A new therapeutic strategy for gastroesophageal reflux disease resistant to conservative therapy and monotherapy in preterm neonates: a clinical trial

Abstract

Background: Gastroesophageal reflux disease (GERD) is one of the most common problems in neonates. The main clinical manifestations of GERD are frequent regurgitation or vomiting associated with irritability, anorexia or feeding refusal, failure to thrive, Sandifer posturing, apnea, bradycardia and stridor in infants. Since the clinical manifestations of GERD are often non-specific in preterm infants, it has been described as the clinical syndrome responding to anti-reflux treatment. Aims: To our knowledge, no clinical trial has compared the efficacy of histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) in preterm infants, nor has any study assessed the effect of adding a prokinetic agent to an acid suppressant and compared them together in these infants, so the present study was conducted. Study design: This study was performed on 58 preterm newborns (mean age, 9.72 ± 6.78 days, 43.2% boys and birth weight of 1,571.9 ± 596.59 grams) with GERD resistant to conservative therapy and monotherapy hospitalized in neonatal wards and NICUs of Shariati and Bahrami Children Hospitals during 2014-2016. Neonates were randomly assigned to a double-blind trial with either oral metoclopramide plus omeprazole (group A) or oral metoclopramide plus ranitidine (group B). After one week and one month, their symptoms and signs were evaluated again. The response rate in each group was the primary outcome and the side effect of drugs in each group was the secondary outcome.

Full text

1/8
www.jpnim.com Open Access eISSN: 2281-0692
Journal of Pediatric and Neonatal Individualized Medicine 2019;8(1):e080125
doi: 10.7363/080125
Received: 2018 Jul 31; revised: 2018 Oct 01; accepted: 2018 Oct 28; published online: 2019 Apr 12
A new therapeutic strategy for
gastroesophageal reux disease
resistant to conservative therapy
and monotherapy in preterm
neonates: a clinical trial
Negar Sajjadian1, Zahra Akhavan2, Peymaneh Alizadeh Taheri3, Mamak
Shariat4
1Department of Neonatology, Tehran University of Medical Sciences, Shariati Hospital, Tehran, Iran
2Department of Pediatrics, Tehran University of Medical Sciences, Bahrami Children Hospital, Tehran,
Iran
3Department of Neonatology, University of Medical Sciences, Bahrami Children Hospital, Tehran, Iran
4Maternal-Fetal & Neonatal Research Center, Tehran University of Medical Sciences, Tehran, Iran
Abstract
Background: Gastroesophageal reux disease (GERD) is one of the most
common problems in neonates. The main clinical manifestations of GERD
are frequent regurgitation or vomiting associated with irritability, anorexia
or feeding refusal, failure to thrive, Sandifer posturing, apnea, bradycardia
and stridor in infants. Since the clinical manifestations of GERD are often
non-specic in preterm infants, it has been described as the clinical syndrome
responding to anti-reux treatment.
Aims: To our knowledge, no clinical trial has compared the efcacy of
histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors
(PPIs) in preterm infants, nor has any study assessed the effect of adding a
prokinetic agent to an acid suppressant and compared them together in these
infants, so the present study was conducted.
Study design: This study was performed on 58 preterm newborns (mean
age, 9.72 ± 6.78 days, 43.2% boys and birth weight of 1,571.9 ± 596.59
grams) with GERD resistant to conservative therapy and monotherapy
hospitalized in neonatal wards and NICUs of Shariati and Bahrami Children
Hospitals during 2014-2016. Neonates were randomly assigned to a double-
blind trial with either oral metoclopramide plus omeprazole (group A) or oral
metoclopramide plus ranitidine (group B). After one week and one month,
their symptoms and signs were evaluated again. The response rate in each
group was the primary outcome and the side effect of drugs in each group was
the secondary outcome.
Original article

2/8 Sajjadian • Akhavan • Taheri • Shariat
Journal of Pediatric and Neonatal Individualized Medicine • vol. 8 • n. 1 • 2019
www.jpnim.com Open Access
Results: Our study showed that both regimens
were effective in the treatment of GERD resistant to
conservative therapy and monotherapy in premature
infants. The response rate of “omeprazole plus
metoclopramide” was signicantly higher than the
response rate of “ranitidine plus metoclopramide”
(91.37 ± 7.5 vs. 77.06 ± 3.38, respectively; p = 0.04)
(primary outcome). There were no drug-related
complications of drugs in both groups in our study
(secondary outcome).
