Relevance: Autism, or more correctly Autism Spectrum Disorder (ASD) is a growing problem in developed as well as developing countries. Its etiology has not been clearly delineated although genetic factors and environmental exposures in early life have been implicated. Although there is supporting evidence for both streams of thought, conclusive proof is lacking.

Critical appraisal: This was a carefully planned and well-executed study. Although a research question was not articulated, one can be derived as follows: Does high(er) exposure to PM2.5, nitric oxide, and nitrogen dioxide during pregnancy (E=Exposure), compared to low(er) exposure (C=Comparison) result in ASD (O=Outcome) among offspring born to these mothers (P=Population)? Although it can be argued that a comparative prospective cohort study is superior to address the question, financial and logistic considerations make a case-control design an attractive option.

The population base for this study was clearly defined in terms of geographic location as well as timeframe. Almost the entire birth cohort over a five-year period was eligible. Multiple databases were scoured to complete the list of eligible pregnancies delivered in institutions as well as at home. These databases enabled identification of gestational age, birth weight, postnatal morbidities, residence and socio-economic status.

Cases were identified using the diagnostic criteria for ASD prevalent in the region. These were based on two standardized instruments used by all clinicians in the region; thus, inter-observer practice variations were eliminated. However, the relationship of these to the current ‘Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition’ (DSM-5) criteria is unclear.

As the control group comprised of the entire birth cohort minus cases, issues such as selection bias, representativeness, matching, confounding and temporal variations in exposure were all neatly eliminated. The investigators chose covariates judiciously, including gender, birth month and year, maternal age, maternal country of origin, and socio-economic status.

Meticulous attention was paid to ascertainment of exposure to the three pollutants with quantification of exposure. This was done by using previously validated methods to obtain air quality data throughout the selected area within units as small as 10 square meters. Thus, the quantity of pollutants at the precise address of each pregnant woman could be determined with considerable accuracy. This facilitated calculation of exposure on a monthly basis, trimester basis and throughout pregnancy. However, the data were shown only for the model representing the entire duration of pregnancy.

Despite considerable effort to minimize bias in this study, some issues deserve attention. For example, it appears that outcome was not ascertained at the age of five years in all children. In fact, the median age for outcome measurement was 4.2 years. The reason(s) for this have not been clarified. It is also unclear whether the median age differed among cases and controls. Since the detection of ASD was through an apparently reactive mechanism (i.e. those with suggestive symptoms underwent detailed examination for a diagnosis), rather than a proactive system (i.e. universal screening of all children at an early age), it is possible that some cases could have been missed either because they were not brought to the notice of clinicians, or their symptoms were mild(er) enough to be missed at the age of outcome ascertainment.

One interesting finding (in this study) that has not been explored is the higher prevalence of ASD observed among children of mothers born in the Philippines and Vietnam, but lower prevalence when mothers were born in India or Hong Kong. The proportion of children with ASD was comparable to the general population among mothers born in China. These are intriguing observations because ASD prevalence is reported to be higher among immigrant families, although (to be fair) maternal birth place does not indicate the timing of immigration.

Can we conclude a causal relationship between air pollutants and development of ASD from this study? Although some of the Bradford-Hill criteria [7] are fulfilled viz Theoretical plausibility, Coherence (to some extent), Dose response relationship (partially), most of the criteria are not met. For example, the ‘Strength of association’ is weak at best, and that too for only one pollutant. The criterion of Temporality can be presumed to be fulfilled since exposure during pregnancy precedes the outcome (ASD). However, exposure ascertainment was done in a retrospective manner. Further, the study did not consider the impact of ongoing postnatal exposure to air pollutants on the development of ASD. Overall, there is limited consistency in the available data for assigning a causal role to air pollution exposure in pregnancy and the development of ASD in the offspring. Some of the inconsistencies have been described already.

Perhaps the most serious threat to causality is with the criterion ‘Specificity in the causes.’ Like most complex disease conditions, ASD also probably results from a complex interplay of both genetic (nature) and environmental (nurture) factors, rather than either alone. Thus any potential ‘cause’ of ASD should be able to explain the well-known variations in incidence/prevalence. For example, if air pollution during pregnancy is a ‘cause’ of ASD, there should be an explanation for the wide variation in prevalence between boys and girls, as well as higher incidence in some families.

