Systematic Review of Nonpharmacological and Nonsurgical
Therapies for Gastroesophageal Reflux in Infants
Arch Pediatr Adolesc Med. 2002;156:109-113
Aaron E. Carroll, MD; Michelle M. Garrison, MPH; Dimitri A. Christakis,
MD, MPH
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.
Arch Pediatr Adolesc Med.
2002;156:109-113
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.
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.
Author/Article Information
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.
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: [log in to unmask]).
Accepted for publication September 28, 2001.
|
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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Edward E.
Rylander, M.D.
Diplomat American
Board of Family Practice.
Diplomat American
Board of Palliative Medicine.