While a diagnosis of Autism is generally formally made between the ages of 2 and 3 years ¹, recent published research (2008) using home video observations and parental interview have found anomalies in eye contact, smiling, sharing and interaction initiation on video as early as 12 months and reported by parents as early as 6 months.⁹

This has implications for age of surveillance screening and Australian researchers, including Professor Cheryl Dissanayake, developmental psychologist, who heads the newly established Olga Tennison Autism Research Centre at Latrobe University Melbourne (Australia), now believe that intense intervention should commence as soon as these children are detected. Research is suggesting that children detected early can make huge strides in improving connection, language and behaviour.^10,¹¹ This early detection is supported by the American Academy of Paediatrics.⁴ Care can be coordinated with paediatricians and a large, hopefully integrated, team of psychologists, occupational therapists, speech therapists, and teachers to provide intense therapy and care and achieve improved outcomes.

Intense behavioural, developmental, or structured teaching interventions applied at least 25 hours a week throughout the year can provide documented improvements in IQ, language, academic performance and behaviour. These should be commenced as early as possible for the best gains.

Medical issues should be attended to concurrently, including childhood illnesses, sleep dysfunction, challenging behaviours and psychiatric conditions that these children may suffer. Bowel dysfunction has been found to be more common in autistic children, although this needs further research due to a lack of controls in studies.⁴

Incidence/prevalence

The number of people with ASD has dramatically increased over the past decade, and problem behaviours in autism are an increasing challenge to families, schools, physicians and other health care professionals.^12,¹³

Researchers are not certain whether this increase is due to broader diagnostic criteria, better detection or a true increase.¹⁴ This is likely to be the result of more precise diagnosis, better service availability and improved awareness of autism.¹⁵ Many studies have confirmed this increased incidence, but have reported differences in incidence depending on the study. It has been reported at 6.7 per 10 000 for autism¹⁶ and 25 per 10 000 for ASD ¹⁷, but also as high as 13 per 10 000 for autism and 60–65 per 10 000 for ASD.¹⁸

US epidemiological data suggest that this increased rise in incidence is slowing in recent years.¹⁷ Prevalence in Australia is difficult to determine as there are inconsistencies in existing data. There is a need to improve data systems across the country.¹⁹

Autism rates were measured to be as low as 4–5 per 10 000 in WA and NSW in 2000.²⁰

Risk factors and causes of autism

Genetic susceptibility, health, nutritional status, and environmental exposures might all contribute to the causation of this complex of disorders.⁵ There is unprecedented pressure for autism researchers to find a cause. This is difficult because of the multitude of brain deficits and genetic variants, and no integrated theory has emerged. Research going forward should assume that autism is an aggregation of myriad independent disorders of impaired sociality, social cognition, communication, and motor and cognitive skills.²¹

Genetic predisposition

Multiple genes are involved in inheritance, which demonstrate great phenotypic variation. If 1 sibling already has an ASD, there is approximately a 5–6% risk of a subsequent sibling having the disorder, and this is higher still with subsequent children.²²

Monozygotic twin studies also show 60% concordance for Autism and 92% for ASD.⁵

Possible involved chromosomes are 2q, 7q, 16p and 19p, and cytogenetic abnormalities have also been found on chromosome 15 and in Fragile X Syndrome.¹

New groundbreaking research published in Nature in March 2009 as an association study of 2 large cohorts (n = 3100 and 1200) of affected children and 6500 controls, found a genome-wide significant association of variants on chromosome 5 for susceptibility for ASD.²³ Especially significant were genes coding for ‘neuronal cell adhesion molecules’, responsible for neuron to neuron communication. These abnormalities are especially seen in the areas of the brain that are structurally abnormal in autism and ASD: namely the frontal, temporal lobes and the amygdala (which is larger than normal in autistic children in the first 2 years of life). Crucially, this work was replicated in 2 other independent cohorts, and has implications for further research.

Genetic screening of at-risk newborns — that is, those with parents or siblings with the disorder — is an emerging science.

Medical causes

A specific medical cause is only found in 6–10% of cases. These include prenatal causes such as congenital rubella, untreated metabolic disorders, anticonvulsants during pregnancy, tuberous sclerosis and severe postnatal infections.¹

Epilepsy

Epilepsy may be associated with autistic regression and impaired mental functioning in childhood autism.²⁴ The incidence of seizures has been estimated to be between 11–39%, and is associated with severe global developmental delay, where the incidence is higher at 42%. With children with ASD and no mental retardation, the incidence is only 6–8%. There are 2 peaks, 1 in children less than 5 years of age, and another peak in adolescence. Electroencephalogram (EEG) abnormalities occur in 10–72% of affected children.²⁵

Immune malfunction

Immune dysfunction has been associated with autism, and further research in this area might be productive. Antenatal levels of fetal protein IgG were found in some mothers who carried children who went on to develop ASD.²⁶

While immune malfunction, deficiency and auto immunity also has some evidence to support causality, no theory is unified and complete.⁵

Nutritional deficiencies

Many nutrients play a role in behavioural and cognitive development. Deficiency of nutrients, such as iron, zinc, calcium, magnesium and iodine may impact on the child’s neurodevelopment and possibly increase the risk of ASD.

