Prenatal risk factors for autism: comprehensive meta-analysis

Background The aetiology of autism is unknown, although prenatal exposures have been the focus of epidemiological research for over 40 years. Aims To provide the first quantitative review and meta-analysis of the association between maternal pregnancy complications and pregnancy-related factors and risk of autism. Method PubMed, Embase and PsycINFO databases were searched for epidemiological studies that examined the association between pregnancy-related factors and autism. Forty studies were eligible for inclusion in the meta-analysis. Summary effect estimates were calculated for factors examined in multiple studies. Results Over 50 prenatal factors have been examined. The factors associated with autism risk in the meta-analysis were advanced parental age at birth, maternal prenatal medication use, bleeding, gestational diabetes, being first born v. third or later, and having a mother born abroad. The factors with the strongest evidence against a role in autism risk included previous fetal loss and maternal hypertension, proteinuria, pre-eclampsia and swelling. Conclusions There is insufficient evidence to implicate any one prenatal factor in autism aetiology, although there is some evidence to suggest that exposure to pregnancy complications may increase the risk.

[1]  S. Klauck,et al.  Genetics of autism spectrum disorder , 2006, European Journal of Human Genetics.

[2]  N. Laird,et al.  Meta-analysis in clinical trials. , 1986, Controlled clinical trials.

[3]  Stine Levy,et al.  A comparison of obstetrical records of autistic and nonautistic referrals for psychoeducational evaluations , 1988, Journal of autism and developmental disorders.

[4]  M. Hod,et al.  Epidemiology of gestational diabetes mellitus and its association with Type 2 diabetes , 2004, Diabetic medicine : a journal of the British Diabetic Association.

[5]  S. Selvin,et al.  Descriptive Epidemiology of Autism in a California Population: Who Is at Risk? , 2002, Journal of autism and developmental disorders.

[6]  P. Links,et al.  Minor physical anomalies in childhood autism , 1980, Journal of autism and developmental disorders.

[7]  T. Matsuishi,et al.  Brief Report: Incidence of and Risk Factors for Autistic Disorder in Neonatal Intensive Care Unit Survivors , 1999, Journal of autism and developmental disorders.

[8]  S. Lai,et al.  Lack of a relation between human neonatal thyroxine and pediatric neurobehavioral disorders. , 2003, Thyroid : official journal of the American Thyroid Association.

[9]  J. Harper,et al.  EARLY ENVIRONMENTAL STRESS AND INFANTILE AUTISM , 1974, The Medical journal of Australia.

[10]  A. Ward A comparison and analysis of the presence of family problems during pregnancy of mothers of “autistic” children and mothers of normal children , 1990, Child psychiatry and human development.

[11]  E. Ritvo,et al.  Brief Report: A comparison of potentially pathologic factors in European children with autism, Down's syndrome, and multiple physical handicaps , 1988, Journal of autism and developmental disorders.

[12]  M. Pittler Systematic Reviews in Health Care: Meta‐analysis in Context , 2010 .

[13]  B. Quarrington,et al.  Pre-, peri-, and neonatal factors and infantile autism. , 1979, Journal of child psychology and psychiatry, and allied disciplines.

[14]  I. Olkin,et al.  Meta-analysis of observational studies in epidemiology - A proposal for reporting , 2000 .

[15]  J. King,et al.  Gestational diabetes and insulin resistance: role in short- and long-term implications for mother and fetus. , 2003, The Journal of nutrition.

[16]  Marjorie Solomon,et al.  Evidence-Based Assessment of Autism Spectrum Disorders in Children and Adolescents , 2005, Journal of clinical child and adolescent psychology : the official journal for the Society of Clinical Child and Adolescent Psychology, American Psychological Association, Division 53.

[17]  C. Gillberg,et al.  Infantile autism: A total population study of reduced optimality in the pre-, peri-, and neonatal period , 1983, Journal of autism and developmental disorders.

