Advances in Neurodevelopmental Disorders

https://doi.org/10.1007/s41252-020-00178-3

ORIGINAL PAPER

Prenatal Factors Influencing the Risk of Autism Spectrum Disorder

Thekra N. Al-maqati 1 & Nourah M. Al-Otaibi 2 & Latifa S. Al-Merbati 2 & Danah M. Al-Dossary 2

# Springer Nature Switzerland AG 2020

Abstract
Objectives This study assessed prenatal risk factors that contribute significantly to autism spectrum disorder (ASD).
Methods A total of 400 online questionnaires were sent to the mothers who had children not older than 12 years of age. Only
76.25% of the questionnaires were fully complete, with 160 of the 305 mothers had a child with ASD while 145 had a
neurotypical child. The risk factors were analyzed using binary logistic regression.
Results The results showed four factors that contributed significantly (p < 0.05) to an increased risk of ASD. Mothers with
relatives having ASD increased the risk five times to having a child with ASD. Mothers who were exposed to anesthesia and
to X-ray in the first trimester also had a risk five times to having a child with ASD. Mothers who took folic acid during the first
trimester decreased their risk 2.9 times to having a child with ASD.
Conclusions Further studies are needed to verify these findings and to investigate the effects of multiple factors on ASD.

Keywords Autism spectrum disorder . Prenatal . Risk factors . Saudi Arabia

Autism spectrum disorder (ASD) is a neurological and de-
velopmental disorder defined by difficulties in social skills,
language development, repetitive behaviors, and restricted
activities or interests. ASD begins at an early age, with
signs appearing between 2 to 3 years of age and tends to
persist throughout life (Masse 2010; Saxena & Chahrour
2017) although, in some instances, diagnosis can occur as
early as 18 months. The potential signs of ASD in babies
and toddlers consist of poor eye contact at 6 months, lack
of reciprocal voiced sounds, smiles, or other nonverbal
means of communication at 6 months. The child typically
fails to respond when called by name at 12 months. The
potential signs of ASD at any given age consist of avoiding
eye contact, repeating words, and struggling to understand
other people’s feelings (Campbell et al. 2017; Szatmari
et al. 2016).
The prevalence of ASD among children is reported in the
United States (US) as 1 in 54, according to the Centers for
* Thekra N. Al-maqati
thekra@psmchs.edu.sa
1
Clinical Laboratory Science Department, Prince Sultan Military
College of Health Sciences, Dhahran, Saudi Arabia
2
Anesthesia Technology Department, Prince Sultan Military College
of Health Sciences, Dhahran, Saudi Arabia
Disease Control and Prevention (CDC). Europe indicates a
median of 18.75 per 10,000, and China reports a lower median
of 11.6 per 10,000 (Salhia et al. 2014). ASD is considered one
of the most common disabilities in the Gulf Cooperation
Council (GCC) countries, and its prevalence is increasing.
Nevertheless, studies of population-based incidence of ASD
are rare in GCC countries.
The prevalence of ASD is 1.4 per 10,000 in Oman, 29 per
10,000 for the pervasive developmental disorder (PDD) in the
UAE, and 4.3 per 10,000 in Bahrain (Salhia et al., 2014). In
Saudi Arabia, there were 42,500 cases of ASD diagnosed in
2002, with many more cases undiagnosed (Yazbak 2004), and
no known officially reported population-based prevalence of
ASD in Saudi Arabia has been established. Most recently, a
study of 22,950 students in Taif, Saudi Arabia, found that the
overall prevalence of ASD in primary schools of the Taif
district, whose students ranged in age from 7 to 12 years,
was 0.035%; the incidence of ASD in males (0.031%) was
higher than in females (0.004%) (AlZahrani, 2013). On the
other hand, several studies have sought to compare rates
among different ethnicities, finding an increased risk of
ASD in black children relative to white children (Becerra
et al. 2014).
Many risk factors may contribute to ASD, which can
be divided into two main groups. First are genetic and
heritable factors, which can affect specific genetic syn-
dromes with around 10% of the cases like Rett

