Vaccine News – Study – Gender-selective toxicity of thimerosal

PubMed.gov – Mar.2009
Abstract
A recent report shows a correlation of the historical use of thimerosal in therapeutic immunizations with the subsequent development of autism; however, this association remains controversial. Autism occurs approximately four times more frequently in males compared to females; thus, studies of thimerosal toxicity should take into consideration gender-selective effects. The present study was originally undertaken to determine the maximum tolerated dose (MTD) of thimersosal in male and female CD1 mice. However, during the limited MTD studies, it became apparent that thimerosal has a differential MTD that depends on whether the mouse is male or female. At doses of 38.4-76.8mg/kg using 10% DMSO as diluent, seven of seven male mice compared to zero of seven female mice tested succumbed to thimerosal. Although the thimerosal levels used were very high, as we were originally only trying to determine MTD, it was completely unexpected to observe a difference of the MTD between male and female mice. Thus, our studies, although not directly addressing the controversy surrounding thimerosal and autism, and still preliminary due to small numbers of mice examined, provide, nevertheless, the first report of gender-selective toxicity of thimerosal and indicate that any future studies of thimerosal toxicity should take into consideration gender-specific differences.
PubMed.gov – 15.Mar.2010
Abstract
Mercury (Hg) exposure from dental amalgam fillings and thimerosal in vaccines is not a major health hazard, but adverse health effects cannot be ruled out in a small and more susceptible part of the exposed population. Individual differences in toxicokinetics may explain susceptibility to mercury. Inbred, H-2-congenic A.SW and B10.S mice and their F1- and F2-hybrids were given HgCl2 with 2.0 mg Hg/L drinking water and traces of (203)Hg. Whole-body retention (WBR) was monitored until steady state after 5 weeks, when the organ Hg content was assessed. Despite similar Hg intake, A.SW males attained a 20-30% significantly higher WBR and 2- to 5-fold higher total renal Hg retention/concentration than A.SW females and B10.S mice. A selective renal Hg accumulation but of lower magnitude was seen also in B10.S males compared with females. Differences in WBR and organ Hg accumulation are therefore regulated by non-H-2 genes and gender. Lymph nodes lacked the strain- and gender-dependent Hg accumulation profile of kidney, liver and spleen. After 15 days without Hg A.SW mice showed a 4-fold higher WBR and liver Hg concentration, but 11-fold higher renal Hg concentration, showing the key role for the kidneys in explaining the slower Hg elimination in A.SW mice. The trait causing higher mercury accumulation was not dominantly inherited in the F1 hybrids. F2 mice showed a large inter-individual variation in Hg accumulation, showing that multiple genetic factors influence the Hg toxicokinetics in the mouse. The genetically heterogeneous human population may therefore show a large variation in mercury toxicokinetics.
US National Library of Medicine – National Institutes of Health – Feb.2015
Results
Developmental Domain: ASD Diagnostic Criteria
Social Communication/Social Interaction
Deficits in social communication and social interaction are core factors in the diagnostic criteria of ASD. Impairments in social communication may present as abnormalities in eye contact, poor integration of verbal and nonverbal behaviors, and difficulties understanding the nonverbal communication of others (American Psychiatric Association, 2013). In some cases, persons with ASD may not participate in conversation or struggle with pragmatic language (American Psychiatric Association, 2013). Impairments in social interaction include difficulties with social-emotional reciprocity, failure to develop peer relationships, and reduced empathetic understanding and/or response (American Psychiatric Association, 2013).
