REVIEW ARTICLE

Gastroesophageal Reflux and Cow Milk Allergy: Is There a Link?

Silvia Salvatore, MD*, and Yvan Vandenplas, MD, PhD‡

ABSTRACT. Gastr
ABSTRACT. Gastroesop
oesophagea
hageall reflux (GER)
(GER) and cow plications. Regurgitation, the effortless return of gas-
milk allergy (CMA) occur frequently in infants younger tric contents into the mouth, is the most common
than 1 year. In recent years, the relation between these 2 presentation of infantile GER, occasionally with pro-
entities has been investigated and some important con-  jectile vomiting.1,2 Regurgitation of at least 1 episode
clusions have been reached: in up to half of the cases of a day occurs in half of 0- to 3-month-old infants,
GER in infants younger than 1 year, there may be an
associ
ass ociati
ation
on wit
with
h CMA
CMA.. In a hig high
h pro
propor
portio
tion
n of cas
cases,
es,
increases to two thirds of infants at 4 months, and
GER is not only CMA associated but also CMA induced. decreases to 5% at 10 to 12 months of age but causes
The frequency of this association should induce pedia- concern in at least 25% of parents.1– 4 The prevalence
tricians to screen for possible concomitant CMA in all of an inc
increa
reased
sed quantity
quantity of GER, documente
documented d by
infants who have GER and are younger than 1 year. With esophageal pH monitoring, in a population of uns-
the exception of some patients with mild typical CMA elected infants is estimated to be 10%. 5 The natural
manife
man ifesta
statio
tions
ns (di
(diarr
arrhea
hea,, der
dermat
matiti
itis,
s, or rhi
rhinit
nitis)
is),, the history of GER is improvement with age with disap-
symptoms of GER associated with CMA are the same as pearance of symptoms in 55% infants by 10 months,
those observed in primary GER. Immunologic tests and in 81% by 18 months, and in 98% by 2 years of life. 6
esophage
esop hagealal pH monitoring
monitoring (with a typictypical
al pH pattern Pathologic GER, or GER disease (GERD), is reflux
characterized by a progressive, slow decrease in esopha-
geal pH between feedings) may be helpful if an associ-
associated with other manifestations, such as, failure
ation between GER and CMA is suspected, although the to thrive or weight loss, feeding or sleeping prob-
clinical response to an elimination diet and challenge is lems, chronic respiratory disorders, esophagitis, he-
the only clue to the diagnosis. This article reviews the matemesis,
mateme sis, stricture, siderop
sideropenic
enic anemia
anemia,, apnea
apnea,, ap-
main features of GER and CMA, focusing on the aspects parent
pare nt lif
life-t
e-thre
hreate
atenin
ningg epi
episod
sodes
es or sud
sudden
den inf
infant
ant
in cocomm
mmon on an
andd th
thee didisc
scre
repa
panc
ncie
iess be
betw
twee
een
n bo both
th death syndrome, and SandifSandifer’s
er’s syndrome. Atypica
Atypicall
conditions. Pediatrics  2002;110:972–984;  cow milk allergy, presentations of GER often occurs in the absence of 
 gastroesophageal reflux, vomiting, (esophageal)
( esophageal) pH moni- regurgitation and vomiting and are mainly related to
toring. recurring respira
respiratory
tory sympto
symptoms.
ms.
Secondary GER is considered a different entity and
ABBREVIATIONS. GER, gastroesophageal reflux; GERD, gastro- can be caused by infections, metabolic and neuro-
esophageal reflux disease; CMA, cow milk allergy; CMI, cow milk logic disorders, and food allergy. Secondary GER is
intolerance; CM, cow milk; Ig, immunoglobulin; CMP, cow milk always GERD. However, even in secondary GERD,
protein; CMFD, cow milk–free diet; AAF, amino acid–based for-
mula; eHF, extensive hydrolysate formula; LES, lower esophageal
vomiting or other symptoms of primary GERD may
sphincter; HPF, high-power field; PPI, proton pump inhibitor; IL, frequently manifest and therefore a clear-cut distinc-
interleukin. tion between primary and secondary GERD is fre-
quently difficult to make. Most review and position
reports on GER mention secondary GERD only brief-

G
astroesoph
astroe sophage
ageal
al ref
reflux
lux (GE
(GER)
R) is def
define
ined
d as ly.7–9 This article specifically focuses on the relation
the inv
involun
oluntar
tary
y pas
passag
sagee of gas
gastric
tric con
conten
tents
ts
 between GER, primary or secondary, and cow milk
into the esophagus. GER is present in virtu-
allergy (CMA).
