The Effect of Thickened-Feed Interventions on Gastroesophageal Reflux

7/27/2019 The Effect of Thickened-Feed Interventions on Gastroesophageal Reflux

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DOI:10.1542/peds.2008-19002008;122;e1268-e1277; originally published online Nov 10, 2008;Pediatrics

Andrea Horvath, Piotr Dziechciarz and Hania Szajewska

Infants: Systematic Review and Meta-analysis of Randomized, Controlled TrialsThe Effect of Thickened-Feed Interventions on Gastroesophageal Reflux in

http://www.pediatrics.org/cgi/content/full/122/6/e1268located on the World Wide Web at:

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rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.Grove Village, Illinois, 60007. Copyright 2008 by the American Academy of Pediatrics. Alland trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elkpublication, it has been published continuously since 1948. PEDIATRICS is owned, published,PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

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REVIEW ARTICLE

The Effect of Thickened-Feed Interventions onGastroesophageal Reflux in Infants: SystematicReview and Meta-analysis of Randomized, ControlledTrials

AndreaHorvath, MD,Piotr Dziechciarz,MD,Hania Szajewska, MD

2nd Department of Paediatrics, Medical University of Warsaw, Warsaw, Poland

The authors have indicated they have no financial relationships relevant to this article to disclose.

ABSTRACT

CONTEXT. Currently, thickened feeds are increasingly being used to treat infants withgastroesophageal reflux, driven in large part by the baby food industry. Previousmeta-analyses have shown that although thickened formulas do not seem to reducemeasurable reflux, they may reduce vomiting. However, because data are limited,there is still uncertainty regarding the use of thickening agents.

OBJECTIVE. Our goal was to systematically evaluate and update data from randomized,controlled trials on the efficacy and safety of thickened feeds for the treatment ofgastroesophageal reflux in healthy infants.

METHODS. The Cochrane Library, Medline, Embase, and CINAHL databases and pro-ceedings of the European and North American pediatric gastroenterology confer-ences (from 2000) were searched in May 2008; additional references were obtainedfrom reviewed articles. Only randomized, controlled trials that evaluated thickenedfeeds used in infants for at least several days for the treatment of gastroesophagealreflux were considered for inclusion. Three reviewers independently performed dataextraction by using standard data-extraction forms. Discrepancies between reviewerswere resolved by discussion between all authors. Only the consensus data wereentered.

RESULTS. Fourteen randomized, controlled trials with a parallel or crossover design,some with methodologic limitations, were included. Use of thickened formulascompared with standard formula significantly increased the percentage of infantswith no regurgitation, slightly reduced the number of episodes of regurgitation andvomiting per day (assessed jointly or separately), and increased weight gain per day; it had no effect on the refluxindex, number of acid gastroesophageal reflux episodes per hour, or number of reflux episodes lasting 5 minutes

but significantly reduced the duration of the longest reflux episode of pH 4. No definitive data showed that oneparticular thickening agent is more effective than another. No serious adverse effects were noted.

CONCLUSIONS. This meta-analysis shows that thickened food is only moderately effective in treating gastroesophagealreflux in healthy infants. Pediatrics 2008;122:e1268e1277

GASTROESOPHAGEAL REFLUX (GER) is defined as the passage of gastric contents into the esophagus, and GERdisease (GERD) is defined as symptoms or complications of GER. GERD presents with vomiting, poor weight

gain, dysphagia, abdominal or substernal pain, esophagitis, and respiratory disorders.1,2 GER/GERD is one of thecommonest gastrointestinal complaints in infancy; the incidence of the condition is reported to be 20% to 40% ininfants.2 Treatment of GER/GERD is aimed at relieving symptoms, maintaining normal growth, preventing compli-cations, and minimizing adverse effects of treatment.2,3 Therapeutic options in infancy include dietary measures(thickened feeds, frequent small meals), positioning (elevating the head of the crib in the supine position), 4 drugs(prokinetic agents such as metoclopramide,4 domperidone, cisapride5,6), and surgery (usually reserved for compli-cated cases).

Currently, thickened feeds are increasingly being used to treat infants with GER/GERD, driven in large part by thebaby food industry. Agents such as rice cereal (more popular in North America), carob-bean gum (also calledlocust-bean gum [more popular in Europe]), carob-seed flour, and sodium carboxymethylcellulose are often used.Three systematic reviews aimed at determining the effect of thickened food on GER/GERD in healthy infants have

been performed. The first review, published in 2002 (search date: November 2000), identified 3 randomized,

www.pediatrics.org/cgi/doi/10.1542/

peds.2008-1900

doi:10.1542/peds.2008-1900

KeyWords

randomized, controlled trial, RCT,

thickeners, spitting up, vomiting, children

Abbreviations

GERgastroesophageal reflux

GERDgastroesophageal reflux disease

RCTrandomized, controlled trial

RRrisk ratio

CIconfidence interval

MDmean difference

WMDweighted mean difference

Accepted for publication Aug 11, 2008

Address correspondence to Hania

Szajewska, MD, Medical University of

Warsaw, 2nd Department of Paediatrics,

01-184 Warsaw, Dzialdowska 1, Poland. E-

mail: [email protected]