There were 21 articles reviewed on social communication and social interaction in persons with ASD published between 1993 and 2013: 13 case-control studies, 7 cross-sectional studies, and 1 surveillance study. Nine studies were conducted in the United States and 12 studies were conducted at outside of the US. Of these 21 articles, 14 address social communication or other language abilities. In samples of children with varying cognitive abilities, some studies showed no significant differences in communication, conversational deficits, and language levels between males and females with ASD (Andersson et al., 2013; Dawson et al., 2007; Nicholas et al., 2008; Pilowsky et al., 1998; Park et al., 2012a, 2012b; Mayes and Calhoun, 2011; Mandy et al., 2012; Sipes et al., 2011; Solomon et al., 2012; Amr et al., 2011). One study found that males with ASD had greater expressive and receptive language skills than females with ASD (Carter et al., 2007) and another study found that females with ASD had more impaired social communication skills than males with ASD (Hartley and Sikora, 2009). Conversely, Park et al. (2012b) found that females with ASD had stronger non-verbal communication abilities than males with ASD. The majority of the literature reviewed on social communication found no difference between males and females with ASD, but there is some inconsistency.
The literature on sex differences in social interaction among persons with ASD (13 of 21 articles reviewed) is also inconsistent but generally suggests no significant sex differences in social interaction skills (Andersson et al., 2013; Dawson et al., 2007; Nicholas et al., 2008; Pilowsky et al., 1998; Mayes and Calhoun, 2011; Park et al. 2012b; Mandy et al., 2012; Sipes et al., 2011; Solomon et al., 2012). In population-level surveillance of eight-year olds, 80 % of children with ASD had poor social-emotional reciprocity with no significant difference between males and females (Nicholas et al., 2008). Szatmari et al. (2012) also found no sex differences in social-emotional reciprocity for children with varying cognitive abilities in a study from the Autism Genome Project. Oppositely, in an age and IQ matched case–control study, female adults with ASD were found to have fewer socio-communication difficulties during interpersonal interaction than male adults with ASD (Lai et al., 2013). Lastly, no sex differences have been noted in emotional reactiveness or being withdrawn (Hartley and Sikora, 2009) and in empathetic understanding and responses (Auyeung et al., 2009).
Cognitive functioning is likely to play a role in these social processes. Lower intellectual abilities are often linked with greater social impairment regardless of sex (Dawson et al., 2007). Among children with high functioning autism (IQ≥70), social skills have been found to be more impaired in female children than male children (Holtmann et al., 2007) and more severe as children aged (McLennan et al., 1993). In contrast, other studies found adult females with high functioning autism to have less socio-communication issues compared to males (Lai et al., 2011) or there were no sex differences in socio-communication skills in older children and adolescents (Holtmann et al., 2007; Kopp and Gillberg, 2011).
Overall, the 21 articles reviewed suggest no difference in social interaction between males and females with ASD and inconsistent differences in social communication between males and females with ASD, although both social interaction and social communication may be influenced by intellectual ability and age.
Restricted, Repetitive Patterns of Behavior, Interests, or Activities
There were 18 articles reviewed on restricted and repetitive patterns of behaviors and interests (RRBI) published between 1993 and 2013: nine cross-sectional studies, seven case–control studies, one cohort study, and one surveillance study. Eleven studies were conducted in the United States and seven studies were conducted in other countries. Based on this review, the literature suggests that males with ASD have more RRBI than females with ASD (Hattier et al., 2011; Carter et al., 2007). When assessing individual facets of RRBI, restricted interests are seen more often in males with ASD than females with ASD independent of cognitive ability (Kohane et al., 2012; May et al., 2012; Mandy et al., 2012; Szatmari et al., 2012). Males with ASD are also more likely to have more routines, rituals, and fascination with parts of objects than females with ASD (Nicholas et al., 2008; Park, et al., 2012b; Beuker et al., 2013). The literature on repetitive motor movements is less consistent: adult males with high functioning autism or Asperger’s syndrome had more repetitive motor movements than adult females with high functioning autism or Asperger’s syndrome in one case-control study (May et al., 2012), but there were no sex differences in repetitive motor movements among persons with autism in two other case-control studies (McLennan et al., 1993; Worley and Matson, 2011), one cross-sectional study (Auyeung et al., 2009), and one population-based cross-sectional study (Nicholas et al., 2008).
