Current Medical Research and Opinion

ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: http://www.tandfonline.com/loi/icmo20

Utilization and safety of proton-pump inhibitors

and histamine-2 receptor antagonists in children
and adolescents: an observational cohort study

A. Ruigómez, S. Johansson, P. Nagy & L. A. García Rodríguez

To cite this article: A. Ruigómez, S. Johansson, P. Nagy & L. A. García Rodríguez (2017):
Utilization and safety of proton-pump inhibitors and histamine-2 receptor antagonists in children
and adolescents: an observational cohort study, Current Medical Research and Opinion, DOI:
10.1080/03007995.2017.1354830

To link to this article: http://dx.doi.org/10.1080/03007995.2017.1354830

Accepted author version posted online: 12

Jul 2017.

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Utilization and safety of proton-pump inhibitors and histamine-2 receptor antagonists in children
and adolescents: an observational cohort study
A. Ruigómez [1], S. Johansson [2], P. Nagy [3], L. A. García Rodríguez [1]

1. Spanish Centre for Pharmacoepidemiologic Research (CEIFE), Madrid, Spain

2. AstraZeneca Gothenburg, Mölndal, Sweden
3. Former employee of AstraZeneca Gothenburg, Mölndal, Sweden

Address for correspondence: Luis A. García Rodríguez, Spanish Centre for Pharmacoepidemiologic
Research (CEIFE), Almirante 28-2, E-28004, Madrid, Spain. E-mail: lagarcia@ceife.es.

Running head: Safety of acid-suppressing drugs in children

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Transparency

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Declaration of funding

This study was funded in part by AstraZeneca Gothenburg, Mölndal, Sweden.

Declaration of financial/other relationships

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AR and LAGR work for CEIFE, which has received research funding from AstraZeneca R&D, Mölndal,
Sweden, and Bayer Pharma AG, Berlin, Germany. LAGR has also received honoraria for serving on
scientific advisory boards for Bayer. SJ is an employee of AstraZeneca R&D, Mölndal, Sweden, and
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owns stock or options. PN was an employee of AstraZeneca at the time the study was conducted and
the manuscript initiated. CMRO peer reviewers on this manuscript have no relevant financial or
other relationships to disclose.
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Acknowledgments
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Writing support was provided by Dr Nesta Hughes of Oxford PharmaGenesis, Oxford, UK, and was
funded by AstraZeneca Gothenburg, Sweden. We gratefully acknowledge the expert input from
Professor Francisco J de Abajo (University of Alcalá, Madrid, Spain) and Professor Ernst Kuipers
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(Erasmus University Medical Centre, Rotterdam, Netherlands) in validating the safety outcomes
cases.
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Abstract
Background—Little is known about the use of acid-suppressing treatments and related safety events
in children.
Objective—We compared patient characteristics and safety outcomes among children prescribed
acid-suppressing drugs for the first time.
Methods—We used The Health Improvement Network to determine the characteristics of children
prescribed a proton pump inhibitor (PPI; esomeprazole or another PPI) or a histamine-2 receptor
antagonist (H2RA) by UK primary care physicians between October 2009 and September 2012. We
compared predefined safety outcomes among the treatment groups in up to 18 months of follow-
up.
Results—The cohorts comprised 8172 patients on PPIs (including 24 patients on esomeprazole) and
7905 on H2RAs. The baseline characteristics were similar between cohorts, although the children in
the PPI cohorts tended to be older. No safety outcomes occurred in the esomeprazole cohort. In the
other-PPIs cohort, 92 safety outcomes occurred, most commonly gastroenteritis (n=36; 39.1%). In

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the H2RAs cohort, 193 safety outcomes occurred, most commonly gastroenteritis (n=62; 32.1%). The
incidence of most safety outcomes was higher in the H2RAs cohort than in the other-PPIs cohort,

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including failure to thrive (3.11 [95% confidence interval (CI): 2.25–4.28] vs 0.49 per 1000 person-
years [95% CI: 0.22–1.07]) and gastroenteritis (5.27 [95% CI: 4.11–6.75] vs 3.04 per 1000 person-
years [95% CI: 2.20–4.20]).

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Conclusion—Esomeprazole is rarely prescribed to children when they first require acid-suppressing
medication, compared with other PPIs/H2RAs. Overall, more safety outcomes occurred in the H2RAs
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cohort than in the PPI cohorts.
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Key Words
acid-suppressing drugs, gastroesophageal reflux disease, children, drug safety,
pharmacoepidemiology, The Health Improvement Network (THIN)
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Introduction
Gastroesophageal reflux is widespread among the pediatric population and is particularly common
in infants, with up to half of those under 3 months old having daily episodes of regurgitation 1.
Although regurgitation resolves spontaneously in most healthy infants by 12–14 months of age 2,
some children develop symptomatic gastroesophageal reflux disease (GERD) 3. GERD among children
is a growing problem 4, particularly in the first year of life and during adolescence. A previous UK
database study showed an incidence of GERD in children of 0.84 per 1000 person-years (1.48 per
1000 person-years among 1-year-old children; 2.26 and 1.75 per 1000 person-years for girls and
boys aged 16–17 years old, respectively) 5.

