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Association between gastroesophageal reflux and pathologic apneas in infants.
Citation preview
REVIEW ARTICLE
Association between gastroesophageal reflux and
pathologic apneas in infants: a systematic review
MARIJE J. SMITS,* MICHIEL P. VAN WIJK,* MIRANDA W. LANGENDAM,† MARC A. BENNINGA* & MERIT M. TABBERS*
*Department of Pediatric Gastroenterology and Nutrition, Emma Children’s Hospital, Academic Medical Center, Amsterdam,
The Netherlands
†Dutch Cochrane Centre, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Key Messages
• There is insufficient evidence for an association between gastro esophageal reflux (GER) and apneas in infants.
High quality studies using uniform inclusion criteria, definitions according to accepted guidelines, and patient
relevant outcome measures are needed.
• The purpose of this systematic review was to determine whether an association between GER and apneas in
infants exists.
• PubMed, EMBASE, and Cochrane databases were searched for studies assessing the relationship between GER
and apneas in infants by means of simultaneous monitoring of GER and apneas.
• One of six included studies found an increase of apneic events after GER, the remaining 5 studies did not find an
association. Two studies assessed apnea followed by GER as well, but did not find sufficient evidence for an
association.
Abstract
Background In infants, apneas can be centrally med-
iated, obstructive or both and have been proposed to
be gastroesophageal reflux (GER) induced. Evidence
for this possible association has never been systemat-
ically reviewed. Purpose To perform a systematic
review using PubMed, EMBASE and Cochrane data-
bases to determine whether an association between
GER and apnea in infants exists. Studies with n ≥ 10
infants, aged <12 months, were included. GER had to
be studied by pH-metry or pH-impedancemetry. GER
episodes were defined as pH <4 for ≥5 s and/or a drop
of >50% of baseline in impedance signal in distal
channels. An apneic event was defined as a cessation
of breathing for >20 s, or ≥10 s with hypoxemia or
bradycardia. An epoch of ≤2 min was used to define
temporal relation between GER and apnea. Method-
ological quality of studies was assessed with Newcas-
tle Ottawa Scale (NOS). Of 1959 abstracts found, 6
articles met the inclusion criteria. All studies had poor
methodological quality. A total of 289 infants were
included. The temporal association of GER followed
by apnea was assessed in all studies, with epochs
varying from 10 s to 2 min. One study found an
increase of apneic events after GER, the remaining 5
studies did not find an association. Two studies
assessed apnea followed by GER as well, but did not
find sufficient evidence for association. This system-
atic review showed insufficient evidence for an
association between GER and apneas in infants. High
quality studies using uniform inclusion criteria,
Address for CorrespondenceMarije Smits, Department of Pediatric Gastroenterology andnutrition, Emma Children’s Hospital, Academic MedicalCenter, Room C2-312, Meibergdreef 9, Amsterdam 1105 AZ,The Netherlands.Tel: 0031-20-5665270;e-mail: [email protected]: 17 April 2014Accepted for publication: 27 June 2014
© 2014 John Wiley & Sons Ltd 1527
Neurogastroenterol Motil (2014) 26, 1527–1538 doi: 10.1111/nmo.12405
Neurogastroenterology & Motility
definitions according to accepted guidelines, and
patient relevant outcome measures are needed.
Keywords apnea, cardiorespiratory monitoring, gas-
tro esophageal reflux, infants, pH-impedance metry,
pH-metry.
Abbreviations: GERD, Gastroesophageal reflux dis-
ease; GER, Gastroesophageal reflux; LCR, Laryngeal
chemical reflexes; LES, Lower esophageal sphincter;
NOS, Newcastle Ottawa Scale; NTS, Nucleus tractus
solitarius; pH-MII, pH impedancemetry; RI, Reflux
index; TLESR, Transient lower esophageal sphincter
relaxation; RAAP, reflux associated apneas.
