Maternal Flu Shot and Kids’ Neuropsychiatric Disorders: Study Offers Reassurance

The association between maternal influenza infection during pregnancy and neuropsychiatric disorders in children didn’t hold up in sibling comparisons, according to a population-based birth cohort study.

In analyses of mother-child pairs, maternal influenza infection was associated with an increased risk of any neuropsychiatric disorder in the discovery cohort from South Korea (adjusted HR 1.09, 95% CI 1.04-1.14) and the replication cohort from Japan (aHR 1.10, 95% CI 1.02-1.19), wrote Dong Keon Yon, MD, PhD, of Kyung Hee University College of Medicine in Seoul, South Korea, and colleagues in JAMA Network Open.

Those associations’ significance evaporated, however, when the children born to mothers with flu during pregnancy were compared with their siblings who were born when their mothers didn’t have flu infections while pregnant:

• Discovery cohort (aHR 0.98, 95% CI 0.89-1.09)
• Replication cohort (aHR 1.04, 95% CI 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 told MedPage Today. “The attenuation of these associations in sibling comparisons highlights the importance of considering shared familial factors when interpreting observational findings.”

While shared familial factors may partly explain the associations seen in the population-based analyses, Yon said, the sibling comparisons involved smaller sample sizes and wider confidence intervals. Thus, those findings also shouldn’t be interpreted as definitive evidence that no association exists between maternal flu during pregnancy and neuropsychiatric outcomes in children, he cautioned.

Given that the study involved pregnant women and children, “we believe it is particularly important to avoid overstating potential risks or creating unnecessary anxiety among expectant mothers,” Yon noted. “Our findings should not change established recommendations for influenza prevention and appropriate clinical management during pregnancy.”

Flu infection during pregnancy is associated with adverse health outcomes for moms and newborns, and maternal flu vaccination is linked to protection against severe infection in infants. The American College of Obstetricians and Gynecologists recommends vaccination with either inactivated or recombinant flu vaccines for women who are or will be pregnant during flu season.

Maternal health factors have been tied to a greater risk of neuropsychiatric outcomes, such as autism spectrum disorder (ASD). But prior research into maternal flu in pregnancy and children’s neuropsychiatric outcomes has delivered inconsistent findings. A 2022 systematic review of 42 studies on the subject found the quality of evidence was limited and heterogeneity between studies was high.

This study aimed to deliver a “more comprehensive and robust assessment” by combining population-level analyses, sibling comparisons, and replication across two countries, Yon explained.

For this binational cohort study, the researchers included women who had a live birth between January 2010 and December 2017. The South Korean discovery cohort included 2,564,435 mother-child pairs (mean maternal age 31.9, 50.5% male offspring), of whom 1.4% were exposed to maternal influenza during pregnancy. The replication cohort included 181,681 pairs (51% male offspring), of whom 6.2% were exposed. Sibling-comparison analyses included 33,191 and 7,842 mother- child pairs in the discovery and replication cohorts, respectively.

The study’s primary outcome was the first postnatal diagnosis of any neuropsychiatric disorder in children, including attention deficit-hyperactivity disorder (ADHD), ASD, intellectual disability, obsessive-compulsive disorder (OCD), and severe neuropsychiatric disorders such as schizophrenia.

In the South Korean discovery cohort, children born to mothers with flu were more likely to develop OCD (aHR 1.37, 95% CI 1.14-1.64) and ADHD (aHR 1.13, 95% CI 1.07-1.19). There were no significant associations with ASD, intellectual disability, or severe neuropsychiatric disorders.

In the Japanese replication cohort, ADHD was the only neuropsychiatric disorder that was significantly more likely among children born to mothers with flu (aHR 1.26, 95% CI 1.11-1.43). Neither of the sibling-comparison cohorts showed significant relationships between maternal flu and any of the five neuropsychiatric disorders.

“The associations observed for OCD and ADHD in the population-level analyses suggest that the relationship between maternal influenza infection and offspring neuropsychiatric outcomes may differ across disorders,” Yon said.

The authors noted that follow-up was limited to childhood and early adolescence, which may not have captured later-onset disorders such as schizophrenia or bipolar disorder. Unmeasured confounding also can’t be ruled out, given limited data on genetic factors or maternal lifestyle and health behaviors.