Age may influence the presentation of RRBI in males and females with ASD. One study found no sex difference among RRBI in toddlers (Sipes et al., 2011), whereas a different study found significantly more RRBI among adult males with ASD compared to females with ASD (Hattier et al., 2011). In summation, most studies reviewed suggested that males with ASD are likely to have more RRBI than females with ASD across levels of cognitive ability, although RRBI may be influenced by age.
Sensory issues are prevalent among persons with ASD (Nicholas et al., 2008) and are included as a RRBI in the DSM 5 (American Psychiatric Association, 2013). Common issues are oversensitivity to touch, sound, smell, taste, and attraction to certain tactile stimuli (American Psychiatric Association, 2013; Baranek et al., 2006; Rogers et al., 2003). Abnormal sensory reactions have been reported to occur in up to 47 % of persons with ASD, which is a rate ten times higher than reported in the general population (Nicholas et al., 2008). Additionally, there is a significant correlation between sensory issues in each of the individual senses (Kern et al., 2007); therefore, impairment is compounded for persons with ASD and sensory abnormalities.
Cross-sectional studies found no observed differences between males and females in sensitivity to sound (Mandy et al., 2012) or sensory sensitivity in general (Louisa et al., 2012; Mayes and Calhoun, 2011; Baranek et al., 2006). Mandy et al. (2012) examined RRBI in children and adolescents 3 to 18 years of age and found that age did not influence the presentation of RRBI. However, Lai et al. (2011) found that adult females with high functioning autism had more lifetime sensory issues than males with ASD. Overall, the majority of articles reviewed that addressed sensory issues in ASD do not suggest a sex difference, although aging may be a factor and should be further explored.
Developmental Domain: other Developmental Endophenotypes
Attention Deficit Hyperactivity Disorder
Attention deficit hyperactivity disorder (ADHD) and corresponding symptoms are common in children with ASD (Bradley and Isaacs, 2006; Nicholas et al., 2008). Previous studies show that 50 % to 83 % of children and teenagers with ASD had hyperactivity and attention problems (Nicholas et al., 2008; Bradley and Isaacs, 2006). There were seven articles that met search criteria and addressed ADHD. These seven articles were published between 2008 and 2012 with five cross-sectional studies and two cohort studies. Two studies were conducted in the United States and five were conducted in other countries.
A study of 7 to 12 year-olds with varying cognitive abilities found that males with ASD had higher levels of hyperactivity and impulsivity than females with ASD and this difference was more pronounced at younger ages (May et al., 2012). Males with high functioning autism from middle childhood to adolescence had higher levels of hyper-activity and inattention in teacher reports as compared to female peers, but there was no difference in parental reports (Mandy et al., 2012). A study of children and young adults aged 5 to 20 with high functioning autism found females had more attention problems (Bryson et al., 2008). A majority of studies found no difference in ADHD co-occurrence between males and females with ASD (Simonoff et al., 2008; Sinzig et al., 2009; Mayes and Calhoun, 2011; Horovitz et al., 2011). In summary, the current literature leans toward no sex differences in the co-occurrence of ADHD and ASD, but there is still inconsistency in the literature and thus, the sex difference is largely inconclusive
Challenging Behavior (Aggressiveness/Temper Tantrums/Oppositional Tendencies)
Challenging behavior is a common associated feature of ASD and includes aggression expressed toward other people, temper tantrums, and oppositional and defiant tendencies. Aggression expressed toward other people and temper tantrums are found in 50 % and 54 % of children with ASD compared to only 28 % and 23 % of children without ASD (Nicholas et al., 2008). The 12 articles in this review that met search criteria and addressed challenging behaviors were published between 2005 and 2012 and included six cross-sectional studies, four case–control studies, one clinical trial, and one surveillance study. Six studies were conducted in the United States and six were conducted in other countries. In general, there were no differences in aggression, temper tantrums, or anger between child sexes, regardless of age or cognitive ability (Kozlowski et al., 2012; Worley and Matson, 2011; Carter et al., 2007; Murphy et al., 2009; Mandy et al., 2012; Quek et al., 2012; Mayes and Calhoun, 2011; Horovitz et al., 2011). One study found that females with ASD had more “challenging behaviors” than males with ASD, although challenging behaviors were not explicitly defined (Dworzynski et al., 2012). Delinquent behavior (Park et al., 2012b) and oppositional defiance (Gadow et al., 2005) were more prevalent in males than in females with ASD in two studies reviewed.