The diagnosis and management of pediatric GERD can be challenging because the disease can
present in different ways in children compared with adults; for example, abdominal pain is a
relatively common mode of presentation in children 6. Symptoms also vary considerably by age
group, and are often hard to interpret 3. In infants, it is difficult to determine whether regurgitation,

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food refusal, and crying are due to acid reflux, presenting a problem in symptom-based diagnosis.
Young children (aged 1–6 years) tend to present with food refusal, regurgitation, and abdominal

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pain, whereas children aged 6–17 years tend to report regurgitation or vomiting, cough, and
epigastric pain or heartburn. As children get older, heartburn and regurgitation become the
predominant presenting symptoms, as in adults 7.

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The objective of treating GERD in children is to relieve symptoms, heal esophagitis, and prevent
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complications. Mild symptoms may be managed by conservative recommendations involving diet or
positioning; for those with troublesome symptoms, treatment with acid-suppressing drugs such as
histamine-2 receptor antagonists (H2RAs) or proton pump inhibitors (PPIs) is often required 8, 9.
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Little is known about drug use and potential safety events associated with these acid-suppressing
treatments in children. Some studies suggest that there may be risks 10, including a potential
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association between PPIs and an increased risk of respiratory tract or gastrointestinal infections 3.
For example, a prospective study performed in children aged 4–36 months, 95 of whom were
healthy controls, 47 were ranitidine users, and 44 were omeprazole users, showed that the use of
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acid-suppressing drugs for 2 months was associated with an increased risk of acute gastroenteritis
and community-acquired pneumonia in children with GERD 11. However, studies reporting risks
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associated with the use of acid-suppressing drugs in children tend to be small, with their own
limitations, suggesting that there is a clear need for further well-designed trials and observational
studies 12.
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Some studies have indicated other potential risks associated with the use of acid-suppressing drugs
in adults, although studies in children are lacking. For example, treatment with PPIs is considered to
be the most common cause of drug-induced acute interstitial nephritis in adults, although no studies
are yet available on childhood cases 10. Furthermore, because reflux esophagitis is prevalent in
pediatric patients with significant neurologic impairment 10, concerns have been raised about
instances of convulsion or seizure in patients receiving PPI therapy; however, our recent study of
8605 adults with seizures, matched to 40 000 controls, showed that the use of PPIs and H2RAs was
not associated with an increased risk of seizures in the overall population or in the cohorts stratified
by epilepsy status 13.
Here, we study clinical conditions as safety outcomes, which, although often having a low rate of
occurrence, are medically significant and can potentially have an underlying drug-related etiology.
The aims of this study were, first, to explore the characteristics of children prescribed esomeprazole,
a PPI other than esomeprazole, or an H2RA for the first time in the primary care setting, and second,
to compare the occurrence of various predefined safety outcomes in up to 18 months of follow-up in
the same patient populations.

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Materials and methods
Data sources
A cohort study using prospectively collected data was performed using The Health Improvement
Network (THIN) primary care database, which contains anonymized information on 3.9 million
patients (approximately 6 % of the UK population) and is representative of the overall population in
terms of age, sex, and geographical location 14. THIN has been validated for use in
pharmacoepidemiology research 15 and contains information entered by primary care physicians
(PCPs) on patient demographics, diagnoses, and prescriptions (including indications for new courses
of therapy), details of specialist referrals, hospital admissions, and laboratory tests results.
Additional free-text comments can also be included in the database and these may be used for
validation purposes. Diagnoses are recorded using Read codes 16, 17, while drugs are coded using data
from the Multi-Functional Standardised Lexicon for European Community Languages (MULTILEX)
classification 18.

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Study design
Children and adolescents aged 0–18 years who were first prescribed an acid-suppressing drug

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between October 1, 2009 and September 30, 2012 were categorized into one of three cohorts
according to ther index treatment: esomeprazole, another PPI (other-PPIs cohort; e.g. lansoprazole,

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omeprazole, pantoprazole, rabeprazole) or an H2RA (e.g. cimetidine, famotidine, nizatidine,
ranitidine). The index (start) date was when a patient was first prescribed the index acid-suppressing
drug. Patients who had been prescribed the index drug at any time before the study period were
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excluded from this study. The cohorts were selected independently. To ensure that children were
not entered into more than one cohort, only the first entry into a cohort was eligible (i.e. if the same
child was later entered into a second cohort then they were excluded from that cohort for the final
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analysis). The study design is summarized in Figure 1.

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The children in the three study cohorts were further categorized according to whether they had
previously been prescribed other acid-suppressing drugs: ‘naïve’ children were defined as those
without any recorded acid-suppressing drug prescriptions before the index date; ‘non-naïve’ children
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were defined as those with one or more previous acid-suppressing drug prescriptions (other than
the index acid-suppressing drug) recorded before the index date (Figure 1).
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To be included in the study, patients had to have at least 1 year of history in the THIN database and
at least 1 year of enrolment with a PCP before the index date. These criteria could not be applied to
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babies under the age of 1 year; however, over 90% of children had their first entry in THIN within
1 month of birth, increasing to 98% within 2 months of birth. This study was approved by the
Cambridgeshire for Research Ethics Committee (reference 10/H0305/35).

