Characteristics of Children Receiving Proton Pump Inhibitors Continuously for Up to 11 Years Duration

Article Outline

• Abstract
• Methods
• Results
  • Patients
  • GERD-Predisposing and Non–GERD-Predisposing Disorders
  • Endoscopic Findings
  • Presenting Symptoms
  • Antireflux Surgery
  • PPI Prescription
  • Adverse Drug Reactions
• Discussion
• References
• Copyright

Objective

To characterize those pediatric patients who receive long-term proton pump inhibitors (PPIs) and to determine the safety of long-term use of PPIs in this population.

Study design

Patient databases were screened for long-term PPI use, defined as more than 9 months of continuous prescription, between 1989 and 2004.

Results

The median duration of PPI use in the 166 patients in the study group was 3 years (range, 0.75 to 11.25 years). A total of 80 patients used PPIs for 3 to 11 years duration; 35 of these for more than 5 years, and 15 for more than 8 years. Mean age at initial prescription was 7.8 years. At least 1 gastroesophageal reflux disease (GERD)-predisposing disorder was present in 79% of the patients; the major disorders were neuromotor (in 66%) and esophageal atresia (in 14.5%). No GERD-predisposing disorder was present in 35 patients (21%). Endoscopic findings included hiatal hernia in 39% and histologically proven Barrett’s esophagus in 4.8%. Omeprazole was used in 90% of the patients; lansoprazole, in 7%. Six adverse reactions seen in 4 patients were potentially related to PPI (nausea and diarrhea, skin rash, agitation, and irritability).

Conclusions

Children with underlying GERD-predisposing disorders compose the majority of long-term PPI users. Few adverse reactions to these drugs occur, and discontinuation of the drug is seldom indicated. These preliminary data suggest that PPIs may be efficacious and safe for continuous use for up to 11 years’ duration in children.

Abbreviations: ALT, Alanine aminotransferase, AST, Aspartate aminotransferase, BCCH, British Columbia Children’s Hospital, GERD, Gastroesophageal reflux disease, GI, Gastrointestinal, H2Ra, Histamine-2-receptor antagonist, IQR, Interquartile range, PPI, Proton pump inhibitor

Until recently, antireflux surgery was the mainstay of treatment for children with severe gastroesophageal reflux disease (GERD), whereas histamine-2-receptor antagonists (H2RAs) were widely used for milder disease. However, both of these modalities have significant shortcomings. In children, surgery carries high rates of early failure and other morbidities,¹ whereas H2RAs are often ineffective in treating severe reflux,², ³, ⁴ and their effect diminishes over time, often within just a few weeks of therapy.⁵, ⁶, ⁷, ⁸ Proton pump inhibitors (PPIs) have the advantages of higher and faster rates of healing of esophagitis compared with H2RA², ³, ⁴ and do not cause tachyphylaxis.

As in adults, in children PPIs are highly efficacious and safe for treating GERD-related signs and symptoms, including the most severe degrees of reflux esophagitis, with rates of symptom relief and cure of esophagitis exceeding 90%.⁹, ¹⁰, ¹¹, ¹², ¹³ Thus it is not surprising that in children, as in adults, PPIs are increasingly being used not only in the short term for healing, but also for long-term maintenance of remission of GERD. However, whereas the safety of omeprazole has been shown in adults for up to 11 years’ continuous use,¹⁴ safety data for prolonged use in children are not yet available. Studies have shown the efficacy and safety of omeprazole or lansoprazole therapy of up to 3 months’ duration in children.⁹, ¹⁰, ¹¹, ¹², ¹³ However, the longest period for which detailed PPI safety and efficacy data are available in children is for up to 2 years’ continuous use of omeprazole.¹⁵ In addition, there are few data indicating which children require long-term PPI therapy.

Consequently, we aimed to characterize pediatric patients who receive long-term treatment at our institution, and to examine the safety of long-term use of PPI in those children.

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Methods 

In this retrospective cohort study, patient databases from British Columbia Children’s Hospital (BCCH) were screened for long-term PPI use, defined as more than 9 months of continuous prescription in patients with follow-up at BCCH. “Index date” was the date on which a PPI was first prescribed, marking the start of data collection. Potential PPI-related adverse drug reactions were identified and recorded. The final encounter for the purposes of data collection was the last recorded visit in the patient’s chart up to August 2004.

