1. health and fitness
2. disease
3. gerd and acid reflux

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Volume 7, Series 4
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Managing the Symptoms of Reflux in Infants
Written By:
Susan R. Orenstein, MD
Professor, Pediatric Gastroenterology
University of Pittsburgh School of Medicine,
Children’s Hospital of Pittsburgh
Pittsburgh, Pennsylvania
Introduction
Several years ago, I wrote an editorial reviewing the
scientific, clinical-trial-based evidence related to dietary
management of gastroesophageal reflux symptoms in
infancy, concluding that the clearest data for efficacy
were found for thickened feeds.1 Thickened formula
feedings had been subjected to more well-designed
controlled clinical trials, including randomization and
double-blinding, with more clear documentation of
efficacy, than any of the drugs used for infant reflux
symptoms. These drugs included both prokinetic
agents (metoclopramide, bethanechol, and
erythromycin) and acid suppressing agents in the
histamine-2 receptor antagonist or proton pump
inhibitor classes.
Thickened feedings had
Thickened feedings had
been shown to improve
been shown to improve
both of the major types of
both of the major types of
reflux symptoms in infants:
reflux symptoms in
regurgitation and crying.
infants: regurgitation and
crying. Furthermore,
controlled clinical trials had demonstrated that the
symptoms improved by thickened feedings extended
beyond regurgitation and crying, to improvement of
sleep and reduction of choking, gagging, and coughing
with feedings. Even better, this conservative
management approach reduced regurgitation
immediately. As additional benefits, thickened feedings
imparted no pharmacologic side effects and had
negligible costs beyond that associated with routine
infant care.
Use of Pharmacotherapy
The several years since that editorial have witnessed a
remarkable increase in the use of pharmacotherapy for
gastroesophageal reflux symptoms in infants. A recent
retrospective database analysis examined data on
roughly one million infants from four U.S. health plans
between 1999 and 2004. The use of a proton pump
inhibitor increased more than seven-fold during this
period. In 2004, about 0.5% of these infants received
one of these particular drugs during their first year of
life.2 A recent report on referrals for persistent infant
regurgitation to a single pediatric gastroenterology
practice criticizes this
Because of their negligible
apparent over-use of
additional cost or risk,
pharmacotherapy for infant
3
thickened feedings are
reflux symptoms. This
more rational to use for
report documents
infants with mild
inadequate use of
symptoms of reflux than
conservative measures
are any of the drugs in our
including thickening of
armamentarium. Their
feedings as well as
efficacy is so clear for the
ineffectiveness of the
symptoms of
pharmacotherapy for the
gastroesophageal reflux,
symptoms being treated.
however, that they are also
This burgeoning of antiuseful as the base of a
reflux pharmacotherapy
pyramid of management
use for infants, and the
when more severe reflux
increasing preponderance
disease is present.
of the more potent acid
suppression provided by proton pump inhibitors, has
taken place in the virtual absence of supportive
documentation from controlled studies regarding
efficacy.4 In most cases, these drugs are used to treat
symptoms consistent with gastroesophageal reflux
disease, in the absence of any specific diagnostic
testing. There are very few published double-blind,
randomized, placebo-controlled trials (DBRPCTs) of
Continued on next page.
proton pump inhibitors in infants, and none show
efficacy for reflux symptoms. In fact, two excellent
DBRPCTs found no difference in improvement of
irritability or other symptoms between a proton pump
inhibitor and placebo, taken for up to two weeks,
despite clear reduction in gastric acidity by the proton
pump inhibitor.5,6 On the registry of clinical trials in
progress (www.clinicaltrials.gov accessed 10-8-07),
there is only a single further (as-yet-unpublished)
well-controlled study of efficacy of a proton pump
inhibitor for infants from 4 weeks to 12 months of
age with symptoms—its findings will be of
considerable interest.4
These data regarding pharmacotherapy for infant
reflux symptoms highlight the benefits of the nonprescription, inexpensive, medication-less aspects of
conservative management.7,8 In controlled clinical trials,
thickening of infant feedings have specifically been
shown to reduce regurgitation frequency, diminish
crying time, improve sleep, and reduce choking,
gagging, and coughing with feedings. These benefits
were initially quantified using dry rice cereal (or other
thickeners, predominantly in studies from non-U.S.
