# Prescription Trends of Medications Used to Treat Sleep Disturbances in School-aged Children: An Interrupted Time-Series Analysis in France, 2016-2023

Zaba Valtuille, Eric Acquaviva, Vincent Trebossen, Naim Ouldali, Aurelie Bourmaud, Stéphane Sclison, Alexandre Gomez, Alexis Revet, Hugo Peyre, Richard Delorme, et al.

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Zaba Valtuille, Eric Acquaviva, Vincent Trebossen, Naim Ouldali, Aurelie Bourmaud, et al. Pre-scription Trends of Medications Used to Treat Sleep Disturbances in School-aged Children: An Interrupted Time-Series Analysis in France, 2016-2023. The Journal of Pediatrics, In press, pp.114502. 10.1016/j.jpeds.2025.114502. hal-04953985

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# Prescription Trends of Medications Used to Treat Sleep Disturbances in School-Aged Children: An Interrupted Time-Series Analysis in France, 2016-2023

Zaba Valtuille, MSc¹,², Eric Acquaviva, PhD³, Vincent Trebossen, MD³, Naim Ouldali, PhD⁴, Aurelie Bourmaud, PhD⁵, Stéphane Sclison, MBA⁶, Alexandre Gomez, BSc⁶, Alexis Revet, PhD⁷,⁸, Hugo Peyre, MD⁹,¹⁰, Richard Delorme, MD³,¹¹, and Florentia Kaguelidou, PhD¹,²

**Objective** To assess rates and trends of hypnotic medication prescriptions for children and adolescents.

**Study design** Cross-sectional study of national dispensing data between January 1, 2016, and December 31, 2023, in France. Prescriptions of hypnotic medications (hydroxyzine, alimemazine, melatonin, and Z-drugs) dispensed to children aged 6-17 years were analyzed. Monthly rates of hypnotic prescriptions per 1000 children were modeled before and after the pandemic onset (March 2020) to assess rate and trend changes. Rate ratios (RRs) were calculated between estimated and expected prescription rates.

**Results** Overall, 2 675 142 prescriptions were dispensed to an average yearly population of 9 963 497 children. In January 2016, prescription rate of hypnotic medications was estimated at 1.9 per 1000 and at 6.8 per 1000 in December 2023, with postpandemic onset rates exceeding the expected by 131% (RR: 2.31, 95% CI: 2.08; 2.54). Prescription trends increased for all medications from -0.1% (95% CI: -0.2; 0.1%) per month prepandemic to +1.4% (95% CI: 1.2; 1.6%) after the pandemic onset for hydroxyzine; +0.1% (95% CI: 0.0; 0.2%) to +0.9% (95% CI: 0.7; 1.0%) for alimemazine; +2.2% (95% CI: 2.0; 2.3%) to +4.4% (95% CI: 3.9; 4.9%) for melatonin; and -3.2% (95% CI: -3.6; -2.8%) to +1.8% (95% CI: 1.4; 2.2%) for Z-drugs. Monthly prescription rates exceeded the expected by 38% (RR: 1.38, 95% CI: 1.31; 1.46) for hydroxyzine; 19% (RR: 1.19, 95% CI: 1.15; 1.22) for alimemazine; 344% (RR: 4.44, 95% CI: 4.07; 4.80) for melatonin; and 419% (RR: 5.19, 95% CI: 4.24; 6.14) for Z-drugs.

**Conclusions** Recent substantial increases in hypnotic medication prescribing for children are possibly related to their persistently deteriorating mental health, changes in prescribing strategies, and/or unmet pre-existing needs. (J Pediatr 2025;280:114502).

Sleep disturbances remain a largely underappreciated health issue in pediatrics, although they concern up to 25% of typically developing children and 50% of those with neurodevelopmental and psychiatric disorders.¹,² They involve a wide range of clinical symptoms and result from complex interactions between contextual and medical conditions.³,⁴

Poor sleep has major detrimental effects not only on the well-being and cognitive abilities of children but also on the functioning of the entire family.⁵⁻⁷ Over the past years and despite recommendations to promote behavioral interventions as first-line treatment for sleep disorders, several studies have reported an increasing use of hypnotic medications, especially melatonin, in children.⁸

The perceived quality of sleep is inherently linked to mental well-being. In this regard, the outbreak of the COVID-19 pandemic and subsequent societal impact took a toll on young people's mental health.⁹ From the early months of the pandemic, higher levels of depressive and anxiety symptoms were reported in children with increased use of mental health care services and prescribing of psychotropic medications.¹⁰,¹¹ A significant worsening of sleep quality was also reported, mainly during lockdown periods.¹²,¹³ However, little is known on whether the pandemic's adverse psychological impact and subsequent sleep disturbances resulted in changes in the prescribing of hypnotic medications over time.