Conclusion: This study showed that combined
therapy led to the response rate of > 70% in each
group, but it was signicantly higher in group A
(> 90%). Both combination therapies led to higher
response rate in comparison with conservative
therapy and monotherapy used before intervention.
Keywords
Gastroesophageal reux disease, preterm, ranitidine,
omeprazole, metoclopramide, combined therapy.
Corresponding author
Peymaneh Alizadeh Taheri, Department of Neonatology, University
of Medical Sciences, Bahrami Children Hospital, Tehran, Iran; postal
address: Bahrami Children Hospital, Shahid Kiai St., Damavand
Ave., Tehran, Iran; phone number: +982173013420; fax number:
+982177568809; email: p.alizadet@yahoo.com.
How to cite
Sajjadian N, Akhavan Z, Taheri PA, Shariat M. A new therapeutic
strategy for gastroesophageal reux disease resistant to conservative
therapy and monotherapy in preterm neonates: a clinical trial. J Pediatr
Neonat Individual Med. 2019;8(1):e080125. doi: 10.7363/080125.
Introduction
Gastroesophageal reux (GER) is a common
phenomenon in otherwise healthy neonates, either
term or preterm [1, 2]. It affects 70-85% of the
infants in their rst two months of life but resolves
spontaneously in nearly all of them by one year of
age [2].
On the other hand, gastroesophageal reux
dis ease (GERD), a term used when GER causes
trouble some symptoms or results in complications,
is reported in 9.8-10.7% of preterm infants [3]. The
incidence reaches 22% in neonates born under 34
weeks’ gestation [4]. The main clinical manifesta-
tions of GERD in infants are frequent regurgitation
or vomiting associated with irritability, anorexia or
feeding refusal, failure to thrive, Sandifer posturing,
apnea, bradycardia and stridor [3-5].
Although GERD is common in preterm
neonates, its diagnosis and treatment in this
population is still a matter of debate [4-6]. Since
the clinical manifestations of GERD in preterm
infants are often non-specic, it has been described
as a clinical syndrome responding to anti-reux
treatment [7]. GERD is empirically diagnosed
and treated in the clinical practice based on the
clinician’s assessment of symptoms. Indications
for testing include treatment failure, diagnostic
uncertainty, and treating (or preventing) GERD
complications [8]. A narrow body of controversial
evidence supports treatment of GERD in preterm
neonates [7-10]. It is advised to consider con-
servative strategies, including changes in the
body position and feeding pattern, as the rst-
line treatment in neonates who experience
troublesome symptoms without signicant clinical
complications [9, 11, 12].
For neonates who do not respond to conserva-
tive measures or experience complications, acid
suppressants including histamine-2 receptor
antagonists (H2RAs) and proton pump inhibitors
(PPIs) have increasingly been used despite
limited and controversial data on their efcacy
and safety [13]. Two different pathophysiologic
mechanisms have been described for GERD in
preterm infants, including acid and nonacid reux
[14]. In this study, metoclopramide was added
to each group to exert its effect on the lower
esophageal sphincter and treat nonacid reux.
Metoclopramide and erythromycin are two
prokinetics available in the USA [15] while the
use of domperidone and cisapride is prohibited
because of their cardiac adverse effects [16,
17]. On the other hand, the adverse effects of
metoclopramide have been reported to occur only
following overdose and long-term administration
of the drug [18].
To our knowledge, no clinical trial has compared
the efcacy of H2RAs and PPIs in preterm infants,
nor has any study assessed the effect of adding a
prokinetic agent to an acid suppressant in these
infants, which was the reason why this study was
conducted.
Patients and methods
This double-blind randomized controlled trial
was conducted to compare the effectiveness of
metoclopramide plus omeprazole with meto-

3/8
Journal of Pediatric and Neonatal Individualized Medicine • vol. 8 • n. 1 • 2019 www.jpnim.com Open Access
A new therapeutic strategy in GERD of premature neonates
clopramide plus ranitidine for GERD in preterm
infants.
Subjects
Fifty-eight preterm neonates hospitalized in
neonatal wards and Neonatal Intensive Care Units
(NICUs) of Bahrami Children’s Hospital and
Shariati Hospital during 2014-2016 with a clinical
diagnosis of GERD were enrolled in this study.
The number of participants was determined by a
prospective power analysis, assuming a power of at
least 90%, a 2-sided alpha of 0.05, and treatment
response based on the studies by Omari et al. [19]
and Kelly et al. [20].
