CC BY-NC-ND
0J Pediatr (Rio J). 2016;xxx(xx):xxx-xxx
ORIGINAL ARTICLE
Prenatal, perinatal and postnatal factors associated with autism spectrum disorder*
Imen Hadjkacem *, Héla Ayadi, Mariem Turki, Sourour Yaich, Khaoula Khemekhem, Adel Walha, Leila Cherif, Yousr Moalla, Farhat Ghribi
University of Sfax, Hedi Chaker Hospital, Department of Child and Adolescent Psychiatry, Sfax, Tunisia Received 19 September 2015; accepted 25 January 2016
KEYWORDS
Autism spectrum
disorder;
Child;
Risk factors; Prenatal; Perinatal; Postnatal
Abstract
Objective: To identify prenatal, perinatal and postnatal risk factors in children with autism spectrum disorder (ASD) by comparing them to their siblings without autistic disorders. Method: The present study is cross sectional and comparative. It was conducted over a period of three months (July-September 2014). It included 101 children: 50 ASD's children diagnosed according to DSM-5 criteria and 51 unaffected siblings. The severity of ASD was assessed by the CARS.
Results: Our study revealed a higher prevalence of prenatal, perinatal and postnatal factors in children with ASD in comparison with unaffected siblings. It showed also a significant association between perinatal and postnatal factors and ASD (respectively p = 0.03 and p = 0.042). In this group, perinatal factors were mainly as type of suffering acute fetal (26% of cases), long duration of delivery and prematurity (18% of cases for each factor), while postnatal factors were represented principally by respiratory infections (24%). As for parental factors, no correlation was found between advanced age of parents at the moment of the conception and ASD. Likewise, no correlation was observed between the severity of ASD and different factors.
After logistic regression, the risk factors retained for autism in the final model were: male gender, prenatal urinary tract infection, acute fetal distress, difficult labor and respiratory infection.
Conclusions: The present survey confirms the high prevalence of prenatal, perinatal and postnatal factors in children with ASD and suggests the intervention of some of these factors (acute fetal distress and difficult labor, among others), as determinant variables for the genesis of ASD.
© 2016 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/).
* Please cite this article as: Hadjkacem I, Ayadi H, Turki M, Yaich S, Khemekhem K, Walha A, et al. Prenatal, perinatal and postnatal factors associated with autism spectrum disorder. J Pediatr (Rio J). 2016. http://dx.doi.org/10.1016/j.jped.2016.01.012
* Corresponding author.
E-mail: hadjkacemimen@yahoo.fr (I. Hadjkacem).
http://dx.doi.org/10.1016/jjped.2016.01.012
0021-7557/© 2016 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Hadjkacem I et al.
Fatores pré-natais, perinatais e pós-natais associados ao transtorno do espectro do autismo
Resumo
Objetivo: Identificar fatores de risco pré-natal, perinatal e pós-natal em criancas com transtorno do espectro do autismo (TEA) ao compará-las a irmaos sem transtornos de autismo. Método: Este estudo é transversal e comparativo. Ele foi conduzido em um período de tres meses (julho a setembro de 2014). Incluiu 101 criancas: 50 criancas com TEAs diagnosticadas de acordo com os critérios do DSM-5 e 51 irmaos nao afetados. A gravidade do TEA foi avaliada pela Escala de Avaliacao do Autismo na Infancia (CARS).
Resultados: Nosso estudo revelou uma prevalencia maior de fatores pré-natais, perinatais e pós-natais em criancas com TEA em comparacao a irmaos nao afetados. Também mostrou uma associacao significativa entre fatores perinatais e pós-natais e TEA (respectivamente p = 0,03 e p = 0,042). Nesse grupo, os fatores perinatais foram principalmente do tipo sofrimento fetal agudo (26% dos casos), longa duracao do parto e prematuridade (18% dos casos em cada fator), ao passo que fatores pós-natais foram representados principalmente por infeccoes respiratórias (24%). No que diz respeito a fatores dos pais, nenhuma correlacao foi encontrada entre a idade avancada dos pais no momento da concepcao e o TEA. Da mesma forma, nenhuma correlacao foi estabelecida entre a gravidade do TEA e fatores diferentes.
Após regressao logística, os fatores de risco de autismo encontrados no modelo final foram: sexo masculino, infeccao pré-natal do trato urinário, sofrimento fetal agudo, parto difícil e infeccao respiratória.
