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  • None of the environmental factors is sufficient to yield autism, but rather a associated with increased risk of autism in their offspring; however, in other studies. The search strategy was adapted appropriately to the other databases, PsycINFO and Chemical factors studied from – in association with autism. During the prenatal period, the factors associated with autism risk were are likely to be resulted from other factors, such as prenatal, perinatal.

    autism Other factors associated with

    Assessing baby teeth, particularly tooth enamel, which begins to form in utero and continues up to one year after birth, 22 can also help determine prenatal exposure. The five most commonly studied heavy metals were mercury, lead, cadmium, aluminum and arsenic. Mercury has received considerable attention because of the similarities in the symptoms of mercury poisoning and autism. However, findings were largely inconsistent Table 3.

    Urinary porphyrins, intermediates in heme biosynthesis, have also been studied as potential biomarkers for mercury exposure in people with autism, as increased porphyrins have been associated with prolonged mercury exposure. Few of the studies in this review investigated mercury exposure from sources other than thimerosal in vaccines and Rh immune globulins.

    Ecological studies have demonstrated an association between environmentally released mercury emissions and significant increases in autism rates, 32 which may be related to residential distance from mercury pollution sources such as industrial or power plant facilities. A systematic review concluded that, due to methodological issues such as small sample size and inconsistent case ascertainment, the relationship between mercury exposure and ASD remains unclear.

    Sixteen studies examined the association between exposure to other heavy metals and ASD or autism by measuring levels mainly in hair samples. Lead, cadmium, aluminum and arsenic were the moststudied heavy metals in children with ASD or autism, but there were conflicting findings Table 3. Most studies found no significant association between aluminum and ASD. None of these studies investigated possible exposure sources. Only a few studies investigated the relationship between drinking water content and autism.

    Exposure to traffic-related air pollution can result in respiratory and cardiovascular disease and certain neurological outcomes by triggering inflammation and oxidative stress, 49 - 51 which are common physiological abnormalities observed in children with ASD. Maternal residence in areas with higher levels of exposure to nitrogen dioxide, 44 , 47 exposure to particulate matter less than 2.

    Also, residing near a freeway during pregnancy, especially during the third trimester, was associated with having children with autism. Since the publication of the Wakefield case series study, 52 which found an increased prevalence of a new variant of autism characterized by gastrointestinal disorders and developmental regression, the safety of MMR vaccine has been questioned, although this paper was later retracted due to false data.

    Nine case-control and two time-series studies 53 - 63 and two systematic reviews 64 , 65 found no significant association between MMR vaccine and ASD or autism, although another timeseries study did. Thimerosal in Rh immune globulins given to pregnant women with Rh incompatibility issues has also been investigated as a source of prenatal mercury exposure. Seven studies demonstrated no significant association between thimerosal-containing childhood vaccines and ASD, 68 - 74 while four studies did.

    Both cohort studies that found significant positive associations used the Vaccine Adverse Events Reporting System database, which has been criticized as potentially biased and unreliable because anyone can report an adverse event after vaccination and diagnoses are not medically validated. The increasing use of antidepressants, antibiotics 85 and acetaminophen 86 has sparked hypotheses of possible links with the use of these medications and synchronous rising ASD prevalence in the s.

    Research on selective serotonin reuptake inhibitors SSRIs; a class of antidepressants in relation to ASD has emerged recently, with reviews indicating biologically plausible evidence of an association from animal and preclinical studies. Three reviews cited several clinical studies that provided evidence for increased ASD prevalence among children exposed to valproic acid or valproate , a teratogenic broad spectrum antiepileptic drug and mood stabilizer, in early pregnancy compared to unexposed children.

    Some studies suggested a possible link between prenatal or early-life antibiotic use and autism. A meta-analysis has indicated no significant association between smoking during pregnancy and ASD. Two studies, including a prospective cohort study, found no association between prenatal alcohol consumption and ASD or autism, , whereas a significant association with heavy prenatal consumption was evident in a small clinic sample.