INTRODUCTION
Gastroesophageal reflux (GER) is the passivemovement
of gastric contents into the esophagus. This occurs
primarily during transient lower esophageal sphincter
relaxation (TLESR).1,2 TLESR is a relaxation of the lower
esophageal sphincter (LES) not preceded by a swallow
and is mediated by a vago-vagal pathway.3
Apnea is the cessation of respiratory airflow and
can be central (no respiratory effort), obstructive
(respiratory effort present but not resulting in airflow
due to upper airway obstruction) or mixed in nature
(no respiratory effort followed by obstruction-like
respiratory efforts).4,5 Clinically significant apnea lasts
>20 s, or for a period of ≥2 breaths accompanied by
significant desaturation, hypoxemia or bradycardia.4,6
The Nucleus Tractus Solitarius (NTS) in the brain-
stem plays a large role in pathogenesis of apneas by
expressing a paradoxical overriding inhibitory
response to signals from peripheral afferents. These
afferents are excited by, for example, hypoxia, hyper-
capnia, and stimulation (e.g. obstruction) of the upper
airways and may lead to respiratory pauses of variable
duration.7,8
Apneas, irrespective of their nature, have been
proposed to be GER induced. The persuasion that
GER and apnea are causally related is embedded in
guidelines for the treatment of GER disease (GERD)
and pathological apneas.9 It is hypothesized that GER-
induced esophageal distension as well as pharyngeal
penetration of GER can activate local vagal stretch and
chemical receptors.10,11 In animal models, distension
of the esophagus can indeed induce apnea and it is
established that laryngeal chemoreceptor reflexes
(LCR) can trigger central apneas in infants.12–14 Thus,
vagal afferents triggered by GER seem to be able to
induce apneas through pathways mediated by the brain
stem. However, a recent study found no effect of feed
thickening, which significantly reduced GER episodes
reaching the proximal esophagus, on the frequency and
duration of apnea episodes.15
Another hypothesis is that apneas cause GER
episodes.16 In a retrospective physiologic study, it has
been shown that all clinically relevant apneas (>20 s)
identified, were followed by a decrease in LES pressure.
Although only manometry was performed in this
study, and occurrence of GER episodes was not
assessed, this decrease in LES pressure putatively
allows GER to occur after apnea.17 This likelihood
further increases when abdominal pressure rises, e.g.,
during arousal and straining after apnea. Furthermore,
obstructive respiratory efforts and repetitive swallow-
ing are long known manifestations of previously
mentioned LCR.18 Apart from inducing apneas, LCR
also causes decrease in LES pressure. LCR can elicit
coughing (as occurs after arousal from apnea) which
increases abdominal pressure, and therefore the chance
of GER occurring in the presence of low LES
pressure.12
Finally, given the close proximity of the GER pattern
generator and breathing control centers in the brain
stem, it could be hypothesized that GER episodes and
apneas temporally relate as result of a common central
pathway.
A substantial amount of studies and non-systematic
reviews have attempted to pinpoint the relationship
between GER and apneas.16,19,20 However, their con-
clusions contradict each other. Therefore, we system-
atically reviewed evidence for an association between
GER and apneas, and vice versa, in infants.
METHODS
Search strategy
We searched Medline, Embase, Cochrane electronic database, andCochrane Controlled Trials Register for prospective studies andsystematic reviews from 1980 up to June 2014. The following keyterms were used: gastro(-o)esophageal reflux, apn(o)ea, ApparentLife Threatening Event, and infant. No language restriction wasapplied. Obtained reviews and articles were hand searched foradditional studies. The full search strategy is available from thecorresponding author.
Inclusion criteria
Two reviewers (MS, MvW) independently judged articles as shownin Figure 1. Full length articles were included if the study met ourinclusion criteria: (i) Prospective study or case–control study, (ii)n > 10 study subjects per patient group investigated with acorrected age <12 months and suspect for GER related symptoms,GERD, apnea and/or apparent life-threatening events (ALTE), (iii)Simultaneous GER investigation (pH-metry or pH-impedance
© 2014 John Wiley & Sons Ltd1528
M. J. Smits et al. Neurogastroenterology and Motility
(pH-MII) measurement and/or manometry) and apnea assessment(cardiorespiratory monitoring), (iv) Apneic events defined as acessation of breath >20 s or ≥10 s with significant desaturationand/or bradycardia, (v) GER events were defined as pH<4 for ≥5 sand/or a drop of >50% of baseline in impedance signal in the distaltwo channels, (vi) Epoch (time window) between GER and apneaor vice versa was defined ≤2 min, (vii) Study aim was to determineany relation between GER and apnea.
Quality assessment
Before data extraction, included full length articles were judgedby two assessors (MS and MvW) for quality, using the Newcas-tle Ottawa Scale (NOS). This scale is a validated tool for scoringthe methodological quality (risk of bias) of comparative obser-vational studies.21,22 As the NOS is aimed at comparativestudies and most included studies were expected to be patientseries, we adjusted the outcome question: ‘was follow up timelong enough for the outcome to occur?’ into ‘was study timelong enough to asses outcomes?’. Also, only in studies incor-porating two or more groups, the latter were divided into anexposed and non-exposed cohort. Definition of an exposedcohort was chosen as defined by authors (e.g. treatment/ notreatment or presence/absence of symptoms at start of study).Similarly, outcome definitions were chosen as defined byauthors (e.g., a decrease in GER, apnea and/or symptoms).Comparability of cohorts was only scored for studies with twoor more patient groups. Furthermore, we added three scoringitems that could be answered with ‘A’, ‘B’ or ‘C’. This modifiedversion of the NOS consists of 11 questions (Table 1). Depend-ing on the answer, questions are rated with one star per item,mapping the methodological quality of the article. There are nocutoff values for this scale, therefore no summary scores werecalculated. In general, the more stars, the higher the quality ofthe article (range 0–11 stars).
