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Maternal Diabetes and the Risk of Autism Spectrum Disorders in the Offspring: A Systematic Review and Meta-Analysis

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Abstract

We performed a systematic literature search regarding maternal diabetes before and during pregnancy and the risk of autism spectrum disorders (ASD) in the offspring. Of the 178 potentially relevant articles, 12 articles including three cohort studies and nine case–control studies were included in the meta-analysis. Both the meta-analyses of cohort studies and case–control studies showed significant associations. The pooled relative risk and 95 % confidence interval (CI) among cohort studies was 1.48 (1.25–1.75, p < 0.001). For case–control studies, the pooled odds ratio and 95 % CI was 1.72 (1.24–2.41, p = 0.001). No indication of significant heterogeneity across studies or publication bias was observed. In conclusion, maternal diabetes was significantly associated with a greater risk of ASD in the offspring.

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Abbreviations

ADI-R:

Autism diagnostic interview-revised

ADOS:

The autism diagnostic observation schedule

ASD:

Autism spectrum disorders

CARS:

The childhood autism rating scale

CI:

Confidence interval

DSM-IV:

The diagnostic and statistical manual of mental disorders, fourth edition

ICD:

International classification of diseases

OR:

Odds ratio

RR:

Relative risk

References

  • Albrecht, S. S., Kuklina, E. V., Bansil, P., Jamieson, D. J., Whiteman, M. K., Kourtis, A. P., et al. (2010). Diabetes trends among delivery hospitalizations in the US, 1994–2004. Diabetes Care, 33, 768–773.

    Article  PubMed Central  PubMed  Google Scholar 

  • American Diabetes Association. (2004). Gestational diabetes mellitus. Diabetes Care, 27(Suppl 1), S88–S90.

    Google Scholar 

  • American Diabetes Association. (2013). Diagnosis and classification of diabetes mellitus. Diabetes Care, 36(Suppl 1), S67–S74.

    Article  PubMed Central  Google Scholar 

  • Anderson, J. L., Waller, D. K., Canfield, M. A., Shaw, G. M., Watkins, M. L., & Werler, M. M. (2005). Maternal obesity, gestational diabetes, and central nervous system birth defects. Epidemiology, 16, 87–92.

    Article  PubMed  Google Scholar 

  • Autism and Developmental Disabilities Monitoring Network Surveillance Year 2008 Principal Investigators; Centers for Disease Control and Prevention. (2012). Prevalence of autism spectrum disorders–Autism and Developmental Disabilities Monitoring Network, 14 sites, United States, 2008. MMWR Surveill Summ, 61, 1–19.

    Google Scholar 

  • Bailey, A., Le Couteur, A., Gottesman, I., Bolton, P., Simonoff, E., Yuzda, E., et al. (1995). Autism as a strongly genetic disorder: evidence from a British twin study. Psychological Medicine, 25, 63–77.

    Article  PubMed  Google Scholar 

  • Bardenheier, B. H., Elixhauser, A., Imperatore, G., Devlin, H. M., Kuklina, E. V., Geiss, L. S., et al. (2013). Variation in prevalence of gestational diabetes mellitus among hospital discharges for obstetric delivery across 23 states in the United States. Diabetes Care, 36, 1209–1214.

    Article  PubMed  Google Scholar 

  • Bell, R., Bailey, K., Cresswell, T., Hawthorne, G., Critchley, J., & Lewis-Barned, N. (2008). Trends in prevalence and outcomes of pregnancy in women with pre-existing type I and type II diabetes. BJOG: An International Journal of Obstetrics and Gynaecology, 115, 445–452.

    Article  Google Scholar 

  • Biri, A., Onan, A., Devrim, E., Babacan, F., Kavutcu, M., & Durak, I. (2006). Oxidant status in maternal and cord plasma and placental tissue in gestational diabetes. Placenta, 27, 327–332.

    Article  PubMed  Google Scholar 

  • Brimacombe, M., Ming, X., & Lamendola, M. (2007). Prenatal and birth complications in autism. Maternal and Child Health Journal, 11, 73–79.

    Article  PubMed  Google Scholar 

  • Buchmayer, S., Johansson, S., Johansson, A., Hultman, C. M., Sparen, P., & Cnattingius, S. (2009). Can association between preterm birth and autism be explained by maternal or neonatal morbidity? Pediatrics, 124, e817–e825.

    Article  PubMed  Google Scholar 

  • Burstyn, I., Sithole, F., & Zwaigenbaum, L. (2010). Autism spectrum disorders, maternal characteristics and obstetric complications among singletons born in Alberta, Canada. Chronic Diseases in Canada, 30, 125–134.