ally all infants and has a wide spectrum of symp-
toms: from occasional physiologic reflux to the infant COW MILK INTOLERANCE AND COW MILK
with severe esophageal and extra-esophageal com- ALLERGY
plications and even sudden infant death syndrome. Cow milk intolerance (CMI) defines any reproduc-
Reflux is best classified as primary physiologic or ible clinical adverse reaction to cow milk (CM). Im-
pathologic (with typical or atypical presentation) and mune-mediated
mune-m ediated CM-related
CM-related adveradversese reactio
reactions
ns is de-
secondary reflux. Reflux is considered physiologic fined as CMA. These classic definitions are accepted
when the infant thrives well and experiences no com- worldwide,, but CMA and CMI are, in many studies,
worldwide studies,
used interchangeably because the immunologic basis
From the *Pediatrics, Clinica Pediatrica di Varese, Universita
Università` dell’Insubria, of the mechanisms involved are frequen frequently
tly undeter-
Brussels, Belgium; and ‡Pediatrics, Academisch Ziekenhuis, Vrije Univer- mined.
mine d. Inc
Increa
reased
sed tot
total
al or spespecif
cific
ic blo
blood
od immu
immuno-no-
siteit Brussel, Brussels, Belgium. globulin
glob ulin (Ig
(Ig)) E or pos
positiv
itivee ski
skin-p
n-prick
rick test sug
sugges
gestt
Received for publication Sep 24, 2001; accepted Mar 25, 2002. type 1, or quic
quick-o
k-onse
nset,
t, foo
foodd all ergy..10 No reliab
allergy reliable
le
Reprint requests to (Y.V.) Academic Hospital, VUB, Laarbeeklaan 101, 1090
Brussels, Belgium. E-mail: yvan.vandenplas@az.vub.ac.be
routine tests for type 2, 3, and 4 cellular mediated
PEDIATRICS (ISSN 0031 4005). Copyright © 2002 by the American Acad- CMA are currently available. Increased circulating,
emy of Pediatrics. fecal, or nasal eosinophil populations or IgG anti- -
 lactoglobulin have not been accepted as proof of  CMA was achieved in 45% to 50% at 1 year, in 60%
definitive diagnosis but may reinforce a clinical sus-
picion.11 Therefore, to simplify this review, we use
CMA for “true” and  “suspected” CMA. Conversely,
CMI related to lactase deficiency is excluded.
CMA is reported in 0.3% to 7.5% of infants (with
82% of symptoms reported within the first 4 months
of life).10 –14 On the basis of strict diagnostic criteria,
the prevalence of confirmed CMA in developed
countries during infancy is approximately 2% to 5%.
Reproducible reactions to cow milk protein (CMP) in
 breastfed infants occur in approximately 0.5%15
Family history of atopy is a predictor for allergy.
The incidence of CMA is 12% when there is no atopic
parent, 20% when there is 1 atopic parent, 32% when
there is 1 atopic sibling, 43% when both parents are
atopic, and as high as 72% when both parents have
the identical type of atopic disease.16 Approximately
30% to 70% of infants with CMA manifest dermato-
logical symptoms, 50% to 60% manifest gastrointes-
tinal symptoms, and 20% to 30% manifest respiratory
symptoms.15,17 This means that the majority of pa-
tients with CMA manifest symptoms involving more
than 1 system, whereas patients with primary GERD
mostly have only 1 system involved. Gastrointestinal
symptoms of CMA include recurrent vomiting, food
refusal, irritability, diarrhea, rectal bleeding, and
malabsorption. Systemic manifestations may include
failure to thrive and anaphylaxis. Only a small pro-
portion of gastrointestinal allergy is IgE-mediated.10
Clinical response to an elimination diet and a chal-
lenge is the diagnostic principle of food allergy. 10,18
Diagnosis of specifically CM protein enteropathy
ideally necessitates the proof of small bowel damage
with patchy partial villous atrophy and increased
intraepithelial lymphocytes.10,11,19
Natural tolerance for CM in infants who are af-
fected by CMA is frequently achieved within the first
years of life. Remission of CMA was reported in 15%
of the affected children by 1 year, in 22% to 28% by
2 years, in 51% by 3 years, in 55% to 67% by 4 years,
and reaching 78% by 6 years. 13,20 More recent, in a
different population, CM tolerance in infants with
Fig 1.  Symptoms attributed to GER and to CMA.
to 75% at 2 years, and in 85% to 90% at 3 years of 
age.15
From the evidence listed above, results show that
GER and CMA both are generally self-limited symp-
toms, possibly interrelated, with only a small propor-
tion of patients ( 10%) who will continue to have the
disease-related symptoms after early infancy.
