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The contribution of environmental exposure to the etiology of autism spectrum disorder

  • University Medical Center Goettingen / Karolinska Institutet / Medical University of Graz


Autism spectrum disorder (ASD) is a neurodevelopmental condition of heterogeneous etiology. While it is widely recognized that genetic and environmental factors and their interactions contribute to autism phenotypes, their precise causal mechanisms remain poorly understood. This article reviews our current understanding of environmental risk factors of ASD and their presumed adverse physiological mechanisms. It comprehensively maps the significance of parental age, teratogenic compounds, perinatal risks, medication, smoking and alcohol use, nutrition, vaccination, toxic exposures, as well as the role of extreme psychosocial factors. Further, we consider the role of potential protective factors such as folate and fatty acid intake. Evidence indicates an increased offspring vulnerability to ASD through advanced maternal and paternal age, valproate intake, toxic chemical exposure, maternal diabetes, enhanced steroidogenic activity, immune activation, and possibly altered zinc–copper cycles and treatment with selective serotonin reuptake inhibitors. Epidemiological studies demonstrate no evidence for vaccination posing an autism risk. It is concluded that future research needs to consider categorical autism, broader autism phenotypes, as well as autistic traits, and examine more homogenous autism variants by subgroup stratification. Our understanding of autism etiology could be advanced by research aimed at disentangling the causal and non-causal environmental effects, both founding and moderating, and gene–environment interplay using twin studies, longitudinal and experimental designs. The specificity of many environmental risks for ASD remains unknown and control of multiple confounders has been limited. Further understanding of the critical windows of neurodevelopmental vulnerability and investigating the fit of multiple hit and cumulative risk models are likely promising approaches in enhancing the understanding of role of environmental factors in the etiology of ASD.
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Cellular and Molecular Life Sciences (2019) 76:1275–1297
The contribution ofenvironmental exposure totheetiology ofautism
spectrum disorder
SvenBölte1,2 · SonyaGirdler2· PeterB.Marschik1,3,4
Received: 6 September 2018 / Revised: 14 November 2018 / Accepted: 4 December 2018 / Published online: 20 December 2018
© The Author(s) 2018
Autism spectrum disorder (ASD) is a neurodevelopmental condition of heterogeneous etiology. While it is widely recognized
that genetic and environmental factors and their interactions contribute to autism phenotypes, their precise causal mechanisms
remain poorly understood. This article reviews our current understanding of environmental risk factors of ASD and their pre-
sumed adverse physiological mechanisms. It comprehensively maps the significance of parental age, teratogenic compounds,
perinatal risks, medication, smoking and alcohol use, nutrition, vaccination, toxic exposures, as well as the role of extreme
psychosocial factors. Further, we consider the role of potential protective factors such as folate and fatty acid intake. Evidence
indicates an increased offspring vulnerability to ASD through advanced maternal and paternal age, valproate intake, toxic
chemical exposure, maternal diabetes, enhanced steroidogenic activity, immune activation, and possibly altered zinc–cop-
per cycles and treatment with selective serotonin reuptake inhibitors. Epidemiological studies demonstrate no evidence for
vaccination posing an autism risk. It is concluded that future research needs to consider categorical autism, broader autism
phenotypes, as well as autistic traits, and examine more homogenous autism variants by subgroup stratification. Our under-
standing of autism etiology could be advanced by research aimed at disentangling the causal and non-causal environmental
effects, both founding and moderating, and gene–environment interplay using twin studies, longitudinal and experimental
designs. The specificity of many environmental risks for ASD remains unknown and control of multiple confounders has
been limited. Further understanding of the critical windows of neurodevelopmental vulnerability and investigating the fit of
multiple hit and cumulative risk models are likely promising approaches in enhancing the understanding of role of environ-
mental factors in the etiology of ASD.
Keywords Autism· Neurodevelopmental disorders· Environment· Etiology· Genes· Twins
Autism spectrum disorder (ASD) is an early onset neurode-
velopmental condition defined in the DSM-5 by alterations
in social communication and interaction in conjunction with
repetitive, inflexible behaviors and circumscribed interests
causing significant impairment in major life areas [1, 2] and
reduced quality of life [3]. Neurodevelopmental conditions
provide an umbrella term inclusive of disorders arising from
extreme variations (neurodiversity) or qualitative altera-
tions in the maturation, architecture, and functioning of the
developing brain and are present in a substantial minority
(10–15%) of the general population [4]. The DSM-5 criteria
for ASD includes a specifier recommending that the poten-
tial role of medical and genetic conditions, and environmen-
tal factors associated with atypical neurodevelopment lead-
ing to ASD be considered. Neurodevelopmental changes in
Cellular andMolecular Life Sciences
* Sven Bölte
1 Department ofWomen’s andChildren’s Health, Karolinska
Institutet & Child andAdolescent Psychiatry, Stockholm
Health Care Services, Center ofNeurodevelopmental
Disorders (KIND), Centre forPsychiatry Research,
Stockholm County Council, Stockholm, Sweden
2 Curtin Autism Research Group, School ofOccupational
Therapy, Social Work andSpeech Pathology, Curtin
University, Perth, WA, Australia
3 Department ofChild andAdolescent Psychiatry
andPsychotherapy, University Medical Center Göttingen,
Göttingen, Germany
4 iDN-interdisciplinary Developmental Neuroscience,
Department ofPhoniatrics, Medical University ofGraz,
Graz, Austria
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1276 S.Bölte et al.
1 3
ASD impact broadly on cognitive abilities (e.g., executive
function, top-down processing, social cognition), the social
brain and other neural structures [58]. ASD also affects
other major physiological systems including the immune,
endocrine, and gut microbiota systems [912]. The cumula-
tive impact of ASD on health related outcomes is evidenced
by an increased risk for somatic and psychiatric illness, and
premature mortality [1315]. Prevalence estimates and
diagnoses rates of ASD have risen substantially in the last
two decades reaching 1–2.5% [16, 17], with some regions
reporting even higher figures [18]. While diagnosis in males
exceeds that of females threefold, the rate of ASD among
girls and women is likely underestimated by male-centric
operationalization of the autism phenotype, female “cam-
ouflaging” and internalizing psychiatric comorbidity [19,
20]. Increased understanding of the autism phenotype has
underpinned the development of effective evidence-based
behavioral interventions [21], and poor etiological insight
limits the development of biological treatments or the dis-
covery of a “cure” [22]. The conceptualization of ASD as a
psychiatric disease has been challenged by evolving societal
perceptions and increasing tolerance of neurodiversity, and
recognition of the role of environmental factors in support-
ing the functioning [23].
Nature andnurture
Although there is wide recognition that ASD has multi-
ple causes, both genetic and environmental in origin, pre-
cise understanding of the exact mechanisms underpinning
atypical neurodevelopment is lacking. Autistic traits and
(subclinical) broader phenotypes of ASD are heritable and
continuously distributed in the general population, with eti-
ologies overlapping with clinical phenotypes [24]. Genome
sequencing data indicates there are hundreds of genes asso-
ciated with ASD, both common and rare (inherited and de
novo), with many shared with other neurodevelopmental,
psychiatric, and neurological conditions [25]. Though the
clinical utility of genetic evidence is presently limited, it
is evolving, enabling in some cases genetic explanations of
ASD, estimation of the likelihood of familial recurrence, and
identification of other associated genetic risks [26]. While
heritability estimates for ASD range from 38 to 55% and
upwards to 95% [27, 28], recent twin and family studies sug-
gest heritability plays a smaller role than previously thought,
indicating a greater role for environmental factors [29, 30].
While one twin study found shared environment plays a
major role in ASD etiology [30], the majority of family and
twin studies suggest non-shared environmental factors, or
factors unshared between family members that make them
dissimilar, are more influential. However, identifying spe-
cific non-shared environmental factors is challenging given
they extend beyond aspects of nurturing, to factors including
measurement error, social chance, random biological noise,
immune reaction and neuroinflammation, and epigenetic and
genetic differences in identical twins [31]. Evidence of non-
shared environmental influences has been found across the
life span and autism spectrum, from autistic traits to extreme
clinical phenotypes of ASD. Complicating the deciphering
of the influence of non-shared environmental factors in the
etiology of ASD is the fact that their key mechanism is likely
cumulative frequency, rather than single causal agents [32].
Given monozygotic twins share 100% of their genetic vari-
ation at a DNA sequence level and dizygotic twins share on
average 50%, twin studies provide a unique opportunity for
modeling the relative contribution of environmental factors
and genetics to ASD phenotypes. Comparing monozygotic
and dizygotic twin pairs and their phenotypic concordance
and discordance enables investigation of the genetic and
environmental contributions (both shared and non-shared)
to presentations of ASD (ACE model) [33].
The environment can be both causal if it is harmful and
precedes ASD, mediating if it influences the causal chain
between a genetic predisposition and ASD, moderating
if it impacts the severity of autism, and protective if it
decreases the risk of ASD. The biological environment
comprises all chemical, bacterial, viral, or physical envi-
ronmental influences and exposures, directly and primarily
acting on the physiology of the individual. Psychosocial
environmental factors denote the psychological, social,
and cultural environments that primarily act on mental
functions and secondarily on physiology. Understanding of
the causal role of environmental factors in the etiology of
ASD can potentially inform both primary prevention and
evidence-based interventions. While the environment is
clearly key in mediating avoidable negative outcomes and
of paramount significance in secondary and tertiary inter-
ventions and supporting autistic individuals in everyday
life, the present article centers on its role in ASD etiology
or putative ASD causality. Although there it is no doubt as
to the role of the psychosocial environment in moderating
ASD, its casual role in rare cases of early, extreme per-
sistent deprivation and hospitalization on psychopathol-
ogy including autistic-like patterns cannot be dismissed.
Finally, while research has examined the role of environ-
mental factors in increasing autism risk, emerging research
balances this focus, reconsidering the environment as a
potentially protective factor in the etiology of ASD.
Research examining the genetic and environmental
contributions to the etiology of ASD has largely exam-
ined factors in isolation, rather than considering the role
of gene–environment interactions through processes such
as epigenetic dysregulation. Epigenetic mechanisms mod-
ify gene expressions controlled by factors other than DNA
sequencing and are potentially reversible. There is evidence
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1277The contribution ofenvironmental exposure totheetiology ofautism spectrum disorder
1 3
that epigenetic mechanisms [34, 35], such as DNA methyla-
tion, play a significant role in ASD etiology in combining
genetic and environmental factors that dysregulate neu-
rodevelopmental processes [36, 37]. A body of emerging
evidence points to multiple hit and threshold models, inte-
grating both genetic and environmental contributions such
as the three-hit concept of vulnerability and resilience, and
the Trigger–Threshold–Target model [38, 39], as fruitful
approaches in understanding the etiology and development
of the autism phenotype.
Environmental factors
Investigated biological environmental risk factors in ASD
include maternal and paternal age, fetal environment (e.g.,
sex steroids, maternal infections/immune activation, obe-
sity, diabetes, hypertension, or ultrasound examinations),
perinatal and obstetric events (e.g., hypoxia), medication
(valproate, selective serotonin reuptake inhibitors), smoking
and alcohol use, nutrition (e.g., short inter-pregnancy inter-
vals, e.g., vitamin D, iron, zinc, and copper), vaccination,
and toxic exposures (air pollution, heavy metals, pesticides,
organic pollutants). Surprisingly, the role of potentially pro-
tective factors such as folate and fatty acid intake and levels
are far less frequently examined. Considering the psycho-
social environment, the relevance of extreme psychosocial
institutional deprivation and maternal stress during flight
and immigration has been discussed in relation to atypical
behavior development, including autistic features. While
there are many postulated mechanisms through which these
environmental factors might generate autistic behaviors and
clinical variants of ASD, inflammation and immune activa-
tion, oxidative stress, hypoxia, and endocrine disruptions
are likely the most pivotal in contributing to atypical neu-
rodevelopment. Although the relevance of these factors may
not be directly causal, but confounded by genetic factors,
understanding is limited by the paucity of research examin-
ing gene–environment interactions.
This review summarizes our understanding of the role of
environmental factors and their postulated mechanisms in
the etiology of ASD. Although several reviews in this field
have been published in recent years [4042], the present
state-of-the art review extends those previous in updating
the literature, capturing studies to August 2018, providing
additional methodological points of discussion, and includ-
ing recent research examining the significance of environ-
mentally mediated elemental metal dysregulation in autism
etiology. Of note, while the DSM-5 definition is used today
and soon ICD-11 [https :// e11/l-m/en] will
be employed in international clinical practice, many studies
reviewed in this article used DSM-IV-TR criteria of ASD
and considered specific ASD diagnoses within the DSM-
IV-TR definition.
Parental age
The significance of advanced parental age is a well-estab-
lished risk factor for chromosomal aberrations, such as
advanced maternal age in Down syndrome. There is accu-
mulating evidence of the relevance of older parental age in
the etiology of psychiatric and neurodevelopmental condi-
tions [43] including bipolar disorder, schizophrenia, sub-
stance use disorders, ADHD, and ASD [44]. While various
hypotheses have been posed as to the biological mechanisms
of maternal and paternal age effects, an association between
advanced parental age and increasing likelihood of malign
de novo mutations has been suggested [45]. This is most
likely explained by a cumulating risk for mutations during
spermatogenesis across the life span [46]. Indeed, de novo
mutations associated with ASD are more often paternal
than maternal [47], with some evidence of linked autism
risk in offspring of older fathers with detected age-related
DNA methylation changes in their sperm [48]. Interestingly,
these effects may even be intergenerational, with advanced
grandparent paternal age on both mother’s and father’s side
linked to ASD, suggesting that parental age-related risk
might accumulate over generations [49]. Neurobiologically,
increased paternal age has been associated with reduced cor-
tical thickness of the right ventral posterior cingulate cortex
It has also been postulated that the increasing risk of
ASD with advancing age is explained by males with autism
risk, in the form of a subclinical broader autism phenotype,
being more likely to father children later in life. If this is
the case, the increasing risk of ASD with advancing pater-
nal age could be explained by genetic predisposition, rather
than biological aging. However, this hypothesis is yet to be
corroborated [51]. Countering this theory is evidence that
young parental aged is associated with some neurodevelop-
mental disorders, for instance ADHD [52], a disorder often
comorbid to ASD [53]. Here, psychosocial factors rather
than biological, such as an unhealthy lifestyle, and economi-
cal and educational disadvantage associated with early par-
enthood, have been put forward as explanations for these
associations [54].
Parental age-related risk in ASD has been found in
cohorts across multiple geographic regions, with evidence
that parental age-related risks for ASD presents indepen-
dently for maternal and paternal age. There is evidence
that parentalage-related risk is at its highest in offspring
where both the mother and father are advanced in age,
and that there is an increasing risk of ASD for couples
with greater age differentials [55]. It is also possible that
advanced paternal age generates a higher risk for female
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1278 S.Bölte et al.
1 3
offspring and higher maternal age for male offspring [56,
57]. Recently, a meta-analysis of 27 observational studies
investigating the association between advanced parental age
and risk of autism [58] found that the lowest parental age
category was associated with a reduced risk of autism in off-
spring [odds ratio (OR) 0.89, 95% confidence interval (CI)
0.75–1.06] and OR 0.81 (95% CI 0.73–0.89) for mothers
and fathers, respectively. Further, the highest parental age
category was associated with an increased risk of autism in
the offspring, with ORs 1.41 (95% CI 1.29–1.55) and 1.55
(95% CI 1.39–1.73) for mothers and fathers, respectively.
Dose–response meta-analysis methods found no association
between maternal age and reduced risk of autism (OR 0.93,
95% CI 0.69–1.24), but a decrease of 10years in paternal
age was associated with a 26% reduced risk of autism (OR
0.74, 95% CI 0.64–0.86). An increase of 10years in mater-
nal age was associated with an 18% higher risk of autism
(OR 1.18, 95% CI 1.10–1.26), and an increase of 10years in
paternal age was associated with a 21% higher risk of autism
(OR 1.21, 95% CI 1.18–1.24).
Fetal environment
Numerous environmental prenatal exposures present within
the immediate environment of the developing fetus such as
sex hormone alterations, maternal obesity, diabetes, hyper-
tension, infections and immune activity, and ultrasound
exposure have been considered in the context of ASD etiol-
ogy. While the origins of these risks might be in genetic
disposition, environmental interactions involving both the
mother and fetus with the potential to compromise the
fetal–maternal–placental system cannot be ignored. Many
of these factors may be the product of the combination of
several underlying pathophysiological processes, such as
the negative effects of imbalanced fetal sex hormone expo-
sure during critical time windows on gene transcription
and expression [59, 60], and subsequent neurotransmitter,
neuropeptide, or immune pathways [61]. Obesity bears
an independent risk for obstetric complications, coronary
heart disease, being overweight, diabetes, and several other
medical conditions in the offspring [62]. Maternal obesity
is also assumed to impact the brain development and cogni-
tive functions of offspring [63]. Severe maternal obesity and
high-fat diet might impact on fetal and offspring neurode-
velopment, through processes including low-grade neuro-
inflammation, increased oxidative stress, insulin resistance,
glucose, and leptin signaling, dysregulated serotonergic and
dopaminergic signaling, perturbations in synaptic plasticity,
and altered DNA methylation patterns [64, 65]. These and
additional risks for neurodevelopment are amplified in the
presence of co-occurring diabetes [66]. Hypertension dur-
ing pregnancy contributes substantially to perinatal mor-
bidity and mortality of both the mother and her child [67].
Hypertension can lead to sequelae of adverse utero condi-
tions, potentially altering fetal development and increasing
the risk of long-term vascular, cognitive, and psychiatric
outcomes in the offspring. High blood pressure is the pri-
mary driver of these adverse outcomes. This is particularly
problematic when it is associated with preeclampsia, which
presents with significant amounts of protein in the urine
and risks of red blood cell breakdown, low blood platelet
count, impaired liver function, kidney dysfunction, swell-
ing, shortness of breath due to fluid in the lungs, and visual
disturbances [68]. Infection during pregnancy activates the
maternal immune system, triggering cytokine signaling,
passing through the placenta, and possibly causing numer-
ous adverse neural effects in the developing fetal brain [69].
Though not established in human studies, animal studies
have linked ultrasound exposure in utero to alterations in
neuroanatomy and function, for example in the hippocampus
Sex steroids
Regarding hormonal alterations, it has been hypothesized
that high fetal exposure to sex steroids may contribute to
ASD risk [71]. This is linked to the male brain theory of
autism which claims that autism can be characterized as
an extreme variant of the male phenotype on the cognitive
and other levels [72]. Evidence supporting this notion is
apparent in the finding that fetal testosterone influences
individual differences in typical development in eye con-
tact behaviors, vocabulary size, restricted interests, men-
talizing, empathy, systemizing, attention to detail, and
autistic traits [59]. In line with this theory, neuroimaging
studies indicate that fetal testosterone affects individual
differences in structural and functional brain develop-
ment. These patterns are consistent with those seen in
sexual dimorphism, autism, and other sex-biased devel-
opmentalconditions [7375]. A genetic study of autism
found evidence that single nucleotide polymorphisms in
sex steroid synthesis genes (ESR2, CYP11B1, CYP17A1,
CYP19A1) were associated with autism traits and autism
without intellectual disability and good verbal skills [76].
A study using a Danish Historic Birth Cohort and Dan-
ish Psychiatric Central Register of amniotic fluid samples
of males measured concentration levels of sex steroids
(progesterone, 17α-hydroxy-progesterone, androstenedi-
oneand testosterone) and cortisol using liquid chroma-
tography–tandemmass spectrometry. Principal component
analysis showed that a generalized latent steroidogenic
factor accounted for the majority of data variance, with
the autism group showing elevations across all hormones
on the latent factor [77].
Fetal testosterone exposure is one of several hypoth-
eses which attempts to explain the male preponderance
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1279The contribution ofenvironmental exposure totheetiology ofautism spectrum disorder
1 3
of neurodevelopmental disorders, especially in ASD [61].
Polycystic ovary syndrome (POS), a syndrome affecting
at least 5% of women of child-bearing age, drives altered
prenatal sex hormone exposure leading to a pattern of
elevated androgens in females and has been examined in
the context of ASD [78]. A nested total population study
of Swedish children aged 4–17years (n = 23, 748 ASD,
208,796 controls) showed increased odds for ASD for both
female and male offspring (OR 1.59, CI 95% 1.34–1.88) of
mothers with POS, with comorbid obesity further increas-
ing the odds for autism (OR 2.13, 95% CI 1.46–3.10) [60].