Follow-up
In order to determine the incidence of various safety outcomes, the cohorts were followed up for up
to 18 months after the study enrolment period. The occurrence of the following predefined
outcomes was assessed: thrombocytopenia, angioneurotic edema, pneumonia, gastroenteritis,
failure to thrive, convulsion/seizures, learning/development disability, and acute interstitial
nephritis. Each outcome had a separate follow-up, excluding patients with antecedents of that
specific outcome before the start date in each respective follow-up. All patients from the three
cohorts were followed up from the start date (first index drug prescription) until the earliest
occurrence of one of the following endpoints: case detection of specific safety outcome, death, or
end of follow-up (March 31, 2014).

Classification of patient characteristics

For all three study cohorts, age, sex, and body mass index were determined at start date, as was the
dose of acid-suppressing drug on the index prescription and the duration of the first treatment
episode with the index drug (defined as the number of days of prescription supply plus a grace
period of 15 days; if at the end of this period there was no further prescription of the index drug
group then use of the drug was considered interrupted).
The indication for treatment with the index drug (GERD-related heartburn, peptic ulcer disease,

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upper gastrointestinal-related symptoms, gastroprotection for concomitant use of non-steroidal

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anti-inflammatory drugs [NSAIDs], or unknown) was determined. This was done by performing a
manual review of a sample of patient records and then, based on the results of the review, creating

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a ranked computer algorithm to automatically assign treatment indication.
The number of prescriptions for the index acid-suppressing drug and for different acid-suppressing

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drugs in the first year after start date was determined, as was the number of different acid-
suppressing drug prescriptions before the start of the study among the non-naïve children. Current
use of comedications at the start date was defined as a supply of the most recent comedication
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prescription that lasted until the start date or ended in the 15 days before the start date.
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Comorbidities were identified from diagnosis codes in THIN. General comorbidity was defined by
organ class (e.g. gastrointestinal, cardiovascular, or renal). Specific comorbidities such as diabetes,
asthma, congenital malformation, and epilepsy were recorded if they had occurred at any time
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before the start of the study, whilst information on gastrointestinal morbidity and related symptoms
was collected for the year before the study start date. Healthcare utilization was determined by
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recording the number of PCP visits, referrals to specialists, and admissions to hospital in the year
before the start date.
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Safety outcomes ascertainment and validation

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We identified 460 patients with a Read code recorded for any of the predefined safety outcomes
(thrombocytopenia, angioneurotic edema, pneumonia, gastroenteritis, failure to thrive,
convulsion/seizures, learning/development disability, and interstitial nephritis) during the follow-up.
An initial validation process, involving a manual review by two study researchers (who were blinded
to specific drug exposure) of the free-text comments included in THIN for these patients, identified
328 potential outcomes. A second review of these potential outcomes was performed by an external
expert board. Final cases for the various safety outcomes were selected when there was agreement
between the external reviewers and the study researchers.
Analysis
Patient and treatment characteristics are presented descriptively. The patient populations and
utilization measures among the three study cohorts were compared, including demographics,
concomitant drug use, comorbidities, healthcare utilization, and pattern of use of acid-suppressing
drugs. For each of the validated safety outcomes, incidence (per 1000 person-years with 95%
confidence intervals [CIs]) was estimated for each study cohort, as well as according to the recency
of use of an acid-suppressing drug. The recency of acid-suppressing drug use was defined as: 1) non-
use, when there was no recorded use between start and safety outcome event date; 2) current use,
when the most recent prescription lasted until the safety outcome event date or ended in the 15
days before; 3) recent use, when the prescription ended between 16 and 365 days before the safety
outcome event date; 4) past use, when the most recent prescription ended more than 366 days
before the safety outcome event date.

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Results
Patient characteristics: prior acid-suppressing drug use and demographics
The final study cohorts comprised 24 patients who were first prescribed esomeprazole, 8148 who
were first prescribed another PPI, and 7905 who were first prescribed an H2RA (Figure 1). Most first-
time users of other PPIs (n=7620; 93.5%) and H2RAs (n=7784; 98.5%) had never been prescribed a
PPI or H2RA aside from the index study drug (i.e. naïve). In contrast, more than half (n=13; 54.2%) of
the esomeprazole cohort had previously been treated with another acid-suppressing drug (i.e. non-
naïve) (Figure 1).

Baseline patient characteristics are shown in Table 1. Children from all three cohorts were frequent
users of healthcare services, with approximately a third having 11 or more PCP consultations in the
year prior to the study start. A higher proportion of patients in the esomeprazole cohort had three
or more referrals to a specialist in the year prior to the start of the study (n=10; 41.6%) compared
with the other-PPIs cohort (n=2903; 35.6%) and H2RAs cohort (n=2168; 27.4%). The PPIs cohorts (i.e.

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the other-PPIs and esomeprazole cohorts) had a greater proportion of girls than boys. Children in
the PPI cohorts tended to be older than those in the H2RAs cohort (in both naïve and non-naïve

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users, data not shown).

