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A Systematic Review of Nonpharmacological and Nonsurgical Therapies for Gastroesophageal Reflux in Infants
Aaron E. Carroll, MD;
Michelle M. Garrison, MPH;
Dimitri A. Christakis, MD, MPH
Arch Pediatr Adolesc Med. 2002;156:109-113.
ABSTRACT
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Background Nonpharmacological and nonsurgical measures are often recommended for
gastroesophageal reflux disease (GERD) in infants, despite ambiguous supporting
evidence.
Objective To conduct a systematic review of rigorously evaluated nonpharmacological
and nonsurgical therapies for GERD in infants.
Design/Methods We searched online bibliographic databases, including MEDLINE, EMBASE,
the Cochrane Collaboration and Clinical Trials Database, and alternative medicine
databases for the terms gastroesophageal reflux and infants. We selected randomized controlled trials of nonpharmacological and
nonsurgical GERD therapies in otherwise healthy infants. Data were extracted
from the selected articles regarding reflux, emetic episodes and intraesophageal
pH.
Results We identified 43 relevant studies, of which 10 met the selection criteria.
These studies examined positioning, pacifier use, and feeding changes. Positioning
at a 60° elevation in an infant seat was found to increase reflux compared
with the prone position. No significant difference was shown between the flat
and head-elevated prone positions. The impact of pacifier use on reflux frequency
was equivocal and dependent on infant position. The protein content of formula
was not found to affect reflux. Although no study demonstrated a significant
reflux-reducing benefit of thickened infant foods compared with placebo, 1
study detected a significant benefit of formula thickened with carob bean
gum compared with rice flour (pH<4 for 5% vs 8% of time). Another study
showed that if supplementing with dextrose 5% water or dextrose 10% water,
the lower-osmolality fluid was associated with less reflux.
Conclusions Many conservative measures commonly used to treat GERD in infants have
no proven efficacy. Although thickened formulas do not appear to reduce measurable
reflux, they may reduce vomiting. Further studies with clinical outcomes are
needed to answer questions about efficacy definitively.
INTRODUCTION
GASTROESOPHAGEAL reflux disease (GERD) is a common disease of infancy,
with a prevalence of as high as 18% in healthy children, and a frequent reason
for visits to primary health care providers.1
Approximately 50% of all healthy infants will vomit more than twice per day.2
A variety of approaches have been used in the treatment of GERD, including
pharmacological and nonpharmacological therapies. As many of the pharmacological
therapies for reflux, eg, metoclopramide hydrochloride (Reglan) and cisapride
(Propulsid), are falling into disfavor or are withdrawn from use, practitioners
may rely more on conservative measures as first-line therapy for GERD. These
nonpharmacological and nonsurgical therapies include positioning changes,
formula changes, and thickening of infant food.
Although these interventions are commonly recommended,3
evidence in support of them is sparse. We therefore undertook a systematic
review to summarize the current state of the evidence. To maximize clarity
and clinical usefulness, we present the results of that review as distinct
evidence summaries detailing the potential benefits and harms of each intervention.
METHODS
We searched several bibliographic databases, including MEDLINE (January
1, 1966, through November 30, 2000), the Cochrane Collaboration and Clinical
Trials Database (as of November 2000), EMBASE (as of November 2000), and multiple
alternative medicine databases. We used the search terms gastroesophageal reflux disease and infants
as medical subject headings and keywords. We restricted the results to studies
that were conducted in human infants and published in the English language.
We reviewed the titles of all returned articles and the bibliographies of
all relevant review articles and selected articles to determine whether the
studies examined nonpharmacological and nonsurgical therapies for infants
with GERD. Articles were immediately excluded if they included drug or surgical
therapies or were obviously not clinical trials.
