European Journal of Paediatric Neurology 39 (2022) 30–34

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European Journal of Paediatric Neurology

journal homepage: www.journals.elsevier.com/european-journal-of-paediatric-neurology

Melatonin usage in children and young adults, a registry-based cohort study

K. Tedroff a, b, c, M. von Euler d, E. Dahlén b, e, *
a
Department of Women’s and Children’s Health, Karolinska Institutet, SE, 171 76, Stockholm, Sweden
b
Region Stockholm, Health and Medical Care Administration, Box 6909, SE, 102 39, Stockholm, Sweden
c
Centre for Psychiatry Research, Stockholm Health Care Services, Region Stockholm, 113 30, Stockholm, Sweden
d
Department of Neurology, Faculty of Medicine and Health, Örebro University, SE, 70182, Örebro, Sweden
e
Karolinska Institutet, Department of Clinical Science and Education, Södersjukhuset, SE-118 83 Stockholm, Sweden

A R T I C L E I N F O A B S T R A C T

Keywords: Sleep disorder is common in children and adolescents, particularly in those with attention deficit hyperactivity
Children and adolescents disorder (ADHD) or autism spectrum disorder (ASD). While non-pharmacological treatment is first line, occa­
Drug utilization sionally an add-on of an oral drug is needed. The endogenous hormone melatonin is increasingly used for sleep
Melatonin
disorders in children and adolescents. In this registry-based cohort study we follow dispensation of melatonin in
Sleep disorder
young individuals, 0–25 years of age, in Stockholm, Sweden during 2016–2019.
In all 9980 individuals, were dispensed melatonin in 2016 and followed for 3 years. Child psychiatrist was the
most common prescribing specialty, 55% of all prescriptions. Only 20% had a recorded diagnosis of sleep dis­
order. The majority, 65% had a neuro psychiatric diagnose. Half of the individuals had at least 4 prescribed drugs
dispensed during the follow-up. Almost half of our cohort were dispensed melatonin during the entire study
period and doses and volumes of drug dispensed increased by 50 and 100%, respectively. Continuous medication
was most common among children 6–12 years, where 7 out of 10 individuals were still adherent after three years.
As long-term safety data is lacking, we find this concerning, and this illustrates the need of long-term follow-up of
melatonin use in children and young individuals.

1. Introduction hygiene routine, and behavioral interventions, is considered first in line

Sleep-related symptoms are common in children and about 25% are
experiencing a problem at some point during childhood [1]. It is even
more prevalent in children with a neurodevelopmental or neuropsy­
chiatric disorder, where up to 25–55% of children with Attention Deficit
Hyperactivity Disorder (ADHD) reports sleep problems [2]. Insomnia,
the most common sleep-disorder, includes difficulty falling asleep (sleep
onset), staying asleep (maintenance), and/or waking up too early in the
morning. Child psychiatrists reports that 1/3 of their patients, with a
variety of behavioral, neurodevelopmental, and psychiatric conditions,
have significant problems with insomnia [3]. Daytime-sleepiness is a
common consequence of insomnia and can result in irritability, school
and learning problems, behavioral problems, decreased quality of life
and well-being, some of the problems can be chronic in character [4,5].
Recently, an experimental study showed that sleep deprivation can
affect executive functions more in individuals with even subclinical
symptoms of inattention compared to those with typical attention [6].
In children, non-pharmacological treatment, emphasizing sleep
when treating sleep problems. Occasionally, an add-on of oral drugs is
recommended. However, very few drugs have been evaluated in chil­
dren, and high-level evidence for effect and safety is lacking [7,8].
Melatonin is an endogenous hormone produced by the pineal gland.
It plays an important role in the development of sleep–wake rhythm and
is released during the night. Some studies have shown promising results
indicating that melatonin can be effective for sleep disorders associated
with ADHD and autism spectrum disorder (ASD) in children, specifically
when sleep onset time have been evaluated [9–11]. Still, conclusive
evidence is lacking concerning dosing, long-time effects and also con­
cerning the effect in other neurodevelopmental disorders or in isolated
sleep problems [9].
In Sweden, there was no product containing melatonin approved for
children before 2018. The drug was prescribed off-label or after an
approved license by the Swedish Medical Products Agency. Since
October 2020, it is possible to buy melatonin over the counter for usage
in adults. However, prescriptions to children and adolescents are still
recommended to be handled by a pediatrician or a child psychiatrist.