syndrome, Fragile-X syndrome, and Angelman syndrome
(Almandil et al. 2019). Second are environmental factors,
such as maternal health and lifestyle during pregnancy,
diseases (e.g., diabetes mellitus), bleeding during preg-
nancy, and exposure to intrauterine infection, all of
which were found to be related to increased risk for
ASD (Chaste & Leboyer 2012). Parents’ age and level
of education may constitute a risk factor for ASD (Ko
et al. 2015); a more well-established risk factor is the
consumption of serotonin-modulating medication during
pregnancy (Hviid et al. 2013). Intake of antibiotic drugs
during pregnancy may also cause abnormal fetal devel-
opment (Kuperman & Koren 2016). Moreover, the
mother’s exposure to anesthesia or X-rays in the first
trimester—the most critically sensitive period during
pregnancy—may constitute a risk factor for ASD.
A study showed that 1–2% of pregnant women receive
non-obstetric operation under general anesthesia (GA) for
many indications, which may affect the fetus’ brain func-
tion and development. Miscarriage following non-
obstetric surgery occurs in approximately 5.8% of cases,
increasing to about 10.5% in the first trimester (Upadya &
Saneesh 2016). Exposure to dental, plain films of the
head, chest including mammogram X-rays for pregnant
women during the first trimester does not appear to cause
undesirable effects, such as termination, suspension of
fetal growth, congenital malformation, mental defect,
and even death of the fetus while abdomen X-ray could
affect the fetus if the radiation doses are equal or greater
than 500 mGy (Abdullahi 2015).
Maternal smoking is related to increased risk of the
child developing PPD, although no such association was
observed for risk of ASD (Rosen et al. 2015; Tran et al.
2013). Iron deficiency affects approximately 40–50% of
pregnant women (Schmidt et al. 2014). Iron is critical for
healthy early neurodevelopmental processes, with low
maternal iron doubling the risk of having a child with
ASD (Schmidt et al. 2014). As the fetus depends on ma-
ternal nutrients, including iron, severe maternal iron defi-
ciency can result in iron deficiency in the infant (Schmidt
et al. 2014). Iron deficiency in early life has been shown
to impair learning, motor development, social skills, and
language ability. Reduced iron status is more common in
children with ASD (Schmidt et al. 2014). For that reason,
pregnant women are encouraged to consume certain sup-
plements that have been correlated with reduced ASD
rates and risks (Lyall et al. 2014). However, the literature
is not always consistent as to which specific prenatal risk
factors are purportedly associated with ASD. The aim of
this retrospective study was to further investigate the re-
lationship between ASD and fetal conditions and to iden-
tify factors potentially relevant to its etiology and
prevention.
Adv Neurodev Disord
Methods
Participants
Participants were mothers of children with or without ASD,
not older than 12 years old. They were recruited from various
ASD centers and regular public schools in the eastern region
of Saudi Arabia. Ethical approval for the study was obtained
from the Ethics Committee of Prince Sultan Military College
of Health Sciences. A total of 400 online questionnaires were
sent to participants via the SMS group between December
2018 and January 2019, of which 305 (76.25%) were com-
plete and included in the analysis. Informed consent was ob-
tained from all mothers included in the study.
Procedure
In two languages (Arabic and English), a structured online
questionnaire was designed and prepared by the researchers
according to the primary objective of the present study. The
questionnaire completion time was estimated to be approxi-
mately 10 min. Questions were validated by a panel of experts
then pilot tested with 60 participants whose data were not
included in the final study sample. Data collected from the
pilot test verified internal consistency of the questionnaire
with the use of SPSS, which revealed a reliability coefficient
(Cronbach’s alpha) of 0.96. The online questionnaires includ-
ed a description of the purpose and importance of the study
and confirmation of informed consent.
Measures
The questionnaire was in two parts. The first included ques-
tions about the characteristics of the child with ASD, assum-
ing the mother answered yes (i.e., Do you have a child with
ASD?). The second included questions addressed to all par-
ticipants to assess 11 prenatal risk factors known to contribute
significantly to increased ASD risk, including marriage with a
close relative (genetic inbreeding), history of illness, mother’s
age at delivery, maternal behaviors during pregnancy (e.g.,
smoking or alcohol consumption), exposure to X-rays, and
medication history.
Data Analyses
The data were analyzed and tested for statistical significance
with the use of SPSS version 20.0 (SPSS, Chicago, IL), with
significance set at p ≤ 0.05 for all analyses. Binary logistic
regression was implemented to examine the association be-
tween ASD and risk factors and to estimate odds ratios (ORs)
and 95% confidence intervals (CIs). The dependent variable
of the study is the presence or absence of ASD diagnosis in the
Adv Neurodev Disord