countries) added to routine formula at a ratio of 1 level
tablespoon of dry rice cereal per 1 fluid ounce of
routine formula.9
Prethickened Formulas
However, several disadvantages of such “home brew”
thickening prompted the design and manufacture of
prethickened formulas. First, while the increase in
caloric density of the “home brew” (thickening
increases a 20 Cal/fl oz standard formula to about
30 Cal/fl oz) allows smaller volume feeds, and thus may
further decrease regurgitation or improve failure to
thrive, parents of adequately nourished infants often
fail to reduce the fed volumes appropriately. Thus the
rice-cereal thickening can contribute to obesity in an
infant. A pediatric gastroenterology office-based data
review documented that many referred infants with
persistent regurgitation were being fed more than
120 Cal/kg/day and nearly all were gaining more than
15 gm/day.3 Secondly, rice-cereal thickening of standard
formula often firms the infant stool. While this result
may be beneficial in the occasional infant with overly
loose stools, problematic constipation is common
enough that many practitioners find it practical to
institute proactive measures when advising rice-cereal
thickening.10 Thirdly, there is the nuisance factor: the
need to transport two types of food, mix them, enlarge
the nipple just right to get adequate flow, and so
Figure 1 Nutrient Effect Enfamil A.R.® LIPIL® vs
Formula with Rice Cereal
forth.7 Finally, perhaps more important but less
definable, is concern about the disturbance by the
added rice cereal of the nutrient profile of the
marketed formulas, which have been carefully
designed to mimic human breast milk, or the effects
of the cereal itself on nutrient absorption.11,12 Whereas
breast milk and standard formulas have 40%–45% of
their calories provided by carbohydrate, rice-cereal
thickening increases this dramatically to 60%, with a
proportionate decrease in fat calories. (Figure 1,
Nutrient Effect)
These considerations prompted design and commercial
development of prethickened formulas.13-16 The
thickening agents for formulas developed in various
countries have varied. In the United States, Enfamil
A.R.®, now Enfamil A.R. LIPIL® with DHA and ARA,
substitutes approximately 30% of the lactose of
routine infant formula with an unmodified, pre-
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Figure 2 Effect of pH on Viscosity16
gelatinized, high-amylopectin (waxy) rice starch (2.2 g
starch/100 mL of prepared Enfamil A.R.® LIPIL®
powder). This composition was designed to allow it to
maintain the nutrient profile, caloric density, and
osmolality of routine infant formula, yet to increase its
viscosity in the stomach. Interestingly, in the bottle
before feeding, its viscosity is a fraction of that of ricecereal thickened formula, but once the pH drops below
5.5, its viscosity rises to the same level that the ricecereal thickened formula reaches. (Figure 2, Effect of pH
on Viscosity) The low initial viscosity allows Enfamil A.R.
LIPIL to flow easily through a standard nipple, yet when
contacting the low pH in the stomach, Enfamil A.R.
LIPIL is designed to provide adequate viscosity to
counter regurgitation.
We have published a multi-center, double-blind,
randomized, placebo-controlled 5-week trial in 104
infants that provided the kind of controlled efficacy
data for this prethickened formula that is usually
reserved for pharmacologic agents.16 The infants
recruited to the study were 2-weeks to 4-months old,
and regurgitating at least 5 times daily. The enrolled
infants actually were regurgitating 12 to 14 times daily,
on average. They also presented with additional
symptoms, including trouble sleeping and chokinggagging-coughing with feedings. Randomized to
Enfamil A.R. (prior to the addition of LIPIL), or to a
comparable standard formula, their symptoms were
documented prospectively during 5 weeks of follow-up.
At the end of the 5 weeks, the infants managed with
the dietary use of a prethickened formula were
experiencing significantly fewer feeds followed by any
regurgitation, a significantly lower total daily
regurgitation volume score, and a significantly lower
percentage of feedings followed by choking-gaggingcoughing than the infants receiving the routine
formula. Among the most symptomatic quartile of
infants, randomization to Enfamil A.R. resulted in
significantly less trouble sleeping than randomization
to the standard formula.
Conclusion
Thickened feedings provide clear benefit of a
conservative approach in the management of healthy
infants with regurgitation. Because of their negligible
additional cost or risk,
thickened feedings are
Thickened feedings
more rational to use for
provide clear benefit of a
conservative approach in
infants with mild
the management of
symptoms of reflux than
healthy infants with
are any of the drugs in our
regurgitation.
armamentarium. Their
efficacy is so clear for the
symptoms of gastroesophageal reflux, however, that
they are also useful as the base of a pyramid of
management when more severe reflux disease is
present. For the occasional infant with failure to thrive
or very loose stools, or in the infant for whom a nonstandard (eg, hypoallergenic extensively hydrolyzed
formula) is required, thickening of formula with rice
cereal may be useful. In most other infants,
prethickened formula, like Enfamil A.R. LIPIL, provides
practical advantages and clear clinical benefit proven
by double-blind, randomized clinical trial.
Continued on next page.
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Promotes development and health
References
1. Orenstein SR. Treatment of symptoms of reflux in infants. Pediatri Persp
News. 2004;3:1-3.
