First-generation antihistamine drugs could increase seizure risk among young children

By Pooja Toshniwal PahariaReviewed by Lily Ramsey, LLMAug 30 2024

In a recent study published in JAMA Network Open, researchers assessed associations between prescriptions of first-generation-type antihistamine drugs and seizures among children.

Study: First-Generation Antihistamines and Seizures in Young Children. Image Credit: MDV Edwards/Shutterstock.com

Background

Generation 1 antihistamines, initially used as tranquilizers and antipsychotics, are now used to treat common cold symptoms and decrease itchy sensations in youngsters.

These drugs can pass through the blood-brain barrier (BBB). Their usage has declined due to their poor selectivity and ability to affect brain wave activity, particularly in children under two years old.

According to research, first-generation antihistamines can cause symptomatic seizures in adults while also influencing electroencephalographic activity and seizure thresholds. Generation 1 antihistamines enhance seizure susceptibility in rats, and genetically manipulated animal models support a relationship to epileptic seizures.

Clinically, antihistamines have been a prevalent cause of acute symptomatic seizures, with changed seizure patterns reported in children with febrile seizures who consumed antihistamines. However, the effect of generation 1 antihistamines on brain waves, as well as their heightened sensitivity in sensitive age groups, has gotten less attention in clinical practice.

About the study

In the present retrospective cohort study, researchers investigated whether the acute prescription of generation 1 antihistamine medications increases the risk of seizures among children.

The study analyzed data from Korea's National Health Insurance Service (NHIS) database. Participants were children with birth dates between 1 January 2002 and 31 December 2005 who consulted emergency departments due to seizures.

Exclusion criteria included children with missing birth records, those experiencing seizures at less than six months of age, and those who did not receive first-generation antihistamine prescriptions before the seizure event.

The researchers diagnosed seizures using the International Classification of Diseases, tenth revision (ICD-10) codes. They completed follow-up on 31 December 2019 and analyzed data between 3 June 2023 and 30 January 2024. Children served as their controls in this case-crossover study.

The study exposure was the prescription of first-generation antihistamines. The primary outcome comprised a seizure event; the date of occurrence was considered the index date.

Multivariate conditional logistic regression models estimated the adjusted odds ratios (AOR) for seizures, with adjustments for age, gender, economic status, residence, perinatal conditions, and index date season.

The models compared generation 1 antihistamine prescriptions 15 days prior to the index date (hazardous period) against two control periods, the first being 31 to 45 days preceding seizure occurrence and the second 61 to 75 days preceding the event.

Stratified subgroup analyses evaluated the relationship with participant characteristics. In sensitivity analyses, researchers used time windows of five and ten days, compared control points from the same period a year prior, evaluated singe-formulation generation 1 antihistamine prescriptions, and excluded individuals using drug combinations.

They additionally adjusted for acute clinical diseases associated with seizures, such as sinusitis, pharyngitis, nasopharyngitis, tonsillitis, purulent otitis media, asthma, upper respiratory tract infections, bronchitis, and bronchiolitis.

Results and discussion

Among 11,729 children who developed seizures, 3,178 [1776 (56%) boys] had received antihistamine prescriptions in the hazard period or control periods but not during both.

Seizures were predominant among children six months to two years old [985 (31%)] and those aged between 25 months and six years [1445 (46%)]. Fifteen days before seizure occurrence, 1,476 first-generation antihistamines were prescribed, 1,239 antihistamine prescriptions during the first control period, and 1,278 prescriptions during the second control period.

After adjusting for confounders, generation 1 antihistamine prescriptions were related to an increased risk of seizures in the hazardous period (AOR, 1.2).

Stratified analyses showed similar results, especially among children six months to two years of age who received first-generation antihistamine prescriptions having a risk of seizure (AOR, 1.5) higher than those between 25 months and six years of age (AOR, 1.1). Sensitivity analyses confirmed the primary results.

Antihistamines may increase seizure risk by various mechanisms, including decreasing hypothalamic neural histamine, which causes neuronal excitability, affecting glutamine synthase, and directly blocking neuronal channels.

These actions increase seizure susceptibility by increasing brain activity related to histamine receptors and H1 receptor malfunction, which govern seizure severity and duration. Infants' brains are vulnerable to antihistamines owing to the developing BBB, which is still evolving at this age.

Incomplete BBB development increases permeability, resulting in more drug penetration into brain tissue. Antihistamines, while safe for adults and older children, may damage newborns. Underdeveloped metabolic pathways and inadequate brain myelination contribute to seizure vulnerability in young infants, increasing the risk of seizures associated with antihistamine usage during infancy.

Conclusion

The study found that first-generation antihistamine prescriptions increased the seizure risk among children by 22%, particularly those aged six months to two years.

The findings underscore the importance of cautious and prudent use of generation 1 antihistamine medicines among young children. Further study is needed to determine the relationship between antihistamine medicine prescriptions and the risk of getting seizures.