PEDIATRICS (ISSNNumbers:Print, 0031-4005;

Online, 1098-4275). Copyright 2008by the

AmericanAcademy of Pediatrics

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controlled trials (RCTs). This systematic review revealedthat although thickened formulas do not seem to re-duce measurable reflux, they may reduce vomiting.7 ACochrane review published in 2002 (search date: De-cember 2001) focused on newborn infants only andreported that there is no current evidence from RCTs toshow that adding feed thickeners to milk for newborninfants is effective in treating GER.8 Another Cochrane

review published in 2004 (search date: January 2003)identified 8 RCTs and revealed that thickened feeds mayreduce the severity and frequency of regurgitation in theshort-term in developmentally normal children aged 1month to 2 years.9

In 2001, the North American Society for PediatricGastroenterology, Hepatology and Nutrition stated in itsposition paper that milk-thickening agents do not im-prove reflux index scores but do decrease the number ofepisodes of vomiting.1 In 2002, the Committee on Nu-trition of the European Society for Pediatric Gastroen-terology, Hepatology and Nutrition recommended thatuntil better information is available, thickening agents

and infant diets containing thickening agents should beused only for selected infants with failure to thrivecaused by excessive nutrient losses associated with re-gurgitation and used only in conjunction with appropri-ate medical treatment and supervision.10

A number of studies have been published since then.There is still uncertainty regarding the use of thickeningagents on one hand, as well as an interest on the part ofcaregivers and practitioners regarding safe and effectivemeasures to reduce symptoms of GER on the other hand.Therefore, our aim was to systematically review and up-date data from RCTs on the efficacy and safety of thickenedfeeds for the treatment of GER in infants. If thickened feeds

are effective, another aim was to determine what type ofthickening agent is most effective. This review includesonly infants who were otherwise in good health.

METHODS

ProceduresWe followed guidelines from the Cochrane Collabora-tion for undertaking and reporting the results of thissystematic review and meta-analysis.11 The CochraneCentral Register of Controlled Trials (CENTRAL, the Co-chrane Library, Issue 2, 2008), Medline (19662008),Embase (19802008), and CINAHL (Cumulative Indexof Nursing and Allied Health Literature) databases and

proceedings from the European and North Americanpediatric gastroenterology conferences (from 2005 on-ward) were searched in May 2008. The reference lists ofidentified studies and key review articles, including pre-viously published meta-analyses, were also searched.

Studies andParticipantsOnly RCTs that evaluated thickened feeds for the treat-ment of GER were considered for inclusion. We re-stricted the review to published trials and applied thefollowing inclusion criteria: otherwise healthy infants(24 months old) with a diagnosis of GER, howeverdefined; patients in the experimental groups received

any thickened feeds at any dosage regimen for at leastseveral days; and patients in the control group receivedplacebo or no intervention.

SearchStrategyThe search strategy included the use of a validated filterfor identifying RCTs, which was combined with a topic-specific strategy using search terms. The following searchterms were used: (gastro-esophageal reflux[r] or idio-

pathic gastro-esophageal refluxor gastro-esophageal reflux dis-ease or GER or GERD or GORD or infantile reflux or regur-

gitation or excessive regurgitation) and (diet intervention orthickened formula or thickened feeding or anti regurgitationformula) and relevant population terms (eg, child* orinfant* to select a study population of infants 24months old), with appropriate truncations and misspell-ings. The search strategy used both key words and Med-ical Subject Headings (MeSH) terms.

OutcomeMeasuresThe primary outcome measures were symptoms, or achange in symptoms, of GER (eg, regurgitation, crying,irritability, vomiting, gagging) assessed subjectively bythe parent/guardian of the child and/or by the treatingphysician; adverse events; and the occurrence of anyclinical complications of GER (eg, respiratory symptoms,weight gain). The secondary outcomes, episodes of re-flux measured by extended esophageal pH monitoring,were the percentage of time during which pH was 4(reflux index); the number of episodes of pH at 4;the number of episodes of pH at 4 lasting 5 minutes;and the duration of the longest episode of pH at 4.Included studies had to report at least 1 of the primaryoutcomes.

Selection of StudiesTwo reviewers (Drs Dziechciarz and Horvath) indepen-dently searched the databases. We excluded studies if thetitle and abstract were not relevant, but we obtained arti-cles for all potentially relevant studies if the abstract con-tained insufficient information to warrant exclusion.

