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Milk Protein–Based Infant
http://www.tandfonline.com/loi/uacn20 ​

Formula Containing Rice Starch and Low Lactose

Reduces Common Regurgitation in Healthy Term
Infants: A Randomized, Blinded, and Prospective
Trial J​ ohn B. Lasekan PhD a​ ​, Hawley K. Linke PhD a​ ​, Jeffery S. Oliver MS a​ ​, Jane D.
Carver PhD MPH b​ ​, Mark M. Blatter MD c​ e ​, Matthew J. Kuchan PhD a​ ​, Jenna M. Cramer

PhD a​ ​& Paul F. Pollack MD d​ a​ ​Pediatric Nutrition R&D, Abbott Nutrition, Abbott Laboratories

, Columbus , Ohio ​b ​Department of Pediatrics , University of South Florida College of

Medicine , Tampa , Florida

​ ​c ​Pittsburgh Pediatric Research, Inc. , Pittsburgh , Pennsylvania d​

Health Grades , Columbus , Ohio e​ ​Pediatric Alliance , Pittsburg , Pennsylvania Published

​
online: 14 Apr 2014.

To cite this article: ​John B. Lasekan PhD , Hawley K. Linke PhD , Jeffery S. Oliver MS , Jane D. Carver PhD MPH , Mark M.
Blatter MD , Matthew J. Kuchan PhD , Jenna M. Cramer PhD & Paul F. Pollack MD (2014) Milk Protein–Based Infant Formula
Containing Rice Starch and Low Lactose Reduces Common Regurgitation in Healthy Term Infants: A Randomized, Blinded,
and Prospective Trial, Journal of the American College of Nutrition, 33:2, 136-146, DOI: ​10.1080/07315724.2013.828578

To link to this article: ​http://dx.doi.org/10.1080/07315724.2013.828578

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Original
Research

Milk Protein–Based Infant Formula Containing Rice Starch and

Low Lactose Reduces Common Regurgitation in Healthy Term
Infants: A Randomized, Blinded, and Prospective Trial

John B. Lasekan, PhD, Hawley K. Linke, PhD, Jeffery S. Oliver, MS, Jane D. Carver, PhD, MPH, Mark M. Blatter,
MD, Matthew J. Kuchan, PhD, Jenna M. Cramer, PhD, Paul F. Pollack, MD

Pediatric Nutrition R&D, Abbott Nutrition, Abbott Laboratories, Columbus, Ohio (J.B.L., H.K.L., J.S.O., M.J.K., J.M.C.);
Department of Pediatrics, University of South Florida College of Medicine, Tampa, Florida (J.D.C.); Pittsburgh Pediatric
Research, Inc., Pittsburgh, Pennsylvania (M.M.B.); Health Grades, Columbus, Ohio (P.F.P.)

Key words: rice starch, low lactose, growth, gastrointestinal tolerance, regurgitation, spit-up, reflux, term infants

