The Causes of Autism

Who are the spectacular authors, what is the title of the study, and what year was it published?

Authors: Emilie Willoch Olstad, Hedvig Marie Egeland Nordeng, Geir Kjetil Sandve, Robert Lyle, and Kristina Gervin.

Title: Effects of prenatal exposure to (es)citalopram and maternal depression during pregnancy on DNA methylation and child neurodevelopment

Year: 2023

What is the study about?

This study focuses on examining the effects of prenatal antidepressant exposure and maternal depression on child neurodevelopmental outcomes and DNA methylation. The authors conducted a comprehensive investigation to explore the association between prenatal exposures, such as (es)citalopram and depression, and their potential influence on the developmental trajectories of children. The study emphasizes the significance of DNA methylation patterns at birth and highlights the importance of considering symptom heterogeneity and developmental course when assessing neurodevelopment. Furthermore, the authors emphasize the need for further research to validate these findings, integrate genetic data, and enhance causal inference through the utilization of machine learning approaches.

What previous research is there on this topic?

Research in pharmacoepidemiology suggests a potential link between prenatal antidepressant exposure and maternal depression during pregnancy, and an increased risk of abnormal neurodevelopmental outcomes in children (Man et al., 2018; Morales et al., 2018; Sujan et al., 2019). Prenatal exposure to antidepressants has been associated with epigenetic differences in cord blood, particularly in DNA methylation of cytosine-phosphate-guanine sites (CpGs) (Viuff et al., 2016; Olstad et al., 2021; Kallak et al., 2021).

However, inconsistent findings across studies may be attributed to small sample sizes, focus on candidate genes, broad exposure definitions, and a lack of depression control groups (Olstad et al., 2021). It is noteworthy that there is little overlap in differentially methylated CpGs identified in epigenome-wide association studies (EWASs) on prenatal antidepressant exposure and cord blood DNAm (Kallak et al., 2021; Cardenas et al., 2019; Schroeder et al., 2012; Gurnot et al., 2015; Non et al., 2014).

Studies examining the relationships between prenatal antidepressant exposure, DNAm in candidate genes, and central nervous system outcomes have yielded insignificant results (Oberlander et al., 2008; Gartstein et al., 2016; Galbally et al., 2020). More extensive EWASs focusing on long-term neurodevelopmental outcomes are warranted, as existing studies have primarily concentrated on limited candidate genes and short-term effects. Associations have also been observed between maternal mental health during pregnancy, DNAm differences in offspring, and CpGs relevant to child neurodevelopment (Ryan et al., 2017; Kallak et al., 2022).

It is essential to disentangle the effects of prenatal antidepressant exposure and untreated maternal depression on DNAm and altered neurodevelopment in offspring. Interestingly, certain neurodevelopmental outcomes, such as ADHD, exhibit phenotypic heterogeneity and diverse developmental courses (Cecil & Nigg, 2022). Prospective studies have indicated an association between DNAm measured at birth and different ADHD symptom trajectories (Walton et al., 2017; Neumann et al., 2020). However, the potential impact of prenatal environmental factors, including antidepressant exposure and maternal depression, on DNAm patterns associated with neurodevelopmental trajectories remains unknown.

CpGs

CpGs refer to cytosine-phosphate-guanine sites, which are areas of DNA in which a cytosine nucleotide is followed by a guanine nucleotide in the DNA sequence. CpGs can be epigenetically modified by methylation, which is the addition of a methyl group to the cytosine ring that can alter the gene’s expression without changing the DNA sequence. Changes in CpG methylation can influence neurodevelopmental outcomes and have been linked to various diseases. In the context of the paper, CpGs were analyzed to identify differentially methylated regions associated with prenatal exposure to antidepressant medication or maternal depression and child neurodevelopmental outcomes.

What methods were used in the study?

