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

Horvath, Piotr Dziechciarz and Hania Szajewska Pediatrics 2008;122;e1268-e1277; originally published online Nov 10, 2008; DOI: 10.1542/peds.2008-1900

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.pediatrics.org/cgi/content/full/122/6/e1268

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

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REVIEW ARTICLE

The Effect of Thickened-Feed Interventions on Gastroesophageal Reux in Infants: Systematic Review and Meta-analysis of Randomized, Controlled Trials
Andrea Horvath, MD, Piotr Dziechciarz, MD, Hania Szajewska, MD 2nd Department of Paediatrics, Medical University of Warsaw, Warsaw, Poland
The authors have indicated they have no nancial relationships relevant to this article to disclose.

ABSTRACT
CONTEXT. Currently, thickened feeds are increasingly being used to treat infants with gastroesophageal reux, driven in large part by the baby food industry. Previous meta-analyses have shown that although thickened formulas do not seem to reduce measurable reux, 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,

www.pediatrics.org/cgi/doi/10.1542/ peds.2008-1900 doi:10.1542/peds.2008-1900

Key Words randomized, controlled trial, RCT, thickeners, spitting up, vomiting, children Abbreviations GER gastroesophageal reux GERD gastroesophageal reux disease RCTrandomized, controlled trial RRrisk ratio CI condence 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. Email: hania@ipgate.pl PEDIATRICS (ISSN Numbers: Print, 0031-4005;

controlled trials on the efcacy and safety of thickened feeds for the treatment of gastroesophageal reux in healthy infants.
METHODS. The Cochrane Library, Medline, Embase, and CINAHL databases and pro-

ceedings of the European and North American pediatric gastroenterology conferences (from 2000) were searched in May 2008; additional references were obtained from reviewed articles. Only randomized, controlled trials that evaluated thickened feeds used in infants for at least several days for the treatment of gastroesophageal reux were considered for inclusion. Three reviewers independently performed data extraction by using standard data-extraction forms. Discrepancies between reviewers were resolved by discussion between all authors. Only the consensus data were entered.
RESULTS. Fourteen randomized, controlled trials with a parallel or crossover design,

Online, 1098-4275). Copyright 2008 by the some with methodologic limitations, were included. Use of thickened formulas American Academy of Pediatrics compared with standard formula signicantly increased the percentage of infants with no regurgitation, slightly reduced the number of episodes of regurgitation and vomiting per day (assessed jointly or separately), and increased weight gain per day; it had no effect on the reux index, number of acid gastroesophageal reux episodes per hour, or number of reux episodes lasting 5 minutes but signicantly reduced the duration of the longest reux episode of pH 4. No denitive data showed that one particular 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 gastroesophageal

reux in healthy infants. Pediatrics 2008;122:e1268e1277

ASTROESOPHAGEAL REFLUX (GER) is dened as the passage of gastric contents into the esophagus, and GER disease (GERD) is dened 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 the commonest gastrointestinal complaints in infancy; the incidence of the condition is reported to be 20% to 40% in infants.2 Treatment of GER/GERD is aimed at relieving symptoms, maintaining normal growth, preventing complications, 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 complicated cases). Currently, thickened feeds are increasingly being used to treat infants with GER/GERD, driven in large part by the baby food industry. Agents such as rice cereal (more popular in North America), carob-bean gum (also called locust-bean gum [more popular in Europe]), carob-seed our, 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 rst review, published in 2002 (search date: November 2000), identied 3 randomized,