Objective: ​Spit-up (regurgitation) reduction with prethickened milk protein–based infant formulas containing rice starch has
been clinically demonstrated in infants with heavy spit-ups but not in otherwise healthy normal infants with
common spit-ups. The objective of this study was to evaluate growth, gastrointestinal tolerance, and efficacy to
reduce common spit-up in normal, healthy term infants fed an investigational rice starch prethickened
lactose-free milk protein–based infant formula.
Methods: ​This double-blind, randomized, parallel study evaluated the investigational rice starch prethickened lactose-free
(low lactose ​< 1​ 00 mg/L) milk protein–based infant formula compared to a standard, commercially available,
iso-nutrient, lactose-containing (100% of carbohydrate) milk-based infant formula (control) for growth and
gastrointestinal tolerance in healthy term infants (​n ​= ​132/group) fed from 14 ​± ​3 days to 112 days of age. Data
were classified and analyzed as evaluable (EV; subjects completing study per protocol) or intent-to-treat data
(ITT; all subjects with available data).
Results: ​Growth as indicated by weight gain (primary variable) and formula intake were not significantly different (​p ​> ​0.05)
between feeding groups (EV or ITT). Though both formulas were well tolerated, spit-up frequency was
significantly lower (​p ​< 0​ .05) in the rice versus control group by 53% at 28 days of age, 54% at 56 days, 48% at
84 days, and 32% at 112 days (EV). Importantly, infants in the rice group were 1.6 to 1.8 times more likely to
report zero spit-up than infants in the control group. The rice group also had higher percentages of soft and
yellow stools.
Conclusions: ​The rice starch prethickened lactose-free milk protein–based formula (rice) supported normal growth and safe
use as the sole source of feeding for normal infants over the first 4 months of life. The rice formula was
efficacious in providing a clinically relevant reduction of spit-up frequency in otherwise healthy term infants.
involuntary movement (reflux) of stomach contents into the
esophagus and spilling out of the mouth [1–4]. Visible regur-
gitation is a common occurrence in healthy infants early in
INTRODUCTIO
life; however, it is relatively benign and usually self-resolving
N by 12 to 14 months of age [3,5–7]. It is distinct from vomit-
ing, which is forcible ejection of gastric contents out the
Common infant regurgitation (alternately referred to as mouth
spit- up, spilling, posseting, wet burps, etc.) is an effortless and
 Address correspondence to: John Lasekan, PhD, Pediatric Nutrition R&D, RP32, Abbott Nutrition, 3300 Stelzer Road, Columbus, OH 43219. E-mail: john.lasekan
@abbott.com Mark M. Blatter is currently at Pediatric Alliance, Pittsburg, Pennsylvania. ​Abbreviations: ​AA ​= ​arachidonic acid, ANOVA ​= ​analysis of variance,
CONTROL ​= ​standard milk protein–based control study formula, DHA ​= ​docosahexaenoic acid, EV ​= ​evaluable subjects, GERD ​= ​gastroesophageal reflux disease, GI ​=
gastrointestinal, HC ​= ​Head circumference, IRB ​= ​institutional review board, ITT ​= ​intent-to-treat (all available data), LES ​= ​lower esophageal sphincter, MRSC ​= ​mean
rank stool consistency, PPI ​= ​proton pump inhibitor, RICE ​= ​investigational milk protein–based study formula prethickened with rice starch, SAE ​= ​serious adverse event.
Journal of the American College of Nutrition, ​Vol. 33, No. 2, 136–146 (2014) C​ ​
Published by Taylor & Francis Group, LLC
136
[8,9]. Gastroesophageal reflux disease (GERD) is diagnosed in
infants when reflux events result in complications including
se- vere symptoms such as erosion of gastroesophageal
junctions, inflammation, esophagitis, blood loss, strictures,
apnea, nutri- ent deficit, reduced growth, and failure to thrive
[1,9]. A recent clinical practice guideline published in 2009,
however, defined GERD more vaguely as reflux that “causes
troublesome symp- toms and/or complications” [3; p. 449]. In
clinical practice, many infants with common spit-up are often
treated, perhaps inappro- priately, with pharmaceuticals
designed for the more serious GERD [3,10].
Among parents of young infants, spit-up is the leading
gas- trointestinal tolerance concern [11,12]. The reported
prevalence of common regurgitation in infants 6 months old
and younger varies substantially depending on geographic,
societal, and eth- nic factors; parental norms; and the
definitions applied and mechanisms of reporting. Based on the
literature, some pop- ulations report a daily prevalence in over
80% of infants dur- ing the first month, declining thereafter.
Other populations may eventually reach that substantial
prevalence level but not until 3 to 4 months of age. There are
also infant populations that never exceed a prevalence of about
40% but sustain that level through the sixth or seventh month
of life. Regardless of early life prevalence data, most reports
agree that diminution in preva- lence begins around 6 to 8
months and resolves around the end of the first year [13]. Most
pediatricians consider common spit-up as part of normal
development and likely to be associated with gastric
immaturity [14,15]. In particular, immaturity of the lower
esophageal sphincter (LES) is presumed paramount for excess
reflux, with small gastric capacity volume and the infant short
esophagus contributing to the visible appearance of
regurgitants [9,14–16].
Notwithstanding the benign connotation of uncomplicated
spit-up, its frequency can be a nuisance and a source of frus-
tration and anxiety for caregivers and produces discomfort for
American College of Nutrition
infantsInfant
[9,17]. Parents Reduces
Formula of infantsSpit-Up
from birth to 6 months fre-
in Healthy
quently seek
Infants a medical remedy (approximately 70% consider
spit-up a problem for their child) and 20% of parents who do
not seek medical attention for spit-up still regard their infant’s
regurgitation as a problem [5,17].
In addition to assurances by health care professionals, a
va- riety of remedies are employed to manage spit-up,
including proper positioning during and after feeding, frequent
burping, feeding small volumes or thickened formulas, using
antireflux medications, and surgical intervention in more
persistent cases [18,19]. Parents in many cultures have
traditionally managed regurgitation by adding starch or cereal
(commonly rice ce- real) to standard infant formulas to induce
thickening. Discon- certingly, these additions tend to produce
inadequate formula mixing, coarse formula texture, and
clogging of the feeding nip- ple orifice. More important,
adding starch or cereal to standard formulas perturbs the
otherwise optimized balance of nutrient content.
Specialized commercial infant formulas, augmented with
rice starch and appropriately modified to provide balanced nu-
trition, offer a preferable alternative for ameliorating regurgi-
tation concerns [20]. One such milk protein–based infant for-
mula prethickened with rice starch has been reported to lower
the frequency of spit-up after 5 weeks of feeding among in-
fants selected for substantial daily reflux at study entry [20].
Heretofore, it was unknown whether such thickened formula
would be effective in significantly reducing spit-up frequency
experienced more commonly by normal infants. Our previous
infant formula studies have indicated that reduction or elimi-
nation of lactose content also lowers spit-up in infants fed a
milk protein–based formula [21] or a rice protein–based for-
mula [22]. Replacing lactose with sucrose in a soy
protein–based infant formula also reduced the incidence of
vomiting [23]. Accordingly, an investigational, rice
starch–thickened, low- lactose, milk protein–based infant
formula was developed and assessed for growth parameters
and regurgitation reduction ef- ficacy in normal term infants. It
was compared to a standard commercially available milk
protein–based infant formula with lactose as the sole source of
carbohydrate and containing no rice starch.

MATERIALS AND
METHODS
Study Design, Subjects, and
Ethics
The study was a controlled, double-blind, randomized,
mul- ticenter 16-week growth and gastrointestinal tolerance
feeding trial in healthy, term infants. It was approved by the
institu- tional review boards or ethics committees at the 6
participating study centers. The study was conducted in
accordance with the Declaration of Helsinki. Signed informed
consent was obtained from parents before randomization into
study groups. The study centers were located in Chapel Hill,
North Carolina; Dubuque, Iowa; Pittsburgh, Pennsylvania; Salt
Lake City, Utah; Tampa, Florida; and West Palm Beach,
Florida. Enrolled infants were healthy, singleton, full-term
(gestational age of 37–42 weeks) and appropriate for
gestational age at birth, with at least 2500 g birth weight. They
were enrolled at 14 ​± ​3 days of age at study entry without
regard to history of common spit-up or other normal infant
gastrointestinal tolerance parameters. Par- ents agreed that the
infant would receive the assigned study formulas as the sole
source of nutrition for the duration of the study.
Study
Feedings
Both study formulas were ready-to-feed liquids provided
by Abbott Nutrition (Columbus, OH). The control formula was
standard commercially available Similac with Iron (control), a
milk protein–based formula with lactose as the sole (100%)

JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION 137

Infant Formula Reduces Spit-Up in Healthy Infants
carbohydrate source. The investigational formula (rice) was an iso-nutritional, milk protein–based formula, prethickened with rice
starch and containing a low level of lactose (​<​100 mg/L) such that it could be referred to as lactose free. The carbohy- drate blend
was corn syrup (50% of total carbohydrate), rice starch (30%), and sucrose (20%). The oil blend for both formu- las consisted of
40% high oleic safflower, 30% coconut, and 30% soy oils, plus supplemental docosahexaenoic acid, arachidonic acid, and
nucleotides. The energy density of both formulas was 676 kcal (2826 kJ)/L. Study formulas were provided in 32 fl oz (947 mL)
cans clinically labeled to protect the identity of the study formulas. All study formulas met or exceeded the levels of nutrients
recommended by the Committee on Nutrition of the American Academy of Pediatrics [24] and the requirements by the Infant
Formula Act of 1980 and its subsequent amendments [25]. ​In vitro t​ hickening experiments demonstrated that when treated with
acid (HCl) the viscosity of the rice formula, but not the control formula, increased (Fig. 1). Viscosity was maximal when the pH
approached 4.0, consistent with the estimated pH of stomach contents measured during gastroesophageal reflux in term infants
[26].
Feeding and Data Collection
Randomization was stratified by gender. Parents were pro- vided with sufficient formula to feed their infant until the next study
visit. They kept records of formula intake (volume and fre- quency); spit-up or vomit frequency; and stool frequency, con-
sistency, and color for each day between enrollment at 14 days of age until 28 days of age (1 month) and for 3 full days
immediately prior to the scheduled study visits at 56 days (2 months), 84 days
50 ​
0​(3
months), and 112 days (4 months) of age. Previous studies by our group indicated that the vast majority of spit-up events
recorded represent very small volumes of gastric contents (data not shown), though others have noted that spit-up/emesis volume
is grossly overestimated by parents [27]. Consequently, parents were not asked to estimate and report regurgitated amounts. Stool
pattern and formula satisfaction questionnaires were also completed at 28, 56, 84, and 112 days of age. Growth mea- surements
(weight, length, head circumference) were obtained at enrollment and at 14-, 28-, 56-, 84-, and 112-day visits using standard
methods [28,29]. Infants were weighed twice in the nude to the nearest 1 g using Pro Plus Pediatric electronic scales
(Health-O-Meter Inc., Bridgeview, IL) calibrated daily. Length was measured twice to the nearest 0.1 cm with the infant in a
recumbent position using O’Leary length boards (Ellard In- struments Ltd, Seattle, WA). Head circumference was measured
around the occipital frontal area to the nearest 0.1 cm using INSER-TAPE (Abbott Nutrition).
Statistical Methods
The study’s primary variable was the average daily weight gain throughout the feeding period. Statistical tests of hypothe- ses
were 2-tailed at a 5% level of significance. Analyses were performed and reported on both an intent-to-treat (ITT) basis and
evaluable subgroup (EV) basis. The ITT analyses included all available data on all randomized subjects, whereas the EV anal-
yses included all data from only those subjects who completed the study according to protocol. The EV subjects met all inclu-
sion and exclusion criteria, completed all study requirements, did not consume any other formula or food during the study period,
and were available for both entry and exit anthropome-
500
try. Categorical variables such as gender, ethnicity, gestational ​450
age and appropriateness, and demographics were analyzed by ​400 350 300
Cochran-Mantel-Haenszel tests controlling for multiple study centers. Continuous variables were analyzed using analysis of
250
variance (ANOVA) controlling for gender and study centers. An-
200
thropometric variables were analyzed using repeated-measures ​150
ANOVA controlling for gender and study centers. Data that were ​100
not normal were transformed using arcsine of the square root. ​Post hoc ​analyses were conducted on some selected variables as
6.7 5 4 3 2
needed. All analyses were done using procedures available in
pH
SAS [30].
Fig. 1. ​pH thickening profile. comparative pH viscosity curves of study formulas. Control (squares with thin lined curve) ​= ​standard milk
protein–based control study formula, rice (triangles with large lined
RESULTS ​curve) ​= ​investigational milk protein–based study formula prethickened with rice starch. Formula viscosity was measured using
a Brookfield
Entry Data and Study Subject Disposition ​DVII ​+ ​viscometer (Brookfield Engineering Laboratories, Middleboro, MA). Formula
viscosity was assessed at pH 6.7 to mimic the “as-fed”
Two hundred sixty-four infants were randomized and
state and at decreasing pH levels following titration with HCl to de-
enrolled, 132 infants per feeding group. There were no sig- ​termine the thickening profile under acidic conditions similar to those
​ ​0.05) between the 2 groups for study ​reported for the esophagus and stomach.
nificant differences (​p >
entry variables, including gender, ethnicity, weight, length, and
138 VOL. 33, NO. 2
Infant Formula Reduces Spit-Up in Healthy Infants
head circumference at birth; age, weight, length, and head circumference at study entry; and premature exit frequency and reason
for exit (Table 1). The subjects in this study were diverse (86% Caucasian; 14% African American, Hispanic, or other), derived
from enrollment sites geographically distributed through Western, Midwestern, Eastern, and Southern United States, and roughly
mirrored the country-wide demographics. One hundred ninety-five subjects (74%) completed the study protocol and 69 (26%)
exited prematurely. Tolerance-related reasons for pre- mature study exit were not significantly different (​p >​ 0​ .05) between the
study groups. They included excessive vomit (4 rice, 7 control), excessive fussiness (16 rice, 10 control), exces- sive gas (13 rice,
13 control), hard stools (9 rice, 6 control), and watery stools (7 rice, 2 control). One hundred forty-four subjects (73 rice, 71
control) completed the study according to protocol, met all inclusion and exclusion criteria, and consumed only the assigned study
formula; consequently, they were included in the
Table 1. ​Demographic and Study Entry Information of Subjects
Rice Control ​p ​Value
Gender, female/male, ​n ​61/71 61/71 ns Ethnicity, ​n ​ns Caucasian 109 117 African American 11 11 Hispanic 9 2 Other 3 2 Premature study exit, ​n
34 35 ns Premature study exit
reasons, ​n ​(%)
Tolerance 22 (65) 20 (57) Failed to return 1 (3) 3 (9) Removed by
investigator
​ ​0.05) in occurrence of serious adverse events between the
EV subgroup. There were no statistically significant differences (​p >
formula groups during this study. Nine infants (6.8%) in the con- trol feeding group and 8 infants (6.1%) in the rice group
reported having at least one serious adverse event, none of which were classified by the study investigators as related to study
formula. No subjects died during the study.