Comorbidities

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As shown in Table 1, most patients in the esomeprazole and other-PPIs cohorts had previously had
an infectious or parasitic disease (n=23; 95.8% and n=7174; 88.0%, respectively). Other commonly
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reported comorbidity categories among these patients were gastrointestinal diseases (n=19; 79.2%
and n=5575; 68.4%, respectively) and respiratory conditions (n=18; 75.0% and n=6294; 77.2%,
respectively). Similarly in the H2RAs cohort, the most widely reported category of comorbidity was
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infectious or parasitic disease (n=5070; 64.1%), followed by gastrointestinal (n=4734; 59.9%) and
respiratory conditions (n=3916; 49.5%).
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When specific individual comorbidities were considered, GERD-heartburn was reported by 33.3%
(n=8), 10.3% (n=836), and 22.3% (n=1764) of the esomeprazole, other-PPIs, and H2RAs cohorts,
respectively. Asthma was particularly widely reported in the other-PPIs cohort (n=1964 [24.1%]
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compared with n=2 [8.3%] in the esomeprazole cohort and n=895 [11.3%] in the H2RAs cohort).
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Supplementary Table 1 shows the breakdown of gastrointestinal and related symptoms in the year
prior to the index acid-suppressing drug prescription. Abdominal pain and nausea/vomiting were the
most frequent complaints in children, followed by cough and dyspepsia.
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Prescription patterns
Over half of the patients in each of the three cohorts received only one prescription for their index
acid-suppressing drug during the year after the study start (esomeprazole, n=13 [54.2%]; other PPI,
n=4797 [58.9%]; H2RAs, n=4778 [60.4%]) (Table 2). In the other-PPIs cohort, the most frequently
prescribed PPI at index date was omeprazole (79.4%), followed by lansoprazole (20.3%). Ranitidine
was the most commonly prescribed H2RA (99.2%) in the H2RAs cohort.

In about half of the patients, the duration of treatment in both the esomeprazole and other-PPIs
cohorts was 16–30 days, while in the H2RAs cohort treatment duration was fewer than 16 days in
about the same proportion of patients. Long treatment duration (over 3 months) occurred in 12.5%
(n=3) of the esomeprazole cohort and 9.6% (n=783) of the other-PPIs cohort, whilst a lower
proportion of patients in the H2RAs cohort had long treatment duration (n=353; 4.5%).

Indication for index prescription

As seen in Table 2, the main indications for patients first prescribed esomeprazole were other
gastrointestinal-related symptoms (defined as abdominal pain, dyspepsia, nausea, vomiting,
flatulence, dysphagia, hyperacidity, chest pain, or regurgitation; n=12; 50.0%), closely followed by
GERD-heartburn (n=9; 37.5%). The indications were similar for patients first prescribed other PPIs
(gastrointestinal-related symptoms, n=3851 [47.3%] and GERD-heartburn, n=1757 [21.6%]). The
main indications for patients first prescribed an H2RA were GERD-heartburn (n=3320; 42.0%)
followed by other gastrointestinal-related symptoms (n=2585; 32.7%).

Comedications

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The use of comedications at the start of the study is shown in Supplementary Table 2. The only
notable difference between the study cohorts in terms of comedication was that 30.9% of patients

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(n=2444) in the H2RAs cohort were current users of antacids at the time of the first H2RA
prescription, compared with 10.1% of patients (n=822) in the other-PPIs cohort and 8.3% of patients
(n=2) in the esomeprazole cohort. A higher proportion of the esomeprazole cohort (16.7%, n=4)

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were using prokinetics than the other-PPIs and H2RAs cohorts (2.8% [n=232] and 2.2% [n=175],
respectively).
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Safety outcomes
There were 285 confirmed predefined safety outcomes during follow-up among children taking acid-
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suppressing drugs (Table 3). Gastroenteritis was the most frequent safety outcome among all the
children (n=98; 34.4%), followed by convulsions/seizures (n=77; 27.0%) and pneumonia (n=53;
18.6%). There were no cases of acute interstitial nephritis. The prevalence of safety outcomes
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overall (and stratified by sex and age) is shown in Table 3.

No safety outcomes occurred during follow-up in the esomeprazole cohort. In the other-PPIs cohort
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(n=8148), 92 validated safety outcomes occurred during follow-up. The most common was
gastroenteritis (n=36; 39.1%), followed by convulsions/seizures (n=21; 22.8%) and pneumonia (n=21;
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22.8%). In the H2RAs cohort (n=7905), the number of safety outcomes was higher than in the other-
PPIs cohort (n=193 vs 92). The number of safety outcomes was 62 (32.1%) for gastroenteritis, 56
(29.0%) for convulsions/seizures, 37 (19.2%) for failure to thrive, and 32 (16.6%) for pneumonia.
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Incidence of safety outcomes overall and according to the recency of exposure to acid-suppressing
drug is shown in Table 4. Although no safety outcomes occurred in the esomeprazole cohort during
current and recent use, one case was noted in relation to past use: a 14-year-old male patient in the
other-PPIs cohort (first omeprazole user) who changed to esomeprazole during follow-up and was a
recent esomeprazole user when he developed a gastroenteritis episode (17.21 per 1000 person-
years [95% CI 3.04–91.27]). We observed higher incidences of most predefined safety outcomes
overall in the H2RAs cohort than in the other-PPIs cohort (Table 4), including failure to thrive (3.11
[95% CI 2.25–4.28] vs 0.49 per 1000 person-years [0.22–1.07]), gastroenteritis (5.27 [4.11–6.75] vs
3.04 per 1000 person-years [2.20–4.20]), convulsions/seizures (4.75 [3.66–6.16] vs 1.75 [1.15–2.68),
and pneumonia (2.66 [9% CI: 1.89–3.75]) vs 1.72 [:1.13–2.63]).