Conclusoes: Esta pesquisa confirma a alta prevalencia de fatores pré-natais, perinatais e pós-natais em criancas com TEA e sugere a intervencao de alguns desses fatores (sofrimento fetal agudo, parto difícil...) como variáveis determinantes para a genese do TEA. © 2016 Sociedade Brasileira de Pediatria. Publicado por Elsevier Editora Ltda. Este e um artigo Open Access sob uma licenca CC BY-NC-ND (http://creativecommons.org/licenses/by-nc-nd/ 4.0/).
PALAVRAS-CHAVE
Transtorno do espectro do autismo; Crianca;
Fatores de risco; Pré-natal; Perinatal; Pós-natal
Introduction
Autism spectrum disorder (ASD) is a complex neurodevel-opmental condition. Based on the 5th edition of Diagnostic Statistical Manual of Mental Disorders (DSM-5), specific diagnostic criteria for childhood autism include social skills and communication deficit associated with restrictive and repetitive behaviors, interests, or activities.1 ASD is currently one of the most common childhood morbidities, presenting in various degrees of severity. The most recent global prevalence of autism was estimated at 0.62%.2
This disorder has grown into a constant challenge for many countries such as Tunisia, as it has a severe impact on both the affected individuals and their families. The financial burden, which has become more acute since the Tunisian revolution, along with the lack of scientific knowledge about the epidemiology, etiology, and natural course of this condition, have rendered the situation more complex.3"5
The spectrum of symptoms and the extreme complexity in the developmental and associated medical conditions within ASD do not necessarily mean a single etiology. Several hypotheses concerning the pathogenesis have been proposed, including the interaction of environmental factors and various genetic predispositions.5,6 Studies based on concordance rates among monozygotic twins and families
suggest a possible role of both genetic and environmental factors in the etiology of ASD.7
A recent study suggests that genetic factors account for only 35-40% of the contributing elements.8,9 The remaining 60-65% are likely due to other factors, such as prenatal, perinatal, and postnatal environmental factors. Since ASDs are neurodevelopmental disorders, neonatally-observed complications that are markers of events or processes that emerge early during the perinatal period may be particularly important to consider.8
To the best of our knowledge, in Tunisia, there are no studies that have considered the relationship between prenatal, perinatal, and postnatal risk factors and ASD.
Thus, the aim of the present study was to identify the pre-, peri-, and postnatal factors associated to ASD by comparing children with ASD to their siblings who do not present any autistic disorders.
Methods Study
This was a cross sectional and comparative study. It was conducted over a period of three months from July to September 2014.
Perinatality and autism spectrum disorder
110 111 112
120 121 122
Population Participants
The sample included 101 children divided into two groups:
1. The first group was composed of 50 autistic children previously identified and followed regularly in the child and adolescent psychiatry department of the Hedi CHAKER Hospital of Sfax (Tunisia). These patients came from different regions of Tunisia, as there are only three child psychiatry departments in the entire country. Subject ages ranged between 3 and 7 years.
2. The second group was composed of 51 non-autistic children, aged between 3 and 12 years.
Inclusion and exclusion criteria
Inclusion criteria.
- For the first group, the study included children who both met the DSM-5 criteria for ASD and whose score at the Child Autistic Rating Scale (CARS) was >30.
- For the second group, the unaffected siblings were included as controls.
In both groups, the children were aged at least 3 years. This criterion for age selection is based on the fact that ASD is identified with a high degree of certainty at the age of 3. Exclusion criteria. Exclusion criteria: known neurogenetic conditions (e.g., tuberous sclerosis, neurofibromatosis, fragile X syndrome, Down syndrome).
The control group shared the same exclusion criteria.
DSM-5 diagnostic criteria for ASD. In DSM-5, ASD encompasses the previous DSM-IV autistic disorder (autism), Asperger's disorder, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified.1
CARS assesses the intensity of ASD symptomatology
It evaluates the severity of autistic behaviors in 14 functional areas by assigning a score from 1 to 4. An overall score is calculated by adding all the grades, to stratify patients into three levels: ''severely autistic'' (score between 37 and 60), ''mildly to moderately autistic'' (score between 30 and 36.5), and ''absence of ASD'' (score less than 30).10 The time for administering this questionnaire is around 20-30 min.
Procedures
All study procedures were approved by the local Research Ethics Committee.
Informal consent from parents or legal guardians of participants was obtained after the nature of the procedures had been fully explained.