Quality Assessment of TrialsTwo reviewers (Drs Dziechciarz and Horvath) indepen-dently, but without being blinded to the authors or

journal, assessed the quality of the studies that met theinclusion criteria. The following strategies associated

with good-quality studies were assessed: generation ofallocation sequences and allocation concealment; blind-ing of investigators, participants, outcome assessors, anddata analysts (yes, no, or not reported); intention-to-treat analysis (yes or no); and comprehensive follow-up(80%).

DataExtractionAll 3 reviewers (Drs Horvath, Dziechciarz, and Szajew-ska) independently performed data extraction by usingstandard data-extraction forms. Discrepancies betweenreviewers were resolved by discussion between all authors.Only the consensus data were entered. For dichotomous

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outcomes, we extracted the total number of participantsand the number of participants who experienced theevent. For continuous outcomes, we extracted the totalnumber of participants and the means and SDs. We com-pared the extracted data to identify errors. Two reviewers(Drs Horvath and Szajewska) entered the data into ReviewManager 5.0 (Nordic Cochrane Centre, Copenhagen, Den-mark, Cochrane Collaboration, 2007) for analysis.

StatisticalMethodsThe data were analyzed by using Review Manager. The

binary measure for individual studies and pooled statis-tics is reported as the risk ratio (RR) between the exper-imental and control groups with 95% confidence inter-vals (CIs). The mean difference (MD) or weighted MD(WMD), as appropriate, between the treatment and con-trol groups was selected to represent the difference incontinuous outcomes (with 95% CIs). One of the objec-tives of our review was to compare thickeners, regardlessof their nature, with placebo or no intervention. There-fore, for this part of the review, if needed, we combined

2 intervention arms into a single treatment group. Whenappropriate, the weights given to each study are based onthe inverse of the variance. We used 2 to assess hetero-geneity and the Higgins I2 statistic to determine the per-centage of total variation across studies resulting fromheterogeneity.12 A value of 0% indicates no observed het-erogeneity, and larger values show increasing heterogene-ity. If there was substantial heterogeneity (50%), wepresent results of both random-effects and fixed-effectsmodels for the main analysis. For simplicity, if heterogene-ity was not revealed, we present results of only the fixed-effects model. Although we planned to visually examinefunnel plots to determine publication bias, there were too

few studies to warrant their generation.

RESULTS

SearchResults andDescription of StudiesTable 1 summarizes the characteristics of the 14 includedstudies involving 877 participants.1326 Except 1 pub-lished as a research letter15 and 1 as an abstract only,22 allwere full peer-reviewed publications. All studies wereRCTs with either a parallel or crossover design. All of themincluded infants who were in good health but diagnosedwith GER or excessive regurgitation and/or vomiting, al-though the definition varied between the trials.

InterventionsThe feed thickeners used in the studies were carob-beangum (7 trials1518,20,23,25), cornstarch (3 trials13,19,26), ricestarch (2 trials22,24), cereal (1 trial14), and soy fiber (1trial21). The duration of the interventions varied from 1to 8 weeks. In 1 RCT,14 an additional intervention (po-sitioning in the placebo group) was used. In anotherRCT,21 thickened soy formula was used, although it wascompared with a standard milk-based formula, whichwas also used as the control for all the other trials.

Methodologic QualityTable 1 shows results of the methodologic quality assess-ment of the included studies. Only 6 trials13,14,21,23,25,26

used an adequate method to conceal allocation. Themethod used in the remaining 8 trials 1520,22,24 was un-clear. Six trials21,2226 were described as double-blinded,1 trial14 was open, and the use of blinding was not clearin the remaining trials. An adequate description of theintention-to-treat analysis was provided for only 8 tri-als.15,17,18,20,2326 The withdrawals and dropouts were de-scribed adequately for 6 studies.13,14,16,19,21,22 Thirteen tri-

als included an adequate number (ie, 80%) ofparticipants in the final analysis, and 1 trial21 included aninadequate number.

ExcludedTrialsCharacteristics of the excluded trials, including the rea-sons for exclusion, are available on request. In brief, thestudies were excluded most often because they were notRCTs, there was no report of any of our predeterminedoutcomes, or they were abstracts of subsequently pub-lished RCTs.

HeterogeneitySignificant heterogeneity was found for the number ofepisodes of regurgitation and vomiting per day (2 18.13, P .0001, I2 94%); the number of episodes ofregurgitation per day (2 168, P .00001, I2 96%);the number of episodes of vomiting per day (2 2.23,P .13, I2 55%); weight gain (2 9.39, P .02, I268%); the reflux index (2 14.2, P .003, I2 79%);and the number of reflux episodes lasting 5 minutes(2 7.84, P .02, I2 74%). Heterogeneity was notsignificant for 2 outcomes only (ie, the number of infantswithout regurgitation [2 1.30, P .52, I2 0%] andthe duration of the longest reflux episode [2 1.00,P .32, I2 0%]).

