the role of gastro-oesophageal reflux in the aetiology of sids

Early Human Development 59 (2000) 127–149www.elsevier.com/ locate /earlhumdev

The role of gastro-oesophageal reflux in theaetiology of SIDS

a,b a,b ,*Megan Page , Heather JefferyaDepartment of Neonatal Medicine, Royal Prince Alfred Hospital, Missenden Rd.,

Camperdown NSW 2050, AustraliabDepartment of Obstetrics and Gynaecology, The University of Sydney, Sydney, Australia

Received 9 February 2000; received in revised form 26 June 2000; accepted 27 June 2000

Abstract

Gastro-oesophageal reflux (GOR) has been identified as a possible cause of SIDS. Severalfeatures of GOR unique to infants presenting with apparent life-threatening events (ALTEs)have led to its ‘pathogenic’ definition. One is that the life-threatening apnoea itself is initiatedby GOR, another is that the ALTE relates to prolonged reflux during sleep, in a vulnerablesleep-state, and finally that the ALTE relates to excessive quantities of GOR. The presumptionof GOR ‘pathology’ as a cause of SIDS however, is questionable in these susceptible infantsfor three reasons: firstly, GOR is physiological and occurs in most infants; secondly, there is nogeneral consensus on what constitutes normal physiological reflux, and thirdly, variation in therecording technique and methods of data analysis and interpretation may account for thedifferences between study groups. It seems likely therefore if GOR is implicated in SIDS,additional factors are involved. Under certain circumstances, physiological GOR may triggerlife-threatening apnoea in apparently healthy infants, that leads to SIDS. One mechanism thatcould explain such a death is reflex apnoea by stimulation of laryngeal chemoreceptors (LCR)during sleep. The conditions under which this could be fatal are the occurrence of gastriccontents refluxed to the level of the pharynx during sleep, in the young infant who hasdepressed swallowing and arousal. That is, the occurrence of GOR to the level of the pharynxduring sleep, an infrequent event that is usually innocuous, could be converted to a fatal eventif swallowing is impaired and arousal depressed, by a variety of mediating factors such asprone sleeping, prematurity, sedatives, seizures or upper respiratory tract infections. Theidentification of LCR responses, particularly in prone sleeping and premature infants providefurther evidence that this mechanism may be implicated in the aetiology of SIDS in apparentlyhealthy infants. 2000 Elsevier Science Ireland Ltd. All rights reserved.

*Corresponding author. Tel.: 1 61-2-9515-8248; fax: 1 61-2-9550-4375.E-mail address: [email protected] (H. Jeffery).

0378-3782/00/$ – see front matter 2000 Elsevier Science Ireland Ltd. All rights reserved.PI I : S0378-3782( 00 )00093-1

128 M. Page, H. Jeffery / Early Human Development 59 (2000) 127 –149

Keywords: Sudden Infant Death syndrome; Gastro-oesophageal reflux; Apparent life-threatening events

1. Introduction

Sudden Infant Death syndrome (SIDS), is defined as ‘The sudden death of aninfant under one year of age which remains unexplained after a thorough caseinvestigation, including performance of a complete autopsy, examination of the deathscene, and review of the clinical history’ [1]. SIDS continues to be one of the leadingcauses of infant mortality after the first month of postnatal life [2].

The most outstanding features of SIDS are that, by definition, death is bothunexpected and unexplained. Furthermore, the age at death occurs predominantlybetween 1 and 4 months, with a peak age at 2 months [1], and death occurs silentlyand during apparent sleep [3].

Several factors which increase the risk for SIDS, for example the prone sleepingposition, have been identified. Despite the identification of such risk factors andsubsequent intervention (by way of public awareness campaigns), SIDS remains asignificant cause of infant mortality. There are therefore, other yet unestablishedfactors which still account for sudden and unexplained infant death.

Gastro-oesophageal reflux (GOR) has been implicated in SIDS, since research inthe late 1970s showed an association between ‘pathological’ reflux and episodes in‘near miss’ SIDS cases. Research carried out to date has not, however, established aclear causal link between ‘pathological’ GOR and SIDS in such cases; nor are theresults applicable to seemingly healthy infants who die suddenly.

Gastro-oesophageal reflux (GOR) refers to the involuntary retrograde movement ofgastric contents into the oesophagus. Several studies using oeosphageal pH moni-toring have demonstrated that GOR occurs commonly in normal infants though notusually clinically apparent [4–6]. In most infants, GOR is little more than aninconvenience and usually only associated with early infancy [7]. This is demon-strated by the fact that the majority of infants are completely free of regurgitation by12 months of age [6] and suggests some maturational effect on the occurrence ofGOR [7,8].

The a priori case for the implication of GOR in SIDS rests on the fact that GORoccurs in the same age range in which SIDS occurs, and occurs in sleep as well as thewaking state. It occurs, furthermore, in most, if not all, infants. The GOR itself is not,however, postulated to be the immediate cause of death as would be the case if itwere due to suffocation from obstruction of the airway. The link to SIDS, if GOR isimplicated, may be through the cardiorespiratory events which are initiated to preventthe reflux being aspirated into the airway. The response it induces must, therefore, bean abnormal one, for clearly, the particular episode of GOR which leads to death isonly one of a very large number which would have occurred in the lifetime of aninfant.