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controlled trials (RCTs). This systematic review revealed that although thickened formulas do not seem to reduce measurable reux, they may reduce vomiting.7 A Cochrane review published in 2002 (search date: December 2001) focused on newborn infants only and reported that there is no current evidence from RCTs to show that adding feed thickeners to milk for newborn infants is effective in treating GER.8 Another Cochrane review published in 2004 (search date: January 2003) identied 8 RCTs and revealed that thickened feeds may reduce the severity and frequency of regurgitation in the short-term in developmentally normal children aged 1 month to 2 years.9 In 2001, the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition stated in its position paper that milk-thickening agents do not improve reux index scores but do decrease the number of episodes of vomiting.1 In 2002, the Committee on Nutrition of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition recommended that until better information is available, thickening agents and infant diets containing thickening agents should be used only for selected infants with failure to thrive caused by excessive nutrient losses associated with regurgitation and used only in conjunction with appropriate medical treatment and supervision.10 A number of studies have been published since then. There is still uncertainty regarding the use of thickening agents on one hand, as well as an interest on the part of caregivers and practitioners regarding safe and effective measures to reduce symptoms of GER on the other hand. Therefore, our aim was to systematically review and update data from RCTs on the efcacy and safety of thickened feeds for the treatment of GER in infants. If thickened feeds are effective, another aim was to determine what type of thickening agent is most effective. This review includes only infants who were otherwise in good health. METHODS Procedures We followed guidelines from the Cochrane Collaboration for undertaking and reporting the results of this systematic review and meta-analysis.11 The Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library, Issue 2, 2008), Medline (1966 2008), Embase (1980 2008), and CINAHL (Cumulative Index of Nursing and Allied Health Literature) databases and proceedings from the European and North American pediatric gastroenterology conferences (from 2005 onward) were searched in May 2008. The reference lists of identied studies and key review articles, including previously published meta-analyses, were also searched. Studies and Participants Only RCTs that evaluated thickened feeds for the treatment of GER were considered for inclusion. We restricted the review to published trials and applied the following inclusion criteria: otherwise healthy infants (24 months old) with a diagnosis of GER, however dened; patients in the experimental groups received

any thickened feeds at any dosage regimen for at least several days; and patients in the control group received placebo or no intervention. Search Strategy The search strategy included the use of a validated lter for identifying RCTs, which was combined with a topicspecic strategy using search terms. The following search terms were used: (gastro-esophageal reux[r] or idiopathic gastro-esophageal reux or gastro-esophageal reux disease or GER or GERD or GORD or infantile reux or regurgitation or excessive regurgitation) and (diet intervention or thickened formula or thickened feeding or anti regurgitation formula) and relevant population terms (eg, child* or infant* to select a study population of infants 24 months old), with appropriate truncations and misspellings. The search strategy used both key words and Medical Subject Headings (MeSH) terms. Outcome Measures The primary outcome measures were symptoms, or a change in symptoms, of GER (eg, regurgitation, crying, irritability, vomiting, gagging) assessed subjectively by the parent/guardian of the child and/or by the treating physician; adverse events; and the occurrence of any clinical complications of GER (eg, respiratory symptoms, weight gain). The secondary outcomes, episodes of reux measured by extended esophageal pH monitoring, were the percentage of time during which pH was 4 (reux 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 primary outcomes. Selection of Studies Two reviewers (Drs Dziechciarz and Horvath) independently searched the databases. We excluded studies if the title and abstract were not relevant, but we obtained articles for all potentially relevant studies if the abstract contained insufcient information to warrant exclusion. Quality Assessment of Trials Two reviewers (Drs Dziechciarz and Horvath) independently, but without being blinded to the authors or journal, assessed the quality of the studies that met the inclusion criteria. The following strategies associated with good-quality studies were assessed: generation of allocation sequences and allocation concealment; blinding of investigators, participants, outcome assessors, and data analysts (yes, no, or not reported); intention-totreat analysis (yes or no); and comprehensive follow-up (80%). Data Extraction All 3 reviewers (Drs Horvath, Dziechciarz, and Szajewska) independently performed data extraction by using standard data-extraction forms. Discrepancies between reviewers 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 participants and the number of participants who experienced the event. For continuous outcomes, we extracted the total number of participants and the means and SDs. We compared the extracted data to identify errors. Two reviewers (Drs Horvath and Szajewska) entered the data into Review Manager 5.0 (Nordic Cochrane Centre, Copenhagen, Denmark, Cochrane Collaboration, 2007) for analysis. Statistical Methods The data were analyzed by using Review Manager. The binary measure for individual studies and pooled statistics is reported as the risk ratio (RR) between the experimental and control groups with 95% condence intervals (CIs). The mean difference (MD) or weighted MD (WMD), as appropriate, between the treatment and control groups was selected to represent the difference in continuous outcomes (with 95% CIs). One of the objectives of our review was to compare thickeners, regardless of their nature, with placebo or no intervention. Therefore, for this part of the review, if needed, we combined 2 intervention arms into a single treatment group. When appropriate, the weights given to each study are based on the inverse of the variance. We used 2 to assess heterogeneity and the Higgins I2 statistic to determine the percentage of total variation across studies resulting from heterogeneity.12 A value of 0% indicates no observed heterogeneity, and larger values show increasing heterogeneity. If there was substantial heterogeneity (50%), we present results of both random-effects and xed-effects models for the main analysis. For simplicity, if heterogeneity was not revealed, we present results of only the xedeffects model. Although we planned to visually examine funnel plots to determine publication bias, there were too few studies to warrant their generation. RESULTS Search Results and Description of Studies Table 1 summarizes the characteristics of the 14 included studies involving 877 participants.1326 Except 1 published as a research letter15 and 1 as an abstract only,22 all were full peer-reviewed publications. All studies were RCTs with either a parallel or crossover design. All of them included infants who were in good health but diagnosed with GER or excessive regurgitation and/or vomiting, although the denition varied between the trials. Interventions The feed thickeners used in the studies were carob-bean gum (7 trials1518,20,23,25), cornstarch (3 trials13,19,26), rice starch (2 trials22,24), cereal (1 trial14), and soy ber (1 trial21). The duration of the interventions varied from 1 to 8 weeks. In 1 RCT,14 an additional intervention (positioning in the placebo group) was used. In another RCT,21 thickened soy formula was used, although it was compared with a standard milk-based formula, which was also used as the control for all the other trials. Methodologic Quality Table 1 shows results of the methodologic quality assessment of the included studies. Only 6 trials13,14,21,23,25,26
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used an adequate method to conceal allocation. The method used in the remaining 8 trials1520,22,24 was unclear. Six trials21,2226 were described as double-blinded, 1 trial14 was open, and the use of blinding was not clear in the remaining trials. An adequate description of the intention-to-treat analysis was provided for only 8 trials.15,17,18,20,2326 The withdrawals and dropouts were described adequately for 6 studies.13,14,16,19,21,22 Thirteen trials included an adequate number (ie, 80%) of participants in the nal analysis, and 1 trial21 included an inadequate number. Excluded Trials Characteristics of the excluded trials, including the reasons for exclusion, are available on request. In brief, the studies were excluded most often because they were not RCTs, there was no report of any of our predetermined outcomes, or they were abstracts of subsequently published RCTs. Heterogeneity Signicant heterogeneity was found for the number of episodes of regurgitation and vomiting per day (2 18.13, P .0001, I2 94%); the number of episodes of regurgitation 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, I2 68%); the reux index (2 14.2, P .003, I2 79%); and the number of reux episodes lasting 5 minutes (2 7.84, P .02, I2 74%). Heterogeneity was not signicant for 2 outcomes only (ie, the number of infants without regurgitation [2 1.30, P .52, I2 0%] and the duration of the longest reux episode [2 1.00, P .32, I2 0%]). Outcomes Symptoms, or Change in Symptoms, of GER Assessed Subjectively by the Parent/Guardian of the Child and/or by the Treating Physician Three RCTs15,21,25 involving 327 participants demonstrated a signicant increase in the rate of infants without regurgitation (RR: 2.9 [95% CI: 1.7 to 4.9]; number needed 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 soy ber (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 control treatment was also associated with a reduction of:
episodes of regurgitation and vomiting per day (2

