ADHD in school‐age children is related to infant exposure to systemic H1‐antihistamines
Authors: Saskia Fuhrmann, Falko Tesch, Marcel Romanos, Susanne Abraham, Jochen Schmitt
Journal: Allergy (2020)

To the Editor, Attention-deficit/hyperactivity disorder (ADHD) and atopic dermatitis (AD) are two highly prevalent diseases in childhood. Many systemic H1-antihistamines (AH), especially 1st-generation agents (AH1) with significant sedating potential, are frequently used to treat AD-related pruritus and AD-related sleeping problems in infants.1 There is, however, no recommendation for systemic treatment with AH within the first year of life. In a small retrospective study of children with AD, we recently observed a significant association of history of antihistamine use and increased risk of ADHD symptoms.2 The objective of the present study was to analyze whether AH exposure within the first 2 years of life represents an independent risk factor for the development of ADHD in children with AD. Moreover, we aimed to investigate whether children, who are exposed to AH, but who do not have AD, have an increased risk for ADHD diagnosis later in childhood. We undertook a birth cohort study based on comprehensive administrative healthcare data provided by a large statutory health insurance from Germany, AOK PLUS, which has also been used in the study of allergies before.3, 4 For the presented birth cohort study, the study database consisted of all subjects born in the years 2005 to 2007 and followed until 2014 (ie, their 7th to 9th birthday) or end of insurance status. Primary outcome of interest was the diagnosis of ADHD. A child was classified as having ADHD if it received at least two ICD-10 diagnoses (ICD-10 Code F90) within the observation period. For subgroup analyses, the population of children with ADHD was further constrained in a second more specific definition to those who additionally either received specific medication (methylphenidate N06BA04 or atomoxetine N06BA09) or behavioral therapy (BT). The onset of the disease has been set to the first day of the quarter when the diagnosis was first recorded. The exposures of interest were AH prescriptions within the first 2 years of life (see Supporting information S4 for respective ATC codes). The following variables were considered as confounders: sex, AD with onset in the first 2 years of life, and pediatrician to children ratio in the ZIP code area. An individual was classified as having AD if the diagnostic code had been documented at least twice (ICD-10 Code L20 or L30) in outpatient care within four quarters. Children with a first diagnosis of AD after their first 2 years of life were excluded. We applied time-to-event analyses with nonparametric cumulative event curves and semiparametric Cox proportional hazard models stratified by antihistamine and AD status and controlled by sex and pediatrician to children ratio. The whole study cohort consisted of 41 484 children. Details on the study population are provided in Table 1. From the 41 484 children included in the present study, a high proportion of 13.4% (n = 5540) were exposed to AH within the first 2 years of life, 10.2% (n = 4234) receiving 1st-generation AH (AH1) (primarily dimetindene). Children without AD, but infant exposure to AH1, had a 35% increased risk for ADHD (HR 1.35; 95%-CI 1.25-1.47, P-value < .001) (Table 2). This effect was also significant for the specific secondary case definition (HR 1.23; 95%-CI 1.05-1.45, P-value < .010). Compared to children without AD and without AH1 exposure in infancy, children with AD and AH1 exposure in infancy had a 47% increased risk for later ADHD (HR 1.47; 95% CI 1.28-1.70, P-value < .001), see Table 2 and Figure S3B. Second-generation AH such as cetirizine (n = 1.194, 2.9%) and desloratadine (n = 550, 1.3%) were less often prescribed than AH1. See Tables S1 and S2 and Figure S3A for the effect of AH on ADHD. This large birth cohort study provides important new evidence that early life exposure to AH, especially AH1, may be an independent risk factor for ADHD development. This effect may be mediated by disturbance of the REM sleep and its secondary effects on brain maturation.5, 6 Especially for neonates and infants where REM sleep is very common, reduction of REM sleep by antihistamines that pass the BBB may increase the risk for later ADHD development.7 This is especially critical if children treated with antihistamines suffer from other atopic diseases such as allergic rhinitis or atopic eczema as indicated by the highest risk for ADHD in children with AD and AH1 exposure in our cohort. The identified relationship between early antihistamine exposure and increased risk for ADHD development may also be explained by a protopathic bias. Sleep disorders and related antihistamine consumption may represent signs of an underlying yet undiagnosed ADHD disease.8, 9 Note that, in 23.6% of the analyzed cases, expositions to antihistamines were unclear as none of the approved indications for antihistamines have been documented in outpatient care. In addition, most of the antihistamines (ie, dimetindene and cetirizine) are OTC medicines in Germany. Nevertheless, we assume that parents do not proactively buy and use antihistamines for very young children for the first time. Despite these limitations, we conclude that exposure to antihistamines may be an independent risk factor for ADHD development with REM sleep disturbance being a potential pathophysiological pathway. This needs to be considered by physicians and parents when the use of AH, especially AH1 in very small children, is intended. Due to the high proportion of children receiving antihistamines early in their life, this finding is of high public health relevance. The use of antihistamines early in life should be considered with caution, and parents should be advised by the physician/pharmacy. The authors thank Yvonne Schmole (Dresden, Germany) for help with the data analyses and the Compulsory Health Insurance AOK PLUS for cooperation in data utilization and for technical support. SF, FT, and MR report no conflicts of interest. SA reports personal fees outside the submitted work and has been investigator, advisor, or lecturer for Novartis, LEO Pharma, Lilly, Sanofi-Aventis, and AbbVie. Unrelated to this study, JS received institutional grants for investigator-initiated research from Sanofi-Aventis, Pfizer, Novartis, and ALK-Abelló and acted as a consultant for Sanofi-Aventis and Novartis. JS, FT, SF, and SA conceptualized and designed the study. FT conducted the statistical analysis and discussed and interpreted the results. SF drafted the initial manuscript, discussed and interpreted the results, and revised the manuscript. MR critically reviewed the manuscript for important intellectual content. All authors reviewed the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.