    The physiological dimension encompasses many recurring themes related to the physiology of the parents and the child with ASD. Parental characteristics, particularly parental age, and pregnancy complications, especially low birth weight and prematurity, have been the most-studied risk factors for ASD Table 5. Five systematic reviews supported the association between advanced parental age and ASD.

    A meta-analysis found the relative risk RR of ASD for mothers aged 35 years or over compared to those aged 25 to 29 years to be 1. Some studies have found paternal and maternal ages to be independent risk factors for ASD after adjusting for spousal age, - and no evidence for a synergistic effect.

    Assisted conception and ASD share risk factors such as high parental age, high rate of prematurity and low birth weight. Some evidence exists for associations between maternal chronic conditions such as weight gain, obesity and diabetes and ASD.

    Two , of four studies found a positive association between maternal chronic conditions aggregate measure and ASD or autism. A metaanalysis found a positive association between maternal gestational diabetes and ASD.

    An association between elevated prenatal testosterone levels and ASD or autism has been implicated in a review of three metaanalyses and a case-control study. Thyroid dysfunction, whether due to prenatal or early-life exposure to the antithyroid effects of heavy metals, to endocrine-disrupting chemicals or to dietary deficiencies, may affect neurodevelopment. A systematic review found perinatal and neonatal pregnancy complications to be significantly associated with ASD.

    Findings were also inconsistent among several other studies. Two systematic reviews , found low birth weight to be a significant risk factor for ASD in children; one of them, a metaanalysis, found a risk ratio RR of 1.

    Since then, three - of five studies , , - have found a significant association between low birth weight and ASD. In most studies, the low birth weight threshold was g. Two 13 , of three systematic reviews 13 , , supported the association between low gestational age and ASD. Since the systematic review, 13 most studies have provided more evidence for this association , , - although two studies did not. Systematic reviews 13 , along with subsequent studies , have also found a significant association between small for gestational age and ASD.

    Other studies have suggested that a deviance in fetal growth and physical development may be associated with ASD onset. Eleven studies, including four cohort studies, found clustering of pregnancy complications to be significantly associated with ASD, , , , , , , , - and only one case-control study did not. However, the types of pregnancy complications examined vary by study. Many studies have explored the association between optimality scores composite measures of compromised prenatal, perinatal and neonatal health overall and ASD.

    Systematic reviews , have found that reduced prenatal and neonatal optimality is more evident than perinatal suboptimality in ASD cases. However, since those reviews, a prospective cohort study has found that having at least four obstetric suboptimality factors mainly prenatal and perinatal in the first birth were significantly correlated with ASD. Systematic reviews , have implicated fetal hypoxia intrauterine deprivation of oxygen in ASD etiology, based on several perinatal factors that may serve as markers of hypoxia, including low Apgar score, caesarean section and growth retardation.

    However, fetal hypoxia has been weakly associated with ASD according to a population- based cohort study. Multiple births have been associated with ASD according to a meta-analysis as well as a cohort study, whereas an ecological study did not find an association. According to a review of research trends, immune dysregulation has been widely studied and possesses the strongest evidence base of the physiological abnormalities in ASD. Several studies have examined the role of autoimmunity in ASD.

    Three case-control studies have consistently demonstrated that antibody reactivity to human fetal brain protein is more prevalent in mothers of children with ASD or specifically autism than in mothers of children who do not have ASD or specifically autism. Two cohort studies and a case-control study found an association between maternal or family history of autoimmune diseases and ASD , or autistic regression, whereas another case-control study found no association.

    Reviews have discussed growing evidence for the role of autoimmunity in ASD, stemming mostly from animal models and human clinical studies, but have indicated a need to identify the functions of the autoantibodies that might be affecting neurodevelopment. Brain inflammation has also been implicated in the etiology of ASD.

    According to the reviews based mainly on animal and human clinical studies, early-life immune insults such as toxic substances, food additives or stress may result in a cascade of excitotoxicity in the brain, - and may be related to dysregulation of glutamate neurotransmission. Emerging evidence, mostly from case-control studies, has shown that increased proinflammatory cytokine production is found in the serum or cerebrospinal fluid of ASD children or the amniotic fluid of their mothers, - although a decreased neonatal level of cytokines has also been observed.