One study of 45 children found lower levels of blood and red cell zinc in autistic children compared with controls.²⁷ More research is required to test this hypothesis.

Environmental exposure to metals and chemicals

Research demonstrates biochemical abnormalities can occur in autism and include liver detoxification impairment via impaired sulfation pathways, mineral imbalances such as reduced zinc/excess copper,²⁸ environmental insults such as heavy metal and organochlorine pesticide exposure,^29,^{30, 31} and gastro intestinal disturbances which are theorised to lead to excessive intestinal permeability and excessive absorption of breakdown products of certain foods leading to opioids intoxicating the brain.

It is well recognised that some industrial chemicals such as lead, methylmercury, polychlorinated biphenyls (PCBs), arsenic and toluene are toxic to brain development and lead to impaired brain function. A further 200 chemicals are neurotoxic to adults, and many more are toxic to laboratory animals.³² More careful precautionary regulation is required to protect fetal brains from possible exposure causing damage at far lower levels than adults.

Lead, mercury and PCBs have proven effects in attention, memory, learning, social behaviour and IQ at only background-population levels.³³ Testing is usually lacking and not carried out for patients with neurodevelopmental problems.

Organochlorines and organophosphate exposure

Researchers in USA, California have identified a possible link between antenatal organochlorine pesticide exposure and increased risk of autism spectrum disorders.³⁴ The study compared all births in the area (over 200 000) and compared these with all cases of ASD (465). They found that children had a 6-fold increased risk of ASD if their mothers lived within 500m of a field sprayed with organochlorines. Limitations to the study were that only a small proportion of mothers living in proximity to spraying in the critical early gestational period of neural development were found to be associated with increased risk (29 mothers, of whom 8 of their children had ASD). The authors comment that more studies are needed to confirm this hypothesis.

A review in 2008 confirmed these findings, reporting on in-utero organochlorine and organophosphate exposure and impaired neurodevelopment.³⁵ It thus is logical to advise mothers to avoid exposure to these harmful substances if possible.

The incidence of ASD has been positively linked in the Pacific North West of the US to times of precipitation, implying possible fallout from airborne pollutants with rain.³⁶

Research centering on the San Francisco Bay (USA) area studied 284 children with ASD and 657 controls and hazardous air pollutant concentrations.³⁷ They found an increased association between autism and exposure to estimated airborne metal concentrations and possibly solvents, namely mercury, nickel, cadmium, trichloroethylene and vinyl chloride. They conclude that more refined exposure studies are required.

Mercury

Mercury is a heavy metal that has also been studied to identify any associations with ASD. A recent population study in Texas found that ASD incidence rises 2.6% per 1000lbs of industrial exposure release, and rises 3.7% with power plant emissions.³⁸ These risks reduced with increasing distance from exposure, reducing to 2% and 1.6% respectively at 10 miles.

A prospective blinded study evaluating 28 children with severe ASD demonstrated that they had higher mercury intoxication-associated urinary porphyrins compared with less severe sufferers, and decreased plasma levels of reduced glutathione, cysteine and sulfate.³⁹ They also had higher oxidised glutathione levels and there was an association with increased autism severity scores with these levels, and also the mercury associated porphyrins. The researchers implied from this that mercury intoxication is significantly associated with autistic symptoms, and that transsulfuration abnormalities observed indicate that this is associated with increased oxidative stress and decreased detoxification capacity.³⁹

A small study from Arizona, USA, measuring levels of mercury, lead, and zinc in baby teeth of children with ASD compared with normal controls, found that autistic children had significantly higher levels of mercury only.⁴⁰ They also had a higher use of oral antibiotics, which in rats inhibits excretion of mercury due to gut flora alteration. This is proposed as a possible mechanism for the higher mercury, and also for the increased incidence of chronic gastrointestinal problems in autistic children.

However, a case controlled study of 400 children compared with 410 controls that explored a possible association with risk of ASD and administration of anti-D globulin during pregnancy, which contains thimerosal, to Rh negative mothers. It showed no increased incidence.⁴¹

This lack of association was further confirmed in another US study conducted in Missouri.⁴²

Clearly, more research into the vexed issue of mercury exposure as a risk factor for autism is needed with larger trials of excellent standard and replicated results.

