Most affected were those aged from 6 months to 24 months, according to the report in the Journal of the American Medical Association Network Open.
“These findings reinforce the importance of cautious first-generation antihistamine prescription in young children and underline the need for further research to fully understand associations between antihistamine use and seizure risk,” the authors from Kyung Hee University Medical Center in Seoul wrote.
The study team sought to assess associations between prescriptions of first-generation antihistamines and seizures in children, using a comprehensive and nationwide dataset. Data were obtained from the National Health Insurance Service database in Korea. The study included children born between January 1, 2002, and December 31, 2005, who visited the emergency department for seizure events (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, codes R56.8, G40, and G41). Data were analyzed from June 3, 2023, to January 30, 2024.
“The widespread use of antihistamines in children for treatment of common cold symptoms and their central nervous system effects, like drowsiness, underscore the importance of being aware of the associated risks,” the researchers suggested.
The study tracked first-generation antihistamine prescriptions 1 to 15 days before index seizure (hazard period) against the control period 1 (31-45 days before the event) and control period 2 (61-75 days before the event).
The results indicated that of 11,729 children who had a seizure event, 3,178 (55.9% were boys) were identified as having been prescribed antihistamines during the hazard or the control period, but not both.
The study found that seizure events were predominantly observed in children aged 6 to 24 months (985 [31.0%]) and 25 months to 6 years (1,445 [45.5%]).
“During the hazard period, 1,476 first-generation antihistamine prescriptions were recorded, in contrast to 1,239 and 1,278 prescriptions during control periods 1 and 2, respectively,” the authors advised. “After multiple confounder adjustments, first-generation antihistamine prescription was associated with an increased seizure event risk during the hazard period (adjusted OR [AOR], 1.22 [95% CI, 1.13-1.31]).”
The researchers added that stratified subgroup analyses showed consistent results, especially in children aged 6 to 24 months who were prescribed first-generation antihistamines. Those children demonstrated a higher risk (AOR, 1.49; 95% CI, 1.31-1.70) than children aged 25 months to 6 years (AOR, 1.11; 95% CI, 1.00-1.24; P = .04 for interaction).
“Furthermore, sensitivity analyses, including adjustment for exposure window periods, evaluation of new first-generation antihistamine prescriptions, comparison of control points from the same period 1 year prior, and exclusion of individuals using combination drugs, confirmed a similarly high risk,” the researchers noted.
First-generation H1 antihistamines—developed in the 1940s and 1950s—initially served as tranquilizers and antipsychotics by crossing the blood-brain barrier (BBB) and suppressing histamine neurotransmission in the central nervous system, according to background information in the article.
“Despite reduced therapeutic use owing to their poor selectivity and interactions with other receptors, these drugs are still widely used for managing rhinorrhea in the common cold or to control an itching sensation in children,” the authors pointed out. “Because first-generation antihistamines can cross the BBB, their effects may extend beyond somnolence and drowsiness to markedly influence brain wave activity. Thus, caution is advised when prescribing these antihistamines to children younger than 2 years, an age group for whom drug safety data are lacking and first-generation antihistamines are generally not recommended.”
A number of previous studies have indicated that first-generation antihistamines can affect brain waves, inducing symptomatic seizures, affecting electroencephalographic (EEG) activity and seizure thresholds in adults with inherent seizure susceptibility and altering resting EEG activity.
“Clinically, antihistamines have been identified as a common trigger of acute symptomatic seizures, and there have been some instances of seizure induction by second-generation antihistamines,” the researchers explained. “Altered seizure patterns were noted in children with febrile seizures who were exposed to antihistamines. However, the impact of first-generation antihistamines on brain waves and the heightened sensitivity to them among vulnerable age groups remains less explored in clinical practice.”
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