How Stress During Pregnancy Can Shape the Developing Fetal Brain

Stress during pregnancy has long been associated with effects on child development, but scientists are still uncovering the precise biological pathways behind this connection. A new study from Boston Children’s Hospital, published in Nature Neuroscience, takes a deep dive into how pregnancy-related stressors influence the developing fetal brain—specifically through changes in the maternal microbiome and the maternal immune system. The findings offer a detailed and data-rich look at how these two systems, acting independently and together, can reshape the brain’s early immune and neural environment.

At the heart of the research is a concept known as the maternal gut–immune axis. This refers to the dynamic relationship between the microorganisms living in the mother’s gut and her immune responses, and how signals from both can reach the developing fetus. Previous studies have linked disruptions in this axis to a higher risk of neurodevelopmental disorders in children. This new work significantly expands that understanding by mapping, in remarkable detail, how these maternal factors alter immune signaling in the fetal brain during critical stages of development.

Mapping the Neuroimmune Landscape of the Developing Brain

The study was led by Brian Kalish, MD, a physician in the Division of Newborn Medicine at Boston Children’s Hospital. His team focused on how two major pregnancy-related stressors—maternal immune activation and changes in the maternal microbiome—affect the fetal brain’s immune environment.

To explore this, the researchers worked with mouse models, which allow close examination of brain development at precise gestational stages. They examined embryos during mid-gestation and late gestation, periods when the brain is rapidly forming and highly sensitive to environmental influences. Rather than looking only at which genes were active, the team wanted to know where in the brain these immune-related genes were expressed and how that spatial organization changed under stress.

To achieve this, they used a powerful technique called in situ spatial transcriptomics, specifically a method known as MERFISH (Multiplexed Error-Robust Fluorescence In Situ Hybridization). This approach allowed them to visualize immune gene activity directly within intact brain tissue, preserving spatial context. They then combined this data with single-cell RNA sequencing, which helped identify specific cell types involved in immune signaling.

The result was a high-resolution atlas of immune gene networks in the developing brain—something that has not existed before for this stage of life. Unlike earlier atlases that focused mainly on adult brains, this dataset captures immune signaling during a critical embryonic window, when the foundations of neural circuits are still being laid.

Independent and Combined Effects of Maternal Stressors

One of the key findings of the study is that the maternal immune system and the maternal microbiome each influence fetal brain development in their own ways. Importantly, they can also act together, producing combined effects that are different from either factor alone.

When the maternal immune system is activated—such as during infection or inflammation—it sends signals that can cross into the fetal environment. Separately, disruptions to the maternal microbiome, which can occur due to diet, illness, or antibiotic use, also alter immune signaling molecules. The researchers found that both of these stressors reshaped the neuroimmune landscape of the fetal brain, changing how immune-related genes were expressed and organized across different brain regions.

These changes are significant because immune signaling is deeply intertwined with brain development. Immune molecules guide processes such as neural differentiation, cell migration, and synapse formation. Altering these signals during development can have long-term consequences.

Sex-Specific Vulnerability in the Developing Brain

Another major insight from the study is the presence of sex-specific responses to maternal stressors. The researchers observed that male and female fetal brains did not respond in the same way to disruptions in the maternal gut–immune axis.

In particular, the male brain showed increased vulnerability in a specific immune signaling pathway. This finding is especially noteworthy because many neurodevelopmental disorders, including autism spectrum disorders, are diagnosed more frequently in males. While the study does not claim a direct causal link, it does provide biological evidence that male brains may be more sensitive to certain prenatal immune disruptions.

A Key Pathway Emerges: CXCL12 and CXCR7

Among the many immune signals examined, one pathway stood out. The researchers identified the CXCL12/CXCR7 signaling pathway as a potential mediator of abnormal neural differentiation when maternal immune and microbiome stressors are present.

This pathway plays an important role in guiding cells during brain development. Disruptions to CXCL12/CXCR7 signaling were associated with altered patterns of neural development, suggesting it could be a promising target for future interventions. While any clinical application is still far off, identifying such a pathway is an important step toward understanding how early-life interventions might one day reduce risk.

Why This Research Matters

From a clinical perspective, this work adds depth to our understanding of how early-life environmental factors influence neurodevelopmental potential. By creating a detailed spatial map of immune signaling in the fetal brain, the study provides a framework for future research into how prenatal conditions translate into long-term neurological outcomes.

For neonatologists, neuroscientists, and developmental biologists, the dataset itself may be just as valuable as the conclusions. It offers a resource for exploring how immune and neural systems interact during development—an area that has been difficult to study until now.

Additional Context: The Role of the Maternal Microbiome

Beyond this specific study, interest in the maternal microbiome has been growing rapidly. The gut microbiome influences immune balance, hormone levels, and metabolic processes. During pregnancy, these effects can ripple outward, affecting placental function and fetal development. Research increasingly suggests that maintaining a healthy and stable microbiome may be an important component of prenatal health, although scientists are still working to define what that means in practical terms.

Additional Context: Immune Signaling and Brain Development

It is also worth noting that immune molecules are not just defenders against infection. In the developing brain, they act as guidance cues, helping neurons find their proper locations and connections. This dual role explains why immune disruptions can have such profound developmental effects, even in the absence of illness in the child.

Looking Ahead

While this study was conducted in mice, its implications reach far beyond animal models. It highlights the need to better understand how maternal health, immune balance, and microbiome composition interact during pregnancy. Future research may explore how nutrition, stress management, infection prevention, and other interventions could help support healthier neurodevelopmental outcomes.

For now, this work stands as one of the most detailed examinations to date of how pregnancy-related stressors shape the developing brain—offering clarity, raising new questions, and opening doors for further investigation.

Research paper:
The Maternal Gut-Immune Axis Programs the Neuroimmune Landscape of the Developing Brain, Nature Neuroscience (2026)
https://www.nature.com/articles/s41593-025-01943-6