RCTs,13,14 n 144, WMD: 1.4 episodes [95% CI: 1.7 to 1.1], in xed-effects model, and 1.4 episodes [95% CI: 2.5 to 0.2], in random-effects model); both corn- and rice-based thickeners were effective (Fig 2).

episodes

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

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TABLE 1 Characteristics of Included Trials

Blinding N 80 26 mo Regurgitation/vomiting 3 times per day 8 8 8 Age Intentionto-Treat Analysis ACA 63/80 Follow-up, n/N Population Inclusion Criteria Duration of Trial, wk Intervention Control

Study

Design

Allocation Concealment No

Chao and Vandenplas14 (2007) Not clear Not clear Yes 166/166 ACA 81/100 81 24 mo

RCT; parallel

Yes

25% strengthened plus postural therapy Standard formula Standard formula

RCT; parallel

Yes

Chao and Vandenplas13 (2007) Iacono et al15 (2002) (letter) Not clear ACA 27/30 1

RCT; parallel

Not clear

Miyazawa et al16 (2004)

RCT; crossover

Not clear

Regurgitation/vomiting 3 times per day 166 4 mo (median: 1.5 mo) Frequent regurgitation/ vomiting caused by uncomplicated GER 30 6 mo Regurgitation/vomiting 3 times per day 27 6 mo 1 Regurgitation 3 times per day 1 4 2