To identify and characterize a cohort of pediatric patients who had received long-term PPI therapy at BCCH, clinical databases from January 1989 through August 2004 were screened for the diagnosis of GERD and PPI use. These included a database of gastrointestinal (GI) endoscopies performed, GI Division outpatient records, and BCCH inpatient charts, as well as databases of PPI users from previous clinical studies. The primary inclusion criterion was long-term PPI use, defined as continuous prescription of drug for 9 months or more.

From these patient records, data were extracted and manually entered into a standardized purpose-designed 38-page data acquisition form. The data collected included patient demographics, associated medical disorders, signs and symptoms of GERD at presentation and at the latest encounter, laboratory values, and adverse drug reactions. Associated medical disorders were categorized as those predisposing to GERD (specifically neurologic impairment, congenital esophageal abnormalities, previous esophageal surgery, cystic fibrosis, and other chronic pulmonary disorders), and those not predisposing to GERD (eg, disorders of the liver, heart, and kidney and Helicobacter pylori status).

Details of PPI prescription included drug dose and the start and end dates for each PPI course, referred to as an “episode.” A “PPI episode” referred to a new start of drug (including the first), a change of dose, or a change of drug. “Exposure” to PPI was defined as the duration for which the patient was prescribed the drug in a continuous fashion, that is, total number of episodes or total number of days. For the same drug, a new PPI episode referred to each new start of drug separated by at least 7 days from the previous episode.

Adverse drug reaction information included the occurrence of new signs or symptoms deemed to be possibly due to PPI and not to an intercurrent illness. Specifically, these were nausea, headache, diarrhea, vomiting, skin rash, abnormal hepatic transaminase values, and abnormal serum urea or creatinine levels.

The data acquisition form was designed using Teleform, an electronic data capture/management system pilot-tested for the purpose of this study. An experienced research associate (W.K.) and the senior investigator (E.H.) extracted patient data from source documentation and completed and submitted the forms. The data collection forms were subsequently scanned into an Access database designed for the study. SAS (version 9.1, SAS Institute, Cary, NC) datasets were used for the statistical analyses. Descriptive statistics were generated. Comparisons between variables were conducted using χ² tests for categorical variables and t-tests and Mann-Whitney tests for continuous variables. Each patient was identified on the form by a unique study number, and confidentiality was maintained.

The study design was approved by the Clinical Research Ethics Board of the University of British Columbia and the Clinical Ethics Board of BCCH.

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Results 

Patients 

A total of 166 patients had a prescription for a PPI for more than 9 months. The mean age of these patients at the time of the index PPI prescription on record was 7.8 years (standard deviation [SD], 4.9) with a range of 4 weeks to 17 years (Table I). Approximately 1/3 of the patients were age 5 years or younger, 1/3 were age 6 to 10 years, and the remaining 1/3 were age 11 to 17 years.

Table I. Patient age at index PPI prescription

Age, years	Frequency, n (%)	Cumulative frequency, n (%)
< 1	14(8.4%)	14(8.4%)
1 to < 2	8(4.8%)	22(13.3%)
2 to 5	35(21.1%)	57(34.3%)
6 to 10	53(31.9%)	110(66.3%)
11 to 17	56(33.7%)	166(100.0%)

GERD-Predisposing and Non–GERD-Predisposing Disorders 

At least 1 GERD-predisposing disorder was present in 131 of the 166 patients (79%). These GERD-predisposing disorders included neuromotor impairment in 66% (with cerebral palsy in 48 [29%]) and other neurologic disorders or syndromes, with a major motor component in 62 patients (37%) (Table II; available at www.jpeds.com); esophageal atresia (with or without fistula) in 24 (14.5%); esophageal duplication cyst in 1 (0.6%); and chronic lung disorders in 38 (22.9%), including cystic fibrosis in 7 (4.2%) and other chronic pulmonary disorders in 31 (18.7%). Several patients had multiple disorders from those mentioned above. Non–GERD-predisposing disorders were present in 107 patients and included diabetes, chronic liver disease, Asperger’s syndrome, and cardiac and renal disorders. The group of 131 patients with at least 1 GERD-predisposing disorder and the 35 patients without any GERD-predisposing disorders are compared in Table III.