Another investigation, underpinned by the same sample,
reported an increased autism risk in offspring in presence
of maternal hirsutism, another condition associated with
hyperandrogenism (OR 1.26–1.64; CI 95% 0.94–2.83)
[79]. A further study examining autistic traits in offspring
of mothers with POS showed higher levels of these traits
in daughters, but not sons, compared to unaffected moth-
ers [80]. Finally, in this line, it has been both reported
that women with POS themselves have an elevated rate of
ASD (OR 1.55, 95% CI 1.32–1.81) [81], and that women
with ASD are at risk for disorders related to steroids [82].
Adiposity is a common global health condition, and while
national rates vary greatly about 20% of adults worldwide are
severely overweight [83]. Mixed findings have been reported
in relation to the association between maternal weight and
risk of ASD, with the overall effect of obesity on autism
and neurodevelopment remaining unclear [84]. A Swedish
study employing matched sibling analysis reported no sig-
nificant association between maternal obesity and offspring
risk of autism [85]. Interestingly, children born to mothers
who were both obese and underweight were at higher risk of
ASD [86], indicating that extreme weight at both ends of the
weight spectrum might be associated with autism. A recent
review summarizing the associated risk of weight for autism
and other neurodevelopmental disorders across 32 articles
and 36 cohorts showed that compared with mothers of nor-
mal weight, the offspring of obese and overweight mothers
had a 17% increased risk of experiencing any neurodevel-
opmental disorder (OR 1.17, 95% CI 1.11–1.24) and a 36%
increased risk for ASD (OR 1.36; 95% CI 1.08–1.70) [87].
Extending this research, additional studies show excess risk
for autism in the presence of maternal obesity when women
gain additional weight during pregnancy [88].
Studies examining the effect of maternal diabetes on autism
in offspring have yielded inconsistent results. A recent
systematic literature review and meta-analyses synthesizing
16 studies [89] demonstrated additional risk for autism in the
presence of maternal diabetes (relative risk = 1.48, 95% CI
1.26–1.75). While high levels of variation in study outcomes
and publication bias were detected, these disappeared when
meta-analysis was restricted to case–control studies, with
the risk of ASD increasing by 62% among diabetic moth-
ers, compared with non-diabetic mothers. There is evidence
that timing might be significant in the association between
maternal diabetes and offspring with ASD. A retrospective
study of 322,323 singleton Californian children born at
28–44weeks examined the effect of intrauterine exposure
to preexisting type 2 diabetes and gestational diabetes. It
reported exposure to maternal gestational diabetes mellitus
diagnosed by 26weeks’ gestation increased the risk of ASD
in offspring by 42% [90].
At a population prevalence of approximately 10%, high
blood pressure disorders are one of the most common preg-
nancy complications [91]. Theses disorders include chronic
hypertension (essential/secondary), white-coat hyperten-
sion, masked hypertension, transient gestational hyperten-
sion, gestational hypertension, and preeclampsia (de novo
or superimposed on chronic hypertension), with pregnancy-
related onset typically occurring in the second trimester
[92]. A recent systematic review and meta-analysis examin-
ing the association between hypertensive disorders of preg-
nancy and risk of neurodevelopmental disorders in offspring
identified 20 studies estimating the risk of ASD, 11 of these
with adjusted estimates covering 777,518 participants with
a pooled OR of 1.35 for ASD risk (95% CI 1.11–1.64) [93].
Infections andimmune activation
Since the detection of the association between autism and
congenital rubella infection, the role of infections and the
immune system in the etiology of autism has been debated
[94, 95]. Accumulating evidence suggests that the immune
system and abnormal immune function, including inflamma-
tion, cytokine dysregulation, and anti-brain autoantibodies,
influence trajectories of autism, playing a role in its etiology
in at least a subset of cases. In addition to rubella, there are
a number of other maternal viral and bacterial infections
associated with ASD risk [96, 97]. In particular, maternal
influenza bears a twofold risk for autism in offspring [98].
While maternal infection in the presence of fever correlates
with risk of ASD, this is attenuated by the use of antipyretic
A Swedish nationwide register-based birth cohort,
born from 1984 to 2007 with follow-up through to 2011
of 2,371,403 persons with 24,414 ASD cases, identified a
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1280 S.Bölte et al.
1 3
30% increase for ASD associated with any maternal inpa-
tient diagnosis of infection [99]. Increased risk for ASD
was associated with infection in all trimesters of pregnancy
suggesting no effect of timing, contrasting the findings of
previous research indicating the timing of infection during
pregnancy was relevant [96]. There is also evidence that
infections increase the risk for ASD with co-occurring intel-
lectual disability [99]. Although it has long been suggested
that cytomegalovirus infection is associated with ASD its
contribution to risk remains unclear, with a recent systematic
review of this literature and meta-analyses of three obser-
vational studies finding that while there was a high rate of
the cytomegalovirus in ASD cases, validity was seriously
hampered by the low number of events in all studies [100].
The relevance of the pathogenesis of maternal infec-
tion to ASD risk may not be associated with the presence
of viruses or bacteria per se, but in the immune response
they invoke, a conclusion supported by research identifying
elevated inflammatory markers and antibodies in pregnant
women with autistic offspring [101, 102]. Additional support
for the maternal immune activation hypothesis is available
from rodent models of neurodevelopmental disorders, with
direct infection in dams associated with behavioral changes
in offspring, including those relevant to autism such as
reduced socialization and vocalizations [103, 104]. Similar
observations have been made following maternal immune
activation in rhesus macaques [105]. While mounting evi-
dence points to the role of maternal immune activation in
ASD risk, refining animal models to enable understanding of
the role of timing in prenatal immune challenge, and paired
and behavioral phenotyping, would potentially improve the
reproducibility of results and maximize the translation of
findings to understanding ASD [106].
Although the hypothesis of harmful immune response
is well established, what remains less clear is how this
response affects the fetus directly. While inflammatory or
regulatory cytokine profiles are postulated to have a role in
the risk of several neurodevelopmental disorders including
autism, through the disruption of cytokine levels, observa-
tions to date are limited to rodent models [107, 108]. Several
pathways to ASD through cytokines have been suggested: a
maternal pathway, whereby cytokines from the mother cross
the placenta; a placental pathway, where maternal immune
activation leads to inflammation and cytokine production in
the placenta; and a fetal pathway, through which maternal
immune activation results in immune and gene dysregulation
in the fetus itself [109]. The significance of serum or plasma
maternal antibodies may not be limited to a single ‘window
of infection’, with evidence that these are not transient, but
persist for many years beyond the infection [110], raising the
possibility that infections or auto-immune conditions prior
to conception present a risk for ASD. Consistent with this
line of thought, a study of the Simons Simplex Collection
reported that mothers of children with ASD were four times
as likely to have circulating antibodies [111].
The immune activation paradigm is underpinned by
findings from exposure models to maternal autoantibodies.
Applying injections of serum containing antibodies into
pregnant mice yielded support for their causality in neurode-
velopmental adversity, with offspring displaying reduced
behavioral exploration, motor control and sociability, higher
anxiety, sensory alterations, and stereotypies compared to
offspring of control dams [112115]. Evidence corroborat-
ing these findings can be found in maternal antibody models
in macaques, with antibody exposure causal in increasing
brain growth and total cerebral volume [116, 117], a well-
established endophenotype of ASD [118].
While medical ultrasound is generally considered safe, some
studies have hypothesized that obstetric diagnostic sonogra-
phy is detrimental to neurodevelopment and may also pose
an ASD risk. Although an older systematic review found no
associated risks for obstetric diagnostic sonography, it high-
lighted that this conclusion was not definitive, as longitudi-
nal studies of neurodevelopmental outcomes were lacking
[119]. A study applying diagnostic ultrasound to pregnant
mice yielded less prosocial behaviors in offspring compared
to sham-exposed controls [120]. Paralleling this research
is the finding that ultrasound may have a role in a multi-
ple hit model of autism, in assaying a possible relationship
between symptoms of autism, ultrasound exposure during
the first trimester of pregnancy and a genetic predisposition
to ASD. Consistent with this notion, findings drawn from the
Simon’s Simplex Collection report that in male children with
ASD, copy number variations and exposure to ultrasound
was associated with lower non-verbal IQ and more repetitive
behaviors, relative to control children [121].
Perinatal risk factors
There is a long history of research examining a large number
of perinatal factors and their association with autism phe-
notypes including prematurity, cesarean delivery, low birth
weight, low Apgar score, and hypoxia. While many of these
factors may have a role in autism risk, they are unlikely to be
primarily causal, but rather comprise part of the epiphenom-
ena of genetic autism disposition, with familial autism load
itself increasing the likelihood of obstetric complications
[122]. Clarity is lacking in regard to the load each of these
factors bear in autism, with no specific pregnancy complica-
tion consistently connected to ASD and perinatal risk shared
with other neurological, psychiatric, and neurodevelopmen-
tal disorders. Recently, several reviews and meta-analyses
have attempted to synthesize these findings. An early review
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1281The contribution ofenvironmental exposure totheetiology ofautism spectrum disorder
1 3
examined 60 obstetric factors finding that abnormal pres-
entation, umbilical cord complications, fetal distress, birth
injury or trauma, multiple birth, maternal hemorrhage, sum-
mer birth, low birth weight, small for gestational age, con-
genital malformation, low 5-min Apgar score, meconium
aspiration, neonatal anemia, ABO or Rh incompatibility, and
hyperbilirubinemia were associated with ASD risk [123]. A
more current review found an increased risk for autism asso-
ciated with cesarean delivery, gestational age 36weeks at
birth, induced labor, no labor, breech presentation, and fetal
distress, although most odds and relative risk ratios were
modest [124]. Parity of four or more children was high-
lighted as a factor connected to decreased autism risk in
one study. Of note, across meta-analyses models complica-
tions resulting from hypoxia emerged as the most consistent
factors associated with ASD risk.
The safety of many medications in pregnancy and lactation
is yet to be established, with the majority of therapeutic deci-
sions made during pregnancy underpinned by a paucity of
evidence. Often studies examining the effects of medica-
tion on offspring are confounded by illnesses, behaviors,
and other risk factors associated with psychiatric illness in
mothers, including risks linked with untreated psychiatric
illness during and after pregnancy. In the ASD literature,
antidepressive and anticonvulsive medications have emerged
as medications of potential relevance or interest.
Valproic acid (VPA) or 2-propylpentanoic acid has long been
used clinically as a treatment for epilepsy and as a mood
stabilizer in bipolar disorder. The use of valproic acid in
pregnancy poses multiple risks for offspring including con-
genital malformations, developmental delay, and cognitive
malfunction [125]. Animal models demonstrate that expo-
sure to valproate impacts both short- and long-term neurode-
velopmental trajectories, interfering with neural migration
pathways at critical points during embryonic development,
and potentially contributing to neural tube defects [126,
127]. In humans epigenetic mechanisms implicated in ASD
may be a key mechanism through which valproate influences
neurodevelopment [3437]. Recently, a large comparative
systematic review and meta-analysis of 29 cohort studies
including 5100 infants examined the impact of using antie-
pileptic drugs during pregnancy or breast feeding on the
neurodevelopment of infants, reporting that only valproate
was associated with more children experiencing cognitive
developmental delay compared with controls (OR 7.40, 95%
CI 3.00–18.46). In a subset of studies examining autism risk
(5 cohort studies, 2551 children, 12 treatments), this risk was
amplified (OR 17.29, 95% CI 2.40–217.60) [128].
Selective serotonin uptake inhibitors (SSRIs)
Depression is one of the most commonly occurring men-
tal disorders worldwide, with 10% of women experiencing
depression during pregnancy, and a subgroup of up to 10%
of these of women in European countries receiving SSRI
treatment during gestation [129]. SSRIs cross the placenta
barrier, potentially triggering a cascade of adverse effects
including reduced serotonin uptake, reduced uterine blood
flow, and hypoxia resulting in brain damage. A systematic
review of the literature aiming to assess the association
between ASD and fetal exposure to antidepressants during
pregnancy, from preconception and across each trimester
of pregnancy, included ten studies with six case–control
studies (117,737 patients) in a meta-analysis [130]. Find-
ings revealed a positive association between SSRI exposure
and ASD, consistent across all trimesters (OR 1.81; 95%
CI 1.49–2.20), which while partially mitigated by control-
ling for past maternal mental illness (OR 1.52; 95% CI
1.09–2.12) remained significant. In line with these findings,
a Swedish epidemiological study published subsequently
to the aforementioned review reported that the risk posed
by SSRI exposure may not be solely a byproduct of con-
founding variables. However, and importantly, the authors
stressed that the absolute risk of autism linked with SSRI
use was small, and that at a population level abstaining from
SSRIs during pregnancy would probably prevent few cases
of autism [131]. The reported association between SSRI use
and ASD etiology has also been recently challenged by a
Canadian retrospective cohort study drawing from 35,906
singleton births finding no association between SSRI expo-
sure in utero and ASD [132]. Research has not found evi-
dence that paternal SSRI use around conception increases
autism risk [131, 133, 134].
Smoking andalcohol
It has long been recognized that maternal (and paternal)
lifestyle and substance use patterns impact fetal and infant
development, with smoking and alcohol consumption among
the most extensively researched and widespread [135, 136].
In a multitude of countries, the rates of smoking and alcohol
use are decreasing [137]. Smoking exposes a developing
fetus to many risks including thousands of potentially harm-
ful chemicals and oxygen deprivation, collectively causing
changes in neurotransmitter activity within the developing
brain [138, 139]. Ethanol consumption during pregnancy
can trigger multiple forms of neurodevelopmental damage,
including fetal alcohol syndrome in cases of heavy drinking
[130, 140, 141].
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1282 S.Bölte et al.
1 3
Research has consistently shown that both smoking and
alcohol use in pregnancy are associated with neurologi-
cal, psychiatric and neurodevelopmental disorders, includ-
ing those often comorbid to ASD, such as ADHD [142].
However, specifically for autism phenotypes, the evidence
is inconsistent and overall rather weak. Several studies have
reported an association between smoking and increased risk
for ASD with intellectual disability, but not without [143,
144]. Two meta-analyses undertaken in in 2015, both inclu-
sive of 15 studies, showed no evidence for smoking as a risk
factor in ASD, even after correcting for multiple confounds
including socioeconomic status and parental psychiatric his-
tory [145, 146]. However, these findings must be interpreted
with caution given that the majority of the primary research
summarized in these meta-analyses failed to be adjusted for
relevant confounders such as birth weight and employed
self-report data collection methods likely biased by social
desirability [147].
A more recent meta-analysis employing population-based
smoking metrics as moderators pointed to the importance of
investigating paternal and secondhand smoking exposure,
in addition to maternal smoking, in understanding the risk
smoking bears in ASD [148]. Research examining the risk
that maternal alcohol consumption poses to autistic behav-
iors has largely focused on the context of fetal alcohol syn-
drome [149]. To date, five cohort or case–control studies
have examined ASD risk through alcohol consumption more
directly, indicating that mild to moderate maternal alcohol
consumption poses no risk for autism [150154]. Our review
of the literature failed to identify any study examining the
role of paternal alcohol use in the risk of autism.
Interpregnancy interval
Maternal nutrition significantly influences the trajectory
of fetal development and is particularly crucial during
pregnancy [155] given it largely determines the nutrients
available to support the growing fetus, placenta and mater-
nal tissues. Deficient and malnourished diets can malign
fetal programming and adversely impact developmental
outcomes. Short intervals between pregnancies can tax
a mother’s system with nutrients, particularly essential
nutrients (9 amino acids, 2 fatty acids, 13 vitamins and 15
minerals), remaining low for months to up to a year after
delivery [156]. The depletion of essential nutrients in the
mother is associated with adverse health outcomes for off-
spring [157] including increased autism risk. In a review
of seven studies (N = 1,140,210), short intervals between
pregnancies bore an increased risk for any ASD (OR 1.90,
95% CI 1.16–3.09) with the association strongest for core
autistic disorder (OR 2.62, 95% CI 1.53–4.50) [158].
Vitamin D
Multiple biological functions in the human body depend
on vitamin D, including calcium homeostasis and metabo-
lism, with mounting evidence that hypovitaminosis D is
associated with a higher incidence of fetal miscarriage,
preeclampsia, gestational diabetes, bacterial vaginosis,
and impaired fetal and childhood growth and development
[159]. Vitamin D receptors and enzymes are active in brain
neurons and glial cells, pointing to a role of vitamin D
in neurodevelopment in utero [160]. A recent systematic
literature review examined seven areas of interest relevant
to the understanding of the association between ASD and
vitamin D including: latitude, season of conception and
birth, maternal migration and ethnicity, the vitamin D sta-
tus of mothers and ASD cases, and the role of vitamin D
as an intervention in both the treatment and prevention of
ASD [161]. This review concluded that there are indica-
tions that deficiencies in vitamin D during early devel-
opment interacts with other risks, possibly contributing
to the etiology of autism. There was also some evidence
that vitamin D may have therapeutic benefits in reducing
autism symptomatology among diagnosed cases. A later
Swedish whole population register-based study found,
that although rare, vitamin D deficiency was associated
with offspring risk of ASD with, but not without, intel-
lectual disability (ORs 2.51 and 1.28, 95% CI 1.22–5.16
and 0.68–2.42) [162].
Iron deficiency is common in pregnant women affecting up
to half of all mothers [163], with maternal iron deficiency
being causal in fetal iron deficiency [164]. Iron is crucial for
neural function in general, and fetal development in particu-
lar, contributing to neurotransmitter synthesis, myelination,
and immune function [165]. Findings examining a possible
association between autism and iron deficiency are conflict-
ing. In the CHARGE case–control study mothers with low
iron intake had double the odds of having a child with ASD,
especially in the presence of other autism risk factors (e.g.,
advanced age, diabetes, hypertension, obesity). However,
this finding was not ratified in a Norwegian birth cohort
[166, 167].
Zinc andcopper
Deficiencies in maternal zinc during pregnancy can be harm-
ful to fetal development having been identified as causal
in neural tube defects and as possibly contributing to ASD
risk [168, 169]. Low levels of zinc have been measured in
the infant hair of individuals with ASD [170], and in mouse
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1283The contribution ofenvironmental exposure totheetiology ofautism spectrum disorder
1 3
models zinc deficiency during development leads to altera-
tions in social behavior [171]. Disruptions in fetal copper
homeostasis during brain development might contribute
to ASD risk, with both elevated and decreased copper lev-
els linked with autism [172174]. Employing a validated
tooth matrix in a twin–cotwin design with monozygotic and
dizygotic twins discordant for ASD, a study tested whether
fetal and postnatal metal dysregulation increases ASD risk.
Findings revealed significant divergences in metal uptake
between ASD cases and their control twins during discrete
developmental periods, and correlations between reduced
zinc uptake and ASD severity and autistic traits [175]. These
findings have been further corroborated in a follow-up study
examining three independent teeth samples from the USA
and UK, which identified the presence of alterations in
fetal and postnatal zinc–copper rhythms in ASD in terms
of cycling duration, regularity, and number of complex fea-
tures [176].
Despite strong evidence to the contrary, no hypothesized role
for an environmental exposure in the etiology of autism has
been pursued with as much sustained vehemence as that of
the combined mumps, measles, and rubella (MMR) vaccina-
tion. Initially based on 12 cases of clinical gastroenterologi-
cal symptoms, this now retraced study proposed a pathway
from MMR vaccination to inflammatory bowel syndrome
to ASD [177]. This study generated worldwide attention
and belief, and is possibly the single most significant factor
contributing to the harmful drop of vaccination rates and
measles outbreaks across a range of countries, where mea-
sles was previously eradicated [178]. For more than a dec-
ade, a multitude of large-scale epidemiological studies have
provided evidence refuting this notion [179, 180] including
the role of vaccinations containing thiomersal in the ASD
etiology [181]. Importantly, the initial paper has now proven
to have been falsified in many aspects, including 3 of the
12 cases never being diagnosed with autism at all, 3 of 9
cases experiencing no regression, and all 12 cases report-
edly typically developing prior to vaccination revealed to
have preexisting developmental concerns [182]. Finally, it
later emerged that the author of the initial study was paid
to undermine the combined MMR vaccination by a lawyer
attempting to raise a speculative class action lawsuit against
drug companies manufacturing the triple vaccine [183], with
the consequence that he was barred from practicing medi-
cine in the UK.