    PubMed  Google Scholar 

  • Burstyn, I., Wang, X., Yasui, Y., Sithole, F., & Zwaigenbaum, L. (2011). Autism spectrum disorders and fetal hypoxia in a population-based cohort: accounting for missing exposures via Estimation-Maximization algorithm. BMC Medical Research Methodology, 11, 2.

    Article  PubMed Central  PubMed  Google Scholar 

  • Chauhan, A., Chauhan, V., Brown, W. T., & Cohen, I. (2004). Oxidative stress in autism: increased lipid peroxidation and reduced serum levels of ceruloplasmin and transferrin–the antioxidant proteins. Life Sciences, 75, 2539–2549.

    Article  PubMed  Google Scholar 

  • Chen, X., & Scholl, T. O. (2005). Oxidative stress: Changes in pregnancy and with gestational diabetes mellitus. Current Diabetes Reports, 5, 282–288.

    Article  PubMed  Google Scholar 

  • Croen, L. A., Grether, J. K., Yoshida, C. K., Odouli, R., & Van de Water, J. (2005). Maternal autoimmune diseases, asthma and allergies, and childhood autism spectrum disorders: A case-control study. Archives of Pediatrics and Adolescent Medicine, 159, 151–157.

    Article  PubMed  Google Scholar 

  • DerSimonian, R., & Laird, N. (1986). Meta-analysis in clinical trials. Controlled Clinical Trials, 7, 177–188.

    Article  PubMed  Google Scholar 

  • Dodds, L., Fell, D. B., Shea, S., Armson, B. A., Allen, A. C., & Bryson, S. (2011). The role of prenatal, obstetric and neonatal factors in the development of autism. Journal of Autism and Developmental Disorders, 41, 891–902.

    Article  PubMed  Google Scholar 

  • Egger, M., Davey Smith, G., Schneider, M., & Minder, C. (1997). Bias in meta-analysis detected by a simple, graphical test. BMJ, 315, 629–634.

    Article  PubMed Central  PubMed  Google Scholar 

  • Eidelman, A. I., & Samueloff, A. (2002). The pathophysiology of the fetus of the diabetic mother. Seminars in Perinatology, 26, 232–236.

    Article  PubMed  Google Scholar 

  • Elhameed, M. A. A., Elbaky, A. E. O. A., & Kamel, E. A. (2011). A controlled study of the risk factors and clinical picture of children with autism in an Egyptian sample. Egypt Journal of Neurology, Neurosurgery and Psychiatry, 48, 271–276.

    Google Scholar 

  • Fernandez-Morera, J. L., Rodriguez-Rodero, S., Menendez-Torre, E., & Fraga, M. F. (2010). The possible role of epigenetics in gestational diabetes: Cause, consequence, or both. Obstetrics and Gynecology International, 2010, 605163.

    Article  PubMed Central  PubMed  Google Scholar 

  • Ferrara, A. (2007). Increasing prevalence of gestational diabetes mellitus: A public health perspective. Diabetes Care, 30(Suppl 2), S141–S146.

    Article  PubMed  Google Scholar 

  • Gardener, H., Spiegelman, D., & Buka, S. L. (2009). Prenatal risk factors for autism: Comprehensive meta-analysis. British Journal of Psychiatry, 195, 7–14.

    Article  PubMed Central  PubMed  Google Scholar 

  • Gardener, H., Spiegelman, D., & Buka, S. L. (2011). Perinatal and neonatal risk factors for autism: A comprehensive meta-analysis. Pediatrics, 128, 344–355.

    Article  PubMed Central  PubMed  Google Scholar 

  • Georgieff, M. K. (2006). The effect of maternal diabetes during pregnancy on the neurodevelopment of offspring. Minnesota Medicine, 89, 44–47.

    PubMed  Google Scholar 

  • Gillberg, C. (1999). Neurodevelopmental processes and psychological functioning in autism. Development and Psychopathology, 11, 567–587.

    Article  PubMed  Google Scholar 

  • Guinchat, V., Thorsen, P., Laurent, C., Cans, C., Bodeau, N., & Cohen, D. (2012). Pre-, peri- and neonatal risk factors for autism. Acta Obstetricia et Gynecologica Scandinavica, 91, 287–300.

    Article  PubMed  Google Scholar 

  • Hayes, D. K., Fan, A. Z., Smith, R. A., & Bombard, J. M. (2011). Trends in selected chronic conditions and behavioral risk factors among women of reproductive age, behavioral risk factor surveillance system, 2001–2009. Preventing Chronic Disease, 8, A120.