Environmental climate factors

Researchers in Louisiana have found that the prevalence of autism in offspring is related to exposure of mothers to severe hurricanes and electrical storms during middle and late gestation (p<0.001), complementing other research suggesting that antenatal events predispose children to having autism.⁴³

Sunshine

There is currently an enormous interest in vitamin D as an important area of health research. Vitamin D supplementation is postulated to potentially reduce the risk of all-cause mortality by up to 7%.⁴⁴

Research postulates that the apparent increase in autism is coincidental with widespread lowered vitamin D levels as a result of advice to avoid sun exposure to reduce risk of skin malignancies.⁴⁵ This hypothesis needs to be supported by solid research. However, animal studies demonstrate that severe vitamin D deficiency during gestation leads to protein dysregulation and abnormal neurodevelopment and similar anatomical changes found to that of autistic children. Children with rickets have autistic markers that disappear with supplementation. Calcitriol is also involved, reducing inflammatory cytokines in the brain, which are increased in autism disorders. Calcitriol responds more to testosterone than oestrogen, so potentially explaining the differences in incidence in males. Dark skinned people also have a higher incidence of autism, and autism-related disorders increase with distance from the equator. This theory and hypothesis is worthy of more research.

Researchers describe 2 cases of scurvy and vitamin D deficiency in children who also had cognitive disorders, highlighting the importance of adequate good quality nutrition and exercise, and dietary histories in at-risk children.⁴⁶

Maternal smoking

A single cross-sectional survey of 546 children and their mothers found that maternal smoking during pregnancy was associated with high fetal testosterone levels, and a low ratio of the length of the 2nd and 4th fingers, which is thought to be related to increased incidence of autism. The observation only held for boys.⁴⁷

Obviously more research is required to make any claims, but due to other known negative effects of maternal smoking, abstinence in pregnancy is strongly recommended.

Fetal testosterone and autism traits

Professor Baron-Cohen has undertaken much work in the area of high fetal testosterone levels being related to an increased incidence of autism later on. He presents recent research to support this linking high fetal amniotic testosterone levels with autistic traits as determined by written tests completed by mothers about their children (n = 74).⁴⁸

This supports earlier work identifying a link between high fetal testosterone and abnormal social development and the concept of an ‘extreme male brain’. Animal research studies have also identified an association.⁴⁹ More prospective work is required in this controversial area.

Pregnancy

A review of articles on epidemiological studies of pre- and perinatal risk factors for ASD demonstrated increased paternal ⁵⁰ and maternal age, maternal place of birth outside of Europe or North America, low birth weight, duration of gestation, and intra partum hypoxia were associated with ASD.⁵¹ Further prospective studies were recommended.

Danish researchers found that maternal age and ‘medicine’ use during pregnancy, but not birth interventions or fetal distress, was associated with an increased risk of autism in offspring. Low birth weight babies and congenital malformations were also positively associated.⁵²

Examination of obstetric data of mothers who have given birth to children with ASD found an association with a wide range of complications: threatened abortion, epidural anaesthesia use, induction of labour, precipitate labours of less than 1 hour, fetal distress, low Apgars of less than 6 at 1 minute and caesarean section were all positive risk factors.⁵³ Because there is no single causal association the conclusion is that underlying genetic factors interact with the environment.

Pregnancy and folic acid

A hypothesis put forward by researchers is that the increased incidence in autism is related to the supplementation of pregnant mothers with folic acid, due to the survival of fetuses who would otherwise miscarry, with a combination of polymorphism of 5-methylenetetrahydrofolate reductase and consequent high homocysteine levels.⁵⁸ They are now surviving in the presence of high folate levels but then after delivery are suffering neurodevelopmental disorders including autism, when the folate levels are not maintained, due to lack of methylation during this critical period. They suggest that detection of these polymorphisms as well as other methionine cycle enzymes would be helpful in detection of at risk infants.

Exercise

Two small studies have found that children with ASD are less active compared with their more ‘normal’ counterparts.⁵⁹ There was no consistency to their exercise pattern.⁶⁰

Table 7.1 provides a summary of the possible risk factors for autism.

Table 7.1 Possible risk factors for autism ^∗

Genetic susceptibility	Male gender
Medical causes	Congenital rubella (maternal) Untreated metabolic disorders (maternal) Anticonvulsants during pregnancy Tuberous sclerosis (maternal) Severe postnatal infections (maternal) Liver detoxification impairment Gastrointestinal disturbances (child) Immune deficiency; auto-immunity