Toxic exposures
The modern world has generated a universe of some 80,000
environmental chemicals released from indoor (furniture,
colors, building material, cosmetics) and outdoor sources
(vehicles, industry, agriculture), with approximately 1000 of
these demonstrating neurotoxicity and many others under or
unstudied. Neurotoxins fall into the categories of air pollut-
ants, heavy metals, persistent organic pollutants, pesticides,
and non-persistent organic pollutants. Xenobiotic agents
may act through diverse pathophysiological pathways in
the immune, gut–brain and endocrine systems, interacting
with genetic factors, thus altering the neurodevelopment of
neural circuitry and synapses, cell migration and connectiv-
ity [184].
Air pollutants
There is a growing body of literature documenting the asso-
ciation between airborne pollutants and ASD, with epidemi-
ological studies undertaken during the last decade recently
summarized in several reviews [185, 186]. Adverse reactions
linked to air pollution include neuroinflammation and oxida-
tive stress [187190], with a recent systematic review and
meta-analysis identifying 23 studies examining its associa-
tion with autism reporting ORs of 1.07 (95% CI 1.06–1.08)
per 10-μg/m3 increase in PM10 exposure (k = 6 studies) and
2.32 (95% CI 2.15–2.51) per 10-μg/m3 increase in PM2.5
exposure (k = 3 studies) [191], concluding that modest evi-
dence exists for the toxicity of air pollution during early
development. These findings provide support for public
health policies aiming to limit exposure to harmful airborne
Heavy metals
Toxic metals occur both naturally and are produced by
industrial processes, being present in ambient air, soil, water
and plants, and medical products. Exposure to heavy metals
can detrimentally impact many bodily functions, inducing
neurological and behavioral impairment [191195]. Several
toxic metals bare a risk in the etiology of autism, in particu-
lar mercury and lead. A recent systematic review and meta-
analysis examining the link between toxic metals and autism
found 48 relevant case–control studies measuring levels of
toxic metals (antimony, arsenic, cadmium, lead, manga-
nese, mercury, nickel, silver, and thallium) in whole blood,
plasma, serum, red cells, hair and urine) [196], with hair
concentrations of antimony [standardized mean difference
(SMD) = 0.24; 95% CI 0.03–0.45] and lead (SMD = 0.60;
95% CI 0.17–1.03) in ASD cases significantly higher than
those of control subjects. ASD cases presented with higher
levels of erythrocyte lead (SMD = 1.55, 95% CI 0.2–2.89)
and mercury (SMD = 1.56, 95% CI 0.42–2.70), and higher
blood lead levels (SMD = 0.43, 95% CI 0.02–0.85). Sensi-
tivity analyses revealed that ASD cases in developed, but
not in developing countries, had lower hair concentrations
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1284 S.Bölte et al.
1 3
of cadmium (SMD = −0.29, 95% CI −0.46 to −0.12).
Similarly, analyses indicated that autistic individuals in low
income, but not high-income countries, had increased lead
concentrations in their hair (SMD = 1.58, 95% CI 0.80–2.36)
and mercury (SMD = 0.77, 95% CI 0.31–1.23). For heavy
metals in ambient air, positive and statistically significant
effects have been found, although the effects are generally
small and not consistent [191].
Herbicides, insecticides, insect repellents, animal repellents,
antimicrobials, fungicides, disinfectants, and sanitizers are
summarized under the label of pesticides. They are all agents
discouraging pests and are explicitly designed to harm and
kill organisms. Several of the active ingredients of these
products target living organisms through their nervous sys-
tems, inhibiting acetylcholinesterase production in the brain,
altering GABA neurotransmission [197, 198]. A review
comprising of seven epidemiological studies conducted in
2014 noted that all studies documented an association across
all classes of pesticides and ASD risk, with several associa-
tions reaching significance. These effects were the largest
for exposures in weeks 1–7 of pregnancy, and postnatally in
weeks 4–12 [185]. A more recent case–control study draw-
ing on data from the CHARGE study [199] found that prox-
imity to organophosphates during pregnancy was associated
with a 60% increase in ASD risk. This risk was amplified
for exposures during the third trimester (OR 2.0; 95% CI
1.1–3.6), and exposures to chlorpyrifos during the second
trimester (OR 3.3; 95% CI 1.5–7.4). Pyrethroid insecticide
exposure immediately prior to conception or during third
trimester posed an increased risk for both ASD and devel-
opmental delay, with ORs ranging from 1.7 to 2.3.
Non‑persistent organic pollutants
These toxins mainly include phthalates and bisphenol, used
primarily in the production of plastics. While they do not
persist in the human body, being at least partially cleared by
bodily processes, their presence in the modern environment
is ubiquitous, potentially posing a risk to the reproductive,
respiratory, and endocrine systems, being possibly involved
in carcinogenesis and adversely effecting neurodevelop-
ment [200, 201]. The role of phthalates in ASD was recently
reviewed and summarized across seven studies, inclusive
of five human studies, three case–control in design and two
cohort studies [202]. One cohort and two case–control stud-
ies reported an association between phthalate and autism.
Concerning bisphenol A, the published literature, mostly
characterized by smaller case–control studies is also con-
flicting, reporting associations ranging from none to rather
substantial links with clinical autism and autistic traits
[203206]. A recent animal model study of maternal and
paternal bisphenol exposure indicated behavioral effects in
the area of anxiety, rather than social behaviors [207].
Persistent organic pollutants
Organic compounds resistant to environmental degradation
accumulate in the environment and food chains with the
potential to negatively influence human health, particularly
through the consumption of animal fat and breast milk. The
Stockholm Convention on Persistent Organic Pollutants was
ratified in 2001, with the aim of banning these pollutants
worldwide. A recent review summarized the evidence of
the potential association between autism and autism rele-
vant phenotypes and persistent organic pollutants for three
major agents: dichlorodiphenyltrichloroethane (DDT), poly-
chlorinated biphenyls (PCBs), and polybromated diphenyl
ethers (PBDEs) [208]. Collectively, these agents have shown
adverse endocrine, immune, and neurodevelopmental effects
in humans [209]. Two studies have investigated the influence
of the pesticide DDT on neurodevelopment in humans and
rats, demonstrating a negative impact on cognitive skills (IQ,
memory) and gene expression in the hypothalamus [210,
211]. Studies on PCBs, previously used in coolantfluids in
electrical apparatus, have focused on cognitive skills, dem-
onstrating negative effects on various intellectual, motor and
verbal outcomes of relevance to autism [212, 213]. A recent
larger case–control study also found organochlorine com-
pounds during pregnancy were associated with ASD [214].
While PBDEs, historically used as fire retardants in furniture
and other products negatively impact on neurodevelopment
[215], the CHARGE study reported no differences in plasma
PBDE levels in autism and typical control cases [216].
Psychosocial factors
Owing to the long-lasting false hypothesis of a psychogenic
causation of autism [217], any possible contributions of
the psychosocial environment to autism etiology have been
largely avoided by research. However, conceptualizations of
mental disorders and maladaptation must not stop at the indi-
vidual, but be understood at a societal level, considering the
potential mismatch between an individual’s skills and needs
and societal expectations and demands. It is well known
and accepted that the psychosocial environment, independ-
ent of etiological considerations, plays a role in modifying
the severity, quality of life and functional outcomes or level
of impairment associated with ASD. Access to early identi-
fication and intervention, supportive and understanding envi-
ronments maximizing adaptation to an autistic individual’s
needs (“inclusion”), and appropriate education and employ-
ment are critical in determining functional abilities and dis-
abilities [3, 218]. Psychosocial factors may also have a role
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1285The contribution ofenvironmental exposure totheetiology ofautism spectrum disorder
1 3
beyond purely modifying outcomes. For instance, it is now
established in human and animal models that intense mater-
nal stress during pregnancy may have long-term biological
and behavioral effects on the child [219221]. In addition,
extreme deprivation in infancy such as that experienced in
institutions with impoverished levels of care, stimulation,
and attention may have adverse effects on developmental
psychopathology and physical development [222].
Maternal migration
Neurodevelopmental biological correlates associated with
prenatal stress in offspring include cognitive function, cer-
ebral processing, and functional and structural brain connec-
tivity involving amygdalae and (pre)frontal cortex, changes
in hypothalamo-pituitary–adrenal axis and the autonomous
nervous system [223]. In autism, the major life event of
maternal immigration has been the most studied cause of
maternal stress, and possibly associated with immune acti-
vation (see above). An alternative explanation, not linked to
stress, is reduced vitamin D levels in dark skinned migrants
moving to the northern hemisphere [224]. Results examining
the association between maternal immigration and autism
are mixed. A 2015 review including ten studies found a
positive association with immigration in three studies, no
connection in five, and a reverse association in two studies
[225]. Six of the ten studies found that giving birth postma-
ternal migration increased ASD risk. A large registry study
from Sweden, not included in the review, reported that third
trimester prenatal stress increased ASD risk (OR 1.58, 95%
CI 1.15–2.17) [226]. Another later Finnish hospital dis-
charge diagnosis study on the matter, focusing on Asperger
syndrome only, found a reduced risk in immigrant families,
including those from Sub-Saharan Africa [227].
Natural disasters
The association of exposure to prenatal maternal stress
(PNMS) and ASD risk or ASD-related cognitive features
has been studied in the context of natural disaster cohorts
that mimic the random allocation of experimental designs.
The Project Ice Storm, the QF2011 Queensland Flood Study,
and a study on the association between the prevalence of
ASD and tropical storms in Louisiana are examples of this
research approach [221, 228, 229]. In the Project Ice Storm
[221], mothers’ objective stress, and subjective distress
during the early stages of pregnancy explained between 23
and 42.7% of the variance in autistic symptoms in 6-year-
olds. Exposure to tropical storms in Louisiana [228] from
1980 to 1995 was employed as a model, examining if risk
for ASD increases in a dose–response pattern parallel with
the severity of PNMS (as inferred from storm severity),
and sensitivity of gestational periods to ASD risk. While a
dose–response relationship for ASD emerged across cohorts,
in contrast to the findings of Project Ice Storm, this was par-
ticularly strong for exposures occurring during the middle
and end stages of gestation. The QF2011, Queensland Flood
Study [229] examined the association between PNMS and
theory of mind challenges. Higher subjective stress, but not
objective hardship predicted poorer theory of mind skills in
130 children at 30months of age.
Institutional deprivation
Children adopted from globally deficient orphanages may
initially show a variety of atypical behaviors, including ste-
reotyped self-stimulation, inability to form deep or genu-
ine attachments, indiscriminate friendliness, and difficulty
establishing appropriate peer relationships. Severe early
deprivation may also be a major contributor to delayed
development and longer-term extreme behaviors, with such
experiences possibly particularly impactful between 6 and
18months of life [222]. The Romanian adoptee study com-
pared 144 children initially raised in Romanian institutions,
but then adopted by UK families, and later followed up at
ages 4, 6, and 11 years with a non-institutionalized sample
of 52 domestic adoptees. Sixteen of the Romanian children
were found to have “quasi-autism” with additional children
presenting with autistic features, while none of the domestic
adoptees presented with any signs of autism. However, by
age 11, a quarter of the children had “lost” their autistic-
like behaviors, with the remaining children demonstrat-
ing both similarities and differences to classic ASD [230].
Importantly, despite their early extreme deprivation, only a
minority of cases developed quasi-autism with the majority
recovering from their early experiences. These findings are
of limited relevance to understanding the etiology of autism
outside of institutional settings given that symptoms resulted
from exposure to extreme psychosocial deprivation.
Protective factors
While the overwhelming majority of research has examined
environmental risk in autism, there is an emerging body of
research examining the role of potentially protective factors,
largely from the field of nutrition and food supplementation,
with several underpinned by findings from the risk factor
literature. Studies indicate prenatal vitamin supplementa-
tion close to delivery might reduce the risk of autism in off-
spring, with folate (vitamin, B9, folic acid, folacin) receiving
considerable attention [231233]. Folate is essential in the
production and maintenance ofcells, to DNA andRNA syn-
thesisand methylation, in preventing changes to DNA and
various other cellular processes, and centrally involved in
cancer prevention [234]. There is wide evidence that pre and
periconceptional folate supplementation supports neural and
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1286 S.Bölte et al.
1 3
neurobehavioral development, bolstering social, cognitive
and verbal functioning [235237]. It has been hypothesized
that in autism, folate may act as a methyl donor, supporting
remethylation during early embryogenesis [232, 233]. While
folate is generally considered not to protect against ASD, it
may buffer additional risks, such as in mothers or infants
who are carriers of gene variants impacting the efficiency
of folate-dependent one-carbon metabolism or fetuses with
neural tube alterations.
Fatty acids including the omega-3 group are assumed to
play a key role in neurodevelopment during early childhood
as well as in regulating cognitive functioning across the life
span [238], with supplementation studies revealing their
benefits to neural efficiency [239]. In autism, the few studies
examining the effect of maternal fatty acid supplementation
or intake on autism and autistic trait outcomes have revealed
inconsistent results. This research is equally counterbal-
anced, with two studies each both identifying and failing to
identify an association between maternal omega 3/omega 6
intake or status and autism related outcomes [240242]. The
many connections between brain functioning and develop-
ment, and gastrointestinal functioning, have been increas-
ingly highlighted in the field of psychiatry, and specifically
in ASD [243, 244]. The role of the gastrointestinal tract, the
largest immune organ in the human body, and the role of
several aspects of immunity and inflammation potentially
relevant to the etiology of ASD have been discussed earlier
in this review. There is evidence that some probiotic bacteria
migrate from the mother to the child [245], with probiotic
supplementation during pregnancy a promising, but as yet
unexplored field of future investigation in autism protective
factors [246].
Research examining the etiology of autism across the last
25years has been dominated by a focus on genetic factors;
however, there is increasing awareness of the potential sig-
nificance of environmental influences in the etiology of
ASD. The results of recent twin and family studies point
toward a greater role for environmental contributions [29,
30], with pessimism toward such approaches decreasing,
some of which was historically fueled by fake research in
the area including unproven claims of vaccinations being
causal of ASD [177]. In addition, given the global increase
in diagnoses rates of ASD and the increasing availability
of funding for research, researchers from all fields of envi-
ronmental science are more and more engaging in autism
In this review, an up-to-date overview of the potential
environmental contributions to autism development and
presumed pathophysiological mechanisms is providedfor
parental age, several aspects of the immediate fetal environ-
ment, obstetric complications, medication during pregnancy,
smoking and alcohol use, nutrition, diverse toxic exposures,
as well as protective nutritional factors and the role psy-
chosocial factors. Evidence, both positive and negative, is
mounting in relation to the role these risks play in the etiol-
ogy of ASD. Several areas are now underpinned by rela-
tively large bodies of evidence such as parental age and SSRI
medication [58, 130132], while others lines of inquiry have
generated relatively little specific evidence such as smoking
and alcohol use [145, 146, 150154].
In the presence a plethora of existing agents, evidence
regarding the impact of environmental toxins on human
health and development in general, and autism in particular,
is lacking. Although the generalizability of animal studies
to humans remains relatively unknown, animal models have
yielded many intriguing insights into the effects and mecha-
nisms of inflammation and immune activation, as well as
the role of toxic agents, in inducing autism-like behaviors in
rodent and other species [103, 104, 112115, 207]. Overall,
understanding the role of environmental exposures in the
etiology of ASD is a broad and complex field, still largely
in its infancy with many current limitations, but also with
many future opportunities.
The etiology of ASD is heterogeneous, as are its phenotypes.
It is both a clinically relevant phenomenon, and a quantita-
tive trait in the general population, with broader subclini-
cal phenotypes frequently present in relatives [247, 248]. In
clinical cases, other neurodevelopmental conditions, psychi-
atric disorders and somatic disorders are often co-occurring
complications [1315]. Finally, diagnoses rates have risen
dramatically in the last 20years, with a parallel widening of
the diagnostic concept undoubtedly one of the driving fac-
tors. The etiology of ASD is complex, with causal factors
unknown in many cases. Collectively, these factors make
research aimed at improving our understanding of the etiol-
ogy of pure autism challenging. Today, up to 15% of autism
variants can be linked to genetic determinants, with future
projections that as much as to 50% of genetic etiologies are
discoverable using sequencing approaches [26]. Even if this
is realized, it leaves considerable space for speculation as to
the etiological role of environmental contributions. Expo-
sure to many factors occurs at a population level, such as in
the case of air pollutants, with their role in autism etiology
far from fully understood. While still largely unexplored,
some effects may result from interactions between environ-
mental factors and genes acting to increase ASD risk, with
several intriguing examples emerging such as between MET
rs1858830 CC genotype on the one hand, and early life stress
and air pollutant exposure on the other [249, 250]. A related
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
1287The contribution ofenvironmental exposure totheetiology ofautism spectrum disorder
1 3
issue is the importance of epigenetic modulation, such as
alterations in DNA methylation through which PCBs, lead,
and bisphenol confer a risk for ASD [251].
Reported autism–environment associations may not be
causal, for example there is doubt as to the causal role of
obstetric complications, which are perhaps more likely to be
epiphenomena of primary genetic risks [122]. In addition,
parental age might be confounded by parents with autism
traits having children later in life, or choosing partners with
high autism traits [252, 253]. Maternal SSRI risks might be
confounded with maternal depression diagnosis and broader
autism phenotypes [254]. These are only a few examples of
the multitude of possible confounders of environmental risk
factors. Many have received little attention in research, such
as the cultural bias apparent in the association of migration
and autism risk, with one study reporting a reduced risk of
Asperger syndrome among immigrant families in Finland.
Such findings might be explained by cultural and famil-
ial factors with clinical experience suggesting that milder
variants of ASD might not be perceived as equally atypi-
cal or impairing by Finnish and immigrant families (with
immigrant families having a higher threshold for perceiving
deviance), leading to referral and diagnostic bias. It might
also be possible that neurodevelopmental disorders are
more stigmatized among immigrants, leading to a tendency
to avoid clinical assessment. Another challenge, remaining
largely unaddressed, is the additive and interactive effects
across environmental factors. For instance, a recent study
showed that associations between pesticide exposures and
ASD were modulated by folate intake during the first month
of pregnancy [255] with evidence of a cumulative risk for
environmental effects in autism [32].
Published research in this field has many shortcomings
in relation to design, with the majority of studies being
retrospective, cross-sectional, case–control, and cohort
approaches, with very few employing experimental or
prospective designs with a priori statement of hypotheses
restricting conclusions in relation to causality. Further, the
majority of case–control studies have been small with impre-
cise measures of exposure. For example, research examining
air pollution exposure employing indirect measures of expo-
sure (such as distance to a freeway where emissions were
measured) have reported associations to autism [256], while
studies measuring emission levels close to the individuals’
homes have not [257]. Further, this line of research should
consider the role of both cultural factors and residential area
in confounding the relationship between pollution exposure
and autism, a notion consistent with positive associations
originating largely from the USA and negative results
emerging from Europe, with socioeconomic status likely to
play a role in both. As in other fields of autism research,
there are high levels of variability in outcome assessments,
ranging from register-based to clinical gold standard, with
both categorical and dimensional scales, limiting compa-
rability. Given the evolving nature of autism as a concept
and changes in community awareness and understanding, it
might be difficult to compare older and new studies in terms
of the autism measured.
Viewed optimistically, the various limitations outlined
above provide many opportunities in directing and improv-
ing future research. Key to understanding the role of envi-
ronmental factors in the etiology of autism is mapping the
critical time points of vulnerability in pregnancy and early
development. Alterations to neuralmigration, laminar dis-
organization, neuron maturation and neurite outgrowth, syn-
aptogenesis and reduced neural network functioning likely
play a crucial role in autism development [258], with vary-
ing levels of susceptibility to adverse environmental influ-
ences during various stages of pregnancy. These critical time
points are still largely unmapped for most agents in relation
to their risk of ASD, with points likely to vary across envi-
ronmental hazards. While an increasing number of studies
have attempted to address this issue, for instance in regards
to the role air pollution plays in ASD risk [259], findings
remain insufficiently robust to support firm conclusions. A
likely fruitful line of research would be for basic human
research and neighboring fields to focus explicitly on the
risk various environmental exposures pose for ASD across
the stages of pregnancy [260].
Clearly, more cross-discipline research is needed to
understand autism etiologies. Multi-hit models of ASD
included genetic and environmental factors and their inter-
action. While they are theoretically well-accepted, the
empirical evidence of their causality in ASD remains weak.
The literature contains several attempts to design such risk
models, for example in examining the association between
genetic disposition and maternal antidepressant use [261].
Despite the evidential methodological challenges, the utility
of these multiple hit models in understanding ASD etiology
should be further explored.
