Study: First-generation antihistamines may increase seizure risk in young children
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Key takeaways:
- Children aged 6 to 24 months had a significantly increased risk for seizure.
- The results raise questions for clinical practice.
A Korean study identified a 22% increased risk for seizure among young children who were prescribed first-generation antihistamines, according to findings published in JAMA Network Open.
Specifically, the researchers calculated that there was a statistically significant increased risk for seizure among children aged 6 months to 2 years who received first-generation antihistamines, but not among children aged 25 months to 6 years, according to a summary of the results written by Frank Max Charles Besag, MD, ChB, a physician from University College London and the East London Foundation National Health Service Trust
More questions than answers?
In a related commentary, Besag said the study’s findings could “pose more questions than they provide answers for the practicing clinician,” including about how the results will translate to clinical practice.
“Should this prevent the clinician from prescribing first-generation antihistamines to this specific group of patients? If there is a better alternative management available, first-generation antihistamines should probably be avoided in younger children, especially for relatively trivial indications,” Besag wrote.
“However,” Besag continued, “it could be argued that, for any medication, the prescriber should perform a valid benefit-risk assessment and, with the limited data available, if the benefit still seems to outweigh the risk, and if no better options appear to be available, it might still be appropriate to prescribe first-generation antihistamines to young patients, with appropriate monitoring.”
‘Need for careful consideration’
Ju Hee Kim, MD, from the department of pediatrics at Kyung Hee University Medical Center in Seoul, South Korea, and colleagues conducted a retrospective cohort study of 3,178 (55.9% boys) children born from 2002 through 2005 in South Korea who were prescribed first-generation antihistamines and experienced a seizure during one of three periods: within 15 days of antihistamine prescription, or 31 to 45 days (control period 1) or 61 to 75 days (control period 2) between prescription and seizure event.
They collected data through the Korean National Health Insurance Service Database up until Dec. 31, 2019.
The first-generation antihistamines included in the study were chlorpheniramine maleate, mequitazine, oxatomide, piprinhydrinate and hydroxyzine hydrochloride. Chlorpheniramine maleate is available over the counter in the United States in allergy and cold medicines.
“First-generation H1 antihistamines, developed in the 1940s and 1950s, initially served as tranquilizers and antipsychotics by crossing the blood-brain barrier and suppressing histamine neurotransmission in the central nervous system,” Kim and colleagues wrote. “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.”
Nearly half of the children in the study (46.4%) were prescribed antihistamines during the hazard period, 39% during control period 1 and 40.2% during control period 2.
Children’s risk for seizure was elevated during the hazard period (adjusted OR = 1.22; 95% CI, 1.13-1.31) compared with the control periods. Children who had never used antihistamines before had an even higher risk for seizures (aOR = 1.25; 95% CI, 1.14-1.35).
Seizure risk was highest within 5 days of antihistamine prescription (aOR = 1.36; 95% CI, 1.23-1.51).
The researchers found seizure risk varied among age groups (P = .04 for interaction). Children aged 6 to 24 months had a significantly higher risk for seizure (aOR = 1.49; 95% CI, 1.31-1.7), whereas children aged 25 months to 6 years (aOR = 1.11; 95% CI, 1-1.24) and 7 years or older (aOR = 1.1; 95% CI, 0.94-1.28) did not.
“Our finding that antihistamines are linked to seizure risk in children 24 months and younger suggests a possible developmental impact,” Kim and colleagues wrote. “Our results may suggest the need for careful consideration when prescribing antihistamines to infants or patients prone to seizures.”
References:
- Besag FMC. JAMA Netw Open. 2024;doi:10.1001/jamanetworkopen.2024.30295.
- Kim JH, et al. JAMA Netw Open. 2024;doi:10.1001/jamanetworkopen.2024.29654.
Perspective
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Nicole Chase, MD, FAAP, FAAAAI, FACAAI
First-generation antihistamines are commonly used by children and adults for relief of seasonal or year-round nasal and/or ocular allergy symptoms, as well as localized skin itch from insect bites, eczema, and/or hives.
In the U.S., widespread availability of over-the-counter (OTC) liquid and dissolvable preparations of first-generation antihistamines facilitate their use in pediatric populations. However, the use of first-generation antihistamines in young children (aged younger than 24 months) is less common than in older children and adults. The decreased use of first-generation antihistamines in young children can generally be attributed to packaging guidelines, which are based on recommendations from respected national organizations such as the AAP.
This study showed a significant (22%) increase in seizure risk associated with first-generation antihistamine prescriptions among young children (aged 6 to 24 months). This is in contrast to data from older children, where an association between seizure incidence and first-generation antihistamine prescription was not seen. The increased risk of seizure in these young children remained consistent across different analyses, including different time-control points and medications.
Pediatricians should consider these findings in the context of an individual risk/benefit ratio when deciding whether to prescribe first-generation antihistamines to children aged younger than 24 months. They may want to consider alternative methods for managing symptoms of rhinorrhea or itching in this age group. In addition, pediatricians can educate parents about the potential risks of first-generation antihistamines and encouraging close monitoring if they are used.
Overall, further investigation into the correlation between first-generation antihistamine use and seizures in young children could help refine guidelines for antihistamine use in pediatric populations and potentially lead to safer treatment options for young children. This could include prospective studies to confirm these findings and establish a causal relationship (especially if data on the frequency of OTC first-generation antihistamine use was included). In addition, further investigation into the causal relationship between first-generation antihistamines and seizures in young children is warranted, including the long-term effects of first-generation antihistamine use on early childhood neurodevelopment.
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