Photo Credit – CDC
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While most people tend to regard the flu as a nasty, but relatively trivial and self-limiting, respiratory infection, it is obvious that for some high risk groups - including children, the elderly, the immunocompromised, and those who are pregnant - influenza can have profound and lasting impacts.
Studies suggest strong links between influenza infection and cardiovascular events like heart attacks and strokes (see also Eur. Resp.J.: Influenza & Pneumonia Infections Increase Risk Of Heart Attack and Stroke).
And we've seen evidence suggesting that repeated influenza infections may be linked to an increase risk of developing Parkinson's later in life (see 2017's Nature Comms: Revisiting The Influenza-Parkinson's Link).
In early 2023, in Neuron: Virus Exposure and Neurodegenerative Disease Risk Across National Biobanks, we also looked at a study published in Cell Neuron which found a statistical linkage between viral illnesses and developing neurodegenerative diseases later in life.
Many studies have found links between maternal influenza infection and damage to the unborn child, as in last January's CIMB Review: Maternal Influenza and Offspring Neurodevelopment).
Historical accounts and studies following the last four influenza pandemics (1918, 1957, 1968, and 2009) all showed distinct increases in maternal mortality, the number stillbirths, and evidence of impaired fetal development.
The best records come from the most recent, and mildest, of these flu pandemics (2009).
- In 2011, in BMJ: Perinatal Outcomes After Maternal 2009/H1N1 Infection a study found pregnant women who were admitted to the hospital with an H1N1 infection experienced a 3 to 4 times higher rate of preterm birth, 4 to 5 times greater risk of stillbirth, and a 4 to 6 times higher rate of neonatal death.
- And in 2019, Study: Outcomes Of Infants Born To Women With Influenza A(H1N1)pdm09 found that women admitted to the ICU with H1N1 were more likely to deliver preterm infants, low birth weight infants, and infants with low Apgar scores than women in the other groups.
We've also seen studies that have attempted to quantify the impact of influenza infection on both pregnant women and their offspring. While some of these studies are more compelling than others, we've seen a wide spectrum of sequelae linked to maternal flu infection, including:
Pregnancy, Influenza & Elevated Psychosis Risks In Adult Offspring
Molecular Psy.: Increased Autism Risk Linked To Prenatal Fever
JAMA Psych: Long-term Risk of Neuropsychiatric Disease After Exposure to Infection In Utero
Systematic Review & Meta-Analysis: First-Trimester Influenza Infection Increases the Odds of Non-Chromosomal Birth Defects
This week the Journal Nature has published another study, this time conducted using live mouse-adapted influenza virus and pregnant lab mice, which finds it is the mothers immune response to the virus that causes damage to the unborn offspring.
This is a lengthy, and highly technical, report so I've just reproduced the link, and abstract, along with some excerpts from a press release from the University of Illinois. Follow the links to read them in their entirety, I'll have a brief postscript after the break.
Influenza A virus during pregnancy disrupts maternal intestinal immunity and fetal cortical development in a dose- and time-dependent mannerAshley M. Otero, Meghan G. Connolly, Rafael J. Gonzalez-Ricon, Selena S. Wang, Jacob M. Allen & Adrienne M. Antonson
Molecular Psychiatry (2024)Cite this article
Abstract
Epidemiological studies link exposure to viral infection during pregnancy, including influenza A virus (IAV) infection, with increased incidence of neurodevelopmental disorders (NDDs) in offspring.
Models of maternal immune activation (MIA) using viral mimetics demonstrate that activation of maternal intestinal T helper 17 (TH17) cells, which produce effector cytokine interleukin (IL)-17, leads to aberrant fetal brain development, such as neocortical malformations. Fetal microglia and border-associated macrophages (BAMs) also serve as potential cellular mediators of MIA-induced cortical abnormalities. However, neither the inflammation-induced TH17 cell pathway nor fetal brain-resident macrophages have been thoroughly examined in models of live viral infection during pregnancy.Here, we inoculated pregnant mice with two infectious doses of IAV and evaluated peak innate and adaptive immune responses in the dam and fetus. While respiratory IAV infection led to dose-dependent maternal colonic shortening and microbial dysregulation, there was no elevation in intestinal TH17 cells nor IL-17. Systemically, IAV resulted in consistent dose- and time-dependent increases in IL-6 and IFN-γ. Fetal cortical abnormalities and global changes in fetal brain transcripts were observable in the high-but not the moderate-dose IAV group. Profiling of fetal microglia and BAMs revealed dose- and time-dependent differences in the numbers of meningeal but not choroid plexus BAMs, while microglial numbers and proliferative capacity of Iba1+ cells remained constant. Fetal brain-resident macrophages increased phagocytic CD68 expression, also in a dose- and time-dependent fashion.Taken together, our findings indicate that certain features of MIA are conserved between mimetic and live virus models, while others are not. Overall, we provide consistent evidence of an infection severity threshold for downstream maternal inflammation and fetal cortical abnormalities, which recapitulates a key feature of the epidemiological data and further underscores the importance of using live pathogens in NDD modeling to better evaluate the complete immune response and to improve translation to the clinic.