95% CI 95% confidence interval

RR rate ratio

From the ¹Center of Clinical Investigations, Inserm CIC1426, Robert Debré University Hospital, APHP.Nord, Paris, France; ⁴EA7323 Perinatal and Pediatric Pharmacology and Therapeutic Assessment, Paris Cité University, Paris, France; ⁵Department of Child and Adolescent Psychiatry, Robert Debré University Hospital, APHP.Nord, Paris Cité University, Paris, France; ⁶Department of General Pediatrics, Pediatric Infectious Disease and Internal Medicine, Robert Debré University Hospital, APHP.Nord, Paris Cité University, Paris, France; ⁷Clinical Epidemiology Unit, INSERM CIC1426, Robert Debré University Hospital, APHP.Nord, Paris Cité University, Paris, France; ⁸IQVIA – Consulting Services & Analytics Department, Paris, France; ⁷Department of Child and Adolescent Psychiatry, Toulouse University Hospital, Toulouse, France; ⁸CERPOP, UMR 1295, Inserm, Toulouse III - Paul Sabatier University, Toulouse, France; ⁹Autism Reference Centre of Languedoc-Roussillon CRA-LR, Excellence Centre for Autism and Neurodevelopmental Disorders CeAND, Montpellier University Hospital, MUSE University, Montpellier, France; ¹⁰Université Paris-Saclay, UVSQ, Inserm, OESP, Team DevPsy, Villejuif, France; and ¹¹Human Genetics & Cognitive Functions, Institut Pasteur, Paris, France

0022-3476/© 2025 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). https://doi.org/10.1016/j.jpeds.2025.114502
The present study aimed to assess the prescription rates of hypnotic medications for children and adolescents, before and more than 3 years after the onset of the COVID-19 pandemic.

## Methods

### Study Setting and Data Sources

We performed a cross-sectional study of population-based, outpatient prescriptions data from January 1, 2016 to December 31, 2023, in France. Data were extracted from the X-ponent database, IQVIA France, a comprehensive pharmacy retail sales database sampling 14 000 pharmacies accounting for approximately 60% of retail pharmacies in mainland France (excluding overseas territories).¹⁴ These pharmacies are selected from cluster-sample surveys stratified by geographical location and activity volume to ensure representativity at the national level. Dispensing data from this sample of pharmacies are then projected through an internal algorithm developed by IQVIA to national estimates which were then used for the current analysis.¹⁵

The study was approved by the national ethics and scientific committee for health research, studies, and evaluations (CESREES, n° 5 006 421) and the French data protection authority (CNIL, n° 921,421) and is publicly available on the [Clinicaltrials.gov](https://Clinicaltrials.gov) database (NCT05260866). Findings were reported following the Strengthening the Reporting of Observational Studies in Epidemiology reporting guidelines.¹⁶

### Medications for Pediatric Insomnia

In France, 3 medications have a marketing authorization for use in pediatric insomnia. Hydroxyzine and alimemazine are sedating, first-generation antihistamines indicated as a second line treatment of sleep onset insomnia from the age of 6 and 3 years, respectively. Also, 2 prolonged-release forms of melatonin are available on prescription only when sleep hygiene measures are insufficient. The first one CIRCADIN has a temporary authorization for use in children above 6 years of age since 2016, and the second, SLENYTO, has a pediatric EU marketing authorization since 2018 for use in children above 2 years of age presenting sleep disturbances and certain neurodevelopmental disorders (eg, autism spectrum disorder, Smith-Magenis syndrome). The Z-drugs, zolpidem and zopiclone, are nonbenzodiazepine hypnotics principally indicated for the treatment of transient insomnia and are used off-label in children under 18 years.

During the study period, we extracted all outpatient prescriptions dispensed to children aged 6-17 years with at least one of the following medications of interest: hydroxyzine (5th level of the Anatomical Therapeutic Chemical classification: N05BB01), melatonin (N05CH01), alimemazine (R06AD01), and Z-drugs: zolpidem (N05CF02) or zopiclone (N05CF01). Prescriptions for children under the age of 6 years were not included in this study because all the above-mentioned medications do not have a marketing

authorization for use in this population and preschoolers are a distinct pediatric population in terms of clinical presentation of sleep disturbances, diagnosis, and subsequent therapeutic needs. Also, we did not include prescriptions of benzodiazepines since these medications are not indicated for the treatment of pediatric insomnia and are prescribed for the treatment of a wide range of disorders (eg, epilepsy). For each prescription, we extracted the date of dispensing, medication dispensed, and the child's date of birth. Prescriptions were further classified into 2 age groups: children (age 6-11 years) and adolescents (age 12-17 years).