Growth, ​Tolerance Formula

​ Intake and Gastrointestinal ​Anthropometric Measures and Formula Intake
The average daily weight gain, the primary study variable, was not significantly different between the formula groups in either the
ITT or EV analyses (Table 2). No other growth mea- sures (weight, length, length gain, and head circumference) were different,
nor was the volume of study formula intake between rice and control groups in either the ITT or EV assessments.
Frequency of Regurgitation (Spit-Up)
Table 3 presents spit-up/vomit as the percentage of feedings with which any such events were associated. Parental report of true
vomit was exceedingly rare throughout the study and was therefore not treated as a separate variable. The rice-fed group
experienced significantly lower frequency of spit-up compared with the control group for the EV subjects at each age assessed.
Mitigation by the investigational formula relative to the con- trol formula was greater among infants at younger ages and lessened
as they matured. At 1, 2, 3, and 4 months of age, ​1 (3) 1 (3)
the reduction in feedings with spit-up was 53%, 54%, 48%,
Illness 0 (0) 2 (6) Other 10 (29) 9 (26) Birth weight, g (​n​) 3409 ​± ​38
and 32%, respectively, among the EV subgroup. The ITT in- fant group reductions were similar (43%, 39%, 30%, and 23%),
3442 ​± ​36

though, as expected, less robust in absolute value and statistical ​(131)​1 ​(131)
significance.
Because some parents may also be concerned about the ex- perience of any regurgitation by their infant, the proportion of subjects
with zero spit-up as assessed by the 3-day diary records is presented in Fig. 2. Infants consuming the rice formula were
significantly more likely (1.6 to 1.8 times more likely) to be free of spit-up at the monthly time points.
Stool Characteristics
Several stool-related variables evaluated at 28 days of age are summarized in Table 4. The control group had significantly lower
mean rank stool consistency (less firm stools), signifi- cantly higher percentage of watery and loose/mushy stools, and lower
percentage of soft and formed stools compared to the rice group. Hard stools were infrequent in both groups: 4.2% in the rice
group and less than 1% in the control group. The predomi- nant stool color observed in the rice group was yellow and that in the
control group was green. Stool frequency was similar
JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION 139
ns
Birth length, cm (​n)​ 50.8 ​± ​0.2
(131)
51.2 ​± ​0.2 (131)
ns
Birth head
circumference, cm (​n)​
34.7 ​± ​0.1 (127)
34.5 ​± ​0.1 (126)
ns
Age at study entry,
days (​n)​
13.4 ​± ​0.2 (132)
13.4 ​± ​0.2 (132)
ns
Weight at study entry,
g
3669 ​± ​39 (132)
3668 ​± ​36 (131)
ns
Length at study entry,
cm
52.1 ​± ​0.2 (132)
52.2 ​± ​0.2 (131)
ns
Head circumference
at study entry, cm
36.1 ​± ​0.1 (132)
36.0 ​± ​0.1 (131)
ns
Evaluable group; completed protocol and assigned formula feeding, ​n
73 71 nt
Control ​= ​standard milk protein–based control study formula, rice ​= ​investiga- tional milk protein–based study formula prethickened with rice starch, ns ​= ​not
 significant (​p ​> ​0.05), nt ​= ​not tested. ​1​Values are mean ​± ​standard error of the mean (​n​).

Infant Formula Reduces Spit-Up in Healthy

Infants

Table 2. ​Study Formula Intake and Anthropometric Growth Measures in

Infants​1

Evaluable Group Intent-to-Treat Group

Rice Control Rice Control

Study formula intake (kcal/kg/day) 28 days 119.6 ​± 2​ .6 (73) 117.7 ​± ​2.1 (71) 118.5 ​± ​2.2 (111) 115.4 ​± ​1.6 (112) 56 days 114.6 ​± ​3.0 (72) 116.0 ​±
2.8 (71) 114.7 ​± ​2.7 (100) 116.7 ​± ​2.8 (98) 84 days 104.1 ​± ​2.6 (70) 106.9 ​± ​2.6 (70) 105.5 ​± ​2.6 (97) 107.2 ​± 2​ .5 (96) 112 days 99.9 ​± ​2.5 (72)
101.2 ​± ​2.4 (71) 99.9 ​± ​2.4 (96) 101.0 ​± ​2.2 (96) Weight gain (g/day) 30.6 ​± ​0.8 (73) 30.5 ​± ​0.8 (71) 30.6 ​± ​0.6 (116) 30.0 ​± ​0.6 (116) Weight: 28
days (g) 4392 ​± ​55 (73) 4330 ​± ​53 (71) 4373 ​± ​48 (115) 4306 ​± ​42 (113) 56 days (g) 5381 ​± ​68 (73) 5337 ​± ​66 (71) 5343 ± ​ ​61 (104) 5271 ​± ​54
(101) 84 days (g) 6119 ​± ​74 (72) 6059 ​± ​79 (71) 6115 ​± ​67 (99) 6020 ​± ​65 (97) 112 days (g) 6758 ​± ​88 (73) 6734 ​± 9​ 7 (71) 6773 ​± ​70 (116) 6718 ​±
75 (116) Length gain (cm/day) 1.07 ​± ​0.03 (73) 1.09 ​± 0​ .02 (71) 1.07 ​± ​0.02 (116) 1.08 ​± ​0.01 (116) Length: 28 days (cm) 54.2 ​± ​0.2 (73) 54.5 ​± ​0.2
(71) 54.3 ​± ​0.2 (115) 54.5 ​± ​0.2 (113) 56 days (cm) 57.8 ​± ​0.2 (73) 57.8 ​± ​0.2 (71) 57.7 ​± ​0.2 (104) 57.6 ​± ​0.2 (101) 84 days (cm) 60.5 ​± ​0.2 (72)
60.3 ​± ​0.2 (71) 60.5 ​± ​0.2 (99) 60.2 ​± ​0.2 (97) 112 days (cm) 63.0 ​± ​0.2 (73) 63.1 ​± ​0.3 (71) 63.0 ​± ​0.2 (116) 63.2 ​± ​0.2 (116) Head circumference
28 days (cm) 37.6 ​± ​0.1 (73) 37.3 ​± ​0.1 (71) 37.6 ​± ​0.1 (115) 37.4 ​± ​0.1 (113) 56 days (cm) 39.4 ​± ​0.1 (73) 39.1 ​± ​0.1 (71) 39.4 ​± ​0.1 (104) 39.1 ​±
0.1 (101) 84 days (cm) 40.7 ​± ​0.1 (72) 40.6 ​± ​0.2 (71) 40.7 ​± ​0.1 (99) 40.5 ​± ​0.1 (97) 112 days (cm) 41.8 ​± 0​ .1 (73) 41.6 ​± ​0.1 (71) 41.9 ​± ​0.1 (116)
41.7 ​± ​0.1 (116)

Control ​= ​standard milk protein–based control study formula; rice ​= ​investigational milk protein–based study formula prethickened with rice starch.