The interviews were conducted with mothers in 78% of the cases, with fathers in 4% of the cases, and with both parents in 18% of the cases, by a properly trained child psychiatrist.
Parents completed a medical history questionnaire with a combination of closed and open-ended questions regarding
pregnancy, labor, and complications during and after birth. 157
Additionally, data were collected with reference to medical 158
record and medical birth book. 159
The studied variables were designed according to the 1®
probable risk factors of ASD from existing literature. The 161
following variables, which were considered for both groups, 162
were classified as parental factors, pre-, peri-, and post- 163
natal characteristics and were codified as binary variables 164
(yes/no). 165
Parental factors: Advanced maternal and paternal age at 166
the time of childbirth (>35 years), consanguinity. 167
Prenatal factors: These consisted of conditions that arose 168
during pregnancy, such as gestational diabetes, which usu- 169
ally develops in the second half of pregnancy; high and 170
low blood pressure; gestational infections; and fetal distress 171
inducing threatened abortion conditions, such as amni- 172
otic fluid loss, bleeding during gestation, and suboptimal 173
intrauterine conditions. Perinatal factors: delivery charac- 174
teristics, such as term birth (premature or post-term birth); 175
delivery types, including forceps or cesarean section; acute 176
fetal distress; and birth weight (low birth weight [<2500 g] 177
and macrosomia [>4000 g]) 178
Postnatal factors: All conditions occurring in the first six 179
weeks after birth, such as respiratory and urinary infections; 180
auditory deficit (a loss of 30dB); and blood disorders such 181
as anemia and thrombopenia. 182
The diagnosis of respiratory and urinary infections was 183
achieved during hospitalizations in pediatric services. 184
Statistical analysis 185
Statistical analysis was done using SPSS software for Win- 186
dows, release 20.0 (IBM Corp. Released 2011. IBM SPSS 187
Statistics for Windows, version 20.0, USA). The analysis 188
included a descriptive study, observing the frequencies for 189
the quantitative variables and means and standard devia- 190
tions for the qualitative variables, as well as an analytical 191
study, using Pearson's correlation coefficient to establish 192
correlations between the two groups. The level of statistical 193
significance was set at p < 0.05 (alpha level of 5%). 194
In the multivariable analysis, logistic regression was 195
performed to identify risk factors for autism, taking into 196
account confounding factors and using the down method of 197
Wald. 198
Initially, all the variables significantly associated with 199
autism were included in the univariable analysis, as well as 200
those found as risk factors in the literature. The significance 201
level was set at 20%. The final model accuracy was verified 202
and calculated according to the Hosmer and Lemeshow test. 203
The results were expressed by the adjusted odds ratio (ORa) 204
with their confidence intervals, 95% CI (ORa). 205
Results 206
Clinical profile of children with ASD 207
This study included 50 children. A male predominance 208
(37 boys and 13 girls) was observed, as well as a moderate 209
socioeconomic level in 90% of cases, and a predominance of 210
+Model ARTICLE IN PRESS
Hadjkacem I et al.
Table 1 Parental age at the time of conception in both groups.
Group 1 Group 2 p-Value
N % N %
Fathers
<35 years 17 34 25 50.9 0.12
>35 years 33 66 26 49.01
Mothers
<35 years 38 72 41 80.4 0.59
>35 years 12 24 10 19.6
the mild to moderate form of ASD at the CARS (62% vs. 38% for the severe form).
213 Parental factors
214 Table 1 shows the distribution of parental age at the
215 moment of conception in both groups. It indicates that
216 the rate of advanced age (>35 years) among parents
217 at the moment of conception was higher in children with
218 ASD than in their siblings (66% vs. 49.01% for fathers and 24%
219 vs. 19.6% for mothers), but the difference was statistically
220 non-significant.
221 In the present study, the rate of consanguinity was 28%
222 (first degree in 31% of cases, second degree in 26% of cases,
223 and third degree in 43% of cases).