    Infections may trigger the chronic inflammation of the CNS, affecting brain development and maturation, which has been implicated in ASD etiology. A systematic review indicated that more research is required to explore this association.

    Neonatal jaundice, a result of elevated serum bilirubin levels hyperbilirubinemia , has been a concern because unconjugated bilirubin can be toxic to the developing CNS. Five studies , , - and two systematic reviews 13 , investigated this risk factor. According to the systematic reviews, hyperbilirubinemia was associated with an increased risk of autism 13 , with a summary effect estimate of 1. While a meta-analysis indicated no significant relationship between neonatal seizures and ASD, four small studies have provided some evidence for a possible association.

    According to a review of research trends, oxidative stress was one of the most-studied physiological abnormalities in ASD, with one of the strongest evidence bases, mainly consisting of clinical and animal studies. Biomarkers included altered levels of oxidative stress defence systems, including metallothioneins and antioxidant enzymes.

    Deficiencies in minerals and levels of trace elements were the most-studied of the nutritional factors in association with ASD, followed by vitamin D deficiency Table 6. Evidence for mineral deficiencies and levels of trace elements in children with ASD or specifically, autism, comes mainly from case-control studies examining hair samples and remains inconclusive.

    Studies looking at associations between levels of zinc, 37 , 95 , , - iron, 37 , , , , - magnesium, 37 , , , , copper, 37 , , , , , , , , molybdenum, 37 , , , , nickel, , , , , and selenium 37 , , , , and ASD have had conflicting results. Calcium deficiencies have also been documented in association with ASD or autism in children, , , , with some inconsistencies. Vitamin D plays a crucial role in various functions, such as neurodevelopment, the anti-inflammatory response and the detoxification pathway.

    It has been suggested that migration may play a role in the etiology of ASD, because of increased autism prevalence rates among immigrants in northern European countries, and because immigrants with dark skin are more prone to vitamin D deficiency due to their skin pigmentation. Furthermore, a systematic review concluded that there was inadequate support for an association, and that more population-based longitudinal studies are needed, given the plausible biological evidence.

    We found few studies on infant feeding methods in relation to ASD, although two case-control studies found that the absence or late initiation of breastfeeding was significantly associated with ASD or autism, , in contrast to findings of an ecological study.

    Evidence supporting an association between folic acid intake and ASD is very sparse, although a recent prospective cohort study found maternal folic acid intake to be protective against ASD, in contrast to an ecological study that found positive correlations between the percentages of prescription prenatal vitamins and pediatric vitamins containing folic acid and ASD incidence.

    Socioeconomic status SES , ethnicity, immigrant status and stress were recurring social factors examined in association with ASD Table 7. The importance of SES emerged as a predictor of ASD risk in nine studies, , , , - but findings were mixed. However, other studies had different results.

    Most studies that examined the relationship between maternal ethnicity and ASD found a significant association, , , , , , with the exception of one study in the United Kingdom. In contrast, another American study found that Black race was associated with increased odds of ASD, particularly with ID, but case ascertainment was more likely from school sources.

    Maternal immigrant status is another social factor that emerged in eight studies , , , - and two systematic reviews 13 , supporting an association with ASD or ASD subtype.

    For example, a decline in autism rates among Hispanic children in the United States was attributed to undocumented immigrant parents' reluctance to seek diagnostic services due to fears of being reported to the authorities and having to face deportation when threatened by anti-immigrant policy enforcement. Prenatal exposure to environmental stressors, including stress-related immunological and neuroinflammatory abnormalities and placental dysfunction that can affect fetal neurodevelopment, may play a role in ASD etiology.

    In addition to the chemical, physiological, nutritional and social dimensions, several other factors emerged that were investigated for association with ASD. Two studies showed that autism births occur in geographical clusters, which could indicate that local factors are involved in the prevalence. Most of the research on the environmental contribution to ASD etiology focussed on physiological or chemical risk factors, and less on social and nutritional factors.