We analyzed studies for adequate inclusion criteria, randomization,
and allocation concealment. Although considerable disagreement exists regarding
how pathologic GERD should be defined, we accepted any study that defined
GERD as reflux into the esophagus with a pH of less than 4.0 for at least
5% of the time, as diagnosed by means of pH probe study findings. Although
this cutoff is frequently used as a diagnostic criterion in research and clinical
practice, it may or may not adequately correlate with symptomatic reflux in
infants.
To meet selection criteria, a study had to randomize otherwise healthy,
full-term infants with GERD to treatment and control groups. Crossover trials
were accepted if infants were exposed in random order to both treatment and
control protocols. Allocation concealment was only considered a requirement
for inclusion when all reviewers agreed that it would be feasible to blind
such a study, and that the absence of effective blinding could bias the outcome.
For example, although blinding may not be feasible in a study of infant positioning,
the results of a pH probe are unlikely to be affected by parent or provider
knowledge of allocation. All disagreements were resolved via consensus.
Unless otherwise indicated, data are given as mean ± SEM.
RESULTS
LITERATURE SEARCH
The systematic literature search identified more than 2500 articles.
After excluding articles that did not describe clinical trials or that examined
drug or surgical therapy, 35 articles remained and were assessed by all 3
reviewers (A.E.C., M.M.G., and D.A.C.). Articles were most commonly excluded
at this stage because they did not describe trials,4-9
or the trials did not specifically study therapies for GERD,10-13
infants with compound medical problems14-17
or premature infants were included,18-21
and a control group or proper randomization was missing.1, 22-25
Other studies were eliminated because they included therapies judged to be
pharmacological in nature.26-27
Ten randomized controlled trials (RCTs) met selection criteria. Of these,
2 RCTs studied positioning28-29;
3 studied thickened infant food30-32;
4 studied formula changes33-36;
and 1 studied nonnutritive sucking.37 Characterisics
of these studies are summarized in Table
1.
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Characteristics of Included Studies
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POSITIONING
Two of the trials investigated the effect of positioning. One studied
the placement of the infant upright in a seat vs lying prone; the other examined
the effect of elevation of the head of the bed.
Does placement upright in an infant seat reduce the
amount of reflux?
There is no evidence to support this intervention. One RCT29 found that placement in an
infant seat (inclined at 60°) was detrimental with respect to GERD. Infants
were randomized and studied in paired 2-hour trials using the pH probe to
measure reflux. Infants in the seat spent a greater proportion of time in
a state of reflux (28.2% ± 6.4%) than did those in the prone position
(12.8% ± 3.7%) and had significantly more episodes of reflux (16.0
± 2.4 vs 10.1 ± 2.3). Although the infant seat has been considered
a treatment for GERD, evidence suggests that it actually exacerbates reflux.
Does elevating the head of the bed reduce the amount
of reflux?
There is no evidence to support this intervention. One RCT28 found no difference in any
measure of reflux between infants in the prone position and those in the prone
position with the head of the bed inclined at 30°. Infants were randomized
and underwent pH probe studies for 3-hour sessions in a crossover trial that
measured the amount of reflux, number of episodes, average length of episodes,
number of long episodes, and length of the longest episode. Among the 90 infants
with GERD, no difference was seen between the positions for any of these measures.
NONNUTRITIVE SUCKING
Does pacifier use reduce reflux?
There is no evidence to support this intervention. Orenstein37 studied 48 infants randomized
to a prone or seated position. In each position, infants underwent pH probe
examination with and without pacifiers in random order for 3 hours. In the
prone position, pacifier use increased the number of episodes of reflux in
2 hours (7.2 ± 1.1 to 12.8 ± 2.3 [P
= .04]). In the seated position, pacifier use decreased the number of reflux
episodes in 2 hours (21.1 ± 3.1 to 14.8 ± 2.6 [P = .03]), but not enough to compensate for the negative effects of
the seated position. Total reflux time and reflux clearance were not significantly
affected by pacifier use in either position.
THICKENED INFANT FOOD
Four RCTs studied the effect of thickened food on GERD. Two studies
compared formula thickened with rice flour with placebo, 1 studied carob bean
gum–thickened formula vs placebo, and 1 compared the 2 thickening agents.
