Background: The proposed study aims to test specific hypotheses on relationships between prenatal environmental risk factors and other developmental indicators of vulnerability for autism spectrum disorders (ASD). ASD represent complex developmental syndromes of the central nervous system and most likely result from multiple etiologies with genetic and environmental contributions. The study capitalizes on archived serum biospecimens in a large sample of cases from a national birth cohort in Finland and national registries containing diagnoses of ASD (Total N > 5,000 cases) in the Finnish Prenatal Study of Autism (FiPS-A) and matched controls. The FiPS-A is based on the Finnish Maternity Cohort (FMC), the largest prenatal serum biobank in the world consisting of virtually all pregnancies in Finland from 1987-2005 (N=1.5 million). Maternal serum samples were obtained from each gravida during pregnancy and are archived in one freezer at a single site, and the Finnish psychiatric registries contain diagnoses of ASD on virtually all cases in the country. We have conducted several studies of prenatal biomarkers in these stored serum samples, demonstrating, among other findings, intriguing associations between autism and prenatal inflammation, thyroid autoantibody, and cotinine. Discovering environmental factors that contribute to ASD is supported by increasing prevalence estimates and epidemiologic studies suggesting pre-/perinatal antecedents such as maternal infections, autoantibodies, smoking, and other factors.In spite of these intriguing findings, no study has related prenatal environmental factors and postnatal developmental trajectories within a single study to ASD. This has created, in our view, a critical barrier to progress in the field. Moreover, in spite of important genetic contributions to ASD, few studies have investigated interactions between familial psychiatric history and environmental factors in ASD. Several intriguing studies including a recent study from our group demonstrated accelerated growth of head circumference (HC) measures in early childhood and delayed developmental milestones in ASD.Hypothesis/Objective: We aim to test the overarching hypothesis that prenatal exposure to specific inflammatory, hormonal, and toxic exposures will be related to postnatal developmental abnormalities, including accelerated growth of HC and delayed developmental milestones, which are in turn associated with autism. We shall also test whether family history of psychiatric disorders and developmental anomalies will interact with the prenatal exposures to increase risk of autism.Specific Aims: We will test the following: (1) Prenatal exposures, namely serologically documented elevated maternal levels of C-reactive protein, thyroid autoantibody, and cotinine (a reliable metabolite of nicotine), will be related to (a) accelerated infant head circumference growth and (b) delayed developmental milestones. (2) Accelerated infant head circumference growth and delayed developmental milestones mediate and/or modify relationships between these exposures and childhood autism. (3) Accelerated head circumference growth will be related to delayed developmental milestones including early signs of comorbid intellectual dysfunction in childhood autism. (4) Family history of psychiatric disorders interacts with prenatal exposures to increase risk of autism.Study Design: The study is based on a nested case-control design in the FiPS-A. Cases of childhood autism born from 1987-2005, and family history of psychiatric disorder, were ascertained by national registry linkages. All diagnosed cases in Finland over the birth years, and controls without ASD, derived from the same national birth cohort, were matched 1:1 on date of birth, sex, birthplace, and residence in Finland. Maternal serum specimens were assayed for C-reactive protein, thyroid peroxidase antibody, and cotinine and analyzed in relation to risk of ASD. Longitudinal HC and developmental milestone data were collected in cases and controls, and growth velocity of HC was analyzed in relation to ASD. We will utilize appropriate statistical approaches, including latent class analysis and longitudinal data analysis, to evaluate the relationship between developmental milestones and autism and test for mediating and modifying relationships between the prenatal exposures, growth velocity of HC during infancy, postnatal developmental milestone measures, and family history of psychiatric disorders.Impact: The study meets critical research needs that relate directly to specific strategies for prevention of environmental insults and the identification of pathogenic mechanisms in ASD, with significant public health impact. This work also offers the promise of facilitating translational research to better understand how these exposures might alter fetal brain development and increase ASD risk. Maternal infections, inflammatory insults, and smoking occur commonly during pregnancy and are modifiable with public health approaches. These studies also offer the promise of identifying pathogenic developmental pathways by which these exposures alter fetal brain development and to target infants at risk. These findings are anticipated to have considerable impact on an emerging and potentially transformative area of research epidemiology and clinical/basic neuroscience, as well as lead to improvements in current public health policy recommendations for care during pregnancy that will prevent cases of ASD.Innovation: The novelty of the study arises from a unique combination of methodologic advantages: (1) validated prospective biomarkers of prenatal environmental factors from archived maternal sera; (2) nationwide, population-based sample of children, and comprehensive national registry information on autism diagnoses from both inpatient and outpatient sources; (3) longitudinal growth velocity data on HC from extensive record abstractions and a powerful statistical approach; (4) extensive data on developmental milestones; (5) controls who represent the source population of the cases; and (6) a large sample (650 cases of ASD and 650 matched controls).
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
