Can Maternal Illness During Pregnancy Alter Neurodevelopment in Children?

Post by Lani Cupo

What is maternal immune activation (MIA)?

Since the 19th century, doctors and researchers have noticed a peculiar correlation—children born in the winter months have a slightly increased risk of developing psychotic disorders, such as schizophrenia, during adolescence and early adulthood. To investigate a potential factor contributing to this relationship, epidemiological studies known as birth-cohort studies (which follow participants from before birth as they age) looked for blood markers in pregnant women that indicated their immune systems were active. They found that the children of women who were sick during pregnancy had increased risks of developing Autism Spectrum Disorders (ASDs) during childhood, and schizophrenia in early adulthood. Interestingly, the associations were not limited to viral infections, even though they were initially found following influenza epidemics, such as the Spanish Flu. Increased rates of psychiatric disorders were also found following prenatal exposure to bacterial infection, such as pneumonia, or parasites, like Toxoplasma gondii. This implies that there is a connection between activation of the maternal immune system itself (Maternal Immune Activation or MIA) and an alteration in neurodevelopment.

The immune system is highly active during pregnancy in order to protect the mother and fetus from invading pathogens. When a pathogen, like the flu virus, enters the mother’s body, it can activate her immune system, causing a chain of reactions that ultimately lead to the release of “pro-inflammatory cytokines”, proteins that are secreted by cells of the immune system and travel throughout the body through the bloodstream. Examples of pro-inflammatory cytokines include interleukin (IL)-6, IL-17, and tumor necrosis factor (TNF) alpha. It is still unclear whether these cytokines can cross the placenta to the fetal compartment, or whether they cause changes to the placenta that impact the fetus.

What do we know?

While birth cohort studies in humans are extremely informative, they are difficult to conduct, as it takes decades to acquire data from before birth to early adulthood and participants often drop out before study completion. Furthermore, it is, of course, unethical to expose pregnant women to infections in order to conduct a controlled experiment manipulating an independent variable of interest. Because of these limitations, experiments that seek to investigate a risk factor over the lifespan often use nonhuman animals, many of which reach the equivalent of adulthood in a matter of months.

In such experiments using animal models, the maternal immune system can be activated with the introduction of compounds that mimic a viral or bacterial infection. This allows researchers to specifically assess the impact of MIA, rather than the effect of a particular pathogen. Studies in mice, rats, rabbits, and nonhuman primates provide robust evidence that MIA can contribute to altered trajectories of neurodevelopment, changing volume in brain regions of particular interest in the study of psychiatric disorders such as the hippocampus, anterior cingulate cortex, amygdala, and thalamus. These brain regions mainly comprise the limbic system, considered crucial to emotion processing and memory formation. There is also evidence for behavioral alterations consistent with psychiatric disorders, such as increased anxiety, decreased sociability, and memory impairment. Despite the considerable consensus that there is an impact of prenatal exposure to MIA on brain development and mental health in offspring, there are many factors to an experimental design that can influence results, including the timing of exposure, the severity of exposure, and timing of experimental outcomes (i.e. when researchers measure the impact in childhood, adolescence, or adulthood). This could in part contribute to the variability seen in many experimental results, with some studies failing to replicate the expected alterations.

The exact mechanisms of how MIA may contribute to changes to brain volume and behavior are unknown. Nevertheless, one hypothesis is that MIA leads to long-lasting alterations in certain immune molecules that help control neural connectivity and function in offspring. This could lead to changes in synapses (connections between neurons) that may last throughout the lifespan. There is some evidence that alterations in limbic regions may be associated with changes in inhibitory GABAergic neurons and overactive excitatory dopaminergic neurons, however, the data are preliminary, and require further investigation. Future research may focus on questions regarding the underlying mechanisms that explain the relationship between MIA and psychiatric symptoms in offspring.

Maternal immune activation and COVID-19

Given the long-term impact MIA can have on a global scale, the current COVID-19 pandemic may convey additional burdens on future generations, a hypothesis identified as a research and public health priority. While preliminary studies have already investigated whether pregnancy alters the severity of COVID-19 response in individuals exposed to the virus, there is, as of yet, no consensus. There is some evidence that COVID-19 may impact the risk for preterm birth, intrauterine growth restriction, and low birth weight, which can have health implications for children. These findings are still preliminary, however, and years of research lie between us and firmly established results.

What does this mean for me?

It is important to know, in humans most maternal infections do not lead to psychiatric disorders in children. If you or someone you love is pregnant and becomes ill, this does not mean that the child will develop a disorder. It is more likely that MIA works in concert with other risk factors, such as genetic predisposition, heavy adolescent drug exposure, or childhood trauma to contribute to the observed increase in risk. 

Additionally, there is no evidence that vaccines administered during pregnancy or early in childhood contribute to the development of ASDs or schizophrenia. Risk-benefit analyses assessing influenza vaccines suggest the benefits of receiving the vaccination outweigh any risk. To date, no study reports adverse fetal or maternal outcomes following receipt of inactivated seasonal influenza vaccinations. If you are pregnant, receiving vaccinations as per physician recommendations can help protect you and your child.

References

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Estes & McAllister. Maternal immune activation: implications for neuropsychiatric disorders. Science. (2017). Access the original scientific publication here.

Guma et al. The role of maternal immune activation in altering the neurodevelopmental trajectories of offspring: A translational review of neuroimaging studies with implications for autism spectrum disorder and schizophrenia. Neurosci Biobehav Rev. (2019). Access the original scientific publication here.

Herberts et al. New adjuvanted vaccines in pregnancy: what is known about their safety? Expert Rev. Vaccines. (2010). Access the original scientific publication here.

Kepinska et al. Schizophrenia and Influenza at the Centenary of the 1918-1919 Spanish Influenza Pandemic: Mechanisms of Psychosis Risk. Frontiers in Psychiatry. (2020). Access the original scientific publication here.

McAlonan et al. Multidisciplinary research priorities for the COVID-19 pandemic. The Lancet Psychiatry. (2020). Access the original scientific publication here.

Nyffeler et al. Maternal immune activation during pregnancy increases limbic GABAA receptor immunoreactivity in the adult offspring: Implications for schizophrenia. Neuroscience. (2006). Access the original scientific publication here.

Racicot et al. Understanding the complexity of the immune system during pregnancy. Am J Reprod Immunol. (2014). Access the original scientific publication here.

Zuckerman et al. Immune Activation During Pregnancy in Rats Leads to a PostPubertal Emergence of Disrupted Latent Inhibition, Dopaminergic Hyperfunction, and Altered Limbic Morphology in the Offspring: A Novel Neurodevelopmental Model of Schizophrenia. Neuropsychopharmacology. (2003). Access the original scientific publication here.