While research to date has largely focused on examin-
ing the environmental risk factors of ASD, examining envi-
ronmental protective factors might be equally, if not more
valuable. Despite wide speculation, very few protective fac-
tors have been systematically studied in ASD, and evidence
is emerging as to the potentially protective role folate and
other nutritional factors might play in buffering ASD risk.
This line of research presents many opportunities including
the identification of mechanisms of prevention and poten-
tial interventions. For instance, the finding in mice models
that risk for obese mothers to have offspring with behavio-
ral problems linked with autism is ameliorated by dietary
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
1288 S.Bölte et al.
1 3
intervention during pregnancy and lactation might be trans-
latable to humans [262, 263].
A promising and still largely ignored line of environmen-
tal research relates to trends in the prevalence of autism.
Specifically, data from Swedish regional registries [18]
show that the increase in ASD rates observed in high-
income countries in recent years is almost exclusively
accounted for by ASD in the normative intellectual range,
while ASD linked with intellectual disability is decreasing.
Other surveillance systems, such as the Center of Disease
Control Autism and Developmental Disabilities Monitor-
ing (ADDM) Network in the USA (
addm.html), have also identified this trend. Further, ASD
risk associated with environmental exposures has been sta-
ble for air pollutants and pesticides, with lifestyle risk factors
such as smoking and alcohol consumption and other poten-
tial hazards related to nutrition and medication in decline
[264]. The potential association between the downward tra-
jectory in the number of ASD cases with associated intel-
lectual disability and the curtailing of several environmen-
tal risk factors is worth investigating. While ASD presents
across all levels of intellectual functioning, the distinction
between ASD with and without challenges is commonly
made on the basis of intellect, making this an important line
of research to pursue. Stratifying ASD on the basis of fac-
tors other than solely intellect, generating more homogenous
groups, would still likely support more conclusive findings
in relation to the etiology of autism. However, despite effort
to subtype ASD and look at environmental and genetic risk
factors within subtypes including sex, comorbidities, ver-
bal abilities, neurocognitive and biological endophenotypes,
these attempts have thus far not been very fruitful [265].
Nevertheless, there are still multiple options for stratifica-
tion to be explored. Several major collaborative efforts in
ASD, such as the EU-AIMS ( specifically aim to
understand biomarkers potentially relevant to stratification
[266268]. Other ongoing longitudinal large-scale projects
such as the Norwegian Mother and Child Cohort Study (fhi.
no/moba-en) [269],the Swedish Lifegene Study (lifegene.
se) [270] or the National Institutes of Health Environmen-
tal influences on Child Health Outcomes Program (
echo) offer opportunities to study the environmental risk
factors in autism and other conditions in detail.
Although ASD is no longer considered a rare condition,
autism research is challenged by studies employing small
sample sizes. The evolving body of autism research shows
that autism is not a tightly bounded clinical entity, but that
traits from low to extreme exist more broadly in the gen-
eral population. Viewing autistic phenotypes as continuous,
rather than categorical, provides an opportunity to under-
pin studies with larger samples, increasing their sensitiv-
ity to small and medium effects. Finally, twin studies pro-
vide a unique opportunity to examine both the genetic and
environmental contributions to ASD etiology. In particular,
contrasting the phenotypes of discordant and monozygotic
twins enables control of genetic factors, providing a pow-
erful strategy to identify disease-associated environmental
factors, independent of underlying genomic sequence vari-
ation [271]. The Roots of Autism and ADHD Twin Study
Sweden (RATSS) [272], a sub-study of the population-based
Child and Adolescent Twin Study Sweden (CATSS) [273], is
the largest collection of deeply clinically phenotyped autism
twins. It primarily applies twin–cotwin analyses to identify
environmental risks contributions to autism phenotypes
on the behavioral and neurobiological level controlling for
genetic and familial factors. It has generated several novel
findings and hypotheses related to the role of non-shared
environment in ASD, such as the potential significance of
altered zinc-copper cycles and dysregulation of other essen-
tial and toxic metals during critical pre- and postnatal devel-
opmental windows [32, 175, 176, 274, 275].
In conclusion, this review provides a broad and updated
review of the potential environmental risks in the etiology
of autism, discussing the limitations of current research and
identifying likely fruitful pathways for future research. The
majority of current research is preclinical in design, limiting
its ability to inform prevention and intervention strategies
in the real world. The ultimate goal of all medical research
must be to make discoveries that improve people’s lives.
Hopefully, future research aimed at understanding the role of
environmental factors in the etiology of ASD will reach this
stage. The current review shows that designing population-
level studies, informed by findings from basic research, is
likely to work toward achieving this goal.
Acknowledgements We thank the Swedish Research Council, Vin-
nova, Formas, FORTE, the Swedish Brain foundation (Hjärnfonden),
Stockholm Brain Institute, Autism and Asperger Association Stock-
holm, Queen Silvia Jubilee Fund, Solstickan Foundation, PRIMA
Child and Adult Psychiatry, the Pediatric Research Foundation at
Astrid Lindgren Children’s Hospital, Sällskapet Barnavård, the Swed-
ish Foundation for Strategic Research, Jerring Foundation, the Swedish
Order of Freemasons, Kempe-Carlgrenska Foundation, Sunnderdahls
Handikappsfond, and the Jeansson Foundation for their contributions to
the Roots of Autism and ADHD Twin Study in Sweden (RATSS). We
further acknowledge the EU-AIMS (European Autism Intervention),
with support from the Innovative Medicines Initiative Joint Undertak-
ing (Grant agreement no. 115300), the resources of which are com-
posed of financial contributions from the European Union’s Seventh
Framework Programme (Grant FP7/2007–2013), from the European
Federation of Pharmaceutical Industries and Associations companies’
in-kind contributions, and from Autism Speaks, as well as the IMI ini-
tiative—EU-AIMS-2-TRIALS for funding of the LEAP twin research.
Compliance with ethical standards
Conflict of interest Sven Bölte declares no direct conflict of inter-
est related to this article. He discloses that he has in the last 5years
acted as an author, consultant or lecturer for Shire, Medice, Roche, Eli
Lilly, Prima Psychiatry, GLGroup, System Analytic, Ability Partner,
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
1289The contribution ofenvironmental exposure totheetiology ofautism spectrum disorder
1 3
Kompetento, Expo Medica, and Prophase. He receives royalties for
text books and diagnostic tools from Huber/Hogrefe, Kohlhammer and
Open Access This article is distributed under the terms of the Crea-
tive Commons Attribution 4.0 International License (http://creat iveco
mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribu-
tion, and reproduction in any medium, provided you give appropriate
credit to the original author(s) and the source, provide a link to the
Creative Commons license, and indicate if changes were made.
1. American Psychiatric Association [APA] (2013) Diagnostic and
Statistical manual of mental disorders (DSM-5), 5th edn. Ameri-
can Psychiatric Association, Arlington
2. Bölte S, Mahdi S, de Vries PJ, Granlund M, Robison JE, Shul-
man C, Swedo S, Tonge B, Wong V, Zwaigenbaum L, Segerer
W, Selb M (2018) The Gestalt of functioning in autism spectrum
disorder: results of the international conference to develop final
consensus international classification of functioning, disability
and health core sets. Autism, Jan 1 (Epub ahead of print)
3. Jonsson U, Alaie I, Löfgren Wilteus A, Zander E, Marschik P,
Coghill D, Bölte S (2016) Quality of life and childhood mental
and behavioural disorders: a critical review of the research. J
Child Psychol Psychiatry 58:439–469
4. Boyle CA, Boulet S, Schieve LA, Cohen RA, Blumberg SJ, Year-
gin-Allsopp M, Visser S, Kogan MD (2011) Trends in the preva-
lence of developmental disabilities in US children, 1997–2008.
Pediatrics 127:1034–1042
5. Happé F, Frith U (2014) Annual research review: towards a
developmental neuroscience of atypical social cognition. J Child
Psychol Psychiatry 55:553–557
6. O’Hearn K, Asato M, Ordaz S, Luna B (2008) Neurodevel-
opment and executive function in autism. Dev Psychopathol
7. Happé F, Frith U (2006) The weak coherence account: detail-
focused cognitive style in autism spectrum disorders. J Autism
Dev Disord 36:5–25
8. DiCicco-Bloom E, Lord C, Zwaigenbaum L, Courchesne E,
Dager SR, Schmitz C, Schultz RT, Crawley J, Young LJ (2006)
The developmental neurobiology of autism spectrum disorder. J
Neurosci 26:6897–6906
9. Kelly JR, Minuto C, Cryan JF, Clarke G, Dinan TG (2017) Cross
talk: the microbiota and neurodevelopmental disorders. Front
Neurosci 11:490
10. Edmiston E, Ashwood P, Van de Water J (2017) Autoimmunity,
autoantibodies, and autism spectrum disorder. Biol Psychiatry
11. James WH (2008) Further evidence that some male-based neu-
rodevelopmental disorders are associated with high intrauterine
testosterone concentrations. Dev Med Child Neurol 50:15–18
12. Estes ML, McAllister AK (2015) Immune mediators in the brain
and peripheral tissues in autism spectrum disorder. Nat Rev Neu-
rosci 16:469–486
13. Hirvikoski T, Mittendorfer-Rutz E, Boman M, Larsson H,
Lichtenstein P, Bölte S (2016) Premature mortality in autism
spectrum disorder. Br J Psychiatry 208:232–238
14. Simonoff E, Pickles A, Charman T, Chandler S, Loucas T, Baird
G (2008) Psychiatric disorders in children with autism spectrum
disorders: prevalence, comorbidity, and associated factors in a
population-derived sample. J Am Acad Child Adolesc Psychiatry
15. Bauman ML (2010) Medical comorbidities in autism: challenges
to diagnosis and treatment. Neurotherapeutics 7:320–327
16. Lyall K, Croen L, Daniels J, Fallin MD, Ladd-Acosta C, Lee BK,
Park BY, Snyder NW, Schendel D, Volk H, Windham GC, News-
chaffer C (2017) The changing epidemiology of autism spectrum
disorders. Annu Rev Public Health 38:81–102
17. Center for Disease Control (2018) Identified prevalence of autism
spectrum disorder ADDM network 2000–2014 combining data
from all sites. https :// d/autis m/data.html.
Accessed 17 Dec 2018
18. Kosidou K, Edvin V, Magnusson C, Dalman C (2017) Autism-
spektrumtillstånd och ADHD bland barn och unga i Stockholms
län: Förekomst i befolkningen samt vårdsökande under åren 2011
till 2016. Centrum för Epidemiologi och Samhällsmedicin. Fak-
tablad 2017:1
19. Lai MC, Lombardo MV, Auyeung B, Chakrabarti B, Baron-
Cohen S (2015) Sex/gender differences and autism: setting the
scene for future research. J Am Acad Child Adolesc Psychiatry
20. Lai MC, Lerch JP, Floris DL, Ruigrok AN, Pohl A, Lombardo
MV, Baron-Cohen S (2017) Imaging sex/gender and autism in
the brain: etiological implications. J Neurosci Res 95:380–397
21. Green J, Garg S (2018) Annual research review: the state of
autism intervention science: progress, target psychological and
biological mechanisms and future prospects. J Child Psychol
Psychiatry 59:424–443
22. Bölte S (2014) Is autism curable? Dev Med Child Neurol
23. Kapp SK, Gillespie-Lynch K, Sherman LE, Hutman T (2013)
Deficit, difference, or both? Autism and neurodiversity. Dev Psy-
chol 49:59–71
24. Constantino JN, Todd RD (2003) Autistic traits in the general
population: a twin study. Arch Gen Psychiatry 60:524–530
25. Vorstman JAS, Parr JR, Moreno-De-Luca D, Anney RJL,
Nurnberger JI Jr, Hallmayer JF (2017) Autism genetics: oppor-
tunities and challenges for clinical translation. Nat Rev Genet
26. Tammimies K, Falck-Ytter T, Bölte S (2016) Quo Vadis clinical
genomics of ASD? Autism 20:259–261
27. Ronald A, Hoekstra RA (2011) Autism spectrum disorders and
autistic traits: a decade of new twin studies. Am J Med Genet B
Neuropsychiatr Genet 156B:255–274
28. Tick B, Bolton P, Happé F, Rutter M, Rijsdijk F (2016) Herit-
ability of autism spectrum disorders: a meta-analysis of twin
studies. J Child Psychol Psychiatry 57:585–595
29. Sandin S, Lichtenstein P, Kuja-Halkola R, Larsson H, Hultman
CM, Reichenberg A (2014) The familial risk of autism. JAMA
30. Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe
T, Miller J, Fedele A, Collins J, Smith K, Lotspeich L, Croen LA,
Ozonoff S, Lajonchere C, Grether JK, Risch N (2011) Genetic
heritability and shared environmental factors among twin pairs
with autism. Arch Gen Psychiatry 68:1095–1102
31. Turkheimer E, Waldron M (2000) Nonshared environment: a
theoretical, methodological, and quantitative review. Psychol
Bull 126:78–108
32. Willfors C, Carlsson T, Anderlid B-M, Nordgren A, Kostrzewa
E, Berggren S, Ronald A, Kuja-Halkola R, Tammimies K, Bölte
S (2017) Medical history of discordant twins and environmental
etiologies of autism. Transl Psychiatry 31:e1014
33. Plomin R, DeFries JC, McClearn GE, McGuffin P (2008) Behav-
ioral Genetics, 5th edn. Worth Publisher, New York
34. Grafodatskaya D, Chung B, Szatmari P, Weksberg R (2010)
Autism spectrum disorders and epigenetics. J Am Acad Child
Psychiatry 49:794–809
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
1290 S.Bölte et al.
1 3
35. Siu MT, Weksberg R (2017) Epigenetics of autism spectrum
disorder. Adv Exp Med Biol 978:63–90
36. Wong CC, Meaburn EL, Ronald A, Price TS, Jeffries AR,
Schalkwyk LC, Plomin R, Mill J (2014) Methylomic analysis of
monozygotic twins discordant for autism spectrum disorder and
related behavioural traits. Mol Psychiatry 19:495–503
37. Schuch V, Utsumi DA, Costa TV, Kulikowski LD, Muszkat M
(2015) Attention deficit hyperactivity disorder in the light of the
epigenetic paradigm. Front Psychiatry 6:126
38. Daskalakis NP, Bagot RC, Parker KJ, Vinkers CH, de Kloet ER
(2013) The three-hit concept of vulnerability and resilience:
toward understanding adaptation to early-life adversity outcome.
Psychoneuroendocrino 38:1858–1873
39. Mottron L, Belleville S, Rouleau GA, Collignon O (2014) Link-
ing neocortical, cognitive, and genetic variability in autism with
alterations of brain plasticity: the trigger-threshold-target model.
Neurosci Biobehav Rev 47:735–752
40. Mandy W, Lai MC (2016) Annual research review: the role of
the environment in the developmental psychopathology of autism
spectrum condition. J Child Psychol Psychiatry 57:271–292
41. Hertz-Picciotto I, Schmidt RJ, Krakowiak P (2018) Understand-
ing environmental contributions to autism: causal concepts and
the state of science. Autism Res 11:554–586
42. Modabbernia A, Velthorst E, Reichenberg A (2017) Environmen-
tal risk factors for autism: an evidence-based review of system-
atic reviews and meta-analyses. Mol Autism 8:13
43. Merikangas AK, Calkins ME, Bilker WB, Moore TM, Gur RC,
Gur RE (2017) Parental age and offspring psychopathology in
the philadelphia neurodevelopmental cohort. J Am Acad Child
Adolesc Psychiatry 56:391–400
44. Janecka M, Mill J, Basson MA, Goriely A, Spiers H, Reichen-
berg A, Schalkwyk L, Fernandes C (2017) Advanced paternal
age effects in neurodevelopmental disorders-review of potential
underlying mechanisms. Transl Psychiatry 7:e1019
45. Goldmann JM, Wong WS, Pinelli M, Farrah T, Bodian D,
Stittrich AB, Glusman G, Vissers LE, Hoischen A, Roach JC,
Vockley JG, Veltman JA, Solomon BD, Gilissen C, Niederhuber
JE (2016) Parent-of-origin-specific signatures of de novo muta-
tions. Nat Genet 48:935–939
46. Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjar-
tarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gud-
jonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason
H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge
M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G,
Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Ste-
fansson K (2017) Parental influence on human germline de novo
mutations in 1548 trios from Iceland. Nature 549:519–522
47. Kong A, Frigge ML, Masson G, Besenbacher S, Sulem P, Mag-
nusson G, Gudjonsson SA, Sigurdsson A, Jonasdottir A, Jon-
asdottir A, Wong WS, Sigurdsson G, Walters GB, Steinberg S,
Helgason H, Thorleifsson G, Gudbjartsson DF, Helgason A,
Magnusson OT, Thorsteinsdottir U, Stefansson K (2012) Rate of
de novo mutations and the importance of father’s age to disease
risk. Nature 488:471–475
48. Atsem S, Reichenbach J, Potabattula R, Dittrich M, Nava C,
Depienne C, Böhm L, Rost S, Hahn T, Schorsch M, Haaf T, El
Hajj N (2016) Paternal age effects on sperm FOXK1 and KCNA7
methylation and transmission into the next generation. Hum Mol
Genet 25:4996–5005
49. Frans EM, Sandin S, Reichenberg A, Langström N, Lichtenstein
P, McGrath JJ, Hultman CM (2013) Autism risk across genera-
tions: a population-based study of advancing grandpaternal and
paternal age. JAMA Psychiatry 70:516–521
50. Kojima M, Yassin W, Owada K, Aoki Y, Kuwabara H, Natsubori
T, Iwashiro N, Gonoi W, Takao H, Kasai K, Abe O, Kano Y,
Yamasue H (2018) Neuroanatomical correlates of advanced
paternal and maternal age at birth in autism spectrum disorder.
Cereb Cortex. https :// r/bhy12 2
51. Hultman CM, Sandin S, Levine SZ, Lichtenstein P, Reichen-
berg A (2011) Advancing paternal age and risk of autism: new
evidence from a population-based study and a meta-analysis
of epidemiological studies. Mol Psychiatry 16:1203–1212
52. Chang Z, Lichtenstein P, D’Onofrio BM, Almqvist C, Kuja-
Halkola R, Sjölander A, Larsson H (2014) Maternal age at
childbirth and risk for ADHD in offspring: a population-based
cohort study. Int J Epidemiol 43:1815–1824
53. Bölte S, Poustka L, Geurts H (2018) Comorbidity: Autism
Spectrum Disorder. In: Banaschewski T, Coghill D, Zuddas A
(eds) Oxford textbook of attention deficit hyperactivity disor-
der. University Press, Oxford
54. Fergusson DM, Woodward LJ (1999) Maternal age and educa-
tional and psychosocial outcomes in early adulthood. J Child
Psychol Psychiatry 40:479–789
55. Sandin S, Schendel D, Magnusson P, Hultman C, Surén P,
Susser E, Grønborg T, Gissler M, Gunnes N, Gross R, Henning
M, Bresnahan M, Sourander A, Hornig M, Carter K, Francis
R, Parner E, Leonard H, Rosanoff M, Stoltenberg C, Reichen-
berg A (2016) Autism risk associated with parental age and
with increasing difference in age between the parents. Mol
Psychiatry 21:693–700
56. Sandin S, Hultman CM, Kolevzon A, Gross R, MacCabe JH,
Reichenberg A (2012) Advancing maternal age is associated
with increasing risk for autism: a review and meta-analysis. J
Am Acad Child Adolesc Psychiatry 51:477–486
57. Croen LA, Najjar DV, Fireman B, Grether JK (2007) Maternal
and paternal age and risk of autism spectrum disorders. Arch
Pediatr Adolesc Med 161:334–340
58. Wu S, Wu F, Ding Y, Hou J, Bi J, Zhang Z (2017) Advanced
parental age and autism risk in children: a systematic review
and meta-analysis. Acta Psychiatr Scand 135:29–41
59. Auyeung B, Lombardo MV, Baron-Cohen S (2013) Prenatal
and postnatal hormone effects on the human brain and cogni-
tion. Pflugers Arch 465:557–571
60. Kosidou K, Dalman C, Widman L, Arver S, Lee BK, Magnus-
son C, Gardner RM (2017) Maternal polycystic ovary syn-
drome and risk for attention-deficit/hyperactivity disorder in
the offspring. Biol Psychiatry 82:651–659
61. Ferri SL, Abel T, Brodkin ES (2018) Sex differences in autism
spectrum disorder: a review. Curr Psychiatry Rep 20:9
62. Baron-Cohen S, Lombardo MV, Auyeung B, Contu L, Hawkes
CA (2017) A review of the impact of maternal obesity on the
cognitive function and mental health of the offspring. Int J Mol
Sci 18(5):E1093
63. Rivera HM, Christiansen KJ, Sullivan EL (2015) The role of
maternal obesity in the risk of neuropsychiatric disorders.