Standard formula

Miyazawa et al17 (2006) Not clear Yes 27/27

RCT; crossover

Not clear

Standard formula

Miyazawa et al18 (2007) Not clear Not clear Not clear Yes 26/26 26 4 mo ACA 60/74 74 6 mo Yes 20/20 20

RCT; crossover

Not clear

2 mo

Standard formula Standard formula Standard formula

Moukarzel et al19 (2007) RCT; parallel

Not clear

Cereal-thickened formula (hydrolyzed rice 90%, cornstarch 5%) Cornstarch-thickened formula (Novalac AR, Paris, France) Formula thickened with carob our (locust-bean gum) (Humana AR 1, Milan, Italy) Locust-bean gum formula 0.45 g/100 mL; or 0.35 g/100 mL Locust- bean gum 0.45 g/100 mL or locust-bean gum 0.35 g/100 mL Locust-bean gum formula 0.35 g/100 mL Pregelatinized cornstarch

Moya et al20 (1999)

RCT; parallel

Not clear

Regurgitation/vomiting 3 times per day GER dened by Orenstein criteria Frequent regurgitation (5 times per day) 4

Ostrom et al21 (2006) Yes ACA 133/179 133 1332 d

RCT; parallel

Yes

Formula with bean gum; formula with corn polymers Soy formula with soy ber (6 g/L)

Standard formula with placebo

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Yes Yes ACA Yes 41/44 14/14 44 14 112 mo 4 mo 2 Yes Yes 20/20 20 14 mo 1 Yes Yes Yes Yes 103/104 96/96 103 96 14120 d 93 35 d 5 4 Regurgitation in association with 25% of feedings (mean: 7.8 times per day) Symptoms of GER 5 regurgitations of at least a small volume (5 mL) or at least 1 regurgitation of at least half of the feeding per day Regurgitation 5 times per day and abnormal esophageal pH monitoring (percentage of time with pH at 4.0 between 10% and 30%) 5 regurgitations per day for 2 baseline days Excessive regurgitation and/or vomiting (mean: 5 regurgitation episodes and 3.5 vomiting episodes)

Tolia et al22 (1999) Wenzl et al25 (2003)

RCT; parallel RCT; crossover

Not clear Yes

Formula plus rice starch Formula with carob-bean gum 0.4%

Standard formula Standard formula

Vandenplas et al23 (1994)

RCT; parallel

Yes

Formula with bean gum (St Johns bread)

Standard formula (not all had the same formula)

RCT; parallel

Not clear

Standard formula Standard formula

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Vanderhoof et al24 (2003) Xinias et al26 (2005)

RCT; parallel

Yes

Prethickened formula (rice starch) Cornstarch-thickened caseinpredominant formula

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ACA indicates available case analysis.

Study or Subgroup 1.1.1 Carob Iacono et al15 2002 Wenzl et al25 2003 Subtotal (95% CI)

Treatment Control Events Total Events Total Weight 28 7 82 14 96 12 1 84 14 98 74.7% 6.3% 81.0%

RR 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]

RR M-H, Fixed, 95% CI

35 13 Total events Heterogeneity: 2 = 1.08, df = 1 (P = .30); I = 7% Test for overall effect: z = 3.46 (P = .0005)

FIGURE 1 Number of infants without regurgitation.

1.1.3 Soy formula with soy fiber Ostrom et al21 2006 Subtotal (95% CI) 11 67 67 3 3 66 66 19.0% 19.0% 3.61 [1.06 to 12.36] 3.61 [1.06 to 12.36]

Total events 11 Heterogeneity: Not applicable Test for overall effect: z = 2.05 (P = .04) Total (95% CI) 163

164 100.0%

2.91 [1.73 to 4.91]

Total events 46 16 Heterogeneity: 2 = 1.30, df = 2 (P = .52); I = 0% Test for overall effect: z = 4.02 (P < .0001)

0.05 0.2 Favors control

5 20 Favors treatment

Study or Subgroup 1.2.1 Corn

Treatment Control Mean SD Total Mean SD Total Weight 0.42 41 41 2.89 1.16 40 40 50.1% 50.1%

MD IV, Random, 95% CI -1.96 [-2.34 to -1.58] -1.96 [-2.34 to -1.58]

MD IV, Random, 95% CI

Chao and Vandenplas13 2007 0.93 Subtotal (95% CI)

