Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a commonly diagnosed neurodevelopmental condition in childhood that is characterized by inattention, hyperactivity, and impulsivity [1,2]. Although ADHD has a strong genetic basis, recent clinical evidence suggests that prenatal factors, particularly maternal mental health during pregnancy, play a critical role in determining the neurodevelopmental risk of offspring [3]. Numerous clinical studies and large-scale cohort analyses have demonstrated that maternal depression is associated with increased risk of ADHD in children [4-6]. These associations persist even after controlling for genetic liability and postnatal environmental exposures, emphasizing the biological impact of maternal mood conditions on fetal brain development.

Dysregulation of stress hormones such as cortisol in the hypothalamic-pituitary-adrenal (HPA) axis is often considered as one of the major biological pathways through which maternal stress may influence fetal neurodevelopment. Elevated maternal cortisol during pregnancy, which is often observed in depressed mothers, crosses the placental barrier and alters fetal neuroendocrine programming, thus elevating blood cortisol levels in offspring [7,8]. This possibly leads to long-term changes in the developing brain’s stress reactivity, particularly in structures such as the prefrontal cortex, hippocampus, and striatum, affecting attentional regulation and executive function [9,10].

In addition, emerging preclinical and clinical evidence links abnormal maternal conditions to alterations in dopaminergic signaling pathways in offspring, inducing neurodevelopmental psychiatric disorders [11-13]. Given the central role of dopamine (DA) in attention, motivation, and reward processing, disruptions in fetal dopaminergic development may mediate the behavioral manifestations of ADHD. These neurobiological changes are further modulated by inflammation, obesity, and epigenetic modifications observed in depressed pregnancies [14,15].

In recent animal studies, continuous administration of corticosterone to pregnant rodents elevated maternal plasma cortisol levels, which in turn led to increased cortisol concentrations in the offspring [16-18]. This indicates that maternal stress during gestation can directly influence the intrauterine environment and fetal physiology. Notably, the offspring of rodents treated with corticosterone during pregnancy have demonstrated ADHD-like behaviors, delayed neurodevelopment, and partial cognitive impairment [19]. Furthermore, multiple rodent models have provided consistent evidence that excessive HPA-axis activation and cortisol elevation represent one of the critical physiological mechanisms influencing offspring behaviors and emotions [16,20,21]. These results suggest that adverse maternal conditions that affect the fetal neuroendocrine system during pregnancy are one of several etiological factors contributing to ADHD. Although evidence links maternal conditions to offspring ADHD, the precise mechanisms remain unclear. This review integrates clinical and experimental findings to outline how prenatal maternal depression may shape ADHD risk through neuroendocrine dysregulation, altered dopaminergic development, and disrupted early neuronal circuit formation.

Clinical evidence of associations between maternal mental disorder and fetal neurodevelopment

ADHD is a prevalent neurodevelopmental disorder typically emerging in childhood. While some analytical studies have suggested that its prevalence has not significantly increased, more recent evidence indicates that the number of individuals diagnosed with ADHD has continued to rise over the past decades, even after accounting for changes in diagnostic criteria, social awareness, and access to medical care [22-25]. Epidemiological studies suggest that while the global average prevalence has remained between 5% and 7%, certain populations, particularly in the United States, reported rates exceeding 10% in 2016 [26,27]. This trend is not solely attributable to a true increase in incidence but also reflects broadening diagnostic criteria such as the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) extension of symptom onset age from 7 to 12 years, along with enhanced assessment tools, improved public awareness, and greater clinical recognition [28]. The etiology of ADHD is multifactorial, encompassing strong genetic components, with heritability ranging between 70% and 80%, as well as environmental determinants [29]. Neurobiological research has implicated abnormalities in dopaminergic signaling, frontostriatal circuitry, and cortical maturation patterns, underlying the core symptoms of inattention, hyperactivity, and impulsivity [30]. Additionally, disruptions in the neuroendocrine system, such as HPA-axis dysregulation, have been observed in patients with ADHD, suggesting broader systemic involvement [8,31].

In parallel, clinical evidence highlights the role of environmental factors, especially those occurring during prenatal and early postnatal periods. Maternal depression, chronic stress during pregnancy, exposure to environmental toxins, nutritional deficiencies, and perinatal complications (e.g., low birth weight, preterm delivery) have all been associated with increased ADHD risk in offspring [32,33]. These environmental exposures may exert their effects by altering fetal brain development and interacting with underlying genetic vulnerabilities in neurodevelopmental trajectories, suggesting that ADHD arises from dynamic and complex gene-environment interactions rather than a single causal pathway. Recognizing this dual framework may be effective in advancing early detection efforts, preventive strategies, and personalized therapeutic interventions.