### Study Measures

We assessed monthly prescription rates per 1000 children in France. Rates were calculated using the counts of dispensed prescriptions (numerator) and appropriate age-specific population estimates derived from the dataset of the National Institute of Statistics and Economic Studies (denominator), both aggregated on a monthly level.¹⁷ Rates were provided overall, by medication of interest, and by age groups (6-11; 12-17 years).

### Statistical Analysis

We conducted an interrupted time series analysis to assess changes in the monthly prescription rate (level) and the monthly rate change (trend) after the onset of the COVID-19 pandemic (March 1, 2020, to December 31, 2023) compared with the period preceding the pandemic onset (January 1, 2016, to February 29, 2020).

Analyses were performed using a quasi-Poisson regression, accounting for data autocorrelation, seasonality, and prepandemic trend. Seasonality was addressed by fitting calendar months as a categorical variable.¹⁸,¹⁹ Residual autocorrelation was assessed through visual inspection of correlograms (autocorrelation and partial autocorrelation functions plots) and was corrected by using the Newey-West method, when needed. Since medical care remained available during the initial pandemic phase, we tested for an immediate change of the prescription rate (level change) and also, a progressive change (trend change) over the period. Hence, the interrupted time series model included time as a continuous variable to assess the baseline (prepandemic) trend, a binary variable indicated the onset of the pandemic to measure the level change, and an interaction term between the time and the binary variable to measure the trend change after the pandemic onset. The validity of all regression models was assessed by visual inspection of correlograms and residual analysis.

Model parameters were interpreted as relative percentage changes with 95% confidence intervals (95% CIs). The trend (95% CIs) after the pandemic onset was assessed by the linear combination of the trend parameters (prepandemic trend and estimated trend change).¹⁸ After the pandemic onset, we also compared the monthly prescription rates estimated by the model based on the observed data, with the expected rates forecast by the model based solely on prepandemic data. Results were expressed as rate ratios (RRs) and
corresponding 95% CIs were calculated through bootstrapping (n = 10 000 replications). All analyses were stratified by specific medication of interest and age groups (6-11; 12-17 years).

All statistical tests were two-sided and *P* values less than .05 were considered statistically significant. All analyses were performed using R software, version 4.2.2.

## Results

Throughout the study period, we retrieved 2 675 142 prescriptions containing at least one hypnotic medication (average yearly number of prescriptions: 334 393 over an average yearly population of 9 963 497 children aged 6 to 17 years. The majority of prescriptions concerned hydroxyzine, n = 1 424 075 (53.2%) and melatonin, n = 1 019 562 (38.1%) whereas prescriptions of alimemazine, n = 212 052 (7.9%) and Z-drugs (zolpidem or zopiclone), n = 85 736 (3.2%) were far less frequent. In addition, the majority of hypnotic prescriptions were dispensed to children aged between 12 and 17 years (n = 1 616 504; 60.4%).

In January 2016, the prescription rate of hypnotic medications was estimated at 1.9 (95% CI: 1.8; 1.9) prescriptions per 1000 children, and in December 2023 at 6.8 (95% CI: 6.5; 7.2) prescriptions per 1000 children (Figure 1). Prepandemic prescription rate was stable. At the pandemic onset, the rate increased by 15.3% (95% CI: 5.8; 25.7), and thereafter, the trend of monthly prescription rate increased by 2.7%

per month (95% CI: 2.5; 3.0). Postpandemic onset trend increases were observed both in children and in adolescents (Figure 1, Table). Overall, prescription rates exceeded the expected rates by 131% (RR: 2.31, 95% CI: 2.08; 2.54) after the pandemic onset (Figure 2).