Cognitive Skills and Intellectual Disability
In a review from 1966 to 2001, Fombonne (2003) found that the median prevalence of intellectual impairment in persons with ASD was 70 % in the studies evaluated. More recent population-based studies have found lower rates of ID in persons with ASD, with a range from 18 % to 55 % (Charman et al., 2011). The National Health Interview Study found 0.71 % of all children aged 3 to 17 from 1998 to 2007 had an ID (Boyle et al., 2011). Our review found 12 articles that met the search criteria and addressed ID or specific cognitive skills. These 12 articles were published between 1983 and 2011, and included seven cross-sectional studies, four case–control studies, and one-surveillance study. Four studies were conducted in the United States and eight were conducted in other countries.
The 12 articles reviewed support a relationship between child sex and co-occurring ID in children with ASD. The sex ratio between males and females without ID is greater than the sex ratio for all levels of cognitive ability combined (Nicholas et al., 2008; Hartley and Sikora, 2009). Consequently, the male to female ratio is lower when there is co-occurring ID compared to when there is no co-occurring ID (Hartley and Sikora, 2009; Nicholas et al., 2008; Yeargin-Allsopp et al., 2003). The ratio of males to females with ASD and co-occurring ID has been seen to range from 1.3:1 (Tsai and Beisler, 1983) to 2.8:1 (Bryson et al., 2008) with a trend toward fewer sex differences as ID becomes more severe (Yeargin-Allsopp et al., 2003). This differential sex difference in ID results in females with ASD, on average, having lower intelligence test scores than males with ASD (Banach et al., 2009; Volkmar et al., 1993).
Specific cognitive skills posited to vary between males and females with ASD include cognitive flexibility, response inhibition, working memory, and attention to detail (Geurts et al., 2004). Female adolescents with high functioning autism were seen to have superior information processing, multiple conceptual tracking, divided attention, and cognitive flexibility compared to male adolescents with high functioning autism (Bolte et al., 2011). In contrast, studies show males with ASD have superior attention to detail, visuo-spatial skills (Auyeung et al., 2009), and inhibitory control (Lemon et al., 2011) compared to females with ASD. There were no sex differences between adults with ASD in the “eyes test” which measures ability to infer mental states through the eyes (Lai et al., 2011). In summary, the 12 journal articles reviewed in this section suggest that females with ASD generally have lower intelligence test scores than males with ASD and that specific cognitive skills may vary by sex.
Developmental Regression
Parents of some children with ASD report a period of typical development followed by a loss in language, social, motor, self-help, imaginative play, or other skills. This developmental regression is usually reported to occur between 15 and 24 months of age (Meilleur and Fombonne, 2009). Our review found six articles that met search criteria and addressed developmental regression. These six articles were published between 2007 and 2013 and comprised two cohort studies, three cross-sectional studies, and one surveillance study. In a population-based surveillance study of children with ASD, 17 % of children had documented developmental regression and that percentage rose if the child had a previous ASD diagnosis (Wiggins et al., 2009). Males had significantly more regression than females and were more likely to regress at a younger age (Wiggins et al., 2009). This higher risk of regression in males was also seen in smaller, non-population based studies (n=4, 8, and 17 female children) (Bernabei et al., 2007; Ekinci et al., 2012; Zhang et al., 2012). In contrast, a cross-sectional study found that females aged 18 months to 15 years had significantly higher occurrence of regression as compared to males (30 % vs. 19 %) (Ben-Itzchak et al., 2013). No difference in the presence of developmental regression between males and females with ASD was observed in a small clinical sample of 20 females (Meilleur and Fombonne, 2009). In sum, the review of sex differences of developmental regression is contradictory and thus inconclusive.
