Epilepsy risk elevated in children with congenital Zika syndrome

New research suggests that in-utero exposure to Zika virus (ZIKV) alone does not increase the risk of epilepsy in early childhood, and the risk increase is limited to children who develop congenital Zika syndrome.

In a large Brazilian population-based cohort, the risk of epilepsy-related hospital admission during the first 4 years of life was 34 times higher among those who were exposed to ZIKV in utero and subsequently developed congenital Zika syndrome than among those who were unexposed (adjusted hazard ratio [aHR], 34.22, 95 percent confidence interval [CI], 29.16-40.16]). [JAMA Pediatr 2025;doi:10.1001/jamapediatrics.2025.4935]

The risk increase peaked at age 7–18 months (aHR, 44.58, 95 percent CI, 35.89–55.36) and decreased thereafter, although remaining 20 times higher relative to unexposed children (19–48 months: aHR, 20.62, 95 percent CI, 14.31–29.72; 0–6 months: aHR, 33.72, 95 percent CI, 24.70–46.04).

Notably, the associations were independent of head circumference, with the risk estimates for epilepsy-related hospitalization similar among children with congenital Zika syndrome who had microcephaly (aHR, 38.76, 95 percent CI, 31.27–48.05), macrocephaly (aHR, 30.36, 95 percent CI, 22.73–40.56), or normocephaly (aHR, 30.36, 95 percent CI, 22.73–40.56).

On the other hand, children exposed to ZIKV in utero but did not develop congenital Zika syndrome did not appear to have an increased risk of epilepsy-related hospital admission compared with their unexposed peers (aHR, 0.66, 95 percent CI, 0.34–1.27).

“Some cases of epilepsy are primary, with no identifiable underlying cause, while others are secondary to structural abnormalities in the central nervous system. An example of the latter is congenital Zika syndrome, where epilepsy is a clinical manifestation in nearly 50 percent of affected children, increasing to approximately 99 percent when microcephaly is also present,” the investigators said. [BMJ Open 2018;8:e021304; Am J Trop Med Hyg 2018;98:1860-1862]

The WHO recommends periodic neurodevelopmental assessments for all children with possible in utero ZIKV exposure, although this recommendation is based mostly on a few studies that have been limited by small sample sizes, epilepsy diagnosis based on maternal reporting, and a lack of distinction between severe and mild epilepsy episodes, they continued. [https://www.who.int/publications/i/item/WHO-ZIKV-MOC-16.3-Rev.1; Am J Trop Med Hyg 2018;98:1860-1862; PLoS Negl Trop Dis 2020;14:e0008874; Epilepsia 2020;61:509-518]

The present data provide important evidence to the field. The investigators emphasized that they used a nationwide linked cohort with a large sample size and focused on the first clinically significant epilepsy episode requiring hospital admission.

“Additionally, we adjusted for potential confounders, including head circumference among children with congenital Zika syndrome and the estimated timing of ZIKV exposure for those exposed without congenital Zika syndrome, while accounting for death as a competing event,” they added.

The analysis included 10,828,887 children (mean gestational age 38.5 weeks, 48.7 percent female). Of these, 2,780 (0.03 percent) were exposed to ZIKV in utero and developed congenital Zika syndrome and 8,361 (0.08 percent) were exposed to ZIKV in utero without developing congenital Zika syndrome.

Children with vs without congenital Zika syndrome were more likely to be born preterm (20 percent vs 9.8 percent) and with low birth weight (35.5 percent vs 7.2 percent). Mothers of children with vs without congenital Zika syndrome also had lower educational levels, with 86.8 percent vs 77.9 percent having less than 12 years of education.