Data extraction
Two assessors (MS, MvW) independently performed structureddata extraction. The data extracted from each article includedauthor and year of enrollment, study setting, methods, type andnumber of subjects, method of GER and apnea assessment,potential follow-up, outcome measures, and results. If disagree-ment between the two reviewers existed, consensus was foundwhere possible, or a third reviewer (MT) made a final judgment.
RESULTS
Literature search and quality assessment
The search strategy generated 1959 titles. No system-
atic reviews were found. Based on title and abstract, 41
studies were selected to potentially meet inclusion
criteria (Fig. 1). After retrieving full text articles and
scoring in- and exclusion criteria, an additional 35
articles were excluded. Reasons for exclusion were: (i)
n < 10 patients included (n = 3). (ii) Definition of GER
and/or apnea did not meet the inclusion criteria or no
definitions were given (n = 20). (iii) Duration of epochs
used to define a temporal association between GER and
apnea, or vice versa, was unclear or >2 min (n = 9). (iv)
Retrospective study or non-systematic review (n = 2)
and (v) other (n = 1).
Finally, six studies could be included for our
systematic review.23–28 Of these, two had a case–
control design,24,25 the other four were patient series.
Data from 289 infants (five studies reported gestational
age: range 24–43 weeks, one reported postnatal age:
range 1–34 weeks23) were included. Studies were con-
ducted in tertiary centers in The United States of
America23,24,26–28 and Europe.25
The two assessors initially agreed on 56 of 66 scored
quality items, with a Cohens Kappa agreement of 0.77
(0.61–0.8 = substantial agreement). Agreement after
discussion was reached in 100% of cases. NOS scoring
items per article are described in Table 1. Overall
quality was considered to be poor. Outcome assess-
ment was blinded in none of the studies and only three
of six define outcome measures. Since only two of six
studies studied >1 patient group, not all NOS scoring
items were applicable for the other four studies.24,25
Due to heterogeneity in design, outcome measures,
and analysis, pooling of results was impossible. There-
fore, studies are discussed separately.
Patient demographics
All but one study included prematurely born infants
(Table 2).23 In general, included infants were suspected
of having apneas and/or GER related symptoms. One
study included a group of ‘symptomatic’ (apneas and/or
bradycardias present or GER after feed) and a group of
‘asymptomatic’ infants25 (no GER symptoms or apneas
present). One study assessed infants after near miss
sudden infant dead syndrome (SIDS).23
GER assessment
All studies using esophageal measurements had a
metric cutoff to determine the presence of GER (e.g.
a pH drop below 4 for 5–15 s; Table 3).23–27 The
study using pharyngeal pH-metry defined GER as
appearance of gastric contents into the mouth,
supported by pH changes measured with pharyngeal
recording.28
Apnea assessment
Ariagno et al. did not report the absolute number of
apneas but the number of apneas per hour (Apnea
Index; Table 3).24 Di Fiore et al. also did not report on
absolute numbers, but displayed results graphically in
© 2014 John Wiley & Sons Ltd 1529
Volume 26, Number 11, November 2014 Systematic review association infant GERD and apnea
the article.26 The other four studies reported on
overall numbers of apneas that may or may not be
classified into central, obstructive and/or mixed or
prolonged and short. For this review only prolonged,
presumed clinically significant, apneas were consid-
ered. De Ajuriaguerra et al. assessed both symptom-
atic and asymptomatic infants and found only one
asymptomatic infant to have apneas (mixed and
obstructive), all other apneas were recorded in symp-
tomatic infants.25
Table 1 Newcastle Ottowa Scale
Ariagno
et al.23Ariagno
et al.24de Ajuriaguerra
et al.25 Di Fiore 26 Di Fiore 27 Menon 28
Selection
(1) Representativeness of the exposed cohort C B* B* B* B* B*
(a) Truly representative of community*
(b) Somewhat representative of community*
(c) Selected group
(d) No description
(2) Selection of the non-exposed cohort na A* A* na na na
(a) Same community as exposed cohort*
(b) Drawn from a different source
(c) No description
(3) Ascertainment of exposure na A* D na na na
(a) Secure record (eg surgical records)*
(b) Structured interview*
(c) Written self report
(d) No description
(4) Outcome not present at start of study na A* na na na na
(a) Yes*
(b) No
Comparability
(1) Comparability of cohorts (design/analysis) na B* B* na na na
(a) Study controls for epoch between GER and Apnea
and vice versa*
(b) Study controls for GER and Apnea*
Outcome
(1) Assessment of outcome E E E E E E
(a) Independent blind assessment*
(b) Record linkage*
(c) Self report
(d) No description
(e) Independent not blinded assessment
(2) Study time long enough A* A* A* A* A* B
(a) Yes*
(b) No
(3) Adequacy of follow-up of cohorts A* A* A* A* A* A*
(a) Complete follow-up*
(b) Subjects lost to follow-up unlikely to introduce bias
(c) Follow-up rate <20% and no description of those lost
(d) No statement
Added items by authors
(1) Were in- and exclusion criteria specified? A* A* B A* A* B
(a) Yes*
(b) Only inclusion criteria specified
(c) No criteria specified
(2) Definitions of outcomes given? A* B B A* A* B
(a) Yes*
(b) No
(3) Was the outcome assessor blinded? C C C C C C
(a) Yes*
(b) No
(c) Unclear
Quality of articles using Newcastle Ottowa Scale including added items by the authors. Depending on the answer, questions are rated with a star.