1​
Values are mean ​± ​standard error of the mean (​n​). No statistically significant differences (​p >
​ ​0.05).
spit-up, less burping, less vomiting, fewer watery stools or bad
smelling stools and were more likely to perceive that their
between the feeding groups. Outcomes were similar for the
child’s hunger was satisfied and were more likely to agree that
ITT and EV evaluations.
the stool consistency was “just right.” Conversely, the parents
of control- fed subjects were statistically less likely to identify
stools that they would cite as “too hard.” More than half of the
Parental Responses to Tolerance and Formula parents in each group found the formula consistency to be just
right (52% rice and 73% control). Most of the remaining
​
Satisfac- tion Questionnaires parents of control- fed subjects perceived that formula was
“somewhat/very thin” and most of the remaining parents of the
Tolerance and formula satisfaction questionnaires
rice-fed subjects viewed the formula as “somewhat/very
completed by parents at 28 days of age revealed many
thick.” Most of the parents (94% rice and 96% control) felt
significant differ- ences between the study groups. Those
that their baby did well or very well on the formula provided.
showing statistically significant differences (​p <​ 0​ .05) are
presented in Table 5. The parents of rice-fed infants
subjectively perceived that their child was doing better in Table 3. ​Frequency of Spit-Up/Vomit (Percentage of
several tolerance areas than the parents of control-fed infants. Feedings)​1
Parents of rice-fed subjects perceived less

Rice Control Mean Difference (Control ​− ​Rice) Reduction (%)​2 ​p ​Value​3

Evaluable group (Age)

28 days 9.1 ​± ​1.1 (73) 19.3 ​± ​2.5 (71) 10.2 53 ​<​0.0005 56 days 8.5 ​± ​1.8 (72) 18.6 ​± ​2.8 (71) 10.1 54 0.001 84 days 11.5 ​± ​2.5 (70) 22.1 ​± ​3.1 (70)
10.6 48 0.003 112 days 13.3 ​± ​2.2 (72) 19.7 ​± ​2.7 (71) 6.4 32 0.046 Intent-to-treat group (Age)
28 days 11.0 ​± ​1.1 (119) 19.2 ​± ​1.9 (120) 8.2 43 ​<​0.0005 56 days 10.9 ​± ​1.8 (100) 17.8 ​± ​2.3 (99) 6.9 39 0.009 84 days 13.6 ​± ​2.3 (97) 19.3 ​± ​2.5
(96) 5.7 30 0.051 112 days 14.8 ​± ​2.0 (96) 19.1 ​± ​2.3 (97) 4.3 23 0.100

Control ​= ​standard milk protein–based control study formula, rice ​= ​investigational milk protein–based study formula prethickened with rice starch.

1​
Values are mean ​± ​standard error of the mean (​n​). ​2​Reduction (%) ​= ​100​∗​(Control –ice)/Control. 3​​ The ​p v​ alues are from analysis of variance of the
arcsine square root–transformed proportion of feedings with spit-up/vomit.

140 VOL. 33, NO. 2

at 70
​
establishing equivalent gastrointestinal parameters in both groups at enrollment, ​post hoc ​statistical analyses were per- 60​
​ formed
from daily diaries created during the initial days of the study feedings. Enrollment, feeding, and evaluation be-
n oitatigrugero rezg nitropers tnafni​
% ​gan at age 14 days, with parents instructed to initiate study formula feeding and diary record
keeping at the first oppor- tunity. Daily information is graphically presented in Fig. 3. Because diary days represented
midnight-to-midnight 24-hour periods, the first recording for most infants covered “partial day” feeding, spit-up, and stool
information (labeled “day 15”). The first full day data of collection for most enrollees was day 16. The frequency of stools for
both groups was not dif- ferent and approximately once per day at (the partial) day 0​ ​15, though subsequent days revealed stool
frequency of nearly twice per day (Fig. 3a). The mean rank stool consistency in both groups was virtually identical at day 15,
diverged some- what (trend only, not statistically different) at day 16, and achieved a significant and sustained separation over
days 17, 18, and 19 (Fig. 3b). Similarly, stool color was predominantly green for both groups initially at day 15 but shifted on sub-
sequent days to yellow in the rice group, while remaining green in the control group (data not shown). Spit-up frequency was not
statistically different at day 15. However, at day 16, spit-up frequency for the rice group had already fallen to a
Table 4. ​Stool Tolerance and Characteristics at 28 Days of Age​1
Evaluable group Rice Control ​p V ​ alue
Stool frequency (no. of stools/day) 2.0 ​± ​0.1 (73) 1.9 ​± ​0.1 (71) ns Mean rank stool consistency 2.82 ​± ​0.06 (73) 2.32 ​± ​0.06 (71) < ​ 0​ .0001 Stool
consistency (%)
Watery 2.3 ​± ​0.6 (73) 11.8 ​± ​2.3 (71) ​<​0.0001 Loose/mushy 33.8 ​± ​3.5 (73) 51.6 ​± ​3.6 (71) 0.0004 Soft 48.1 ​± ​3.7 (73) 29.8 ​± ​3.5 (71) 0.0002
Formed 14.0 ​± ​2.1 (73) 6.3 ​± ​1.9 (71) 0.0013 Hard 1.7 ​± 0​ .7 (73) 0.5 ​± ​0.4 (71) 0.0884 Stool color (%)
Yellow 67.6 ​± ​4.1 (73) 25.4 ​± ​3.8 (71) ​<​0.0001 Green 15.7 ​± ​3.3 (73) 35.0 ​± ​4.1 (71) ​<0​ .0001 Brown 16.7 ​± ​3.3 (73) 38.3 ​± ​4.5 (71) 0.0005 Black
0.0 ​± ​0.0 (73) 1.3 ​± ​0.6 (71) 0.0158 Intent-to-treat group
Stool frequency (no. of stools/day) 2.0 ​± ​0.1 (119) 1.9 ​± ​0.1 (120) ns Mean rank stool consistency 2.80 ​± ​0.06 (118) 2.25 ​± ​0.05 (120) ​<​0.0001
Stool consistency (%)
Watery 4.2 ​± ​0.9 (118) 15.5 ​± ​2.2 (120) ​<​0.0001 Loose/mushy 37.0 ​± ​2.8 (118) 51.4 ​± ​2.9 (120) 0.0010 Soft 39.6 ​± ​2.8 (118) 27.0 ​± ​2.7 (120)
0.0003 Formed 15.1 ​± ​1.8 (118) 5.4 ​± ​1.3 (120) ​<0​ .0001 Hard 4.2 ​± ​1.1 (118) 0.7 ± ​ ​0.3 (120) 0.0022 Stool color (%)
Yellow 66.8 ​± ​3.3 (118) 27.9 ​± ​3.2 (120) ​<​0.0001 Green 16.1 ​± ​2.5 (118) 37.3 ​± ​3.3 (120) ​<0​ .0001 Brown 17.0 ​± ​2.6 (118) 31.4 ​± ​3.3 (120)
0.0020 Black 0.1 ​± ​0.1 (118) 3.5 ​± ​1.1 (120) 0.0007
Control ​= ​standard milk protein–based control study formula, rice ​= ​investigational milk protein–based study formula prethickened with rice starch, ns ​= ​not