Research efforts have concentrated on identifying the occurrence and duration ofGOR in infants with apparent life-threatening events (ALTE) also known as ‘near-

M. Page, H. Jeffery / Early Human Development 59 (2000) 127 –149 129

miss’ SIDS episodes. During these apparent life-threatening events the infant is foundapnoeic, cyanotic or pale and requires stimulation or resuscitation for revival. Theirparticular relevance to investigation of possible causes and mechanisms of death inSIDS infants is based on the assumption that ‘near-miss’ SIDS infants and thoseinfants who die of SIDS have similar pathologic mechanisms. The overwhelmingnumber of reports define the extent of GOR in these infants as ‘severe’, ‘abnormal’ or‘pathological’ [9–25].

This paper is designed to critically examine the methodologies employed in themeasurement of GOR, and to highlight why the outcome measures of GORoccurrence and duration are limited as an indicator for SIDS risk. If GOR is themechanism for SIDS, this paper suggests it is by virtue of an ‘abnormal’ response toa physiological stimulus, rather than its occurrence per se.

2. Aetiology of GOR and SIDS

Support for the concept that GOR may be causally related with prolonged apnoeaand SIDS in certain infants was originally reported in the late 1970s [12,26]. BothLeape [26] and Herbst [12] implicated GOR as the cause of respiratory signs in‘near-miss’ SIDS infants based on several observations. The occurrence of reflux wasidentified by barium studies in all infants [12,26] and confirmed by Herbst [12] usingoesophageal motility and pH measurements. During the pH measurements, fiveinfants had an episode of apnoea and cyanosis immediately following an episode ofGOR as defined by a drop in oesophageal pH [12]. In all these infants a diagnosis ofGOR was made, and treatment was instituted. In almost all infants the respiratorysymptoms improved or completely resolved [12,26]. One infant died howeverfollowing the withdrawal of GOR therapy. An autopsy was conducted, and thefindings were consistent with SIDS [12].

The authors concluded that gastro-oesophageal reflux in these infants inducedrespiratory arrest, and may be the mechanism of death in some SIDS infants. Theyalso highlighted the apparent lack of clinical evidence or history of vomiting, thusimplicating ‘occult’ GOR events in the production of the response.

3. Measurement of GOR

As a result of the initial reports, investigations of infants presenting with ‘near-miss’ SIDS episodes have included tests to evaluate GOR. In young infants severaldiagnostic procedures have been utilised to evaluate GOR. These include the bariumswallow [14,17,27–30], technetium milk scan [14,17,27,28,31–33], ultrasound [34–36], oesophageal acid test [27,30,37–40], oesophageal manometry [27,37,38,41–43]and most commonly extended oesophageal pH monitoring [44–57].

Of these methods, the most useful is pH monitoring as it can be used over longtime periods and can be quantified. The other methods serve specific needs and shallbe mentioned briefly.


Barium swallow is useful for detection of anatomical abnormalities such asoesophageal stricture, hiatus hernia and to define whether reflux reaches the proximaloesophagus, the pharynx and larynx. The predictive value of the test is limited by theshort duration of observation for reflux.

Gastro-oesophageal scintiscan is a nuclear medicine scan performed under agamma counter after ingestion of technetium-labelled milk. The advantages include anon-invasive test, low in radiation with the ability to detect reflux, gastric emptyingrate and pulmonary aspiration but insensitive for quantitative studies of reflux andless sensitive than barium for the detection of anatomical abnormalities. There ishowever, no standard method of application of this test.

Oesophageal acid test used in adults to reproduce symptoms, especially painassociated with acid-reflux, but used infrequently in children and rarely in infants.

Oesophageal manometry in infants has been used primarily as a research toolbecause of technical difficulties with catheter size and perfusion rates. Miniaturecatheters perfused at low rates have enabled short-term studies of the oesophagealbody and lower sphincter [43] and solid-state manometry has enabled longerphysiological studies during sleep with the added ability to detect pharyngealswallowing reliably [58].

Oesophageal endoscopy and biopsy allow direct visualisation of the oesophagealmucosa and assessment of the severity of reflux oesophagitis through the use of smallfiberoptic endoscopes. Interpretation of biopsies in children are less certain.

Intraluminal multiple electrical impedance (IMP) measures gastrointestinalmotility through a pattern of electric impedance during GOR [59]. Recordings aremade via a catheter combining electrodes for impedance measurements. The claimedbenefits of the IMP technique are that it facilitates the detection of all GOR, whereaspH metry is confined to the measurement of acid GOR [59], however, this methodhas not yet been evaluated as a diagnostic test.

Oesophageal pH monitoring involves the placement of a probe in the desired siteof the oesophagus via the nose or mouth and is based on the continual measurementof the oesophageal pH over a period of time. The normal pH of the oesophagus isbetween 5 and 7 and therefore the probe is capable of detecting the reflux of acidcontents from the stomach. A reflux episode is defined as a drop in oesophageal pH,to a pH less than 4 for greater than 15 s.