Does thickening food with rice flour reduce the amount
of reflux?
There is no evidence to support this intervention. Bailey et al31 randomized infants to
receive plain apple juice or apple juice thickened with rice flour. Infants
received at least 3 feedings of both juice types during 20 to 24 hours in
the following 4 positions: prone, prone and elevated 30°, supine, or unrestricted.
Reflux was measured by means of a pH probe for 2 hours postprandially. There
was no difference between the 2 types of juice in any position, except in
the 30° elevated prone position, in which reflux time was increased with
thickened juice. Orenstein et al32 assessed
reflux by means of technetium Tc 99m sulfur colloid 500-µCi scintigraphy
in 20 infants undergoing paired feeding consisting of infant formula alone
or formula thickened with rice cereal. The feedings were given 48 to 72 hours
apart, and the infants underwent 90-minute postprandial studies. The type
of formula had no statistically significant impact on the amount of reflux.
However, a significant decrease was found in the number of episodes of frank
emesis (1.2 ± 0.7 vs 3.9 ± 0.9 per 90 postprandial minutes).
Does thickening food with carob bean gum preparation
reduce the amount of reflux?
There is no evidence to support this intervention. In one RCT,34 20 infants were randomized
to receive the control formula (80% casein and 20% whey) or the thickened
formula. Both groups also received positional treatment and parental reassurance.
Parents kept a regurgitation diary for 1 week, and a 24-hour pH study was
performed before and after treatment. Both groups noted improvements compared
with baseline, but no significant difference was found in pH monitoring results
between the control and treatment groups. There were some intragroup improvements,
which led the authors to conclude that thickened formulas reduced the reflux
index. However, no significant differences were found between the groups before
and after the trial. Parental diaries recorded improvement in the number of
regurgitations in both groups, with no significant difference between them.
Is thickening food with carob bean gum more successful
than rice flour in reducing reflux?
Yes. In 1 crossover RCT,30
24 infants received a traditional formula thickened with rice flour or a formula
thickened with carob bean gum, and formulas were alternated in a nonrandom
alteration study. All infants underwent 24-hour pH probe studies. The infants
were then randomized to receive 1 of the 2 formulas for the next 2 weeks,
with parents scoring their reflux symptoms on diary cards. Parental diaries
showed reduction over time in the symptomatic scores for both formulas. The
mean (± SD) reductions were significantly greater, however, with the
carob bean gum–thickened formula (symptomatic score reduction, 70.4%
± 6.0% vs 48.7% ± 6.2% [P<.01];
reduction in episodes of emesis, 58.1% ± 5.6% vs 34.1% ± 8.8%
[P<.05]).
FORMULA CHANGES
Two RCTs investigated the effect of formula composition on GERD, with
equivocal results.
Does the composition of formula have any effect on
reflux?
There is no evidence to support this intervention. Tolia et al35 randomized 28 infants
to receive casein-predominant, soy-based, and whey-predominant formulas in
random order. The infants were given 1 serving of each formula on 3 consecutive
days and then underwent measuring for gastric emptying time and reflux by
means of scintigraphy. No difference was seen in spitting and vomiting between
the formulas. The differences in volume of reflux for each formula were not
statistically significant. Another small study33
monitored reflux in 3 infants with GERD by means of a 24-hour pH probe for
casein- and whey-based formulas. All 3 infants showed improvement in emesis
while receiving the whey-based formulas (1.3 ± 0.6 vs 4.3 ±
0.6 [P<.01]), although the difference between
the formulas, based on the results of the pH probe testing, was not statistically
significant.
CALORIC DENSITY AND OSMOLALITY
Does the caloric density or osmolality of feedings
affect reflux?