2. Barron JJ, Tan H, Spalding J, et al. Proton pump utilization patterns in
infants. J Pediatr Gastroenterol Nutr. 2007;45:421-427.
3. Khoshoo V, Edell D, Thompson A, Rubin M. Are we overprescribing
antireflux medications for infants with regurgitation? Pediatrics.
2007;120:946-949.
4. Orenstein SR, Hassall E. Infants and proton pump inhibitors: tribulations,
no trials (Invited editorial). J Pediatr Gastroenterol Nutr. 2007;45:395-398.
5. Omari TI, Haslam RR, Lundborg P, Davidson GP. Effect of omeprazole on acid
gastroesophageal reflux and gastric acidity in preterm infants with
pathological acid reflux. J Pediatr Gastroenterol Nutr. 2007;44:41-44.
6. Moore DJ, Tao BS, Lines DR, Hirte C, et al. Double-blind placebo-controlled
trial of omeprazole in irritable infants with gastroesophageal reflux.
J Pediatr. 2003;143:219-223.
7. Shalaby TM, Orenstein SR. Efficacy of telephone teaching of conservative
therapy for infants with symptomatic gastroesophageal reflux referred by
pediatricians to pediatric gastroenterologists. J Pediatr. 2003;142:57-61.
8. Orenstein SR, McGowan JD. Efficacy of conservative therapy as taught in
the primary care setting for infant reflux symptoms: Prospective validated
assessment by the I-GERQ-R. J Pediatr. 2007;In press.
10. Mascarenhas R, Landry L, Khoshoo V. Difficulty in defecation in infants with
gastroesophageal reflux treated with smaller volume feeds thickened with
rice cereal. Clin Pediatr. 2005;44:671-673.
11. Shulman R, Boutton T, Klein P. Impact of dietary cereal on nutrient
absorption and fecal nitrogen loss in formula-fed infants. J Pediatr.
1991;118:39-43.
12. Bosscher D, Van Caille-Bertrand M, Van Dyck K, et al. Thickening infant
formula with digestible and indigestible carbohydrate: availability of
calcium, iron, and zinc in vitro. J Pediatr Gastroenterol Nutr.
2000;30:373-378.
13. Vandenplas Y, Hachimi-Idrissi S, Casteels A, et al. A clinical trial with an
“anti-regurgitation” formula. Eur J Pediatr. 1994;153:419-423.
14. Borrelli O, Slavia G, Campanozzi A, et al. Use of a new thickened formula for
the treatment of symptomatic gastroesophageal reflux in infants.
Ital J Gastroenterol Hepatol. 1997;29:237-242.
15. Baldassarre M, Franco MT, Crudele A, et al. Effetto di una formula ad elevata
viscosita (Enfamil pre-gel, Mead Johnson) nel lattante con reflusso
gastroesofageo sintomatico. Riv Ital Pediatr. 2001;27:137-141.
16. Vanderhoof JA, Moran JR, Harris CL, et al. Efficacy of a pre-thickened infant
formula: A multi-center, double blind, randomized, placebo-controlled
parallel group trial in 104 infants with symptomatic gastroesophageal
reflux. Clin Pediatr. 2003;42:483-495.
9. Orenstein SR, Magill HL, Brooks P. Thickening of infant feedings for therapy
of gastroesophageal reflux. J Pediatr. 1987;110:181-186.
Enfamil A.R.®® LIPIL®®
• Clinically shown to provide approximately four times as many spit-up free feedings1*
• Nutritionally balanced with a nutrient profile similar to routine infant formula
• More reliable preparation than adding rice cereal to formula
• Milk based
• Includes LIPIL, our blend of DHA and ARA, nutrients also found in breast milk, that promote
brain and eye development2-9
* Based on a clinical study of Enfamil A.R. before the addition of LIPIL in infants who regurgitate frequently (5 or more regurgitations per day), comparing frequency of spit up after feeding
Enfamil A.R. to the same babies at the beginning of the study.
1. Vanderhoof JA et al. Clin Pediatr. 2003;42:483-495. 2. Birch EE et al. Pediatr Res. 1998;44:201-209. 3. Birch EE et al. Dev Med Child Neurol. 2000;42:174-181. 4. Birch EE et al. Am J Clin Nutr.
2002;75:570-580. 5. Hoffman DR et al. J Pediatr. 2003;142:669-677. 6. Hoffman DR et al. FASEB J. 2003;17:A727-A728. Abstract 445.1. 7. Hoffman DR et al. J Pediatr Gastroenterol Nutr. 2000;31:540-553.
8. Birch EE et al. Am J Clin Nutr. 2005;81:871-879. 9. Morale SE et al. Early Hum Dev. 2005;81:197-203.
LIPIL promotes development and health
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