There are no cutoff values for this scale. In general, more stars mean a higher methodological quality.
© 2014 John Wiley & Sons Ltd1530
M. J. Smits et al. Neurogastroenterology and Motility
Association of GER and apnea
GER causing apnea (n = 6) Only one study found a
significant increase of apneic events after GER,28 the
other five studies did not find an association (Table 4).
Of the latter five, Ariagno et al. report one of 45 infants
to have an apneic event associated with GER (<2 min
following GER). In this infant, 24 of the total recorded
study apnea (n = 31) were recorded.23 De Ajuriaguerra
reported one apnea occurring <1 min after a GER
episode. In this study, no correlation between apnea
and GER was found in either the symptomatic infant
group (n = 14) or the entire study population (n = 20).
No further details for association in the six asymp-
tomatic infants were reported.25 The two studies by Di
Fiore et al., found neither apneas nor cardiorespiratory
events to be associated with GER, nor did GER
increase the duration of apnea episodes.26,27
Ariagno et al. (2001) reported reflux associated
apneas (RAAP) in 24 infants, i.e., the number of apneas
occurring within 1 min after a GER event, which were
found in 62% of infants. Cisapride treatment adminis-
tered in this study did not reduce RAAP significantly.
Authors stated that, although acid GER and mixed
apneas were reduced in the cisapride group, not enough
evidence was present to claim GER is causally related
to apnea, nor that treatment of GER related symptoms
will significantly improve management of infants with
persistent apneas.24
Apnea causing GER and assessment of common
etiology (n = 2) Di Fiore et al. assessed GER induced
by apneas. Nine percent of GER events were preceded
by a cardiorespiratory event.27 The other study from Di
Fiore et al. found 85% of apneas related to GER were
followed by arousal within 30 s and significant more
apneas of >10 s occurred before or during GER as
compared to apneas immediately after GER. Authors
concluded these findings suggest arousal is associated
with termination of GER, rather than apneas are able
to induce GER.26 None of the included studies specif-
ically searched for a common etiology of GER and
apnea.
Medical therapy in studies (n = 4) Three out of six
studies reported on medical therapy that infants
received during the study, whereas apnea therapy was
abated prior to the commencement of one study.25
Ariagno et al. (2001) found that 8 days of cisapride
therapy significantly reduced the number of GER
episodes of ≥5 min (p = 0.026), the RI (p = 0.017) and
overall mixed apneas compared to baseline, but it did
not reduce RAAP.24 The effect of administered raniti-
dine or metoclopramide on GER or apnea parameters
was not reported in the studies by Di Fiore et al.26,27
There was no significant difference in the number of
GER events (p = 0.34) or reflux index (RI, p = 0.94)
between infants with or without caffeine and/or the-
ophylline therapy.26,27 Accordingly, Ariagno et al.
(2001) stated that caffeine therapy had no effect on
GER parameters (no p-values reported).24
DISCUSSION
This systematic review shows insufficient evidence for
any association between GER and apneas in infants.
Figure 1 Flow chart of included studies.
© 2014 John Wiley & Sons Ltd 1531
Volume 26, Number 11, November 2014 Systematic review association infant GERD and apnea
Tab
le2
Patientdem
ograp
hics
Author
Subjects(n)
Age
Male,
n(%
)Inclusioncriteria
Exclusioncriteria
Med
icationduring
study
Recording
(hours)
Atbirth
(GA
weeks)
Atstudy
(weeks)
Ariagnoetal.23
45
-10�
8PNA
25(56%)
NearmissSID
Sterm
infants
Failure
tothrive
nr
17.95�
3.25
Vomiting
Recurren
tpneu
monia
Ariagnoetal.24
24
28.8
�3.1
35.6
�4GA
16(67%)
Hospitalized
infants
suspect
forGER,ap
nea
and/orfeed
ing
intolerance.