Table II. Underlying neuromotor impairments

Syndromes with a major motor component⁎

Angelman’s syndrome

Autonomic dysfunction NYD

Banyan-Riley-Ruvalcaba syndrome

Cerebral dysgenesis

CHARGE syndrome

Chromosomal abnormality unknown

Chromosome 4p monosomy

Chromosome 9 short-arm deletion

Chromosome 22 deletion

Chromosome 4 abnormality

Cornelia de Lange syndrome

Cri du chat syndrome

Dandy-Walker syndrome

Down syndrome

Duchenne muscular dystrophy

Glutaric acidura type 1

Goldenhaar syndrome

Leigh syndrome

Metachromatic leukodystrophy

Microcephaly

Mitochondrial disorder

Rett syndrome

Trisomy 21

VACTERL association

X-linked mental retardation

Neurologic disorders without syndromes†

Autism with motor component

Brainstem dysfunction NYD

Cerebral palsy, etiology unknown

Central nervous system lupus

Global delay NYD

Perinatal hypoxia

Postencephalitis

Posttraumatic

Prematurity

Table III. Comparison of several demographic, clinical, and PPI prescription features between pediatric patients with and with GERD-predisposing disorders

	GERD-predisposing disorders, n = 131 (79%)	None, n = 35 (21%)	P
Age, years, median (IQR)	8(4to12)	8(3to12)	.790
Fundoplication before PPI index, n (%)	21/29(72.4%)	2(66.7%)	1.000
Fundoplication after PPI index, n (%)	8/29(27.6%)	1 (33.3%)	1.000
Median number of presenting symptoms (IQR)	3(3to4)	3(2to4)	.007
Respiratory symptoms, n (%)	75(57.3%)	12(34.3%)	.016
Vomiting, n (%)	95(72.5%)	18(51.4%)	.017
Regurgitation, n (%)	39(29.8%)	13(37.1%)	.404
Dysphagia, n (%)	28(21.4%)	7(20%)	.860
Nausea, n (%)	3(2.3%)	9(25.7%)	<.0001
Gagging/retching, n (%)	27(20.6%)	3(8.6%)	.100
Abdominal pain, n (%)	42(32.1%)	19(54.3%)	.015
Irritability, n (%)	31(23.7%)	2(5.7%)	.018
Failure to thrive, n (%)	48(36.6%)	3(8.6%)	.001
Anemia, n (%)	16(12.2%)	1(2.9%)	.127
EGD before PPI use, n (%)	99(75.6%)	25(71.4%)	.616
EGD findings (before PPI use)
Erosive esophagitis, n (%)	66/99(66.7.1%)	15/25(60%)	.532
Histological esophagitis, n (%)	14/99(14.1%)	6/25(24%)	.231
Strictures, n (%)	14/99(14.1%)	1/25(4%)	.165
Hiatal hernia, n (%)	22(28.2%)	2(11.1%)	.131
Proven histological Barrett’s esophagus, n (%)	6/99(6%)	2/25(8%)	.283
PPI prescription
Duration of follow-up, median (IQR)	1146(676to1918)	677(469to1309)	.024
Duration of PPI exposure, median (IQR)	1085(564to1680)	512(402to826)	.0003
Dose of PPI, median (IQR)	20(20to40)	20(15to40)	.203

Endoscopic Findings 

Approximately 74.7% of the patients (124/166) underwent an upper GI endoscopy on or before their PPI index date; the rest underwent endoscopy at a later date. The findings included erosive esophagitis in 81 patients (65.3%), histological esophagitis in 20 (16.1%), and normal endoscopy and histology in 23 (18.6%). Esophageal stricture was present in 15 patients (12.1%). Twelve patients (9.7%) had suspected Barrett’s esophagus, which was confirmed histologically in 8 patients (4.8%) by the presence of goblet cell metaplasia with acid mucin. As shown in Table III, there were no significant differences in the prevalence of these findings between the 2 groups with and without GERD-predisposing disorders. All but 1 of these 8 patients was age 11 years or older. During upper GI endoscopy, the locations of the major esophagogastric landmarks are routinely documented, and hiatal hernia is considered present if the tops of the gastric folds are proximal to the diaphragmatic pinchcock. By this criterion, hiatal hernia was present in 28% of the patients with GERD-predisposing disorders and in 11% of those without such disorders. There were no significant differences in these findings between the groups with and without GERD-predisposing disorders (Table III). Only 7 patients (4.2%) exhibited evidence of H. pylori at index PPI prescription, all diagnosed by gastric biopsy.