Maternal mental health, particularly depressive disorders, plays a significant role in shaping a child’s emotional and behavioral development, influenced by a complex interplay of environmental and biological factors, as well as empathic dynamics within the parent–child relationship [4,34]. When biological and environmental determinants are considered together, prenatal maternal depression stands out as one of the most direct and biologically consequential factors, influencing the fetal brain during critical periods of structural and functional development [10,35]. Unlike paternal or postnatal influences, the impact of prenatal maternal depression occurs through alterations in the intrauterine environment shaped by maternal neuroendocrine and inflammatory states, thereby affecting systems related to attention, executive functioning, and emotional regulation [9,10,36]. These reports underscore the necessity of early detection and management of maternal depression during pregnancy, not only for maternal well-being but also for the neurodevelopmental health of the child. A recent study suggests that the biological link between maternal mental health and fetal neurodevelopment is particularly pronounced in mothers exhibiting comorbid depression and ADHD symptoms during pregnancy [37]. This dual condition reflects the convergence of emotional dysregulation and executive dysfunction, leading to neuroendocrine instability and behavioral disorganization that can alter the intrauterine environment through sustained cortisol elevation, inflammatory cytokine activation, and disrupted circadian rhythms [38-40]. Such perturbations are linked to a substantially heightened risk of ADHD in offspring compared to exposure to maternal depression alone, suggesting that multiple maternal risk factors act synergistically to amplify neurodevelopmental vulnerability through intertwined biological and environmental mechanisms [36,37]. These findings underscore the importance of early identification and integrated prenatal mental-health interventions, while further research is needed to clarify the precise mechanistic pathways and clinical implications of maternal comorbidities (Table 1).

Based on clinical evidence and given the profound influence of the intrauterine environment, various studies have focused on identifying the mechanistic pathways through which maternal psychopathology, especially depression and ADHD, influences fetal brain development. Among these pathways, the neuroendocrine system has emerged as a central mediator, linking maternal emotional dysregulation to alterations in fetal neurodevelopment [8,9,37]. Dysregulation of the HPA-axis, commonly observed in both depressive and ADHD symptomatology, may lead to elevated levels of circulating glucocorticoids such as cortisol during pregnancy. Therefore, these stress hormones can cross the placenta and disrupt the development of fetal brain regions critical for attention, arousal regulation, and executive function [38,39]. Furthermore, inflammatory pathways and neurochemical imbalances such as heightened cytokine activity and dopaminergic dysfunction, highlight a potential biological convergence between maternal depression and ADHD, both of which may independently and synergistically affect fetal development [13,14]. Neuroendocrine mechanisms examining how dysregulated stress and reward systems in the mother can shape neurodevelopmental risk trajectories in her child are discussed next.

Stress-related neuroendocrine function and its interaction with neuromodulators

Considering clinical relevance, it becomes increasingly important to understand how maternal psychological states, particularly during pregnancy, are biologically shaping the developing fetal brain. Epidemiological findings have highlighted a clear link between maternal stress and offspring ADHD, while parallel studies have explored the physiological mechanisms underlying this association. The neuroendocrine system has increasingly been considered as a central intermediary, translating maternal emotional dysregulation into neurochemical alterations that influence fetal brain development. Next, several key hormonal and neuromodulatory pathways are explored that directly connect maternal neuroendocrine function to offspring ADHD, and are summarized in Table 2 [19,41,43-45,48-51,53,55,56,60,62].

As the principal glucocorticoid released through HPA-axis activation, cortisol critically modulates neurodevelopment and emotional regulation. Prolonged elevation of cortisol under depressive or chronic stress conditions downregulates dopaminergic signaling in the mesolimbic pathway, reduces serotonin (5-hydroxytryptamine, 5-HT) synthesis in the raphe nuclei, and suppresses brain-derived neurotrophic factor (BDNF) expression, thereby impairing synaptic plasticity and neuronal resilience within the prefrontal cortex and hippocampus [19,41-43]. These neurochemical alterations contribute to the core features of ADHD such as inattention, impulsivity, and depressive symptoms, which include anhedonia and cognitive dysfunction. Thus, dysregulated cortisol secretion may act as a key mediator linking prenatal maternal stress or depression to neurodevelopmental vulnerability in offspring.