Preterm neonates aged < 28 days who were
born at 28-37 weeks’ gestation and did not respond
to conservative anti-GERD treatments (including
postural change, reduction of the feeding volume,
increased frequency of feedings, hypoallergenic
formulas, and use of hypoallergenic regimens
by mothers) and monotherapy were considered
eligible.
Neonates were excluded if they had any
signicant underlying condition (e.g., major con-
genital abnormalities, gastrointestinal or neuro-
logical disorders) or diseases (e.g., sepsis, apnea
of prematurity), required invasive or noninvasive
ventilation or were administered any muscle
relaxant or sedative medication.
Diagnosis
In our study, a diagnosis of GERD was made
if there was regurgitation or vomiting associated
with at least two other clinical GERD-related
problems, such as apnea, failure to thrive, Sandifer
syndrome, etc. Since pH monitoring is not available
in many centers and is not safe in some clinical
situations like apnea, GERD was diagnosed based
on clinical manifestations by two neonatologists
and an expert master nurse. The term “resistant
to conservative therapy and monotherapy” was
applied when the response rate was above 50%
but below 70%, so all patients showed relative
responses that did not satisfy the treatment team
and parents. This denition and the high positive
response to combination therapy also emphasized
the diagnosis of GERD in each patient. Other
diagnoses were ruled out based on the clinical
manifestations of the patients; for example – if
there were vomiting, apnea and failure to thrive
– sepsis, intraventricular hemorrhage, etc. were
ruled out by clinical examination, lab tests, brain
sonography, etc. The duration of conservative
treatment and then monotherapy was about 3-7
days each, according to a careful balance of risk
and benets between the severity of clinical
problems and the response rate.
Feeding
Feeding started on the rst day as follows:
1. in neonates 28-32 weeks / 1,000-1,500 g, 2 mL/
kg breast milk was given every 2 hours via a
nasogastric tube;
2. in neonates > 32 weeks / > 1,500 g, breastfeeding
or bottle feeding started with a volume tolerated
by the infant every 2-3 hours.
After the rst day, the feeding volume was
increased by 10-20 mL/kg/day to a maximum
volume of 170-200 mL/kg/day according to the
neonate’s feeding tolerance. Feeding was stopped
once the clinical problems became severe (for
example recurrent apnea or vomiting) and re-started
as soon as the infant regained feeding tolerance.
The mode of feeding was continuous when a
nasogastric tube was used. Apnea was considered
a sign of GERD if it was associated with vomiting,
regurgitation, or other clinical GERD-related
manifestation like Sandifer syndrome. All patients
received total parenteral nutrition (TPN) according
to our NICU protocol. As far as they could tolerate
feeding, TPN was tapered gradually.
All patients were breastfed except those who
had a family history or other clinical presentations
of allergies. These patients received hypoallergic
formulas for 5-7 days until their mothers’ breastmilk
was free of cow’s milk proteins after using a
hypoallergic regimen.
Trial
The study protocol was approved by the research
ethics committee of Tehran University of Medical
Sciences and registered in the Iranian Registry of
Clinical Trials (IRCT: 2016030226876N1). Written
informed consent was obtained from parents or
guardians of all infants before enrollment.
The neonates who met the inclusion and
exclusion criteria were randomly assigned (in
blocks of two per site) to a double-blind clinical
trial to receive omeprazole plus metoclopramide or
ranitidine plus metoclopramide for a 30-day period.
The random allocation sequence was generated by
an independent statistician.

4/8 Sajjadian • Akhavan • Taheri • Shariat
Journal of Pediatric and Neonatal Individualized Medicine • vol. 8 • n. 1 • 2019
www.jpnim.com Open Access
Patients in group A received oral omeprazole 0.5
mg/kg/dose twice daily plus metoclopramide 0.1
mg/kg/dose twice daily. Patients in group B received
oral ranitidine 1 mg/kg/dose twice daily plus
metoclopramide 0.1 mg/kg/dose twice daily. Before
initiation of pharmacotherapy, a checklist including
demographic data (age, gender, birth weight, and
weight at presentation) and symptoms attributed to
GERD was lled by a neonatologist (researcher).
At the end of the rst week, the patients were re-
evaluated by the same neonatologist and post-
treatment weight and symptoms were recorded. The
patients were then re-evaluated after one month to
assess further changes in the presenting symptoms.
Changes in the total number of GERD-related
signs and symptoms from baseline to the end of
treatment were considered as the primary outcome.
Secondary outcomes were dened as complications
in either group following oral administration of
metoclopramide, ranitidine, and omeprazole.