Discussion

This study used THIN, a UK primary care database, to investigate the patient and treatment
characteristics and incidence of key safety outcomes during up to 18 months of follow-up in children
and adolescents who had been prescribed esomeprazole, another PPI, or a H2RA for the first time. A
surprising finding of this study is that esomeprazole was prescribed with a much lower frequency
than other PPIs or H2RAs by UK PCPs during the study period. In adults, evidence suggests that
esomeprazole provides more effective acid control than other PPIs 19-21. Studies have also shown
that esomeprazole treatment in children and infants 22 with verified GERD is effective and well
tolerated. A randomized, uncontrolled, double-blind study of children aged 1–11 years with

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endoscopically verified GERD indicated that esomeprazole was generally well tolerated, and the
frequency and severity of GERD-related symptoms were significantly reduced during the active

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treatment period. Overall, only 9.3% of patients reported 13 treatment-related adverse events, the
most common being diarrhea (2.8%) 23. Adolescents aged 12–17 years with GERD have reported
significant improvements in health-related quality of life (HRQL) with esomeprazole treatment

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compared with baseline scores, indicating that GERD had a negative effect on HRQL 24. The limited
number of patients prescribed esomeprazole in our study restricted the analysis that could be
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performed to compare the characteristics and safety outcomes between the three study cohorts.

Although we found no major differences between the three study cohorts with respect to
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comorbidities and comedication, we did observe that patients in the H2RAs cohort tended to be
younger than those in the esomeprazole and other-PPIs cohorts and were more likely to be naïve
users of acid-suppressing drugs, suggesting that H2RAs were most often the PCPs’ first choice of acid-
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suppressing drug. We also noted that the most common indication for the index acid-suppressing
drug prescription amongst the other-PPIs cohort was other gastrointestinal-related symptoms,
rather than GERD-heartburn. This adds to the evidence 7 that GERD presents more diversely in
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children than in adults.

No predefined safety outcomes were observed in the small cohort of first-time esomeprazole users.
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In the H2RAs cohort, the number of validated safety outcomes was higher than in the other-PPIs
cohort (193 vs 92), although the number of patients in the two cohorts was similar. Gastroenteritis
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was the most frequent predefined safety outcome among the other-PPIs and H2RAs cohorts,
followed by convulsions and pneumonia. There were no cases of acute interstitial nephritis in any
cohort. The incidences of most safety outcomes (failure to thrive, convulsions/seizures,
gastroenteritis, learning/developmental disability, and pneumonia) were higher in the H2RAs cohort
than in the other-PPIs cohort.

The THIN database has strong external validity 15 and is representative of the general UK population
with respect to age, sex, and geographical region 14. Large sample sizes were used for the analysis of
the data from the other-PPIs and H2RAs cohorts (approximately 16 000 patients in these cohorts
combined). Analysis of first-time esomeprazole users was restricted as the cohort contained only 24
patients; this is an indication that esomeprazole is much less commonly prescribed than other PPIs
or H2RAs to children in the UK when they first require an acid-suppressing drug.

A limitation of the current study is that THIN does not report use of over-the-counter (OTC)
medications. However, prescription medications are free for patients under 18 years of age in the
UK, and healthcare is easily accessed, which is likely to encourage prescription rather than use of
OTC products. Also, as THIN data are prescription-based, they do not give information on adherent
to treatment, especially when patients receive only one prescription and there is no record of a
timely repeat prescription. Further, it would have been ideal if we could have evaluated the doses of
the acid-suppressing drugs given in this study; the dose of H2RAs and PPIs prescribed to children
tends to be based on their weight. However, we had limited information in THIN on the weight of
the children, and the small number of exposed cases prevented sub-analyses related to exposure
characteristics (e.g. dose, duration).

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Although PPIs are widely considered more effective than H2RAs in relieving symptoms of GERD in
adults 25, and pharmacologic tolerance to H2RAs can occur in as little as 2 weeks 26, leading to a

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tendency for a shorter treatment duration with H2RAs, the effectiveness of PPIs in infants and
children with GERD is not yet as well established because there have been relatively few studies in
children. One systematic review of randomized controlled trials of PPIs in children found a lack of

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efficacy of PPIs in young infants but an equivalent efficacy to other acid-suppressing medications in
older children and adolescents 27. Furthermore, a potential association between PPI use and an
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increased risk of respiratory tract and gastrointestinal infections, bone fractures, and
hypomagnesemia 12, 28 has been reported, although these safety concerns were based on only a few
small studies 12. However, our study indicates that the incidence of both pneumonia and
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gastroenteritis was higher in the H2RAs cohort than in the other-PPIs cohort. Furthermore, although
our previous study was conducted in adults, it did not find an association between the use of
PPIs/H2RAs and an increased risk of seizures, including in those with diagnosed epilepsy 13.
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In addition, a study of boys taking PPI therapy continuously for at least 1 year (about one-third of
whom had neurologic impairment) reported that PPI therapy was effective and well tolerated
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despite some biochemical, endoscopic, and histological changes 29. Indeed, it has long been known
that neurologic impairment predisposes children to the most severe and chronic GERD 30, and more
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recently these children have been reported to respond poorly to anti-reflux surgery but may
particularly benefit from PPI therapy 31.
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In conclusion, this cohort study in UK primary care has shown that esomeprazole is relatively rarely
prescribed to children and adolescents when they first require acid-suppressing medication,
compared with other PPIs and H2RAs. Although this limited the analyses that could be conducted on
the esomeprazole cohort in our study, our data demonstrate that more safety events occurred
during follow-up among patients newly prescribed H2RAs than in those newly prescribed PPIs.
Overall, a lack of pediatric studies in this therapy area demonstrates a clear need for further
research to better understand the efficacy and safety of PPIs in children.
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esophageal reflux in children: an evidence-based systematic review. Paediatr Drugs 2009;11(3):185–
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2. Martin AJ, Pratt N, Kennedy JD, Ryan P, Ruffin RE, Miles H, et al. Natural history and familial
relationships of infant spilling to 9 years of age. Pediatrics 2002;109(6):1061–7.
3. Vandenplas Y. Management of paediatric GERD. Nat Rev Gastroenterol Hepatol
2014;11:147–57.
4. Vakil N. Disease definition, clinical manifestations, epidemiology and natural history of
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Benninga. Efficacy of Proton-Pump Inhibitors in Children With Gastroesophageal Reflux Disease: A
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reflux disease. J Pediatr Gastroenterol Nutr 2002;35(2):119–36.
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Continuously for Up to 11 Years Duration. The Journal of Pediatrics 2007:262–67.