    Within these dimensions, however, the vast literature is riddled with inconsistent findings. Biomarkers of heavy metal exposure, particularly mercury, from levels measured in biological specimens such as hair, blood and urine have been studied intensely, but its association with ASD remains uncertain due to conflicting findings.

    Because most of these studies only measure biomarkers of heavy metal, and do not ascertain actual exposure sources, temporality of association is unknown. Furthermore, many of the biomarker studies had small sample sizes.

    These findings are consistent with a recent systematic review by Rossignol and colleagues 11 published in , after the completion of our review , who examined the association between environmental toxicant exposure and ASD.

    In contrast, emerging evidence for the association between traffic-related air pollutants and ASD or autism has been relatively consistent, although further research is required to establish specificity of association and improve external validity beyond the American landscape. Despite numerous studies exploring the relationship between MMR or thimerosalcontaining vaccines and ASD, there is a lack of convincing support for this association. Additionally, evidence of an association between fetal or childhood exposure to various medications and ASD is limited to a few studies.

    A lack of association between tobacco smoke exposure and ASD is also apparent, although some studies have indicated a possible link with PDD-NOS, warranting further study on ASD subgroups separately if causal relationships are to be elucidated. Moreover, studies on exposure to occupational chemicals, pesticides and alcohol were limited.

    The most widely and consistently implicated physiological factors in ASD onset include advanced parental age, low birth weight, prematurity and clustering of pregnancy complications. A consistent association between hyperbilirubinemia and ASD has been demonstrated as well. More research is warranted on the effects of advanced grandparental age on ASD, based on preliminary findings.

    Emerging epidemiological evidence for immune abnormalities related to autoimmunity and brain inflammation have also been reported in children with ASD or their mothers. However, further work is required to establish temporality of association and to elucidate their possible role in ASD etiology. More research is also needed to understand other physiological factors such as birth characteristics, maternal chronic conditions, hormones and child conditions in relation to ASD.

    Studies have indicated a potential relationship between chronic conditions such as pregnancy weight gain or maternal diabetes and ASD. However, due to heterogeneity and lack of specificity of exposures, further research is warranted. Evidence for a link between earlier birth order, greater parity and short interpregnancy intervals and ASD exists, although the etiological contribution is not clear. The association between oxidative stress and ASD has been demonstrated by a limited number of small epidemiological studies.

    The relationship between nutritional factors and ASD has not been well studied compared to that with chemical and physiological factors. The current literature suggests that associations between social factors such as SES and ethnicity and ASD may vary across countries, depending on possible case ascertainment biases. However, maternal immigrant status has been consistently correlated with ASD. Whether this may relate to SES, adaptation to a new environment, stress or changes in vitamin D exposure as suggested by some studies requires further investigation.

    Overall, the lack of consistency, temporality and specificity of the associations observed in many studies precludes the establishment of causality. Longitudinal studies may be helpful in establishing temporality to identify possible causal relationships. Consistent methods of measuring exposure and case ascertainment and consideration for potential confounders could reduce heterogeneity. Underlying mechanisms of some of these associations need to be investigated through further biological research.

    Of the reviews that have explored possible risk factors of ASD to date, none have examined the entire scope of the environmental contribution to ASD.

    We conducted a comprehensive, systematic search of the literature. Although all relevant articles may not have been retrieved in this review, a large number of potentially contributing factors were identified that can provide an adequate picture of the breadth of environmental contribution to ASD etiology. Although the search strategy to retrieve relevant ASD articles aimed for comprehensiveness, key scientific journals were not hand-searched and no searches were performed on citations referenced in included studies and grey literature.

    Furthermore, more information on environmental factors may have been missed if articles covering them also dealt with animal models or genetic studies, which were excluded.

    This is evident for research in immune abnormalities and oxidative stress, because articles retrieved were fewer in number although reviews have indicated a vast amount of research, likely from clinical and animal studies. Because the aim of this scoping review was to assess the current state of knowledge of environmental risk factors of ASD, quality assessment of these studies was not performed to assess the strength of evidence.