Prenatal, perinatal, and postnatal factors (Table 2) 224
Table 2 displays a comparison of prenatal, perinatal, and 225
postnatal factors between both groups. Despite the fact 226
that no statistically significant differences were observed 227
between prenatal factors in the groups (p = 0.13), the preva- 228
lence was higher in the first group (50% vs. 35.3%). Table 2 229
shows that perinatal factors were more frequent in the first 230
group, with a rate of 60% vs. 11.8% in the second group, a sta- 231
tistically significant difference (p = 0.03). The most frequent 232
perinatal factors found in the ASD group were acute fetal 233
distress (26%), prematurity, and difficult labor observed in 234
18% in each case. 235
As for postnatal factors, they were associated with 236
ASD (40% in the first group vs. 9.8% in the second group, 237
p = 0.042); these postnatal factors were primarily a type of 238
respiratory infection (24% of the cases in the first group). 239
Table 2 Correlation between pre-, peri-, and postnatal factors in both groups.
Group 1 (n = 50) Group 2 (n = 51) p-Value
N % N %
Prenatal factors 25 50 18 35.3 0.13
Exposure to cigarette smoking 11 22 6 11.8 0.16
Urinary infection 6 12 2 3.9 0.16
Hypertension in pregnancy 5 10 3 5.9 0.48
Threatened abortion 5 10 3 5.9 0.48
Gestational diabetes 4 8 1 2 0.2
Hypotension 1 2 0 0 0.49
Perinatal factors 30 60 6 11.8 <0.01
Acute fetal distress 13 26 3 5.9 0.006
Prematurity 9 18 0 0 0.001
Exceeding the term 1 2 1 2 1
Difficult labor 9 18 3 5.9 0.06
Low birth weight3 6 12 1 2 0.06
Macrosomiab 3 6 1 2 0.36
Postnatal factors 20 40 5 9.8 <0.01
Respiratory infection 12 24 1 2 0.001
Urinary infection 3 6 1 2 0.36
Auditory deficit0 2 4 0 0 0.24
Blood diseased 1 2 2 3.9 1
a Low birth weight <2500 g. b Macrosomia >4000 g. c Auditory deficit (a loss of 30dB).
d Blood disease includes, in the G1, one case of anemia, and in the G2, one case of anemia and one case of thrombopenia.
Perinatality and autism spectrum disorder
Table 3 Adjusted analysis of risk factors of ASD.
Covariates Univariable analysis Multivariable analysis
OR p-Value ORa 95% CI (ORa) p-Value
Gender 2.15 0.07 2.5 [0.9-6.9] 0.07
Exposure to cigarette smoking 2.11 0.16 - - -
Urinary infection 3.34 0.16 5.7 [0.8-38.2] 0.07
Gestational diabetes 4.34 0.2 - - -
Acute fetal distress 5.6 0.006 5.2 [1.2-21.6] 0.02
Prematurity 0.001 - - -
Difficult labor 3.51 0.06 3.6 [0.8-16] 0.09
Low birth weight 6.8 0.06 - - -
Respiratory infection 15.7 0.001 22.2 [2.5-191.03] 0.005
■ Light to moderate autism ■ severe autism
p=.16 P=.5
64% „67^ 65%
Prenatal factors Perinatal factors Postnatal factors
Figure 1 Distribution of prenatal, perinatal, and postnatal factors according to the severity of ASD (a total of 50 cases).
240 Table 3 shows that after logistic regression, the risk fac-
241 tors for autism that remained in the final model were: male
242 gender, prenatal urinary tract infection, acute fetal distress,
243 difficult labor, and respiratory infection.
244 Fig. 1 shows the distribution of prenatal, perinatal, and
245 postnatal factors according to the severity of autism.
246 No association was observed between the severity of
247 autism and the prenatal, perinatal, and postnatal factors.
248 Discussion
249 The present study discusses prenatal, perinatal, and postna-
250 tal complications, as well as some parental characteristics,
251 that could be considered as risk factors for ASD.