Data analysis
The SPSS® for Windows version 21.0 was used
for data analysis (SPSS Inc., Chicago, IL, USA).
Descriptive data are reported as mean and standard
deviation (SD) for numerical and number (percent)
for categorical data. Post-treatment results were
compared against baseline data using two-sided
paired t-test for differences in the mean values
and chi-square test and Fisher’s exact test (two-
sided) for differences in the percentage of response
to treatment. A p-value of < 0.05 was considered
signicant.
Results
Fifty-eight preterm newborns (43.2% male,
56.8% female) with a mean age of 9.72 ± 6.78
days (range: 1-28 days) and a mean birth weight
of 1,571.9 ± 596.59 g were studied. There was
no signicant difference in demographic data and
baseline characteristics between the two groups
(Tab. 1).
The most frequent gastrointestinal-related
signs and symptoms were vomiting and Sandifer
syndrome. The most frequent respiratory-related
signs and symptoms were apnea and cyanosis. No
case of hematemesis, anemia, coughing, seizure
and stridor was reported (Tab. 2). The number of
patients with baseline and post-treatment GERD-
associated clinical manifestations, categorized by
the treatment group, are presented in Tab. 2.
The response rate of all clinical manifestations
in the “omeprazole plus metoclopramide” group
was signicant except for rumination and cyanosis
(intra-group comparison).
In the ranitidine plus metoclopramide group,
the response rate of irritability, cyanosis, and
failure to thrive was not signicant (intra-group
comparison).
This study showed that both ranitidine
plus metoclopramide and omeprazole plus
metoclopramide were effective in reducing the
frequency of GERD symptoms in premature
neonates. The response rate in both groups was >
75%, but the response rate of the “omeprazole plus
metoclopramide” group was signicantly higher
(91.37 ± 7.5 vs. 77.06 ± 3.38, respectively; p =
0.04). The response rate after one month was the
same as the response rate after one week in both
groups (Tab. 2).
Discussion
Despite the fact that GERD is a common
condition in preterm infants, its therapeutic
management remains controversial [7].
The main aims of GERD management in
infants are to maintain symptomatic relief, provide
Table 1. Patients’ characteristics in the two intervention groups.
Patients’ characteristics
Omeprazole plus
metoclopramide
(n = 29)
Ranitidine plus
metoclopramide
(n = 29)
p-value
Gender
Girls, n (%) 15 (51.7%) 18 (62.1%) 0.426
Boys, n (%) 14 (48.3%) 11 (37.9%)
Age, mean ± SD, days at intervention 9.41 ± 7.54 10.03 ± 6.05 0.731
Birth weight, mean ± SD, g 1,567.04 ± 603.88 1,600.36 ± 591.28 0.322
Weight at presentation, mean ± SD, g 1,548.89 ± 624.93 1,558.04 ± 545.13 0.446
Gestational age at birth, mean ± SD, weeks 31.48 ± 3.08 31.93 ± 3.07 0.593
Corrected gestational age, mean ± SD, weeks at intervention 33 ± 3.46 33.54 ± 2.91 0.537

5/8
Journal of Pediatric and Neonatal Individualized Medicine • vol. 8 • n. 1 • 2019 www.jpnim.com Open Access
A new therapeutic strategy in GERD of premature neonates
Table 2. GERD-related signs and symptoms before and one week after intervention.