## Changes in Hydroxyzine Use

In January 2016, the rate of hydroxyzine use was 1.4 prescriptions per 1000 children and the prepandemic trend was not significant (-0.1% per month, 95% CI -0.2; 0.1%) (Table; Figure 3A). Following the pandemic onset, no immediate level change was observed; however, the trend significantly changed and increased by 1.4% per month (95% CI: 1.2; 1.6%). After the pandemic onset, prescription rates exceeded the expected rates by 38% (RR: 1.38, 95% CI: 1.31; 1.46) (Figure 2). The trend change following the pandemic onset was more pronounced in children aged 12-17 years than in those aged 6-11 years (Table; eFigure 1; available at www.jpeds.com). Prescription rates exceeded the expected rates by 21% (RR: 1.21, 95% CI: 1.16; 1.26) in children aged 6-11 years and by 46% (RR: 1.46, 95% CI: 1.38; 1.54) in those aged 12-17 years (Figure 2).

## Changes in Alimemazine Use

In January 2016, the rate of alimemazine prescriptions was 0.2 per 1000 children with a slightly increasing prepandemic trend (0.1% per month, 95% CI: 0.0; 0.2%) (Table; Figure 3B). Following the onset of the pandemic, no immediate

<figure><img src="image_4.png" /><figcaption>**Figure 1.** Monthly rates of hypnotic medication prescriptions overall and by age group *bold black line* indicates overall monthly estimated prescription rates per 1000 children aged 6-17 years. *Green line* indicates monthly estimated prescription rates per 1000 children aged 12-17 years. *Blue line* indicates monthly estimated prescription rates per 1000 children aged 6-11 years. *Vertical broken line* shows the pandemic onset in March 2020. Before the COVID-19 pandemic onset: January 2016; February 2020. After the COVID-19 pandemic onset: March 2020; December 2023.</figcaption></figure>
<table><caption>Table. Changes in monthly prescriptions rates and trends by hypnotic medication and age group</caption><thead><tr><th rowspan="3">Outcome</th><th colspan="3">Before the pandemic onset (Jan 2016-Feb 2020)</th><th colspan="6">After the pandemic onset (March 2020-December 2023)</th></tr><tr><th rowspan="2">Level Jan. 2016*<br>(95% CI)</th><th rowspan="2">Trend† (95% CI)</th><th rowspan="2">P value</th><th rowspan="2">Change in level†<br>(95% CI)</th><th rowspan="2">P value</th><th rowspan="2">Change in trend†<br>(95% CI)</th><th rowspan="2">P value</th><th rowspan="2">Trend† (95% CI)</th><th rowspan="2">Level Dec. 2023*<br>(95% CI)</th></tr><tr><th>Change in trend†</th><th>(95% CI)</th></tr></thead><tbody><tr><td>Monthly prescription rate of all hypnotic medications</td><td>1.9 (1.8; 1.9)</td><td>0.0% (-0.1; 0.1)</td><td>.92</td><td>15.3% (5.8; 25.7)</td><td>.0012</td><td>2.7% (2.4; 3.0)</td><td>&lt;.0001</td><td>2.7% (2.5; 3.0)</td><td>6.8 (6.5; 7.2)</td></tr><tr><td>6-11 years</td><td>1.3 (1.2; 1.4)</td><td>0.2% (0.0; 0.3)</td><td>.0078</td><td>18.8% (9.9; 28.4)</td><td>&lt;.0001</td><td>2.9% (2.7; 3.2)</td><td>&lt;.0001</td><td>3.1% (2.9; 3.3)</td><td>6.1 (5.9; 6.4)</td></tr><tr><td>12-17 years</td><td>2.4 (2.3; 2.5)</td><td>-0.1% (-0.3; 0.0)</td><td>.14</td><td>14.1% (3.6; 25.6)</td><td>.0073</td><td>2.5% (2.1; 2.9)</td><td>&lt;.0001</td><td>2.4% (2.4; 2.7)</td><td>7.4 (7.0; 7.9)</td></tr><tr><td>Monthly prescription rate of hydroxyzine</td><td>1.4 (1.4; 1.5)</td><td>-0.1% (-0.2; 