Stress during pregnancy, triggered by immune activation, infections, or changes in gut health, may have lasting effects on a child’s brain development, increasing the risk of neurodevelopmental disorders later in life. A new genetic study in mice, published in Nature Neuroscience, sheds light on this process at a molecular level by mapping the neuroimmune environment of the developing fetal brain with unprecedented spatial detail.
Led by researchers at Boston Children’s Hospital in the United States, the study shows that prenatal stress can alter immune signalling pathways in the fetal brain during critical stages of development, potentially interfering with how brain cells grow, migrate, and form connections, processes essential for healthy cognitive and behavioural outcomes.
Considering that around 11.4% of Indian children aged two to nine years are affected by neurodevelopmental disorders (NDDs), equating to one in every eight children, this study could provide crucial insights into how maternal stress and immune challenges during pregnancy shape the fetal brain’s neuroimmune landscape, potentially uncovering mechanisms that contribute to the development of these disorders.
Mapping how stress alters the developing brain
The Nature Neuroscience study focused on how maternal stress affects immune signalling in the fetal brain during mid and late gestation. Using an advanced technique known as multiplexed in situ spatial transcriptomics, researchers were able to see which immune-related genes were active, in which brain regions, and at what developmental stage. This approach goes beyond earlier genetic studies by preserving spatial context, crucial for understanding brain wiring.
“Our study establishes a detailed spatial transcriptomic resource of immune gene networks during a critical window of embryonic brain development,” said Brian Kalish, a physician in the division of newborn medicine at Boston Children’s Hospital and the study’s lead researcher.
The team specifically examined two types of prenatal stressors: maternal immune activation (MIA), which can occur during infections, and maternal microbiome depletion, reflecting disruptions in gut bacteria. Both conditions are known to activate immune responses in the mother, but their effects on the fetal brain had not been mapped in such detail before.
The authors explained the rationale of their work clearly, “Immune molecules and their cognate receptors are developmentally regulated in brain and dynamically expressed in the context of neurodevelopmental disorders. Despite the importance of immune molecules to brain wiring, a comprehensive map of the neuroimmune landscape is lacking in developing brain.”
To address this gap, the researchers analysed immune ligands and receptors in the developing mouse brain and then assessed how this landscape changed following maternal immune challenges.
The findings revealed that maternal stress during pregnancy can significantly alter immune gene expression in the fetal brain, with sex-specific patterns emerging as a key theme.
One of the most striking observations was the disruption of a specific immune signalling pathway known as the ‘CXCL12/CXCR7 chemokine network’. This pathway plays a critical role in guiding neural progenitor cells, early brain cells that eventually differentiate into neurons and glial cells, to their correct locations.
The researchers found that both maternal immune activation and microbiome depletion altered this pathway in similar ways, suggesting a common mechanism through which different stressors may impair brain development. According to the authors, these disruptions could cause neural stem cells to develop incorrectly as neurons, potentially leading to structural or functional brain abnormalities.
“Our study revealed notable sex-specific patterns in gene expression and spatial architecture within developing brain,” the authors noted. “We observed changes in the CXCL12/CXCR7 chemokine network after maternal immune activation and microbiome depletion, suggesting a potential common mechanism underlying neural progenitor abnormalities.”
For your daily dose of medical news and updates, visit: HEALTH
Importantly, male fetuses appeared more vulnerable to certain immune disruptions than females, an observation that aligns with epidemiological data showing higher rates of autism and some other neurodevelopmental disorders in boys.
“Unlike previous atlases focused on the adult brain, our dataset captures dynamic immune signalling interactions at a stage when the brain is highly vulnerable,” Kalish said.
From a clinical perspective, the implications are significant. “As a neonatologist, this work adds to our understanding of early-life environmental factors that may impact neurodevelopmental potential and lends insights for potential interventions,” he added.
However, it is important to note that this is an animal study.
Why it matters
The relevance of these findings becomes clearer when placed in the broader context of existing research, which increasingly links maternal psychological stress, immune activation, and inflammatory responses during pregnancy to long-term neurodevelopmental outcomes in children, particularly in settings where early detection and prenatal mental health support remain limited.
A major PLOS study has estimated that about one in eight Indian children aged 2–9 years may have at least one neurodevelopmental condition, including speech or language delays, autism, or intellectual disability. The authors cautioned that this figure is likely a conservative estimate due to limitations in surveillance and diagnosis.
“The data suggested that the NDD burden can be substantially reduced in India by addressing the risk factors which are amenable to public health interventions,” the study noted.
Maternal mental health is increasingly recognised as one such modifiable risk factor. A 2017 prospective study from Bengaluru, involving over 2,600 pregnant women, examined how maternal psychological distress and cortisol levels affected infant development. The researchers found compelling evidence linking prenatal stress to delayed motor and cognitive development in infants.
“Maternal psychological distress is a major public health problem and needs timely detection and intervention to prevent any adverse pregnancy outcome,” the authors wrote. They added that elevated cortisol, a biological marker of stress, was associated with poorer scores on standardised developmental assessments in infancy.
Building on this, a 2022 review synthesised findings from neuroimaging, immunology, and behavioural research to show that inflammation may be a key mechanism linking maternal stress to altered fetal brain development. The review highlighted how maternal stress can activate inflammatory pathways that influence placental function and fetal brain structure, even before birth.
“Evidence documenting the effects of maternal psychological stress on offspring brain development has become increasingly grounded in understanding mechanistic pathways involving stress-sensitive aspects of maternal–placental–fetal biology, particularly inflammation,” the authors wrote.
The review also pointed to promising interventions. Psychological therapies that reduce stress during pregnancy have been shown not only to improve maternal mental health but also to reduce inflammation, suggesting a potential dual benefit for both mother and child.
Further reinforcing this link, another study tracking inflammatory biomarkers during pregnancy found that immune profiles in the third trimester predicted children’s neurodevelopmental trajectories during the first two years of life. While maternal stress alone was not always a strong predictor, its interaction with the immune response significantly influenced developmental outcomes.
More recently, a 2024 population-based cohort study from Japan identified several perinatal risk factors associated with neurodevelopmental referrals at age three. These included lack of social support during pregnancy, maternal psychiatric history, postnatal depression, and male infant gender, once again highlighting the combined influence of psychological, social, and biological stressors.
A 2025 review highlighted that prenatal immune stress, often triggered by maternal immune activation, is a major risk factor for neurodevelopmental and psychiatric disorders such as autism and schizophrenia. The authors noted that immune-inflammatory pathways, particularly those driven by interleukin-6 (IL-6), can disrupt developing brain cells, concluding that “a mechanistic understanding of the impact of prenatal immune stress on brain development provides a fundamental addition in translational and clinical neurology and psychiatry.”
This story is done in collaboration with First Check, which is the health journalism vertical of DataLEADS.