    Our scoping review examined research conducted between and on environmental factors potentially associated with ASD, grouped into four categories: We found that physiological factors including advanced parental age, low birth weight, prematurity, hyperbilirubinemia and clustering of pregnancy complications have been consistently reported as risk factors for ASD. While evidence for an association with traffic-related air pollutants is emerging, research on nutritional factors associated with ASD is limited.

    Of the factors in the social dimension, immigrant status has been consistently associated with ASD, which warrants further research. Large prospective studies, adjusting for sociodemographic confounders, are needed to resolve inconsistencies, especially in the area of heavy metal exposure, where evidence for an association with ASD is still inconclusive.

    Because there are a variety of associations with ASD, the etiology is likely multifactorial. Future studies should continue exploring how these different factors may be interrelated. Overall, the lack of consistency, temporality and specificity of associations between environmental factors and ASD remains the largest barrier to establishing causal relationships.

    National Center for Biotechnology Information , U. Author information Copyright and License information Disclaimer. This article has been cited by other articles in PMC. ASD, autism spectrum disorder, autism, environmental exposure, etiology. Highlights The environmental factors most commonly studied in association with ASD were physiological and chemical factors.

    Research on nutritional and social factors is limited. Older parental age, low birth weight, premature birth, neonatal jaundice and clustering of pregnancy complications were consistently reported to be associated with ASD. Introduction Autism spectrum disorder ASD is a group of neurodevelopmental disorders with varying levels of severity in impairment in social communication and interaction, and restricted repetitive behaviours, interests and activities.

    Open in a separate window. Process for searching and screening research on autism spectrum disorders found in three electronic databases, published between and Results The literature encompassed a wide scope of research investigating potential environmental risk factors associated with ASD.

    TABLE 1 Final selection of research articles on associations between environmental factors and autism spectrum disorder, by dimension and article type. Final selection of articlesa on associations between environmental factors and autism spectrum disorder, by subject and article type. Final selection of articles on associations between environmental factors and autism spectrum disorder, by subject and time period, — and — TABLE 2 Chemical factors studied from — in association with autism spectrum disorder, by article type and subtheme.

    TABLE 4 Associations of prenatal, perinatal or postnatal exposure to air pollutants in children with autism spectrum disorder or autism, found in studies published — TABLE 5 Physiological factors studied from — in association with autism spectrum disorder, by article type and subtheme. TABLE 6 Nutritional factors studied from — in association with autism spectrum disorder, by article type and subtheme.

    TABLE 7 Social factors studied from — in association with autism spectrum disorder, by article type and subtheme. Discussion Most of the research on the environmental contribution to ASD etiology focussed on physiological or chemical risk factors, and less on social and nutritional factors.

    Strengths and limitations Of the reviews that have explored possible risk factors of ASD to date, none have examined the entire scope of the environmental contribution to ASD.

    Conclusion Our scoping review examined research conducted between and on environmental factors potentially associated with ASD, grouped into four categories: Diagnostic and Statistical Manual of Mental Disorders: Trends in the prevalence of developmental disabilities in US children, — Prevalence of autism spectrum disorder among children aged 8 years — Autism and Developmental Disabilities Monitoring Network, 11 sites, United States, Estimated prevalence of autism spectrum disorders among children 2—14 years of age in three Canadian regions — [Internet].

    Incidence of autism spectrum disorders: Diagnostic change and the increased prevalence of autism. The rise in autism and the role of age at diagnosis. Genetic heritability and shared environmental factors among twin pairs with autism. Understanding and determining the etiology of autism. Environmental toxicants and autism spectrum disorders: A review of research trends in physiological abnormalities in autism spectrum disorders: Pre-, peri- and neonatal risk factors for autism.

    Acta Obstet Gynecol Scand. Exploring the environmental contribution. Nutritional and environmental approaches to preventing and treating autism and attention deficit hyperactivity disorder ADHD: J Altern Complement Med. Enhancing the scoping study methodology: Use of birth certificates to examine maternal occupational exposures and autism spectrum disorders in offspring. Parental occupational exposures and autism spectrum disorder.