Outcomes

Symptoms, or Change in Symptoms, of GER AssessedSubjectively by the Parent/Guardian of the Child and/or bythe Treating PhysicianThree RCTs15,21,25 involving 327 participants demon-strated a significant increase in the rate of infants with-out regurgitation (RR: 2.9 [95% CI: 1.7 to 4.9]; numberneeded to treat: 6 [95% CI: 4 to 10]) (Fig 1). Both carob(2 RCTs, n 194, RR: 2.75 [95% CI: 1.6 to 4.9]) and soyfiber (1 RCT, n 133, RR: 3.6 [95% CI: 1.1 to 12.4])thickeners were effective.

The use of thickened formula compared with a con-trol treatment was also associated with a reduction of:

episodes of regurgitation and vomiting per day (2RCTs,13,14 n 144, WMD: 1.4 episodes [95% CI:1.7 to 1.1], in fixed-effects model, and 1.4 epi-sodes [95% CI: 2.5 to 0.2], in random-effectsmodel); both corn- and rice-based thickeners wereeffective (Fig 2).

episodes of regurgitation per day (7 compari-sons,17,19,20,21,26 n 369, WMD: 0.6 episode [95% CI:0.7 to 0.5], in fixed-effects model, and 1.8 epi-sodes [95% CI: 2.7 to 0.8], in random-effectsmodel). All studied thickeners (ie, corn, carob, and soy



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fiber) were effective (Fig 3). In the study by Miyazawaet al,17 children fed with locust-bean gum formula alsohad fewer episodes of regurgitation than those fedcontrol formula. However, data were expressed asmedian values with interquartile ranges and, thus,could not be included in the meta-analysis.

episodes of vomiting per day (2 RCTs,19,26 n 156,WMD: 0.9 episode [95% CI: 1.3 to 0.55], infixed-effects model, and 0.97 episode [95% CI: 1.5to 0.4], in random-effects model). In both trials,cornstarch was used as a thickening agent (Fig 4).

episodes of irritability (1 RCT,13 cornstarch-thickened

formula, n 81, RR: 0.12 [95% CI: 0.02 to 0.93]). crying and dysphagia (1 RCT,19 cornstarch-thickened

formula, n 60, RR: 1.7 [95% CI: 0.3 to 9.5]).

regurgitation symptoms (eg, irritability, coughing,choking, night awakening) (1 RCT,13 cornstarch-thick-ened formula, n 81, RR: 0.27 [95% CI: 0.08 to0.88]).

Weight Gain (g/day)Only 4 trials13,14,20,26 provided data on weight gain in sucha way that the data could be included in the meta-analysis. The pooled results showed that compared withcontrols, thickening of infant formula was associated

with a statistically significant increase in weight gain (4RCTs, n 265, WMD: 3.55 g/day [95% CI: 2.6 to 4.5],in fixed-effects model, and 3.7 g/day [95% CI: 1.55 to5.80], in random-effects model) (Fig 5). Conversely, Ia-cono et al15 found that the weight/height ratio was sim-ilar in both groups at all times. In addition, Ostrom et al 21

reported that weight gain did not differ between thegroups: infants in both groups gained 32 to 33 g/day. Inthe study by Miyazawa et al (2007),18 the weight gainover 1 week with locust-bean gumthickened formulawas similar to that with the standard formula. The au-thors did not provide information on variability, whichprecluded including the results of these studies in the

meta-analysis.

Esophageal pH MonitoringThe pooled results of 4 trials,19,22,23,26 regardless of thethickening agent used, revealed no significant differencein the reflux index (percentage of time during which thepH was 4) between the groups (4 RCTs, n 217,WMD: 1.15% [95% CI: 2.6 to 0.3], in fixed-effectsmodel, and 1.64% [95% CI: 5.0 to 1.7], in random-effects model). However, the subgroup analysis based onthe thickening agent used revealed a significant differ-ence in infants treated with cornstarch-thickened for-mula compared with the control group (2 RCTs,19,26 n

Study or Subgroup

1.2.1 Corn

Chao and Vandenplas13 2007Subtotal (95% CI)

Heterogeneity: Not applicableTest for overall effect: z= 10.06 (P< .00001)

1.2.2 Rice

Chao and Vandenplas14 2007

Subtotal (95% CI)

Heterogeneity: Not applicable

Test for overall effect: z= 3.84 (P= .0001)

Total (95% CI)

Heterogeneity: = 0.67; = 18.13, df= 1 (P< .0001); I= 94%


Mean

0.93

1.61

SD

0.42

0.76

Total

4141

3131

72

Mean

2.89

2.38

SD

1.16

0.83

Total

4040

3232

72

Weight

50.1%50.1%

49.9%49.9%

100.0%

IV, Random, 95% CI

-1.96 [-2.34 to -1.58]-1.96 [-2.34 to -1.58]

-0.77 [-1.16 to -0.38]-0.77 [-1.16 to -0.38]

-1.37 [-2.53 to -0.20]

Treatment Control MD MD

IV, Random, 95% CI

-2 -1 0 1 2Favors treatment Favors control

FIGURE 2

Number of episodes of regurgitation and vomiting per day.

