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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. Due to the progress of autism in recent decades, a wide range of studies have been done to identify the etiological factors of autism. It has been found that genetic and environmental factors are both involved in autism pathogenesis. Hence, in this review article, a set of environmental factors involved in the occurrence of autism has been collected, and finally, some practical recommendations for reduction of the risk of this devastating disease in children are represented.
Autism described by Asperger (in 1938) and Kanner (in 1943) is a severe neurodevelopmental disorder and belongs to autism spectrum disorders (ASDs), including autism, Asperger syndrome, Rett syndrome, unidentified pervasive developmental disorders, and childhood disintegrative disorder.[2,3] Autism is 4–5 times more common among boys than girls.[4,5,6] The most prominent clinical and phenotypic features of autism are extensive disabilities in social and behavioral communications, language impairment or inability to speak, and strong tendency toward stereotyped and repetitive patterns of behavior.[7,8] Regarding statistical reports, the prevalence of autism had increased from 4–5 cases per 10,000 children in 1980s to 30–60 cases in 1990s, and through astonishing increase, there are about 8.0 per 1000 children aged 8 years in 2004 and 9.0 per 1000 in 2006 or 1 in every 110 children aged 8 years in 2006. In 2012, a combined ASD prevalence of 11.3 per 1000 children aged 8 years or 1 in 88 children was published by the Autism and Developmental Disabilities Monitoring Network.[7,10] With regard to its progressive increase over the last two decades, and lack of effective treatment, and moreover, the difficulties imposed on the society and families of autistic children, the importance of investigation on causes of this disease and effort to prevent it become clear. There is growing body of evidence about genetic factors enrolment which is supporting autism etiology through genetic mutations (e.g., heritability and twins).[12,13] According to the important role of epigenetics in autism etiology, a lot of genes have been studied, and in some cases, opposite results obtained.[14,15] Studying identical twins and lack of complete concordance among them and excessive genetic studies with no conclusive results unveils the importance of environmental risk factors and their role in etiology of autism.[16,17] Hence, the interactions between susceptible genes and environmental factors have been proposed as the major mechanism of autism etiology.[18,19]
Currently, epigenetic and its complex mechanisms are presented as the most momentous mediator in the environment and genome interactions. Environmental factors can affect the quality and quantity of gene expression without changing the DNA sequence through epigenetic mechanisms, including DNA methylation, changes in histone proteins, and expression of noncoding RNAs. This way, they can be transferred to the next cellular generation or even the next organism generation.[20,21] As a result, exposure to harmful environmental factors can change the expression of developmental key genes in critical periods of embryo formation and increases the risk of genomic imprinting diseases such as autism.[22,23]
None of the environmental factors is sufficient to yield autism, but rather a collection of them can be involved in the incidence of autism. In this article, regarding mother and child exposure time to risk factors, they are divided into prenatal, natal, and postnatal risk factors.
Physical, mental, and psychological health and financial state throughout the pregnancy are important factors affecting fetal development and health. An unhealthy mother who is not mentally and physically healthy and well nourished might be unable to have a healthy neonate. A set of prenatal risk factors which increase a child's susceptibility to autism is presented in Table 1.
Advanced parental age (particularly paternal age) has been identified as one of the most important risk factors of autism.[25,26,27,28,29] In many studies, maternal and paternal age older than or equal to 34 years has been found associated with increased risk of autism in their offspring; however, in other studies, the relationship between child autism and the age of both parents or even the age of one parent[24,31,32,33,34] is rejected. Intriguingly, the relationship between increased risk of autism and elevated paternal age has been approved in most studies.[28,32,33,34,35,36,37,38,39,40] Particularly, a study was conducted among Iranian people in 2010 to explore the presence or absence of association between parental age and risk of autism. Based on this study, autism risk increases by 29% for every 10-year elevation in fathers’ age. In other words, fathers aged between 34 and 39 had a nearly two-fold greater risk, and those who are older than 40 have more than two-fold (2.58) greater risk to have an affected child in comparison to who ones aged 25-29 years old. In other studies in Japan and China, similar relationships were explored between paternal age and increased risk of autism. Lack of any correlation between maternal age and susceptibility of autism in these three mentioned studies has critical importance. The probable explanation for this phenomenon is the formation of de novo mutations in germline cells and modifications in DNA methylation, which can result in general epigenetic alterations in the expression of neural development genes and, finally, disorders in sperm genomic imprinting. As a result, the probability of neural impairments, such as autism, would be increased.[28,36,37] Advanced paternal age also affects immune system function and, consequently, the development of the nervous system.