Corticotropin-releasing hormone (CRH) is a hypothalamic peptide that initiates the HPA-axis response to stress, triggering the secretion of adrenocorticotropic hormone (ACTH) from the pituitary. In a preclinical study, sustained elevation of CRH was associated with heightened anxiety, hyperarousal, and emotional dysregulation [44]. CRH hyperactivity has also been found to reduce serotonergic neurotransmission and GABAergic inhibitory tone, increasing excitability and affective instability [45]. In prenatal contexts, maternal CRH levels, especially during the second and third trimesters, influence fetal brain development and stress responsivity. These effects are particularly prominent in limbic structures such as the amygdala and hippocampus, which are implicated in ADHD pathophysiology and mood disorders [46]. Therefore, excessive maternal CRH activity may predispose the fetal neuroendocrine system to maladaptive stress reactivity and emotional dysregulation.

ACTH, secreted by the anterior pituitary gland in response to CRH stimulation, facilitates the release of cortisol from the adrenal cortex. While ACTH itself does not cross the placenta, its role in maintaining elevated maternal cortisol indirectly affects fetal neurodevelopment. Persistent upregulation of ACTH leads to prolonged cortisol exposure in utero and its cascade has been linked to downregulation of dopaminergic signaling, impaired prefrontal cortex development, and increased emotional reactivity in offspring [47-49]. Additionally, elevated ACTH levels correlate with reduced neurogenesis and impaired synaptic connections in the hippocampus and amygdala of the fetal brain [50]. Such changes may increase the likelihood of attention dysregulation, poor executive function, and heightened emotional adaptation.

Thyroid-stimulating hormone (TSH) and thyroid hormones (T3/T4) are essential for normal brain development, synaptogenesis, and neurochemical homeostasis. Hypothyroidism, reflected by elevated TSH and decreased circulating T3/T4 levels, has been associated with reduced 5-HT and norepinephrine (NE) availability in the central nervous system [51]. During pregnancy, even subclinical maternal hypothyroidism can have adverse consequences on fetal cortical development and neurotransmitter regulation [52]. Furthermore, thyroid hormones interact with DA metabolism and downregulate neural excitability and attention processes [53]. In both ADHD and depression, altered thyroid function has been observed as a comorbid factor contributing to symptom severity and treatment resistance [51,54]. Thus, dysregulated maternal thyroid function during gestation may act as an underappreciated contributor to long-term neurodevelopmental disturbances in children.

Prolactin, a pituitary hormone traditionally associated with lactation, also plays an important regulatory role in emotional and neuroendocrine responses to stress. Prolactin secretion is inversely regulated by DA; thus, when DA activity decreases in depressive states, prolactin levels tend to rise. In turn, elevated prolactin can further suppress dopaminergic tone via negative feedback [55,56]. During pregnancy, prolonged prolactin elevation may dysregulate maternal motivation, reward processing, and circadian rhythms, all of which are critical to maternal-infant bonding and postnatal emotional responsiveness. Moreover, chronic hyperprolactinemia has been linked to reduced cognitive flexibility and increased affective lability in both animal and human studies, indicating its potential impact on intergenerational transmission of ADHD or affective symptoms [57,58].

Chronic low-grade inflammation, often seen in stress-related and depressive disorders, is characterized by elevated levels of specific inflammatory cytokines such as interleukin-6 (IL-6) or tumor necrosis factor-alpha (TNF-α) [59]. These cytokines can influence brain function both directly by crossing the blood-brain barrier and indirectly by modulating the metabolism of 5-HT, DA, and glutamate. For example, IL-6 is known to reduce tryptophan availability for 5-HT synthesis, while TNF-α disrupts dopaminergic transmission in pain-related pathways [60,61]. During pregnancy, maternal inflammation can impair placental function and fetal nutrient delivery, as well as disrupt neurogenesis and synapse formation [62]. These alterations have been implicated in the emergence of ADHD-like phenotypes and affective dysregulation in offspring, underscoring the role of maternal immune activation in shaping early neurodevelopmental processes.