Presenting Symptoms 

Most of the patients (149; 90.9%) had more than 1 presenting symptom (Table III). In the group with GERD-predisposing disorders, significantly greater proportions of patients had vomiting, abdominal pain, failure to thrive, and irritability. In general, symptoms were more frequent in those patients with underlying GERD-predisposing disorders (Table III).

Approximately 76% of the patients (n = 126) reported at least 1 GERD symptom at their last visit; 24% had no symptoms. However, the median number of symptoms significantly declined from 3 (interquartile range [IQR], 2) recorded on the initial presentation to 1 (IQR, 1) recorded on the last presentation.

Antireflux Surgery 

A total of 32 patients (19.3%) underwent fundoplication, 23 before the PPI index date and 9 during follow-up. For the 9 patients who underwent fundoplication after the PPI index date, the median time from that date to the surgery was 368 days (range, 97 to 1141 days). In those 9 patients, the stated or inferred reasons for fundoplication were poor response to PPI therapy in 6 and patient request in 3. Two of the 9 patients returned to PPI therapy during follow-up.

PPI Prescription 

The duration of continuous exposure to PPI is shown in Table IV. The median duration of follow-up (between the presentation date and date of last encounter) was 3.0 years. The patients had PPI exposure for most of this time (median, 2.75 years). PPI prescription during the follow-up period was continuous in 21 patients (13%), at least 65% of the time in 104 patients (63%), and < 50% of the time in 31 patients (19%).

Table IV. Duration of continuous-use exposure to PPI

Years on PPI	Patients on PPI, n (%)	Cumulative frequency of patients, n (%)
<2	49(29.5%)	49(29.5%)
2	37(22.2%)	86(51.7%)
3	30(18%)	116(69.7%)
4	15(9%)	131(78.7%)
5	10(6%)	141(84.7%)
6	5(3%)	146(87.7%)
7	5(3%)	151(90.7%)
8	7(4.1%)	158(94.8%)
9	3(2%)	161(96.8%)
10	3(2%)	164(98.8%)
11	2(1.2%)	166(100%)
Total	166(100%)	166(100%)

Median daily dose was 20 mg (range, 4 to 90 mg); median total dose-exposure per patient was 22 g (range, 2.2 to 178 g).

Most of the patients (141; 85%) used omeprazole only. Seven patients (4.2%) used lansoprazole only; 1 used another PPI only; 10 used omeprazole and lansoprazole (not concurrently); 5 used omeprazole and another PPI; and 2 used omeprazole, lansoprazole, and another PPI. The 166 patients had a total of 452 PPI episodes, of which 423 (93.6%) were of more than 30 days’ duration. Omeprazole was prescribed in 405 of these episodes (89.6%), lansoprazole in 32 (7.1%), and other PPIs in 15 (3.3%).

A total of 136 patients (81.9%) had no gaps between PPI episodes; that is, for the periods that they were prescribed medication, they took it continuously. In the remaining patients, the median duration of gaps in PPI episodes was 108 days (IQR, 290 days). The median number of PPI episodes per patient was 2 (range, 1 to 8). The median duration of PPI prescription per patient was 916 days, approximately 2.5 years (IQR, 923 days). The minimum was 273 days, and the maximum was 4103 days (11.24 years). The daily dose ranged from 4 to 90 mg; the median daily dose was 20 mg (IQR, 20 mg). Only 2 patients received 90 mg, and 11 received 80 mg. The duration of follow-up and hence the duration of PPI exposure was significantly longer in patients with GERD-predisposing disorders; however, there were no differences in the dose of PPI between the groups with and without GERD-predisposing disorders (Table III).

For omeprazole, the median number of episodes was 2 (IQR, 3 episodes). The median duration was 897 days (IQR, 934 days). The median dose was 1.1 mg/kg (IQR, 0.9 mg/kg), and the total daily dose was 20 mg (IQR, 20.0 mg). The median absolute daily dose was 20 mg (range, 4 to 90 mg).

For lansoprazole, the median number of episodes of use per patient was 1 (IQR, 1), with a minimum of 1 and maximum of 3. The median duration of use per patient was 915 days (IQR, 930 days), with a minimum of 80 days and a maximum of 4108 days. The median dose was 1.4 mg/kg (IQR, 1.7 mg/kg), with a minimum of 0.4 and a maximum of 3.7 mg/kg. The median absolute daily dose was 30 mg (IQR, 45.0 mg), with a minimum of 7.5 and a maximum of 90 mg.

