Systematic Review of Nonpharmacological and Nonsurgical Therapies for
Gastroesophageal Reflux in Infants

Arch Pediatr Adolesc Med. 2002;156:109-113

Author Information
<http://archpedi.ama-assn.org/issues/v156n2/rfull/#aainfo>   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
POA10190
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
<http://archpedi.ama-assn.org/issues/v156n2/rfull/#r1>  Approximately 50% of
all healthy infants will vomit more than twice per day. 2
<http://archpedi.ama-assn.org/issues/v156n2/rfull/#r2>
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
<http://archpedi.ama-assn.org/issues/v156n2/rfull/#r3>  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 plusmnSEM.



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
<http://archpedi.ama-assn.org/issues/v156n2/rfull/#r4>  or the trials did
not specifically study therapies for GERD, 10-13
<http://archpedi.ama-assn.org/issues/v156n2/rfull/#r10>  infants with
compound medical problems 14-17
<http://archpedi.ama-assn.org/issues/v156n2/rfull/#r14>  or premature
infants were included, 18-21
<http://archpedi.ama-assn.org/issues/v156n2/rfull/#r18>  and a control group
or proper randomization was missing. 1
<http://archpedi.ama-assn.org/issues/v156n2/rfull/#r1> , 22-25
<http://archpedi.ama-assn.org/issues/v156n2/rfull/#r22>  Other studies were
eliminated because they included therapies judged to be pharmacological in
nature. 26 <http://archpedi.ama-assn.org/issues/v156n2/rfull/#r26> , 27
<http://archpedi.ama-assn.org/issues/v156n2/rfull/#r27>  Ten randomized
controlled trials (RCTs) met selection criteria. Of these, 2 RCTs studied
positioning 28 <http://archpedi.ama-assn.org/issues/v156n2/rfull/#r28> , 29
<http://archpedi.ama-assn.org/issues/v156n2/rfull/#r29> ; 3 studied
thickened infant food 30-32
<http://archpedi.ama-assn.org/issues/v156n2/rfull/#r30> ; 4 studied formula
changes 33-36 <http://archpedi.ama-assn.org/issues/v156n2/rfull/#r33> ; and
1 studied nonnutritive sucking. 37
<http://archpedi.ama-assn.org/issues/v156n2/rfull/#r37>  Characterisics of
these studies are summarized in Table 1
<http://archpedi.ama-assn.org/issues/v156n2/fig_tab/poa10190_t1.html> .
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 RCT 29
<http://archpedi.ama-assn.org/issues/v156n2/rfull/#r29>  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% plusmn6.4%) than did those in
the prone position (12.8% plusmn3.7%) and had significantly more episodes of
reflux (16.0 plusmn2.4 vs 10.1 plusmn2.3). 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 RCT 28
<http://archpedi.ama-assn.org/issues/v156n2/rfull/#r28>  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. Orenstein 37
<http://archpedi.ama-assn.org/issues/v156n2/rfull/#r37>  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 plusmn1.1 to 12.8 plusmn2.3 [P = .04]).
In the seated position, pacifier use decreased the number of reflux episodes
in 2 hours (21.1 plusmn3.1 to 14.8 plusmn2.6 [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 al 31
<http://archpedi.ama-assn.org/issues/v156n2/rfull/#r31>  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 al 32
<http://archpedi.ama-assn.org/issues/v156n2/rfull/#r32>  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 plusmn0.7 vs 3.9 plusmn0.9 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
<http://archpedi.ama-assn.org/issues/v156n2/rfull/#r34>  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
<http://archpedi.ama-assn.org/issues/v156n2/rfull/#r30>  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
(plusmn SD) reductions were significantly greater, however, with the carob
bean gum–thickened formula (symptomatic score reduction, 70.4% plusmn6.0% vs
48.7% plusmn6.2% [P<.01]; reduction in episodes of emesis, 58.1% plusmn5.6%
vs 34.1% plusmn8.8% [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 al 35
<http://archpedi.ama-assn.org/issues/v156n2/rfull/#r35>  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 study 33
<http://archpedi.ama-assn.org/issues/v156n2/rfull/#r33>  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 plusmn0.6 vs 4.3 plusmn0.6 [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 Dillard 36
<http://archpedi.ama-assn.org/issues/v156n2/rfull/#r36>  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 plusmn1 SD, 12.0 plusmn11.3 and
12.6 plusmn8.0, respectively, vs 28.6 plusmn28.4 [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 <http://archpedi.ama-assn.org/issues/v156n2/rfull/#r38>  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
<http://archpedi.ama-assn.org/issues/v156n2/rfull/#r39>
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
<http://archpedi.ama-assn.org/issues/v156n2/rfull/#r46>  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
<http://archpedi.ama-assn.org/issues/v156n2/rfull/#r47>  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
<http://archpedi.ama-assn.org/issues/v156n2/rfull/#r47>  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]
<mailto:[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.