Clinical manifestations
Omeprazole plus
metoclopramide
(n = 29)
Ranitidine plus
metoclopramide
(n = 29)
Inter-group p-value
Irritability, n (%)
Pre-intervention 4 (13.8%) 3 (10.3%) 0.31
Post-intervention 0 (0%) 1 (3.4%)
Response rate 100% 66.6%
Intra-group p-value 0.001 0.103
Weight-gain failure, n (%)
Pre-intervention 3 (10.3%) 1 (3.4%) 0.56
Post-intervention 0 (0%) 1 (3.4%)
Response rate 100% 0%
Intra-group p-value 0.001 NA
Regurgitation, n (%)
Pre-intervention 5 (17.2%) 4 (13.8%) 0.313
Post-intervention 1 (3.4%) 0 (0%)
Response rate 80% 100%
Intra-group p-value 0.026 0.001
Vomiting, n (%)
Pre-intervention 16 (55.2%) 17 (58.6%) 0.553
Post-treatment 1 (3.4%) 2 (6.9%)
Response rate 93.7% 88.2%
Intra-group p-value 0.035 0.021
Rumination, n (%)
Pre-intervention 7 (24.1%) 3 (10.3%) 0.313
Post-intervention 1 (3.4%) 0 (0%)
Response rate 85.7% 100%
Intra-group p-value 0.07 0.001
Sandifer position, n (%)
Pre-intervention 11 (37.9%) 9 (31%) 0.754
Post-intervention 1 (3.4%) 1 (3.4%)
Response rate 90.9% 88.8%
Intra-group p-value 0.019 0.012
Wheezing, n (%)
Pre-intervention 1 (3.4%) 1 (3.4%) NA
Post-intervention 0 (0%) 0 (0%)
Response rate 100% 100%
Intra-group p-value 0.0001 0.0001
Apnea, n (%)
Pre-intervention 13 (44.8%) 17 (58.6%) 0.15
Post-intervention 2 (6.9%) 0 (0%)
Response rate 84.6% 100%
Intra-group p-value 0.019 0.0001
Cyanosis, n (%)
Pre-intervention 8 (27.6%) 4 (13.8%) 0.053
Post-intervention 1 (3.4%) 2 (6.9%)
Response rate 87.5% 50%
Intra-group p-value 0.09 0.124
Overall response rate, %, mean ± SD 91.37 ± 7.5 77.06 ± 3.38 0.04
Intra-group p-value means p-value between Pre and Post intervention in every group.
Inter-group p-value means p-value between two groups of intervention.
GERD: gastroesophageal reux disease.

6/8 Sajjadian • Akhavan • Taheri • Shariat
Journal of Pediatric and Neonatal Individualized Medicine • vol. 8 • n. 1 • 2019
www.jpnim.com Open Access
adequate growth, and prevent GERD-related
complications and recurrence of symptoms [21].
In case of uncomplicated GERD, a stepwise
therapeutic approach based on conservative
strategies is strongly advised. However, when
symptoms do not subside in spite of conservative
measures, pharmacological therapy should be
considered [22].
H2RAs and PPIs have been increasingly used
as the main drugs in the management of pediatric
GERD [23]. Recent guidelines suggest that a
4-week trial of a PPI or H2RA be considered for
infants with a signicant regurgitation associated
with symptoms such as unexplained feeding
problems, abnormal behavior, and unfavorable
weight gain [24].
H2RAs act by binding competitively with
histamine to the H2 receptors of the gastric wall
to reduce the secretion of hydrochloric acid by the
parietal cells and increase intragastric pH [20].
Ranitidine is the main H2RA used in NICUs
[25]. Kuusela [26] showed that ranitidine at a
dose of 0.5 mg/kg/q12h intravenously effectively
kept gastric pH above 4 in critically ill preterm
infants, whereas the optimal dose was 1.5 mg/
kg/q8h intravenously in critically ill term
infants. However, the chronic use of ranitidine is
discouraged due to the frequent development of
tachyphylaxis within 6 weeks [2, 21].
PPIs act as long-term blockers of the gastric
proton pump, which catalyzes the nal phase of
the acid secretory process, hindering both basal
and stimulated acid secretion by the parietal cells.
The prescription of PPIs as therapeutic agents for
the treatment of GERD in the pediatric population
has largely increased over the last 10 years, in
particular after the therapeutic failure of H2
blockers [27]. They are being increasingly used
in neonatal units. Moore et al. [28] reported that
omeprazole at a daily dose of 0.7 mg/kg results
in an increase in the gastric pH, a signicant
decrease in acid GER frequency, and a decline in
the esophageal acid exposure.
Despite the widespread use of acid suppressants
in infants with GERD, the overall available
evidence on the safety and efcacy of these
medications in preterm infants is quite limited
[25]. Most of these medications have been neither
assessed nor approved for use in preterm infants.
In this study, we compared the efcacy of
ranitidine plus metoclopramide with omeprazole
plus metoclopramide in clinical improvement of
GERD in preterm infants. According to a study
by Omari et al. [19], the use of esomeprazole in
preterm infants is associated with a signicant
decrease in the number of GERD-related
symptoms, a remarkable reduction of the overall
esophageal acid exposure, and a lower frequency
of acid bolus reux episodes whereas non-acid
GER features are not affected. However, these
results were not controlled for placebo effects;
therefore, they should be conrmed in further
placebo-controlled trials.
On the other hand, Orenstein et al. [29] assessed
the efcacy of lansoprazole versus placebo in
a large cohort of both term and symptomatic
preterm infants and reported no advantage over
placebo in the reduction of symptoms attributed
to GERD (i.e., crying, regurgitation, feeding
refusal, back arching, wheezing, and coughing).