[18]  D. Spiegelman,et al.  Evaluation of old and new tests of heterogeneity in epidemiologic meta-analysis. , 1999, American journal of epidemiology.

[19]  L. Burd,et al.  A comparison of the effects of parental risk markers on pre- and perinatal variables in multiple patient cohorts with fetal alcohol syndrome, autism, Tourette syndrome, and sudden infant death syndrome: an enviromic analysis. , 2003, Neurotoxicology and teratology.

[20]  E. Deykin,et al.  Pregnancy, delivery, and neonatal complications among autistic children. , 1980, American journal of diseases of children.

[21]  C. Gillberg Maternal age and infantile autism , 1980, Journal of autism and developmental disorders.

[22]  U. Gabbay,et al.  Season of birth and autistic disorder in Israel. , 1995, The American journal of psychiatry.

[23]  C. Gillberg,et al.  A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. , 1989, Journal of child psychology and psychiatry, and allied disciplines.

[24]  Abraham Weizman,et al.  Obstetric complications in individuals diagnosed with autism and in healthy controls. , 2006, Comprehensive psychiatry.

[25]  H. Merckelbach,et al.  Birth Patterns in Mentally Retarded Autistic Patients , 2000, Journal of autism and developmental disorders.

[26]  R. T. Lie,et al.  Down's syndrome and paternal age in Norway. , 2002, Paediatric and perinatal epidemiology.

[27]  C. Gillberg,et al.  Autism in immigrants: children born in Sweden to mothers born in Uganda. , 1995, Journal of intellectual disability research : JIDR.

[28]  Cathleen K. Yoshida,et al.  Neonatal Hyperbilirubinemia and Risk of Autism Spectrum Disorders , 2005, Pediatrics.

[29]  S. Dalsgaard,et al.  Variation in Incidence of Neurodevelopmental Disorders With Season of Birth , 2007, Epidemiology.

[30]  M. Stewart,et al.  Etiological implication of maternal age and birth order in infantile autism , 1983, Journal of autism and developmental disorders.

[31]  R. Yolken,et al.  Autism and head circumference in the first year of life , 2004, Biological Psychiatry.

[32]  Alexander Kolevzon,et al.  Prenatal and perinatal risk factors for autism: a review and integration of findings. , 2007, Archives of pediatrics & adolescent medicine.

[33]  Douglas G. Altman,et al.  Systematic Reviews in Health Care: Meta-Analysis in Context: Second Edition , 2008 .

[34]  Esben Agerbo,et al.  Risk factors for autism: perinatal factors, parental psychiatric history, and socioeconomic status. , 2005, American journal of epidemiology.

[35]  M. Stevens,et al.  Season of Birth Effects in Autism , 2000, Journal of clinical and experimental neuropsychology.

[36]  S. Paterson–Brown,et al.  Is there an incremental rise in the risk of obstetric intervention with increasing maternal age? , 1998, British journal of obstetrics and gynaecology.

[37]  M. Brimacombe,et al.  Prenatal and Birth Complications in Autism , 2006, Maternal and Child Health Journal.

[38]  M. Lauritsen,et al.  Effects of familial risk factors and place of birth on the risk of autism: a nationwide register-based study. , 2005, Journal of child psychology and psychiatry, and allied disciplines.

[39]  C. Cans,et al.  Trends, perinatal characteristics, and medical conditions in pervasive developmental disorders. , 2006, Developmental medicine and child neurology.

[40]  D. Altman,et al.  Measuring inconsistency in meta-analyses , 2003, BMJ : British Medical Journal.

[41]  P. Bolton,et al.  Pervasive Developmental Disorder and Obstetric Complications in Children and Adolescents with Tuberous Sclerosis , 2001, Autism : the international journal of research and practice.

[42]  J. Piven,et al.  Magnetic resonance imaging and head circumference study of brain size in autism: birth through age 2 years. , 2005, Archives of general psychiatry.

[43]  John E. Cooper,et al.  Diagnostic and Statistical Manual of Mental Disorders (4th edn, text revision) (DSM-IV-TR) , 2001, British Journal of Psychiatry.