Adverse Drug Reactions 

Only 6 signs or symptoms possibly related to PPI use were seen in 4 patients (2.4%). The details of these events and their outcomes are given in Table V.

Table V. Adverse drug reactions possibly related to PPI use

Table VI (available at www.jpeds.com) shows the distribution of biochemical test values in the patients who underwent more than 1 test. For example, of the 112 patients who had more than 1 aspartate aminotransferase (AST) measurement, 80 (71.4%) were normal and 9 (8%) were “always abnormal.” Of those 9, none had values greater than twice the upper limit of normal, and all were taking other medications concurrently with a PPI. Tests for hepatitis B and C were negative in the 5 patients tested. Three patients had AST levels that went from normal at the first measurement to abnormal at the last measurement, 3 had alanine aminotransferase (ALT) levels that did the same, and 1 had AST and ALT levels that did the same. Again, no patient had an enzyme level higher than twice the upper limit of normal, and tests for hepatitis B and C were negative in all 3 of the 7 patients tested. Use of other medications concurrently with a PPI was common in this group; these medications included anticonvulsant agents known to affect hepatic transaminase values. In the 2 patients in whom creatinine levels went from normal to abnormal, the abnormal levels were only negligibly elevated (by < 5% above the upper limit of normal), and in the 2 patients in whom creatinine levels were “always abnormal,” primary renal disease was present. There were no significant differences among the patients with abnormalities in creatinine, AST, or ALT in PPI type, dose, or duration, or in the presence or type of comorbid disorders.

Table VI. Comparison of first and last recorded laboratory values during an approximate 3-year follow-up of 166 pediatric patients with GERD

First lab result	Last lab result	Number of patients (%)
AST (n = 112)
Normal	Normal	86(76.8%)
Normal	Abnormal	4(3.6%)
Abnormal	Normal	10(8.9%)
Abnormal	Abnormal	12(10.7%)
ALT (n = 111)
Normal	Normal	95(85.6%)
Normal	Abnormal	5(4.5%)
Abnormal	Normal	6(5.4%)
Abnormal	Abnormal	5(4.5%)
Creatinine level (n = 72)
Normal	Normal	66(91.7%)
Normal	Abnormal	2(2.8%)
Abnormal	Normal	2(2.8%)
Abnormal	Abnormal	2(2.8%)

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Discussion 

Some have alleged that long-term PPI therapy is overused in adults.¹⁶ For example, in various series, reported indications for PPI therapy were nonulcer dyspepsia in 6% to 21%, uninvestigated dyspepsia in 7% to 33%, and use of nonsteroidal anti-inflammatory drugs (mostly uninvestigated) in 5% to 42%; in 1 series, only 27% of the patients on long-term PPI therapy had undergone endoscopy.¹⁶ Although it is possible that the same trends might also apply children, there are no data supporting this, and in the present series, all children had GERD documented by investigation, including endoscopy. Therefore, our series focuses only on the severe end of the spectrum of GERD, those needing treatment with PPIs or surgery.

In this study, we identified and characterized a cohort of 166 children with GERD who were prescribed a PPI continuously for a long duration. As is well recognized, certain disorders predispose persons to the most severe and chronic GERD through various mechanisms,¹, ¹⁷, ¹⁸ and it is these children—who often respond poorly to antireflux surgery—who stand to especially benefit from long-term PPI therapy. Most patients in this study had GERD-predisposing disorders and exhibited significantly more symptoms at presentation, a higher prevalence of failure to thrive, and a lower prevalence of nausea than those without underlying disorders (Table III). This profile is consistent with the nature of many of the underlying disorders themselves; children with neurologic impairment and syndromes often are unable to report symptoms. Thus in this group, there should be a high degree of suspicion for GERD based on observed physical signs as well as reported symptoms. Although only 21% of all our patients had no major underlying disorder, this study provides new information on the safety of PPI use in this group of patients, which is becoming increasingly more recognized and treated.

There is no standard definition of what constitutes “long-term” PPI use.¹⁶ We adopted an arbitrary definition of at least 9 months of continuous prescription to avoid capturing data on patients taking short courses of PPIs. Although our methodology does not allow us to determine compliance, our patients attended regularly for follow-up and prescription renewal, were severely affected with GERD, and had symptomatic responses to PPI, and thus it is likely that most took the medications on a regular basis.