    PubMed Central  PubMed  Google Scholar 

  • Herrera, E., & Ortega-Senovilla, H. (2010). Disturbances in lipid metabolism in diabetic pregnancy: Are these the cause of the problem? Best Practice and Research Clinical Endocrinology and Metabolism, 24, 515–525.

    Article  PubMed  Google Scholar 

  • Higgins, J. P., & Thompson, S. G. (2002). Quantifying heterogeneity in a meta-analysis. Statistics in Medicine, 21, 1539–1558.

    Article  PubMed  Google Scholar 

  • Huerta, J. M., Tormo, M. J., Egea-Caparros, J. M., Ortola-Devesa, J. B., & Navarro, C. (2009). Accuracy of self-reported diabetes, hypertension and hyperlipidemia in the adult Spanish population. DINO study findings. Revista Espanola de Cardiologia, 62, 143–152.

    Article  PubMed  Google Scholar 

  • Hultman, C. M., Sparen, P., & Cnattingius, S. (2002). Perinatal risk factors for infantile autism. Epidemiology, 13, 417–423.

    Article  PubMed  Google Scholar 

  • International Diabetes Federation. (2013) IDF Policy Briefing: Diabetes in Pregnancy: Protecting Maternal Health. Accessed July 10, 2013, from http://www.idf.org/sites/default/files/Policy_Briefing_DiabetesInPregancy.pdf.

  • Juul-Dam, N., Townsend, J., & Courchesne, E. (2001). Prenatal, perinatal, and neonatal factors in autism, pervasive developmental disorder-not otherwise specified, and the general population. Pediatrics, 107, E63.

    Article  PubMed  Google Scholar 

  • Keil, A., Daniels, J. L., Forssen, U., Hultman, C., Cnattingius, S., Soderberg, K. C., et al. (2010). Parental autoimmune diseases associated with autism spectrum disorders in offspring. Epidemiology, 21, 805–808.

    Article  PubMed Central  PubMed  Google Scholar 

  • Kolevzon, A., Gross, R., & Reichenberg, A. (2007). Prenatal and perinatal risk factors for autism: a review and integration of findings. Archives of Pediatrics and Adolescent Medicine, 161, 326–333.

    Article  PubMed  Google Scholar 

  • Krakowiak, P., Walker, C. K., Bremer, A. A., Baker, A. S., Ozonoff, S., Hansen, R. L., et al. (2012). Maternal metabolic conditions and risk for autism and other neurodevelopmental disorders. Pediatrics, 129, e1121–e1128.

    Article  PubMed Central  PubMed  Google Scholar 

  • Leonard, H., de Klerk, N., Bourke, J., & Bower, C. (2006). Maternal health in pregnancy and intellectual disability in the offspring: A population-based study. Annals of Epidemiology, 16, 448–454.

    Article  PubMed  Google Scholar 

  • Levy, S. E., Mandell, D. S., & Schultz, R. T. (2009). Autism. Lancet, 374, 1627–1638.

    Article  Google Scholar 

  • London, E. A. (2000). The environment as an etiologic factor in autism: A new direction for research. Environmental Health Perspectives, 108(Suppl 3), 401–404.

    PubMed Central  PubMed  Google Scholar 

  • Lyall, K., Pauls, D. L., Spiegelman, D., Ascherio, A., & Santangelo, S. L. (2012). Pregnancy complications and obstetric suboptimality in association with autism spectrum disorders in children of the Nurses’ Health Study II. Autism Research, 5, 21–30.

    Article  PubMed Central  PubMed  Google Scholar 

  • Ming, X., Stein, T. P., Brimacombe, M., Johnson, W. G., Lambert, G. H., & Wagner, G. C. (2005). Increased excretion of a lipid peroxidation biomarker in autism. Prostaglandins Leukotrienes and Essential Fatty Acids, 73, 379–384.

    Article  Google Scholar 

  • National Institute for Health and Care Excellence. (2009). NICE clinical guidelines 63: Diabetes in pregnancy: Management of diabetes and its complications from pre-conception to the postnatal period. Accessed July 10, 2013, from http://guidance.nice.org.uk/CG63.

  • Newschaffer, C. J., Croen, L. A., Daniels, J., Giarelli, E., Grether, J. K., Levy, S. E., et al. (2007). The epidemiology of autism spectrum disorders. Annual Review of Public Health, 28, 235–258.

    Article  PubMed  Google Scholar 

  • Okura, Y., Urban, L. H., Mahoney, D. W., Jacobsen, S. J., & Rodeheffer, R. J. (2004). Agreement between self-report questionnaires and medical record data was substantial for diabetes, hypertension, myocardial infarction and stroke but not for heart failure. Journal of Clinical Epidemiology, 57, 1096–1103.