Excess/Absence of Fear
Excess or absence of fear is more common in children with ASD than other children (Evans et al. 2005; Nicholas et al., 2008). In a population-based surveillance of eight-year olds, Nicholas et al. (2008) found that 32 % of children with ASD had atypical fear noted in service records compared to 6 % of children with ASD symptoms but no ASD diagnosis. Three articles met search criteria and addressed excess or absence of fear. All three of these articles were published in the United States between 1990 and 2011 and were two cross-sectional studies and one case–control study. In these studies, females with ASD had more specific phobias than males with ASD (Gadow and DeVincent, 2012; Matson and Love, 1990) and more unusual fears (Mayes et al., 2013). One study conducted by Matson and Love (1990) found more fear in typically developing female children compared to male children and no significant difference in fear between typically developing female children and female children with ASD. Given the sparse amount of research on this topic, further exploration is warranted to understand sex differences in fear among persons with ASD.
Safety Issues (Self-Injury/Elopement)
About 50 % of children with ASD engage in self-injurious behavior (Richards et al., 2012; Baghdadli et al., 2003; Duerden et al., 2012). Four studies met search criteria and three pertained to self-injurious behavior. All three of these studies were cross-sectional designs with two being conducted in Europe and one in the United States. No difference in self-injurious behavior was found between males and females with ASD (Richards et al., 2012; Baghdadli et al., 2003; Duerden et al., 2012).
Elopement, also known as wandering off, is a rising concern among parents of children with ASD. One online survey addressing elopement met our search criteria. This survey was conducted in the United States in 2013 and found that 49 % of parents reported that their child with an ASD wandered off at least once after the age of four years (Anderson et al., 2012). Results also found that sex did not influence the prevalence of elopement, although children with more intellectual impairment were more likely to elope (Anderson et al., 2012). Few conclusions can be drawn since there is little research on elopement and other safety issues in children with ASD and associated sex differences.
Psychiatric Domain
Anxiety/Mood Disorders
Symptoms of anxiety and mood disorders are more prevalent in children with ASD than in typically developing children (Worley and Matson, 2011; Nicholas et al., 2008). Among children who met a surveillance definition for an ASD, 55 % had abnormal mood or affect compared to 26 % of children with at least one symptom of an ASD but no ASD diagnosis (Schendel et al., 2009). The Special Needs Autism Project in the UK found 44 cases of emotional disorder per 100 children with ASD (Simonoff et al., 2008). Moreover, among eight-year-old children who met a surveillance definition for an ASD, 3 % had anxiety, 2 % had emotional disorder, 2 % had mood disorder, and less than 2 % had obsessive-compulsive disorder (OCD), depression, bipolar, or oppositional defiant disorder (Levy et al., 2010). Nine studies were found that met search criteria and addressed anxiety or mood disorders. These nine studies were published between 2005 and 2012 and included five cross-sectional studies and four case–control studies. Four of the studies were conducted in the United States and five were conducted in other countries.
The literature on sex differences in co-occurring anxiety or mood disorders and ASD is mixed and dependent on cognitive abilities. In some studies, females with high functioning autism were at greater risk for internalizing psychopathology than both male children with ASD and typically developing female children (Solomon et al., 2012; Mandy et al., 2012). These studies are supported by a Finnish report that found female children with ASD had lower scores on a test associated with major depressive disorder compared to male children with ASD (Mattila et al., 2010). Other studies found no sex differences in the of co-occurrence of anxiety or depression in children with ASD and varying cognitive abilities (Quek et al., 2012; Gadow et al., 2005; Park et al., 2012b; Simonoff et al., 2008; Mayes and Calhoun, 2011; Lai et al., 2011). In the general population, females have more panic attacks, generalized anxiety disorders and males have more social anxiety (American Psychiatric Association, 2013). Based on this review, the current literature is inconclusive on whether a sex difference in children with ASD and co-occurring anxiety or mood disorders exists, although a few studies suggest more anxiety and mood disorders in females than males with ASD.