Heterogeneity: Not applicable Test for overall effect: z = 10.06 (P < .00001) 1.2.2 Rice Chao and Vandenplas14 2007 1.61 Subtotal (95% CI) 0.76 31 31 2.38 0.83 32 32 49.9% 49.9% -0.77 [-1.16 to -0.38] -0.77 [-1.16 to -0.38]

Heterogeneity: Not applicable Test for overall effect: z = 3.84 (P = .0001) Total (95% CI) 72 72 100.0% -1.37 [-2.53 to -0.20] -2 -1 0 1 2 Favors treatment Favors control

Heterogeneity: = 0.67; = 18.13, df = 1 (P < .0001); I = 94% Test for overall effect: z = 2.30 (P = .02)

FIGURE 2 Number of episodes of regurgitation and vomiting per day.

ber) were effective (Fig 3). In the study by Miyazawa et al,17 children fed with locust-bean gum formula also had fewer episodes of regurgitation than those fed control formula. However, data were expressed as median 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], in xed-effects model, and 0.97 episode [95% CI: 1.5 to 0.4], in random-effects model). In both trials, cornstarch was used as a thickening agent (Fig 4). formula, n 81, RR: 0.12 [95% CI: 0.02 to 0.93]). formula, n 60, RR: 1.7 [95% CI: 0.3 to 9.5]).

episodes of irritability (1 RCT,13 cornstarch-thickened crying and dysphagia (1 RCT,19 cornstarch-thickened regurgitation symptoms (eg, irritability, coughing,

with a statistically signicant increase in weight gain (4 RCTs, n 265, WMD: 3.55 g/day [95% CI: 2.6 to 4.5], in xed-effects model, and 3.7 g/day [95% CI: 1.55 to 5.80], in random-effects model) (Fig 5). Conversely, Iacono et al15 found that the weight/height ratio was similar in both groups at all times. In addition, Ostrom et al21 reported that weight gain did not differ between the groups: infants in both groups gained 32 to 33 g/day. In the study by Miyazawa et al (2007),18 the weight gain over 1 week with locust-bean gumthickened formula was similar to that with the standard formula. The authors did not provide information on variability, which precluded including the results of these studies in the meta-analysis. Esophageal pH Monitoring The pooled results of 4 trials,19,22,23,26 regardless of the thickening agent used, revealed no signicant difference in the reux index (percentage of time during which the pH was 4) between the groups (4 RCTs, n 217, WMD: 1.15% [95% CI: 2.6 to 0.3], in xed-effects model, and 1.64% [95% CI: 5.0 to 1.7], in randomeffects model). However, the subgroup analysis based on the thickening agent used revealed a signicant difference in infants treated with cornstarch-thickened formula compared with the control group (2 RCTs,19,26 n

choking, night awakening) (1 RCT,13 cornstarch-thickened formula, n 81, RR: 0.27 [95% CI: 0.08 to 0.88]). Weight Gain (g/day) Only 4 trials13,14,20,26 provided data on weight gain in such a way that the data could be included in the metaanalysis. The pooled results showed that compared with controls, thickening of infant formula was associated
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Study or Subgroup 1.3.3 Corn Moukarzel et al19 2007 Moya et al20 1999 Xinias et al26 2005 Subtotal (95% CI)

Treatment Control Mean SD Total Mean SD Total Weight 2 2.3 2.9 1.6 2.57 2.71 28 6 51 85 5.2 3.1 4.5 2.1 4.31 2.01 32 6 45 83 13.2% 9.5% 15.0% 37.7%

MD 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]

MD IV, Random, 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 fiber Ostrom et al21 2006 Subtotal (95% CI) 2 0.2 67 67 2.4 0.3 66 66 17.5% 17.5% -0.40 [-0.49 to -0.31] -0.40 [-0.49 to -0.31]

Heterogeneity: Not applicable Test for overall effect: z = 9.03 (P < .00001) 1.3.5 Carob Miyazawa et al16 2006 (350) 1.85 Miyazawa et al17 2006 (450) 1.83 Moya et al20 1999 2.2 Subtotal (95% CI) 0.5 0.4 1 13 14 8 35 3.23 4.25 4.5 0.6 0.5 2.1 13 14 6 33 16.9% 17.1% 10.8% 44.8% -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]

Heterogeneity: = 0.44; = 14.28, df = 2 (P = .0008); I = 86% Test for overall effect: z = 4.39 (P < .0001) Total (95% CI) 187 182 100.0% -1.76 [-2.72 to -0.80] -2 -1 0 1 2 Favors treatment Favors control

Heterogeneity: = 1.37; = 168.00, df = 6 (P < .00001); I = 96% Test for overall effect: z = 3.59 (P = .0003)

FIGURE 3 Number of episodes of regurgitation per day.