Although each technique has particular diagnostic advantages, extendedoesophageal pH monitoring is considered the most sensitive and specific method fordetecting the presence of GOR [44,45,48,50,52,54,55,57,60,61]. One particularadvantage of this technique is that the outcome can be defined in quantitative terms.The outcome measures reported include: (1) the number of GOR episodes, (2) thenumber of episodes lasting 5 min or more, (3) the duration of the longest GORepisode, and (4) the percentage of the total study time that the pH is below 4 (refluxindex). More complex scoring systems involving mathematical manipulation of theseindices have been derived [62,63], however such scores tend to obscure the actualfrequency and duration of GOR episodes. It also allows prolonged monitoring withother physiological recordings in order to observe associated cardiorespiratory events


in ‘at risk’ infants. The ability to accurately detect and measure quantities of refluxusing oesophageal pH monitoring has enabled the procedure to be utilised to not onlyevaluate the incidence of GOR in infants presenting with ‘near-miss’ SIDS episodesbut also to characterise and quantitate the patterns of reflux implicated in the cause ofthese events. Further discussion will therefore entail technical and methodologicalaspects of pH monitoring and how they have been interpreted with respect to the roleof GOR in SIDS.

4. GOR in infants presenting with apparent life-threatening events (ALTE)

Several reflux characteristics have been identified in infants presenting withapparent life-threatening events. The first is that the life-threatening apnoea itself isinitiated by GOR, the second that the ALTE relates to prolonged reflux during sleepin a vulnerable sleep-state, and the third that the ALTE relates to excessive quantitiesof GOR. It is proposed by some investigators that these characteristics of GOR arepathogenic since they are unique to infants presenting with life-threatening events.Whether these characteristics represent a truly unique and pathological refluxphenomenon is questionable, as the respiratory response to GOR and the quantity ofreflux measured by the pH probe is dependent not only on the patient but on amultitude of technical and methodological factors. Each of these factors may beresponsible for the outcome.

4.1. GOR and apnoea

Several studies have attempted to determine whether a causal relationship existsbetween episodes of GOR and apnoea in infants presenting with life-threateningevents. Some investigations have demonstrated that GOR and apnoea are temporallyrelated [12,13,22,26,35,64], whilst other studies have been unable to confirm thisrelationship [9,19,21,25,65,66]. The reason for this discrepancy is unclear. Thetechnical limitations of pH probe monitoring and methodological shortcomings makesinterpretation and comparison of the findings difficult in many cases.

4.1.1. Technical limitationsThere are several technical limitations relating to pH probe monitoring and its

ability to characterise the relationship between GOR and apnoea. One is the presenceof a pH probe in the upper airway and upper gastro-intestinal tract which may alterthe natural occurrence of apnoea and GOR [17,67].

Another is that the level reached by the reflux stimulus can only be accuratelydetermined at the point in the oesophagus where the tip of the pH probe is positioned.The majority of studies in infants have attempted to associate apnoea with acidchanges measured at the level of the distal oesophagus [9,13,19,22,25,65]. In younganimals however, stimulation of the upper oesophagus has been seen to produce moreprofound cardio-respiratory effects than stimulation in the lower oesophagus [68,69].


In conflict with this evidence are human infant studies examining spontaneous refluxevents in the proximal oesophagus which did not find any association between GORand apnoea [20,65]. Apnoea may only be provoked by more proximal refluxstimulating airway, rather than oesophageal receptors [70]. Such stimulation would bea consequence of refluxed material coming into contact with the pharynx first, whichhas been demonstrated by other techniques to occur regularly in ALTE infants[14,17,35].

Finally, reflux of neutral gastric contents may induce apnoea. However such refluxwould go undetected by the pH probe for up to 2 h after milk feeding in infants [71]because the probe cannot detect GOR at the same neutral pH of the oesophagus.

4.1.2. Methodological limitationsGOR and apnoea are events which occur both frequently and independently. They

may therefore occur concurrently by chance alone, giving the impression of atemporal relationship [72].

Several studies have examined whether GOR measured by pH probe at the level ofthe distal oesophagus increases the occurrence of apnoea from spontaneous levels[9,14,25]. Although brief obstructive apnoea of $ 3 s occurred more commonlyduring GOR compared with control [9], these studies failed to show an associationbetween reflux episodes and central apnoea of $ 3 s [9] or of longer duration ( $ 10 s)[14,25]. These authors concluded that apnoea was equally likely to occur sponta-neously as it was during GOR.

Failure to observe any association between GOR and apnoea may be a conse-quence of focusing on events in the lower oesophagus, whereas cardio-respiratoryevents may occur as a consequence of refluxed material coming into contact with theupper airway [64]. Compared with control values, GOR to the level of the pharynxincreased the probability of short apnoea ( | 3 s) by a factor of 8, and prolongedapnoea ( . 20 s or less if accompanied by decrease in heart rate to , 100 bpm) by afactor of 14. This study group consisted of nine preterm and one term infant(gestational age 28–36 weeks at 2–4 weeks postnatal age). It is unclear whether theseapnoeic responses would be evoked in older infants, at the age at which SIDS deathspeak, or whether pharyngeal GOR-induced apnoeic pauses are limited to thesepreterm infants in the first weeks of life. There is other evidence to suggest that upperairway protective apnoeic pauses induced by air stimulation of the trigeminal nerve inboth term and preterm infants become blunted with increasing gestational andpostnatal age [73].