significant (​p ​> ​0.05). ​1​Values are mean ​± ​standard error of the mean (​n​). The statistical analyses of stool consistency and stool color were performed on the arcsine

square root of the proportion.

JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION 141
50​40​30​20​10​
28 (p=0.0502)
~Age
RICE
CONTROL
Fig. 2. ​Percentage (%) of infants experiencing zero regurgitation events by age (days). Control (pattern bars) ​= ​standard milk protein–based
control study formula, rice (dark filled bars) ​= ​investigational milk protein–based study formula prethickened with rice starch.
Equivalence of Randomized Study Groups
To assess the physiologic homogeneity among our enrolled populations and to confirm that randomization was successful
56 (p=0.0014)
84 (p=0.0060)
112 (p=0.0276)
Infant Formula Reduces Spit-Up in Healthy Infants
Infant Formula Reduces Spit-Up in Healthy Infants
Table 5. ​Parental Responses to Formula Feeding, Tolerance, and Acceptability Questionnaires at 28 Days of Age Showing
Significant Differences between Study Groups
Outcome questions
​ ​72–73)
Rice (% sub- jects; ​n =
​ hosen
Control (% sub- jects; ​n C
= ​Responses
70–71)

​
pValue ​Intake-related questions Spit-up with
feeding?
Never/rarely 75 48 0.001
Frequent burping? Never/rarely 56 34 0.011 Vomited after feeding?
Never/rarely 96 89 0.007
Hunger satisfied?
Always/frequently
97 89 0.013
Stool-related
questions Watery stools? Never/rarely 82 42 0.001 Stools too hard? Never/rarely 88 99 0.008 Stool consistency
just right? Always/frequently
78 56 0.005
Stool odor very bad? Never/rarely 53 29 0.002 Formula satisfaction
questions Formula
consistency?
Just right Somewhat/very thin Somewhat/very thick

52​444

73​207
0.001
Formula
consistency?
Just right 0.001
Somewhat/very
thin 52 73 Somewhat/very 4 20
thick 44 7 How baby did on
formula?
Age 19 days
Very well Well

75​19

51​45
0.026
Fig. 3. ​Daily diary reports for markers of gastrointestinal tolerance fol- lowing the introduction of study formula on day 14. Control (squares
Control ​= ​standard milk protein–based control study formula, rice ​= ​investiga- tional milk protein–based study formula prethickened with rice starch.
with light color) ​= ​standard milk protein–based control study formula; rice (triangles with dark color) ​= ​investigational milk protein–based study
formula prethickened with rice starch: (a) stool frequency (number of stools/day), no significant differences at any of the 5 day time points (​p ​>
0.05); (b) mean rank stool consistency, significant differences (​p
statistically significant lower level than that for the control group (Fig. 3c).
4​ 3​ 2​ 1​
3.5​ 2.5​ 1.5​ 0.5​0
Age 15
Age 16
Age 17
Age 18
Age 19 days
days
days
days
days ​a​3.5
3