Neg
baselinepH
study(n
=12)*
Caffeine‘
n=12before
Cis
n=9afterCis
†
2reco
rdings
of15-16
PositivepH
study*
Surgeryduringtreatm
ent(n
=1)
8day
stherap
ywithCis
(0.10mg/kg/6hrs)
Rep
eatmeasu
remen
t>8day
s
afterstartCis
(n=4)
Nasal
O†su
ppl
n=12before
Cis
n=12afterCis
PSG/pH
studybefore
+afterCis
deAjuriaguerra
etal.25
20
31(27.5-36.5)
38.7
(73-43)PCA
11(55%)
Hospitalized
premature
born
infants
=/>
37weeksPCA
nr
Caffeineab
ated
>7day
sprior
tostudy
6.18
(3.95-6.80)
Symptomatic:ap
neasan
d/or
bradycardiasorregu
rgitation
afterfeed
(n=14)
Asymptomatic
infants
(n=6)
DiFiore
etal.26
119
28�
237�
4PCA
nr
Hospitalized
premature
infants
Congenital
malform
ations
Xan
thinen=26‡
12overnight
SymptomsofGER
<1500gat
birth
Nasal
O†su
ppl
n=40
Apneas,
bradycardia
and/or
desaturations
Ran
itidinean
d/or
Metoclopramiden=15
DiFiore
etal.27
71
29.4
�3
37.3
�2.6
GA
43(61%)
Hospitalized
premature
infants
<44weeksat
measu
remen
t§Congenital
malform
ations
Caffeinen=5¶
12overnight
Referredforcardiorespiratory
andGER
overnightmonitoring
Needforven
tilarsu
pport
Ran
itidinean
d/or
Metoclopramide
n=3
Men
onetal.28
10
28-40
1-4
PCA
nr
Hospitalized
infants
nr
nr
1.4
(n=6)
2-3
(n=4)
Postfeed
ingregu
rgitation
Idiopatic
prolongedap
nea/A
OP
*Refl
uxindex
within
2SD
ofmeanacco
rdingto
criteria
Van
den
plasetal.9†Noeffect
onGER
values.‡EffectonRInsp=0.94.§<34weeksGA
atbirth.¶ N
oeffect
onnumber
ofGER
even
ts(ns,
p=0.34).PNA,postnatal
age;
PCA,postco
nceptional
age;
GA,gestational
age;
SID
S,su
dden
infantdeath
syndrome;
PSG,polysomnograp
hy=cardiorespiratory
monitoring;
GER,gastro
esophageal
reflux;AOP,ap
nea
ofprematurity;Cis,cisapride;
nr,notreported
.
© 2014 John Wiley & Sons Ltd1532
M. J. Smits et al. Neurogastroenterology and Motility
Tab
le3
GER
andap
nea
param
eters
Author
GER
Apnea
GER
test
GER
andGERD
defi
nition
Number
ofGER
episodes,
(%ofall)/R
IApnea
test
Apnea
defi
nition
No.Ofap
nea
orApnea
Index
pH
MII
GERD
TypeApnea
Duration
+ad
dition
Ariagno
etal.23
pH-m
etry
pH
<4≥1
5s
na
nr
n=356
Respeffort
ECG
ApC
>10s
n=341*
Ariagno
etal.24
pH-m
etry
pH
<4≥5
sna
RI>2SD
†Before
Cis/24h
(mean,SD)
After
Cis/24h
(mean,SD)
p-value
Respeffort
Nasal
airfl
ow
ECG
O2saturation
AIbefore
Cis
AIafterCis
p-value
n=91.7
�45.3
n=73.4
�65.3
0.068
Short
ApC
10–1
5s
0.62�
0.89
0.54�
0.68
0.4
RI16.6
�15.2
RI9.1
�8.4
0.017
LongApC
>15s
0.36�
0.70
0.41�
0.89
0.3
Obstructive
>10s+Resp
effort
0.09�
0.15
0.04�
0.14
0.2
ApM,ApC,
ApO
>3s+10s
0.5
�0.47
0.3
�0.36
0.026
de Ajuriaguerra
etal.25
pH-m
etry
pH
<4≥1
5s
na
RI>10.4%
n=134
Respeffort
Nasal
airfl
ow
Heart
rate
O†
saturation
ApC
>10s
n=26
GERD
in
symptomatic
infants:
n=10(71%)
ApO
+ApM
>10s+Resp
effort
n=113
GERD
in
asymptomatic
infants:
n=2(22%)
Isolated
Bradycardias
<80bpm
n=46
DiFiore
etal.26
pH-m
etry
pH
<4≥5s
na
RI (cutoff
nr)
n=6255
Respeffort
ECG
Heart
rate
O†saturation
ApC,ApO,
ApM
>10s
Noex
actnumbers‡
pH
<4per
12h
NoGER
episodes
/12h:n=53�
41
17�
14%
ApC,ApO
orApM