Study or Subgroup 1.5.1 Corn Moukarzel et al19 2007 Xinias et al26 2005 Subtotal (95% CI)

Treatment Control Mean SD Total Mean SD Total Weight 0.5 0.8 1.45 1.65 28 51 79 1.2 1.1 2.74 1.37 32 54.9% 45 45.1% 77 100.0%

MD 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]

MD IV, Random, 95% CI

Heterogeneity: = 0.10; = 2.23, df = 1 (P = .13); I = 55% Test for overall effect: z = 3.29 (P = .001) Total (95% CI) 79 77 100.0% -0.97 [-1.54 to -0.39] -2 -1 0 1 2 Favors treatment Favors control

Heterogeneity: = 0.10; = 2.23, df = 1 (P = .13); I = 55% Test for overall effect: z = 3.29 (P = .001)

FIGURE 4 Number 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)

Treatment Control Mean SD Total Mean SD Total Weight 29.2 4.35 28.5 12.1 29.1 3.9 22.5 2.4 19 51 41 31 142 28.4 24.3 23.6 20 7.2 8.1 3.5 2.5 6 45 40 32 9.6% 16.8% 35.1% 38.5%

MD 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]

MD IV, Random, 95% CI

123 100.0%

Heterogeneity: = 2.69; = 9.39, df = 3 (P = .02); I = 68% Test for overall effect: z = 3.38 (P = .0007)

-20 -10 0 10 20 Favors control Favors treatment

FIGURE 5 Weight gain (g/day).

156, WMD: 3.6% [95% CI: 6 to 1.2], in both xedand random-effects models) but no signicant difference in those treated with rice-thickened formula (1 RCT,22 n 41, MD: 1.9% [95% CI: 0.3 to 4.1]) or with carob-bean gum compared with the control group (1 RCT,23 n 20, MD: 2% [95% 6.9 to 2.7]) (Fig 6). One RCT26 (n 96) revealed no signicant reduction in 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 reux episodes

lasting 5 minutes (WMD: 0.8 episode [95% CI: 1.7 to 0.12] in xed-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) revealed a signicant reduction in the duration of the longest reux episode of pH at 4 in infants treated with thickened food (WMD: 8.1 minutes [95% CI: 11.9 to 4.3]) (Fig 8). This effect was a result of the cornstarch formula only26 (MD: 8.5 minutes [12.4 to 4.6]); no such effect was seen with the carob-bean gum thickener23 (MD: 1.2 minutes [95% CI: 17.4 to 19.8]).
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Study or Subgroup 1.9.1 Rice Tolia et al22 1999 Subtotal (95% CI)

Treatment Control Mean SD Total Mean SD Total Weight 5 3.6 18 18 3.1 3.6 23 23 28.6% 28.6%

MD IV, Random, 95% CI 1.90 [-0.32 to 4.12] 1.90 [-0.32 to 4.12]

MD IV, Random, 95% CI

Heterogeneity: Not applicable Test for overall effect: z = 1.68 (P = .09) 1.9.2 Corn Moukarzel at el19 2007 Xinias et al26 2005 Subtotal (95% CI) 5.64 5.14 6.8 6.2 28 51 79 7.77 7.72 11.4 7 32 45 77 24.8% 27.1% 51.9% -2.13 [-5.41 to 1.15] -4.60 [-7.26 to -1.94] -3.56 [-5.95 to -1.17]

Heterogeneity: = 0.73; = 1.31, df = 1 (P = .25); I = 24% Test for overall effect: z = 2.92 (P = .004) 1.9.3 Carob bean gum Vandenplas et al23 1994 11.1 Subtotal (95% CI) 6.1 10 10 13.2 4.7 10 10 19.5% 19.5% -2.10 [-6.87 to 2.67] -2.10 [-6.87 to 2.67]

Heterogeneity: Not applicable Test for overall effect: z = 0.86 (P = .39) Total (95% CI) 107 110 100.0% -1.64 [-4.97 to 1.68] -10 -5 0 5 10 Favors treatment Favors control

Heterogeneity: = 8.79; = 14.20, df = 3 (P = .003); I = 79% Test for overall effect: z = 0.97 (P = .33)

FIGURE 6 Reux index (percentage of time during which pH was 4).