In studies that increase in maternal age manifests a correlation with autism,[24,30,31,41,42,43,44] chromosomal abnormalities and trinucleotide repeat expansion in the ovule, and increase in the obstetric intervention may be proposed as probable reasons. On the other hand, being small for gestational age can increase the risk of autism due to lack of physical maturity, inability, and poor maternal cares. Mothers who are younger than 20 may be exposed to intrauterine growth retardation of fetus and preterm birth, which both of them are potent for, associated with increased risk of autism.[30,31,41]
Metabolic syndrome, bleeding, and mother infection during pregnancy are some of mother's physical diseases which are related to child autism. Maternal bleeding during pregnancy which is associated with a significant 81% elevated risk of autism, and metabolic syndrome, including diabetes,[26,46,47] hypertension,[31,48] and obesity,[48,49] paves the way for hypoxia (deficiency of oxygen) in utero which results in deficient brain development and induction of myelination changes, membrane adhesion, and deficiency in hippocampal neurons (a brain area which is highly involved in autism).[23,50] Maternal viral infections in the first trimester of pregnancy, including rubella,[51,52,53] measles, mumps, chicken pox,[45,51] influenza,[45,51,54] herpes,[51,55] pneumonia, syphilis, varicella zoster, and cytomegalovirus[45,56] and bacterial infections in the second trimester which require hospitalization, increase the risk of autism in embryo. Such relationship is due to abnormal maternal immune activation and, consequently, elevated levels of inflammatory cytokines which affect the embryonic brain development and increase the risk of autism and other neuropathophysiological status.[57,58]
According to the importance and impact of family unit, parental behavior, and their communication patterns on the formation of children's personality and emotions, the association between parental psychiatric history and risk of child mental disorders, especially autism, is obvious. For example, the association of parental psychiatric history such as schizophrenia with a nearly three-fold increased risk of autism[30,60,61,62,63] or the relationship between mother's depression,[20,60,61,62,63] anxiety,[40,61,64,65,66,67,68,69,70] and personality disorders and susceptibility to autism has been proved in many studies.
In addition to mothers who have experienced mental illnesses throughout their lives and are recognized as mentally illness, those who undergo mental problems such as depression, anxiety, and considerable stress during 21–32 weeks of gestation, a period of heightened plasticity for fetal formation and development can have irremediable effects, through epigenetic mechanism, on the expression of fetus stress response genes, the genes involved in neurobiology, metabolism, and physiology that can persist across the lifespan. Mother's inappropriate psychological state, especially great and long-lasting stresses which may result in some other personality disorders such as aggression in mothers, can expose the fetus to elevated levels of cortisol through interrupting mother's HPA axis, amplifying adrenal steroids such as cortisol and increasing placental permeability to these hormones, basically. Consequently, fetal developmental programming (through epigenome) would be highly affected, and through interrupting the fetal stress response system, the way for different physical and mental impairments including autism would be paved. On the other hand, rates of subclinical anxiety problems are increased among males and siblings in middle childhood.
Maternal prenatal medication use can be associated with a 46% increased risk of fetus autism. Researches about different kinds of drugs have revealed a significant 68% increased risk of autism in relation to prenatal psychiatric medication use. The negative effect of prenatal medication use is caused by their placental crossing and disturbing fetal development, based on many studies. For example, use of antiepileptic drugs, as well as valproic acid, leads to fetal valproate syndrome, increases oxidative stress and varied gene expression pattern, and subsequently results in developmental delays, deficient motor activities and social behaviors, and finally, postnatal growth alterations.[45,75,76] Moreover, it is confirmed that paracetamol (acetaminophen), which is widely used as an analgesic/antipyretic drug, can induce apoptosis and necrosis that are observed in autistic brains. In addition, paracetamol (acetaminophen) induces oxidative stress and immune dysregulation in humans. Furthermore, positive connection between antidepressant medications and autism has been demonstrated in many studies.[78,79,80] The relationship between susceptibility to autism and taking some other medications has been identified, such as thalidomide, a painkiller, misoprostol, a prostaglandin analog drug for the prevention and treatment of gastric ulcers, in the first trimester, and β2-adrenergic agonists such as terbutaline to treat asthma.[83,84]
Considering economic, social, educational, and psychological aspects of family's life, autistic children and their families are of poor state, mainly. Basically, these families inevitably experience unhealthy, inappropriate sociality and unrehabilitated life conditions because of financial problems, occupational and psychological stresses.[86,87,88] Inaccessibility to health care and recreational facilities represented in infection and impaired physical health. Furthermore, exposure to stress and anxiety (such as shared living place with couple's families) imposes psychological tension for the parents, especially pregnant mother, and increasing susceptibility to child autism during pregnancy.[40,65,66]