Study or Subgroup

1.1.1 Carob

Iacono et al15 2002

Wenzl et al25 2003Subtotal (95% CI)

Total events

Heterogeneity: = 1.08, df= 1 (P = .30); I= 7%

Test for overall effect: z= 3.46 (P = .0005)

1.1.3 Soy formula with soy fiber

Ostrom et al21 2006Subtotal (95% CI)

Total events


Test for overall effect: z= 2.05 (P = .04)

Total (95% CI)

Total events

Heterogeneity: = 1.30, df= 2 (P = .52); I= 0%

Test for overall effect: z= 4.02 (P < .0001)

Events

28

7

35

11

11

46

Total

82

1496

6767

163

Events

12

1

13

3

3

16

Total

84

1498

6666

164

Weight

74.7%

6.3%81.0%

19.0%19.0%

100.0%

M-H, Fixed, 95% CI

2.39 [1.31 to 4.37]

7.00 [0.99 to 49.69]2.75 [1.55 to 4.88]

3.61 [1.06 to 12.36]3.61 [1.06 to 12.36]

2.91 [1.73 to 4.91]

Treatment Control RR RR

M-H, Fixed, 95% CI

0.05 0.2 1 5 20Favors control Favors treatment

2

2

FIGURE 1

Number of infants without regurgitation.



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156, WMD: 3.6% [95% CI: 6 to 1.2], in both fixed-and random-effects models) but no significant differ-ence in those treated with rice-thickened formula (1RCT,22 n 41, MD: 1.9% [95% CI: 0.3 to 4.1]) orwith carob-bean gum compared with the controlgroup (1 RCT,23 n 20, MD: 2% [95% 6.9 to 2.7])(Fig 6).

One RCT26 (n 96) revealed no significant reductionin the number of acid GER episodes per hour (MD: 2.5[95% CI: 5.6 to 0.64]). Three RCTs19,23,26 (n 176)revealed no reduction in the number of reflux episodes

lasting 5 minutes (WMD: 0.8 episode [95% CI: 1.7to 0.12] in fixed-effects model, and 1.1 episodes [95%CI: 3.1 to 0.95], in random-effects model) (Fig 7).Finally, the pooled results of 2 RCTs23,26 (n 116) re-vealed a significant reduction in the duration of thelongest reflux episode of pH at 4 in infants treated withthickened food (WMD: 8.1 minutes [95% CI: 11.9 to4.3]) (Fig 8). This effect was a result of the cornstarchformula only26 (MD: 8.5 minutes [12.4 to 4.6]); nosuch effect was seen with the carob-bean gum thickener23

(MD: 1.2 minutes [95% CI: 17.4 to 19.8]).

Study or Subgroup

1.3.3 Corn

Moukarzel et al19 2007

Moya et al20 1999

Xinias et al26 2005Subtotal (95% CI)

Heterogeneity: = 0.05; = 2.21, df= 2 (P= .33); I= 10%

Test for overall effect: z= 5.27 (P< .00001)

1.3.4 Soy formula with soy fiberOstrom et al21 2006Subtotal (95% CI)



1.3.5 Carob

Miyazawa et al16 2006 (350)

Miyazawa et al17 2006 (450)

Moya et al20 1999Subtotal (95% CI)



Total (95% CI)

Heterogeneity: = 1.37; = 168.00, df= 6 (P< .00001); I= 96%


Mean

2.3

2.9

2.57

2

1.85

1.83

2.2

SD

2

1.6

2.71

0.2

0.5

0.4

1

Total

28

6

5185

6767

13

14

835

187

Mean

5.2

4.5

4.31

2.4

3.23

4.25

4.5

SD

3.1

2.1

2.01

0.3

0.6

0.5

2.1

Total

32

6

4583

6666

13

14

633

182

Weight

13.2%

9.5%

15.0%37.7%

17.5%17.5%

16.9%

17.1%

10.8%44.8%

100.0%

IV, Random, 95% CI

-2.90 [-4.20 to -1.60]

-1.60 [-3.71 to 0.51]

-1.74 [-2.69 to -0.79]-2.09 [-2.87 to -1.31]

-0.40 [-0.49 to -0.31]-0.40 [-0.49 to -0.31]

-1.38 [-1.80 to -0.96]

-2.42 [-2.76 to -2.08]

-2.30 [-4.12 to -0.48]-1.97 [-2.85 to -1.09]

-1.76 [-2.72 to -0.80]


IV, Random, 95% CI


FIGURE 3Number of episodes of regurgitation per day.