[44]  E. Deykin,et al.  Viral exposure and autism. , 1979, American journal of epidemiology.

[45]  M. Frydenberg,et al.  Obstetric Complications and Risk for Severe Psychopathology in Childhood , 2001, Journal of autism and developmental disorders.

[46]  T. Fukuda,et al.  Neonatal factors in infants with Autistic Disorder and typically developing infants , 2005, Autism : the international journal of research and practice.

[47]  Mark Weiser,et al.  Advancing paternal age and autism. , 2006, Archives of general psychiatry.

[48]  S. Bryson,et al.  Pregnancy and birth complications in autism and liability to the broader autism phenotype. , 2002, Journal of the American Academy of Child and Adolescent Psychiatry.

[49]  A. Bailey,et al.  Autism as a strongly genetic disorder: evidence from a British twin study , 1995, Psychological Medicine.

[50]  S. Santangelo,et al.  What is known about autism: genes, brain, and behavior. , 2005, American journal of pharmacogenomics : genomics-related research in drug development and clinical practice.

[51]  C. Lord,et al.  Pre- and perinatal factors in high-functioning females and males with autism , 1991, Journal of autism and developmental disorders.

[52]  B. Pasamanick,et al.  Some etiologic and prognostic factors in early infantile autism and psychosis. , 1975, Pediatrics.

[53]  D O Stram,et al.  Meta-analysis of published data using a linear mixed-effects model. , 1996, Biometrics.

[54]  Stephen J. Sharp,et al.  Meta-analysis regression , 1998 .

[55]  J. Martin,et al.  Births: final data for 2000. , 2002, National vital statistics reports : from the Centers for Disease Control and Prevention, National Center for Health Statistics, National Vital Statistics System.

[56]  Susan L. Santangelo,et al.  What is Known About Autism , 2005 .

[57]  W. McMahon,et al.  The UCLA-University of Utah epidemiologic survey of autism: prenatal, perinatal, and postnatal factors. , 1990, Pediatrics.

[58]  M. Konstantareas,et al.  Season of birth in infantile autism , 1986, Child psychiatry and human development.

[59]  J. Keogh,et al.  Autism following a history of newborn encephalopathy: more than a coincidence? , 2006, Developmental medicine and child neurology.

[60]  S. Greenland,et al.  Methods for trend estimation from summarized dose-response data, with applications to meta-analysis. , 1992, American journal of epidemiology.

[61]  S. Folstein,et al.  The etiology of autism: pre-, peri- and neonatal factors. , 1993, Journal of the American Academy of Child and Adolescent Psychiatry.

[62]  E. Torrey,et al.  Early childhood psychosis and bleeding during pregnancy , 1975, Journal of autism and childhood schizophrenia.

[63]  J. Attia,et al.  Basic concepts in meta‐analysis: a primer for clinicians , 2006, International journal of clinical practice.

[64]  S. Nielsen,et al.  Season of birth in infantile autism and other types of childhood psychoses , 1994, Child psychiatry and human development.

[65]  J. Townsend,et al.  Prenatal, Perinatal, and Neonatal Factors in Autism, Pervasive Developmental Disorder-Not Otherwise Specified, and the General Population , 2001, Pediatrics.

[66]  M. Væth,et al.  Perinatal risk factors and infantile autism , 2006, Acta psychiatrica Scandinavica.

[67]  Yoko Tanoue,et al.  Epidemiology of infantile autism in southern Ibaraki, Japan: Differences in prevalence in birth cohorts , 1988, Journal of autism and developmental disorders.

[68]  Pär Sparén,et al.  Perinatal Risk Factors for Infantile Autism , 2002, Epidemiology.

[69]  S. Gubbay,et al.  Childhood Autism: An Investigation of Aetiological Factors in Twenty-five Cases , 1970, British Journal of Psychiatry.

[70]  J. Sterne,et al.  Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. , 2000, Journal of clinical epidemiology.