    J Autism Dev Disord. Maternal residence near agricultural pesticide applications and autism spectrum disorders among children in the California Central Valley. Tipping the balance of autism risk: Urinary porphyrin profiles as a biomarker of mercury exposure: J Toxicol Environ Health. Porphyrinuria in childhood autistic disorder: A prospective assessment of porphyrins in autistic disorders: Urinary porphyrin excretion in neurotypical and autistic children.

    An investigation of porphyrinuria in Australian children with autism. J Toxicol Environ Health A. Porphyrinuria in Korean children with autism: Biomarkers of environmental toxicity and susceptibility in autism. A biomarker of mercury body-burden correlated with diagnostic domain specific clinical symptoms of autism spectrum disorder. Environmental mercury release, special education rates, and autism disorder: Proximity to point sources of environmental mercury release as a predictor of autism prevalence.

    Reduced levels of mercury in first baby haircuts of autistic children. A prospective study of prenatal mercury exposure from maternal dental amalgams and autism severity. Acta Neurobiol Exp Wars ; 69 2: Seafood consumption and blood mercury concentrations in Jamaican children with and without autism spectrum disorders.

    Heavy metals and trace elements in hair and urine of a sample of Arab children with autistic spectrum disorder. Maedica Buchar ; 6 4: Low-level chronic mercury exposure in children and adolescents: Toxicological profile for mercury [Internet]. Mercury concentrations and metabolism in infants receiving vaccines containing thiomersal: Pediatric neurobehavioral diseases in Nevada counties with respect to perchlorate in drinking water: An ecological study on childhood autism.

    Int J Health Geogr. Ambient air pollution and autism in Los Angeles County, California. Perinatal exposure to hazardous air pollutants and autism spectrum disorders at age 8. Traffic-related air pollution, particulate matter, and autism.

    Autism spectrum disorders in relation to distribution of hazardous air pollutants in the San Francisco Bay area. Ambient air pollution and the progression of atherosclerosis in adults. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children.

    MMR vaccination and pervasive developmental disorders: Age at first measles-mumps-rubella vaccination in children with autism and school-matched control subjects: Lack of association between measles-mumps-rubella vaccination and autism in children: Pediatr Infect Dis J.

    An epidemiological study on Japanese autism concerning routine childhood immunization history. Jpn J Infect Dis. The combined measles, mumps, and rubella vaccines and the total number of vaccines are not associated with development of autism spectrum disorder: Lack of association between measles virus vaccine and autism with enteropathy: MMR-vaccine and regression in autism spectrum disorders: Measles vaccination and antibody response in autism spectrum disorders.

    No evidence for links between autism, MMR and measles virus. No effect of MMR withdrawal on the incidence of autism: J Child Psychol Psychiatry. Autism rates associated with nutrition and the WIC program. J Am Coll Nutr. Vaccines for measles, mumps and rubella in children. Cochrane Database Syst Rev. Association of autistic spectrum disorder and the measles, mumps, and rubella vaccine: Arch Pediatr Adolesc Med. A comparative evaluation of the effects of MMR immunization and mercury doses from thimerosal-containing childhood vaccines on the population prevalence of autism.

    Elevated levels of measles antibodies in children with autism. Thimerosal exposure in infants and developmental disorders: Prenatal and infant exposure to thimerosal from vaccines and immunoglobulins and risk of autism. Association between thimerosal-containing vaccine and autism. Safety of thimerosal-containing vaccines: Thimerosal and the occurrence of autism: Autism and thimerosal-containing vaccines: Am J Prev Med.

    A two-phased population epidemiological study of the safety of thimerosal-containing vaccines: Neurodevelopmental disorders after thimerosal-containing vaccines: Exp Biol Med Maywood ; 6: Thimerosal exposure in infants and neurodevelopmental disorders: A comprehensive list of these factors is collected in this review. Regarding these factors, it would be essential to point out some requirements to prevent child autism.