Alternatively, the severity of the response may be related to the sensitivity of theinfant. In infants presenting with ‘near-miss’ SIDS episodes, apnoea was induced bysimulation of acid reflux into the mid-oesophagus [13]. Similar simulations duringactive sleep in younger healthy infants aged 36–40 weeks resulted in the prolongationof breath-to-breath intervals. The longest intervals reported however were only 1 s induration [74].

Despite the uncertainty in results due to technical and methodological limitations, itis still possible that GOR evokes apnoeic events in some infants. It is clear however,that not all reflux events provoke this response. This suggests that additional factors


may be involved in order to precipitate life-threatening apnoea. One possible riskfactor identified is reflux of the gastric contents into the pharynx. Whether adifferential risk applies to infants presenting with ‘near-miss’ SIDS and, normalhealthy infants, is not yet known.

4.2. GOR in sleep

Studies in ‘near-miss’ infants have proposed that a relationship between GOR andsleep is involved in the production of life-threatening apnoeic responses. In ALTEinfants, reflux occurs most commonly during wakefulness [9,65,75,76], however, itspresence in the oesophagus in these infants is most prolonged in sleep [75,76].Similar findings have been reported in adults and normal infants [77–79] and ittherefore seems likely that delayed clearance of reflux in sleep represents a truephysiological change associated with sleep.

Studies have shown that oesophageal acid clearance is a two-step process [80,81].The first step involves oesophageal emptying carried out by a series of peristalticwaves [82]. Swallow-induced peristalsis (i.e. primary peristalsis) [83–85] andsecondary peristalsis (waves initiated by oesophageal distension) [80,84,86] havebeen identified as responses to GOR.

The second step of acid clearance is the acid neutralisation of the oesophaguswhich is achieved by saliva [87]. The saliva has a buffering effect, and is carried intothe oesophagus by primary peristalsis, and therefore swallow-induced peristalsis isthe major mechanism of oesophageal acid clearance [81,83,84]. Swallowing however,is depressed during sleep in both adults [88,89], and infants [90], and this contributesto the delayed clearance of refluxed gastric contents in sleep as compared withwakefulness.

Some authors claim that GOR in sleep in ALTE infants is more prolongedcompared with non-ALTE infants [18,23,91]. This relationship has not always beenconfirmed [65,92]. It may be that differences in acid clearance during sleep in ALTEinfants may be attributed to other factors which effect the mechanisms of acidclearance (primary and secondary peristalsis), which were not reported in thesestudies. These factors may include the volume of the bolus in the oesophagus [86,93],the pH of the reflux stimulus [84,94], or the upper level reached by the refluxstimulus [65,95], and movement arousals [89].

Alternatively, other mechanisms have also been implicated in delayed acidclearance. These include failure to increase swallowing in response to oesophagealacidification [79] and oesophageal dysmotility [85,96,97]. Despite the reportedsensory or motor abnormalities responsible for delayed acid clearance in theseinfants, they did not present with ‘near-miss’ SIDS episodes. It follows therefore thatthere must be doubts about the implications of delayed acid clearance during sleepand the production of apnoea in ‘near-miss’ SIDS infants.

Several studies claim that prolonged GOR in sleep may be a major determinant ofreflux associated respiratory disease and SIDS [11,15,16,98]. These authors suggestthat an excessive reflux score obtained from a mathematical manipulation of thereflux episodes which occurred in the period 2 h after feeding, correlated with the


presence of respiratory symptoms caused by GOR [11,16]. Evidence for GOR insleep as the causal factor is thus postulated by these authors since treatment of GORresults in subsequent improvement or even the resolution of the respiratory symptomsover time. There are some limitations however, with such an interpretation, becauseno account was taken of the fact that the symptoms may simply improve with thematuration of the infant, and because respiratory function (which was not measured)was not demonstrably correlated with specific episodes of GOR.

A more objective study suggests that GOR severity, as measured by pH probeoutcome parameters, is not directly related to respiratory symptoms [11]. The authorsmeasured respiratory function by thoracic gas volume, airways resistance, andmaximum expiratory flow at functional residual capacity. They also measured anumber of GOR indices namely, number of episodes, number of episodes . 5 minand reflux index. The authors failed to demonstrate any association between GORindices and lung function.

4.3. GOR and sleep state

Other studies suggest a possible role for sleep-state related GOR in infantspresenting with a ‘near-miss’ SIDS episode [65,75,76], in that it occurs mostcommonly in active sleep, but rarely in quiet sleep. This is of particular relevancesince during active sleep, reflexes which protect the airway against aspiration andprovide respiratory defence against asphyxia are depressed compared with quietsleep. For example, in active sleep, airway obstruction no longer excites augmentedintercostal muscle activity [99], the onset of hypoxaemia is accelerated as a result ofreduced oxygen stores in the lungs [100], ventilatory augmentation in response tohypoxaemia is depressed [100,101], reflex arousal from hypoxaemia is delayed [101]and cough reflexes are depressed [102].

More recent studies have demonstrated the same sleep-state /GOR association in acohort of 74 normal, healthy term infants [5] and older infants with symptomsindicative of GOR [66,95]. The findings suggest that sleep-state related reflux is aphysiological occurrence and not limited to infants presenting with life-threateningevents.

