A national birth cohort study of prenatal factors and neurodevelopmental psychiatric disorders

In this re-submitted application, we seek to evaluate maternal biomarkers of oxidative stress in relation to
schizophrenia (SZ) and autism spectrum disorders (ASD) in offspring, their relationships with one another, and
with other environmental exposures during development. The proposal is based on the Finnish Prenatal
Studies of Schizophrenia (FiPS-S), and Autism (FiPS-A), the largest seroepidemiologic studies of prenatal
exposures in these disorders to date, and the first to utilize a national birth cohort. This nested case-control
study draws on the Finnish Maternity Cohort (FMC), which consists of virtually all pregnancies in Finland from
1987-2017; the total sample size is approximately 1 million. Maternal prenatal serum samples were obtained
and archived from each gravida, and the Finnish psychiatric registries contain validated diagnoses of SZ and
ASD on virtually all hospitalized and non-hospitalized cases in Finland. We have identified large samples of
SZ and ASD case and control offspring and demonstrated relationships between several prenatal biomarkers
and these disorders in this cohort. Although maternal oxidative stress causes abnormal fetal development, is
associated with developmental insults, and leads to brain and behavioral abnormalities concordant with SZ and
ASD, no previous study has ever examined relationships between this prenatal factor and psychiatric
diagnostic outcomes in offspring. We aim to address the role of maternal exposure to oxidative stress and
these disorders by assays of maternal serum specimens in pregnancies from large samples of case and
matched control offspring. We will test the hypothesis that maternal biomarkers of the antioxidant defense
system are negatively associated with SZ and ASD in offspring and a pro-oxidant biomarker is positively
associated with these outcomes. We will also evaluate whether correlations observed between these maternal
biomarkers in control offspring are disrupted in SZ and ASD offspring. Moreover, we shall assess whether sex
and perinatal complications modify relationships between maternal oxidative stress biomarkers and SZ/ASD.
For this purpose, maternal serum samples from SZ and ASD cases and matched controls will be analyzed for
biomarkers of oxidative stress. This research has the potential to result in a better understanding of prenatal
risk factors for SZ and ASD. Since oxidative stress is a common pathogenic mechanism that is caused by
several types of environmental insults which have been implicated in these disorders, the study offers the
potential for their prevention by reducing these exposures and may suggest new pathogenic mechanisms in
future translational studies. In summary, the proposed work builds on an existing national birth cohort, and is
anticipated to impact an emerging and potentially transformative area of research epidemiology and
clinical/basic neuroscience, leading to improvements in public health policy.

Grant Number: 5R01ES030966-05
NIH Institute/Center: NIH
Principal Investigator: Alan Brown