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Figure 1.
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†
Study design. *Based on first prescription in study period. Less than 1 year since first health contact
ǂ
recorded (not applied to infants under 1 year old). As we originally ascertained the three cohorts
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independently, children could be selected in more than one cohort. We retained only the first use of
one of the study drugs as eligible and excluded these children with a later entry in another cohort.
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§
Lost during follow-up (patients who were no longer registered in THIN in the last database update).
¶
Naive: defined as having never received a prescription for an acid-suppressing drug at any time
before the start of the study.
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Table 1

Baseline patient characteristics including demographics and healthcare utilization

Esomeprazole cohort Other-PPIs H2RAs

(n=24) cohort cohort
(n=8148) (n=7905)

Sex
Male 11(45.8) 3368 (41.3) 3886 (49.2)
Female 13 (54.2) 4780 (58.7) 4019 (50.8)
Age (yrs)
<1 2 (8.3) 860 (10.6) 3961(50.1)
1–5 4 (16.7) 384 (4.7) 643 (8.1)

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6–11 2 (8.3) 1016 1 (12.5) 1265 (16.0)

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12–18 16 (66.7) 5888 (72.3) 2036 (25.8)
Visits to primary care physician in year before study start

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0–2 2 (8.3) 1269 (15.6) 1062 (13.4)
3–5 6 (25.0) 1871 (23.0) 1979 (25.0)
6–10
11+
Referral in year before study start
9 (37.5)
7 (29.2)
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2387 (29.3)
2621 (32.2)
2565 (32.4)
2299 (29.1)
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None 6 (25.0) 2821 (34.6) 3063 (38.7)
1–2 8 (33.3) 2424 (29.7) 2674 (33.8)
3–5 5 (20.8) 1666 (20.4) 1417 (17.9)
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6+ 5 (20.8) 1237 (15.2) 751(9.5)

Hospitalization in year before study start
None 17 (70.8) 6484 (79.6) 5369 (67.9)
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1+ 7 (29.2) 1664 (20.4) 2536 (32.1)

Reported smoking status
Non-smoker 8 (33.3) 3604 (44.2) 1250 (15.8)
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Smoker 2 (8.3) 486 (6.0) 109 (1.4)

Ex-smoker 0 (0.0) 132 (1.60) 40 (0.5)
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Unknown 14 (58.3) 3926 (48.2) 6506 (82.3)

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Body mass index (kg/m )
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<20 8 (33.3) 2084 (25.6) 2025 (25.6)

20–24 1 (4.2) 1132 (13.9) 500 (6.3)
25–29 0 (0.0) 481 (5.9) 193 (2.4)
≥30 0 (0.0) 431(5.3) 164 (2.1)
Unknown 15 (62.5) 4020 (49.3) 5023(63.5)
Alcohol consumption
No recorded consumption 0 (0.0) 707 (8.7) 268 (3.4)
Yes 0 (0.0) 222 (2.7) 52 (0.6)
Unknown 24 (100) 7219 (88.6) 7585 (96.0)
Prior general comorbidity
 Esomeprazole cohort Other-PPIs H2RAs
(n=24) cohort cohort
(n=8148) (n=7905)

Infectious/parasitic disease 23 (95.8) 7174 (88.0) 5070 (64.1)

Endocrine 3 (12.5) 718 (8.8) 411 (5.2)
Hematologic 5 (20.8) 513 (6.5) 261 (3.3)
Cardio/circulatory disease 7 (29.2) 2516 (30.9) 2855 (36.1)
Gastrointestinal 19 (79.2) 5575 (68.4) 4734 (59.9)
Respiratory 18 (75.0) 6294 (77.2) 3916 (49.5)
Renal-urinary diseases 6 (25.0) 2654 (32.6) 1299 (16.4)
Central nervous system 5 (20.8) 783 (9.6) 336 (4.3)
Values are n (%).
H2RA = histamine-2 receptor antagonist; PPI = proton pump inhibitor.

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Table 2
Index drug indication and prescription patterns at index prescription and during the year after.