[71]  F. Previc Prenatal influences on brain dopamine and their relevance to the rising incidence of autism. , 2007, Medical hypotheses.

[72]  Cathleen K. Yoshida,et al.  Maternal autoimmune diseases, asthma and allergies, and childhood autism spectrum disorders: a case-control study. , 2005, Archives of pediatrics & adolescent medicine.

[73]  C. Gillberg,et al.  Do children with autism have March birthdays? , 1990, Acta psychiatrica Scandinavica.

[74]  J. Sterne,et al.  Meta‒Analysis in Stata™ , 2008 .

[75]  J. Eagles,et al.  A comparison of obstetric and neonatal complications between children with autistic disorder and their siblings. , 2007, Journal of intellectual disability research : JIDR.

[76]  H. Nagaraja,et al.  Timing of Prenatal Stressors and Autism , 2005, Journal of autism and developmental disorders.

[77]  S. Bryson,et al.  Obstetrical suboptimality in autistic children. , 1988, Journal of the American Academy of Child and Adolescent Psychiatry.

[78]  Megan L. Wier,et al.  Congenital anomalies associated with autism spectrum disorders. , 2006, Developmental medicine and child neurology.

[79]  P. Links,et al.  Minor physical anomalies in childhood autism. Part I. Their relationship to pre- and perinatal complications , 1980, Journal of autism and developmental disorders.

[80]  Eric Fombonne,et al.  The Changing Epidemiology of Autism. , 2005 .

[81]  Christoph Schmitz,et al.  The Developmental Neurobiology of Autism Spectrum Disorder , 2006, The Journal of Neuroscience.

[82]  J. Hallmayer,et al.  Perinatal factors and the development of autism: a population study. , 2004, Archives of general psychiatry.

[83]  R. Dean,et al.  PERINATAL COMPLICATIONS AS PREDICTORS OF INFANTILE AUTISM , 2002, The International journal of neuroscience.

[84]  A. Biri,et al.  Oxidant status in maternal and cord plasma and placental tissue in gestational diabetes. , 2006, Placenta.

[85]  C. Newschaffer,et al.  Heritable and nonheritable risk factors for autism spectrum disorders. , 2002, Epidemiologic reviews.

[86]  S. Folstein,et al.  Macrocephaly in children and adults with autism. , 1997, Journal of the American Academy of Child and Adolescent Psychiatry.

[87]  M. Byrne,et al.  Brief report: A case-control study of obstetric complications and later autistic disorder , 1996, Journal of autism and developmental disorders.

[88]  Herng‐Ching Lin,et al.  Delayed parenthood and the risk of cesarean delivery--is paternal age an independent risk factor? , 2006, Birth.

[89]  L. Sears,et al.  Autism and Associated Medical and Familial Factors: A Case Control Study , 2003 .

[90]  C. Begg,et al.  Operating characteristics of a rank correlation test for publication bias. , 1994, Biometrics.

[91]  P. Bolton,et al.  Season of birth: issues, approaches and findings for autism. , 1992, Journal of child psychology and psychiatry, and allied disciplines.

[92]  P. Szatmari,et al.  Stoppage rules and genetic studies of autism , 1988, Journal of autism and developmental disorders.

[93]  P. Bolton,et al.  Obstetric complications in autism: consequences or causes of the condition? , 1997, Journal of the American Academy of Child and Adolescent Psychiatry.

[94]  L. Burd,et al.  Prenatal and perinatal risk factors for autism , 1999, Journal of perinatal medicine.

[95]  S. E. Mouridsen,et al.  Brief report: Parental age in infantile autism, autistic-like conditions, and borderline childhood psychosis , 1993, Journal of autism and developmental disorders.

[96]  A. Samueloff,et al.  The pathophysiology of the fetus of the diabetic mother. , 2002, Seminars in perinatology.

[97]  D. Farine,et al.  High delivery intervention rates in nulliparous women over age 35. , 1995, European journal of obstetrics, gynecology, and reproductive biology.