However, as the enrolled infants did not undergo
pH-metry, the authors hypothesized a causal role
of predominant nonacid reux events, for which
PPIs are ineffective.
Our study showed that both ranitidine
plus metoclopramide and omeprazole plus
metoclopramide were effective in reducing the
frequency of GERD symptoms in premature
neonates. The response rate in both groups was
> 75%, but the response rate of the “omeprazole
plus metoclopramide” group was signicantly
higher (91.37 ± 7.5 vs. 77.06 ± 3.38, respectively;
p = 0.04).
Some studies [30-33] have reported a
signicant risk of infections associated with the
use of both H2RAs and PPIs and necrotizing
enterocolitis associated with H2RAs in very low
birth weight preterm infants.
According to a systematic review and meta-
analysis performed by Lau Moon Lin et al. [34],
a total of 108 (57 prospective) studies involving
2,699 patients (2,745 metoclopramide courses)
were surveyed. The most common adverse
effects reported in children were extra-pyramidal
symptoms, diarrhea, and sedation, which were
reversible and of no long-term signicance.
Dysrhythmia, respiratory distress/arrest, neuro-
leptic malignant syndrome, and tardive dys-
kinesia occurred rarely.
On the other hand, according to the FDA
Gastrointestinal Drugs Advisory Committee
Meeting, the adverse effects of metoclopramide
have been reported only with overdose and long-
term administration of the drug [18]. Another
meta-analysis of metoclopramide in children
below 2 years with GERD conrmed a decrease

7/8
Journal of Pediatric and Neonatal Individualized Medicine • vol. 8 • n. 1 • 2019 www.jpnim.com Open Access
A new therapeutic strategy in GERD of premature neonates
in GERD symptoms [35]. However, this effect
comes at the cost of signicant adverse effects,
including drowsiness, restlessness, and extra-
pyramidal reactions in 10-20% of the patients in
our search and up to 34% of the patients in earlier
studies [35].
We found no complications in either group
following the use of oral ranitidine or omeprazole
plus metoclopramide (secondary outcome) in the
present study.
In conclusion, although both “omeprazole
plus metoclopramide” and “ranitidine plus
metoclopramide” were safe and highly effective
in controlling reux symptoms in GERD of
premature infants in this study, the response
rate of “omeprazole plus metoclopramide”
was signicantly higher. On the other hand,
the combination of each acid suppressant with
metoclopramide increased the response rate
in comparison with monotherapy with an acid
suppressant before intervention. It seems that
the synergistic effect of an acid suppressant
with metoclopramide on the lower esophageal
sphincter increases the response rate in these
patients. We suggest combined therapy in
GERD of preterm neonates not responding
to conservative treatments and monotherapy.
This combined therapeutic regimen prevented
mortality, morbidity, and surgery in these
patients. We found no complications in these
patients following combined therapy. We suggest
similar studies to be undertaken in larger sample
sizes in this age group to determine the efcacy
of these combination therapies.
Highlights
The highlights of the paper are presented in Tab. 3.
Acknowledgments
The Authors wish to thank the nurses of Neonatal Wards and NICUs
of Bahrami Children Hospital and Shariati Hospital for data monitoring
and management and Research Development Center of Bahrami
Children Hospital.
Conict of interest
Authors mention that there is no conict of interest in this study.
Funding
No sources of funding were used to conduct this study or prepare this
manuscript.
References
1. Randel A. AAP releases guideline for the management of
gastroesophageal reux in children. Am Fam Physician.
2014;89(5):395-7.
2. Czinn SJ, Blanchard S. Gastroesophageal Reux Disease in
Neonates and Infants. Paediatr Drugs. 2013;15(1):19-27.
3. Jadcherla SR, Slaughter JL, Stenger MR, Klebanoff M, Kelleher K,
Gardner W. Practice Variance, Prevalence, and Economic Burden
of Premature Infants Diagnosed with GERD. Hospital Pediatrics.
2013;3(4):335-41.
4. Dhillon AS, Ewern AK. Diagnosis and management of gastro-
esophageal reux in preterm infants in neonatal intensive care units.
Acta Pediatr. 2004;93(1):88-93.
5. Frakaloss G, Burke G, Sanders MR. Impact of Gastroesophageal
Reux on Growth and Hospital Stay in Premature Infants. J Pediatr
Gastroentral Nutr.1998;26(2):146-50.
6. Tipnis NA, Tipnis SM. Controversies in the Treatment of Gastro-
esophageal Reux Disease in Preterm Infants. Clin Perinatol.