Prenatal stress and maternal psychopathology disrupt fetal neurodevelopment primarily through sustained HPA-axis activation and associated inflammatory responses. Elevated CRH, ACTH, and cortisol, together with increased placental glucocorticoid transfer and reduced 11β-hydroxysteroid dehydrogenase type-2 activity, create a neurotoxic intrauterine environment marked by heightened IL-6 and TNF-α signaling [59,63,64]. These changes downregulate key neuromodulators (DA, NE, 5-HT) and neurotrophic factors, impairing the prefrontal and hippocampal maturation critical for attention and emotional regulation [65-69]. The compounded disruption of dopaminergic and neurotrophic systems forms a mechanistic bridge between prenatal stress and long-term ADHD-related phenotypes. Moreover, comorbid maternal ADHD may amplify these biological cascades through additive genetic and hormonal influences [37]. Understanding these integrative pathways will guide early identification and intervention strategies in vulnerable populations (Fig. 1).

Characteristics of neurodevelopment in attention-deficit/hyperactivity disorder

Prenatal stress-induced neuroendocrine dysregulation, including alterations in cortisol, DA, and BDNF signaling, may shape distinctive neurodevelopmental trajectories. These early disruptions particularly appear to affect frontostriatal and limbic maturation, forming the basis of the functional impairments observed in ADHD. To better understand the neurobiological mechanisms of ADHD, it is informative to compare it with other neurodevelopmental disorders, such as autism spectrum disorder (ASD) and intellectual disability (ID), which exhibit different patterns of structural and functional development.

A comparative analysis of neurodevelopmental features across ADHD, ASD, Rett syndrome, and ID reveals distinct patterns in structural, synaptic, and molecular domains, which reflect the heterogeneous nature of these disorders [70-74]. In individuals with ADHD, studies using structural magnetic resonance imaging (MRI) typically show either normal anatomy or subtle delays in brain maturation, particularly in prefrontal regions [75]. Unlike the more overt structural anomalies found in other disorders, ADHD is primarily characterized by functional dysregulation. Synaptic morphology in ADHD is largely preserved in terms of the number and shape; however, synaptic efficiency is compromised, with decreased responsiveness to key neuromodulators such as DA, NE, 5-HT, and glutamate [76-78]. These abnormalities are particularly prominent in frontostriatal and mesocorticolimbic circuits, which mediate attention, execution, and emotional regulation [79]. Furthermore, common variants in genes such as the DA transporter gene (DAT1), DA D4 receptor gene (DRD4), and synaptosome-associated protein 25 gene (SNAP25) have been implicated [80]. This manifests as impaired synaptic responsiveness, which contributes to core ADHD symptoms without gross structural deficiencies.

In contrast to ADHD, ASD displays more prominent macrostructural and microstructural abnormalities. Visualization such as MRI often shows early macrocephaly, atypical cortical folding, and differences in minicolumn organization [79,80]. Synaptically, ASD is marked by excessive synaptic growth, immature dendritic spines, and deficits in synaptic pruning, suggesting an inefficient network [81,82]. Neurochemically, reduced GABAergic and heightened glutamatergic signaling contribute to excitation/inhibition imbalances [83,84]. Molecularly, mutations in genes involved in synapse formation, such as SH3 and multiple ankyrin repeat domains protein 3 (SHANK3), neurexin (NRXN), and calcium voltage-gated channel auxiliary subunit beta 2 (CACNB2), are common [85]. These biological features align with clinical phenotypes including sensory over-responsivity and impaired social cognition.

By contrast, ID involves global and diffuse impairment across cortical and subcortical structures, including reduced brain volume, abnormal cortical layering, and compromised synaptic development with immature synapses and decreased dendritic complexity [74]. The genetic causes of ID are diverse, including single-gene mutations in fragile X mental retardation 1 (FMR1) and methyl-CpG-binding protein 2 (MECP2), as well as chromosomal deletions or duplications [86]. Functionally, individuals with ID present with generalized cognitive and adaptive function deficits, reflecting the extensive neurodevelopmental disruption.

Overall, although all three disorders involve altered neurodevelopment, ADHD is characterized by relatively preserved brain structures and functional dysregulation, unlike ASD and ID where anatomical and genetic abnormalities are more prominent (Table 3). This distinction highlights ADHD as a neurodevelopmentally unique condition, driven less by the misbuilding of brain architecture and more by the misfiring at molecular and circuit levels. Viewing ADHD through this functional aspect shifts both research and therapy toward improving synaptic efficiency and neuromodulatory balance rather than focusing solely on structural biomarkers, emphasizing pharmacological and behavioral strategies that strengthen network connectivity and resilience.

