Gestational Influenza and Fetal Brain Abnormalities: Evidence from Epidemiological Studies

Since the 1918–1919 Spanish flu pandemic, clinicians have observed developmental delays, cognitive deficits, and psychiatric disorders in children born to mothers who contracted influenza during pregnancy. The earliest epidemiological studies were only able to establish a correlation between gestational influenza and the risk of psychiatric disorders in children. However, the results were imprecise, as they relied on indirect data such as seasonal flu peaks, women’s recollections of illness, and approximate gestational timing. Due to the limitations of diagnostic tools, it was long impossible to accurately assess either the strength of the effect or the specific risks associated with different stages of pregnancy.

The first laboratory-confirmed study on this association was conducted in 2004 and published in the Archives of General Psychiatry under “Serologic Evidence of Prenatal Influenza in the Etiology of Schizophrenia.” The researchers analyzed archived blood samples collected from pregnant women during flu epidemics in California (USA) between 1959 and 1966. This allowed them to accurately determine past infections based on antibody concentrations. Each sample was matched to the gestational age at the time of collection. The development of schizophrenia-spectrum disorders was assessed in the offspring 30 to 38 years later. The researchers evaluated the risk for specific diagnoses, including schizophrenia, schizoaffective disorder, delusional disorder, psychotic disorder, and schizotypal personality disorder.

The study found that the highest risk of schizophrenia-related disorders occurred when maternal infection took place during the first trimester—within the first 97 days of pregnancy. In such cases, the risk of psychiatric disorders in offspring was seven times higher than in the control group of children born to uninfected mothers. A moderately elevated risk was also observed in the first half of the second trimester, approximately up to day 142 of gestation. Overall, influenza infection during the first half of pregnancy tripled the risk of schizophrenia-spectrum disorders in offspring.

According to the researchers’ calculations, this risk disappeared by the beginning of the second half of pregnancy. They reported no association between maternal influenza infection and schizophrenia-spectrum disorders in the offspring during the late second or third trimesters—defined as the period from day 143 of gestation to the third day after birth.

These findings were later used to estimate the population-level impact of gestational influenza on schizophrenia risk, given the widespread prevalence of influenza. The analysis showed that approximately 14% of global schizophrenia cases may be attributable to maternal flu infection during early or mid-pregnancy.

The 2004 study proved methodologically robust and impactful, becoming a cornerstone for subsequent research. Over the past two decades, it has been cited nearly 1,500 times. For example:

  • It was referenced by an international research team in 2013 studying the link between maternal influenza and the risk of bipolar disorder in offspring. Their results showed that prenatal flu infection at any stage of pregnancy increases the risk of bipolar disorder fourfold. The findings were published in the article “Gestational Influenza and Bipolar Disorder in Adult Offspring.”
  • Danish researchers cited the study in their 2010 publication “Maternal Infection Requiring Hospitalization During Pregnancy and Autism Spectrum Disorders.” They found that maternal fever and severe illness requiring hospitalization were risk factors for autism spectrum disorders (ASD) in children—including impaired social interaction, communication deficits, repetitive behaviors, and abnormal cerebellar development. As in the 2004 study, the highest risk to the embryo was during the first trimester.
  • American researchers also built on the 2004 findings in their investigation of the molecular mechanisms linking perinatal influenza to disrupted development of the embryonic cerebral cortex. Using an animal model, their work contributed to understanding how flu infection affects fetal brain development. This study is discussed in the following section.

Prenatal Influenza Impairs Cortical Development Based on Infection Dose and Gestational Timing

In 2024, U.S. researchers investigated the impact of gestational influenza on offspring cortical development using a mouse model. Pregnant mice were infected with the H3N2 influenza virus during a gestational period equivalent to the end of the first trimester in humans. The strain used mimics common seasonal influenza viruses circulating in human populations.

The researchers found that cortical thinning occurred in all infected fetuses, regardless of viral load. However, a higher infection dose led to significantly more degradation of the embryonic cortical plate, which was particularly evident when examining cortical layers of the developing fetal brain:

Image source:https://pmc.ncbi.nlm.nih.gov/articles/PMC11649561/

Figure A shows primary somatosensory cortex segments of the right hemisphere based on maternal viral load: control (Con), moderate dose (X31mod), and high dose (X31hi). Green: TBR1-positive neurons, important for cortical layer formation. Red: SATB2-positive neurons, whose deficiency is associated with autism, developmental delay, intellectual disability, and speech impairment.
Researchers observed consistent results in both hemispheres. Other panels in the figure quantify cortical degradation based on infection dose.

To explore the causes of cortical reduction, scientists examined immune cell presence in the fetal brain. Prenatal influenza was found to increase immune cell numbers, particularly under high infection doses. The differences are visualized in the following figure:

Image source:https://pmc.ncbi.nlm.nih.gov/articles/PMC11649561/

Figure F shows immune cell counts by maternal viral dose.

  • Y-axis: immune cell types
  • X-axis: infection levels — control (Con), moderate (X31mod), and high (X31hi).
    Other panels (B–E, G–M) show:
    Quantified immune cell counts across brain regions
    • Immuno-mapping across the embryonic brain (panel A)
    • Immune cell proliferation dynamics (panel I)

Researchers propose a threshold effect:

  • Little to no difference in immune cell numbers between control and moderately infected mothers
  • Sharp increase in immune cells in fetuses from highly infected mothers, especially in meningeal regions (see panel L)

Additionally, the phagocytic activity of immune cells in the fetal brain was significantly elevated at high infection doses, again revealing a threshold-dependent effect.

Follow-up RNA sequencing revealed abnormal gene activity in offspring whose mothers had received high infection doses, whereas such changes were absent in the moderate infection group. Researchers conclude that there is a maternal viral load threshold beyond which fetal brain damage becomes pronounced and irreversible.

Preventing Neurodevelopmental Disorders Through Influenza Control

Psychiatrists argue that preventing influenza during pregnancy may reduce the incidence of mental illness. For example, the 2010 review “Maternal Infection and Schizophrenia: Implications for Prevention” estimates that prenatal influenza prevention could lower schizophrenia rates by approximately 30%.
The review recommends vaccination, describing it as follows:
“Vaccination is the foundation of influenza prevention. It is a safe and effective intervention that has prevented millions of cases and saved tens of thousands of lives. There is no evidence of adverse perinatal outcomes or congenital disabilities linked to influenza vaccination.”

The American College of Obstetricians and Gynecologists recommends inactivated or recombinant flu vaccines for pregnant individuals. Their article “Influenza During Pregnancy: Prevention and Treatment” states:
“As an integral part of prenatal and postpartum care, influenza vaccination is the safest and most effective method of prevention.”
They also suggest consulting local public health guidelines for mask usage and prophylactic medications.

Finally, the Centers for Disease Control and Prevention (CDC) have published specific guidelines in “Influenza and Pregnancy”. In addition to vaccination, they recommend avoiding contact with ill individuals, frequent handwashing, and ensuring access to clean air.

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