0.1)</td><td>.35</td><td>-2.4% (-8.5; 4.1)</td><td>.46</td><td>1.4% (1.2; 1.7)</td><td>&lt;.0001</td><td>1.4% (1.2; 1.6)</td><td>2.3 (2.2; 2.4)</td></tr><tr><td>6-11 years</td><td>1.0 (1.0; 1.1)</td><td>0.0% (-0.1; 0.1)</td><td>.77</td><td>-8.3% (-13.7; -2.6)</td><td>.005</td><td>1.1% (0.9; 1.3)</td><td>&lt;.0001</td><td>1.1% (1.0; 1.3)</td><td>1.4 (1.3; 1.4)</td></tr><tr><td>12-17 years</td><td>1.8 (1.7; 1.9)</td><td>-0.1% (-0.2; 0.0)</td><td>.18</td><td>2.7% (-5.3; 1.13)</td><td>.53</td><td>1.4% (1.1; 1.7)</td><td>&lt;.0001</td><td>1.3% (1.1; 1.6)</td><td>3.1 (3.0; 3.3)</td></tr><tr><td>Monthly prescription rate of allimemazine</td><td>0.2 (0.2; 0.2)</td><td>0.1% (0.0; 0.2)</td><td>.0212</td><td>-1.2% (-5.2; 3.0)</td><td>.58</td><td>0.8% (0.6; 0.9)</td><td>&lt;.0001</td><td>0.9% (0.7; 1.0)</td><td>0.3 (0.3; 0.3)</td></tr><tr><td>6-11 years</td><td>0.2 (0.2; 0.2)</td><td>-0.4% (-0.5; -0.3)</td><td>&lt;.0001</td><td>-5.5% (-12; 1.5)</td><td>.12</td><td>0.4% (0.1; 0.7)</td><td>.003</td><td>0.0% (-0.2; 0.3)</td><td>0.1 (0.1; 0.1)</td></tr><tr><td>12-17 years</td><td>0.2 (0.2; 0.2)</td><td>0.4% (0.3; 0.5)</td><td>&lt;.0001</td><td>3.3% (-3.1; 10.1)</td><td>.32</td><td>0.6% (0.3; 0.9)</td><td>&lt;.0001</td><td>1.0% (0.8; 1.2)</td><td>0.5 (0.5; 0.5)</td></tr><tr><td>Monthly prescription rate of melatonin</td><td>0.1 (0.1; 0.1)</td><td>2.2% (2.0; 2.3)</td><td>&lt;.0001</td><td>155.3% (115.4; 202.6)</td><td>&lt;.0001</td><td>2.2% (1.6; 2.8)</td><td>&lt;.0001</td><td>4.4% (3.9; 4.9)</td><td>4.3 (4.0; 4.7)</td></tr><tr><td>6-11 years</td><td>0.1 (0.1; 0.1)</td><td>2.2% (2.0; 2.4)</td><td>&lt;.0001</td><td>188.3% (144.1; 240.5)</td><td>&lt;.0001</td><td>2.2% (1.7; 2.8)</td><td>&lt;.0001</td><td>4.5% (4.0; 5.0)</td><td>4.9 (4.5; 5.3)</td></tr><tr><td>12-17 years</td><td>0.1 (0.1; 0.1)</td><td>2.1% (1.9; 2.3)</td><td>&lt;.0001</td><td>123% (87.1; 165.8)</td><td>&lt;.0001</td><td>2.2% (1.6; 2.8)</td><td>&lt;.0001</td><td>4.4% (3.9; 4.9)</td><td>3.9 (3.5; 4.2)</td></tr><tr><td>Monthly prescription rate of Z-drugs</td><td>0.2 (0.2; 0.2)</td><td>-3.2% (-3.6; -2.8)</td><td>&lt;.0001</td><td>29.1% (8.7; 53.3)</td><td>.0036</td><td>5.1% (4.5; 5.7)</td><td>&lt;.0001</td><td>1.8% (1.4; 2.2)</td><td>0.2 (0.1; 0.2)</td></tr><tr><td>6-11 years</td><td>0.02 (0.02; 0.03)</td><td>-1.8% (-2.3; -1.4)</td><td>&lt;.0001</td><td>-19.4% (-36.2; 1.8)</td><td>.075</td><td>4.3% (3.5; 5.1)</td><td>&lt;.0001</td><td>2.4% (1.8; 2.9)</td><td>0.0 (0.0; 0.0)</td></tr><tr><td>12-17 years</td><td>0.3 (0.3; 0.4)</td><td>-3.3% (-3.7; -2.9)</td><td>&lt;.0001</td><td>37.5% (14.7; 64.9)</td><td>.0006</td><td>5.0% (4.3; 5.6)</td><td>&lt;.0001</td><td>1.5% (1.1; 1.9)</td><td>0.3 (0.2; 0.3)</td></tr></tbody></table>

significant level change was observed, however, the trend changed significantly and increased by 0.9% (95% CI: 0.7; 1.0%) per month. After the pandemic onset, monthly rates of prescriptions exceeded the expected rates by 19% (RR: 1.19, 95% CI: 1.15; 1.22) (Figure 2). Level and trend changes were higher in adolescents compared with children (Table; eFigure 2; available at www.jpeds.com). Alimemazine monthly prescription rates exceeded the expected rates by 4% (RR: 1.04, 95% CI: 1.02; 1.06) in children aged 6-11 years and by 19% (RR: 1.19, 95% CI: 1.16; 1.21) in those aged 12-17 years (Figure 2).