252 Parental factors
19.6% for maternal age and two-thirds vs. almost 50% for 262
paternal age). 263
Theories advocating the association between parental 264
age and increased risk for ASDs include the potential for 265
more genetic mutations in the gametes of older fathers and 266
mothers, as well as a less favorable in utero environment in 267
older mothers, with more obstetrical complications such as 268
low birth weight, prematurity, and cerebral hypoxia.11 269
Moreover, according to some studies, high prevalence of 270
chronic diseases among older women could contribute to 271
expand the risk of adverse birth outcomes.12,14 Data from 272
the literature trying to explain the increased risk for ASD' s 273
among older mothers have incriminated the high risk of 274
obstetric complications observed in these mothers.11,12,14 275
Furthermore, congenital anomalies are also more com- 276
mon in the fetuses and infants of older mothers, and these 277
conditions contribute in increasing the risk of ASD. 278
In the present study, a rate of 28% of consanguinity was 279
observed. In the literature, it is stated that consanguinity 280
increases the chances of inheriting a bad DNA fit, which 281
will definitely result in a birth defect. Inbred disorders may 282
cause other abnormalities, and ASD can also be brought on 283
by other conditions.15 Since the control group, in the present 284
study, was represented by the siblings conceived and born 285
from the same biological parents, consanguinity could not 286
be evaluated as a risk factor for ASD. 287
Prenatal, perinatal and postnatal factors 288
In the present survey, no correlation was observed between 289
the severity of ASD and prenatal, perinatal, and postnatal 290
factors. The present results are in agreement with some 291
recent studies.16,17 Conversely, some hypothesis have been 292
raised, indicating that the light form of autism would show 293
weaker or no association with obstetric risk factors. 294
Previous studies have linked advanced maternal and paternal age to increased risk for ASDs.11,12
In the present study, the chose 35 years as the age cut-off for both parents. This choice was based the recommendations of many authors.11"13 Despite the fact that a correlation between advanced age at the moment of the conception of both parents and ASD was not observed, the frequency of parents aged over 35 years was higher in children with ASD than their siblings (respectively 24% vs.
Prenatal factors 295
In the present study, the occurrence of maternal infection 296
was higher among cases when compared to controls (12% for 297
the first group vs. 3.9% for controls). 298
According to many studies, adverse intrauterine environ- 299
ment resulting from maternal bacterial and viral infections 300
during pregnancy is a significant risk factor for several 301
neuropsychiatric disorders including ASD.15 The association 302
between intrauterine inflammation, infection, and ASD is based on both epidemiological studies and case reports. This association is apparently related to maternal inflammatory process; hence, maternal immune activation may play a role in neuro-developmental perturbation.
In large population studies, researchers have not identified a specific infection, but rather an increased rate of ASD, especially when the maternal infection is rather severe and requires hospitalization.15,18
Among the prenatal factors identified in this study, exposure to cigarette tobacco (passive smoking) was noted in 22% of cases. Retrospective epidemiological studies have observed, among mothers of children with ASD, a significantly increased percentage of women who were exposed to tobacco during the conception of the child. Therefore, maternal smoking was considered as a potential maternal confounding factor, as well as other toxic chemicals.6
Some authors have demonstrated that maternal cigarette smoking during pregnancy may have a commutative impact on the lineage of her reproductive cells; it is also associated with an increased rate of spontaneous abortions, preterm delivery, reduced birth weight, among others.19 The findings regarding its relation with ASD are still controversial.20"22
The present study showed that the frequency of gesta-tional diabetes was higher in the first group (8% vs. 2% in the second group).
According to some authors, gestational diabetes is mainly associated with disturbed fetal growth and increased rate of a variety of pregnancy complications.23 It also affects fine and gross motor development and increases the rate of learning difficulties and of attention deficit hyperactiv-ity disorder, a common comorbid neurobehavioral problem in ASD. The negative effects of maternal diabetes on the brain may result from intrauterine increased fetal oxidative stress and epigenetic changes in the expression of several genes. The increased risk observed might be related to other pregnancy complications that are common in diabetes, or to effects on fetal growth rather than to complications of hyperglycemia. It is also unknown whether optimal control of diabetes will further decrease this association.23
Because of its rising incidence, maternal diabetes has been considered, by several studies, as an obvious candidate to be associated with ASD, whereas others have failed to demonstrate such associations.15,20,23
In the current survey, hypertension, hypotension, and threatened abortion were more frequent in the first group (respectively 10% vs. 5.9%, 2% vs. 0%, and 10% vs. 5.9% in the second group). These conditions are generally related to fetal loss and adverse infant outcomes, such as prematurity, intrauterine growth retardation, still birth, and neonatal death indicating fetal distress. Likewise, fetal hypoxia is one of the manifestations of fetal distress and has been reported to induce conditions such as placental abruption, threatened premature delivery, emergency cesarean section, forceps delivery, spontaneous abortion, and varying degrees of cerebral damage.4,5 Accordingly, ASD was linked to fetal distress: oxygen deprivation could damage vulnerable regions in the brain, such as the basal ganglia, hippocampus, and lateral ventricles. Some neuroimaging studies have demonstrated abnormalities in these regions among patients with ASD compared with controls.5,14
Hadjkacem I et al.