    Article  PubMed  Google Scholar 

  • Onore, C., Careaga, M., & Ashwood, P. (2012). The role of immune dysfunction in the pathophysiology of autism. Brain, Behavior, and Immunity, 26, 383–392.

    Article  PubMed Central  PubMed  Google Scholar 

  • Ornoy, A., Ratzon, N., Greenbaum, C., Wolf, A., & Dulitzky, M. (2001). School-age children born to diabetic mothers and to mothers with gestational diabetes exhibit a high rate of inattention and fine and gross motor impairment. Journal of Pediatric Endocrinology and Metabolism, 14(Suppl 1), 681–689.

    PubMed  Google Scholar 

  • Piven, J., Simon, J., Chase, G. A., Wzorek, M., Landa, R., Gayle, J., et al. (1993). The etiology of autism: Pre-, peri- and neonatal factors. Journal of the American Academy of Child and Adolescent Psychiatry, 32, 1256–1263.

    Article  PubMed  Google Scholar 

  • Rapin, I. (2002). The autistic-spectrum disorders. New England Journal of Medicine, 347, 302–303.

    Article  PubMed  Google Scholar 

  • Rizzo, T. A., Dooley, S. L., Metzger, B. E., Cho, N. H., Ogata, E. S., & Silverman, B. L. (1995). Prenatal and perinatal influences on long-term psychomotor development in offspring of diabetic mothers. American Journal of Obstetrics and Gynecology, 173, 1753–1758.

    Article  PubMed  Google Scholar 

  • Rodier, P. M., Ingram, J. L., Tisdale, B., Nelson, S., & Romano, J. (1996). Embryological origin for autism: developmental anomalies of the cranial nerve motor nuclei. Journal of Comparative Neurology, 370, 247–261.

    Article  PubMed  Google Scholar 

  • Schanen, N. C. (2006). Epigenetics of autism spectrum disorders. Hum Mol Genet, 15(2), R138–R150.

    Article  PubMed  Google Scholar 

  • Solomon, C. G., Willett, W. C., Carey, V. J., Rich-Edwards, J., Hunter, D. J., Colditz, G. A., et al. (1997). A prospective study of pregravid determinants of gestational diabetes mellitus. The Journal of the American Medical Association, 278, 1078–1083.

    Article  Google Scholar 

  • Stern, M. (2011). Insulin signaling and autism. Frontiers in Endocrinology, 2, 54.

    Article  PubMed Central  PubMed  Google Scholar 

  • Stroup, D. F., Berlin, J. A., Morton, S. C., Olkin, I., Williamson, G. D., Rennie, D., et al. (2000). Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. The Journal of the American Medical Association, 283, 2008–2012.

    Article  Google Scholar 

  • Van den Bergh, B. R. (2011). Developmental programming of early brain and behaviour development and mental health: a conceptual framework. Developmental Medicine and Child Neurology, 53(Suppl 4), 19–23.

    Article  PubMed  Google Scholar 

  • Wells, G. A., Shea, B., O’Connell, D., Peterson, J., Welch, V., Losos, M., et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses. Accessed January 30, 2013, from http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm.

  • Wong, V. C., & Hui, S. L. (2008). Epidemiological study of autism spectrum disorder in China. Journal of Child Neurology, 23, 67–72.

    Article  PubMed  Google Scholar 

  • Yao, Y., Walsh, W. J., McGinnis, W. R., & Pratico, D. (2006). Altered vascular phenotype in autism: correlation with oxidative stress. Archives of Neurology, 63, 1161–1164.

    Article  PubMed  Google Scholar 

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Acknowledgments

This study was funded by the National Natural Science Foundation of China (No. 81172687) and the Doctoral Fund of Ministry of Education of China (No. 20110171110053). Dr. Wei Bao was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, USA.

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Authors and Affiliations

  1. Department of Maternal and Child Health, School of Public Health, Sun Yat-Sen University, Guangzhou, 510080, China

    Guifeng Xu, Jin Jing & Buyun Liu

  2. Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, 45229, USA

    Katherine Bowers

  3. Epidemiology Branch, Division of Epidemiology, Statistics, and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, MD, 20852, USA

    Wei Bao

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  1. Guifeng Xu
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  2. Jin Jing
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  4. Buyun Liu
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Correspondence to Jin Jing or Wei Bao.

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Registration: This review was registered at the PROSPERO as CRD42012003373.

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Xu, G., Jing, J., Bowers, K. et al. Maternal Diabetes and the Risk of Autism Spectrum Disorders in the Offspring: A Systematic Review and Meta-Analysis. J Autism Dev Disord 44, 766–775 (2014). https://doi.org/10.1007/s10803-013-1928-2

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