## Changes in Melatonin Use

In January 2016, the rate of melatonin prescriptions was 0.1 per 1000 children and adolescents, and the prepandemic prescription trend was increasing by 2.2% (95% CI: 2.0; 2.3%) per month (Table; Figure 3C). Following the pandemic onset, the prescription rate increased by 155.3% (95% CI: 115.4; 202.6%). The trend also significantly changed and increased by 4.4% (95% CI: 3.9; 4.9%) per month. Prescription rates of melatonin exceeded the expected rates by 344% (RR: 4.44, 95% CI: 4.07; 4.80) (Figure 2). Level and trend changes following the pandemic onset were similar in the 2 age groups (Table; eFigure 3; available at www.jpeds.com). Monthly rates of melatonin prescriptions exceeded the expected rates by 404% (RR: 5.04, 95% CI: 4.62; 5.46) in children aged 6-11 years and by 290% (RR: 3.90, 95% CI: 3.57; 4.23) in those aged 12-17 years (Figure 2).

## Changes in Z-Drugs Use

In January 2016, the rate of Z-drugs prescriptions was 0.2 per 1000 children, with a decreasing prepandemic trend of 3.2% (95% CI: -3.6; -2.8%) per month (Table; Figure 3D). Following the pandemic onset, an immediate level increase of 29.1% (95% CI: 8.7; 53.3%) was observed. The trend also changed significantly and increased by 1.8% (95% CI: 1.4; 2.2%) per month. Prescription rates of Z-drugs exceeded the expected rates by 419% (RR: 5.19, 95% CI: 4.24-6.14), although absolute rates remained overall very low (Figure 2). The trend change following the pandemic onset was more pronounced in adolescents than in children (Table; eFigure 4; available at www.jpeds.com). Monthly rates of Z-drugs prescriptions exceeded the expected rates by 151% (RR: 2.51, 95% CI: 2.12; 2.89) in children aged 6-11 years and by 428% (RR: 5.28 95% CI: 4.34; 6.22) in those aged 12-17 years (Figure 2).

## Discussion

Prescriptions of hypnotic medications for children substantially rose during the COVID-19 pandemic with increases ongoing more than 3 years after the outbreak. Given prepandemic data, relative increases in prescription rates were substantial for melatonin, especially in children aged 6-11 years, and Z-drugs in adolescents. Important increases

<footnote>*Level corresponds to the monthly prescriptions per 1000 children estimated by the model.</footnote>

<footnote>†Model estimates for trend and changes in level and trend are presented as relative percent changes (95% CI).</footnote>
<figure><img src="image_5.png" /><figcaption>**Figure 2.** Rate ratios (RRs) and 95% CI of estimated and expected monthly rates of hypnotic medication prescriptions following the pandemic onset. Prescription RRs were calculated as the average of the ratios between monthly prescription rates estimated by the model based on observed data, and expected rates forecast by the model setting the binary variable indicating the onset of the pandemic to zero. *Grey squares* represent RRs for children aged 6-17 years. *Blue squares* represent RRs for children aged 6-11 years. *Green squares* represent RRs for children aged 12-17 years. *Vertical dotted line* indicates no relative change between estimated and expected prescription rates (RR = 1).</figcaption></figure>

were also noted for hydroxyzine and alimemazine prescriptions, particularly among children aged 12-17 years.

Sleep deprivation and sleep-related problems can lead to a wide range of issues in children, including impaired health, decreased cognitive abilities, and compromised emotional well-being.²⁰⁻²² Consequences often extend beyond the affected child, to significantly impact the functioning of the entire family.⁷,²³,²⁴ Hence, recognizing and addressing sleep disturbances in children became a paramount clinical need in recent times. In addition, improvements in the diagnosis of several neurodevelopmental disorders highly comorbid with sleep dysregulation, such as autism or attention deficit-hyperactivity disorder, has also boosted the therapeutic demand.²⁵,²⁶ Guidelines to treat children with sleep impairment recommend cognitive-behavioral interventions, including sleep hygiene education, as first-line therapeutic strategy. Only when these interventions prove to be ineffective, short-term treatment with low-dose melatonin is recommended.⁸,²⁵,²⁷,²⁸ However, non-pharmacological approaches are not widely available and parents often struggle to adhere to behavioral recommendations on a daily basis.²⁷,²⁹ Hence, off-label use of melatonin to treat insomnia