Perinatal factors
In the present series, perinatal factors were very significantly associated with ASD (p = 0.03). This result is consistent with the literature.4,24 In fact, complications occurring during labor affect the neurodevelopment of the fetus and infant in later stages, and can contribute toward the risk of ASD.
The current research also suggests that obstetric factors occur more frequently in ASD children than in their unaffected siblings. The present results corroborate other studies reporting an association between perinatal factors and ASD.
Perinatal factors were represented by a long duration of delivery and prematurity in 18% of the cases each one and suffering acute fetal in 26% of the cases. Therefore, it is admitted that these conditions may lead to fetal distress and asphyxia, resulting in brain damage. Fetal oxygen deprivation has been proposed to increase the risk for ASD. Recently, research has highlighted the occurrence of ASDs in very preterm infants, in addition to already identified developmental disorders.4,14,24
Postnatal factors
The present findings are in agreement with previous studies suggesting that postnatal events may increase the risk for ASDs in some children.4 In fact, a significant association between postnatal factors and ASD (p = 0.042) has been observed.
In the present study, an association was observed between both urinary and respiratory infections and ASD. These findings could be explained by the release of cytokines as immune responses of the baby to these infections, which can affect neural cell proliferation and differentiation. These impairments are known to be associated with ASD.5,25
Hearing deficits were more common in the first group (4% vs. 0% in the second group). The present results corroborate those of Fombonne,26 who reported, in a meta-analysis, that the prevalence of sensory deficits in autism vary from 0.9% to 5.9%.
Rosenhall et al.,27 in a study conducted on 199 children and adolescents with ASD, estimated that the prevalence of hearing impairment in autism is ten times higher than in general population (11%). They also observed that 7.9% of the patients had an moderate hearing loss, 3.5% were profoundly deaf, and 18% had hyperacusis in the audiogram, even after controlling for the age factor. More recently, Kielinen et al.28 observed, in a population of children with autism, that 8.6% had a mild hearing loss, 7% a moderate deficit, and 1.6% severe deficiency (hearing loss in more than 60dB at audiometry).
The strength of the present study lies in its precise confirmation of the ASD, the active participation of parents, and resorting to unaffected siblings as controls. This last feature may help to identify risk factors and to control for hereditary background, family environment, and maternal predisposition to complications in pregnancy or birth. Nonetheless, there are some limitations, namely the limited number of samples. Therefore, the present results should be completed by epidemiological studies with a larger scale and
Perinatality and autism spectrum disorder
in larger populations. To face the issue of ASD and consanguinity, a larger population with and without consanguinity should be evaluated.
In the present study, no individual factor in the prenatal period was consistently significant as a risk factor for ASD. In the literature, some of these factors were associated with autism; therefore, they should be considered as potential risk factors, as well as perinatal and postnatal events.
Prenatal, perinatal, and postnatal factors for ASD should be considered in the broadest sense: these events of the fetal, newborn, and infant environment could interact or contribute in combination with other co-factors (environmental and genetic, among others) to characterize ASD. Scores indicate that rather than focusing on a single factor, future studies should investigate the combination of several factors.
Conflicts of interest
The authors declare no conflicts of interest.
References
1. American Psychiatric Association. Autism spectrum disorder [Fact Sheet]. American Psychiatric Association; 2013. Available from: http://www.dsm5.org/Documents/Autism% 20Spectrum%20Disorder%20Fact%20Sheet.pdf [05.12.13].
2. Elsabbagh M, Divan G, Koh YJ, Kim YS, Kauchali S, Marcin C, et al. Global prevalence of autism and other pervasive developmental disorders. Autism Res. 2012;5:160-79.
3. Zahorodny W, Shenouda J, Howell S, Rosato NS, Peng B, Mehta U. Increasing autism prevalence in metropolitan New Jersey. Autism. 2014;18:117-26.
4. Gomes PT, Lima LH, Bueno MK, Araujo LA, Souza NM. Autism in Brazil: a systematic review of family challenges and coping strategies. J Pediatr (Rio J). 2015;91:111-21.
5. Gardener H, Spiegelman D, Buka SL. Perinatal and neonatal risk factors for autism: a comprehensive meta-analysis. Pediatrics. 2011;128:344-55.
6. Tchaconas A, Adesman A. Autism spectrum disorders: a pediatric overview and update. Curr Opin Pediatr. 2013;25:130-44.