Front Neurosci 9:194
64. Edlow AG (2017) Maternal obesity and neurodevelopmental
and psychiatric disorders in offspring. Prenat Diagn 37:95–110
65. Godfrey KM, Reynolds RM, Prescott SL, Nyirenda M, Jaddoe
VW, Eriksson JG, Broekman BF (2017) Influence of maternal
obesity on the long-term health of offspring. Lancet Diabetes
Endocrinol 5:53–64
66. Burstyn I, Sithole F, Zwaigenbaum L (2010) Autism spectrum
disorders, maternal characteristics and obstetric complications
among singletons born in Alberta, Canada. Chronic Dis Can
67. Raio L, Bolla D, Baumann M (2015) Hypertension in preg-
nancy. Curr Opin Cardiol 30:411–415
68. Armaly Z, Jadaon JE, Jabbour A, Abassi ZA (2018) Preeclamp-
sia: novel mechanisms and potential therapeutic approaches.
Front Physiol 9:973
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
1291The contribution ofenvironmental exposure totheetiology ofautism spectrum disorder
1 3
69. Smith SE, Li J, Garbett K, Mirnics K, Patterson PH (2007)
Maternal immune activation alters fetal brain development
through interleukin-6. J Neurosci 27:10695–10702
70. Li P, Wang PJ, Zhang W (2015) Prenatal exposure to ultrasound
affects learning and memory in young rats. Ultrasound Med Biol
71. Baron-Cohen S, Auyeung B, Nørgaard-Pedersen B, Hougaard
DM, Abdallah MW, Melgaard L, Cohen AS, Chakrabarti B, Ruta
L, Lombardo MV (2015) Elevated fetal steroidogenic activity in
autism. Mol Psychiatry 20:369–376
72. Baron-Cohen S (2002) The extreme male brain theory of autism.
Trends Cogn Sci 6:248–254
73. Ashwin E, Chakrabarti B, Knickmeyer R (2011) Why are
autism spectrum conditions more prevalent in males. PLoS Biol
74. Lombardo MV, Ashwin E, Auyeung B, Chakrabarti B, Lai MC,
Taylor K, Hackett G, Bullmore ET, Baron-Cohen S (2012) Fetal
programming effects of testosterone on the reward system and
behavioral approach tendencies in humans. Biol Psychiatry
75. Lombardo MV, Ashwin E, Auyeung B, Chakrabarti B, Taylor
K, Hackett G, Bullmore ET, Baron-Cohen S (2012) Fetal testos-
terone influences sexually dimorphic gray matter in the human
brain. J Neurosci 32:674–680
76. Chakrabarti B, Dudbridge F, Kent L, Wheelwright S, Hill-Caw-
thorne G, Allison C, Banerjee-Basu S, Baron-Cohen S (2009)
Genes related to sex steroids, neural growth, and social-emo-
tional behavior are associated with autistic traits, empathy, and
Asperger syndrome. Autism Res 2:157–177
77. Baron-Cohen S, Auyeung B, Nørgaard-Pedersen B, Hougaard
DM, Abdallah MW, Melgaard L, Cohen AS, Chakrabarti B, Ruta
L, Lombardo MV (2015) Elevated fetal steroidogenic activity in
autism. Mol Psychiatry 20:369–376
78. Nandi A, Chen Z, Patel R, Poretsky L (2014) Polycystic ovary
syndrome. Endocrinol Metab Clin North Am 43:123–147
79. Lee BK, Arver S, Widman L, Gardner RM, Magnusson C, Dal-
man C, Kosidou K (2017) Maternal hirsutism and autism spec-
trum disorders in offspring. Autism Res 10:1544–1546
80. Palomba S, Marotta R, Di Cello A, Russo T, Falbo A, Orio F,
Tolino A, Zullo F, Esposito R, La Sala GB (2012) Pervasive
developmental disorders in children of hyperandrogenic women
with polycystic ovary syndrome: a longitudinal case-control
study. Clin Endocrinol (Oxf) 77:898–904
81. Cesta CE, Månsson M, Palm C, Lichtenstein P, Iliadou AN,
Landén M (2016) Polycystic ovary syndrome and psychiatric
disorders: co-morbidity and heritability in a nationwide Swedish
cohort. Psychoneuroendocrinology 73:196–203
82. Pohl A, Cassidy S, Auyeung B, Baron-Cohen S (2014) Uncover-
ing steroidopathy in women with autism: a latent class analysis.
Mol Autism 5:27
83. OECD (2017) https :// h-syste ms/Obesi
ty-Updat e-2017.pdf
84. Sanchez CE, Barry C, Sabhlok A, Russell K, Majors A, Kollins
SH, Fuemmeler BF (2018) Maternal pre-pregnancy obesity and
child neurodevelopmental outcomes: a meta-analysis. Obes Rev
85. Gardner RM, Lee BK, Magnusson C, Rai D, Frisell T, Karlsson
H, Idring S, Dalman C (2015) Maternal body mass index dur-
ing early pregnancy, gestational weight gain, and risk of autism
spectrum disorders: results from a swedish total population and
discordant sibling study. Int J Epidemiol 44:870–883
86. Getz KD, Anderka MT, Werler MM, Jick SS (2016) Maternal
pre-pregnancy body mass index and autism spectrum disorder
among offspring: a population-based case–control study. Paediatr
Perinat Epidemiol 30:479–487
87. Sanchez CE, Barry C, Sabhlok A, Russell K, Majors A, Kollins
SH, Fuemmeler BF (2018) Maternal pre-pregnancy obesity and
child neurodevelopmental outcomes: a meta-analysis. Obes Rev
88. Li M, Fallin MD, Riley A, Landa R, Walker SO, Silverstein M,
Caruso D, Pearson C, Kiang S, Dahm JL, Hong X, Wang G,
Wang MC, Zuckerman B, Wang X (2016) The association of
maternal obesity and diabetes with autism and other develop-
mental disabilities. Pediatrics 137:e20152206
89. Wan H, Zhang C, Li H, Luan S, Liu C (2018) Association of
maternal diabetes with autism spectrum disorders in offspring:
a systemic review and meta-analysis. Medicine (Baltimore).
90. Xiang AH, Wang X, Martinez MP, Walthall JC, Curry ES,
Page K, Buchanan TA, Coleman KJ, Getahun D (2015) Asso-
ciation of maternal diabetes with autism in offspring. JAMA
91. Gillon TER, Pels A, von Dadelszen P, MacDonell K, Magee
LA (2014) Hypertensive disorders of pregnancy: a systematic
review of international clinical practice guidelines. PLoS One
92. Raio L, Bolla D, Baumann M (2015) Hypertension in pregnancy.
Curr Opin Cardiol 30:411–415
93. Maher GM, O’Keeffe GW, Kearney PM, Kenny LC, Dinan TG,
Mattsson M, Khashan AS (2018) Association of hypertensive
disorders of pregnancy with risk of neurodevelopmental disor-
ders in offspring: a systematic review and meta-analysis. JAMA
94. Meltzer A, Van de Water J (2017) The role of the immune sys-
tem in autism spectrum disorder. Neuropsychopharmacology
95. Hutton J (2016) Does Rubella Cause Autism: a 2015 Reap-
praisal? Front Hum Neurosci 10:25
96. Atladóttir HO, Thorsen P, Østergaard L, Schendel DE, Lemcke
S, Abdallah M, Parner ET (2010) Maternal infection requiring
hospitalization during pregnancy and autism spectrum disorders.
J Autism Dev Disord 40:1423–1430
97. Zerbo O, Qian Y, Yoshida C, Grether JK, Van de Water J, Croen
LA (2015) Maternal infection during pregnancy and autism spec-
trum disorders. J Autism Dev Disord 45:4015–4025
98. Atladóttir HÓ, Henriksen TB, Schendel DE, Parner ET (2012)
Autism after infection, febrile episodes, and antibiotic use during
pregnancy: an exploratory study. Pediatrics 130:e1447–e1454
99. Lee BK, Magnusson C, Gardner RM, Blomström Å, Newschaffer
CJ, Burstyn I, Karlsson H, Dalman C (2015) Maternal hospi-
talization with infection during pregnancy and risk of autism
spectrum disorders. Brain Behav Immun 44:100–105
100. Maeyama K, Tomioka K, Nagase H, Yoshioka M, Takagi Y,
Kato T, Mizobuchi M, Kitayama S, Takada S, Nagai M, Sakak-
ibara N, Nishiyama M, Taniguchi-Ikeda M, Morioka I, Iijima
K, Nishimura N (2018) Congenital cytomegalovirus infection in
children with autism spectrum disorder: systematic review and
meta-analysis. J Autism Dev Disord 48:1483–1491
101. Brown AS, Surcel HM, Hinkka-Yli-Salomäki S, Cheslack-Post-
ava K, Bao Y, Sourander A (2015) Maternal thyroid autoantibody
and elevated risk of autism in a national birth cohort. Prog Neu-
ropsychopharmacol Biol Psychiatry 57:86–92
102. Brown AS, Sourander A, Hinkka-Yli-Salomäki S, McKeague
IW, Sundvall J, Surcel HM (2014) Elevated maternal C-reactive
protein and autism in a national birth cohort. Mol Psychiatry
103. Malkova NV, Yu CZ, Hsiao EY, Moore MJ, Patterson PH (2012)
Maternal immune activation yields offspring displaying mouse
versions of the three core symptoms of autism. Brain Behav
Immun 26:607–616
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
1292 S.Bölte et al.
1 3
104. Kaidanovich-Beilin O, Lipina T, Vukobradovic I, Roder J,
Woodgett JR (2011) Assessment of social interaction behaviors.
J Vis Exp 48:e2473
105. Bauman MD, Iosif AM, Smith SE, Bregere C, Amaral DG, Pat-
terson PH (2014) Activation of the maternal immune system dur-
ing pregnancy alters behavioral development of rhesus monkey
offspring. Biol Psychiatry 75:332–341
106. Careaga M, Murai T, Bauman MD (2017) Maternal immune acti-
vation and autism spectrum disorder: from rodents to nonhuman
and human primates. Biol Psychiatry 81:391–401
107. Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER, McCue
T, Codelli JA, Chow J, Reisman SE, Petrosino JF, Patterson PH,
Mazmanian SK (2013) Microbiota modulate behavioral and
physiological abnormalities associated with neurodevelopmental
disorders. Cell 155:1451–1463
108. Smith SE, Li J, Garbett K, Mirnics K, Patterson PH (2007)
Maternal immune activation alters fetal brain development
through interleukin-6. J Neurosci 27:10695–10702
109. Abdallah MW, Larsen N, Grove J, Nørgaard-Pedersen B, Thorsen
P, Mortensen EL, Hougaard DM (2013) Amniotic fluid inflam-
matory cytokines: potential markers of immunologic dysfunc-
tion in autism spectrum disorders. World J Biol Psychiatry
110. Zimmerman AW, Connors SL, Matteson KJ, Lee LC, Singer HS,
Castaneda JA, Pearce DA (2007) Maternal antibrain antibodies
in autism. Brain Behav Immun 21:351–357
111. Brimberg L, Sadiq A, Gregersen PK, Diamond B (2013) Brain-
reactive IgG correlates with autoimmunity in mothers of a child
with an autism spectrum disorder. Mol Psychiatry 18:1171–1177
112. Dalton P, Deacon R, Blamire A, Pike M, McKinlay I, Stein
J, Styles P, Vincent A (2003) Maternal neuronal antibodies
associated with autism and a language disorder. Ann Neurol
113. Singer HS, Morris C, Gause C, Pollard M, Zimmerman AW,
Pletnikov M (2009) Prenatal exposure to antibodies from mothers
of children with autism produces neurobehavioral alterations: a
pregnant dam mouse model. J Neuroimmunol 211:39–48
114. Braunschweig D, Golub MS, Koenig CM, Qi L, Pessah IN, Van
de Water J, Berman RF (2012) Maternal autism-associated IgG
antibodies delay development and produce anxiety in a mouse
gestational transfer model. J Neuroimmunol 252:56–65
115. Camacho J, Jones K, Miller E, Ariza J, Noctor S, de Water JV,
Martínez-Cerdeño V (2014) Embryonic intraventricular exposure
to autism-specific maternal autoantibodies produces alterations
in autistic-like stereotypical behaviors in offspring mice. Behav
Brain Res 266:46–51
116. Bauman MD, Iosif AM, Ashwood P, Braunschweig D, Lee A,
Schumann CM, Van de Water J, Amaral DG (2013) Maternal
antibodies from mothers of children with autism alter brain
growth and social behavior development in the rhesus monkey.
Transl Psychiatry 3:e278
117. Martin LA, Ashwood P, Braunschweig D, Cabanlit M, Van de
Water J, Amaral DG (2008) Stereotypies and hyperactivity in
rhesus monkeys exposed to IgG from mothers of children with
autism. Brain Behav Immun 22:806–816
118. Sacco R, Gabriele S, Persico AM (2015) Head circumference
and brain size in autism spectrum disorder: a systematic review
and meta-analysis. Psychiatry Res 234:239–251
119. Bricker L, Garcia J, Henderson J, Mugford M, Neilson J, Rob-
erts T, Martin MA (2000) Ultrasound screening in pregnancy: a
systematic review of the clinical effectiveness, cost-effectiveness
and women’s views. Health Techn Assess 4:1–193 (i–vi)
120. McClintic AM, King BH, Webb SJ, Mourad PD (2014) Mice
exposed to diagnostic ultrasound in utero are less social and
more active in social situations relative to controls. Autism Res
121. Webb SJ, Garrison MM, Bernier R, McClintic AM, King BH,
Mourad PD (2017) Severity of ASD symptoms and their correla-
tion with the presence of copy number variations and exposure
to first trimester ultrasound. Autism Res 10:472–484
122. Bolton PF, Murphy M, Macdonald H, Whitlock B, Pickles A,
Rutter M (1997) Obstetric complications in autism: conse-
quences or causes of the condition? J Am Acad Child Adolesc
Psychiatry 36:272–281
123. Gardener H, Spiegelman D, Buka SL (2011) Perinatal and neo-
natal risk factors for autism: a comprehensive meta-analysis.
Pediatrics 128:344–355
124. Wang C, Geng H, Liu W, Zhang G (2017) Prenatal, perinatal,
and postnatal factors associated with autism: a meta-analysis.
Medicine (Baltimore) 96:e6696
125. Meador KJ (2008) Effects of in utero antiepileptic drug exposure.
Epilepsy Curr 8:143–147
126. Jentink J, Loane MA, Dolk H, Barisic I, Garne E, Morris JK,
de Jong-van den Berg LT (2010) Valproic acid monotherapy in
pregnancy and major congenital malformations. N Engl J Med
127. Fuller LC, Cornelius SK, Murphy CW, Wiens DJ (2002) Neural
crest cell motility in valproic acid. Reprod Toxicol 16:825–839
128. Veroniki AA, Rios P, Cogo E, Straus SE, Finkelstein Y, Kealey
R, Reynen E, Soobiah C, Thavorn K, Hutton B, Hemmelgarn BR,
Yazdi F, D’Souza J, MacDonald H, Tricco AC (2017) Compara-
tive safety of antiepileptic drugs for neurological development in
children exposed during pregnancy and breast feeding: a system-
atic review and network meta-analysis. BMJ Open 7:e017248
129. Charlton RA, Jordan S, Pierini A, Garne E, Neville AJ, Hansen
AV, Gini R, Thayer D, Tingay K, Puccini A, Bos HJ, Nybo
Andersen AM, Sinclair M, Dolk H, de Jong-van den Berg LT
(2015) Selective serotonin reuptake inhibitor prescribing before,
during and after pregnancy: a population-based study in six
European regions. BJOG 122:1010–1020
130. Mezzacappa A, Lasica PA, Gianfagna F, Cazas O, Hardy P, Fal-
issard B, Sutter-Dallay AL, Gressier F (2017) Risk for autism
spectrum disorders according to period of prenatal antidepressant
exposure: a systematic review and meta-analysis. JAMA Pediatr
131. Rai D, Lee BK, Dalman C, Newschaffer C, Lewis G, Magnus-
son C (2017) Antidepressants during pregnancy and autism in
offspring: population based cohort study. BMJ 358:j2811
132. Brown HK, Ray JG, Wilton AS, Lunsky Y, Gomes T, Vigod SN
(2017) Association between serotonergic antidepressant use dur-
ing pregnancy and autism spectrum disorder in children. JAMA
133. Viktorin A, Levine SZ, Altemus M, Reichenberg A, Sandin S
(2018) Paternal use of antidepressants and offspring outcomes in
Sweden: nationwide prospective cohort study. BMJ 361:k2233
134. Viktorin A, Uher R, Reichenberg A, Levine SZ, Sandin S (2017)
Autism risk following antidepressant medication during preg-
nancy. Psychol Med 47:2787–2796
135. WHO (2015) Prevalence of tobacco smoking. http://www.who.
int/gho/tobac co/use/en/. Accessed 17 Dec 2018
136. WHO (2010) Total alcohol per capita (15 + years) consumption,
in litres of pure alcohol. ol/consu
mptio n_level s/total _adult _perca pita/en/. Accessed 17 Dec 2018
137. Ng M, Freeman MK, Fleming TD, Robinson M, Dwyer-Lindgren
L, Thomson B, Wollum A, Sanman E, Wulf S, Lopez AD, Mur-
ray CJ, Gakidou E (2014) Smoking prevalence and cigarette
consumption in 187 countries, 1980–2012. JAMA 311:183–192
138. Albuquerque CA, Smith KR, Johnson C, Chao R, Harding R
(2004) Influence of maternal tobacco smoking during pregnancy
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
1293The contribution ofenvironmental exposure totheetiology ofautism spectrum disorder
1 3
on uterine, umbilical and fetal cerebral artery blood flows. Early
Hum Dev 80:31–42
139. Muneoka K, Ogawa T, Kamei K, Mimura Y, Kato H, Takigawa
M (2001) Nicotine exposure during pregnancy is a factor which
influences serotonin transporter density in the rat brain. Eur J
Pharmacol 411:279–282
140. Lebel C, Mattson SN, Riley EP, Jones KL, Adnams CM, May
PA, Bookheimer SY, O’Connor MJ, Narr KL, Kan E, Abaryan
Z, Sowell ER (2012) A longitudinal study of the long-term con-
sequences of drinking during pregnancy: heavy in utero alcohol
exposure disrupts the normal processes of brain development. J
Neurosci 32:15243–15251
141. Irner TB (2012) Substance exposure in utero and developmental
consequences in adolescence: a systematic review. Child Neu-
ropsychol 18:521–549
142. Huizink AC, Mulder EJ (2006) Maternal smoking, drinking or
cannabis use during pregnancy and neurobehavioral and cog-
nitive functioning in human offspring. Neurosci Biobehav Rev
143. Tran PL, Lehti V, Lampi KM, Helenius H, Suominen A, Gissler
M, Brown AS, Sourander A (2013) Smoking during pregnancy
and risk of autism spectrum disorder in a Finnish National Birth
Cohort. Paediatr Perinat Epidemiol 27:266–274
144. Kalkbrenner AE, Braun JM, Durkin MS, Maenner MJ, Cunniff C,
Lee LC, Pettygrove S, Nicholas JS, Daniels JL (2012) Maternal
smoking during pregnancy and the prevalence of autism spec-
trum disorders, using data from the autism and developmen-
tal disabilities monitoring network. Environ Health Perspect
145. Rosen BN, Lee BK, Lee NL, Yang Y, Burstyn I (2015) Maternal
smoking and autism spectrum disorder: a meta-analysis. J Autism
Dev Disord 45:1689–1698
146. Tang S, Wang Y, Gong X, Wang G (2015) A meta-analysis
of maternal smoking during pregnancy and autism spectrum
disorder risk in offspring. Int J Environ Res Public Health
147. Dietz PM, Homa D, England LJ, Burley K, Tong VT, Dube SR,
Bernert JT (2011) Estimates of nondisclosure of cigarette smok-
ing among pregnant and nonpregnant women of reproductive age
in the United States. Am J Epidemiol 173:355–359
148. Jung Y, Lee AM, McKee SA, Picciotto MR (2017) Maternal
smoking and autism spectrum disorder: meta-analysis with popu-
lation smoking metrics as moderators. Sci Rep 7:4315
149. Mukherjee R, Layton M, Yacoub E, Turk J (2011) Autism and
autistic traits in people exposed to heavy prenatal alcohol: data
from a clinical series of 21 individuals and nested case control
study. Adv Ment Health Intellect Disabil 5:42–49
150. Eliasen M, Tolstrup JS, Nybo Andersen AM, Gronbaek M,
Olsen J, Strandberg-Larsen K (2010) Prenatal alcohol exposure
and autistic spectrum disorders—a population-based prospec-
tive study of 80 552 children and their mothers. Int J Epidemiol
151. Perrone-McGovern K, Simon-Dack S, Niccolai L (2015) Prenatal
and perinatal factors related to autism, IQ, and adaptive function-
ing. J Genet Psychol 176:1–10
152. Visser JC, Rommelse N, Vink L, Schrieken M, Oosterling IJ,
van der Gaag RJ, Buitelaar JK (2012) Narrowly versus broadly
defined autism spectrum disorders: differences in pre and peri-
natal risk factors. J Autism Dev Disord 43:1505–1516
153. Williams G, Oliver JM, Allard A, Sears L (2003) Autism and
associated medical and familial factors: a case control study. J
Dev Physic Disab 15:335–349
154. Gallagher C, McCarthy FP, Ryan RM, Khashan AS (2018)
Maternal alcohol consumption during pregnancy and the risk of
autism spectrum disorders in offspring: a retrospective analysis of
the millennium cohort study. J Autism Dev Disord48:3773–3782
155. Jackson AA, Robinson SM (2001) Dietary guidelines for
pregnancy: a review of current evidence. Public Health Nutr
156. van Eijsden M, Smits LJ, van der Wal MF, Bonsel GJ (2008)
Association between short interpregnancy intervals and term
birth weight: the role of folate depletion. Am J ClinNutr
157. Cheslack Postava K, Winter AS (2015) Short and long inter-
pregnancy intervals: correlates and variations by pregnancy
timing among U.S. women. Perspect Sex Reprod Health
158. Kozuki N, Walker N (2013) Exploring the association between
short/long preceding birth intervals and child mortality: using
reference birth interval children of the same mother as compari-
son. BMC Public Health 13(Suppl 3):S6
159. Wu G, Bazer FW, Cudd TA, Meininger CJ, Spencer TE (2004)
Maternal nutrition and fetal development. J Nutr 134:2169–2172
160. Heyden EL, Wimalawansa SJ (2017) Vitamin D: effects on
human reproduction, pregnancy, and fetal well-being. J Steroid
Biochem Mol Biol 180:41–50
161. Mazahery H, Camargo CA Jr, Conlon C, Beck KL, Kruger MC,
von Hurst PR (2016) Vitamin D and autism spectrum disorder:
a literature review. Nutrients 8:236
162. Magnusson C, Lundberg M, Lee BK, Rai D, Karlsson H, Gardner
R, Kosidou K, Arver S, Dalman C (2016) Maternal vitamin D
deficiency and the risk of autism spectrum disorders: population-
based study. BJPsych Open 2:170–172
163. WHO (2001) Iron deficiency anaemia: assessment, prevention
and control. World Health Organization, Geneva
164. Tchernia G, Archambeaud MP, Yvart J, Diallo D (1996) Eryth-
rocyte ferritin in human neonates: maternofetal iron kinetics
revisited. Clin Lab Haematol 18:147–153
165. Beard JL, Connor JR (2003) Iron status and neural functioning.
Annu Rev Nutr 23:41–58
166. Schmidt RJ, Tancredi DJ, Krakowiak P, Hansen RL, Ozonoff S
(2014) Maternal intake of supplemental iron and risk of autism
spectrum disorder. Am J Epidemiol 180:890–900
167. Surén P, Roth C, Bresnahan M, Haugen M, Hornig M, Hirtz
D, Lie KK, Lipkin WI, Magnus P, Reichborn-Kjennerud T,
Schjølberg S, Davey Smith G, Øyen AS, Susser E, Stoltenberg
C (2013) Association between maternal use of folic acid supple-
ments and risk of autism spectrum disorders in children. JAMA
168. Velie EM, Block G, Shaw GM, Samuels SJ, Schaffer DM, Kull-
dorff M (1999) Maternal supplemental and dietary zinc intake
and the occurrence of neural tube defects in California. Am J
Epidemiol 150:605–616
169. Chowanadisai W, Graham DM, Keen CL, Rucker RB, Mes-
serli MA (2013) Neurulation and neurite extension require the
zinc transporter ZIP12 (slc39a12). Proc Natl Acad Sci USA
170. Yasuda H, Yoshida K, Yasuda Y, Tsutsui T (2011) Infantile zinc
deficiency: association with autism spectrum disorders. Sci Rep
171. Grabrucker S, Jannetti L, Eckert M, Gaub S, Chhabra R,
Pfaender S, Mangus K, Reddy PP, Rankovic V, Schmeisser MJ,
Kreutz MR, Ehret G, Boeckers TM, Grabrucker AM (2014)
Zinc deficiency dysregulates the synaptic ProSAP/Shank scaf-
fold and might contribute to autism spectrum disorders. Brain
172. Li SO, Wang JL, Bjorklund G, Zhao WN, Yin CH (2014) Serum
copper and zinc levels in individuals with autism spectrum dis-
orders. NeuroReport 25:1216–1220
173. Russo AJ, Devito R (2011) Analysis of copper and zinc plasma
concentration and the efficacy of zinc therapy in individuals with
Asperger’s syndrome, pervasive developmental disorder not
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
1294 S.Bölte et al.
1 3
otherwise specified (PDD-NOS) and autism. Biomark Insights
174. Li SO, Wang JL, Bjorklund G, Zhao WN, Yin CH (2014) Serum
copper and zinc levels in individuals with autism spectrum dis-
orders. NeuroReport 25:1216–1220
175. Arora M, Reichenberg A, Willfors C, Austin C, Gennings C,
Berggren S, Lichtenstein P, Anckarsäter H, Tammimies K, Bölte
S (2017) Fetal and postnatal metal dysregulation in autism. Nat
Commun 8:15493
176. Curtin P, Austin C, Curtin A, Gennings C, Arora M, for the
Emergent Dynamical Systems Group, Tammimies K, Willfors
C, Berggren S, Siper P, Rai D, Meyering K, Kolevzon A, Mol-
lon J, David AS, Lewis G, Zammit S, Heilbrun L, Palmer RF,
Wright RO, Bölte S, Reichenberg A (2018) Dynamical features
in fetal and postnatal zinc-copper metabolic cycles predict the
emergence of autism spectrum disorder. Sci Adv 4:eaat1293
177. Wakefield AJ, Murch SH, Anthony A, Linnell J, Casson DM,
Malik M, Berelowitz M, Dhillon AP, Thomson MA, Harvey P,
Valentine A, Davies SE, Walker-Smith JA (1998) Ileal-lymphoid-
nodular hyperplasia, non-specific colitis, and pervasive develop-
mental disorder in children. Lancet 351:637–641
178. ECDC (2018) Measles in the EU/EEA: current outbreaks, latest
data and trends—January 2018: https ://ecdc.europ
event s/measl es-eueea -curre nt-outbr eaks-lates t-data-and-trend
s-janua ry-2018
179. Madsen KM, Hviid A, Vestergaard M, Schendel D, Wohlfahrt J,
Thorsen P, Olsen J, Melbye M (2002) A population-based study
of measles, mumps, and rubella vaccination and autism. N Engl
J Med 347:1477–1482
180. Fombonne E, Zakarian R, Bennett A, Meng L, McLean-Hey-
wood D (2006) Pervasive developmental disorders in Montreal,
Quebec, Canada: prevalence and links with immunizations. Pedi-
atrics 118:e139–e150
181. Taylor LE, Swerdfeger AL, Eslick GD (2014) Vaccines are not
associated with autism: an evidence-based meta-analysis of case-
control and cohort studies. Vaccine 32:3623–3629
182. Deer B (2011) How the case against the MMR vaccine was fixed.
BMJ 342:c5347
183. https ://brian t-summa ry.htm. Accessed 1 Aug
184. Grandjean P, Landrigan PJ (2014) Neurobehavioural effects of
developmental toxicity. Lancet Neurol 13:330–338
185. Kalkbrenner AE, Schmidt RJ, Penlesky AC (2014) Environmen-
tal chemical exposures and autism spectrum disorders: a review
of the epidemiological evidence. Curr Probl Pediatr Adolesc
Health Care 44:277–318
186. Yang C, Zhao W, Deng K, Zhou V, Zhou X, Hou Y (2017) The
association between air pollutants and autism spectrum disorders.
Environ Sci Pollut Res Int 24:15949–15958
187. Campbell A, Araujo JA, Li H, Sioutas C, Kleinman M (2009)
Particulate matter induced enhancement of inflammatory mark-
ers in the brains of apolipoprotein E knockout mice. J Nanosci
Nanotechnol 9:5099–5104
188. Gerlofs-Nijland ME, van Berlo D, Cassee FR, Schins RP, Wang
K, Campbell A (2010) Effect of prolonged exposure to diesel
engine exhaust on proinflammatory markers in different regions
of the rat brain. Particle Fibre Toxicol 7:12
189. Levesque S, Taetzsch T, Lull ME, Kodavanti U, Stadler K, Wag-
ner A, Johnson JA, Duke L, Kodavanti P, Surace MJ, Block ML
(2011) Diesel exhaust activates and primes microglia: air pollu-
tion, neuroinflammation, and regulation of dopaminergic neuro-
toxicity. Environm Health Perspect 119:1149–1155
190. Grahame TJ, Klemm R, Schlesinger RB (2014) Public health
and components of particulate matter: the changing assessment
of black carbon. J Air Waste Manag Assoc 64:620–660
191. Lam J, Sutton P, Kalkbrenner A, Windham G, Halladay A,
Koustas E, Lawler C, Davidson L, Daniels N, Newschaffer C,
Woodruff T (2016) A systematic review and meta-analysis of
multiple airborne pollutants and autism spectrum disorder. PLoS
One 11:e0161851
192. Apel K, Hirt H (2004) Reactive oxygen species: metabolism,
oxidative stress, and signal transduction. Annu Rev Plant Biol
193. Ercal N, Gurer-Orhan H, Aykin-Burns N (2001) Toxic metals and
oxidative stress part I: mechanisms involved in metal-induced
oxidative damage. Curr Top Med Chem 1:529–539
194. Matés JM, Segura JA, Alonso FJ, Márquez J (2010) Roles
of dioxins and heavy metals in cancer and neurological dis-
eases using ROS-mediated mechanisms. Free Radic Biol Med
195. Rahman SM, Kippler M, Tofail F, Bölte S, Hamadani JD, Vahter
M (2017) Manganese in drinking water and cognitive abilities
and behavior at 10 years of age: a prospective cohort study. Envi-
ron Health Perspect 125:057003
196. Saghazadeh A, Rezaei N (2017) Systematic review and meta-
analysis links autism and toxic metals and highlights the impact
of country development status: higher blood and erythrocyte lev-
els for mercury and lead, and higher hair antimony, cadmium,
lead, and mercury. Prog Neuropsychopharmacol Biol Psychiatry
79(Pt B):340–368
197. Voorhees JR, Rohlman DS, Lein PJ, Pieper AA (2017) Neurotox-
icity in preclinical models of occupational exposure to organo-
phosphorus compounds. Front Neurosci 10:590
198. Shelton JF, Hertz-Picciotto I, Pessah IN (2012) Tipping the bal-
ance of autism risk: potential mechanisms linking pesticides and
autism. Environ Health Perspect 120:944–951
199. Shelton JF, Geraghty EM, Tancredi DJ, Delwiche LD, Schmidt
RJ, Ritz B, Hansen RL, Hertz-Picciotto I (2014) Neurodevelop-
mental disorders and prenatal residential proximity to agricul-
tural pesticides: the CHARGE study. Environ Health Perspect
200. Ventrice P, Ventrice D, Russo E, De Sarro G (2013) Phthalates:
european regulation, chemistry, pharmacokinetic and related tox-
icity. Environ Toxicol Pharmacol 36:88–96
201. Ejaredar M, Nyanza EC, Ten Eycke K, Dewey D (2015) Phtha-
late exposure and children’s neurodevelopment: a systematic
review. Environ Res 142:51–60
202. Jeddi MZ, Janani L, Memari AH, Akhondzadeh S, Yunesian M
(2016) The role of phthalate esters in autism development: a
systematic review. Environ Res 151:493–504
203. Stein TP, Schluter MD, Steer RA, Guo L, Ming X (2015) Bis-
phenol a exposure in children with autism spectrum disorders.
Autism Res 8:272–283
204. Kardas F, Bayram AK, Demirci E, Akin L, Ozmen S, Kendirci
M, Canpolat M, Oztop DB, Narin F, Gumus H, Kumandas S, Per
H (2016) Increased serum phthalates (MEHP, DEHP) and bis-
phenol a concentrations in children with autism spectrum disor-
der: the role of endocrine disruptors in autism etiopathogenesis.
J Child Neurol 31:629–635
205. Kondolot M, Ozmert EN, Ascı A, Erkekoglu P, Oztop DB,
Gumus H, Kocer-Gumusel B, Yurdakok K (2016) Plasma phtha-
late and bisphenol a levels and oxidant-antioxidant status in autis-
tic children. Environ Toxicol Pharmacol 43:149–158
206. Rahbar MH, Swingle HM, Christian MA, Hessabi M, Lee M,
Pitcher MR, Campbell S, Mitchell A, Krone R, Loveland KA,
Patterson DG Jr (2017) Environmental exposure to dioxins,
dibenzofurans, bisphenol A, and phthalates in children with and
without autism spectrum disorder living near the Gulf of Mexico.
Int J Environ Res Public Health 14:E1425
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
1295The contribution ofenvironmental exposure totheetiology ofautism spectrum disorder
1 3
207. Harris EP, Allardice HA, Schenk AK, Rissman EF (2018) Effects
of maternal or paternal bisphenol A exposure on offspring behav-
ior. Horm Behav 101:68–76
208. Ye BS, Leung AOW, Wong MH (2017) The association of envi-
ronmental toxicants and autism spectrum disorders in children.
Environ Pollut 227:234–242
209. Hertz-Picciotto I, Park HY, Dostal M, Kocan A, Trnovec T, Sram
R (2008) Prenatal exposures to persistent and non-persistent
organic compounds and effects on immune system development.
Basic Clin Pharmacol Toxicol 102:146–154
210. Ribas-Fitó N, Torrent M, Carrizo D, Muñoz-Ortiz L, Júlvez J,
Grimalt JO, Sunyer J (2006) In utero exposure to background
concentrations of DDT and cognitive functioning among pre-
schoolers. Am J Epidemiol 164:955–962
211. Shutoh Y, Takeda M, Ohtsuka R, Haishima A, Yamaguchi S,
Fujie H, Komatsu Y, Maita K, Harada T (2009) Low dose effects
of dichlorodiphenyltrichloroethane (DDT) on gene transcription
and DNA methylation in the hypothalamus of young male rats:
implication of hormesis-like effects. J Toxicol Sci 34:469–482
212. Schantz SL, Widholm JJ, Rice DC (2003) Effects of PCB expo-
sure on neuropsychological function in children. Environ Health
Perspect 111:357–576
213. Stewart PW, Lonky E, Reihman J, Pagano J, Gump BB, Darvill
T (2008) The relationship between prenatal PCB exposure and
intelligence (IQ) in 9-year-old children. Environ Health Perspect
214. Lyall K, Croen LA, Sjödin A, Yoshida CK, Zerbo O, Kharrazi M,
Windham GC (2017) Polychlorinated biphenyl and organochlo-
rine pesticide concentrations in maternal mid-pregnancy serum
samples: association with autism spectrum disorder and intel-
lectual disability. Environ Health Perspect 125:474–480
215. Herbstman JB, Sjödin A, Kurzon M, Lederman SA, Jones RS,
Rauh V, Needham LL, Tang D, Niedzwiecki M, Wang RY, Perera
F (2010) Prenatal exposure to PBDEs and neurodevelopment.
Environ Health Perspect 118:712–719
216. Hertz-Picciotto I, Bergman A, Fängström B, Rose M, Krakow-
iak P, Pessah I, Hansen R, Bennett DH (2011) Polybrominated
diphenyl ethers in relation to autism and developmental delay: a
case-control study. Environ Health 10:1
217. Van Schalkwyk GI, Volkmar FR (2015) Autism spectrum disor-
ders. in theory and practice. Psychoanal Study Child 69:219–241
218. Thompson C, Bölte S, Falkmer T, Girdler S (2018) To be under-
stood: transitioning to adult life for people with autism spectrum
disorder. PLoS One 13:e0194758
219. Abbott PW, Gumusoglu SB, Bittle J, Beversdorf DQ, Stevens
HE (2018) Prenatal stress and genetic risk: how prenatal stress
interacts with genetics to alter risk for psychiatric illness. Psy-
choneuroendocrinology 90:9–21
220. Glover V (2011) Annual research review: prenatal stress and the
origins of psychopathology: an evolutionary perspective. J Child
Psychol Psychiatry 52:356–367
221. King S, Dancause K, Turcotte-Tremblay AM, Veru F, Laplante
DP (2012) Using natural disasters to study the effects of prenatal
maternal stress on child health and development. Birth Defects
Res C Embryo Today 96:273–288
222. St. Petersburg-USA Orphanage Research Team (2008) The
effects of early social-emotional and relationship experience on
the development of young orphanage children. UK: Wiley-Black-
well Publishing Ltd. Monographs of the Society for Research in
Child Development; No. 73
223. Van den Bergh BRH, van den Heuvel MI, Lahti M, Braeken M,
de Rooij SR, Entringer S, Hoyer D, Roseboom T, Räikkönen
K, King S, Schwab M (2017) Prenatal developmental origins
of behavior and mental health: The influence of maternal stress
in pregnancy. Neurosci Biobehav Rev. https ://
neubi orev.2017.07.003
224. Dealberto MJ (2011) Prevalence of autism according to mater-
nal immigrant status and ethnic origin. Acta Psychiatr Scand
225. Crafa D, Warfa N (2015) Maternal migration and autism risk:
systematic analysis. Int Rev Psychiatry 27:64–71
226. Class QA, Abel KM, Khashan AS, Rickert ME, Dalman
C, Larsson H, Hultman CM, Långström N, Lichtenstein P,
D’Onofrio BM (2014) Offspring psychopathology following
preconception, prenatal and postnatal maternal bereavement
stress. Psychol Med 44:71–84
227. Lehti V, Cheslack-Postava K, Gissler M, Hinkka-Yli-
Salomäki S, Brown AS, Sourander A (2015) Parental migra-
tion and Asperger’s syndrome. Eur Child Adolesc Psychiatry
228. Kinney DK, Miller AM, Crowley DJ, Huang E, Gerber E (2008)
Autism prevalence following prenatal exposure to hurricanes and
tropical storms in Louisiana. J Autism Dev Disord 38:481–488
229. Simcock G, Kildea S, Elgbeili G, Laplante DP, Cobham V, King
S (2017) Prenatal maternal stress shapes children’s theory of
mind: the QF2011 Queensland Flood Study. J Dev Orig Health
Dis 8:483–492
230. Rutter M, Kreppner J, Croft C, Murin M, Colvert E, Beckett C,
Castle J, Sonuga-Barke E (2007) Early adolescent outcomes of
institutionally deprived and non-deprived adoptees. III. Quasi-
autism. J Child Psychol Psychiatry 48:1200–1207
231. Van den Bergh BRH, van den Heuvel MI, Lahti M, Braeken M,
de Rooij SR, Entringer S, Hoyer D, Roseboom T, Räikkönen
K, King S, Schwab M (2011) Prenatal vitamins, one-carbon
metabolism gene variants, and risk for autism. Epidemiology
232. Schmidt RJ, Tancredi DJ, Ozonoff S, Hansen RL, Hartiala J,
Allayee H, Schmidt LC, Tassone F, Hertz-Picciotto I (2012)
Maternal periconceptional folic acid intake and risk of autism
spectrum disorders and developmental delay in the CHARGE
(CHildhood Autism Risks from Genetics and Environment) case-
control study. Am J Clin Nutr 96:80–89
233. Castro K, Klein Lda S, Baronio D, Gottfried C, Riesgo R, Perry
IS (2016) Folic acid and autism: what do we know? Nutr Neuro-
sci 19:310–317
234. Kamen B (1997) Folate and antifolate pharmacology. Semin
Oncol 24(5 Suppl 18):S18-30–S18-39
235. Julvez J, Fortuny J, Mendez M, Torrent M, Ribas-Fito N, Sunyer
J (2009) Maternal use of folic acid supplements during preg-
nancy and four-year-old neurodevelopment in a population-based
birth cohort. Paediatr Perinat Epidemiol 23:199–206
236. Schlotz W, Jones A, Phillips DI, Gale CR, Robinson SM, God-
frey KM (2010) Lower maternal folate status in early pregnancy
is associated with childhood hyperactivity and peer problems in
offspring. J Child Psychol Psychiatry 51:594–602
237. Lintas C (2018) Linking genetics to epigenetics: the role of folate
and folate related pathways in neurodevelopmental disorders.