in children substantially increased in the last 20 years together with that of other hypnotic medications in several countries.³⁰⁻³⁴ In France, an increase in melatonin prescriptions was observed before the pandemic onset, although rates remained low compared with other European countries.³⁰,³¹ However, no increases in the pediatric prescriptions of sedative antihistamines were observed, with the exception of alimemazine in adolescents. Further, pediatric off-label prescriptions of Z-drugs were found to be declining over time, probably because of rising concerns regarding their unfavorable safety profile.

The advent of the COVID-19 pandemic introduced a unique set of challenges to children and adolescents, influencing their sleep patterns. The mental health burden of the pandemic amongst children and adolescents and subsequent psychotropic medication use has been extensively documented worldwide.¹⁰,³⁵⁻³⁹ In parallel, higher levels of sleep-related problems were also reported with increased prevalence of insomnia,⁴⁰,⁴¹ delayed bedtime hours,⁴²,⁴³ and decreased sleep quality.¹² Our findings confirm the significant and persistent uplift in the therapeutic demand for sleep disturbances in children after the pandemic onset, with prescribing
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<figure><img src="image_8.png" /></figure>

<figure><img src="image_9.png" /><figcaption>**Figure 3.** Changes in prescription rates and trends by hypnotic medication *black dots* indicate observed data. *Grey bold lines* indicate estimated prescription rates based on observed data using the quasi-Poisson regression model with corresponding 95% CI. *Red dotted lines* indicate the expected rates forecast by the quasi-Poisson model during the same time period setting the binary variable indicating the onset of the pandemic to zero. *Vertical broken line* shows the pandemic onset in March 2020. Before the COVID-19 pandemic onset: January 2016; February 2020. After the COVID-19 pandemic onset: March 2020; December 2023.</figcaption></figure>

trends still increasing more than 3 years later. Many reasons may explain our study findings. First, the anxiety surrounding the pandemic, coupled with the quarantine measures, and subsequent alterations to daily life and social interactions, may have left a lasting imprint on mental wellbeing and consequently sleep patterns, with persistent difficulties reported even long after the easing of restrictions.⁴⁴,⁴⁵ In this regard, the increase in the use of sedative antihistamines and Z-drugs observed in our study is consistent with reports of severe depressive and anxious symptoms, especially among adolescents, during this period. Indeed, these hypnotic medications, notably antihistamines, are preferentially prescribed to treat sleep disturbances with comorbid mood and anxiety disorders because of their sedative properties and in the absence of evidence to support the use of melatonin in these clinical situations.⁴⁶ In addition, given the incremental health care demand and the limited availabilities of pediatric or sleep specialists during the pandemic, visits to physicians with no previous experience in these fields may have triggered inappropriate hypnotic prescriptions in children.

Second, a significant contributing factor to the persistent rise in hypnotic prescribing may be the escalating screen time among children. The pandemic fueled the growth of online interactions through social media and use of electronic devices as a direct consequence of school closures and limited peer

interaction.⁴⁷,⁴⁸ Numerous studies underline the detrimental effect of these practices on sleep duration and quality.⁴⁹⁻⁵² Pharmacological approaches to adjust sleep-wake cycle are only justified when adopting healthy sleep habits has proven to be ineffective and daytime function is compromised.⁸ The explosive rise in melatonin and Z-drugs prescriptions after the pandemic outbreak suggests that appropriate sleep hygiene and/or other nonpharmacological cognitive-behavioral interventions may not have been sufficiently implemented before the initiation of hypnotic treatment. It is important to underline that treatment by hypnotic medications, especially long-term, is not devoid of serious adverse events.⁸ In particular, treatment with melatonin, an endogenous pineal hormone, is often considered to be harm-free, although there is evidence from placebo-controlled trials that treated children present more nonserious adverse events.⁵³ The absence of solid evidence for melatonin's efficacy in various sleep disorders, recommendations on optimal daily dosing, and long-term follow-up of continuously treated children, precludes the benefit-risk evaluation of melatonin treatment in children.²⁵,⁵⁴,⁵⁵

Lastly, an additional reason behind the explosive postpandemic increase in melatonin prescriptions involves the availability of SLENYTO, a prolonged-release melatonin, as a reimbursed medication from the French Social Security System on April 1, 2020. Indeed, before that date, another
prolonged-release melatonin (CIRCADIN) was already authorized for use in children over the age of 6 years presenting associated neuro developmental comorbidities, but the treatment was expensive and not fully reimbursed. Therefore, families sought to purchase cheaper over-the-counter alternatives or filled for compounded pharmacy preparations that are not captured in our study database. Consequently, we cannot exclude a shift of melatonin prescriptions to cover the needs of previously untreated or inadequately treated children.