In summary, it seems unlikely that the extended duration of GOR episodes in sleepcontributes to life-threatening events observed in some infants. Should apnoea beevoked by GOR however, the response may be enhanced in active sleep, comparedwith quiet sleep. This suggests that the response of the individual to GOR in sleepmay be of greater relevance than the amount of GOR.

4.4. Diagnosis of ‘pathological’ GOR

‘Pathological’ GOR is diagnosed by oesophageal pH studies, the extent of thepathology being measured by a statistically increased amount of GOR in ALTEinfants compared with either non-ALTE or normal infants [10,21–24,103]. Adiagnosis of pathogenic reflux is taken to mean that the quantity of reflux is causing


the life-threatening response. However, whether the GOR in ALTE infants representsa pathologic process or simply represents physiology, is not clear.

The presumption of pathology is questionable for two reasons: firstly, there is nogeneral consensus on what constitutes normal reflux; and secondly, variation in therecording technique and methods of data analysis and interpretation may account forthe differences between study groups.

4.4.1. Normal GOR (Table 1)There are six studies which have used the oesophageal pH probe to report control

values for GOR, the results summarised in Table 1. The validity of the first threestudies listed in Table 1 is questionable. Although their subjects were selected for noclinical history of GOR, they were hospitalised for other problems [63,104] or nohistory was reported [105], so it is difficult to determine what population theyrepresent. Furthermore, because the infants were selected over a wide age range (1month to 3 years), there was no control for maturation [63,104,105].

The other three studies examined a large number of asymptomatic neonates [4–6].Vandenplas and Sacre-Smits described normal values for reflux from 24-h pHrecordings in 92 bottle-fed neonates, aged 5–15 days. However the method ofselection and prior health of these infants was not reported [6]. Gouyon et al. selected46 control infants from a neonatal unit, 50% of whom were preterm. They werestudied at a postnatal age of 2–21 weeks [4]. The possible impact of developmentalchanges however were not taken into account. Jeffery and Heacock [5] monitored 74normal, healthy newborn infants for 4 h following their morning milk feed during thefirst week of life. All the infants were born at term gestation following a normalpregnancy. Under these circumstances, the authors found physiological GOR wascommon and not usually evident. In addition, they found GOR to be sleep-staterelated. GOR occurred most commonly in wakefulness. In sleep, it occurred mostcommonly in the active sleep state, reflux being found to be a rare occurrence in quietsleep.

4.4.2. Comparative studiesThe results from the first five studies in Table 1 are not suitable for comparison

between themselves or, comparison with ALTE data, for the reason that anydifferences between them may be attributable to methodological variation. Further-more, the means and standard deviations calculated from these studies are in-appropriate because the distribution of data on reflux outcomes is not normal, henceare not appropriately descriptive of the data, and incapable of being analysed byparametric statistical techniques. Methodological factors that may influence theoutcome of any reflux study have been identified. These are described below underappropriate headings.

4.4.2.1. Duration of the pH probe study. It has been a generally accepted conceptthat GOR can only be diagnosed accurately by 24-h oesophageal pH probe studies[44,45,48,50,52,54–57]. The assessment of the test’s accuracy is postulated to rest ontwo factors, its ability to statistically distinguish between the presence of symptoms


Tab

le1

Aut

hor

and

Subj

ects

Age

GO

Rde

finiti

onPr

obe

posi

tion

Infa

ntpo

sitio

nD

urat

ion

Feed

type

Res

ults

Com

men

ts

year

(n)

Jolle

y,24

1m

onth

–pH

,4

515

s2.

5cm

abov

eLO

SU

prig

ht18

–24-

hliq

uid

diet

(mea

n6SD

)Su

bjec

ts:

1978

2ye

ars

Supi

neun

spec

ified

Aw

ake

RI

1.26

1.3

Asy

mpt

omat

icfo

rG

OR

Asl

eep

RI

0.16

0.2

Hos

pita

lised

uprig

htR

I1.

161.

4A

naly

sed

.2

hpo

stfe

ed

supi

neR

I0.

361.

1

Boi

xO

choa

,20

2m

onth

s–pH

,4

2.5

cmab

ove

LOS

Upr

ight

24-h

norm

alfo

od(m

ean6

SD)

Subj

ects

:

1980

3ye

ars

Supi

neun

spec

ified

Tota

lR

I1.

866

1.6

Asy

mpt

omat

icfo

rG

OR

Pron

eU

prig

htR

I1.

806

1.3

Det

ails

not

repo

rted

Supi

neR

I1.

596

2.9

Supi

ne,p

rone

,sem

i-sea

ted

Pron

eR

I3.

286

3.5

Rec

ordi

ngs

for

4h

Tota

lR

I10

.66

8.2

awak

ean

d4

has

leep

Long

est

(min

)8.

076

7.19

tota

ldu

ratio

nan

alys

ed

Sond

heim

er,

61–

24pH

,4

.8s

13%

ofoe

soph

agea

lSu

pine

head

13

9h

App

leju

ice

(mea

n6SD

)Su

bjec

ts:

1980

mon

ths

leng

thab

ove

LOS

elev

ated

at1

312

han

dco

wTo

tal

RI

1.76

0.5

Had

feed

ing

prob

lem

s

308

angl

e4

35

18h

milk

form

ula

epis

odes

/h0.

560.