    The following advice and suggestions are useful for parents to pass the highly significant period of pregnancy with confidence, especially those who have had experience of autistic children, and are about to prevent giving birth to another suffered infant. Given that autism is an epigenetic disorder in which environmental risk factors are the most momentous mediators in its pathogenesis, detection of these factors can help parents avoid the danger of autism onset in their children.

    By following the mentioned tips, parents can provide a lower risk condition for the outbreak of autism. This study was supported by Isfahan University of Medical Sciences.

    National Center for Biotechnology Information , U. J Res Med Sci. Published online Feb Author information Article notes Copyright and License information Disclaimer. This article has been cited by other articles in PMC. Abstract Autism is a developmental disability with age of onset in childhood under 3 years old , which is characterized by definite impairments in social interactions, abnormalities in speech, and stereotyped pattern of behaviors.

    Autism, environmental factors, etiological factors. Table 1 Prenatal risk factors. Open in a separate window.

    Parental age Advanced parental age particularly paternal age has been identified as one of the most important risk factors of autism. Maternal physical health Metabolic syndrome, bleeding, and mother infection during pregnancy are some of mother's physical diseases which are related to child autism.

    Maternal mental health According to the importance and impact of family unit, parental behavior, and their communication patterns on the formation of children's personality and emotions,[ 59 ] the association between parental psychiatric history and risk of child mental disorders, especially autism, is obvious. Familial socioeconomic status Considering economic, social, educational, and psychological aspects of family's life, autistic children and their families are of poor state, mainly.

    Lesser Postnatal risk factors have crucial roles in susceptibility to autism, and a set of them is mentioned in Table 3. Recommendations Advanced parental age particularly paternal age has important role in autism incidence in their neonate;[ 25 , 26 , 27 , 28 , 29 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , , ] therefore, it is suggested that the best time to have a child especially for father is under the age of Families with more than one autistic child would have increased risk to have an affected infant because the presence of more than one older affected sibling causes a two-fold increase in the risk of autism in the next children.

    These families are further at risk regarding those who have only one autistic child Although the severity of autism is higher in the female gender, the prevalence of autism in boys is 3—4 folds greater than girls. The investigation of families and relatives of both autistic and healthy children has revealed the fact that familial psychiatric history is more common among autistic children's families and relatives with regard to healthy children;[ 30 , 60 ] hence, in addition to genetic susceptibility, environmental factors are also involved in the incidence of such diseases and make mental problems appear in children differently from their parents.

    Due to the direct effect of maternal emotional state on fetal health, mothers must avoid occupational and mental stresses. Mothers, who tolerate mental stresses such as family problems, stressful living places, financial problems, and loneliness, expose their children to different learning and mental problems such as autism[ 20 , 40 , 64 , 86 , 90 , 93 , ]. Mother exposure to some chemicals such as pesticides, air and water pollutants, and heavy metals and other chemicals can affect fetal health negatively through epigenetic alterations of gene expression and neurodevelopmental process such as changing neuronal migration.

    Moreover, newborns must not be exposed to trihalomethane, tetrachloroethylene, trichloroethylene, and other chemicals[ ]. The quality of mother—infant interactions during the postnatal period has great importance; that's why mothers are supposed to provide proper care for their children.

    The absence of such emotional mother—infant relation has a great effect on the postnatal development of neural and signaling pathways in addition to affecting secretion of some hormones such as dopamine, oxytocin, and serotonin. Due to side effects of mother's prenatal medication that is mentioned previously,[ 26 ] it is highly recommended that mothers should avoid taking any medication during pregnancy.

    Moreover, without prescription, the children must not be given medications such as paracetamol acetaminophen for pain and fever management following vaccinations in early infancy[ 77 , , ].

    Maternal smoking and alcohol consumption should be strictly forbidden during pregnancy, because in various studies, it has been proved that prenatal maternal smoking or even passive smoking includes polycyclic aromatic hydrocarbons, metals, and other chemicals with known adverse health effects, which may cause fetal hypoxia and affect fetal brain development. Natural childbirth has priority over cesarean section because cesarean is especially prevalent among mothers who give birth to autistic children[ 47 ].

