The Hidden Cost of a Bad Flu: How Severe Illness During Pregnancy Rewires the Fetal Brain
The Hidden Cost of a Bad Flu: How Severe Illness During Pregnancy Rewires the Fetal Brain
When a pregnant woman catches a severe illness—say, a nasty bout of influenza—the immediate concern is her own health. Will she recover? Does she need hospitalization? But a growing body of research suggests there may be another, quieter consequence: subtle changes to the developing brain of her unborn child. These changes dont guarantee anything, but they can shift the odds.
Neurodevelopmental conditions like autism spectrum disorder and ADHD affect roughly 10% of the American population. For decades, scientists have struggled to pinpoint exactly where, when, and how these conditions begin. But one pattern has stubbornly repeated: severe illness during pregnancy is linked to a higher risk of neurodevelopmental disorders in offspring. Now, researchers at the Salk Institute have peeled back a layer of that mystery by looking not at genes themselves, but at the chemical tags sitting on top of them.
What Weve Known for Decades
The story starts with the flu. Years ago, epidemiologists noticed that mothers who had suffered influenza infections during their second or third trimester reported a higher incidence of psychiatric disorders in their children. At first, scientists wondered if the virus itself was to blame. But when researchers analyzed blood samples from these mothers, they found something else: elevated levels of IL-6, a protein that promotes inflammation as part of the immune response. The culprit wasnt necessarily the infection—it was the mothers immune reaction to it.
This insight allowed scientists to create animal models of the phenomenon. Instead of infecting mice with influenza, they used a viral mimetic called Poly(I:C) to trigger a similar immune response. The model, known as maternal immune activation (MIA), has become well characterized over the years. But most of that characterization has focused on behavior and electrophysiology—not epigenetics.
“We wanted to look at what epigenetic changes were happening throughout development,” says Margarita Behrens, Ph.D., a research professor at Salk and co-corresponding author of the new study. “To potentially cause the behavioral, psychiatric and electrophysiological observations other scientists have made.”
The Epigenome: A Malleable Instruction Manual
If DNA is the instruction manual for a cell, the epigenome is the set of sticky notes, highlights, and crossed-out lines that determine which instructions actually get followed. One of the most common epigenetic marks is methylation—small chemical tags called methyl groups that attach to DNA and can turn genes on or off. Unlike the genetic code itself, the epigenome is malleable. It can change in response to the environment, including during fetal development.
Behrens and her team, including co-corresponding author Joseph Ecker, Ph.D., monitored the epigenomes of mouse frontal cortex cells throughout fetal development. Some mice had healthy mothers. Others had mothers whose immune systems had been activated. The researchers analyzed neurons from mid-gestation through two weeks after birth, searching for changes in gene activity and methylation patterns.
The results, published in Molecular Psychiatry, were striking. Thousands of epigenetic differences separated the two groups. The offspring of immune-activated mothers showed particularly distinct epigenomes in deep-layer neurons—cells that play a crucial role in the brains circuitry. Many of these differences appeared near genes linked to autism spectrum disorder.
Tbr1: A Master Regulator Blocked at the Door
One of the most intriguing findings involved a transcription factor called Tbr1. This protein acts as a major regulator of the developing brain, helping to define deep-layer neurons. In the immune-activated mice, the researchers found more Tbr1 than normal. But heres the twist: the areas of the genome that Tbr1 typically interacts with were downregulated. Despite an influx of Tbr1 available to bind to the genome, increased methylation was blocking it from doing its job.
“Even more specifically, sites where the transcription factor Tbr1 binds were more methylated than normal in deep-layer neuron-specific regions at birth,” the study reports. These Tbr1 sites are also strongly related to autism spectrum disorder.
When the team compared their findings to the SFARI Gene Database—a well-known database of autism-associated genomic alterations—they found that around 25% of the high-confidence genes linked to autism were also dysregulated in their dataset. “That was a significant overlap,” says Jessica Arzavala, co-first author of the study and a graduate student in Behrenss lab.
From Epigenetics to Electricity
Epigenetic changes are one thing. But do they actually affect how neurons function? To answer that, the team collected electrophysiological recordings of the deep-layer neurons after the offspring were born. Their analysis confirmed that deep-layer neuron development was impaired by maternal immune activation. The epigenetic changes werent just molecular curiosities—they had functional consequences.
“Infection changes the odds of whether neurodevelopment is affected—not everyone who gets sick during pregnancy is going to definitively have a child with a neurodevelopmental disorder,” Ecker emphasizes. Thats an important caveat. Maternal illness is a risk factor, not a guarantee.
What This Means for Expectant Mothers
The study adds novel insight into the underlying causes of some neurodevelopmental disorders. It demonstrates that prenatal immune challenges can leave lasting marks on the brains circuitry, changes that carry into adulthood. But it also raises many questions. Scientists still dont know exactly when these epigenetic changes occur during brain development, or when the most vulnerable window for severe illness might be.
“We are closer now to understanding the consequences of maternal infection, but this is only just the beginning of the story,” says Ecker. Behrens adds: “Its just the tip of the iceberg.”
For now, the practical takeaway is not to panic—but to pay attention. Severe illness during pregnancy is a known risk factor for a reason, and this research helps explain why. It also points toward future possibilities: if scientists can identify the exact epigenetic changes involved, they might one day develop maternal or fetal therapeutics that prevent or reduce the risk of neurodevelopmental disorders.
In the meantime, the best advice remains what doctors have always said: take illness seriously during pregnancy, get vaccinated when appropriate, and talk to your healthcare provider about any concerns. The epigenome may be malleable, but so is the care we can provide.
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Mike Brown
Mike Brown – One of those authors who helps readers not get lost in today's news flow. He dives into political affairs as well as world events, social trends, and everyday stories that matter to everyone. The main focus of his work is fact-checking, clear language, and the ability to lay out the key points so that the reader gets a comprehensive and reliable picture of the topic in just a few minutes.
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