2Fe

dap

ple

juic

ean

dco

ws

Long

est

(min

)8.

162.

8m

ilkfo

rmul

aev

ery

4h

oron

dem

and

Tota

ldu

ratio

nan

alys

ed

Gou

yon,

4636

–46

pH,

4.

15s

2–5

cmab

ove

LOS

Supi

ne24

-hhu

man

milk

,(m

ean6

SD)

Infa

nts:

1986

wee

kshu

man

ised

Tota

lR

I2.

863.

00G

esta

tiona

lage

28–4

1w

eeks

milk

and

No

epis

odes

/h0.

336

0.35

50%

pret

erm

form

ula

for

Epis

odes

.5

min

0.09

60.

13To

tal

dura

tion

anal

ysed

pret

erm

sLo

nges

t(m

in)

11.5

613

.3

M.

Page,

H.

Jeffery/

Early

Hum

anD

evelopment

59(2000)

127–149

137

Table 1. Continued

Author and Subjects Age GOR definition Probe position Infant position Duration Feed type Results Comments

year (n)

Vandenplas, 92 5–15 pH , 4 middle 1 /3 of Prone 24-h bottle fed (mean6 SD) Subjects:

1987 days oesophagus (5–6/day) Total RI 1.260.91 Asymptomatic for GOR

Episodes /24 h 7.7366.51 No details given

No . 5 min/24 h 0.6460.51 Total duration analysed

Longest (s) 2306115

Jeffery, 74 461 days pH , 4 5 15 s 6 cm above LOS Supine 4-h 37 breast mean and 95% CI (per hour) Subjects:

1991 37 formula AW Asymptomatic for GOR

Episodes 2.65 (5.34–8.66) Selected randomly

Duration 8.40 (5.20–11.60) Mothers normal pregnancy

AS and delivery

Episodes 1.87 (1.45–2.29) Infants born at term

Duration 12.1 (9.04–15.16) gestation (37–42 weeks)

IS Sleep state measured

Episodes 0.77 (0.17–1.37) Analysed . 2 h post feed

Duration 7.55 (4.18–10.92) Results expressed as:

QS Episodes /h

Episodes 0.22 (0.00–0.47) Duration (min/h)

Duration 5.25 (2.13–8.37) in each sleep state

Abbreviations: RI – Reflux Index; AW – Wakefulness; AS – Active Sleep; IS – Indeterminate Sleep; QS – Quiet Sleep; LOS – Lower Oesophageal Sphincter.


or disease secondary to GOR and normal control infants [46,47,49,51,53,106], and itsreproducibility [107,108]. The statistical thresholds and manipulations are biased bytheir retrospective nature, because the symptoms or disease status are known beforethe test is undertaken. Furthermore, reproducibility has been ascertained usingcorrelations of paired results and absolute differences [107,108], such tests do notadequately describe the relative change between two test results. More sophisticatedstatistical analysis involving a logarithmic transformation of the data in order todetermine relative differences between test outcomes [109] demonstrates a lack ofreproducibility between reflux parameters of 24-h studies [110]. These factors wouldsuggest that diagnostic accuracy and reproducibility of 24-h pH probe studies arequestionable.

Reflux studies of shorter monitoring periods have been subject to criticism on thegrounds of supposed diagnostic inaccuracy, non-reproducibility and artificial studyconditions (i.e. not under physiological circumstances) [44,45,48,52,54,56,57,111,112]. Against that, several authors have claimed diagnostic accuracy usingabbreviated studies [5,62,113–115].

As to the claim of shorter studies not being carried out under physiologicalconditions, the criticism is based on the view that any child being supine, fasted ( . 2h after feeding) and asleep will have reflux [54] and hence this condition is notrepresentative of the normal infant [56]. The contrary view would however, seem tobe the case, for newborn infants do spend much of their time asleep in the supineposition beyond 2 h after feeding. This contrary view is supported by the data inTable 1 which shows that reflux does occur in healthy infants. Indeed, Sondheimerconcluded that the differences between normal and pathological GOR will bemaximised under such conditions [116]. On balance therefore, there is little evidenceto support that one duration for oesophageal pH probe studies is superior to the otherfor diagnostic purposes.

4.4.2.2. Type of feed. Several differences have been identified in reflux outcomesaccording to the feed given to the infant. One study has compared the reflux index(i.e. % time pH , 4) following apple juice and formula feeding [117]. Followingapple juice feeds, the mean reflux index was 43.8% whilst only 5.1% following milkformula over the complete duration of the study (18–24 h). Another study by thesame primary author reported differences in the amount of GOR according to the typeof milk formula [118]. The mean percent of GOR following whey-hydrolysateformula (48.5%) was significantly greater than casein-predominant formula (39.7%).The result for soy formula (44.6%) was not significantly different to these twoformulae. Another study has reported that the duration of GOR episodes aresignificantly shorter in breast, compared with formula fed infants in the active sleepstate [119]. Yet another study has shown that the fat content of milk formula effectsreflux outcomes within 2 h of a feed. The reflux incidence increases with low fat milkas compared with a higher fat content [120].

4.4.2.3. Age of the infant. The amount of reflux experienced by an infant is at aminimum in the first 2 weeks of life. Reflux then peaks at 3 to 4 months, andsubsequently decreases with increasing chronological age [6,121].