    Regarding the protective properties of unsaturated fatty acids[ , , , ] and folic acid[ , , , , ], in addition, the effects of iron deficiency, folate, methionine,[ 50 , , , , ] and vitamins[ , , , , , ] on susceptibility to autism highlight the importance of an appropriate diet during pregnancy.

    Considering the profound impacts of different vitamins on physical health, the impact of Vitamin D on significant biological processes such as DNA repair and its anti-inflammatory quality on brain tissue,[ , , , ] and the roles of vitamin A and other vitamins in brain development,[ 53 ] it is better to eat foods enriched with different vitamins and iron in addition to taking vitamin supplements and folic acid during pregnancy.

    Furthermore, eating foods such as fish which is enriched with omega-3 and other unsaturated fatty acids help in the normal development of the embryo. Appropriate postnatal care prevents the problems with lack of Vitamin D and other crucial components[ , ]. Based on some studies, prolonged exposure to elevated temperature during pregnancy and susceptibility to child autism are related.

    Due to the negative impacts of activation and aberrations of the maternal and fetal immune systems and increased level of cytokines on neural development of embryos and infants, mothers must care about their health during pregnancy as well as their newborn's health to stop probable infections, especially in the 1 st month of infant lives.

    Financial support and sponsorship This study was supported by Isfahan University of Medical Sciences. Conflicts of interest There are no conflicts of interest. PK contributed in the conception of the work, revising the draft, approval of the final version of the manuscript, and agreed for all aspects of the work. MK contributed in the conception of the work, conducting the study, revising the draft, approval of the final version of the manuscript, and agreed for all aspects of the work.

    Lyons V, Fitzgerald M. Asperger and Kanner , the two pioneers of autism. J Autism Dev Disord. Autism and autism spectrum disorders: Diagnostic issues for the coming decade.

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    Volkmar FR, Pauls D. Centers for Disease Control and Prevention. Prevalence of autism spectrum disorders- autism and developmental disabilities monitoring network, 14 sites, united states, Daly MJ, Chakravarti A. A genome-wide linkage and association scan reveals novel loci for autism. Complex aetiology for a heterogeneous disorder.

    RORA and autism in Isfahan population: A complicated epigenetic relationship. Cell J Yakhteh ; Global methylation profiling of lymphoblastoid cell lines reveals epigenetic contributions to autism spectrum disorders and a novel autism candidate gene, RORA, whose protein product is reduced in autistic brain. Ronald A, Hoekstra RA.

    Autism spectrum disorders and autistic traits: A decade of new twin studies. Genetic heritability and shared environmental factors among twin pairs with autism. Contributions of the environment and environmentally vulnerable physiology to autism spectrum disorders. How environmental and genetic factors combine to cause autism: Perera F, Herbstman J. Prenatal environmental exposures, epigenetics, and disease. Bollati V, Baccarelli A. Heredity Edinb ; Prospects for epigenetic epidemiology.

    Age-specific epigenetic drift in late-onset Alzheimer's disease. Perinatal factors and the development of autism: Advanced parental age and the risk of autism spectrum disorder.

    Prenatal risk factors for autism: Advancing parental age and autism: Parental age and autism spectrum disorders. Independent and dependent contributions of advanced maternal and paternal ages to autism risk. Risk factors for autism: Perinatal factors, parental psychiatric history, and socioeconomic status. Perinatal risk factors for infantile autism. Effects of familial risk factors and place of birth on the risk of autism: A nationwide register-based study.

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    The role of environmental factors in the development of autism is a crucial area of study. thalidomide and valproic acid has been linked to increased risk of autism. Scientists use the term "environmental" to refer to influences other than . Likewise, no correlation was observed between the severity of ASD and different factors. After logistic regression, the risk factors retained for autism in the final. Environmental factors associated with autism spectrum disorder: a . adapted appropriately to the other data- bases . ASD or autism, although another time-.



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