>15s
Noex
actnumbers‡
DiFiore
etal.27
pH-M
IIpH<4
+50%
fall
MIIbaseline
2distal
chan
nels
nr
n=1183(29%)
Respeffort
ECG
Heart
rate
O†saturation
ApC
>10s
n=1419
WA
pH>4+
DpH
>1
n=341(8%)
ApO
>10s
n=657
NA
pH>4
n=1709(41%)
ApM
>10s
n=42
Acidonly
pH
<4≥5s
+noMII
even
t
n=931(22%)
Bradycardia
<80bpm
n=456
O2 desaturation
<85%
n=10383
CR
even
tsAp+brady+
desaturation
n=12957
Men
on
etal.28
Pharyngeal
pH-m
etry
Visibilityof
GER
in
mouth,DpH
=su
pport
na
nr
n=44
Respeffort
Nasal
airfl
ow
ECG
Prolonged
>20s
n=100
Short
<20s+Brady
<100bpm
See
commen
t§
*In
46measu
remen
ts(1
subject
studiedtw
ice).†Asco
mpared
tostan
dardvalues
Refl
uxindex
acco
rdingto
Van
den
plasetal.33‡Apneas>
15san
d>10s30sbefore,afteran
dduringGER
inarticle
wereprovided
inahistogram
(noex
actfigu
res).§Notmatch
ingourap
nea
defi
nition,therefore
notdisplayed
here.
RI,refluxindex
(%oftimeesophagealpH<4);GER,gastroesophagea
lreflux;GERD,
GERdisease;WA,weakly
acid
GER;NA,non-acidGER;Cis,CisparideRespeffort
=respiratory
effort;Ap,ap
nea;ApC,central
apnea;ApO,obstructiveap
nea;ApM,mixed
apnea;AI,ap
nea
index
:
noofap
neasper
hour;
CR
even
t,cardiorespiratory
even
t;ECG,electrocardigram;DpH,ch
ange
inpH;brady,bradycardia;bpm,beats
per
minute;desat,desaturation;nr,
notreported
;na,
not
applicable;SD,stan
darddev
iation.
© 2014 John Wiley & Sons Ltd 1533
Volume 26, Number 11, November 2014 Systematic review association infant GERD and apnea
Most available studies addressing this topic are meth-
odologically inadequate in terms of sample size,
design, outcome measures, and analysis, or use tech-
niques that are no longer state of the art. Therefore, we
only included a small number of studies with clinically
relevant criteria for GER and apnea that met interna-
tionally accepted standards and had a clear definition
of temporal relation, with epochs of 2 min maxi-
mum.4,9,29 Even with these strict inclusion criteria,
data from the six included studies were too heteroge-
neous to be pooled.
In general, all included studies have methodological
limitations. Firstly, not all GER events are same in
terms of acidity, proximal extent, and volume and
could, therefore, trigger other neuroregulatory mecha-
nisms through different mechano- and chemorecep-
tors. Five of six included studies used pH-metry to
evaluate GER instead of pH-MII technology, which
enables differentiation between these different types of
GER.27 pH-metry, as compared to pH-MII measure-
ments, misses out on non-acid (pH >7) and weakly acid
(4< pH ≤7) GER episodes, while the latter have been
shown the predominant type of GER in infancy.30–32
Secondly, all but one study25 did not categorize the
apneas into central, obstructive or mixed for their
analysis. It might be that central and obstructive
apneas are differently related to GER, as immaturity
of the central nervous system and LCR, respectively,
are considered the most likely underlying mechanism
in infants.