Schizophrenia
Schizophrenia is a mental disorder that involves delusions, disorganized behavior, disorganized speech, hallucinations, and restrictions in the range and intensity of emotions (American Psychiatric Association, 2013). Schizophrenia typically presents between 18 and 30 years of age with earlier onset associated with male sex. Lifetime prevalence of schizophrenia is near 0.2 % (American Psychiatric Association, 2013) The prevalence of schizophrenia in eight-year olds with ASD is less than 1 % (Levy et al., 2010). Two articles met search criteria and addressed schizophrenia. These two articles were published in 2005 and 2010 and were both case–control studies. Review of the two studies found conflicting results on sex differences and the co-occurrence of ASD and schizophrenia or schizophrenia spectrum traits. A parental survey of 6 to 12 year olds with ASD found schizophrenia spectrum traits to be twice as prevalent in females compared to males (57 %: 28 %) independent of ID (Gadow and DeVincent, 2012). Conversely, in a group of 6 to 12 year olds with ASD and ID, schizophrenia was more common in males than females (Tsakanikos et al., 2011). Again, the literature is relatively sparse due to the late onset of schizophrenia and the rarity of co-occurring schizophrenia: future research is warranted.
Medical Domain
Birth defects/Chromosomal Disorders /Genetic Disorders
Population-based surveillance data from the 2008 ADDM report found that among children with ASD, less than 1 % had a co-occurrence of fragile X syndrome, Down syndrome, chromosomal disorders, or other genetic and congenital diagnoses (Levy et al., 2010). It is likely that these rates are under-reported because investigation of ASD co-occurring conditions was not the focus of the ADDM surveillance effort. However, a cohort study of children in Georgia found a similar prevalence of chromosomal disorders and Down syndrome in persons with ASD (Schendel et al., 2009).
There were four studies reviewed that met search criteria and addressed ASD sex differences in birth defects, chromosomal disorders, and genetic disorders: two systematic reviews, one case–control study, and one surveillance study. Co-occurring birth defects, such as impairments to the central nervous system, cardiovascular system, genitourinary system, or musculoskeletal system, appear more often in males than females with ASD. Among children with ASD, the male to female ratio was 9:1 if a child had a co-occurring birth defect and 3.6:1 if the child did not have a co-occurring birth defect (Schendel et al., 2009).
A review conducted by Reilly (2009) found that males with ASD have more co-occurring Down syndrome than females with ASD and the male to female ratio among children with both ASD and Down syndrome may be near the overall ASD prevalence ratio of 4:1. A review conducted by Wiznitzer (2004) found no difference between males and females with ASD and the co-occurrence of tuberous sclerosis. Clifford et al. (2007) found that about 70 % of males aged 5 to 80 with fragile X syndrome had co-occurring ASD while 23 % of females in the same age range with fragile X had co-occurring ASD. The difference in co-occurrence of ASD between males and females may suggest a greater association between the two conditions in males as compared to females.
It is important to note that birth defects, chromosomal disorders, and genetic disorders are rare and seldom studied. Therefore, the results on sex differences for co-occurring ASD and chromosomal and genetic conditions are inconclusive.