CMA AND GER
The age-dependent and similar clinical presenta-
tion (Fig 1) suggests a relation between GER and
CMA.21 From the above reported prevalence of GER
and CMA, combined theoretical expected prevalence
(if a causal relationship exists between the 2 diseases)
results in a figure of 0.03% to 0.7% of infants who
experience pathologic reflux and CMA to 0.2% to
4.9% of infants who present with physiologic regur-
gitation and CMA. More than 20 years ago, Buis-
seret22 reported the presence of vomiting, colic, dif-
ficult infant feeding, growth retardation,
psychological disturbance, and diarrhea in 79 chil-
dren with CMA. Later, enteropathy (with IgE plas-
macytes) was found in 3 (20%) of 15 infants who
presented with recurrent vomiting.23 More recent, a
CM-free diet (CMFD) was evaluated in 10 of 14
infants who had GER and did not respond to phar-
macological reflux treatment: 2 (20%) of 10 im-
proved.24 Kelly et al25 reported on 10 patients who
had long-standing symptoms attributed to GERD
(vomiting, abdominal pain, poor growth, and poor
appetite) and did not respond to standard treatment
(including a Nissen fundoplication in 6 children) and
had persistent eosinophilic esophagitis; a dramatic
clinical and histologic improvement was found in all
patients after an amino acid– based formula (AAF)
was started. In accordance with a diagnosis of pri-
mary CMA, there was not only the obvious clinical
response to the elimination diet with disappearance
of all symptoms but also the clinical relapse in 7 of 
the 10 infants during an open challenge with CM
proteins. In 5 Italian studies (some of them may have
repetitive inclusion of patients), the association of 
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       3
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    i
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       †        †
    l     D    o   g    A   m
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   :     R    p    i    s
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   r    t
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    G      N     3    8    2    –    4    4    2    0     1    1     1    2    4    3    3    2    8     1    1     1  ,    s    r    u
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    2    8    1    6    1    1    1    8    0     3    1    1    3    2    2    5    4    6    1    0     0     t     f     t
   s     1     1     1    a    8    o
   e
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   u
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   e    c    f
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    t
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   o    u   e     E   y    E   y    E    l    y    E    A    y    E    y    E    y    E   y    E    A     E     l    y   r     h
    t    s
   p    o    s     l     l     l     l     l     l     l    e    e
 ,     i
   e    r    a     G   n    G   n    G   n   n    G    M    n    G    n    G    n    G   n    G    M     G     i    p   s
   g    e         o         o         o   o          R   o         o         o        o          R         m   s    e    d
    R     b    i   s     C     C    a    a    i    u
   u     A    R    A    R    A    A    R    A    F    E    R    A    A    R    A    A    R    A    R    A    F    E    A     f     d    t
   s
    S    D     E
    M     M     M     E     E
    M     M     G
    E     M     E
    M     M     E     E
    M     M     M     G    s    w    u
    M    e     t     3
 .     C    G    C    G    C    C    G    C    H    e     G    C    C    G    C    C    G    C    G    C    H    e     C     t    a
   e    s
   g    e
     2    c    n   e    s
     E     l  .
    i
    d    e    s
    l    e
   e    h
   a    o     5    4     5     2     8     6     0     4     2     6     9     i    n     l     h     t
     L     t
    1    1     2     1     1     9     4     0     1     1     1    a    t
     B    o     1     2     1     h   n   s
     A     T    N     H    C    I     A
     T     F    *        †       ‡
 GER and CMA has been reported in 15% to 21% of  An Italian group identified a typical pH tracing
infants with symptoms suggesting GER or CMA and
in 16% to 42% of infants who had previously re-
ceived a diagnosis of GERD. 26 –30 Reflux symptoms
disappeared within 2 weeks of AAF in 13 consecu-
tive infants who presented with persisting vomiting
and were unresponsive to medical reflux treatment;
3 had documented esophagitis, and 7 had multiple
food allergy unresponsive to extensive hydrolysate
formula (eHF).31 Similarly, AAF was effective in 13
(81%) of 16 infants with symptoms that were sugges-
tive CMA (9 of 16 with persistent vomiting and
documented esophagitis in 7) and resistant to eHF
and GER treatment. The 3 nonresponders did not
react during a challenge with eHF, making the CMA
diagnosis questionable.32 Last, in 19 infants with ir-
ritability and vomiting (with esophagitis in 9) resis-
tant to eHF and antireflux medications, symptoms
disappeared in all patients within 2 weeks after start-
ing AAF. After a period of 2 to 12 months, a double-
 blind, placebo-controlled challenge was performed:
12 infants were still intolerant of other formula (3
patients of soy and 9 of eHF).33 Details of the studies  
are shown in Tables 1 and 2.