* Corresponding author. Department of Clinical Science and Education, Södersjukhuset S1 KI SÖS Pediatrik Kull, 118 83, Stockholm, Sweden.
E-mail address: elin.dahlen@ki.se (E. Dahlén).

https://doi.org/10.1016/j.ejpn.2022.05.007
Received 23 December 2021; Received in revised form 8 March 2022; Accepted 22 May 2022
Available online 25 May 2022
1090-3798/© 2022 The Authors. Published by Elsevier Ltd on behalf of European Paediatric Neurology Society. This is an open access article under the CC BY
license (http://creativecommons.org/licenses/by/4.0/).
K. Tedroff et al.
Nevertheless, in Sweden, UK, and other high-income countries, the
use of melatonin has seen an explosive increase in pediatric use during
the last years [12–14].
Between 2014 and 2017 in Stockholm, Sweden, our preliminary
investigation identified a steep increase in numbers of children having
melatonin dispensed and in the dispensed doses. This is concerning, as
evidence for treating sleep problems in children with melatonin is
limited and long-term safety data is lacking.
2. Aim
The overall aim was to assess the drug utilization of melatonin in
children and young adults including adherence to medication, comor­
bidity and the prescribing specialists in Stockholm, Sweden during
2016–2019.
3. Materials and methods
This is a registry-based cohort study of all children and young adults
in Region Stockholm (an urban area with a population of 2 267 970
individuals in 2016). All individuals 0–25 years of age with at least one
prescription of melatonin (ATC-code N05CH01) dispensed in 2016 were
included. These individuals were followed for three years until
December 31, 2019, thus the total study period reach from 2016 to
2019. The individuals were divided into four different age categories at
the index year 2016: 0–6 years, 7–12 years, 13–17 years, and 18–25
years.
Data source: We used individual-level patient data from the Stock­
holm regional health care data warehouse (VAL). The data base contains
encrypted, anonymized data on diagnoses, hospitalizations, and con­
sultations in hospital-based specialist care, consultations in primary
care, and prescription claims for all individuals in the region.
Measurements: Number of individuals, number of prescriptions,
number of defined daily doses (DDDs). DDD is a volume measure defined
as the assumed average maintenance dose per day for a drug used for its
main indication in adults. The DDDs are assigned to drugs by the WHO
Collaborating Centre in Oslo. The DDD for melatonin is 2 mg [15].
Sleeping medication other than melatonin was defined with ATC-
codes as: N05BB01 hydroxyzine, R06AD01 alimemazine, R06AD02
promethazine, N05CD benzodiazepine derivatives, N05CF benzodiaze­
pine related drugs, N05CM other hypnotics and sedatives.
In this study polypharmacy was denoted if an individual was
dispensed four or more different types of medications (different ATC-
codes) during 2016 including melatonin.
For the diagnosis of a sleep disorder an ICD 10 code registered in
2015–2016 were required. The following codes were included: G470
Insomnia unspecified, G472 Circadian rhythm sleep disorders, G478
Other sleep disorders, G479 sleep disorder, unspecified, F510 Nonor­
ganic insomnia, F512 Nonorganic disorder of the sleep-wake state, F518
Other sleep disorders, or F519 Sleep disorder not due to a substance or