participant’s child. Logistic regression analysis was used to
explore the 11 ASD risk factors.
Results
Of the initial 400 women who agreed to participate in this
study, only166 satisfactorily completed the first part of the
questionnaire, which summarized the characteristics of chil-
dren with ASD (Table 1). Only 305 (76.25%) questionnaires
were fully completed, 160 (52.5%) of which reported having a
child with ASD while 145 (47.5%) reported having a
neurotypical child. Six women were ultimately excluded due
to inadequate completion of the second part of the
questionnaire.
In Table 1, 64 (38%) of the 160 children with ASD were in
the middle order among his/her siblings, and the most com-
monly reported age group for children with ASD was 4–
6 years old (28%). Sixty-eight (41%) of the children with
Table 1 Characteristics of the children with ASD
Variable Frequency (%)
ASD were diagnosed with ASD after 2 years of age, whereas
16 (9%) of them were diagnosed within 6 months after deliv-
ery. The most common age group of mothers at the time of
pregnancy with a child with ASD was 20–30 years old (54%).
Severe ASD was diagnosed in 6% of the children, while 81
(49%) were classified as mild. The most frequently observed
signs among these children were the delay of speech (40%),
followed by flapping and poor eye contact (both 25%).
The 11 risk factors were analyzed and tested for statistical
significance with binary logistic regression, including esti-
mates of ORs and 95% CIs (Table 2). The results found that
the factors that contribute significantly to the risk of ASD
consist of relatives with ASD (OR = 5.31, CI = 2.70–10.47),
exposure to anesthesia (OR = 3.04, CI = 1.53–6.01), exposure
to X-rays in the first trimester (OR = 3.63, CI = 1.47–8.98),
and absence of folic acid consumption in the first trimester
(OR = 0.34, CI = 0.171–0.676). Of the 87 mothers exposed
to anesthesia, 44% of them had a child with ASD, and 26%
had been exposed within the first trimester of the pregnancy.
Seven percent and 36% of mothers who had a child with ASD
were exposed to GA and regional anesthesia, respectively,
compared to 5% and 8% for mothers whose child was
neurotypical (Table 3).

Child’s order Discussion

Oldest 48 (29%)
Middle 64 (38%) ASD is a disorder characterized by difficulties with commu-
Youngest 54 (32%) nication skills, language development, and repetitive behav-
Child’s age ior. Over the past years, the prevalence of ASD has increased,
1–3 years 35 (21%) according to the latest reports from US and Europe. However,
4–6 years 46 (28%) there is no officially reported population prevalence of ASD in
7–9 years 41 (25%) Saudi Arabia. Recently, progress is being made in elucidating
10–12 years 44 (26%) the association between some of the risk factors and rising
Age of ASD diagnosis ASD prevalence; however, there remains no clear explanation
6 months after delivery 16 (9%) of the factors that caused ASD prevalence to rise so abruptly.
1 year after 36 (22%) This retrospective online questionnaire obtained data from
2 year after 46 (28%) mothers to identify the prenatal factors associated with an
> 2 years 68 (41%) increased risk of ASD. The data showed that 64 of the 166
Classification children with ASD were the “middle child” (i.e., having at
Mild 81 (49%) least one older and one younger sibling). This finding corrob-
Moderate 74 (45%) orated those from a previous study on birth order effect in
Severe 11 (6%) ASD that analyzed data from three publicly available ASD
First ASD behaviors noticed family collections in the US, finding those middle children
Flapping 41 (25%) were at higher risk of developing ASD (Turner et al. 2011).
Lack of feeling 17 (10%) Physicians play a crucial role in the early diagnosis of ASD
Delay of speech 67 (40%) using criteria outlined in the most recent version of the
Poor eye contact 41 (25%) Diagnostic and Statistical Manual of Mental Disorders
Age of mother during pregnancy (DSM-5), which specifies that the disorder typically manifests
20–30 years 90 (54%) by the age of 3 (Campbell et al., 2017; Pearson et al. 2012;
30–40 years 70 (42%) Szatmari et al. 2016). We found that 68 of the 166 children
≥ 40 6 (4%) with ASD referred to our study were diagnosed after 2 years of
age, while 46 children were diagnosed by the age of 2.
 Adv Neurodev Disord

