Pregnancy represents a major life occurrence characterized by a range of social, psychological, and hormonal alterations that can induce stress (Bennett et al., 2004). Perinatal mental disorders represent a prevalent and impactful spectrum of morbidities during the period of both antenatal and postpartum, ranging in severity from mild symptoms of anxiety and depression to psychosis (O'Hara and Wisner, 2014). The prevalence of perinatal anxiety and depression varied across countries, regions, and settings (Roddy Mitchell et al., 2023), affecting around 1 in 10 women in high-income countries (Dennis et al., 2017; Woody et al., 2017) whereas 1 in 4 women in low- and middle-income countries (LAMICs) (Roddy Mitchell et al., 2023). The developmental origins of health and disease (DOHaD) hypothesis underscores the criticality of early developmental factors in shaping mental health, and human potential, and highlights the significance of prenatal maternal well-being during prenatal stages and fetal growth as primary determinants of an individual's vulnerability to negative health effects in later life (Insel and Wang, 2010).

The prenatal period of potential deterioration of a woman's mental health may have negative implications for offspring well-being (Lasater et al., 2017). The existing literature including our previous study has shown that perinatal maternal mental health problems like anxiety (Rees et al., 2019), depression (Rogers et al., 2020), and perceived stress (Graignic-Philippe et al., 2014), are correlated with unfavorable offspring neurodevelopmental domains, including language (Rogers et al., 2020), cognitive (Wu et al., 2022), motor (Simcock et al., 2018), adaptive behavior (Rogers et al., 2020) or social-emotional competences (Porter et al., 2019; Zhang et al., 2023). Deterioration in prenatal maternal mental health may lead to structural and functional impairment of the fetal brain, which negatively impact their neurodevelopment. Prenatal maternal stress may alter regional brain volumetric growth, cortical folding patterns, microstructural integrity, and functional connectivity of the developing fetal brain (Wu et al., 2022). Prenatal maternal depression and anxiety are associated with elevated fetal cortisol levels, which will impair the placental function, disrupt fetal hypothalamic-pituitary-adrenal axis activity, and alter brain function (Rogers et al., 2020).

Brain-derived neurotrophic factor (BDNF) is an essential growth factor that plays a crucial role in facilitating neural development and promoting synaptic plasticity (Park and Poo, 2013). It promotes neuronal survival and growth, increases synaptic plasticity, impacts neuronal function and morphology, and participates in cognitive processes such as memory and learning (Lu et al., 2014). Dysregulation of BDNF signaling is implicated in the pathogenesis of various neuropsychiatric disorders such as depression, Huntington's disease, and Alzheimer's disease (Cattaneo et al., 2016). Currently, precise quantification of brain BDNF levels in living human subjects is not feasible. Given the immature fetal blood-brain barrier, their circulating BDNF levels reflect that in the central nervous system (CNS) (Maisonpierre et al., 1990). The relationships between maternal prenatal mental health and cord blood BDNF levels were inconsistently reported in the literature. Sonmez et al. found that prenatal maternal major depression was associated with decreased BDNF levels in cord blood (Sonmez et al., 2019), whereas non-significant findings were shown in other studies (Akbaba et al., 2018; Dingsdale et al., 2021; Lommatzsch et al., 2006). Similarly, studies investigating the link between cord blood BDNF and maternal symptoms of anxiety have yielded divergent results (Akbaba et al., 2018; Dingsdale et al., 2021; Uguz et al., 2013). Uguz et al. observed lower levels of cord blood BDNF in infants born to mothers with prolonged generalized anxiety disorder (GAD) during pregnancy compared to those born to healthy mothers (Uguz et al., 2013). However, no significant associations were found by other studies in this regard (Akbaba et al., 2018; Dingsdale et al., 2021). Neonatal BDNF levels may also correlate with developmental outcomes. Cord blood levels of BDNF were found positively associated with neurodevelopment of children at one-year old, particularly with personal-social skills (Yu et al., 2016). However, few studies have investigated the association between BDNF and the neurodevelopment of children at 2 years of age. The most accelerated stage of human neurodevelopment throughout the lifespan occurs from conception to the age of 2 (Murray et al., 2018). Within this temporal window, cortical architecture undergoes rapid maturation, alongside the establishment of complex neural connections (Hüppi et al., 1998; Ouyang et al., 2020; Pfefferbaum et al., 1994). Infants progressively manifest cognitive, linguistic, and motor skills, typically becoming measurable by the age of 2, which is also recommended for the early detection of neurodevelopment (Marlow et al., 2008).

Furthermore, to the best of our knowledge, no study has thus far explored the role of BDNF in the relationship between prenatal maternal mental health and offspring neurodevelopment. In this study, we evaluated the potential biological pathway from prenatal maternal mental health including depression, anxiety and perceived stress to neurodevelopment in 2-year-old children through cord blood BDNF in a prospective cohort.