Of the 166 patients, 48% took a PPI for 3 to 11 years; most (66%) were started on the drug at age 6 years or older. Although this reflects our approach over the period analyzed (January 1989 through August 2004), it does not necessarily reflect our current practice; with more data and experience, we have become increasingly comfortable starting PPI therapy in younger children, and not only for failures of H2RA. In the present study, 14 patients were started on a PPI before age 1 year, but most of these patients were referred to us while already receiving a PPI. This age group is under study for PPI pharmacokinetic and safety parameters. Nevertheless, under 1 year of age, we prescribe PPIs in only very carefully selected patients, as there are relatively few indications for PPI use in this age group.¹⁹, ²⁰, ²¹, ²²

Although 76% of patients took a PPI for at least 2/3 of the time monitored, the patients with GERD-predisposing disorders had a significantly greater degree of exposure to PPIs, indicating that they were less likely or able to withdraw from PPI therapy. Most of the documented experience in this study is with omeprazole. This is partly for historical reasons, because we started using it in children in 1989 and it was the first PPI for which efficacy, dosing, and safety data were available for children.⁹ The other PPI for which considerable pediatric data are now available is lansoprazole; the considerable shorter-term data available suggest that efficacy and safety rates for this drug are similar to those for omeprazole.¹¹, ¹², ¹³

That PPIs are efficacious in even the most severely affected children is confirmed by symptom resolution or significant decrease in symptom frequency from presentation to final visit. This was previously shown in shorter follow-up studies.⁹, ¹⁰, ¹⁵ Along the same lines, it is not surprising that the cohort maintained on PPI included a significant proportion (14%) who had failed at least 1 antireflux procedure. The high failure rates of open and laparoscopic antireflux surgery in children are well recognized,¹ and in our center, the number of new antireflux surgery procedures has fallen from approximately 50 per year to 5 per year today. In our series, 9 patients (5%) on long-term PPI therapy were referred for surgery at the physician’s or patient’s instigation, but 2 of these returned to PPI therapy during follow-up.

The endoscopic findings are of particular interest. Hiatal hernia was found on at least 1 endoscopy in 39% of the patients; this is a higher prevalence than reported previously.²⁰, ²¹, ²² That most hernias were seen in the GERD-predisposing patients is not surprising—children with neurologic disorders, repaired esophageal atresia, and chronic lung disease have many reasons to develop hernias.¹⁷, ¹⁸ But even in the absence of these disorders, hernias tend to be present in children with severe GERD.¹⁷, ¹⁸

Of the 12 patients (15%) with suspected Barrett’s esophagus on endoscopy, 8 (5%) were documented. This is a higher percentage than reported previously and suggests in children with severe GERD, Barrett’s esophagus may be more prevalent than previously considered. However, this group of patients with severe GERD is highly selected, and thus the findings may not be generalizable to other settings.

The adverse drug reactions considered associated with PPI therapy were nausea, vomiting, diarrhea, skin rash, and irritability. These occurred in only 4 patients. Although the incidence of reactions was very low (6/528 patient-years), our retrospective analysis likely underestimates their true incidence. Nevertheless, it does appear that no serious reactions occurred, and that those that possibly may be attributable to PPIs were of sufficient discomfort or inconvenience so as to cause permanent discontinuation of the drug in only 3 of the 166 patients. No significant effect on liver or renal function was seen.

In conclusion, in the present study, most of the children on long-term PPI therapy had an underlying systemic disorder that predisposed them to severe reflux. These children had more symptoms than those without such GERD-predisposing conditions, but both groups experienced significant symptomatic improvement from long-term PPI therapy. There were no serious adverse drug reactions, and it was very seldom necessary to discontinue PPI therapy because of an adverse reaction. Although prospective studies are needed to determine the true prevalence of PPI-attributable reactions, this preliminary study suggests that in children, long-term use of PPIs is efficacious and may be safe for periods up to 11 years. Although these findings should provide some reassurance to pediatric prescribers and families, an important caveat is that gastric acid has many important physiological functions, and the goal in healing should not be to make patients achlorhydric. Further analysis of other parameters over time is needed, such as gastric histology, vitamin B₁₂ levels, and other nutritional indices.

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