Table 2 Prenatal risk factors for ASD

Variables (Do you have an autistic child?) Yes No OR 95% CI P value

N = 160 N = 145

Yes No Yes No

Between the age of 0–6 months, did your child 38 (24%) 122 (76%) 51 (35%) 94 (65%) 0.658 0.363–1.191 .167
fall on their head?
Does the child have any relatives with ASD? 70 (44%) 90 (56%) 16 (11%) 129 (89%) 5.319 2.701–10.474 .000
Had you been exposed to anesthesia during your 68 (43%) 92 (57%) 19 (13%) 126 (87%) 3.040 1.536–6.018 .001
pregnancy?
Did you regularly consume alcohol back then? 2 (1.3%) 158 (24%) 0 (0%) 145 (100%) 11,773,778.459 0.000 1.000
Were you a smoker at the time? 8 (5%) 152 (95%) 6 (4%) 139 (96%) 0.690 0.177–2.681 .592
Did you take folic acid during the first trimester? 115 (72%) 45 (28%) 127 (88%) 18 (12%) 0.340 0.171–0.676 .002
Did you take antibiotics during the first trimester? 59 (37%) 101 (63%) 24 (17%) 121 (83%) 1.306 0.647–2.633 .456
Were you exposed to X-rays during the first trimester? 52 (33%) 108 (67%) 9 (6%) 136 (94%) 3.634 1.470–8.985 .005
Are you and the child’s father related? 44 (28%) 116 (72%) 46 (32%) 99 (68%) 0.927 0.508–1.693 .806
Did you follow organic nutrition in the first trimester? 38 (24%) 122 (67%) 37 (16%) 122 (84%) 0.813 0.381–1.733 .591
Was there any problem with your delivery? 26 (16%) 134 (84%) 20 (14%) 125 (86%) 1.186 0.554–2.538 .661

OR odds ratios, CI confidence intervals

Common “red flags,” indicating possible ASD, include com-
munication impairment, social impairment, and impairments
of interests, activities, and/or behaviors (Johnson & Myers
2007; Masse 2010). According to our results, 40% of children
with ASD had a speech delay and poor eye contact, while 25%
had repetitive hand and finger mannerisms.
Using standardized scales, physicians have generally iden-
tified the severity of ASD as a determinant of behavior. We
found that 81 cases were classified as mild, while 11 were
classified as severe. A possible barrier to successful ASD di-
agnosis in children with severe symptomatology may be the
difficulty in differentiating severe ASD from a severe intellec-
tual disability. At the same time, those with mild symptoms
may be misdiagnosed as having a language disorder or social
anxiety (Sun et al. 2015).
The associations between maternal age and risk for ASD
differ among population-based studies. Some studies reported
that the age of both parents is associated with increased risk
for ASD, whereas others state that only maternal age is asso-
ciated (Durkin et al. 2008; Wu et al. 2017). Importantly,
higher maternal age was associated with a 41% increased risk
of ASD, and older paternal age was associated with a 55%
increased risk. Our study, however, found that lower maternal
age was associated with an increased risk of ASD in children.
Of the women aged between 20 and 30 years at the time of
their child’s birth, 54% had a child with ASD, whereas only
4% of women over 40 had a child with ASD. This discrepancy
in our results in relation to previous studies may be due to the
fact that fewer women have children beyond the age of 40
which resulted in small sample size, different methodology,
and other study variables.
Four of the eleven known risk factors were found to
contribute significantly to an elevated ASD risk in our
study. Relatives with ASD were significantly associated
with ASD (OR = 5.31, CI = 2.70–10.47), a finding con-
sistent with previous studies reporting that ASD is both
familial and heritable. The possibility of having another
child with ASD increases 25 times relative to the general
population if the mother already has a child with ASD
(Abrahams & Geschwind 2008).