Thirdly, administration of medication modulating
GER and apnea could have influenced results of the
included studies. This has been shown in several
pediatric and adult studies.33,34
Nevertheless, only three studies did report on the
effect of medication administered.24,26,27 Of those,
Cisapride is unavailable nowadays due to associated
cardiac side effects and Metoclopramide is no longer
Table 4 Association of GER and apnea
Author Epoch
GER followed by apnea Apnea followed by GER Association
GER-Apnea
according to
authors?Measure Outcome Measure Outcome
Ariagno et al.23 ≤2 min Aps after GER/ total Aps 1/341 (0.2%) - No
Aps during GER/ total Aps 31/341 (9.1%)
Ariagno et al.24 ≤1 min Infants with ≥1 Ap after
GER (RAAP)*14 (62%) - Not enough
evidence
de Ajuriaguerra
et al.25≤1 min Aps after GER/ total Aps 1/139 (0.7%) - No
ApsC during GER/total ApsC 2/26 (7.7%)
ApsM+ApsO during GER/
total ApsM+ApsO
11/113 (9.7%)
Brady after GER/ total Brady 8/46 (17.4%)
Brady during GER/ total Brady 1/46 (2.1%)
DiFiore et al.26 ≤30 s Aps of >10 s before, during or
after acid GER/ total GER
532/ 6255 (8.5%) Number of Aps >10 s
before, during or
after acid GER
More Aps before
+ during GER
compared to
during/after
GER (p = 0.01)†
No
Aps >15 s before, during or
after acid GER/ total GER
64/6255 (1%) Number of Aps >15 s
before, during or
after acid GER
Trend toward
more Aps before
+ during GER
compared to
after GER
Exact figures +significance nr
Infants with ≥1 GER episode
associated with Ap >10 s/
total infants
83/119 (69.7%)
Infants with ≥1 GER episode
associated with Ap >15 s/
total infants
27/119 (23%)
DiFiore et al.27 ≤30 s Aps after GER/all Aps 72/2118 (3.4%) GER after CR event 378/4164 (9%) No
CR events after GER/ all
CR events
375/12 957 (<3%)
Menon et al.28 10 s post-GER
periods
Aps in after-GER periods/
all Aps
8/100 (8%) - Yes
Mean freq Aps in post-GER
periods vs freq Aps during
GER free periods
p < 0.05†
*RAAP, reflux associated apnea, Cisapride treatment reduced RAAP (not significant s, p = 0.12). †No exact numbers or calculations reported. GER,
gastroesophageal reflux; Ap, apnea; Aps, Apneas; ApsC, central apneas; ApsO, obstructive apneas; ApsM, mixed apneas; CR event, cardiorespiratory
event (including all apnea, solitary bradycardia and solitary oxygen desaturations); nr, not reported.
© 2014 John Wiley & Sons Ltd1534
M. J. Smits et al. Neurogastroenterology and Motility
advocated for infant GERD after being linked to tardive
dyskinesia.35,36 From the studies reporting on medica-
tion, apnea therapy (caffeine and/or theophylline)
appeared to have no effect on GER parameters, nor
did anti-GER medication seem to influence GER
related apnea, implying GER and apnea are not asso-
ciated. Still, considering the lack of data provided, no
firm conclusions can be drawn.
Finally, statistical analysis of the association
between GER and apneas was very poor across
included studies. None of the studies used a GER or
apnea specific association index, whereas mean values
and standard deviations were sparsely provided. This
makes interpretation of the data difficult. Although
current available association indices for GER-related
symptoms all have their limitations, it is indispensable
to prove the presence of association between GER and
apneas.37 New association indices specifically aimed at
the relation between GER and respiratory events might
proof suitable alternatives for future research. How-
ever, no golden standard exists yet.29,38
One study that showed a positive association
between GER and apnea, used pharyngeal pH-metry
to assess GER.28 Due to its position, the catheter is
unable to detect distal GER events not reaching the
pharynx, which can theoretically trigger apnea through
esophageal distension and subsequent vagal activation.
In addition, simultaneous recording time of GER and
apneas in the study of Menon et al. was very short,
with a mean of 1.4 h for six children and 2–3 h for the
remaining four infants. For clinical use, a minimum of
18 h recording of GER is commonly used to reliable
associate symptoms with GER.39 Recently, the influ-
ence of recording time on the association found was
clearly shown, confirming the need for prolonged
monitoring.40
In general, GER is universally present in infants,
with 50% of infants of 0–3 months having visible
regurgitation at a daily basis. Normative values of the
total amount of acid and weakly/non-acid GER not
reaching the mouth are unknown, but the amount of
distal acid GER episodes alone in healthy infants can
reach up to 56 episodes. Apneas are a relative rare
phenomenon in mature infants, especially after the
first days of life. With a large physiological amount of
GER episodes (further enhanced by posture, frequent
liquid feeds, and anatomical properties of the infants
upper gastrointestinal tract) and little apneas, associa-
tion can be found as a result of chance. Especially with
small sample sizes and with inadequate definitions of
GER, apneas and association indices. Moreover, even if
a causal relation exists, a reduction in apneas does not
necessarily reduce the number of GER events signifi-
cantly, because most GER events will occur simply
because all infants, including completely healthy
babies, experience GER events frequently. In addition
to the paucity of high quality evidence on this topic, a
recent study even states GER is associated with
interruptions of sleep in infants (arousals), which
implies nocturnal GER episodes are likely to amplify
respiratory reflexes.40
A better understanding of the association of GER and
respiratory mechanisms (i.e., apneas) in infants will
have great diagnostic and therapeutic consequences for
this group of patients and could potentially lead to
shortened hospital stay and a reduction in healthcare
costs. GERD is diagnosed in up to 50% infants admitted
for recurrent apneas and frequently accompanied by
costly and invasive diagnostics and even therapeutic
approaches like antireflux surgery.41–43 Thus, there is a
clear need well-powered studies.