Study or Subgroup

1.5.1 Corn





Total (95% CI)



Mean

0.5

1.45

SD

0.8

1.65

Total

28

5179

79

Mean

1.2

2.74

SD

1.1

1.37

Total

32

4577

77

Weight

54.9%

45.1%100.0%

100.0%

IV, Random, 95% CI

-0.70 [-1.18 to -0.22]

-1.29 [-1.89 to -0.69]-0.97 [-1.54 to -0.39]

-0.97 [-1.54 to -0.39]


IV, Random, 95% CI


FIGURE 4Number of episodes of vomiting per day.

Study or Subgroup

Moya et al20 1999

Xinias et al26 2005

Chao and Vandenplas13 2007

Chao and Vendenplas14 2007

Total (95% CI)



Mean

29.2

28.5

29.1

22.5

SD

4.35

12.1

3.9

2.4

Total

19

51

41

31

142

Mean

28.4

24.3

23.6

20

SD

7.2

8.1

3.5

2.5

Total

6

45

40

32

123

Weight

9.6%

16.8%

35.1%

38.5%

100.0%

IV, Random, 95% CI

0.80 [-5.28 to 6.88]

4.20 [0.12 to 8.28]

5.50 [3.89 to 7.11]

2.50 [1.29 to 3.71]

3.68 [1.55 to 5.81]


IV, Random, 95% CI

-20 -10 0 10 20Favors control Favors treatment

FIGURE 5

Weight gain (g/day).



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Adverse EventsOf the 14 trials included in the review, adverse effectswere only reported in 3 trials (Table 2).19,24,26 Iacono et

al,15 while not describing any adverse events, reportedthat 14 patients were suspended from the study becauseof the onset of diarrhea. Also, Miyazawa et al16 did not

Study or Subgroup

1.9.1 Rice

Tolia et al22 1999Subtotal (95% CI)



1.9.2 Corn

Moukarzel at el19 2007




1.9.3 Carob bean gum

Vandenplas et al23 1994Subtotal (95% CI)



Total (95% CI)



Mean

5

5.64

6.8

11.1

SD

3.6

5.14

6.2

6.1

Total

1818

28

5179

1010

107

Mean

3.1

7.77

11.4

13.2

SD

3.6

7.72

7

4.7

Total

2323

32

4577

1010

110

Weight

28.6%28.6%

24.8%

27.1%51.9%

19.5%19.5%

100.0%

IV, Random, 95% CI

1.90 [-0.32 to 4.12]1.90 [-0.32 to 4.12]

-2.13 [-5.41 to 1.15]

-4.60 [-7.26 to -1.94]-3.56 [-5.95 to -1.17]

-2.10 [-6.87 to 2.67]-2.10 [-6.87 to 2.67]

-1.64 [-4.97 to 1.68]


IV, Random, 95% CI


FIGURE 6

Reflux index (percentage of time during which pH was4).

Study or Subgroup

1.12.1 Corn





1.12.2 Carob




Total (95% CI)



Mean

1.61

2.9

7.7

SD

2.68

3.4

4.27

Total

28

5179

1010

89

Mean

1.37

5.4

8.8

SD

1.68

4.2

2.9

Total

32

4577

1010

87

Weight

41.1%

37.2%78.3%

21.7%21.7%

100.0%

IV, Random, 95% CI

0.24 [-0.91 to 1.39]

-2.50 [-4.04 to -0.96]-1.08 [-3.76 to 1.60]

-1.10 [-4.30 to 2.10]-1.10 [-4.30 to 2.10]

-1.07 [-3.09 to 0.95]


IV, Random, 95% CI


FIGURE 7

Number of reflux episodes lasting 5 minutes.

Study or Subgroup

1.13.1 Carob




1.13.2 Corn




Total (95% CI)

Heterogeneity: = 1.00, df= 1 (P= .32); I= 0%


Test for subgroup differences: = 1.00, df= 1 (P= .32), I= 0%

Mean

31.1

10.8

SD

23.4

8.9

Total

1010

5151

61

Mean

29.9

19.3

SD

18.9

10.5

Total

1010

4545

55

Weight

4.2%4.2%

95.8%95.8%

100.0%

IV, Fixed, 95% CI

1.20 [-17.44 to 19.84]1.20 [-17.44 to 19.84]

-8.50 [-12.42 to -4.58]-8.50 [-12.42 to -4.58]

-8.09 [-11.93 to -4.25]


IV, Fixed, 95% CI


FIGURE 8

Duration of the longest reflux episode.



9/13

report any adverse events, but they still found that in-fants who received thickened formula had a slightlyhigher number of bowel movements and had difficultysucking the thickened formula.