Possibly. Sutphen and Dillard36
studied the effect of dextrose 5% water (D5W), dextrose 10% water (D10W),
and a glucose polymer solution (Polycose; Ross Laboratories, Columbus, Ohio)
when rehydrating children with carbohydrate solutions. Nineteen infants underwent
pH probe monitoring as they received each solution 1 time in a random order
while undergoing the pH probe study. The total minutes of esophageal reflux
were significantly lower while receiving the D5W and glucose polymer solutions
than while receiving the D10W solution (mean ± 1 SD, 12.0 ±
11.3 and 12.6 ± 8.0, respectively, vs 28.6 ± 28.4 [P<.05]). No significant difference was found in the results in the
first postprandial hour, but results became significant when observed for
2 hours postprandially.
COMMENT
Although often used, these nonpharmacological, nonsurgical approaches
to the management of infant GERD lack a sound evidence base. None of the interventions
discussed in this review significantly improved reflux. Thickening infant
formulas, however, reduced the frequency of frank emesis. Medical textbooks
are often used as a proxy for the prevailing opinions of experts.38 In the case of GERD, many textbooks continue to recommend
the use of conservative measures, including thickening of juice and formula
and upright positioning, despite their lack of proven efficacy.39-45
Many pediatricians and pediatric gasroenterologists prescribe these
therapies despite their lack of evidence, often as a means of including parents
in the treatment plan when reassurance seems insufficient. Although no evidence
suggests that these nonpharmacological therapies are unsafe, they often carry
hidden burdens. Wedges (devices that keep infants sleeping at an incline)
can be expensive and cumbersome to use, and reliance on them may lead to undue
anxiety on occasions when parents fail to use them. Thickening infant foods
necessitates bottle feeding, thereby requiring that breastfeeding mothers
express breast milk rather than nurse directly. This may be inconvenient and
may have an impact on mother-child bonding.
The limitations of this study are that we included only articles and
textbooks written in the English language. The number of well-designed clinical
trials of nonpharmacological and nonsurgical therapies for reflux is small.
Therefore, a potential effect of some of these therapies may have been missed
because of the small sample size. This review does not prove that these therapies
do not work; it illustrates that no conclusive evidence exists to prove that
they do work. Certainly, more studies are needed to answer questions about
efficacy definitively.
This systematic review, like others before,46
identified significant gaps in what we know about treating GERD in infants.
No quality RCTs have examined changes in feeding volume or frequency. Another
area for potential improvement in future research is in the outcome measures
used. Thus far, most of the studies have used pH probes to diagnose and monitor
GERD. Although pH probes are an objective measure, and thus not subject to
bias, they may not reflect clinical symptoms, which constitute the outcome
of greatest interest to parents. One potential scoring system might be the
25-point Infant Gastroesophageal Reflux Questionnaire GERD score based on
11 items, including frequency and amount of vomiting, feeding, weight gain,
comfort, crying, hiccups, arching, and apnea.47
This test was shown to have a 100% positive predictive value and 94% to 98%
negative predictive value in a clinical study of its validity.47
Despite potential problems with bias and comparability between studies, clinical
scores may be a more clinically relevant outcome measure in the study of infant
GERD.
| What This Study Adds
Nonpharmacological and nonsurgical measures are often recommended for
infant gastroesophageal reflux disease, although the evidence in support of
them is ambiguous. This review systematically evaluated rigorous studies of
these therapies to document their efficacy. Through this review, we hope to
make it clear to practitioners that many of these therapies have no proven
efficacy. More studies of nonpharmacological and nonsurgical measures are
necessary in the future.
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AUTHOR INFORMATION
Accepted for publication September 28, 2001.
Corresponding author: Aaron E. Carroll, MD, Robert Wood Johnson Clinical
Scholars Program, H-220 Health Sciences Center, Box 357183, Seattle, WA 98195-7183
(e-mail: acarro{at}u.washington.edu).
From the Robert Wood Johnson Clinical Scholars Program (Dr Carroll),
the Department of Pediatrics (Drs Carroll and Christakis), and the Child Health
Institute (Ms Garrison and Dr Christakis), University of Washington, Seattle.
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