Clin Genet. https ://
238. Karr JE, Alexander JE, Winningham RG (2011) Omega-3 poly-
unsaturated fatty acids and cognition throughout the lifespan: a
review. Nutr Neurosci 14:216–225
239. Bauer I, Crewther S, Pipingas A, Sellick L, Crewther D (2014)
Does omega-3 fatty acid supplementation enhance neural effi-
ciency? A review of the literature. Hum Psychopharmacol
240. Lyall K, Munger KL, O’Reilly ÉJ, Santangelo SL, Ascherio A
(2013) Maternal dietary fat intake in association with autism
spectrum disorders. Am J Epidemiol 178:209–220
241. Steenweg-de Graaff J, Tiemeier H, Ghassabian A, Rijlaarsdam
J, Jaddoe VW, Verhulst FC, Roza SJ (2016) Maternal fatty acid
status during pregnancy and child autistic traits: the generation
R study. Am J Epidemiol 183:792–799
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
1296 S.Bölte et al.
1 3
242. Julvez J, Méndez M, Fernandez-Barres S, Romaguera D, Vioque
J, Llop S, Ibarluzea J, Guxens M, Avella-Garcia C, Tardón A,
Riaño I, Andiarena A, Robinson O, Arija V, Esnaola M, Ballester
F, Sunyer J (2016) Maternal consumption of seafood in preg-
nancy and child neuropsychological development: a longitudinal
study based on a population with high consumption levels. Am
J Epidemiol 183:169–182
243. Rudzki L, Szulc A (2018) Immune Gate of Psychopathology-
the role of gut derived immune activation in major psychiatric
disorders. Front Psychiatry 9:205
244. Isaksson J, Pettersson E, Kostrzewa E, Diaz Heijtz R, Bölte S
(2017) Brief report: association between autism spectrum disor-
der, gastrointestinal problems and perinatal risk factors within
sibling pairs. J Autism Dev Disord 47:2621–2627
245. Dotterud CK, Avershina E, Sekelja M, Simpson MR, Rudi K,
Storrø O, Johnsen R, Øien T (2015) Does maternal perinatal pro-
biotic supplementation alter the intestinal microbiota of mother
and child? J Pediatr Gastroenterol Nutr 61:200–207
246. Berding K, Donovan SM (2016) Microbiome and nutrition in
autism spectrum disorder: current knowledge and research needs.
Nutr Rev 74:723–736
247. Bölte S, Poustka F (2006) The broader cognitive phenotype of
autism in parents: how specific is the tendency for local pro-
cessing and executive dysfunction? J Child Psychol Psychiatry
248. Bölte S, Knecht S, Poustka F (2007) A case-control study of
personality style and psychopathology in parents of subjects with
autism. J Autism Dev Disord 37:243–250
249. Volk HE, Kerin T, Lurmann F, Hertz-Picciotto I, McConnell R,
Campbell DB (2014) Autism spectrum disorder: interaction of
air pollution with the MET receptor tyrosine kinase gene. Epi-
demiology 25:44–47
250. Heun-Johnson H, Levitt P (2017) Differential impact of Met
receptor gene interaction with early-life stress on neuronal mor-
phology and behavior in mice. Neurobiol Stress 8:10–20
251. Keil KP, Lein PJ (2016) DNA methylation: a mechanism linking
environmental chemical exposures to risk of autism spectrum
disorders? Environ Epigenet 2:dvv012
252. Nordsletten AE, Larsson H, Crowley JJ, Almqvist C, Lichtenstein
P, Mataix-Cols D (2016) Patterns of nonrandom mating within
and across 11 major psychiatric disorders. JAMA Psychiatry
253. Gratten J, Wray NR, Peyrot WJ, McGrath JJ, Visscher PM, Godd-
ard ME (2016) Risk of psychiatric illness from advanced paternal
age is not predominantly from de novo mutations. Nat Genet
254. Ingersoll B, Meyer K, Becker MW (2011) Increased rates of
depressed mood in mothers of children with ASD associated
with the presence of the broader autism phenotype. Autism Res
255. Schmidt RJ, Kogan V, Shelton JF, Delwiche L, Hansen RL, Ozo-
noff S, Ma CC, McCanlies EC, Bennett DH, Hertz-Picciotto I,
Tancredi DJ, Volk HE (2017) Combined prenatal pesticide expo-
sure and folic acid intake in relation to autism spectrum disorder.
Environ Health Perspect 125:097007
256. Volk HE, Lurmann F, Penfold B, Hertz-Picciotto I, McConnell
R (2013) Traffic-related air pollution, particulate matter, and
autism. JAMA Psychiatry 70:71–77
257. Gong T, Almqvist C, Bölte S, Lichtenstein P, Anckarsäter H,
Lind T, Lundholm C, Pershagen G (2014) Exposure to air pollu-
tion from traffic and neurodevelopmental disorders in Swedish
twins. Twin Res Hum Genet 17:553–562
258. Courchesne E, Pramparo T, Gazestani VH, Lombardo MV,
Pierce K, Lewis NE (2018) The ASD Living Biology: from cell
proliferation to clinical phenotype. Mol Psychiatry. https ://doi.
org/10.1038/s4138 0-018-0056-y
259. Flores-Pajot MC, Ofner M, Do MT, Lavigne E, Villeneuve PJ
(2016) Childhood autism spectrum disorders and exposure to
nitrogen dioxide, and particulate matter air pollution: a review
and meta-analysis. Environ Res 151:763–776
260. Heyer DB, Meredith RM (2017) Environmental toxicology: sen-
sitive periods of development and neurodevelopmental disorders.
Neurotoxicology 58:23–41
261. Ackerman S, Schoenbrun S, Hudac C, Bernier R (2017) Inter-
active effects of prenatal antidepressant exposure and likely
gene disrupting mutations on the severity of autism spectrum
disorder. J Autism Dev Disord 47:3489–3496
262. Kang SS, Kurti A, Fair DA, Fryer JD (2014) Dietary interven-
tion rescues maternal obesity induced behavior deficits and
neuroinflammation in offspring. J Neuroinflammation 11:156
263. Rodriguez JS, Rodríguez-González GL, Reyes-Castro LA,
Ibáñez C, Ramírez A, Chavira R, Larrea F, Nathanielsz PW,
Zambrano E (2012) Maternal obesity in the rat programs male
offspring exploratory, learning and motivation behavior: pre-
vention by dietary intervention pre-gestation or in gestation.
Int J Dev Neurosci 30:75–81
264. Nevison CD (2014) A comparison of temporal trends in United
States autism prevalence to trends in suspected environmental
factors. Environ Health 13:73
265. Fein D, Helt M (2017) Facilitating autism research. J Int Neu-
ropsychol Soc 23:903–915
266. Charman T, Loth E, Tillmann J, Crawley D, Wooldridge C,
Goyard D, Ahmad J, Auyeung B, Ambrosino S, Banaschewski
T, Baron-Cohen S, Baumeister S, Beckmann S, Bölte S,
Bourgeron T, Bours C, Brammer M, Brandeis D, Brogna C,
de Bruijn Y, Chakrabarti B, Cornelissen I, Dell’ Acqua F,
Dumas G, Durston S, Ecker C, Faulkner J, Frouin V, Garcés P,
Ham L, Hayward H, Hipp J, Holt RJ, Isaksson J, Johnson MH,
Jones EJH, Kundu P, Lai M-C, Liogier D’ardhuy X, Lombardo
MV, Lythgoe DJ, Mandl R, Mason L, Meyer-Lindenberg A,
Moessnang C, Mueller N, O’Dwyer L, Oldehinkel M, Oranje
B, Pandina G, Persico AM, Ruggeri B, Ruigrok ANV, Sabet
J, Sacco R, San Jóse Cáceres A, Simonoff R, Toro R, Tost H,
Waldman J, Williams SCR, Zwiers MP, Spooren W, Murphy
GDM, Buitelaar JK (2017) The EU-aims longitudinal european
autism project (LEAP): clinical characterization. Mol Autism
267. Loth E, Charman T, Mason L, Tillmann J, Jones EJH, Wool-
dridge C, Ahmad J, Auyeung B, Brogna C, Ambrosino S,
Banaschewski T, Baron-Cohen S, Baumeister S, Beckmann C,
Brammer M, Brandeis D, Bölte S, Bourgeron T, Bours C, de
Bruijn Y, Chakrabarti B, Crawley D, Cornelissen I, Acqua FD,
Dumas G, Durston S, Ecker C, Faulkner J, Frouin V, Garces
P, Goyard D, Hayward H, Ham LM, Hipp J, Holt RJ, Johnson
MH, Isaksson J, Kundu P, Lai MC, D’ardhuy XL, Lombardo
MV, Lythgoe DJ, Mandl R, Meyer-Lindenberg A, Moessnang
C, Mueller N, O’Dwyer L, Oldehinkel M, Oranje B, Pandina G,
Persico AM, Ruigrok ANV, Ruggeri B, Sabet J, Sacco R, Cáceres
ASJ, Simonoff E, Toro R, Tost H, Waldman J, Williams SCR,
Zwiers MP, Spooren W, Murphy DGM, Buitelaar JK (2017) The
EU-AIMS longitudinal european autism project (LEAP): design
and methodologies to identify and validate stratification biomark-
ers for autism spectrum disorders. Mol Autism 8:24
268. Isaksson J, Tammimies K, Neufeld J, Cauvet E, Lundin K,
Buitelaar JK, Loth E, Murphy DGM, Spooren W, Bölte S, The
EU-AIMS LEAP group (2018) EU-AIMS longitudinal european
autism project (LEAP): the autism twin cohort. Mol Autism 9:26
269. Magnus P, Birke C, Vejrup K, Haugan A, Alsaker E, Daltveit
AK, Handal M, Haugen M, Høiseth G, Knudsen GP, Paltiel L,
Schreuder P, Tambs K, Vold L, Stoltenberg C (2016) cohort
profile update: the Norwegian mother and child cohort study
(MoBa). Int J Epidemiol 45:382–388
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
1297The contribution ofenvironmental exposure totheetiology ofautism spectrum disorder
1 3
270. Almqvist C, Adami HO, Franks PW, Groop L, Ingelsson E, Kere
J, Lissner L, Litton JE, Maeurer M, Michaëlsson K, Palmgren
J, Pershagen G, Ploner A, Sullivan PF, Tybring G, Pedersen NL
(2011) LifeGene–a large prospective population-based study of
global relevance. Eur J Epidemiol 26:67–77
271. Bell JT, Spector TD (2011) A twin approach to unraveling epi-
genetics. Trends Gen 27:116–125
272. Bölte S, Willfors C, Berggren S, Norberg J, Poltrago L, Mevel
K, Coco C, Fransson P, Borg J, Sitnikov R, Toro R, Tammimies
K, Anderlid BM, Nordgren A, Falk A, Meyer U, Kere J, Landén
M, Dalman C, Ronald A, Anckarsäter H, Lichtenstein P (2014)
The roots of autism and ADHD twin study in Sweden (RATSS).
Twin Res Hum Genet 17:164–176
273. Anckarsäter H, Lundström S, Kollberg L, Kerekes N, Palm C,
Carlström E, Långström N, Magnusson PK, Halldner L, Bölte
S, Gillberg C, Gumpert C, Råstam M, Lichtenstein P (2011) The
child and adolescent twin study in Sweden (CATSS). Twin Res
Hum Genet 14:495–508
274. Neufeld J, Kuja-Halkola R, Mevel K, Cauvet É, Fransson P, Bölte
S (2017) Alterations in resting state connectivity along the autism
trait continuum: a twin study. Mol Psychiatry23:1659–1665
275. Myers L, Van’t Westeinde A, Kuja-Halkola R, Tammimies K,
Bölte S (2018) 2D:4D ratio in neurodevelopmental disorders: a
twin study. J Autism Dev Disord48:3244–3252
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
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... Genetic and environmental factors, as well as their interactions, contribute to autism phenotypes, although their precise causal mechanisms are still debated in the literature. 19 While the diagnosis can be made as soon as 2 years of age, in LMIC there is still a considerable delay. 20 21 An ideal developmental screening tool for children living in LMICs must be brief, cost-effective, based on appropriate data and good psychometric properties available in local languages, validated on a representative population of healthy children, and require minimal training 22 23 These characteristics permit the overcoming of difficulties in using or adapting tools originally designed for a different context. ...
... Seventy-four children of this sample (aged [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] were also screened with the M-CHAT-R, and 2 were at risk of ASD (2.7%). ...
... The mean age of the Kenyan children was 18.9 months (SD=2.8, range [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30], and that of the Italian children was 19.3 (SD=2.6, range [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]. ...
Full-text available
Background Children in low-income and middle-income countries (LMICs) are at a substantially increased risk of delayed physical, emotional and sociocognitive outcomes, with consequential neurodevelopmental disorders. Evidence based, cost-effective and culturally appropriate screening tools are recommended for early identification of developmental disorders. Methods The present study aims to assess the feasibility of early screening for neurodevelopmental disorders in children living in informal settlements in Nairobi, Kenya (Korogocho). The selected tools (ie, the CDC checklist and the Modified Checklist for Autism in Toddlers, Revised (M-CHAT-R)), widely used in high-income countries, are applied in two different populations: one from Kenya (LMIC) and one from Italy, to compare the different scores. Results Of 509 children screened, 8.6% were classified at-risk based on the results of the screening tools. Significant risk factors are history of low birth weight and Apgar score, presence of neurological disorders, malnutrition and/or rickets, younger age of the child and older age of the mother. Caesarean section delivery, first pregnancy and mothers’ older age were common risk factors among the Kenyan and the Italian samples. The Italian sample had a significantly greater rate of missed milestones. Conclusions Our data demonstrate the feasibility of using the CDC and M-CHAT-R tools in informal settlement dwellers. Further studies are needed to explore the opportunity for early diagnosis of developmental disorders in LMICs.
... This study includes data from the ABIS-Study (All Babies in Southeast Sweden), a longitudinal, population-based cohort study based on data collected from 16 365 families with children born between October 1997 and October 1999 in Southeast Sweden. ABIS-Study aims to investigate how environmental and genetic factors influence the development of immune-mediated diseases, which include ADHD and ASD, where immune mechanisms may play a role [17]. The children included in the ABIS-Study have been followed from birth onwards, and questionnaires data, biological samples, and register data of diseases (based on medical records) have been collected at birth and age of 1, 3,5,8,[10][11][12][17][18][19], and 23-25 years. ...
... ABIS-Study aims to investigate how environmental and genetic factors influence the development of immune-mediated diseases, which include ADHD and ASD, where immune mechanisms may play a role [17]. The children included in the ABIS-Study have been followed from birth onwards, and questionnaires data, biological samples, and register data of diseases (based on medical records) have been collected at birth and age of 1, 3,5,8,[10][11][12][17][18][19], and 23-25 years. A total of 6 233 young adults who were included in the ABIS-Study at birth and answered the questionnaire at 17-19 years follow-up, were included in this prospective case-control sub study (Fig. 1). ...
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Background Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are childhood-onset disorders associated with functional and psychosocial impairments that may persist into adulthood, leading to serious personal and societal costs. Objective This study aimed to examine the socio-economic difficulties, physical and mental comorbidities, and psycho-social vulnerabilities associated with ADHD, ASD, and their co-occurrence among young adults. Methods 16 365 families with children born 1997–1999, were involved in the prospective population-based ABIS study (All Babies in Southeast Sweden). A total of 6 233 ABIS young adults answered the questionnaire at the 17–19-year follow-up and were included in this case–control study. Diagnoses of ADHD and ASD from birth up to 17 years of age were obtained from the Swedish National Diagnosis Register. N=182 individuals received a single diagnosis of ADHD, n=78 of ASD, and n=51 received both diagnoses and were considered the co-occurrence group. Multiple multinomial logistic regression analyses were performed. Results In the univariate analyses all three conditions were significantly associated with concentration difficulties, worse health quality, lower socio-economic status, lower faith in the future, less control over life, and lower social support. In the adjusted analyses, individuals with ADHD were almost three-times more likely to have less money compared with their friends (aOR 2.86; p < .001), experienced worse sleep quality (aOR 1.50; p = .043) and concentration difficulties (aOR 1.96; p < .001). ASD group were two-fold more likely to experience concentration difficulties (aOR 2.35; p = .002) and tended not to have faith in the future (aOR .63; p = .055), however, showed lesser risk-taking bahaviours (aOR .40; p < .001). Finally, the co-occurrence was significantly associated with unemployment (aOR 2.64; p = .007) and tended to have a higher risk of autoimmune disorders (aOR 2.41; p = .051), however, showed a 51% lower risk of stomach pain (aOR .49; p = .030). Conclusions All these conditions significantly deteriorated several areas of life. ADHD/ASD co-occurrence is a heavy burden for health associated with several psychosocial vulnerabilities, that shared a similar morbidity pattern with ADHD although showed less risk cognitive and behavioral profile, similar to the ASD group. Long-term follow-up and support for individuals with these conditions over the life course are crucial.
... The current scientific consensus suggests that the following environmental factors may contribute to the development of autism [39][40][41]: (i) higher parental, especially paternal, age; (ii) adverse prenatal influences (e.g., infections during pregnancy, extreme intrauterine hormonal, especially testosterone effects [42], poor quality of maternal nutrition, maternal substance use and smoking, maternal health, heavy metal pollution or air pollution); (iii) perinatal complications (e.g., umbilical cord abnormalities, meconium amniotic fluid aspiration, low birth weight, etc.) [43]; (iv) low socioeconomic status. It is important to emphasize, however, that none of these factors are autism-specific; they increase the susceptibility of many other mental or physical disorders in addition to ASD. ...
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Autism spectrum disorder (ASD) is a neurodevelopmental condition with symptoms that affect the whole personality and all aspects of life. Although there is a high degree of heterogeneity in both its etiology and its characteristic behavioral patterns, the disorder is well-captured along the autistic triad. Currently, ASD status can be confirmed following an assessment of behavioral features, but there is a growing emphasis on conceptualizing autism as a spectrum, which allows for establishing a diagnosis based on the level of support need, free of discrete categories. Since ASD has a high genetic predominance, the number of genetic variations identified in the background of the condition is increasing exponentially as genetic testing methods are rapidly evolving. However, due to the huge amount of data to be analyzed, grouping the different DNA variations is still challenging. Therefore, in the present review, a multidimensional classification scheme was developed to accommodate most of the currently known genetic variants associated with autism. Genetic variations have been grouped according to six criteria (extent, time of onset, information content, frequency, number of genes involved, inheritance pattern), which are themselves not discrete categories, but form a coherent continuum in line with the autism spectrum approach.
... Autism spectrum disorders (ASDs) encompass a wide range of phenotypic expressions and are rooted in complex etiologies involving an interplay of environmental and genetic factors [1][2][3][4]. Diagnosis is currently based solely on behavioral criteria, and despite investigations of various potential diagnostic biomarkers, including metabolic markers, none have emerged as universally applicable or sufficiently specific [5][6][7][8]. This complexity highlights the need to explore subgroups within ASD that are characterized by specific genetic, metabolic, and behavioral markers. ...
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Introduction Autism spectrum disorder (ASD) encompasses a heterogeneous group with varied phenotypes and etiologies. Identifying pathogenic subgroups could facilitate targeted treatments. One promising avenue is investigating energy metabolism, as mitochondrial dysfunction has been implicated in a subgroup of ASD. Lactate, an indicator of energy metabolic anomalies, may serve as a potential biomarker for this subgroup. This study aimed to examine cerebral lactate (Lac+) levels in high-functioning adults with ASD, hypothesizing elevated mean Lac+ concentrations in contrast to neurotypical controls (NTCs). Materials and methods Magnetic resonance spectroscopy (MRS) was used to study cerebral Lac+ in 71 adults with ASD and NTC, focusing on the posterior cingulate cortex (PCC). After quality control, 64 ASD and 58 NTC participants remained. Lac+ levels two standard deviations above the mean of the control group were considered elevated. Results Mean PCC Lac+ levels were significantly higher in the ASD group than in the NTC group (p = 0.028; Cohen’s d = 0.404), and 9.4% of the ASD group had elevated levels as compared to 0% of the NTCs (p = 0.029). No significant correlation was found between blood serum lactate levels and MRS-derived Lac+ levels. Limitations A cautious interpretation of our results is warranted due to a p value of 0.028. In addition, a higher than anticipated proportion of data sets had to be excluded due to poor spectral quality. Conclusion This study confirms the presence of elevated cerebral Lac+ levels in a subgroup of adults with ASD, suggesting the potential of lactate as a biomarker for mitochondrial dysfunction in a subgroup of ASD. The lower-than-expected prevalence (20% was expected) and moderate increase require further investigation to elucidate the underlying mechanisms and relationships with mitochondrial function.
