Seizures and First-Generation Antihistamines in Young Children

Source: Kim JH, Ha EK, Han B, et al. First-generation antihistamines and seizures in young children. JAMA Netw Open. 2024;7(8):e2429654; doi: 10.1001/jamanetworkopen.2024.29654.Investigators from multiple institutions in South Korea conducted a retrospective study to evaluate the association between recent use of first-generation antihistamines and seizures in children.For the study, they reviewed the Korean National Health Insurance Service database, which includes demographic, health care encounter, diagnostic, and prescription data on the entire population. Children born between 2002 and 2005 who had an emergency department (ED) visit with an ICD-10 diagnosis of seizure prior to 2020 were identified. For the study, a case-crossover design was used, in which only patients with a seizure who had a prescription for a first-generation antihistamine during the “hazard period” (1–15 days before the seizure event), control period 1 (31-45 days prior), or control period 2 (61-75 days) were included. The number of seizures occurring during the hazard period was compared to the number during control period 1 and control period 2 using conditional logistic regression, in which each child served as their own control. Age and other possible confounders were included in the model. Subgroup analyses including patients from different age groups (6–24 months, 25 months–6 years, ≥7 years), were conducted. In addition, the analyses were repeated when the hazard period was reduced to 1–10 and 1–5 days before the index seizure.Data were analyzed on 3,178 children with a seizure and prescription for a first-generation antihistamine during the hazard period or 1 of the control periods. Among these patients, 31.0% were 6–24 months old at the time of the index seizure, and 45.5% were 25 months to 6 years old. The number of seizures occurring during the hazard period was 1,476, compared to 1,239 in control period 1 and 1,278 during control period 2. After adjusting for confounders, the risk of a seizure was significantly higher during the hazard period than control periods (adjusted odds ratio [AOR], 1.22; 95% confidence interval [CI], 1.13, 1.31). The risk of a seizure during the hazard period was greater than during the control periods in children 6–24 months old (aOR, 1.49; 95% CI, 1.31, 1.70), but not in those 25 months–6 years old (aOR, 1.11; 95% CI, 1.00, 1.24) or ≥7 years old (aOR, 1.10; 95% CI, 0.94, 1.28). The risk of seizure also was increased in models in which the hazard period was shortened to 1–10 days or 1–5 days before the index event (aOR, 1.25; 95% CI, 1.15, 1.36; and aOR, 1.36; 95% CI, 1.23, 1.51, respectively).The authors conclude that recent exposure to first-generation antihistamines was associated with an increased risk of seizure in young children.Dr Thompson has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.Prescription of medication in children must consider the balance of benefit vs risk. This is especially true in younger patients, a population for whom efficacy and safety data may be lacking or unclear. At-risk patients with comorbidities may not tolerate some medications.The neurologic effects of first-generation antihistamines have been studied previously,1 the theoretical mechanism for seizure risk has been discussed elsewhere,2 and other authors have cautioned against their widespread use in children.3 The current study brings to light the potential clinical impact of these agents in young children.The current investigators sought to define the risk of seizures in children treated with first-generation antihistamines, which are used widely for light sedation and management of allergic and upper respiratory infection symptoms. The authors used a large study cohort with a design chosen to limit the effects of confounding variables. Their results indicate a risk of seizures for these children, most significantly (22% higher) in the 6–24 months age group.It is notable that the increased risk for seizures that was identified was clinically evident in a restricted age population. This suggests that perhaps neurobiological and neurodevelopmental factors were responsible for this finding.The authors of the study and accompanying editorial4 appropriately conclude that caution must be used when prescribing these agents to young patients. The study does not, however, provide any information to guide the use of newer antihistamines or the risk of antihistamines in pediatric patients with a prior history of seizures.Careful risk/benefit consideration is essential when prescribing first-generation antihistamines; it may be best to use other substitute medications in children 6–24 months of age.