One of the challenges when conducting research
addressing the association between GER and apnea in
symptomatic infants is the lack of consensus regarding
criteria which are needed to identify an infant as
‘symptomatic’. According to clinical guidelines, GERD
is defined as GER causing troublesome symptoms and
complications, with apneas mentioned as one of those
possible complications.9 Similar, only when the num-
ber of apneas per hour exceeds a threshold, a patient is
classified into one of the apneic sleeping disorder
syndromes (either central, obstructive or mixed).44
However, theoretically, every single GER episode
could trigger a significant apneic event and vice versa.
Therefore, when defining inclusion criteria, it is of
importance to realize that assessing the association
between GER and apnea is different from diagnosing
GERD or an apnea syndrome in clinical practice.
More generally, successful execution of randomized
clinical trials is often obstructed by difficulties of
recruiting research groups of sufficient size due to
ethical dilemmas both for medical ethical committees
and parents.
We suggest future studies assess premature and
mature infants separately, to distinguish the possible
different pathophysiological mechanisms of apnea of
prematurity and persistent apneas after reaching full
term. Furthermore, the use of state-of-the-art tech-
niques that include at least pH-MII for the detection of
all GER episodes is essential to find an association
between a normal and ubiquitous physiological phe-
nomenon as GER and a relatively rare phenomenon as
pathological apneas. Additional esophageal manometry
further enables assessment of predominant neurologi-
cal mechanism behind GER: TLESRs.2,45 For apnea, a
clear cut definition according to the latest standards
© 2014 John Wiley & Sons Ltd 1535
Volume 26, Number 11, November 2014 Systematic review association infant GERD and apnea
should be used, dividing apneas into central, obstruc-
tive, and mixed.4 Calculations on association of GER
and apneas must be based on best available association
indices and a well described epoch for association. To
sufficiently power studies, Barriga et al. demonstrated
that a prolonged measurement increases the possibility
to detect an association. Indeed, in recordings of
<12 hrs or with <70 GER episodes and <10 symptoms
(apneas) per 24 h, finding an association between GER
and symptoms is mathematically impossible.38 This
problem might be partially overcome by elongating the
measurements artificially with a mathematical
algorithm generated by computer systems. While a
recent study showed that GER distributions can indeed
be reproduced in silico, future research will need to
show if symptoms such as apneas can be predicted by
computer models in a similar way.46
In conclusion, despite substantial literature on the
association between GER and apnea in infants, this
systematic review identified only six articles that met
our inclusion criteria and were suitable for data
extraction. This indicates there is a lack of high quality
data addressing this topic. We found insufficient
evidence for an association between GER and apnea
in infants. Nevertheless, it might be that GER is
causally related to apnea in a selected group of infants.
To adequately identify if this group exists and what the
nature of this hypothesized GER-apnea association is,
there is a need for high quality, well-powered studies
using uniform inclusion criteria, definitions according
to accepted guidelines, state-of-the-art techniques,
reliable symptom association indices, and patient
relevant outcome measures.
ACKNOWLEDGMENTS
We would like to thank Dhr. A. Leenders of the AMC library(Medical Library, Academic Medical Centre, Amsterdam, TheNetherlands) for conducting the literature.
FUNDING
No funding was secured for this study.
DISCLOSURE
The authors have no financial relationships relevant to this articleto disclose. None of the authors received an honorarium, grant orother form of payment to produce the manuscript.
AUTHOR CONTRIBUTION
MJS wrote the first draft of the manuscript. All authors acceptresponsibility for the reported content and declare they all haveparticipated in the concept, design, draft, and revision of thismanuscript. All authors have approved this version of themanuscript; MJS conceptualized and designed the study, scoredall abstracts and full text articles, drafted the initial manuscript,and approved the final manuscript as submitted; MPWwas secondrater of abstracts and full text articles for systematic review,reviewed and revised the manuscript, and approved the finalmanuscript as submitted; MWL, MAB reviewed and revised themanuscript, and approved the final manuscript as submitted;MMT was deciding rater of full text articles for systematic review,senior author, reviewed and revised the manuscript, and approvedthe final manuscript as submitted.
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