Study or Subgroup 1.12.1 Corn Moukarzel et al19 2007 Xinias et al26 2005 Subtotal (95% CI)

Treatment Control Mean SD Total Mean SD Total Weight 1.61 2.68 2.9 3.4 28 51 79 1.37 1.68 5.4 4.2 32 45 77 41.1% 37.2% 78.3%

MD 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]

MD IV, Random, 95% CI

Heterogeneity: = 3.27; = 7.79, df = 1 (P = .005); I = 87% Test for overall effect: z = 0.79 (P = .43) 1.12.2 Carob Vandenplas et al23 1994 Subtotal (95% CI) 7.7 4.27 10 10 8.8 2.9 10 10 21.7% 21.7% -1.10 [-4.30 to 2.10] -1.10 [-4.30 to 2.10]

Heterogeneity: Not applicable Test for overall effect: z = 0.67 (P = .50) Total (95% CI) 89 87 100.0% -1.07 [-3.09 to 0.95] -10 -5 0 5 10 Favors treatment Favors control

Heterogeneity: = 2.24; = 7.84, df = 2 (P = .02); I = 74% Test for overall effect: z = 1.04 (P = .30)

FIGURE 7 Number of reux episodes lasting 5 minutes.

Study or Subgroup 1.13.1 Carob

Treatment Control Mean SD Total Mean SD Total Weight 29.9 18.9 10 10

MD IV, Fixed, 95% CI

MD IV, Fixed, 95% CI

10 Vandenplas et al23 1994 31.1 23.4 10 Subtotal (95% CI) Heterogeneity: Not applicable Test for overall effect: z = 0.13 (P = .90) 1.13.2 Corn Xinias et al26 2005 Subtotal (95% CI)

4.2% 1.20 [-17.44 to 19.84] 4.2% 1.20 [-17.44 to 19.84]

10.8

8.9

51 51

19.3 10.5

45 45

95.8% -8.50 [-12.42 to -4.58] 95.8% -8.50 [-12.42 to -4.58]

Heterogeneity: Not applicable Test for overall effect: z = 4.25 (P < .0001) Total (95% CI) 61 55 100.0% -8.09 [-11.93 to -4.25] Heterogeneity: = 1.00, df = 1 (P = .32); I = 0% -20 -10 0 10 20 Test for overall effect: z = 4.13 (P < .0001) Favors treatment Favors control Test for subgroup differences: = 1.00, df = 1 (P = .32), I = 0%

FIGURE 8 Duration of the longest reux episode.

Adverse Events Of the 14 trials included in the review, adverse effects were only reported in 3 trials (Table 2).19,24,26 Iacono et
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al,15 while not describing any adverse events, reported that 14 patients were suspended from the study because of the onset of diarrhea. Also, Miyazawa et al16 did not

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TABLE 2 Adverse Effects

Study Chao and Vandenplas (2007) Chao and Vandenplas13 (2007) Iacono et al15 (2002) (letter)
14

Thickening Agent Hydrolyzed rice 90%, cornstarch 5% Cornstarch Locust-bean gum

Adverse Effects No signicant difference in stool frequency or consistency (only outcome) Not reported No adverse effects described; however, 14 patients in the thickenedformula group were suspended from the study because of the onset of diarrhea during the rst 2 wk of the study 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 signicantly greater than that with the standard formula; mothers reported that their infants seemed to have difculty sucking the thickened formula (5 of 27) Not reported Not reported 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 signicant and 3 of 28 vs 2 of 32 not signicant) Not reported Not reported Not reported Not reported Not reported No difference in the incidence of serious adverse events; no difference in any of the 4 variables recorded daily (fussiness, constipation, diarrhea, or gas) None dropped out; no adverse effects caused by the intervention were observed

Miyazawa et al16 (2004)

Locust-bean gum

Miyazawa et al17 (2006) Miyazawa et al18 (2007) Moukarzel et al19 (2007)

Locust-bean gum Locust-bean gum Cornstarch

Moya et al20 (1999) Ostrom et al21 (2006) Tolia et al22 (1999) Wenzl et al25 (2003) Vandenplas et al23 (1994) Vanderhoof et al24 (2003)

Bean gum or corn polymers Soy ber Rice starch Carob-bean gum Carob-bean gum Rice starch

Xinias et al26 (2005)