... Induced labour, no labour, breech presentation, foetal discomfort, gestational age less than 36 weeks, and caesarean delivery all increase the risk of autism. 5 Five main types of ASDs are distinguished. These are childhood disintegrative disorder, pervasive developmental disorder, Asperger's syndrome, Rett's disorder, and autistic disorder. ...
... These results have shown significant changes in all behavioral parameters and correlated with other investigations conducted on animal models. These observations were mimicked as behavioral abnormalities reported in autistic children [20,[53][54][55][56][57][58]. These findings explored the behavioral patterns that indicated neurodevelopmental delay and impairments of social behavior in rat models (developmental and maturational data) and altered olfactory, muscle-strength, attention, and sensorimotor gating functioning. ...
... All of this results in cognitive processes such as attention or memory showing reduced performance compared to the ASD population without epilepsy. This may be because, in childhood, neuronal plasticity mechanisms are at their peak, trying to consolidate attention and memory mechanisms via the assimilation of environmental stimuli [63]. However, the existence of an SD will have a negative effect and reduce the ability to integrate knowledge from acquired context stimuli, as it will reduce cognitive alertness, preventing proper attentional focus, limiting the information captured by the child's sensory system from being recorded and stored in memory [64]. ...
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Autism Spectrum Disorder (ASD) and epilepsy are increasingly prevalent comorbidities in our society. These two disorders are often accompanied by other comorbidities, such as sleep disorders, significantly impacting the quality of life of individuals with ASD and epilepsy. To date, clinical approaches have primarily been descriptive in nature. Therefore, this study aimed to analyze the relationship between ASD, epilepsy, and sleep disorders, exploring neurobiological dysfunctions and cognitive alterations. A total of 22 scientific articles were selected using a systematic literature review following the criteria established using the PRISMA model. The selected articles were gathered from major databases: Medline, PubMed, PsycINFO, Google Scholar, and Web of Science. Inclusion criteria specified that study participants had an official diagnosis of ASD, the article precisely described the evaluation parameters used in the study participants, and individual characteristics of the sleep disorders of the study participants were specified. The results indicate, firstly, that the primary cause of sleep disorders in this population is directly linked to abnormal serotonin behaviors. Secondly, significant alterations in memory, attention, and hyperactivity were observed. In conclusion, sleep disorders negatively impact the quality of life and neurocognitive development of the pediatric population with ASD and epilepsy.
Autism is a neurodevelopmental disorder that starts in early childhood and persists over the lifespan. A combination of genetic factors and environmental factors around birth contribute to its etiology. Autistic individuals show differences and difficulties in social interaction and communication as well as repetitive, stereotypical behavior and interests. The diagnostic procedure is complex and should be carried out in a specialized assessment unit. Diagnostic assessment is based on behavioral observation and a careful evaluation of developmental history. A wide range of potential differential diagnoses should be considered. Autistic adults have a higher risk of developing psychiatric disorders such as anxiety and depression. Psychotherapeutic treatment that is adapted to autism-related difficulties can be helpful. Co-occurring conditions should be treated in accordance with disorder-specific guidelines. Psychopharmacological treatment of co-occurring conditions is, in most cases, only recommended as an addition to behavioral interventions. Autistic people often experience difficulties in social participation, which can be targeted with sociotherapeutic interventions.
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Background: Autism spectrum disorder (ASD) is a complicated disorder. Up to 50% of its variance could be related to environmental factors. Aim: Environmental risk factors for ASD were studied among cases and controls. Additionally, the effects of some targeted interventional approaches on the severity of ASD and language abilities were compared. Methodology: This study was conducted on 61 autistic children (3-12 years) who visited the outpatient clinic for "Children with ASD" from September 2021 to February 2022. They were subjected to the Childhood Autism Rating Scale, and the Arabic Preschool Language Scale. The control subjects (N=62) were selected from volunteers. A questionnaire was designed for studying the environmental risk factors. Children with ASD were then divided into two groups: Group a (N=30) received phoniatric therapy; Group b (N=31) received phoniatric therapy and dietary supplementation. After 3 months, both groups were reassessed. Results: Risk factors such as maternal exposure to disinfectants and cleaners (78.7%), moderate maternal (39.3 %) and paternal (47.5 %) educational level, pregnancy in Summer (19.6%), delivery in Spring (19.6%) and prematurity (91.8%), showed significant statistical difference between cases and control subjects (P=0.01,0.00,0.04,0.00 respectively). Following intervention, the
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Background: Autism spectrum disorder (ASD) is a complicated disorder. Up to 50% of its variance could be related to environmental factors. Aim: Environmental risk factors for ASD were studied among cases and controls. Additionally, the effects of some targeted interventional approaches on the severity of ASD and language abilities were compared. Methodology: This study was conducted on 61 autistic children (3-12 years) who visited the outpatient clinic for "Children with ASD" from September 2021 to February 2022. They were subjected to the Childhood Autism Rating Scale, and the Arabic Preschool Language Scale. The control subjects (N=62) were selected from volunteers. A questionnaire was designed for studying the environmental risk factors. Children with ASD were then divided into two groups: Group a (N=30) received phoniatric therapy; Group b (N=31) received phoniatric therapy and dietary supplementation. After 3 months, both groups were reassessed. Results: Risk factors such as maternal exposure to disinfectants and cleaners (78.7%), moderate maternal (39.3 %) and paternal (47.5 %) educational level, pregnancy in Summer (19.6%), delivery in Spring (19.6%) and prematurity (91.8%), showed significant statistical difference between cases and control subjects (P=0.01,0.00,0.04,0.00 respectively). Following intervention, the
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Preeclampsia is a serious complication of pregnancy where it affects 5–8% of all pregnancies. It increases the morbidity and mortality of both the fetus and pregnant woman, especially in developing countries. It deleteriously affects several vital organs, including the kidneys, liver, brain, and lung. Although, the pathogenesis of preeclampsia has not yet been fully understood, growing evidence suggests that aberrations in the angiogenic factors levels and coagulopathy are responsible for the clinical manifestations of the disease. The common nominator of tissue damage of all these target organs is endothelial injury, which impedes their normal function. At the renal level, glomerular endothelial injury leads to the development of maternal proteinuria. Actually, peripheral vasoconstriction secondary to maternal systemic inflammation and endothelial cell activation is sufficient for the development of preeclampsia-induced hypertension. Similarly, preeclampsia can cause hepatic and neurologic dysfunction due to vascular damage and/or hypertension. Obviously, preeclampsia adversely affects various organs, however it is not yet clear whether pre-eclampsia per se adversely affects various organs or whether it exposes underlying genetic predispositions to cardiovascular disease that manifest in later life. The current review summarizes recent development in the pathogenesis of preeclampsia with special focus on novel diagnostic biomarkers and their relevance to potential therapeutic options for this disease state. Specifically, the review highlights the renal manifestations of the disease with emphasis on the involvement of angiogenic factors in vascular injury and on how restoration of the angiogenic balance affects renal and cardiovascular outcome of Preeclamptic women.
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Autism spectrum disorder (ASD) has captured the attention of scientists, clinicians and the lay public because of its uncertain origins and striking and unexplained clinical heterogeneity. Here we review genetic, genomic, cellular, postmortem, animal model, and cell model evidence that shows ASD begins in the womb. This evidence leads to a new theory that ASD is a multistage, progressive disorder of brain development, spanning nearly all of prenatal life. ASD can begin as early as the 1st and 2nd trimester with disruption of cell proliferation and differentiation. It continues with disruption of neural migration, laminar disorganization, altered neuron maturation and neurite outgrowth, disruption of synaptogenesis and reduced neural network functioning. Among the most commonly reported high-confidence ASD (hcASD) genes, 94% express during prenatal life and affect these fetal processes in neocortex, amygdala, hippocampus, striatum and cerebellum. A majority of hcASD genes are pleiotropic, and affect proliferation/differentiation and/or synapse development. Proliferation and subsequent fetal stages can also be disrupted by maternal immune activation in the 1st trimester. Commonly implicated pathways, PI3K/AKT and RAS/ERK, are also pleiotropic and affect multiple fetal processes from proliferation through synapse and neural functional development. In different ASD individuals, variation in how and when these pleiotropic pathways are dysregulated, will lead to different, even opposing effects, producing prenatal as well as later neural and clinical heterogeneity. Thus, the pathogenesis of ASD is not set at one point in time and does not reside in one process, but rather is a cascade of prenatal pathogenic processes in the vast majority of ASD toddlers. Despite this new knowledge and theory that ASD biology begins in the womb, current research methods have not provided individualized information: What are the fetal processes and early-age molecular and cellular differences that underlie ASD in each individual child? Without such individualized knowledge, rapid advances in biological-based diagnostic, prognostic, and precision medicine treatments cannot occur. Missing, therefore, is what we call ASD Living Biology. This is a conceptual and paradigm shift towards a focus on the abnormal prenatal processes underlying ASD within each living individual. The concept emphasizes the specific need for foundational knowledge of a living child's development from abnormal prenatal beginnings to early clinical stages. The ASD Living Biology paradigm seeks this knowledge by linking genetic and in vitro prenatal molecular, cellular and neural measurements with in vivo post-natal molecular, neural and clinical presentation and progression in each ASD child. We review the first such study, which confirms the multistage fetal nature of ASD and provides the first in vitro fetal-stage explanation for in vivo early brain overgrowth. Within-child ASD Living Biology is a novel research concept we coin here that advocates the integration of in vitro prenatal and in vivo early post-natal information to generate individualized and group-level explanations, clinically useful prognoses, and precision medicine approaches that are truly beneficial for the individual infant and toddler with ASD.
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The objective of this retrospective analysis of the longitudinal Millennium Cohort Study was to examine whether maternal alcohol consumption in pregnancy (MACP) is associated with the development of childhood autism spectrum disorders (ASD). Data on MACP and ASD were obtained from parental questionnaires. There were 18,168 singleton mother–child pairs with data on MACP, and 12,595 answered the question on ASD when the children were 11 years old. No statistically significant association was found between MACP and ASD for light (OR 0.78, 95% CI 0.48–1.29), moderate (OR 0.89, 95% CI 0.35–2.27), or heavy (OR 1.54, 95% CI 0.56–4.21) MACP. Alcohol consumption during pregnancy was not associated with the risk of developing ASD in this study cohort.
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Objective To examine the association between paternal antidepressant use at conception and offspring preterm birth, malformations, autism spectrum disorder, and intellectual disability. Design Observational prospective cohort study with regression methods, and negative control comparison. Setting Sweden nationwide. Participants 170 508 children conceived from 29 July 2005 and born in 2006-07, followed up to 2014 at age 8-9 years. This cohort included 3983 children born to fathers receiving antidepressant treatment during the conception period (that is, from four weeks before conception to four weeks after), a control group of 164 492 children not exposed to paternal antidepressant use, and a negative control comparison group of 2033 children born to fathers who did not use antidepressants during the conception period but began antidepressant treatment later during the pregnancy period (that is, from four weeks after conception to childbirth). Main outcome measure Offspring preterm birth, malformation diagnosed at birth, diagnosis of autism spectrum disorder, and diagnosis of intellectual disability. Results Paternal antidepressant use during conception was not associated with preterm birth (adjusted odds ratio 0.91 (95% confidence interval 0.79 to 1.04)) or malformations (1.06 (0.90 to 1.26)) using logistic regression, compared with offspring born to unexposed fathers. No association was seen between antidepressant use during conception and autism (adjusted hazard ratio 1.13 (0.84 to 1.53)) or intellectual disability (0.82 (0.51 to 1.31)) using Cox regression. In children whose fathers initiated antidepressant treatment during pregnancy, results were similar for all outcomes apart from intellectual disability, which had an increased adjusted hazard ratio (1.66 (1.06 to 2.59)). Compared with the 2033 children whose fathers initiated antidepressant treatment during pregnancy, the 3983 children exposed to paternal use of antidepressants at conception had no differences in preterm birth, malformation, and autism, but a reduced risk of intellectual disability (adjusted hazard ratio 0.49 (0.26 to 0.93)). Conclusion Paternal intake of antidepressants during the period around conception is safe with respect to the risk of the four major adverse outcomes in offspring—preterm birth, malformation, autism, or intellectual disability.
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Metals are critical to neurodevelopment, and dysregulation in early life has been documented in autism spectrum disorder (ASD). However, underlying mechanisms and biochemical assays to distinguish ASD cases from controls remain elusive. In a nationwide study of twins in Sweden, we tested whether zinc-copper cycles, which regulate metal metabolism, are disrupted in ASD. Using novel tooth-matrix biomarkers that provide direct measures of fetal elemental uptake, we developed a predictive model to distinguish participants who would be diagnosed with ASD in childhood from those who did not develop the disorder. We replicated our findings in three independent studies in the United States and the UK. We show that three quantifiable characteristics of fetal and postnatal zinc-copper rhythmicity are altered in ASD: the average duration of zinc-copper cycles, regularity with which the cycles recur, and the number of complex features within a cycle. In all independent study sets and in the pooled analysis, zinc-copper rhythmicity was disrupted in ASD cases. In contrast to controls, in ASD cases, the cycle duration was shorter (F = 52.25, P < 0.001), regularity was reduced (F = 47.99, P < 0.001), and complexity diminished (F = 57.30, P < 0.001). With two distinct classification models that used metal rhythmicity data, we achieved 90% accuracy in classifying cases and controls, with sensitivity to ASD diagnosis ranging from 85 to 100% and specificity ranging from 90 to 100%. These findings suggest that altered zinc-copper rhythmicity precedes the emergence of ASD, and quantitative biochemical measures of metal rhythmicity distinguish ASD cases from controls.
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Interaction between the gastrointestinal tract (GI) and brain functions has recently become a topic of growing interest in psychiatric research. These multidirectional interactions take place in the so-called gut-brain axis or more precisely, the microbiota-gut-brain axis. The GI tract is the largest immune organ in the human body and is also the largest surface of contact with the external environment. Its functions and permeability are highly influenced by psychological stress, which are often a precipitating factor in the first episode, reoccurrence and/or deterioration of symptoms of psychiatric disorders. In recent literature there is growing evidence that increased intestinal permeability with subsequent immune activation has a major role in the pathophysiology of various psychiatric disorders. Numerous parameters measured in this context seem to be aftermaths of those mechanisms, yet at the same time they may be contributing factors for immune mediated psychopathology. For example, immune activation related to gut-derived bacterial lipopolysaccharides (LPS) or various food antigens and exorphins were reported in major depression, schizophrenia, bipolar disorder, alcoholism and autism. In this review the authors will summarize the evidence and roles of such parameters and their assessment in major psychiatric disorders.
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The second to fourth digit (2D:4D) ratio is of interest in autism spectrum disorder (ASD). Studies on the relationship of this ratio with other neurodevelopmental disorders (NDDs) are lacking. Investigating the association between the ratio and NDDs in twins can provide insight into genetic and/or environmental factors driving the ratio. Hand images were collected in N = 238 twins with NDDs or typical development from 70 monozygotic and 49 dizygotic pairs to examine ratios and their associations to DSM-5 defined categorical NDDs, autistic traits, zygosity, and sex. There were small associations for males between the ratios and any NDD and ADHD diagnoses. Males had lower ratios than females. Future studies exploring the ratio alongside physical anomalies could provide etiological insight into NDDs. Electronic supplementary material The online version of this article (10.1007/s10803-018-3588-8) contains supplementary material, which is available to authorized users.
There is growing evidence that epigenetic dysregulation plays a role in neurodevelopmental disorders. In humans, folate is one of the main donors of the methyl group required for the synthesis of S‐adenosyl methionine which in turn is needed for DNA and histone methylation as key neurodevelopment processes. Folate deficiency during pregnancy has been correlated with neural tube defects and with a higher incidence of neurocognitive and/or neurobehavioral deficits. A similar outcome may be exerted by gene polymorphisms in folate or folate related pathways. This has been documented by numerous case/control association studies performed on neurodevelopmental disorders such as Autism Spectrum Disorder and Attention Deficit Hyperactivity Disorder. In this regard, the folate cycle represents a “perfect model” of how genetics influences epigenetics. Gene variants in folate and folate related pathways can be considered risk factors for neurodevelopmental disorders and should therefore be assessed by genetic testing in pregnant women. High‐risk women should be considered for folate supplementation during pregnancy. Here, we (1) review all published case/control association studies on gene polymorphisms in folate and folate related pathways performed on neurodevelopmental disorders (2) provide an overview of neurodevelopment and DNA methylation changes occurring at this time (3) describe the biological basis of neurodevelopmental disorders and recent evidence of their epigenetic dysregulation. This article is protected by copyright. All rights reserved.
Importance Although research suggests an association between hypertensive disorders of pregnancy (HDP) and autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and other neurodevelopmental disorders in offspring, consensus is lacking. Given the increasing prevalence of hypertension in pregnancy, it is important to examine the association of HDP with neurodevelopmental outcome. Objective To synthesize the published literature on the association between HDP and risk of neurodevelopmental disorders in offspring in a systematic review and meta-analysis. Data Sources On the basis of a preprepared protocol, a systematic search of PubMed, CINAHL, Embase, PsycINFO, and Web of Science was performed from inception through June 7, 2017, supplemented by hand searching of reference lists. Study Selection Two investigators independently reviewed titles, abstracts, and full-text articles. English-language cohort and case-control studies were included in which HDP and neurodevelopmental disorders were reported. Data Extraction and Synthesis Data extraction and quality appraisal were performed independently by 2 reviewers. Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed throughout. Main Outcomes and Measures Random-effects meta-analyses of estimated pooled odds ratios (ORs) for HDP and ASD and for HDP and ADHD. Stand-alone estimates were reported for all other neurodevelopmental disorders. Results Of 1166 studies identified, 61 unique articles met inclusion criteria. Twenty studies reported estimates for ASD. Eleven of these (including 777 518 participants) reported adjusted estimates, with a pooled adjusted OR of 1.35 (95% CI, 1.11-1.64). Ten studies reported estimates for ADHD. Six of these (including 1 395 605 participants) reported adjusted estimates, with a pooled adjusted OR of 1.29 (95% CI, 1.22-1.36). Subgroup analyses according to type of exposure (ie, preeclampsia or other HDP) showed no statistically significant differences for ASD or ADHD. Thirty-one studies met inclusion criteria for all other neurodevelopmental disorders. Individual estimates reported for these were largely inconsistent, with few patterns of association observed. Conclusions and Relevance Exposure to HDP may be associated with an increase in the risk of ASD and ADHD. These findings highlight the need for greater pediatric surveillance of infants exposed to HDP to allow early intervention that may improve neurodevelopmental outcome.
Although advanced paternal and maternal age at birth (PA/MA) increases the risk of autism spectrum disorder (ASD), the underlying neurobiological mechanisms are not fully understood. To explore the neuroanatomical correlates of advanced PA/MA, the current study conducted brain morphometric analyses in 39 high-functioning adult males with ASD and 39 age-, intellectual level-, and parental socioeconomic background-matched, typically developed (TD) males. Whole-brain analysis revealed that the regional gray matter volume (GMV) in bilateral posterior cingulate cortex (PCC) and precuneus (PCU) were significantly smaller in the individuals with ASD than in TD subjects (false discovery rate-corrected P = 0.014). Additional analyses of the constituents of GMV reduction in these brain regions revealed that the cortical thickness of the right ventral PCC was significantly thinner (P = 0.014) and the surface area of bilateral PCU was significantly smaller (left: P = 0.001; right: P = 0.049) in the adults with ASD, compared with TD subjects. Although the analyses were exploratory, the thinner cortical thickness of right ventral PCC was significantly correlated with older PA in the ASD individuals (P = 0.028). The current findings shed new light on the neurobiological mechanisms underlying the link between advanced PA and ASD.