In utero exposure to flu spells increased risk of childhood seizures

Infants born to mothers who contracted influenza infection during pregnancy are at heightened risk of seizures, particularly febrile seizures, during childhood, according to a large study. 

Analysis of data from more than 1 million mother-offspring pairs from Taiwan’s Maternal and Child Health Database showed that the cumulative risk of seizures was elevated among offspring whose mothers had prenatal influenza infection than among offspring whose mothers had not been exposed to such infection during pregnancy (all seizures: adjusted hazard ratio [aHR], 1.09, 95 percent confidence interval [CI], 1.05–1.14; p<0.001). [JAMA Netw Open 2024;7:e2434935]

When stratified by seizure type, in utero exposure to influenza raised the risk of febrile convulsions by 11 percent (aHR, 1.11, 95 percent CI, 1.06–1.17; p<0.001) but not the risk of epilepsy (aHR, 1.04, 95 percent CI, 0.97–1.13; p=0.27).

Looking at the timing of influenza infection, the investigators noted a slight increase in the risk of all seizures, febrile convulsions, and epilepsy during the third trimester, although this risk increase was not significant.

Several factors influenced the risk of all seizures among children born to mothers who had influenza during pregnancy. These included maternal age (25–29 vs <25 years: aHR, 0.90, 95 percent CI, 0.86–0.94; p<0.001), gestational hypertension (aHR, 1.78, 95 percent CI, 1.18–2.69; p<0.001), mode of delivery (caesarean delivery: aHR, 1.09, 95 percent CI, 1.05–1.14; p<0.001), male offspring sex (aHR, 1.28, 95 percent CI, 1.23–1.32; p<0.001), birth weight (2,000–2,499 vs ≥2,500 g: aHR, 1.27, 95 percent CI, 1.17–1.38; p<0.001), and gestational age (32–36 vs ≥37 weeks: aHR, 1.23, 95 percent CI, 1.14–1.33; p<0.001).

The findings were robust to sensitivity analyses adjusted for maternal age, family income, urbanization, or pregnancy-related complications.

This study aligns with an international study wherein prenatal exposure to influenza infection was also associated with increased risk of childhood seizures (HR, 1.17, 95 percent CI, 1.07–1.28), including febrile seizure (HR, 1.20, 95 percent CI, 1.07–1.34) but not epilepsy (HR, 1.07, 95 percent CI, 0.81–1.41), according to the investigators. [Arch Dis Child 2022;107:153-159]

“During pregnancy, it is broadly believed that a state of generalized immunosuppression develops, which makes the mother more susceptible to certain infectious diseases. These pathogens may have unfavourable foetal and neonatal consequences, due to intrauterine transmission via the placenta,” the investigators noted.

In animal studies, “general inflammatory changes in vessels, vascular dysfunction, with increased proinflammatory cells and cytokines were found in pregnant mice with influenza A virus infection. This phenomenon can lead to poor placental maturation, restricted foetal growth, and molecular evidence of foetal brain hypoxia… Hypoxia-affected grey matter is more electrosensitive and could precede a seizure attack,” they pointed out. [Proc Natl Acad Sci U S A 2020;117:24964-24973]

The investigators highlighted the mentioned evidence as a possible explanation for the higher risk of seizures observed among children born to mothers who contracted influenza during pregnancy.

“Further studies are needed to elucidate the mechanisms underlying childhood neurological development,” they said.

The study included 1,316,107 mother-offspring pairs, of whom 75,835 offspring (51.9 percent male) were born to mothers (predominant maternal age 25–29 years) who had influenza during pregnancy. Compared with mother without a history of prenatal influenza infection, those who did had a slightly higher prevalence of placenta previa or abruption (1.6 percent vs 1.4 percent; p<0.001).