Perinatal risk factors for mental disorders in the offspring and in their mothers

Abstract: Mental disorders are common in the population, but their etiology remains largely unknown. Early-life factors have been hypothesized to be potential risk factors; however, current evidence is conflicting and incomplete. This thesis aimed to evaluate cesarean delivery and infections as early-life risk factors for mental disorders, as well as the impact of cesarean delivery on maternal suicidality. In Study I, we systematically synthesized the literature on the association between cesarean delivery and the risk of neurodevelopmental and psychiatric disorders in the offspring, and then quantified the extent of this association in a meta-analysis. Of the 6,953 identified articles, 61 studies comprising over 20 million deliveries were included and meta-analyzed using randomeffect models. We found that, compared to birth by vaginal delivery, cesarean delivery births were associated with significantly increased odds of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD). We found that the estimates were less precise for intellectual disabilities, obsessive-compulsive disorder (OCD), and eating disorders. No significant associations were observed for depression/affective psychoses or non-affective psychoses. Estimates were comparable for emergency and elective cesarean delivery. This study highlighted the need to explore potential mechanisms underlying the described associations and showed that current literature overall suffered from unmeasured confounding. Study II, which was prompted by Study I, further explored the association between cesarean delivery and the risk of neurodevelopmental and psychiatric disorders in the offspring using data from the Swedish national registers, while taking previously identified knowledge gaps into consideration. This population-based birth cohort study identified 1,179,341 individuals born between 1990 and 2003 and followed up through 2013. We found that, compared with vaginal delivery, cesarean delivery was associated with 10-30% increased risk of ADHD and intellectual disability, irrespective of cesarean delivery modality (i.e., planned or intrapartum). Planned cesarean delivery was associated with 10-20% higher risk of ASD, communication disorders, and learning disorders. Cesarean delivery was not associated with psychiatric disorders. However, when the analyses were repeated in clusters of relatives, where shared genetic and environmental factors were adjusted for, cesarean delivery was no longer associated with any outcome. Overall, the findings suggested that the association between cesarean delivery and neurodevelopmental disorders was likely not causal but could be explained by unmeasured familial factors. Study III estimated the incidence and the risk of suicide attempts and deaths during the first postpartum year in mothers who delivered via cesarean vs. vaginally. All deliveries in Sweden between 1973 and 2012 were identified (n=4,016,789). The mothers were followed since delivery for 12 months or until the date of one of the outcomes, death by other causes or emigration. During the 12-month follow-up, 504 (0.098%) suicide attempts were observed in the cesarean delivery group and 2,240 (0.064%) in the vaginal delivery group, while 11 (0.0037%) deaths by suicide were registered in the cesarean delivery group and 109 (0.0029%) in the vaginal delivery group. Compared to vaginal delivery, cesarean delivery was associated with a 46% increased risk of suicide attempts, but not of deaths by suicide. The subgroup analyses suggested that mothers’ country of birth likely modified the association between cesarean delivery and the risk of suicide attempts and deaths by suicide, which may have clinical implications. In summary, the findings indicated that postpartum maternal suicidal behaviors were uncommon in Sweden. Improved understanding of the association between cesarean delivery and maternal suicidal behaviors may promote more interventions to improve maternal mental health and further reduce suicidal risks. Study IV examined the association between prenatal and early childhood infections and the subsequent risk of OCD and tic disorders in a Swedish population-based cohort. The cohort identified 2,949,080 singletons born in Sweden between 1973 and 2003, and followed through 2013. The exposures were prenatal maternal (and paternal, as an internal control) infections and early childhood infections in the offspring (i.e., during the first three years of life). Results showed that, at the population level, and after adjusting for parental psychiatric history and autoimmunity, both prenatal maternal (but not paternal) and early childhood infections were associated with 19-33% increased risk of OCD and tic disorders. However, all associations fully attenuated to the null in the sibling models. Overall, the results do not support a causal association between prenatal maternal or early-life infections and the development of OCD or tic disorders. Instead, familial factors (e.g., genetic pleiotropy) may explain both the propensity to infections and the liability to OCD and tic disorders. Large scale genome-wide association studies are motivated to provide novel insights into genetic correlations between immunerelated phenotypes and OCD and tic disorders. Overall, this thesis expanded our knowledge on the role of two perinatal risk factors, cesarean delivery and early-life infections, in the development of child and maternal mental health outcomes. The thesis outlines a series of research and clinical implications, as well as directions for future studies.