DISCUSSION

Principal FindingsThe objective of this review was to provide some reso-lution to the uncertainty regarding the use of thickeningagents, as an adjunct to infant formula, for the treatmentof GER in generally healthy infants. With the limitedevidence available, we found that thickening agents sig-nificantly increased the percentage of infants with noregurgitation. Food thickening also reduced some symp-toms of GER assessed subjectively by the parent/guard-ian of the child and/or by the treating physician. Thistherapeutic benefit was reproducible regardless of theclinical outcome measure studied (ie, number of epi-sodes of regurgitation and vomiting per day, number ofepisodes of regurgitation per day, and number of epi-sodes of vomiting per day). Still, although the differenceswere statistically significant, the reduction may be ofquestionable clinical significance (eg, reduction in regur-gitation by 0.6 episode per day). The use of thickenedformulas was also associated with increased weight gain,which, in contrast, may be potentially clinically impor-tant, particularly if these formulas are used over a longerperiod of time. Although some parameters of pH moni-toring were in favor of thickened formulas (eg, signifi-cant reduction in the duration of the longest refluxepisode of pH at 4), others did not show significantdifferences between the groups (eg, the pooled results of

4 trials, regardless of the thickening agent used, revealedno significant reduction in the reflux index). It is note-worthy, however, that even if there was a significantdifference, the clinical meaning of it is unclear. Regret-fully, a paucity of data did not allow us to concludewhether any particular thickening agent is definitely

more effective than another. These updated results areconsistent with the results of previous reviews but in-cluded more RCTs (14 trials compared with 8 RCTs inthe most recent Cochrane review9 and 3 RCTs in thereview by Carroll et al7). Thus, these results more pre-cisely define the effects of thickening agents on GERoutcomes.

Study LimitationsThis systematic review has several limitations. Only alimited number of trials were available for review. Theirmethodologic quality varied. For example, one of theimportant limitations of the included trials was unclearor inappropriate allocation concealment, which may re-sult in overestimation of the intervention effect.27 Anadditional limitation is that despite the studys double-

blind design, some physicians and parents may havesuspected the intervention because all thickened formu-las have a specific texture. Again, this can overestimatethe effect and skew the results in favor of either treat-ment, depending on the biases of the investigators.Other concerns apart from methodology may come fromthe fact that the manufacturer of the thickened formulasupported several RCTs; it is not clear if all steps neces-sary to avoid bias were taken. We found statistical het-erogeneity when pooling several outcomes. This was

TABLE 2 Adverse Effects

Study Thickening Agent Adverse Effects

Chao and Vandenplas14 (2007) Hydrolyzed rice 90%, cornstarch 5% No significant difference in stool frequency or consistency (only outcome)

Chao and Vandenplas13 (2007) Cornstarch Not reported

Iacono et al15 (2002) (letter) Locust-bean gum No adverse effects described; however, 14 patients in the thickened-

formula group were suspended from the study because of the onset of

diarrhea during the first 2 wk of the study

Miyazawa et al16 (2004) Locust-bean gum No infant had any complications during the study; however, the number

of bowel movements with locust-bean gum at the concentration of

0.35 g/100 mL was slightly but significantly greater than that with the

standard formula; mothers reported that their infants seemed to have

difficulty sucking the thickened formula (5 of 27)

Miyazawa et al17 (2006) Locust-bean gum Not reported

Miyazawa et al18 (2007) Locust-bean gum Not reported

Moukarzel et al19 (2007) Cornstarch Refusal to eat and failure to gain adequate gain were reported in both the

experimental and control groups (accordingly 3 of 28 vs 3 of 32 not

significant and 3 of 28 vs 2 of 32 not significant )

Moya et al20 (1999) Bean gum or corn polymers Not reported

Ostrom et al21 (2006) Soy fiber Not reported

Tolia et al22 (1999) Rice starch Not reported

Wenzl et al25 (2003) Carob-bean gum Not reported

Vandenplas et al23 (1994) Carob-bean gum Not reported

Vanderhoof et al24

(2003) Rice starch No difference in the incidence of serious adverse events; no difference inany of the 4 variables recorded daily (fussiness, constipation, diarrhea,

or gas)

Xinias et al26 (2005) Cornstarch None dropped out; no adverse effects caused by the intervention were

observed



10/13

addressed by using a random-effects meta-analysis. Fi-nally, because of the limited data, we did not test forpublication bias. Given these considerations, some cau-tion must be exercised in interpreting the strength of theevidence presented.

Safety

There was no evidence that the thickened foods differedfrom the control formulas in terms of safety. However,trials were powered for effectiveness and were short-term. Given that adverse events were rare in the in-cluded trials, a large-scale RCT would be required todetect any small but real differences in the incidence ofadverse effects. This issue is important, because on the

basis of the available literature, there is concern that theuse of thickening agents may result in harmful events.The use of carob thickeners as therapy for GER wasassociated with diarrhea28 or an allergic reaction.29 Theuse of rice-thickened feedings was described as a cause ofincreased coughing.30 There is also the possibility that

thickening agents may have an effect on the bioavail-ability of dietary nutrients, causing decreased intestinalabsorption of carbohydrates, fat, calcium, iron, zinc, andcopper and altering mucosal and endocrine respons-es.3136 The results of in vitro studies suggest that the

bioavailability of calcium, iron, and zinc in infant for-mula may be decreased by thickening with nondigestiblecarbohydrates, although not by thickening with addedstarch.37 In some, but not all, animal studies, addingcarob-bean gum to the diet decreased growth.38,39