2009;36(1):153-64.
7. Birch JL, Newell SJ. Gastrooesophageal reux disease in preterm
infants: current management and diagnostic dilemmas. Arch Dis
Child. 2009;94(5):F379-83.
8. Gyawali CP, Kahrilas PJ, Savarino E, Zerbib F, Mion F, Smout
AJPM, Vaezi M, Sifrim D, Fox MR, Vela MF, Tutuian R, Tack
J, Bredenoord AJ, Pandolno J, Roman S. Modern diagnosis of
GERD: the Lyon Consensus. Gut. 2018;2018:1-12.
9. Kultursay N. Gastroesophageal reux (GER) in preterms: current
dilemmas and unresolved problems in diagnosis and treatment.
Turk J Pediatr. 2012;54(6):561-9.
10. Aceti A, Corvaglia L. Gastroesophageal reux disease in
the neonatal intensive care unit. J Pediatr Health. 2010;4(4):
405-12.
11. Jadcherla SR, Chan CY, Moore R, Malkar M, Timan CJ, Valentine
CJ. Impact of feeding strategies on the frequency and clearance
of acid and nonacid gastroesophageal reux events in dysphagic
neonates. J Parenter Enteral Nutr. 2012;36(4):449-55.
Table 3. Highlights of the paper are presented.
• GERD is one of the most common problems in premature
neonates.
• The therapeutic management of GERD in premature
neonates is still a matter of debate.
• Two therapeutic regimens including “omeprazole plus
metoclopramide” and “ranitidine plus metoclopramide”
were compared in preterm neonates with GERD resistant
to conservative therapy and monotherapy.
• Both combined regimens were effective in GERD of
premature neonates.
• The response rate was signicantly higher in “omeprazole
plus metoclopramide” group.
• The combination of each acid suppressant with
metoclopramide led to higher response rate in
comparison with monotherapy before intervention.
GERD: gastroesophageal reux disease.

8/8 Sajjadian • Akhavan • Taheri • Shariat
Journal of Pediatric and Neonatal Individualized Medicine • vol. 8 • n. 1 • 2019
www.jpnim.com Open Access
12. van Wijk MP, Benninga MA, Dent J, Lontis R, Goodchild L,
McCall LM, Haslam R, Davidson GP, Omari T. Effect of Body
Position Changes on Postprandial Gastroesophageal Reux and
Gastric Emptying in the Healthy Premature Neonate. J Pediatr.
2007;151(6):585-90.
13. Corvaglia L, Monari C, Martini S, Aceti A, Faldella G.
Pharmacological Therapy of Gastroesophageal Reux in Preterm
Infants.Gastroenterol Res Pract. 2013;2013:714564.
14. Condino AA, Sondheimer J, Pan Z, Gralla J, Perry D, O’Connor JA.
Evaluation of infantile acid and nonacid gastroesophageal reux
using combined PH monitoring and impedance measurement. J
Pediatr Gastroentral Nutr. 2006;42(1):16-21.
15. Hibbs AM. Gastroesophageal Reux and Gastroesophageal Reux
Disease in the neonate. In: Martin RJ, Fanaroff A, Walsh M
(Eds.). Neonatal-perinatal Medicine disease of the fetus and infant.
Philadelphia: Elsevier Saunders, 2015.
16. Djeddi D, Kongolo G, Lefaix C, Mounard J, Léké A. Effect of dom-
peridone on QT interval in neonates. J Pediatr. 2008;153(5):663-6.
17. Brieng Document for FDA Gastrointestinal Drugs Ad vi-
sory Committee Meeting Regarding Serotonin (5-hydroxy-
tryptamine) Receptor 4 Agonists – Experience Related to
Cisapride. Available at: https://www.fda.gov/downloads/
AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/
GastrointestinalDrugsAdvisoryCommittee/UCM279739.pdf, date
of publica tion: November 17, 2011, last access: April 2017.
18. Approval Package for: Metoclopramide Oral Solution USP, 5 mg/5
mL. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/
anda/2009/071402orig1s008.pdf, last access: September 2009.
19. Omari T, Lundborg P, Sandström M, Bondarov P, Fjellman M,
Haslam R, Davidson G. Pharmacodynamics and systemic exposure
of esomeprazole in preterm infants and term neonates with
gastroesophageal reux disease. J Pediatr. 2009;155(2):222-8.
20. Kelly EJ, Chateld SL, Brownlee KG, Ng PC, Newell SJ, Dear PR,
Primrose JN. The effect of intravenous ranitidine on the intragastric
pH of preterm infants receiving dexamethasone. Arch Dis Child.