On the other hand, isolation of mother and breakdown in communications and social interactions can negatively affect her psychological state and endanger both mother and embryo's health. There are numerous researches evaluating the relationship between parental education and risk of child autism and have variable conclusions which confirmed the correlation between low level of parental education and risk of autism, and some others indicate strength correlation between highly educated parents and incidence of autism.[91,92,93]
Table 2 suggests natal risk factors which increase the fetal risk of autism. Abnormal gestational age, preterm (<35 weeks) and postterm pregnancy (>42 weeks), is associated with a significantly increased risk of autism.[30,40,47,92,94,95] Prenatal risk factors such as bleeding during pregnancy and natal risk factors such as fetal complications including fetal distress, umbilical-cord complications such as fetal nuchal cord and cesarean delivery (26% increased risk of autism) are all involved in hypoxia (lack of oxygen) and consequently increasing susceptibility to child autism.[31,42,47,95] Fetal nuchal cord occurred significantly more frequent among children with autism (23.2%) regarding the controls (6.3%) and it causes fetal deficiency in blood, oxygen, and nutrition, which would affect fetal brain development and results in damage to the newborn central nervous system if the inadequate blood flow is severe or enough long-lasting. Three brain regions, including basal ganglia, hippocampus, and lateral ventricles, are highly vulnerable to hypoxia. Autistic children's brain exhibit larger lateral ventricles, morphological hippocampal abnormalities, and increased dopaminergic activity (what hypoxia causes).
Postnatal risk factors have crucial roles in susceptibility to autism, and a set of them is mentioned in Table 3. Low birth weight, jaundice, and postnatal infection are some of the most significant risk factors. A neonate with birth weight, which is the result of three potential factors (genetic growth potential, duration of pregnancy and rate of fetal growth) minor than 2500 g considered as low birth weight and associated with a two-fold increase in the risk of autism.[31,47,93,97,98] Postnatal jaundice is a result of high bilirubin production caused by increased breakdown of fetal erythrocytes and a low hepatic excretory capacity resulting from general immaturity of the liver and it can be associated with death during a sensitive period (around the 40 weeks of pregnancy) or susceptibility to mental disorders, especially a four-fold increase in autism if survive.[30,40,47,99,100] In addition to prenatal maternal infection during pregnancy, postnatal infections such as meningitis mumps, varicella, unknown fever, and ear infections on the first 30 days of life are correlated with high risk of autism.[102,103]
Among the environmental factors which are probable to cause autism, vaccines can be noted. Epidemiological studies have found no association between measles, measles, as well as mumps, vaccines (as environmental risk factors), and increased risk of autism.[101,104] Contrary to directly related or unrelated factors to autism, some factors have protective roles. Unsaturated fatty acids can be cited as these factors. The biological effects of such fatty acids, such as linoleic acid, omega-3, and omega-6, on the retinal and brain development in utero, signal transduction, gene expression, and as components of cell membranes[106,107] in the first 2 months of pregnancy (the most critical period of embryonic physical development) are highly important to such an extent that high maternal intake of omega-6 and linoleic acid is inversely associated with ASD risk in offspring, corresponding to a 34% reduction in autism risk, and in contrary, lower than 5% of ω-3 fatty acid intake had significant increase in offspring ASD risk. Therefore, fatty acids consumption of different diets has an inverse effect on risk of autism. In addition to unsaturated fatty acids, taking folic acid 3 months before pregnancy and during the 1st month of pregnancy can provide protection against autism in mothers and infants who have one copy of MTHFR 677 C>T allele at least. Maternal folic acid supplementation intake during early pregnancy is associated with less behavioral problems in offspring at 18 months age, reduced risk of severe language delay at age 3, improved verbal and attention competence at 4 years, subordinate scores of childhood hyperactivity at age 8 years, and particularly decrease the risk of autism.
Autism is a multifactorial neurodevelopmental disorder which is caused by genetic and environmental factors. The prevalence of autism has been increased over the last decades. About every disorder, prevention is more important than cure. Among the risk factors of autism, environmental ones attracted the attention of most of the scientists because prevention is possible by avoiding from them.
There are a lot of environmental risk factors which influence autism pathogenesis by their epigenetic effects. These factors are divided into three categories, included prenatal, natal, and postnatal risk factors. Each category allocates to the specific period of neonate development. A collection of these factors is involved in the pathogenesis of autism. 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.
There are no conflicts of interest.