present an update on this topic with focus on long-term consequences of inflammation during childhood and in adults. The immature brain can be exposed to inflammation in connection with viral or bacterial infection during pregnancy or as a result of sterile central nervous system (CNS) insults. Through efficient anti-inflammatory and reparative processes, inflammation may resolve without any harmful effects on the brain. Alternatively, inflammation contributes to injury or enhances CNS vulnerability. Acute inflammation can also be shifted to a chronic inflammatory state and/or adversely affect brain development. Hypothetically, microglia are the main immunocompetent cells in the immature CNS, and depending on the stimulus, molecular context, and timing, these cells will acquire various phenotypes, which will be critical regarding the CNS consequences of inflammation. Inflammation has long-term consequences and could speculatively modify the risk of a variety of neurological disorders, including cerebral palsy, autism spectrum disorders, schizophrenia, multiple sclerosis, cognitive impairment, and Parkinson disease. So far, the picture is incomplete, and data mostly experimental. Further studies are required to strengthen the associations in humans and to determine whether novel therapeutic interventions during the perinatal period can influence the occurrence of neurological disease later in life. Copyright © 2012 American Neurological Association.
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              The genetic basis of non-syndromic intellectual disability: a review

              Intellectual disability (ID), also referred to as mental retardation (MR), is frequently the result of genetic mutation. Where ID is present together with additional clinical symptoms or physical anomalies, there is often sufficient information available for the diagnosing physician to identify a known syndrome, which may then educe the identification of the causative defect. However, where co-morbid features are absent, narrowing down a specific gene can only be done by ‘brute force’ using the latest molecular genetic techniques. Here we attempt to provide a systematic review of genetic causes of cases of ID where no other symptoms or co-morbid features are present, or non-syndromic ID. We attempt to summarize commonalities between the genes and the molecular pathways of their encoded proteins. Since ID is a common feature of autism, and conversely autistic features are frequently present in individuals with ID, we also look at possible overlaps in genetic etiology with non-syndromic ID.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                25 April 2016
                2016
                : 11
                : 4
                : e0153655
                Affiliations
                [1 ]Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
                [2 ]Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, Chengdu, 610041, China
                [3 ]Department of Pediatrics, University of California San Francisco, San Francisco, CA, 94143, United States of America
                Columbia University, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: JH DM. Performed the experiments: JH TZ. Analyzed the data: JH. Contributed reagents/materials/analysis tools: JH. Wrote the paper: JH TZ. Contributed to the critical review and final approval of the submitted manuscript: YQ DM.

                Article
                PONE-D-16-01256
                10.1371/journal.pone.0153655
                4844149
                27110944
                1eadd33d-c4ff-4565-ab94-5b7e4299ed65
                © 2016 Huang et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 13 January 2016
                : 2 April 2016
                Page count
                Figures: 3, Tables: 4, Pages: 12
                Funding
                Funded by: the National Science Foundation of China
                Award ID: No.81330016, 81300524, 81172174, 81270724 and 81200462
                Award Recipient :
                Funded by: the State Commission of Science Technology of China
                Award ID: 2013CB967404,2012BAI04B04
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100002338, Ministry of Education of the People's Republic of China;
                Award ID: IRT0935,313037
                Award Recipient :
                Funded by: the Science and Technology Bureau of Sichuan province
                Award ID: 2014SZ0149
                Award Recipient :
                Funded by: clinical discipline program (neonatology) from the Ministry of Health of China
                Award ID: 1311200003303
                Award Recipient :
                This work was supported by the National Science Foundation of China (No. 81330016, 81300524, 81172174, 81270724 and 81200462), grants from the State Commission of Science Technology of China (2013CB967404, 2012BAI04B04), grants from the Ministry of Education of China (IRT0935, 313037), grants from the Science and Technology Bureau of Sichuan province (2014SZ0149, 2016TD0002), and a grant of clinical discipline program (neonatology) from the Ministry of Health of China (1311200003303).
                Categories
                Research Article
                Research and Analysis Methods
                Mathematical and Statistical Techniques
                Statistical Methods
                Meta-Analysis
                Physical Sciences
                Mathematics
                Statistics (Mathematics)
                Statistical Methods
                Meta-Analysis
                Medicine and Health Sciences
                Diagnostic Medicine
                Research and Analysis Methods
                Research Design
                Cohort Studies
                Physical Sciences
                Mathematics
                Statistics (Mathematics)
                Statistical Data
                Medicine and Health Sciences
                Pediatrics
                Research and Analysis Methods
                Research Design
                Case-Control Studies
                Biology and Life Sciences
                Developmental Biology
                Neonates
                Research and Analysis Methods
                Database and Informatics Methods
                Database Searching
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                All relevant data are within the paper and its Supporting Information files.

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