Association between gastroesophageal reflux and pathologic apneas in infants.
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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
>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
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
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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