CONCLUSIONSANDFUTURE RESEARCH

On the basis of the results of 14 RCTs, many of which

had methodologic limitations and some that were rela-tively small, thickening foods were only moderately ef-fective in treating GER in otherwise healthy infants. Forsome outcomes, although the differences betweengroups were statistically significant, the effect may be ofquestionable clinical significance. More data are needed.The safety of thickening foods and the cost-effectivenessof this therapy need to be defined. Because many trialswere company funded, independent trials are needed.Additional investigations comparing thickening foodswith other treatment options would be worthwhile. Inthe absence of definitive data to show that a particularthickening agent is more effective than another, if the

physician feels that treating this usually self-limited con-dition is important he or she can guide the initial treat-ment according to the patients preference, cost, andproduct availability.

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DOI:10.1542/peds.2008-1900

2008;122;e1268-e1277; originally published online Nov 10, 2008;PediatricsAndrea Horvath, Piotr Dziechciarz and Hania Szajewska

Infants: Systematic Review and Meta-analysis of Randomized, Controlled TrialsThe Effect of Thickened-Feed Interventions on Gastroesophageal Reflux in

& ServicesUpdated Information

http://www.pediatrics.org/cgi/content/full/122/6/e1268including high-resolution figures, can be found at:

References

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Errata

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13/13

ERRATA Hoilette LK, Clark SJ, Gebremariam A, Davis MM. Usual Source ofCare and Unmet Need Among Vulnerable Children: 19982006.PEDIATRICS 2009;123(2): e214 e219

An error occurred in the article by Hoilette et al, published in the February

2009 issue of Pediatrics (doi:10.1542/peds.2008-2454). On page e216, Table

1 should have read:

doi:10.1542/peds.2009-0360

Horvath A, Dziechciarz P, Szajewska H. The Effect of Thickened-Feed Interventions on Gastroesophageal Reflux in Infants:Systematic Review and Meta-analysis of Randomized, ControlledTrials. PEDIATRICS 2008;122(6): e1268 e1277

An error occurred in the article by Horvath et al, titled published in the

December 2008 issue of Pediatrics (doi:10.1542/peds.2008-1900). On page

e1272, in Figure 1 (Number of infants without regurgitation), the left graph

label should read Favors control and the right graph label should read

Favors treatment.

doi:10.1542/peds.2009-0200

American Academy of Pediatrics, Section on Ophthalmology,American Association for Pediatric Ophthalmology andStrabismus, American Academy of Ophthalmology, and American

Association of Certified Orthoptists. Red Reflex Examination inNeonates, Infants, and Children. PEDIATRICS 2008;122(6): 14011404

An error occurred in the AAP policy statement Red Reflex Examination in

Neonates, Infants, and Children (doi:10.1542/peds.2008-2624). Under the

heading Suggested Eye Drops for Dilation in Infants, the component

concentrations for Cyclomydril in the last sentence were incorrect and

should be: cyclopentolate 0.2% and phenylephrine 1% (Cyclomydril). We

regret the error.

doi:10.1542/peds.2009-0135

TABLE 1 Age and Race of Uninsured Children, and Children Reportingno Usual Source ofCare, NHIS 1998 & 2006

Demographics Uninsured Uninsured No USC No USC

1998 2006 1998 2006

Age (years) Proportion (95% CI) Proportion (95% CI) Proportion (95% CI) Proportion (95% CI)

N 8 746 854 N 7 250 542 N 2 208 722 N 2 358 232

n 1993 n 1080 n 552 n 345

05 30.1 (27.732.7) 25.9 (22.729.5) 16.5 (13.120.5) 17.8 (13.323.6)

611 34.7 (32.037.5) 34.7 (31.038.7) 34.0 (28.839.5) 28.2 (21.935.5)

1217 35.2 (32.837.7) 39.3 (35.743.1) 49.6 (44.354.9) 54.0 (47.060.8)

Race/Ethnicity

White 46.0 (42.849.2) 39.2 (35.043.6) 37.0 (31.642.7) 32.7 (25.540.8)Black 15.3 (13.117.) 12.7 (10.415.5) 13.7 (10.318.0) 11.1 (7.116.8)

Hispanic 33.0 (30.236.0) 42.5 (38.2 -46.8) 41.6 (36.347.2) 50.9 (43.558.4)

Asian 5.7 (4.18.0) 5.6 (4.07.7) 7.7 (5.211.2) 5.0 (2.69.4)

1254 ERRATAb 5di il d d f

The Effect of Thickened-Feed Interventions on Gastroesophageal Reflux

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