Could air pollution have gender-specific effects? A recent systematic review exploring whether environmental toxins could have a gender-specific effect reported that exposure to thimerosal, some organochlorine pesticides, and even environmental pollution were associated with greater neurotoxicity among boys than girls with similar exposure [8]. Less consistent but significant effect on boys were observed with exposure to organophosphorus pesticides, and polychlorinated biphenyls. Another recent review suggested that the link between nature and nurture in development of ASD could be through epigenetic modifications [9]. Likewise, a systematic review exami-ning potential genetic susceptibility to environmental toxins reported that 8 of 10 included studies identified several polymorphisms to be far more common in those with ASD than unaffected individuals [1].

It is well recognized that children belonging to immigrant families/communities have a higher risk of developing ASD than those born to native mothers [10]. This study [6] also showed some variations on the basis of maternal ethnicity. However, there was no consistency in terms of the country of origin of the mothers (as explained previously).

Conclusion: This well conducted case control study showed a weak association between maternal exposure to nitric oxide (air pollution) during pregnancy and the subsequent identification of ASD in their offspring. However, the study does not contribute to building a cause-and-effect hypothesis between pollution and ASD.

Funding: None; Competing interests: None stated.

Joseph L Mathew

Department of Pediatrics,
PGIMER, Chandigarh, India.
Email: [email protected]

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2. Lam J, Sutton P, Kalkbrenner A, Windham G, Halladay A, Koustas E, et al. A systematic review and meta-analysis of multiple airborne pollutants and autism spectrum disorder. PLoS One. 2016;11:e0161851.

3. Flores-Pajot MC, Ofner M, Do MT, Lavigne E, Villeneuve PJ. Childhood autism spectrum disorders and exposure to nitrogen dioxide, and particulate matter air pollution: A review and meta-analysis. Environ Res. 2016;151:763-76.

4. Jeddi MZ, Janani L, Memari AH, Akhondzadeh S, Yunesian M. The role of phthalate esters in autism development: A systematic review. Environ Res. 2016; 151:493-504.

5. Cimino AM, Boyles AL, Thayer KA, Perry MJ. Effects of neonicotinoid pesticide exposure on human health: a systematic review. Environ Health Perspect. 2017;125:155-62.

6. Pagalan L, Bickford C, Weikum W, Lanphear B, Brauer M, Lanphear N, et al. Association of prenatal exposure to air pollution with autism spectrum disorder. JAMA Pediatr 2018 Nov 19. doi:10.1001/jamapediatrics.2018.3101. [Epub ahead of print].

7. No authors listed. The Bradford Hill Criteria. Available from: http://www.southalabama.edu/coe/bset/johnson/bonus/Ch11/Causality%20criteria.pdf. Accessed December 10, 2018.

8. Kern JK, Geier DA, Homme KG, King PG, Bjørklund G, Chirumbolo S, et al. Developmental neurotoxicants and the vulnerable male brain: a systematic review of suspected neurotoxicants that disproportionally affect males. Acta Neurobiol Exp (Wars). 2017;77:269-96.

9. Hamza M, Halayem S, Mrad R, Bourgou S, Charfi F, Belhadj A. Epigenetics’ implication in autism spectrum disorders: A review. Encephale. 2017;43:374-81 [Article in French].

10. Crafa D, Warfa N. Maternal migration and autism risk: systematic analysis. Int Rev Psychiatry. 2015;27:64-71.

Effect of air pollution on human health is the most complex yet important aspect of public health, and the spectrum of diseases that list air pollution as one of the key risk factors is ever expanding. In case of congenital and acquired neurological and neuropsychiatric disorders, role of air pollution is being studied with interest. Strong evidence of association with preeclampsia, abortions, and preterm birth, low birth weight and intrauterine growth retardation exists in literature [1-6]. Similarly, studies point at air pollution being a risk factor for Attention Deficit Hyperactivity Disorder (ADHD) [7].

Funding: None; Competing interests: None stated.

Arun Sharma

Department of Community Medicine,
University College of Medical Sciences, Delhi, India.
Email: [email protected] 

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