Table 3 Type of anesthesia mothers were exposed to during pregnancy

Variables (Do you have an autistic child?) Yes No

N = 160 N = 145

Were you exposed to anesthesia If yes, what type of anesthesia General anesthesia Regional anesthesia General Regional anesthesia
during your pregnancy? you exposed to? anesthesia
10 (7%) 58 (36%) 8 (5%) 11 (8%)
At which trimester you exposed First Second Third First Second Third
to anesthesia? 40 (26%) 16 (10%) 11 (7%) 4 (2.8%) 7 (4.8%) 8 (5.5%)
Adv Neurodev Disord
Exposure to anesthesia during the first trimester of preg-
nancy was also significantly associated with ASD (OR = 3.04,
CI = 1.53–6.01). Of the 87 mothers exposed to anesthesia,
44% had a child with ASD, and 26% had been exposed within
the first trimester. Furthermore, 7% and 36% of mothers with
a child with ASD were exposed to GA and regional anesthe-
sia, respectively, differing from the 5% and 8% rates found in
mothers of neurotypical children. One study reported that 1–
2% of pregnant women received non-obstetric operation un-
der GA for various indications, which may affect the
neurodevelopment of the fetus (Upadya & Saneesh 2016).
Exposure to GA may contribute to increasing the risk of
ASD (Huberman Samuel et al., 2019). Other significant or
suggestive associations were observed with exposure to X-
rays during the first trimester (OR = 3.63, CI = 1.47–8.98).
Conversely, another study failed to find significant associa-
tions between ASD and X-ray exposure (Zhang et al. 2010).
Iron deficiency affects roughly 40–50% of pregnant women
and is crucial for promoting healthy early neurodevelopmental
processes in children who have ASD (Schmidt et al. 2014). The
intake of folic acid during pregnancy can reduce the risk of
ASD regardless of ethnicity (Surén et al. 2013). Moreover,
our results suggest that mothers who had not taken folic acid
during the first trimester increased the risk of having a child
with ASD. However, our study identified factors that showed
no association with increased risk of ASD, such as maternal
smoking, antibiotic intake, nutrition, alcohol intake, and com-
plications from delivery. Exposure to cigarette smoking was not
considered an increased risk factor of ASD in another study
(Wang et al. 2017). However, antibiotic intake, maternal nutri-
tion, alcohol intake, and complications from delivery were
found by others to be significantly associated with ASD
(Wang et al. 2017; Zhang et al. 2010). This contradiction with
previous studies might be due to factors that could interact and
act in combination with other co-factors in the development of
ASD. Also, most of the earlier studies focused on one factor
individually with a large sample size.
Limitations and Future Research Directions
This study is not without limitations. The relatively small
sample size was due to few ASD centers in the region, and
mothers who had a child with ASD were not particularly mo-
tivated to participate in this study. Although the rate of
mothers logging into the research site link was high, the rate
of questionnaires that were fully completed was lower. We did
not ensure that the age and gender of children with the non-
autistic were matched. We included children under 12 years
old to make mothers answer more reliably. One of the limita-
tions of the survey was that we did not specify how close the
relative was. That is probably why the relative risk is lower
than reported in other studies where it is limited to risk related
to a sibling, vs. a more distant relative a cousin. Moreover, we
did not collect demographic data such as education, race, and
marital status of mothers which may indirectly contribute to
the risk status of children.
Author Contributions TN supervised the data collection, drafted the man-
uscript, performed the statistical analysis, and led the analysis and inter-
pretation of the data; NM conceived the study, led in its design and
coordination, participated in the interpretation of the data, and helped to
draft the manuscript; LS helped to conceive of the study and participated
in the design and interpretation of the data; DM helped to conceive the
study and participated in the design and interpretation of the data. All the
authors read and approved the final manuscript.
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflict of
interest.
Ethical Approval All procedures performed in studies involving human
participants followed the ethical standards of Prince Sultan Military
College of Health Sciences in Dhahran, Saudi Arabia, and with the
1964 Helsinki declaration and its later amendments.
Informed Consent Informed consent was obtained from all individual
participants included in the study.
References
Abdullahi, M. G. (2015). The effects of x-rays (radiation) on embryonic
and fetal during developmental pregnancy stages. Journal of
Nuclear Medicine & Radiation Therapy, 06(04), 4–7. https://doi.
org/10.4172/2155-9619.1000231.
Abrahams, B. S., & Geschwind, D. H. (2008). Advances in autism ge-
netics: On the threshold of a new neurobiology. Nature Reviews
Genetics, 9(5), 341–355. https://doi.org/10.1038/nrg2346.
Almandil, N. B., Alkuroud, D. N., AbdulAzeez, S., AlSulaiman, A.,
Elaissari, A., & Borgio, J. F. (2019). Environmental and genetic
factors in autism spectrum disorders: special emphasis on data from
Arabian studies. International Journal of Environmental Research
and Public Health, 16(4), 658. https://doi.org/10.3390/
ijerph16040658.
AlZahrani, A. (2013). Prevalence and clinical characteristics of autism
spectrum disorders in school-age children in Taif- KSA.
International Journal of Medical Science and Public Health, 2(3),
578–582. https://doi.org/10.5455/ijmsph.2013.160420133.
Becerra, T. A., von Ehrenstein, O. S., Heck, J. E., Olsen, J., Arah, O. A.,
Jeste, S. S., Rodriguez, M., & Ritz, B. (2014). Autism spectrum
disorders and race, ethnicity, and nativity: a population-based study.
Pediatrics, 134(1), e63–e71. https://doi.org/10.1542/peds.2013-
3928.
Campbell, S. B., Moore, E. L., Northrup, J., & Brownell, C. A. (2017).
Developmental changes in empathic concern and self-understanding
in toddlers at genetic risk for autism spectrum disorder. Journal of
Autism and Developmental Disorders, 47(9), 2690–2702. https://
doi.org/10.1007/s10803-017-3192-3.
Chaste, P., & Leboyer, M. (2012). Autism risk factors: genes, environ-
ment, and gene-environment interactions. Dialogues in Clinical
Neuroscience, 14(3), 281–292. https://doi.org/10.2217/epi.11.19.
Durkin, M. S., Maenner, M. J., Newschaffer, C. J., Lee, L., Cunniff, M.,
Daniels, J. L., Kirby, R. S., Leavitt, L., Miller, L., Zahorodny, W., &
Schieve, L. A. (2008). Original contribution advanced parental age