4.4.2.4. Position of the pH probe in the oesophagus. The number and duration ofreflux episodes recorded has been shown to be dependent on the location of the tip ofthe pH probe in the oesophagus. The maximum number and duration of GORepisodes is registered with the pH probe situated in the lower oesophagus. Thisdecreases substantially the more proximal the probe is positioned [122–125].

4.4.2.5. Position of the infant. Several different positions have been evaluated todetermine their effect on the incidence and clearance of GOR. It has been found thatthe incidence of reflux in asymptomatic babies is significantly lower in the prone ascompared with supine, and left and right lateral positions [126]. It has also beenfound to be significantly lower in infants with GOR when the infant is in the proneposition and the head elevated between 30 and 458 than when in the upright position[127].

Results for the effect of upright versus supine position on GOR are conflicting.Some suggest GOR is increased in the upright compared with supine position[63,128]. Boix-Ochoa by contrast, reports reflux in the supine position to be morefrequent than it is in the upright position [105].

4.4.2.6. Post-cibal versus fasted. Despite reports that normal infants have frequentGOR in the 2 h post-prandial period [121,129], a significant limitation of pH probemonitoring, is that due to the normally slightly alkaline pH of the oesophagus,alkaline GOR cannot be detected [130]. Following a milk feed, the gastric contentsare neutralised for up to 2 h therefore GOR is rarely detected during this period[6,129,130]. Accurate detection of acid reflux will only be available in the ‘fasted’( . 2 h post cibal) period.

4.4.2.7. State of wakefulness compared with sleep and sleep state. The frequency andduration of reflux episodes is dependent not only on the state of wakefulness versussleep but also on the sleep state. Episodes of reflux occur most commonly wheninfants are awake [5,9,52,65,75,76,121]. When infants are asleep, reflux occurs mostcommonly in the active sleep state [5,19,65,66,75,76,92,95], and only rarely in quietsleep.

4.4.2.8. Number of subjects. Studies on infants using oesophageal pH monitoring,have shown there is a great deal of inter and intrasubject variability with respect toboth the number and duration of reflux episodes [108–110]. The underlyingvariability of the amount of reflux must be taken into account when interpreting theresults [110]. As a result, the outcomes reported from small studies may not havesufficient power to demonstrate a significant difference (a Type II error). Conversely,it may also increase the likelihood of a Type I error, that is showing differenceswhich are not reproducible.

It follows therefore that reliable comparative pH probe studies require conditionswhich are kept constant between groups of infants [116]. Large study groups are alsorequired to accumulate enough statistical power [131] to account for variability inGOR [132] in order to detect any real differences should they exist [110].


4.4.2.9. Statistical analysis. Another confounding factor making interpretation of theliterature difficult are the statistical analyses utilised to detect differences betweengroups, or the statistical thresholds used to define ‘physiological’ as opposed to‘pathological’. Comparative studies have used parametric statistics such as thecomparisons of means (Student’s t-test) [9,16,20,91], and setting parameters ofnormal reflux by several standard deviations from the mean [10,21,23,24]. Refluxparameters are not normally distributed [133]. Using statistics which have assump-tions regarding the normality of distribution of data (i.e. parametric statistics) on datawhich does not conform to the assumed distribution may lead to erroneous findings[134]. In this instance, non-parametric statistics which make no such assumptions,may offer a more valid method of analysis.

More recently a study by Vandenplas et al. described non-parametric outcomes for509 infants at risk for SIDS with suspected GOR [135]. The 95% confidence intervalsdemonstrated that the reflux index in these infants could be as high as 13% and aslow as 0%. It is therefore an unrealistic aim to expect to identify a diagnosticthreshold value for acid exposure recorded. Such a range in infants with suspectedGOR pathology renders them inseparable from infants with physiological GOR.

4.4.2.10. Other factors influencing pH probe studies. The type of electrode (glass orantimony) [136], type of pH recording device and the software program utilised[137], will also effect pH probe study outcomes.

4.4.2.11. Summary of comparative studies. Even if GOR is the mechanism for ALTEin these infants, it is unclear from the literature whether the GOR is ‘pathological’ perse or whether the differences in GOR reported between these infants (compared withother ‘normal infants’) is due to any one of the above variables. It follows therefore,that comparative data are only useful if variables known to affect the outcomemeasures, listed above, are controlled in experimental protocols.

4.4.3. GOR in infants considered to be ‘at risk’ of SIDSOne possible way to overcome these methodological difficulties is to define what

constitutes normal physiological reflux, and then compare this with a group of infantsconsidered to be at risk for SIDS, while the known confounding variables are keptconstant. Two studies have examined the occurrence, frequency and responses toGOR during sleep in infants considered at increased risk for SIDS, namely formula-fed [138] and preterm infants [139].

The first study compared GOR outcomes in breast and formula fed infants [119],and the second between term and preterm infants (at term post conceptional age)[140]. The purpose of both studies was to assess whether there are levels of suchmeasurements which might be considered normal and whether these are different in‘at risk infants’. In order to exclude the influence of extraneous factors (e.g. sleepingposition) on the results, such factors were kept constant in all tests. This allowed forthe direct comparison of the resultant data sets.