Participants

The participants in this study were mothers and their children who were part of the Norwegian Mother, Father and Child Cohort Study (MoBa), which is a population-based birth cohort study conducted by the Norwegian Institute of Public Health. The study focused on live, singleton births with cord blood samples available in the MoBa biobank, and women using certain medications were excluded from the analysis. Three groups of participants were specifically examined: those exposed prenatally to (es)citalopram, those exposed prenatally to maternal depression, and propensity score-selected controls who were unexposed to antidepressants and maternal depression.

Initially, the study had a sample size of 3276 participants. However, after excluding individuals based on specific criteria, the final number of participants included in the analysis was 958. This final group consisted of 306 individuals who were prenatally exposed to (es)citalopram, 308 individuals who were prenatally exposed to maternal depression, and 344 individuals who were selected as propensity score-matched controls and were unexposed to antidepressants and maternal depression.

Dependent Variables

Prenatal Exposure to (es)citalopram, maternal depression, DNA methylation, child neurodevelopmental outcomes through parent self-reports at various time periods assessed through the Child Behavior Checklist and the Ages and Stages Questionnaire.

What were the findings?

No significant differences were found in DNA methylation (DNAm) associated with prenatal (es)citalopram exposure or maternal depression.

The proportion of children with ADHD was significantly higher among those exposed to (es)citalopram during pregnancy compared to the controls. The same trend was seen with exposure to maternal depression, but it was not statistically significant.

The study found a significant effect of (es)citalopram exposure on neurodevelopmental outcomes, including ADHD symptoms at 1.5 and 5 years of age, when compared to children prenatally exposed to unmedicated maternal depression.

The research showed a significant effect of several DNA methylation sites on psychomotor skills at 3 years of age, relating to multiple genes important in neurogenesis, neuronal differentiation, early embryonic development, and cellular growth.

However, there were no significant interaction effects found between (es)citalopram exposure and DNAm on any of the neurodevelopmental outcomes.

The study observed variability in the developmental course of neurodevelopmental outcomes between children, highlighting the complexity and heterogeneity of these conditions.

No significant associations were found between cord blood DNAm at birth and later developmental trajectories of ADHD symptoms.

Differentially methylated DNA sites were found between distinct developmental trajectories of communication and psychomotor skills, which are associated with several genes involved in neurodevelopment and neurological conditions.

The study found that many of the significant DNA methylation findings in cord blood had weak correlations with the same locations in brain tissue, suggesting that these peripheral biomarkers might not strongly reflect brain DNA methylation.

What are the implications of the findings?

DNA methylation at birth may serve as potential predictive molecular markers of later abnormal neurodevelopmental outcomes in children prenatally exposed to (es)citalopram and depression.

The study highlights the importance of considering symptom heterogeneity and developmental course when assessing neurodevelopment in the context of prenatal exposure to antidepressants and maternal depression.

Further studies are needed to replicate the findings, assess the functional impact of DNA methylation on neuronal differentiation and developmental processes, integrate genetic data, and improve causal inference using machine learning approaches. These studies can provide a better understanding of the causal relationships and properties of observational studies using molecular data.

It is worth noting that autism diagnosis or assessments aimed at assessing autism were not included in this study. Nevertheless, the implications of the study regarding ADHD diagnosis and ADHD symptoms might be extended to autism, especially in regards to the study by Rong, Yang, & Wang (2021) that found that that 38.5 % of those with ASD are currently experiencing ADHD and 40.2% of those with ASD experienced ADHD in their lifetime.

What other research within the library is this one related to?

The study by James et al. (2004) examined certain substances (metabolites) in the blood of children with and without autism. Initially, children with autism had unbalanced levels of these substances, with some being too high and others too low. After introducing two interventions, including the addition of certain substances (folinic acid, betaine, and methylcobalamin), the balance improved significantly.

The study by El-Ansary et al. (2020) found that there was a complete separation of autistic and control participants using nine biomarkers, which provides insight into the possible pathophysiology of the autism, particularly in relation to oxidative stress, energy metabolism, mitochondrial dysfunction, and apoptosis.

Can I read the full study somewhere?

Right here.