known physiological condition, unspecified.
Co morbidities from the following ICD 10 groups were included:
cognitive developmental disorder (F70-79), psychiatric disorder
(F20–29, F30–39, F41, F42) neuropsychiatric disorder (F84, F90-98),
visual impairment (H54.0, H54.1, H54.2), or epilepsy (G40, G41). For
the identification of a comorbidity a diagnosis between 2013 and 2016
was required.
The prescribing specialty was identified through the prescribing
physician’s workplace, i.e., a secondary care pediatric clinic or child
psychiatry clinic. The prescribing specialty was divided into five groups:
child psychiatrist, pediatrician, general psychiatrist, general practi­
tioner, and other specialty.
Ethical approval was obtained from the Swedish Ethical Review
Authority, (no 2020–03473).
31
European Journal of Paediatric Neurology 39 (2022) 30–34
3.1. Statistical analysis
Descriptive statistics including frequencies and proportions was used
to describe the study population. A t-test was used to calculate differ­
ences between groups and a significance level of 0.05 was applied. The
median number of DDDs per individual was calculated as well as the min
and max of DDDs dispensed.
Adherence to melatonin was measured as a refill of a prescription
within 12 months i.e., melatonin dispensed at least two times within 12
months for the same individual.
4. Results
In total, 9980 individuals 0–25 years were dispensed at least one
prescription of melatonin in 2016 i.e., the study population (Fig. 1).
Among them, 5454 were males and 4526 were females.
The prevalence of dispensed melatonin in 2016 was 1.4%, 1.5%
among males and 1.3% among females (Table 1). Across the different
age categories, the prevalence was 0.2% in preschoolers 0–5 years, 1.4%
in school children 6–12 years, 3.4% among adolescents 13–17 years, and
1.2% among young adults 18–25 years.
Polypharmacy (i.e., ≥4 different ATC-codes) was identified in 4567
individuals (46%) and was more common among females than males
(56% vs. 37%; p-value <0.01). Among the 9980 individuals with
melatonin, 27% (n = 2648) were dispensed at least one other medica­
tion for sleep disorder in 2016. Females had more often additional
medications, compared to males (41% vs. 23%; p-value <0.01). The
number of individuals with a recorded diagnosis of sleep disorder was
1953 (20%). In total, 8374 individuals (84%) were having at least one
recorded diagnosis of a comorbidity during 2013–2016.
In total, 32 147 prescriptions of melatonin were dispensed in 2016.
The most common prescribing specialties were child psychiatrist (55%),
pediatrician (25%), and general psychiatrist (13%) (Table 2).
The most common strength of dispensed Melatonin was 2 mg tablets/
capsules (67% of all prescriptions), followed by 3 mg tablets/capsules
(13%) and an oral solution of 1 mg/ml (10%) (Fig. 2). The mean overall
dose was 2.26 mg melatonin, 2.37 mg when prescribed by a general
psychiatrist, and 2.11 mg by a general practitioner. The mean dose
melatonin increased from 2.17 among children 6–12 years old, to 2.33
among young adults aged 18–25 years. Among children 0–5 years of age,
76% of all the prescriptions were the oral solution of 1 mg/ml.
Fig. 1. Flowchart describing the inclusion of the study population.
K. Tedroff et al. European Journal of Paediatric Neurology 39 (2022) 30–34