2
2.5​
1.5​1
Age 15
Age 16
Age 17
Age 18 days
days
days
days

bc
< 0​ .01) at days 17, 18, and 19; and (c) frequency of spit-up/vomit (% associated with feeding) in the study groups, significant differences at days
16 (​p ​= ​0.01), 17 (​p <
​ 0​ .01), 18 (​p ​= ​0.01), and 19 (​p =
​ ​0.03).
Natural Evolution of Regurgitation Patterns
Although the feeding groups were predictably similar at en-
control group was substantially worse than those for the upper rollment, their divergent evolution over time in regards to the
quartile of the rice group. percent of feedings with regurgitation is reported in Table 6 (ITT). Though each feeding group included
some infants who never spit-up (0%) and some who spit-up with virtually every
DISCUSSION ​feeding (100%), the rice formula appeared to shift the regurgita- tion equilibrium lower across the entire
rice-fed population. This
The primary study goal was to demonstrate the ability of the trend can be observed in the table where, as a group, the rice-fed
investigational formula to support normal growth for healthy population not only shows sustained reduction over time in mean
term infants during the first 4 months of feeding. The study percentage of feeds with spit-up, but unlike the control subjects,
was further designed to verify that infants (1) tolerated the by day 20, the median level of spit-up in the rice subjects has
new formula well, (2) experienced no significant serious ad- dropped permanently to zero. Also clear is that the spit-up ex-
verse events due to its exclusive consumption, and (3) derived perience for the most afflicted quartile (75th percentile) of the
the potential physiologic benefit from its consumption (vis-`a-vis
142 VOL. 33, NO. 2
Age 19 days
40 353025​201510​5​
0Age 15 days
Age 16 days
Age 17 days
Age 18 days
Infant Formula Reduces Spit-Up in Healthy Infants
Table 6. ​Distribution of Infant Populations Based on Percentage of Feedings Associated with Any Regurgitation Event as
Reported in Daily Diaries
Mean% Feeds
Median% Feeds
w/Spit-Up 25th Percentile​∗ ​
Maximum ​
w/Spit-Up 75th Percentile​∗ ​ Reported​∗∗
Day Control Rice Control Rice Control Rice Control Rice Control Rice
15–16 28.9 13.6 0 0 14.9 9.4 60.0 24.3 100
68.8 17–19 19.1 11.8 0 0 12.5 3.3 29.9 18.9 100
66.7 20–22 16.8 9.7 0 0 10.9 0 25.3 15.1 100
77.5 23–25 16.9 8.9 0 0 4.2 0 25.6 15.5 100
69.0 26–28 18.0 9.6 0 0 12.3 0 28.0 13.2 100
91.7 53–55 18.3 10.8 0 0 5.4 0 28.9 15.9 100 100 81–83 19.7 13.7 0 0 8.9 0 33.1 18.9 100 100 109–111 19.1 15.0 0 0 12.2 0 30.0 24.5 100 100
Control ​= ​standard milk protein–based control study formula, rice ​= ​investigational milk protein–based study formula prethickened with rice starch. ​∗​Infants were

segregated into quartiles based on the percentage of feedings associated with one or more regurgitation events for each infant on the days of life indicated. ∗∗​
​ The