Head Size / Encephalopathy
Head size, specifically an enlarged head circumference or macrocephaly, has been associated with ASD (Wallace and Treffert, 2004). Three articles were reviewed that examined differences in head size between males and females with ASD. Studies include two case–control studies and one cross-sectional study. Two studies were conducted in the US and one study was conducted in Italy. A cross-sectional study by Fombonne et al. (1999) found no difference in head size between males and females aged 2 to 16 with ASD. Sacco et al. (2007) also found no difference in head size between males and females aged 3 to 16 with ASD. In contrast, Aylward et al. (2002) found larger head sizes in male adults and children compared to female adults and children with ASD, but the female sample size was low (n=9).
Abnormal Eating and Gastrointestinal Issues
In a population-based study conducted by Nicholas et al. (2008), about 54 % of children with ASD had an abnormality in eating, drinking, or sleeping, which is nearly 40 % higher than that of children with at least one symptom of ASD but no diagnosis (Nicholas et al., 2008). Some studies have shown an increase in certain gastrointestinal symptoms among persons with ASD, including constipation (Ibrahim et al., 2009) and diarrhea (Wang et al., 2006), while other studies found no significant increase in overall gastrointestinal symptoms or symptoms such as esophageal reflux, vomiting, and abdominal discomfort (Ibrahim et al., 2009; Wang et al., 2006; Valicenti-McDermott et al., 2007). However, little research on gastrointestinal issues has been conducted at a population level and no studies were found that compared males to females on gastrointestinal response. More research is needed to determine if there is an association between gastrointestinal symptoms and ASD and whether the association differs between the sexes.
Four studies were found that compared the sexes and addressed food selectivity. These four studies were conducted in the United States between 2006 and 2010 and included one case–control and three cross-sectional designs. In general, review of these studies found food selectivity and feeding issues to be more frequent in children with ASD than children without ASD (Valicenti-McDermott et al., 2007; Ibrahim et al., 2009), although limited research is available in this area. There was no difference between child sexes in over or under-eating in a study of children with high functioning autism (Worley and Matson, 2011) and no differences between the sexes in eating abnormalities in two studies conducted in children with ASD and varying cognitive abilities (Mayes and Calhoun, 2011; Horovitz et al., 2011). Based on this limited review, it appears unlikely that there is a difference in eating habits between males and females with ASD.
Seizures/ Epilepsy
Epilepsy and other seizure disorders co-occur in 5 % to 40 % of children with ASD and there is differential prevalence based on ID (Baird et al., 2008; Nicholas et al., 2008). This review found three articles that met search criteria and addressed seizures or epilepsy. These three articles were published between 2008 and 2013 and consist of a cohort study, one cross-sectional study, and one meta-analysis. Females with ASD were found to have more epilepsy than males with ASD; the male to female ratio drops to near 2:1 in children with ASD and co-occurring epilepsy, but this may be partly due to differential ID (Amiet et al., 2008; Bolton et al., 2011; Ben-Itzchak et al., 2013). There may be an increased likeliness in females with ASD to have co-occurring epilepsy or seizure disorder; however, the literature is sparse so a conclusion cannot be drawn. Further research is needed to enhance current knowledge of sex differences in children with ASD and epilepsy or seizure disorder.
Sleep Disturbances
In a systematic review of parental sleep surveys, sleep problems were present in 50 % to 80 % of children with ASD compared to 9 % to 50 % in matched typically developing children (Kotagal and Broomall, 2012). There were six articles reviewed that met search criteria and addressed sleep disturbances. These six articles were published between 2004 and 2012 and included two case–control studies, two cohort studies, and two cross-sectional studies. Four were conducted in the United States and three were conducted in other countries. Based on this review, some studies found no sex differences in sleep problems among persons with ASD (Liu et al., 2006; Wiggs and Stores, 2004; Mayes and Calhoun, 2011; Horovitz et al., 2011), one study found that female children with ASD have less sleep problems than male children with ASD (Sivertsen et al., 2012), and one study found female children with ASD have more sleep problems than male children with ASD (Hartley and Sikora, 2009). The minimal amount of research in this area leads to inconsistent results and prevents definitive conclusions on whether a sex difference exists in sleep disturbance.
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