Table 1 Table 3
Number of individuals with dispensed melatonin in 2016 by age category (n = The median number of prescriptions and DDDs of melatonin dispensed annually
9980). per individual 2016–2019 by sex and age category.
Age category Age group (years) Median (min- 2017 2018 2019
max) 2016
0–5 N 6–12 13–17 18–25 0–25
(5%) N (%) N (%) N (%) N (%) Number of prescriptions/individual
Sex
Total 368 2809 4175 2628 9980
Males 2 (1–31) 4 (1–47) 4 (1–43) 4 (1–45)
(100) (100) (100) (100) (100)
Females 2 (1–34) 3 (1–37) 3 (1–44) 3 (1–45)
Males 235 1935 2069 1215 5451
Age categories
(64) (69) (50) (46) (55)
0–5 years 2 (1–20) 5 (1–19) 5 (1–20) 6 (1–25)
Females 133 874 2106 1413 4526
6–12 3 (1–34) 4 (1–47) 4 (1–44) 4 (1–45)
(36) (31) (50) (54) (45)
years
Number of prescriptions 1227 11 336 12 706 6878 32 147
13–17 2 (1–31) 3 (1–34) 3 (1–37) 3 (1–27)
Number of individuals with: 169 961 1840 1597 4567
years
Polypharmacy (at least 4 (46) (34) (44) (61) (46)
18–25 years 2 (1–25) 3 (1–24) 3 (1–19) 3 (1–35)
ATC-codes)
Number of DDDs/individual
Sleeping medication other 96 391 1194 967 2648
Sex
than melatonin (26) (14) (29) (37) (27)
Males 100 (0–1000) 100 120 (0–750) 150
Recorded diagnosis for sleep 167 520 808 458 1953
(0–1000) (14–1000)
disorder (45) (19) (19) (17) (20)
Females 100 (0–750) 100 150 150
Recorded diagnosis of 206 2405 3554 2209 8374
(0–800) (14–1500) (14–1500)
comorbidity (any) (56) (86) (85) (84) (84)
Age categories
Cognitive developmental 17 140 109 86
0–5 years 50 (0–500) 50 100 (0–400) 100
disorder
(25–400) (25–500)
Psychiatric disorder <10 288 1752 1497
6–12 100 (0–600) 100 100 (0–750) 150
Neuropsychiatric disorder 161 2246 2620 1447
years (25–600) (14–750)
Visual impairment <10 <10 <10 <10
13–17 100 (25–1000) 100 150 (0–600) 150
Epilepsy 43 101 78 58
years (0–750) (14–750)
18–25 90 (0–750) 100 150 (0–750) 150
years (0–1000) (14–1500)

Table 2
Number of melatonin prescriptions dispensed in 2016 by prescribing specialty.
The proportion of individuals adherent (refill of a melatonin pre­
Prescribing Age group (years) scription within 12 months) to melatonin was higher among males
specialty
0–5 N 6–12 N 13–17 N 18–25 N 0–25 N compared to females (77% and 73% respectively after one year; p-value
(5) (%) (%) (%) (%) <0.01; Fig. 3a).
Child 327 (27) 7305 (65) 8822 (69) 1317 17 771 The proportion of individuals who were adherent was highest among
psychiatrist (19) (55) children 6–12 years. After one year, the adherence to melatonin was
Pediatrician 855 (70) 3764 (33) 3012 (24) 407 (6) 8038 (25) 87% among children 6–12 years, 76% among those 0–5 years, 75%
General <10 (0) 47 (0) 212 (2) 3810 4071 (13)
among those 13–17 years and 62% among those 18–25 years (Fig. 3b).
psychiatrist (55)
General 19 (1.5) 126 (1) 243 (2) 720 (11) 1108 (3)
practitioner 5. Discussion
Other 24 (1.5) 94 (1) 417 (3) 624 (9) 1159 (4)
Total 1227 11 336 12 706 6878 32 147 This study shows that a substantial number of children in the
(100) (100) (100) (100) (100)
Stockholm Region use melatonin continuously, in adolescents 3.4%. Of
the 1.4% of all children and young individuals who were dispensed
melatonin in 2016, 50% of males and 40% of females continued to use
melatonin throughout the 3 years follow up. During this period, the
median DDDs/individual increased by on average 50% and the amounts
of dispensed drugs increased by 100%. Additionally, we found that only
1/5 had a recorded sleep disorder diagnosis. Many had comorbid di­
agnoses and polypharmacy was common.
In a study based on national Swedish data, 2% of the boys and 1.5%

Fig. 2. The number of melatonin prescriptions dispensed during 2016 by

strength and prescribing specialty.