and the risk of autism spectrum disorder. American Journal of
Epidemiology, 53726(8), 1268–1276. https://doi.org/10.1093/aje/
kwn250.
Huberman Samuel, M., Meiri, G., Dinstein, I., Flusser, H., Michaelovski,
A., Bashiri, A., & Menashe, I. (2019). Exposure to general anesthe-
sia may contribute to the association between cesarean delivery and
autism spectrum disorder. Journal of Autism and Developmental
Disorders, 49(8), 3127–3135. https://doi.org/10.1007/s10803-019-
04034-9.
Hviid, A., Melbye, M., & Pasternak, B. (2013). Use of selective serotonin
reuptake inhibitors during pregnancy and risk of autism. New
England Journal of Medicine, 369(25), 2406–2415. https://doi.org/
10.1056/NEJMoa1301449.
Johnson, C. P., & Myers, S. M. (2007). Identification and evaluation of
children with autism spectrum disorders and the council on children
with disabilities. American Academy of Pediatrics, 120(5), 1183–
1215. https://doi.org/10.1542/peds.2007-2361.
Ko, W.-R., Huang, J.-Y., Chiang, Y.-C., Nfor, O. N., Ko, P.-C., Jan, S.-
R., Lung, C.-C., Chang, H.-C., Lin, L.-Y., & Liaw, Y.-P. (2015).
Risk of autistic disorder after exposure to general anaesthesia and
surgery. European Journal of Anaesthesiology, 32(5), 303–310.
https://doi.org/10.1097/EJA.0000000000000130.
Kuperman, A. A., & Koren, O. (2016). Antibiotic use during pregnancy:
how bad is it? BMC Medicine, 14(1), 1–7. https://doi.org/10.1186/
s12916-016-0636-0.
Lyall, K., Schmidt, R. J., & Hertz-Picciotto, I. (2014). Maternal lifestyle
and environmental risk factors for autism spectrum disorders.
International Journal of Epidemiology, 43(2), 443–464. https://
doi.org/10.1093/ije/dyt282.
Masse, J. (2010) Autism Spectrum Disorders. In C. McNeil & T. L.
Hembree-Kigin (Eds.), Parent-child interaction therapy. Issues in
clinical child psychology. Springer.
Pearson, D. A., Aman, M. G., Arnold, L. E., Lane, D. M., Loveland, K.
A., Santos, C. W., Casat, C. D., Mansour, R., Jerger, S. W., Ezzell,
S., Factor, P., Vanwoerden, S., Ye, E., Narain, P., & Cleveland, L.
A. (2012). High concordance of parent and teacher attention-deficit/
hyperactivity disorder ratings in medicated and unmedicated chil-
dren with autism spectrum disorders. Journal of Child and
Adolescent Psychopharmacology, 22(4), 284–291. https://doi.org/
10.1089/cap.2011.0067.
Rosen, B. N., Lee, B. K., Lee, N. L., Yang, Y., & Burstyn, I. (2015).
Maternal smoking and autism spectrum disorder: A meta-analysis.
Journal of Autism and Developmental Disorders, 45(6), 1689–
1698. https://doi.org/10.1007/s10803-014-2327-z.
Salhia, H. O., Al-nasser, L. A., Taher, L. S., & Al-khathaami, A. M.
(2014). Systemic review of the epidemiology of autism in Arab
Gulf countries. Neurosciences (Riyadh), 19(4), 291–296.
Saxena, A., & Chahrour, M. (2017). Autism spectrum disorder. In G.
Ginsburg, & H. Willard (Eds.), Genomic and Precision Medicine
(pp. 301–316). Elsevier. https://doi.org/10.1016/B978-0-12-