highest percentage of feedings with regurgitation events reported by any infant in the group on the days of life indicated.
regurgitation). The investigational formula falls into the broad category of so-called thickened, prethickened, and thickening
formulas. The composition of such formulas varies substantially in regard to protein type, oil blends, carbohydrate ingredients,
level of processing, and the type of thickening agent used. Pre- vious reports regarding some formulas in this category describe
negative attributes, including impeded formula delivery through normal formula bottle nipples, nutritional deficit due to improper
final composition [9], excessive caloric intake, and weight gain [2,31]. The comparator for the current study was a standard
commercially available infant formula with a long history of safe use and a reputation for being well tolerated. There were no
differences noted between the 2 study groups in volume or caloric intake of formulas, unlike effects observed for rice or rice
cereal–thickened formula studied in infants 2 weeks to 6 months of age, who showed increases in formula consumption and/or
 weight gain compared to standard formula [20,31]. Daily weight gain (primary study variable) was not different between the 2
study formula groups and was consistent with normative data reported by Nelson et al. [32]. Lengths and head circum- ferences
were also consistent with normative data. There were no statistically significant differences in serious adverse events and no
differences in number of infants or reasons for premature study exit. Therefore, the investigational rice starch–augmented
milk-based formula (rice) supported normal growth and safe use in healthy term infants.
Notably, many previous reports of reflux/regurgitation preva- lence or intervention have been conducted in ethnically and socially
homogenous populations [1,2,5,7,13,20,31,33–36]. Furthermore, when most formulas containing cereal, starches, gums, or other
purported thickeners have been clinically eval-
uated, subject enrollment has been restricted to infants demon- strating frequent and/or heavy spit-up patterns; subjects have been
assessed via a diverse set of regurgitation parameters; the acceptable age for enrollment has been broad, spanning several stages of
infant development; and studies have utilized small group sizes inadequate to compensate for the implicit devel- opmental
heterogeneity of the enrolled population [1,2,20,31]. This study, evaluating a large, unselected, and developmentally equivalent
population, drew subjects representing the ethnic and regional diversity of the United States. It sought to appreciate regurgitation
evolution and treatment efficacy among normal, healthy infants displaying a spectrum of regurgitation patterns, similar to the
range of infants seen daily in clinics and pediatri- cians’ offices.
Infants fed the rice formula experienced significantly fewer spit-ups following feeding than those fed the control formula. During
the study, rice-fed infants had up to 54% less regurgita- tion than control-fed (EV) group and up to 43% reduction among the ITT
group. Furthermore, rice-fed infants were significantly more likely (1.6 to 1.8 times more likely) to be spit-up free at the monthly
time points. When queried subjectively, 75% of parents of rice-fed infants compared to 51% of parents of the control-fed infants
believed that their infant did very well on the formula. These results suggest that the rice formula is a suit- able intervention for
infants experiencing normal regurgitation events.
It is proposed that gut maturation plays an important role in the etiology and subsequent resolution of reflux or spit-up [9,13,14].
Boix-Ochoa and Canals [14] demonstrated that new- born infants’ LES pressure increased with age and corresponded somewhat
to the reduction in reflux during the first 3 months of
JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION 143
Infant Formula Reduces Spit-Up in Healthy compartment in less than 2 hours, and transit of digested
Infants materials through the intesti- nal tract and appearance as fecal
matter is a variable process of generally up to 36 hours [37].
The earliest data therefore confirm that randomization
life. Though the study identified that effective LES maturation produced 2 groups of similar gut maturation/activity as well as
peaked at 5 to 7 weeks of age in their Spanish population demographic and anthropometric similarities (Table 1).
studied ca. 1976, the universality of maturation timing in other Accordingly, this study could avoid de- pendence on
infant populations has not been established. In fact, the high measuring reduction from a group baseline that might have
variabil- ity described in regurgitation reports for infants been complicated or abetted by diverse developmen- tal
worldwide, as well as familial and genetic studies of similar changes and focus instead on comparison between infants
adult disorders, suggest that comparability of study receiving different formulas as they proceed through identical
populations (age, ethnicity, social mores) must be considered growth stages. This strategy also eliminated the biased appear-
when interpreting intervention data and clinical application ance of “improvement” shown to be perceived by parents
[1,3]. when any change iin formula is introduced [38–40].
To our knowledge, this is the only regurgitation-specific Several features of the rice formula may have contributed
formula intervention study that enrolled healthy, normal term to the regurgitation benefits it provides. One feature is the
infants of similar age (14 ​± ​3 days of age) and immatu- rity incor- porated rice starch, which produces a small inherent
with demonstrably similar gastrointestinal parameters at increase in formula viscosity, slightly higher than that of a
baseline. The subjects were followed for the appearance (or standard formula. The thicker fluid offers more resistance to
lack thereof) of patterns associated with normal infant spit-up. transit from the stom- ach into the esophagus. This viscosity,
The daily feeding and tolerance diaries initiated shortly after however, is not substantial enough to prevent the rice formula
enrollment at 14 days of age demonstrated expected equiva- from passing freely through the standard feeding nipple
lence among formula-fed infants in terms of stool and spit-up orifice. The second contributing fac- tor may be that gastric
characteristics at the outset, followed by rapid divergence (Ta- acidity may cause the formula to increase in viscosity
ble 3). The distinctions between day 15/16 stool divergence (thickening), as demonstrated ​in vitro ​in Fig. 1. A similar
and day 15/16 regurgitation values divergence are consistent pH-induced viscosity shift was demonstrated ​in vitro ​for a
with the knowledge that milk feedings—the source of different milk-based formula containing rice starch [20]. A
regurgitation contents—generally exit the stomach third contributing factor is the low lactose or lactose-free
 formu- lation of the rice formula. Although lactose intolerance
per se i​ s uncommon in infants, reduction or elimination of
lactose in formula has been shown by us [21,22] and others
[23] to reduce spit-up/vomit frequency in infants.
The rice formula may be useful for feeding certain
infants not represented in this study. For example, some infant
regurgitation warrants the use of proton pump inhibitor or
antacid therapies. Because the investigational formula employs
2 mechanisms of action that are not dependent on gastric
acidity, it may be used as an adjuvant or complementary
treatment to help manage and reduce reflux in those infants
while also providing the assur- ance of a balanced nutrition.
Infants undergoing drug therapies would still need human milk
or infant formula for nutrition. It should be noted, however,
that there is some concern regard- ing overprescription and
overuse of antireflux drugs in infants [10,41,42]. A study by
Khoshoo et al. [10] indicated that of 44 infants experiencing
gastroesophageal reflux, 42 were tak- ing antireflux
medications, but only 8 (19%) showed clinically abnormal
acid reflux as measured by a pH-probe study. When in- fants
with normal pH-probe findings discontinued medication,
reflux symptoms did not worsen. The use of the rice formula
maybe a useful alternative in reducing the overprescription and
overuse of antireflux drugs.
As stated above, however, common spit-up, spilling,
regur- gitation, and wet burps cause concern among parents
even in the absence of apparent medical issues. It is frequently
the reason new parents reach out to their health care profes-
sional [11,12]. With or without physician assistance, parents
fre- quently change formulas despite the fact that reassurance,
144 VOL. 33, NO. 2
to parents with infants receiving the control formula. In ad-
dition to the reflux amelioration noted with the rice formula,
there are other gastrointestinal tolerance advantages. The
higher percentages of soft stools and yellow stools observed in
the rice group reflect stool qualities produced by human
milk–fed infants [44,45].
CONCLUSIO
N
In summary, this study demonstrated that a new
low-lactose or lactose-free milk-based infant formula with
added rice starch supports normal growth and safe use similar
to that provided by standard commercial milk-based infant
minor behavioral changes associated with feeding (including
position- ing, size of feeds, appropriate burping), and the
passage of time can eliminate most common infant
regurgitation [3,43]. When formula switching does occur,
various investigators have pointed out an overreliance on
nonstandard formulas like protein hy- drolysates and soy,
regardless of whether the switch is logically related to the
infant’s intolerance symptoms [38–40]. Whether driven by
parental demands or physician caution, unnecessary formula
switching and pharmacologic intervention can create a sense
among parents that their infant is abnormal and expose the
infant to needless risk.
In that regard, the observations made from this clinical
study support the use of the investigational low-lactose, rice
starch– augmented formula to help reduce or eliminate
regurgitation concerns for many families and their health care
providers. The new formula was associated with an increase
(1.6 to 1.8 times) in the proportion of infants who were spit-up
free and substantially reduced the frequency of spit-up by 32%
to 54% for individual afflicted infants. These substantial and
clinically significant im- provements compare favorably
against the results obtained from a recent meta-analysis of
most antiregurgitation infant formu- las. Horvath et al.
concluded that despite scoring statistically significant
differences, the reduction in spit-up amounted to ap-
proximately only 0.9 episodes per day per infant in the treat-
ment groups [1]. In addition, subjective parent questionnaires
in our study provided supporting evidence that parents with in-
fants receiving the rice formula perceived less spit-up and less
burping and believed that their infant did very well compared
formula. In addi-
Infant tion, the
Formula rice formula
Reduces significantly
Spit-Up in Healthy lowers the
frequency of
Infants regurgitation/spit-up associated with feeding
compared to the control formula. We conclude that the rice
formula can be a sim- ple, safe, noninvasive, drug-free,
first-step nutritional solution for managing or ameliorating
uncomplicated spit-up or regurgi- tation.
ACKNOWLEDGMENT
S
The authors thank the infants, parents, and clinical study
cen- ter staffs at the Hilltop Medical Research Associates, Salt
Lake City, Utah; Hilltop Medical Research Associates, West
Palm Beach, Florida; Medical Associates Clinic, PC Dubuque,
Iowa; North Carolina Children’s & Young Adults’ Clinical
Research Foundation Chapel Hill, North Carolina; Pittsburgh
Pediatric Research, Inc., Pittsburgh, Pennsylvania; University
of South Florida Tampa, Florida; and the clinical study team at
 Abbott Nutrition.
FUNDIN
G Vanderhoof J, Yeung CY, Moran JR, Lifshitz F: Nutritional
The study was supported by Abbott Nutrition, Abbott
Labo- ratories, Columbus, Ohio. A potential competing
interest is that authors J.B.L., H.K.L., J.S.O., M.J.K., J.M.C.,
and P.F.P. are current or retired employees of Abbott
Nutrition, the sponsor of this study.
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Received June 21, 2013; revision accepted July 22,
2013.