In general, the median number of prescriptions dispensed was higher

among males than females. In 2016, the median number of dispensed
prescriptions per individual was 2 among males and 2 among females.
The corresponding numbers for 2019 were 4 and 3, respectively
(Table 3). The highest dose of melatonin was found among individuals
Fig. 3a. Proportion of individuals adherent to melatonin (refill of a melatonin
18–25 years of age, in this group the maximum dose per day was 8 mg. prescription within 12 months) by sex.

32
K. Tedroff et al.
Fig. 3b. Proportion of individuals adherent (refill of a melatonin prescription
within 12 months) by age category.
of the girls claimed at least one prescription of melatonin in 2017 which
is a slightly higher figure than in our cohort [8]. In the same study,
Kimland and co-authors show an exponential increase between the years
2008 and 2017 which could explain this difference [8].
In our cohort, continuous medication was most common amongst
children 6–12 years (87% after one year and 69% after three years),
declining to be lowest in the oldest age group, 18–25 years, where 62%
had continued melatonin dispensation after one year. A lower adherence
in adolescents and younger adults may not be surprising. A study of
adherence to ADHD-medication in adolescents found 61% to be
adherent to their medication [16]. Similar results were found in a study
of young adults with asthma, where 60% were adherent to their
controller medication after 1.5 years [17]. It can be hypothesized that
adolescents and younger adults have a higher degree of autonomy than a
younger child. A suggested reason is that adverse events, among those
sleeping problems, make adolescents skip medication at times [16].
Comorbidities were common in our cohort and present in 84% of the
children and young adults (Table 1). This is similar to findings in pre­
vious epidemiological melatonin studies [8,18] and not surprising as a
sleep disorder often is concomitant with other conditions such as
neuropsychiatric diagnoses [19] and cerebral palsy [20]. It could also be
a side effect to medications such as ADHD-medication [21]. Surpris­
ingly, only 20% of those who had melatonin prescribed also had a
recorded ICD-10 diagnosis of any sleep disorder. Comorbid diagnoses
were very common, and in some of these diagnoses, such as in many
neuropsychiatric diagnoses (i.e., ADHD and ASD), sleep problems are so
frequent it may be viewed as superfluous to record it [22]. Also, in ep­
ilepsy sleep problems are presumed to be deleterious to seizure control
and may thus motivate treatment even though a formal sleep disorder
may not be present [23]. Lastly, no recording of a diagnosis, even if
relevant, is a well-known phenomenon in other diagnoses such as stroke,
TIA, myocardial infarct, and migraine and is hypothesized to be the
effect of a physician work overload and the lack of administrative time
[24,25]. This is concerning, a missing diagnosis has been shown to result
in suboptimal treatment of chronic disease [24,25]. Furthermore, it
makes registry based follow up difficult.
A substantial part of the cohort also had several other prescription
medications (other than for sleeping problems). Dispensation of drugs
from at least four different ATC-codes were found in 37% and 56% of
male and female patients, respectively. Similar findings were made in
both a Norwegian and a Swedish nation-wide study of children up to the
age of 17 years [8,18]. In general, at least in Sweden, females use more
prescription medication than males [26]. This is the case, particularly
during puberty and in early adulthood, but not all of the sex difference
can be explained by hormonal contraceptives [26]. Dispensation of
other sleep medication was more common in females, 41% vs. 23% of
males. The dispensation of other sleep medications increased with age.
Overall, proof for the efficacy of all types of sleep medication in children
is weak. A meta-analysis from 2019 showed little evidence for all sleep
medications, however, there was some level of evidence for melatonin
33
European Journal of Paediatric Neurology 39 (2022) 30–34
and diphenhydramine, with diphenhydramine having the weaker evi­
dence [21].
The most common prescriber specialty was child psychiatry which
was rather surprising as there are almost three times more pediatricians
than child psychiatrist in Stockholm and Sweden [27]. In total pedia­
tricians and child psychiatrist prescribed for the up to 20-year-old age