7. Mamidala MP, Polinedi A, PTV PK, Rajesh N, Vallamkonda OR, Udani V, et al. Prenatal, perinatal and neonatal risk factors of autism spectrum disorder: a comprehensive epidemiological assessment from India. Res Dev Disabil. 2013;34:3004-13.
8. Froehlich-Santino W, Londono Tobon A, Cleveland S, Torres A, Phillips J, Cohen B, et al. Prenatal and perinatal risk factors in a twin study of autism spectrum disorders. J Psychiatr Res. 2014;54:100-8.
9. Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T, et al. Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry. 2011;68:1095-102.
10. Schopler E, Reichler RJ, DeVellis RF, Daly K. Toward objective classification of childhood autism: Childhood Autism Rating Scale (CARS). J Autism Dev Disord. 1980;10:91-103.
11. Parner ET, Baron-Cohen S, Lauritsen MB, J0rgensen M, Schieve LA, Yeargin-Allsopp M, et al. Parental age and autism spectrum disorders. Ann Epidemiol. 2012;22:143-50.
12. Sandin S, Hultman CM, Kolevzon A, Gross R, MacCabe JH, Reichenberg A. Advancing maternal age is associated with increasing risk for autism: a review and meta-analysis. J Am Acad Child Adolesc Psychiatry. 2012;51:477-86.
13. Jolly M, Sebire N, Harris J, Robinson S, Regan L. The risks associated with pregnancy in women aged 35 years or older. Hum Reprod. 2000;15:2433-7.
14. Polo-Kantola P, Lampi KM, Hinkka-Yli-Salomaki S, Gissler M, Brown AS, Sourander A. Obstetric risk factors and autism spectrum disorders in Finland. J Pediatr. 2014;164:358-65.
15. Guinchat V, Thorsen P, Laurent C, Cans C, Bodeau N, Cohen D. Pre-, peri- and neonatal risk factors for autism. Acta Obstet Gynecol Scand. 2012;91:287-300.
16. Haglund NG, Kallen KB. Risk factors for autism and Asperger syndrome. Perinatal factors and migration. Autism. 2011;15:163-83.
17. Glasson EJ, Bower C, Petterson B, de Klerk N, Chaney G, Hallmayer JF. Perinatal factors and the development of autism: a population study. Arch Gen Psychiatry. 2004;61:618-27.
18. Dodds L, Fell DB, Shea S, Armson BA, Allen AC, Bryson S. The role of prenatal, obstetric, and neonatal factors in the development of autism. J Autism Dev Disord. 2011;41:891-902.
19. Kiechl-Kohlendorfer U, Ralser E, Pupp Peglow U, Reiter G, Griesmaier E, Trawoger R. Smoking in pregnancy: a risk factor for adverse neurodevelopmental outcome in preterm infants? Acta Paediatr. 2010;99:1016-9.
20. Hultman CM, Sparen P, Cnattingius S. Perinatal risk factors for infantile autism. Epidemiology. 2002;13:417-23.
21. Larsson M, Weiss B, Janson S, Sundell J, Bornehag CG. Associations between in door environmental factors and parental-reported autistic spectrum disorders in children 6-8 years of age. Neurotoxicology. 2009;30:822-31.
22. Lee BK, Gardner RM, Dal H, Svensson A, Galanti MR, Rai D, et al. Brief report: maternal smoking during pregnancy and autism spectrum disorders. J Autism Dev Disord. 2012;42:2000-5.
23. Ornoy A, Ratzon N, Greenbaum C, Wolf A, Dulitzky M. Schoolage children born to diabetic mothers and to mothers with gestational diabetes exhibit a high rate of inattention and fine and gross motor impairment. J Pediatr Endocrinol Metab. 2001;14:681-9.
24. Mann JR, McDermott S, Bao H, Hardin J, Gregg A. Pre-eclampsia, birth weight, and autism spectrum disorders. J Autism Dev Dis-ord. 2010;40:548-54.
25. Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah I, Van de Water J. Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain Behav Immun. 2011;25:40-5.
26. Fombone E. Prevalence of childhood disintegrative disorder. Autism. 2002;6:149-57.
27. Rosenhall U, Nordin V, Sandstrom M, Ahlsen G, Gillberg C. Autism and hearing loss. J Autism Dev Disord. 1999;29:349-57.
28. Kielinen M, Rantala H, Timonen E, Linna SL, Moilanen I. Associated medical disorders and disabilities in children with autistic disorder: a population-based study. Autism. 2004;8:49-60.