Intestinal permeability tests were positive in 85%
of infants who had GER-CMA that was resistant to
eHF32 and were 95% accurate in identifying CMA
in 25 infants who presented with chronic vomiting. 27
Intestinal permeability tests, based on differential
sugar absorption tests with determination of urinary
excretion of large molecules such as lactulose or cel-
lobiose compared with small molecules such as man-
nitol, revealed an abnormal cellobiose/mannitol ra-
tio (2 standard deviations over the mean from
normal subjects) in infants with CMA. 27 However,
intestinal permeability studies are not easily per-
formed in all hospitals, are aspecific for CMA, and
have a limited sensitivity in infants without enterop-
athy.21,34
In 3 studies (from the same group) on infants with
GER-CMA, increased -lactoglobulin antibodies
were shown to have a sensitivity of 90% to 100% and
a specificity of 78% to 90% as a predictive factor of  Endoscopy and esophageal biopsies are recom-
efficacy of a CMFD. 28 –30 However, the absence of  mended when esophagitis is suspected. Basal cell
difference between the level of  -lactoglobulin anti-
 bodies in control infants versus infants with CMA 35
has as well been reported. Even the absence of any
diagnostic help of IgG–-lactoglobulin antibodies for
allergic manifestations was suggested. 36
(“phasic” pattern, a progressive and slow decrease in
esophageal pH between 2 feedings) in 12 (86%) of 14
infants with GER-CMA, in 24 (96%) of 25 infants
with only CMA, and in 0 of 47 infants with primary
GER or 0 of 49 control infants. 28 The probe was
positioned at 87% of the nose   lower esophageal
sphincter (LES) distance, calculated using Strobel’s
formula. The authors speculated that a low basal
resting tone of the LES, more than inappropriate
relaxations of the LES, may be implicated. These
findings were confirmed by the same center in a
larger group of infants (phasic pH-metry in 87% of 
infants with GER-CMA and not in patients with GER
or in control subjects).29 However, others have con-
tradicted these findings, reporting a phasic pH trac-
ing in 5% of infants with CMA and in 4% of patients
with GER.26 Selection of patients, diagnosis of CMA
and/or GER, and challenge tests were not standard-
ized, making comparisons among all of the afore-
mentioned reports hazardous. Besides, for proving
objective phasic results, a double-entry analytical ta-
ble (constituted by the number of recordings of each
pH value during each 30-minute fraction after feed-
ing) of pH-monitoring data is needed. 29
From the above studies, symptoms disappeared in
all,23,25,27,33 part,26,30 –32 or a minority (2 of 10) 24 of 
infants who had GERD symptoms resistant to classic
GER therapy and were on a CMFD and relapsed
during challenge. Routine immunologic allergic tests
and family or patient’s medical history of allergy
were not consistently positive or always predictive
for the response to the CMFD (Tables 2 and 3). Nev-
ertheless, CMA-related GER seems age-related and
limited to young infants; as in older children, CMA
symptoms evolve to cutaneous symptoms (atopic
dermatitis), respiratory symptoms (wheezing,
asthma, rhinitis), or lower gastrointestinal motility
disturbance (constipation), especially when there is a
positive family history of allergy. 37
ESOPHAGITIS
hyperplasia, papillary elongation, and intraepithelial
or lamina propria inflammatory cell infiltration are
histologic criteria for esophagitis.38,39 Eosinophilic
infiltration is still a poorly characterized entity and
should be interpreted with caution as it is not a

TABLE 3. Summary of the Results of CMA-GER Studies

Disease Total No. CMFD Challenge SBB FH CMAs CMAH
of Points
 /N  % /N  %  /N  %  /N  %  /N  % /N  %
CMAGER 219† 216/219 99 197/209 94 96/124* 77 53/139 38 52/199 26 54/199 27
GER only 291 35/84 42 0/38 0 0/28 0 47/194 24 1/161 1 0/75 0
Disease Total No. PRICK Total IgE EOS -Lacto Ab Phasic pHm PT
of Points
 /N  %  /N  %  /N  %  /N  %  /N  %  /N  %
CMAGER 219† 102/194 53 29/80 36 47/141 33 125/129 97 39/62 63 18/20 90
GER only 291 3/87 3 0/87 0 0/206 0 35/194 18 3/142 2 1/16 6
* For SBB, the data of 2 studies 28,29 were not included as the results of CMA-GER and CMA-only were not reported separately.
† As 3 studies come from the same group, some patients may be reincluded.
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