In animal research, sustained elevations of systemic glucocorticoids were observed in a pup model derived from pregnant dams repeatedly administered corticosterone during gestation [16]. The offspring exhibited ADHD-like behaviors, particularly inattention and hyperactivity, accompanied by reduced hippocampal BDNF expression and impaired long-term potentiation in CA1 neurons [19]. Notably, in the absence of overt structural abnormalities in dendritic spine density or cortical lamination, this animal model exhibited marked glutamatergic hypoactivity, underscoring a functional rather than structural neurodevelopmental delay.

These findings align with other prenatal stress models, including those involving maternal restraint stress and dexamethasone exposure. Restraint stress induces long-lasting downregulation of GABAergic interneurons in the medial prefrontal cortex and heightened HPA-axis reactivity, whereas dexamethasone exposure reduces hippocampal BDNF, dendritic complexity, and Ca²⁺/calmodulin-dependent protein kinase II (CaMKII)/mitogen-activated protein kinase (MAPK) signaling, resulting in impaired synaptic plasticity and cognitive performance [87–89]. Collectively, these models indicate that prenatal stress disrupts neuromodulatory and intracellular signaling that is critical for synaptic function and development, validating the high-cortisol pup model as a translational platform for studying ADHD pathophysiology.

Conclusion

ADHD, although traditionally viewed as a disorder of behavioral and executive control, is better conceptualized as a functionally rooted neurodevelopmental condition shaped by prenatal biological susceptibility among multiple interacting factors. Evidence shows that maternal risk factors, particularly prenatal depression and neuroendocrine dysregulation, exert lasting effects on offspring neurodevelopment. Elevated maternal cortisol, ACTH, CRH, and inflammatory cytokine levels disrupt fetal brain development during critical structural and synaptic windows, impairing dopaminergic, glutamatergic, and GABAergic balance without causing overt malformations. This functional disruption distinguishes ADHD from ASD and ID, which often involve measurable anatomical changes.

Animal studies show that, even without cortical malformations, deficiencies in synaptic plasticity, neuromodulator responsiveness, and kinase signaling produce persistent ADHD-like phenotypes. Clinical imaging similarly reveals delayed cortical maturation and dysregulated connectivity in ADHD, without consistent microstructural anomalies. Thus, ADHD appears to arise from a mismatch between functional signaling and preserved anatomy, a concept with important therapeutic implications.

Importantly, while these prenatal biologically driven vulnerabilities lay the foundation for ADHD, postnatal environmental factors can either exacerbate or ameliorate symptom progression. For example, early psychosocial interventions in life in high-risk infants have been shown to buffer neurobehavioral dysregulation [90]. Moreover, interventions targeting epigenetic remodeling, such as maternal exercise, omega-3 supplementation, and regulated light/dark cycles, have demonstrated beneficial effects on offspring attention and emotional regulation in both preclinical and clinical settings [91,92].

Effective ADHD management may benefit from incorporating integrative and preventive strategies alongside pharmacologic therapy, targeting the effects of prenatal stress while promoting postnatal neural plasticity. Strategies combining neuroendocrine monitoring, behavioral support, and environmental enrichment could reduce reliance on stimulants and promote lasting functional improvement. Recognizing ADHD as functionally disrupted but structurally preserved supports more adaptive and biologically informed interventions.

Article information

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

Funding

This research was supported by a grant from the Jeju National University Hospital Research Fund of Jeju National University College of Medicine in 2023.

Fig. 1.

Proposed neuroendocrine mechanism linking maternal stress to offspring attention-deficit/hyperactivity disorder (ADHD) risk. Maternal stress or depression during prenatal or early life leads to hypothalamic-pituitary-adrenal (HPA)-axis overactivation, resulting in dysregulation of the neuroendocrine-catecholamine axis. This includes elevated corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), cortisol, and inflammatory cytokine levels, along with reduced dopamine (DA), norepinephrine (NE), serotonin (5-HT), gamma-aminobutyric acid (GABA), and brain-derived neurotrophic factor (BDNF) levels. Suppressed neurotrophic support contributes to developmental neuroanatomical alterations, including impaired synaptic density and pruning in the prefrontal cortex (PFC), dopaminergic depletion in the basal ganglia, and immature synaptic development in the hippocampus. These changes manifest as behavioral phenotypes in offspring, increasing the risk of ADHD, emotional dysregulation, and neurocognitive delays.

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