Fetal brain impacted when mom fights severe flu: New mouse study explains how
Peer-Reviewed Publication
UNIVERSITY OF ILLINOIS COLLEGE OF AGRICULTURAL, CONSUMER AND ENVIRONMENTAL SCIENCES
URBANA, Ill. -- A bad case of the flu during pregnancy can increase the risk for fetal neurodevelopmental disorders such as schizophrenia and autism spectrum disorder. But it’s not the virus itself doing the damage; it’s the mother’s immune response.
New University of Illinois Urbana-Champaign research using live mouse-adapted influenza virus improves upon previous mouse experiments to explain the process on a cellular and molecular level. It also indicates fetal brain changes are more likely once the severity of the mother’s infection meets a specific threshold.
“Our data provide really compelling evidence for an infection severity threshold, which mimics what we see in humans. There are only a subset of maternal infections that are going to be severe enough to cause concerns like this. That said, pregnant people should definitely get the flu vaccine to reduce their risk,” said senior study author Adrienne Antonson, assistant professor in the Department of Animal Sciences, part of the College of Agricultural, Consumer and Environmental Sciences at Illinois.
The study is one of only a handful to investigate maternal infection in mice using live influenza virus at doses that replicate seasonal flu outbreaks in humans. “That means our results are more relevant to human pathological infection,” said lead study author Ashley Otero, a doctoral student in the Neuroscience Program at Illinois.
Antonson’s team infected pregnant mice with live influenza A virus, rather than a viral mimic — an inert molecule that mimics viral behavior — used by most research groups in recent decades. The viral mimic elicits the innate immune response, broadly categorized as non-specific inflammation, that occurs within 24 to 48 hours of infection.
These studies have provided important clues about which inflammatory proteins are made by the mother and how they interact with the fetal brain. But Otero says viral mimics may prompt slightly different immune responses than the live virus in both mother and fetus, and they fail to capture what happens during the mother’s adaptive immune response, which occurs later and helps an animal “remember” past infections.
To address these issues, the team subjected the mice to one of two doses of the virus — representing a moderate or severe infection — at the moment in gestation closest to the end of the first trimester in humans. Then, at two and seven days post-infection, they tracked how the infection progressed in the lungs and intestines of the mother, as well as how products from the mother’s immune response interacted with the fetal brain. They also measured the physical properties of fetal brains, including the thickness of the cortex, which has been linked to neurodevelopmental disorders in humans.
(SNIP)
Antonson emphasizes that maternal infection is only one of many risk factors for neurodevelopmental disorders.
“These disorders are caused by a multitude of elements, including environmental factors, genetics, pharmacological exposures, and more. We're focusing on just this in-utero period, but the early postnatal period is important, and adolescence is important. It’s just one slice of a very complicated pie.”
The study, “Influenza A virus during pregnancy disrupts maternal intestinal immunity and fetal cortical development in a dose- and time-dependent manner,” is published in Molecular Psychiatry [DOI: 10.1038/s41380-024-02648-9]. The research was supported by the Roy J. Carver Charitable Trust (grant #23-5683), USDA NIFA Research Capacity Fund (Hatch project #ILLU-538-940), the Department of Animal Sciences, and the College of ACES.Antonson is also affiliated with the Beckman Institute, the Microbial Systems Initiative, and the Carl R. Woese Institute for Genomic Biology at Illinois.
This study adds to the growing list of evidence that influenza (and other viral infections) can sometimes have a profound, and long-term, impact on the host.
At the same time we've seen many studies confirming the safety and benefits of flu vaccination and the early use of antivirals in protecting the lives of pregnant women and their unborn child, including:
Pediatrics: Maternal Flu Vaccination Extends Protection To Infants
Clinical Infectious Diseases: Flu Vaccine May Reduce Incidence of Stillbirth
JID: Benefits Of Early Use of Influenza Antivirals In Pregnancy
While seasonal flu vaccines only provide moderate protection against infection, they do a much better job at reducing the severity of the illness (see CDC MMWR: Interim 2023-2024 Flu Vaccine Effectiveness Estimates).
While there is no doubt we need better seasonal flu vaccines, even a little protection can make the difference between a mild, self-limiting illness, and something much worse.And as this study points out, the risks to the unborn child go up with the severity of the maternal infection. If you can reduce the severity, you should also reduce the chances of neurodevelopmental disorders.
