A recent Molecular Psychiatry study investigates the association between maternal oxidative stress during pregnancy and early childhood mental disorders.
Background
Many children develop mental disorders concomitant with emotional and behavioral problems (EBP). Mental disorders in children are associated with mood disorders like anxiety and depression, as well as neurodevelopmental disorders like autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD).
Childhood EBP can be classified as internalizing or externalizing EBP. Internalizing EBP is associated with anxiety, depression, and somatic complaints, whereas externalizing EBP includes aggression, impulsivity, inattention, hyperactivity, and opposition.
Approximately 20% of school-aged children suffer from EBP, with these numbers expected to rise due to the coronavirus disease 2019 (COVID-19) pandemic. Previous studies have shown that EBP significantly impacts children’s education, health, and quality of life.
Childhood EBP also influences the emotional disorders diagnosed during adolescence and adulthood. Therefore, it is imperative to detect and treat EBP in early childhood to prevent mental disorders in adulthood.
Prenatal, perinatal, and postnatal exposure to differential environmental conditions like tobacco smoke and prescription medications impacts fetal programming, early brain development, and long-term neuropsychiatric outcomes.
Several studies have shown that early-life exposure to socioeconomic adversities contributes to the development of EBP through the induction of downstream biological pathways linked to inflammation and oxidative stress (OS). Therefore, the identification of prenatal factors, in addition to a better understanding of the underlying mechanisms linked to EBP, will enable the development of effective preventive strategies and therapeutics.
OS refers to imbalanced free radical production and antioxidant capacity that causes oxidative damage to macromolecules like protein, DNA, and ribonucleic acid (RNA). A common byproduct of oxidative DNA damage is 8-hydroxy-2′-deoxyguanosine (8-OHdG), which is the most prominent biomarker of OS.
Oxidative RNA damage is assessed by estimating 8-hydroxyguanine (8-OHGua). Due to higher detectable concentration, 8-OHGua is a more suitable biomarker of OS.
Previous studies have shown that certain environmental factors, such as low socioeconomic position and prenatal lifestyle factors, influence OS, which leads to adverse neurodevelopment and EBP, particularly anxiety and depression. Maternal OS during pregnancy also impacts the mother’s health and fetal development through placental perfusion and malnutrition.
About the study
The current study investigated the association between maternal OS during pregnancy and offspring EBP. Study participants were recruited from the Barwon Infant Study (BIS) cohort in Australia, which comprised 1,074 mother-infant pairs. All women who delivered before 32 weeks of pregnancy or had children diagnosed with a genetic disease or major congenital malformation were excluded from the study.
Clinical data and biospecimens were collected at birth and four weeks, three, six, nine, 12, and 18 months, as well as two and four years of age. Maternal urine samples were collected at the 36-week pregnancy appointment and analyzed to detect OS biomarkers using liquid chromatography-mass spectrometry (LC-MS/MS).
Children between 1.5 and five years of age were assessed for EBP using the Child Behavior Checklist (CBCL). This checklist contained 99 items scored on a three-point Likert scale ranging from zero (not true), one (somewhat true), and two (very true). The Strengths and Difficulties Questionnaire (SDQ) was also used to assess EBP in children.
Study findings
Most mothers were older than 25 years of age and were non-smokers. The researchers assessed the correlation between maternal OS biomarkers including 8-OHGua and 8-OHdG during pregnancy and persistent total EBP in early childhood. A higher mat8-OHGua36w was positively correlated with children’s total EBP at ages two and four years.
Although a positive association between the oxidative RNA damage biomarker 8-OHGua and EBP in children was observed, this type of association was not observed with oxidative DNA damage biomarker 8-OHdG.
Increased levels of 8-OHdG were robustly associated with EBP in children, particularly with the manifestation of anxiety and depression in early childhood. However, after adjusting for potential confounding factors, total EBP estimates were altered by less than 10%. A poor association between mat8-OHdG36w and childhood EBP indicated the limited capacity of this biomarker in predicting later EBP in the child.
Some of the modifiable risk factors identified for EBP included lower maternal education, residential socioeconomic disadvantage, tobacco smoking, and prescription medication use. Maternal OS biomarker levels during pregnancy were also strongly associated with increased depressive symptoms in early childhood.
Conclusions
Social and prenatal lifestyle environmental factors significantly influence the development of EBP in children. This manifestation has been linked to higher 8-OHGua levels, a maternal oxidative RNA damage biomarker, during pregnancy. The study findings also provide novel insights into the role of maternal OS stress during pregnancy on fetal programming of mental disorders.