800685-6.00016-3.
Adv Neurodev Disord
Schmidt, R. J., Tancredi, D. J., Krakowiak, P., Hansen, R. L., & Ozonoff,
S. (2014). Maternal intake of supplemental iron and risk of autism
spectrum disorder. American Journal of Epidemiology, 180(9),
890–900. https://doi.org/10.1093/aje/kwu208.
Sun, X., Allison, C., Auyeung, B., Zhang, Z., Matthews, F. E., Baron-
Cohen, S., & Brayne, C. (2015). Validation of existing diagnosis of
autism in mainland China using standardised diagnostic instru-
ments. Autism : The International Journal of Research and
Practice, 19(8), 1010–1017. https://doi.org/10.1177/
1362361314556785.
Surén, P., Roth, C., Bresnahan, M., Haugen, M., Hornig, M., Hirtz, D.,
Lie, K. K., Lipkin, W. I., Magnus, P., Reichborn-Kjennerud, T.,
Schjølberg, S., Smith, G. D., Øyen, A. S., Susser, E., &
Stoltenberg, C. (2013). Association between maternal use of folic
acid supplements and risk of autism spectrum disorders in children.
Obstetrical & Gynecological Survey, 68(6), 416–418. https://doi.
org/10.1097/01.ogx.0000431313.84585.bd.
Szatmari, P., Chawarska, K., Dawson, G., Georgiades, S., Landa, R.,
Lord, C., Messinger, D. S., Thurm, A., & Halladay, A. (2016).
Prospective longitudinal studies of infant siblings of children with
autism: lessons learned and future directions. Journal of the
American Academy of Child and Adolescent Psychiatry, 55(3),
179–187. https://doi.org/10.1016/j.jaac.2015.12.014.
Tran, P. L., Lehti, V., Lampi, K. M., Helenius, H., Suominen, A., Gissler,
M., Brown, A. S., & Sourander, A. (2013). Smoking during preg-
nancy and risk of autism spectrum disorder in a Finnish national
birth cohort. Paediatric and Perinatal Epidemiology, 27(3), 266–
274. https://doi.org/10.1111/ppe.12043.
Turner, T., Pihur, V., & Chakravarti, A. (2011). Quantifying and model-
ing birth order effects in autism. PLoS One, 6(10), e26418. https://
doi.org/10.1371/journal.pone.0026418.
Upadya, M., & Saneesh, P. J. (2016). Anaesthesia for non-obstetric sur-
gery during pregnancy. Indian Journal of Anaesthesia, 60(4), 234–
241. https://doi.org/10.4103/0019-5049.179445.
Wang, C., Geng, H., Liu, W., & Zhang, G. (2017). Prenatal, perinatal, and
postnatal factors associated with autism: a meta-analysis. Medicine,
96(18), e6696. https://doi.org/10.1097/MD.0000000000006696.
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.
Acta Psychiatrica Scandinavica, 135(1), 29–41. https://doi.org/10.
1111/acps.12666.
Yazbak, F. E. (2004). Autism seems to be increasing worldwide, if not in
London. BMJ (Clinical Research Ed.), 328(7433), 226–227. https://
doi.org/10.1136/bmj.328.7433.226-c.
Zhang, X., Lv, C. C., Tian, J., Miao, R. J., Xi, W., Hertz-Picciotto, I., &
Qi, L. (2010). Prenatal and perinatal risk factors for autism in China.
Journal of Autism and Developmental Disorders, 40(11), 1311–
1321. https://doi.org/10.1007/s10803-010-0992-0.
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