The first study reported that the type of milk feed effects the duration of GORepisodes in active sleep only [119]. Breast fed infants had significantly shorter


episodes than formula-fed. It may be, that the increased risk of SIDS in formula-fedinfants is related to the increased exposure to the pathologic stimulus or precipitatingfactor. The mechanism by which this response may be evoked however, is notapparent. By contrast, the second study reported that preterm infants, by term age hadfewer and shorter episodes of GOR compared with term infants in active sleep andwakefulness [140]. The group considered ‘at risk’ therefore had a decreased exposureto the pathologic stimulus.

5. Conclusion in respect of GOR studies

It seems unlikely that a quantitative ‘physiological /pathological’, ‘normal’ /ALTEor ‘risk factor’ distinction exists. This is because GOR occurs to varying degrees inmost infants (Table 1). Therefore any causal connection between GOR and SIDSmust be capable of explaining why sudden death occurs (also) in seemingly healthy,normal infants. Any examination directed at explaining the phenomenon by referenceto ‘near-miss’ or ‘at risk’ cases suffers from not taking into account either‘pathological’ cases of GOR that do not have an ALTE, or ‘non-pathological’ casesof GOR that die from SIDS.

This analysis suggests that if GOR is the trigger for sudden and unexplained death,that the response of the individual to the GOR episode may be of more relevance thanthe occurrence of GOR per se. Furthermore, the response it induces must be anabnormal one, for clearly, the particular episode of GOR which leads to death is onlyone of a large number which would have occurred in any particular infant. Thereforeadditional factors must operate to promote life-threatening cardio-respiratory eventsinitiated by GOR. One risk factor is the height reached by the reflux stimulus.

6. Pharyngeal GOR — a possible mechanism for SIDS

Of the mechanisms that have been considered, one of the most striking andpotentially lethal is the activation of the laryngeal chemoreflex (LCR). This reflex hasbeen described extensively in tracheostomised animals (with or without anaesthesia),is activated by direct fluid stimulation of the laryngeal mucosa and leads to a complexseries of responses in the young animal, including apnoea, bradycardia, swallowing,startle, hypertension, and regional redistribution of blood flow [141]. The reflex isage-related and confined to the young infant [142].

The LCR has been examined in animals that are surgically intact and asleep [143],surgically intact and anaesthetised [58], tracheostomised and anaesthetised[141,142,144–154], and tracheostomised and sleeping [102,155,156]. The differingmethodologies used in these studies result in different responses. An analysis of thesestudies demonstrates that LCR-induced apnoea is only life-threatening when thesubject is anaesthetised and when the stimulus is applied directly to the larynx (via atracheostomy) [141,142,144–154], or has stimulated the larynx via the pharynx [58].This suggests that after pharyngeal fluid stimulation, LCR-induced apnoea could be


fatal if the mechanisms that protect the airway from fluid entry, such as swallowing,arousal and expiratory reflexes, are depressed in the infant [58].

The findings from other studies indirectly support this hypothesis. For example,sedative drugs such as phenothiazines have been implicated in SIDS [157]. In normalinfants, during sleep, phenothiazines depressed the incidence of spontaneous arousals,increased the number of central apnoeas and induced obstructive apnoeas [158]. Thelikely mechanism for the association observed between phenothiazines and SIDS, isthat swallowing rate is significantly reduced following pharyngeal reflux whichrenders the infants susceptible to LCR-mediated responses [159]. Mechanisms otherthan drugs, that impair airway protection and arousal and therefore could beimplicated in ALTEs and SIDS, include temporal lobe seizures [160], that have beenrecorded during the sleep of infants presenting with ALTEs [14], and upperrespiratory tract infections. Many SIDS victims have a history of respiratory tractinfections prior to death [161], with recovery of virus from the respiratory tract [162],but they are not usually severe enough to account for the fatal outcome. Infection hasbeen reported to alter sleep and respiratory patterns [163] and sleep fragmentationmay impair arousal [164]. Furthermore, infections such as respiratory syncytial virusaugment a laryngeal-induced reflex apnoea [165], possibly by altering the sensitivityof pharyngeal / laryngeal receptors.

The strongest support for this hypothesis however, is found in studies that haveexamined the LCR in human infants. When supine, infusion of fluid did not evoke theLCR complex of responses (as described above), in healthy term infants [90]. Theresponses that did occur were swallowing, arousal and expiratory reflexes, whereasbreathing was always maintained. Indeed, these responses are most likely mediatedby receptors in the pharynx as opposed to laryngeal receptors, because there was noalteration in breathing. Nonetheless, infants are potentially at-risk for LCR-inducedacute life-threatening or fatal apnoeic events, because responses consistent with theLCR have been reported in the preterm and hospitalised infant [166–169].

The most striking evidence however is the finding that, even in healthy terminfants, airway protection is compromised in the prone position following infusion ofminute volumes of fluid into the pharynx during active sleep [170]. When prone andin active sleep, swallowing frequency was significantly lower, and the decrease inrespiratory rate greater, with no compensatory increase in arousal followingpharyngeal fluid stimulation compared with the supine position [170]. This findingendorses the ‘back to sleep’ advice. Although babies are likely to have more GOR inthis position, the infant’s ability to protect the upper airway from potentially fatalLCR-mediated responses is superior.

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the role of gastro-oesophageal reflux in the aetiology of sids

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