Esomeprazole Other-PPIs cohort H2Ras

cohort (n=8148) cohort
(n=24) (n=7905)

Number of prescriptions
1 (just the index prescription) 13 (54.2) 4797 (58.9) 4778 (60.4)
2–3 5 (20.8) 1847 (22.7) 1787 (22.6)
4–5 2 (8.3) 583 (7.2) 577 (7.3)
6+ 4 (16.7) 921 (11.3) 763 (9.7)
Duration of treatment
<16 days 6 (25.0) 1442 (17.7) 4045 (51.2)

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16–30 days 12 (50.0) 4474 (54.9) 2515 (31.8)
1–3 months 3 (12.5) 1449 (17.8) 992 (12.5)

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>3 months 3 (12.5) 783 (9.6) 353 (4.5)
Individual drug at index prescription
Esomeprazole
Omeprazole
Lansoprazole
24 (100)

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6468 (79.4)
1656 (20.3)
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Pantoprazole 14 (0.2)
Rabeprazole 10 (0.1)
Famotidine 1 (0.01)
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Cimetidine 58 (0.7)
Nizatidine 1 (0.01
Ranitidine 7845 (99.2)
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Indication of index prescription (manual review)

GERD-heartburn 9 (37.5) 1757 (21.6) 3320 (42.0)
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Peptic ulcer disease – 442 (5.4) 167 (2.1)

*
Other GI-related symptoms 12 (50.0) 3851 (47.3) 2585 (32.7)
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Concomitant use of NSAIDs 2 (8.3) 452 (5.5) 188 (2.4)

(gastroprotection)
Unknown 1 (4.2) 1646 20.2) 1645 (20.8)
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Use of other acid-suppressing drugs prior to index prescription

None (naïve patients) 11 (45.8) 7620 (93.5) 7784 (98.5)
Other PPI only 7 (29.2) 1 (0.0) 121 (1.5)
H2RAs only 2 (8.3) 482 (5.9) -
Other PPIs and H2RAs 4 (16.7) 45 (0.6) -
Values are n (%)
*Abdominal pain (most common), dyspepsia, nausea, vomiting, flatulence, dysphagia, hyperacidity, chest
pain or regurgitation.
GERD = gastroesophageal disease; GI = gastrointestinal; H2RA = histamine-2-receptor antagonist; NSAID =
non-steroidal anti-inflammatory drug; PPI = proton pump inhibitor.
 Table 3
The frequency of the predefined safety outcomes during follow-up overall.
Safety outcome Male Female Total
<1 yr 1–11 yr 12–18 yr <1 yr 1–11 yr 12–18 yr

Angioneurotic edema 0 (0.0) 1 (1.1) 1 (7.7) 0 (0.0) 1 (1.8) 0 (0.0) 3 (1.1)

Convulsion/seizures 9 (14.8) 34 (38.1) 2 (15.4) 13 (27.1) 13 (23.6) 6 (31.6) 77 (27.0)
Failure to thrive 19 (31.1) 6 (6.7) 0 (0.0) 12 (25.0) 6 (10.9) 0 (0.0) 43 (15.1
Gastroenteritis 22 (36.1) 26 (29.2) 7 (53.8) 14 (29.2) 18 (32.7) 11 (57.9) 98 (34.4)
Learning/develop disability 1 (1.6) 5 (5.6) 0 (0.0) 3 (6.3) 0 (0.0) 0 (0.0) 9 (3.2)
Pneumonia 10 (16.4) 16 (18.0) 3 (23.1) 6 (12.5) 16 (29.1) 2 (10.5) 53 (18.6)
Thrombocytopenia 0 (0.0) 1 (1.1) 0 (0.0) 0 (0.0) 1 (1.8) 0 (0.0) 2 (0.7)
Interstitial nephritis 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Total 61 89 13 48 55 19 285

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Values are n (%).

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 Table 4
Incidence of safety outcomes according to recency of exposure to acid-suppressing drug.
Esomeprazole use Other PPI use H2RA use
Events Incidence Events Incidence Events Incidence
Angioneurotic edema
Non-use 3 0.12 (0.04–0.36) 0 0 1 0.09 (0.02–0.51)
Current use 0 0 1 0.35 (0.06–1.98) 0 0
Recent use 0 0 2 0.24 (0.07– 0.87) 0 0
Past use 0 0 0 0 2 0.55 (0.15–2.00)
Overall 0 0 2 0.16 (0.04–0.58) 1 0.08 (0.01–0.46)
Convulsion/seizures
Non-use 77 3.25 (2.60–4.06) 47 4.59 (3.46–6.10) 18 1.68 (1.06–2.65)
Current use 0 0 14 5.18 (3.09–8.68) 7 4.08 (1.98–8.39)

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Recent use 0 0 13 1.62 (0.95–2.77) 41 5.21 (3.85–7.07)
Past use 0 0 3 1.06 (0.36–3.10) 11 3.15 (1.76–5.63)

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Overall 0 0 21 1.75 (1.15–2.68) 56 4.75 (3.66–6.16)
Failure to thrive
Non-use
Current use
Recent use
43
0
0
1.78 (1.32–2.40)
0
0
33
6
4
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3.19 (2.27–4.47)
2.17 (0.99–4.72)
0.49 (0.19–1.26)
7
10
23
0.64 (0.31–1.31)
5.71 (3.10–10.47)
2.91 (1.94–4.36)
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Past use 0 0 0 0 3 0.85 (0.29–2.49)
Overall 0 0 6 0.49 (0.22–1.07) 37 3.11 (2.25–4.28)
Gastroenteritis
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Non-use 97 4.12 (3.38–5.02) 57 5.59 (4.32–7.23) 34 3.24 (2.32–4.53)