We used nationwide population prescription data for this study, and although prescriptions fills are only proxies to actual hypnotic medication intake, they do reflect specific therapeutic needs. Further, our findings are based on a time-series statistical analysis which adequately accounts for prepandemic trends. However, we acknowledge some limitations to our study. First, we did not analyze individual patient-level data. Thus, observed increases may be due to either an increase in the number of children exposed or an increase in the number of prescriptions per child. Second, we were unable to explore sex differences in the use of hypnotic medications, shown in previous studies,³⁰ since the X-Ponent database did not reliably record these data throughout the study period. Third, we did not explore children's indication for hypnotic prescribing, comorbidities, and/or comedications dispensed, as the X-Ponent is a retail pharmacy database without the possibility to identify unique users and their medical diagnoses or prescriptions in a longitudinal manner. Lastly, we may have underestimated therapeutic needs for sleep disturbances. In the absence of information on medical indications, we limited our analysis to medications that are either approved for pediatric insomnia or mainly indicated for the treatment of insomnia. Hence, we disregarded the off-label use of additional psychotropic medications that are sometimes prescribed to treat pediatric insomnia, such as neuroleptics or sedative antidepressants.

In conclusion, we provide evidence of recent substantial increases in hypnotic medication prescribing for children that were ongoing more than 3 years after the pandemic onset. These increases are possibly related to children's persistently deteriorating mental health, changes in medical prescribing strategies, and unmet pre-existing therapeutic needs. Hence, future research should focus on identifying underlying factors and particularly, any mental health stressors that urgently need to be alleviated. In the aftermath of the pandemic, sleep disturbances in children are becoming a serious public health issue that calls for holistic approaches to intervention. Treatment options should be tailored to the unique needs of this population, and support for children and families to implement adequate sleep hygiene should be enhanced. Without the latter, pharmacological options will fail to improve their sleep in a sustainable manner. ■

### CRediT authorship contribution statement

**Zaba Valtuille:** Writing – review & editing, Writing – original draft, Visualization, Validation, Software, Methodology, Formal analysis, Data curation, Conceptualization.

**Eric Acquaviva:** Writing – review & editing, Validation, Supervision, Methodology, Conceptualization. **Vincent Trebessen:** Writing – review & editing, Supervision. **Naim Ouldali:** Writing – review & editing, Supervision, Methodology, Formal analysis, Conceptualization. **Aurelie Bourmaud:** Writing – review & editing, Supervision. **Stéphane Sclion:** Writing – review & editing, Methodology, Data curation. **Alexandre Gomez:** Writing – review & editing, Supervision, Methodology, Data curation. **Alexis Revet:** Writing – review & editing, Supervision, Methodology. **Hugo Peyre:** Writing – review & editing, Supervision, Methodology. **Richard Delorme:** Writing – review & editing, Supervision, Methodology. **Florentia Kaguelidou:** Writing – review & editing, Supervision – original draft, Visualization, Validation, Supervision, Resources, Project administration, Methodology, Funding acquisition, Formal analysis, Conceptualization.

### Declaration of Competing Interest

S.S. and A.G are employees of IQVIA France. N. Ouldali reports travel grants from GSK, Pfizer, and Sanofi.

This study was supported by the Agence Nationale de la Recherche (grant n°ANR-21-COVR-0010-01) and the Fondation de France (grant n° APHP220322). The funders of the study had no role in study design, data collection, data analysis, data interpretation, preparation and review of the manuscript; or the decision to submit the manuscript for publication. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Submitted for publication Oct 24, 2024; last revision received Jan 21, 2025; accepted Feb 1, 2025.

Reprint requests: Prof. Florentia Kaguelidou, PhD, Clinical Investigations Center, Inserm CIC1426, Paris Cité University, Robert Debré University Hospital, 48 boulevard Sérurier, Paris 75019, France. E-mail: florentia.kaguelidou@aphp.fr

### Data Statement

Data sharing statement available at www.jpeds.com.

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