group. This is much satisfactory and in line with Swedish guidelines, i.e.,
that sleep medication in children should be prescribed by specialists in
children. While psychiatrists prescribed for those 18–25 years old.
General practitioners mainly prescribed for the 20–25 years old but
overall, prescriptions made by general practitioners only accounted for
3%.
Most concerning to us is the long-term use and increased doses of
melatonin observed in our cohort. There are some, albeit small, ran­
domized clinical studies of melatonin in young persons but long-term
studies are lacking [21,28]. Even though little harm has been
described in the pediatric melatonin trials they have all been limited to a
shorter treatment time (1–13 weeks, median 4 weeks) [20]. From a
historical perspective, several endogenous substances and hormones
originally considered to be harm free and without side effects have
eventually proven to hold unwanted side effects when given as an
add-on or replacement therapy. This is the case for estrogen, during the
1980s-2000 commonly prescribed to alleviate postmenopausal symp­
toms to a large proportion of women. During the first decade of 2000
studies showed that estrogen replacement therapy significantly in­
creases risk of breast cancer [29]. Another example, in men with late
onset sexual dysfunction and low levels of serum testosterone, the
endogenous sex hormone testosterone has been used as a supplement
(TST) for more than 70 years [30]. However, during the last decades
reports have addressed the risks of polycythemia and hyperestrogenism
in men treated with TST and prompted the need for a Cochrane review,
that is currently ongoing [31]. Other commonly known examples of
when endogenous substances have unwanted or serious side effects
when taken at higher doses are, endogenous steroids, and thyroid hor­
mones. For Melatonin, there are conflicting results regarding the effect
on sperm quality and count in men exposed to long term melatonin
treatment [32–34]. In women, melatonin in doses 7.5–300 mg has
shown suppression of ovulation and lower levels of luteinizing hormone
[35]. Thus, to treat children and young adults with high doses of
melatonin for a prolonged period might ultimately result in unwanted
medical problems and pharmacoepidemiological studies are urgently
needed.
It is particularly important to increase the knowledge base related to
melatonin use since it is well known that insomnia and sleep related
problems will decrease quality of life, health related fitness as well as
cognitive performance in children and adolescents [4,36,37]. Thus,
there is a need of effective and safe options to alleviate these problems in
the young as well as in the adult population.
The strength of this study is that it uses all diagnoses recorded in the
health care system in an entire geographically well-defined Region,
including Primary care diagnoses. Thus, it provides a cohort that can be
followed over time in registries using variables such as numbers of in­
dividuals, dispensations, DDD, adherence, prescribing physician and
doses prescribed. Also, as all data on dispensed drugs comes from the
Swedish Prescribed Drug Register, virtually all dispensations are
included [38]. A limitation though is that we don’t have the indication
of the prescribed medication. Furthermore, dispensed medication is not
equivalent to ingested medication. However, dispensing data is an
accepted proxy which has been shown to be accurate, particularly when
measuring adherence to medication [39,40].
In conclusion, we show that almost half of our cohort of individuals
up to 25 years of age in Stockholm, Sweden, were dispensed melatonin
during the entire 3-year study period. Doses and volumes of drug
dispensed increased by 50 and 100%, respectively which we find con­
cerning as long-term data on melatonin use in young persons is limited.
K. Tedroff et al.
Funding
KT was supported by grants provided by the Stockholm Region (ALF-
funding). MvE received grants from Region Örebro (ALF-funding). The
funding was provided as unrestricted grants, and the funding bodies did
not influence the work, the analyses, or the interpretations, for which
the authors are responsible.
Disclaimer
ED is employed at the Swedish Medical Products Agency, the views
expressed in this study are the personal views of the author and not
necessarily the view of the Government agency.
Declaration of competing interest
None.
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