1993;69(1):37-9.
21. Ferreira CT, Carvalho Ed, Sdepanian VL, Morais MB, Vieira MC,
Silva LR. Gastroesophageal reux disease: exaggerations, evidence
and clinical practice. J Pediatr (Rio J). 2014;90(2):105-18.
22. Lightdale JR, Gremse DA. Section on gastroenterology, hepatology,
and nutrition. Gastroesophageal Reux. Management guidance for
the pediatrician. J Pediatrics. 2013;131(5):e1684-95.
23. Vandenplas Y, Rudolph CD, Di Lorenzo C, Hassall E, Liptak
G, Mazur L, Sondheimer J, Staiano A, Thomson M, Veereman-
Wauters G, Wenzl TG, North American Society for Pediatric
Gastroenterology Hepatology and Nutrition, European Society
for Pediatric Gastroenterology Hepatology and Nutrition.
Pediatric gastroesophageal reux clinical practice guidelines: joint
recommendations of the North American Society for Pediatric
Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and
the European Society for Pediatric Gastroenterology, Hepatology,
and Nutrition (ESPGHAN). J Pediatr Gastroenterol Nutr.
2009;49(4):498-547.
24. National Institute for Health and Care Excellence. Gastro-
oesophageal reux disease: recognition, diagnosis and management
in children and young people. (NICE guideline; no. 1). Available at:
https://www.nice.org.uk/guidance/ng1, date of publication: January
2015, last access: July 2018.
25. Malcolm WF, Gantz M, Martin RJ, Goldstein RF, Goldberg
RN, Cotten CM, National Institute of Child Health and Human
Development Neonatal Research Network. Use of medications for
gastroesophageal reux at discharge among extremely low birth
weight infants. Pediatr. 2008;121(1):22-7.
26. Kuusela AL. Long term gastric pH monitoring for determining
optimal dose of ranitidine for critically ill preterm and term
neonates. Arch Dis Child. 1998;78(2):F151-3.
27. Barron JJ, Tan H, Spalding J, Bakst AW, Singer J. Proton pump
inhibitor utilization patterns in infants. J Pediatr Gastroenterol Nutr.
2007;45(4):421-7.
28. Moore DJ, Siang-Kuo Tao B, Lines DR, Hirte C, Heddle ML,
Davidson GP. Double-blind placebo-controlled trial of omeprazole
in irritable infants with gastroesophageal reux. J Pediatr.
2003;143(2):219-23.
29. Orenstein SR, Hassall E, Furmaga-Jablonska W, Atkinson S,
Raanan M. M. Multicenter, double-blind, randomized, placebo-
controlled trial assessing the efcacy and safety of proton pump
inhibitor lansoprazole in infants with symptoms of gastroesophageal
reux disease. J Pediatr. 2009;154(4):514-20.
30. Guillet R, Stoll BJ, Cotten CM, Gantz M, McDonald S, Poole
WK, Phelps DL, National Institute of Child Health and Human
Development Neonatal Research Network. Association of H2-
blocker therapy and higher incidence of necrotizing enterocolitis in
very low birth weight infants. Pediatr. 2006;117(2):e137-42.
31. Terrin G, Passariello A, De Curtis M, Manguso F, Salvia G, Lega
L, Messina F, Paludetto R, Canani RB. Ranitidine is associated with
infections, necrotizing enterocolitis, and fatal outcome in newborns.
Pediatr. 2012;129(1):e40-5.
32. Canani RB, Terrin G. Gastric acidity inhibitors and the risk of
intestinal infections. Curr Opin Gastroenterol. 2010;26(1):31-5.
33. Santana RNS, Santos VS, Ribeiro-Júnior RF, Freire MS, Menezes
MAS, Cipolotti R, Gurgel RQ. Use of ranitidine is associated with
infections in newborns hospitalized in a neonatal intensive care
unit: a cohort study. BMC Infect Dis. 2017;17(1):375.
34. Lau Moon Lin M, Robinson PD, Flank J, Sung L, Dupuis LL. The
Safety of Metoclopramide in Children: A Systematic Review and
Meta-Analysis. Drug Saf. 2016;39(7):675-87.
35. Craig WR, Hanlon-Dearman A, Sinclair C, Taback S, Moffatt M.
Metoclopramide, thickened feedings, and positioning for gastro-
esophageal reux in children under two years. Cochrane Database
Syst Rev. 2004;(4):CD003502.