Current use 0 0 14 5.11 (3.05–8.57) 9 5.13 (2.70–9.72)
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Recent use 1 17.21 (3.04–91.27) 21 2.65 (1.73–4.05) 43 5.43 (4.04–7.31)

Past use 0 0 6 2.14 (0.98–4.67) 12 3.43 (1.96–5.99)
Overall 0 0 36 3.04 (2.20–4.20) 62 5.27 (4.11–6.75)
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Learning/developmental disability
Non-use 9 0.37 (0.20–0.71) 4 0.38 (0.15–0.99) 4 0.36 (0.14–0.94)
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Current use 0 0 0 0 0 0
Recent use 0 0 3 0.37 (0.12–1.07) 2 0.25 (0.07–0.91)
Past use 0 0 2 0.69 (0.19–2.50) 3 0.84 (0.29–2.47)
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Overall 0 0 4 0.33 (0.13–0.84) 5 0.42 (0.18–0.97)

Pneumonia
Non-use 53 2.19 (1.68–2.87) 26 2.49 (1.70–3.65) 16 1.46 (0.90–2.37)
Current use 0 0 11 3.99 (2.23–7.12) 8 4.55 (2.31–8.95)
Recent use 0 0 15 1.84 (1.11–3.03) 19 2.37 (1.52–3.70)
Past use 0 0 1 0.34 (0.06–1.95) 10 2.81 (1.53–5.16)

Overall 0 0 21 1.72 (1.13–2.63) 32 2.66 (1.89–3.75)

Thrombocytopenia
 Non-use 2 0.08 (0.02–0.29) 0 0 2 0.18 (0.05–0.65)
Current use 0 0 0 0 0 0
Recent use 0 0 0 0 0 0
Past use 0 2 0.66 (0.18–2.40) 0 0

Overall 0 0 2 0.16 (0.04–0.58) 0 0

Acute interstitial nephritis

0 0 0 0 0 0
Incidence per 1000 person-years with 95% confidence interval.
Drug exposure categories were defined as: current use, when the most recent prescription lasted until
the safety outcome event date or ended in the 15 days before; recent use, when the prescription ended
between 16 and 365 days before the safety outcome event date; past use, when the most recent
prescription ended more than 366 days before the safety outcome event date; and non-use, when

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there was no recorded use between start and safety outcome event date.

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H2RA = histamine-2 receptor antagonist; PPI = proton pump inhibitor.

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Supplementary online materials
Supplementary Table 1

Specific gastrointestinal comorbidity and related symptoms in the year prior to index prescription.

Symptom Esomeprazole Other-PPIs cohort H2RAs cohort

cohort (n=24) (n=8148) (n=7905

Dysphagia 0 (0.0) 90 (1.1) 66 (0.8)

GI bleeding 0 (0.0) 67 (0.8) 39 (0.5)
Dyspepsia 4 (16.7) 1440 (17.6) 580 (7.3)
Nausea/vomiting 6 (25.0) 1569 (19.2) 1730 (21.8)
Flatulence 0 (0.0) 22 (0.3) 23 (0.3)
IBS 0 (0.0) 119 (1.5) 30 (0.4)

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Abdominal pain 4 (16.7) 2202 (26.9) 1631 (20.5)
Chest pain 0 (0.0) 472 (5.8) 204 (2.6)

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Laryngitis/hoarseness 0 (0.0) 72 (0.9) 51 (0.6)
Cough 4 (16.7) 1094 (13.4) 1127 (14.2)
Sore throat 2 (8.3) 848 (10.4) 429 (5.4)
Values are n (%).
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GI = gastrointestinal; H2RA = histamine-2 receptor antagonist; IBS = irritable bowel syndrome; PPI =
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proton pump inhibitor.
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Supplementary Table 2
Current use of comedication at start date (index prescription)
Comedication Esomeprazole Other-PPIs H2RAs
cohort cohort cohort
(n=24) (n=8148) (n=7905)
Antacids 2 (8.3) 822 (10.1) 2444 (30.9)
Prokinetic 4 (16.7) 232 (2.8) 175 (2.2)
NSAIDs 0 (0.0) 347 (4.3) 125 (1.6)
Paracetamol 0 (0.0) 344 (4.2) 301 (3.8)
Oral steroids 1 (4.2) 147 (1.8) 77 (1.00)
Anxiolytic/antidepressants 0 (0.0) 139 (1.7) 35 (0.4)
Antiepileptics 0 (0.0) 107 (1.3) 59 (0.7)
Oral contraceptives 0 (0.0) 577 (12.1) 119 (3.0)

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(n=8812 females)

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Antibiotics 0 (0.0) 375 (4.6) 289 (3.7)
β-agonists 1 (4.20) 521 (6.4) 341 (4.3)

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Disease-modifying antirheumatic drugs 2 (8.30) 35 (0.4) 11 (0.1)
Values are n (%).

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Current use was defined as use within the 15 days before the start of the study.
H2RA = histamine-2 receptor antagonist; NSAID = non-steroidal anti-inflammatory drug; PPI = proton
pump inhibitor.
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