A comprehensive binational birth cohort study published in JAMA Network Open reveals that while initial population-level analyses showed a modest association between maternal influenza infection during pregnancy and childhood neuropsychiatric disorders, these links vanished when researchers conducted sibling-comparison analyses, offering reassurance to expectant mothers.
Sibling Tests Erase Link Between Prenatal Flu and Disorders
- What the study tested: Researchers looked at whether catching the flu during pregnancy raises a child’s risk of developing conditions like ADHD, autism, or obsessive-compulsive disorder later in life.
- The initial findings: Standard population data hinted at a slight increase in risk for certain disorders, but this approach could not account for shared family genetics or home environments.
- The definitive sibling test: When comparing children from the same mother where one was exposed to flu in utero and one was not, the statistical link completely disappeared.
Binational Cohort Data and Population-Level Findings
Led by Dong Keon Yon, MD, PhD, of Kyung Hee University College of Medicine in Seoul, South Korea, researchers investigated the relationship between maternal influenza infection and subsequent neuropsychiatric diagnoses in offspring. The investigation utilized a discovery cohort from South Korea and a replication cohort from Japan, including live births between January 2010 and December 2017.
In initial population-level mother-child pair analyses, maternal influenza exposure during pregnancy correlated with an elevated risk of any neuropsychiatric disorder in both the South Korean discovery cohort (adjusted HR 1.09, 95% CI 1.04-1.14) and the Japanese replication cohort (aHR 1.10, 95% CI 1.02-1.19). Breaking down specific conditions in the South Korean cohort, children born to mothers with documented influenza infections showed higher likelihoods of developing obsessive-compulsive disorder (aHR 1.37, 95% CI 1.14-1.64) and attention deficit-hyperactivity disorder (aHR 1.13, 95% CI 1.07-1.19). Meanwhile, the Japanese replication cohort identified a significant association solely with ADHD (aHR 1.26, 95% CI 1.11-1.43). Neither cohort demonstrated significant associations with autism spectrum disorder, intellectual disability, or severe neuropsychiatric conditions such as schizophrenia.
Sibling-Comparison Analyses Neutralize Initial Associations
The statistics changed dramatically once the investigative team applied sibling-comparison methodologies to control for unmeasured familial confounding factors, such as shared genetics and common household environments. Within the sibling-comparison subgroups—comprising 33,191 mother-child pairs in the South Korean cohort and 7,842 pairs in the Japanese cohort—the previously observed associations lost statistical significance entirely.
For the discovery cohort, the adjusted hazard ratio dropped to 0.98 (95% CI 0.89-1.09). For the replication cohort, the adjusted hazard ratio adjusted to 1.04 (95% CI 0.88-1.22). None of the five individual neuropsychiatric categories maintained a statistically significant relationship with maternal influenza infection when evaluated through sibling comparisons.
| Cohort Analysis Type | South Korean Discovery Cohort (aHR & 95% CI) | Japanese Replication Cohort (aHR & 95% CI) |
|---|---|---|
| Population-Level Pair Analysis | 1.09 (1.04–1.14) | 1.10 (1.02–1.19) |
| Sibling-Comparison Analysis | 0.98 (0.89–1.09) | 1.04 (0.88–1.22) |
“The key message is that the modest associations observed in population-level analyses should not be interpreted as evidence that maternal influenza infection directly causes neuropsychiatric disorders in offspring,” Yon explained to MedPage Today. He noted that while shared familial factors help explain population-level outcomes, the sibling comparisons featured smaller sample sizes and wider confidence intervals, meaning the data cannot entirely rule out subtle effects.
Binational Evaluation Resolves Inconsistencies in Prior Research
Prior literature examining this research question has often suffered from high study heterogeneity and limited evidence quality, as highlighted by a 2022 systematic review encompassing 42 studies. By pooling large-scale national databases across two distinct countries and executing rigorous sibling-matched controls, the current binational evaluation aimed to resolve past inconsistencies.
Study authors acknowledged specific limitations, including a follow-up window restricted to childhood and early adolescence, which prevents observation of later-onset conditions like schizophrenia or bipolar disorder. Despite these boundaries, investigators emphasize that clinical guidance should remain unchanged. The American College of Obstetricians and Gynecologists maintains its recommendation for inactivated or recombinant influenza vaccination throughout flu season for individuals who are or will be pregnant, as immunization remains vital for preventing severe maternal and infant complications.
References
- JAMA Network Open: Association of Maternal Influenza Infection With Neuropsychiatric Disorders in Offspring
- MedPage Today: Maternal Flu Shot and Kids’ Neuropsychiatric Disorders: Study Offers Reassurance
- American College of Obstetricians and Gynecologists (ACOG): Influenza Vaccination During Pregnancy Guidelines