Cornstarch

report any adverse events, but they still found that infants who received thickened formula had a slightly higher number of bowel movements and had difculty sucking the thickened formula. DISCUSSION Principal Findings The objective of this review was to provide some resolution to the uncertainty regarding the use of thickening agents, as an adjunct to infant formula, for the treatment of GER in generally healthy infants. With the limited evidence available, we found that thickening agents signicantly increased the percentage of infants with no regurgitation. Food thickening also reduced some symptoms of GER assessed subjectively by the parent/guardian of the child and/or by the treating physician. This therapeutic benet was reproducible regardless of the clinical outcome measure studied (ie, number of episodes of regurgitation and vomiting per day, number of episodes of regurgitation per day, and number of episodes of vomiting per day). Still, although the differences were statistically signicant, the reduction may be of questionable clinical signicance (eg, reduction in regurgitation by 0.6 episode per day). The use of thickened formulas was also associated with increased weight gain, which, in contrast, may be potentially clinically important, particularly if these formulas are used over a longer period of time. Although some parameters of pH monitoring were in favor of thickened formulas (eg, signicant reduction in the duration of the longest reux episode of pH at 4), others did not show signicant differences between the groups (eg, the pooled results of

4 trials, regardless of the thickening agent used, revealed no signicant reduction in the reux index). It is noteworthy, however, that even if there was a signicant difference, the clinical meaning of it is unclear. Regretfully, a paucity of data did not allow us to conclude whether any particular thickening agent is denitely more effective than another. These updated results are consistent with the results of previous reviews but included more RCTs (14 trials compared with 8 RCTs in the most recent Cochrane review9 and 3 RCTs in the review by Carroll et al7). Thus, these results more precisely dene the effects of thickening agents on GER outcomes. Study Limitations This systematic review has several limitations. Only a limited number of trials were available for review. Their methodologic quality varied. For example, one of the important limitations of the included trials was unclear or inappropriate allocation concealment, which may result in overestimation of the intervention effect.27 An additional limitation is that despite the studys doubleblind design, some physicians and parents may have suspected the intervention because all thickened formulas have a specic texture. Again, this can overestimate the effect and skew the results in favor of either treatment, depending on the biases of the investigators. Other concerns apart from methodology may come from the fact that the manufacturer of the thickened formula supported several RCTs; it is not clear if all steps necessary to avoid bias were taken. We found statistical heterogeneity when pooling several outcomes. This was
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addressed by using a random-effects meta-analysis. Finally, because of the limited data, we did not test for publication bias. Given these considerations, some caution must be exercised in interpreting the strength of the evidence presented. Safety There was no evidence that the thickened foods differed from the control formulas in terms of safety. However, trials were powered for effectiveness and were shortterm. Given that adverse events were rare in the included trials, a large-scale RCT would be required to detect any small but real differences in the incidence of adverse effects. This issue is important, because on the basis of the available literature, there is concern that the use of thickening agents may result in harmful events. The use of carob thickeners as therapy for GER was associated with diarrhea28 or an allergic reaction.29 The use of rice-thickened feedings was described as a cause of increased coughing.30 There is also the possibility that thickening agents may have an effect on the bioavailability of dietary nutrients, causing decreased intestinal absorption of carbohydrates, fat, calcium, iron, zinc, and copper and altering mucosal and endocrine responses.3136 The results of in vitro studies suggest that the bioavailability of calcium, iron, and zinc in infant formula may be decreased by thickening with nondigestible carbohydrates, although not by thickening with added starch.37 In some, but not all, animal studies, adding carob-bean gum to the diet decreased growth.38,39 CONCLUSIONS AND FUTURE RESEARCH On the basis of the results of 14 RCTs, many of which had methodologic limitations and some that were relatively small, thickening foods were only moderately effective in treating GER in otherwise healthy infants. For some outcomes, although the differences between groups were statistically signicant, the effect may be of questionable clinical signicance. More data are needed. The safety of thickening foods and the cost-effectiveness of this therapy need to be dened. Because many trials were company funded, independent trials are needed. Additional investigations comparing thickening foods with other treatment options would be worthwhile. In the absence of denitive data to show that a particular thickening agent is more effective than another, if the physician feels that treating this usually self-limited condition is important he or she can guide the initial treatment according to the patients preference, cost, and product availability. REFERENCES
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PEDIATRICS Volume 122, Number 6, December 2008

e1277

The Effect of Thickened-Feed Interventions on Gastroesophageal Reflux in Infants: Systematic Review and Meta-analysis of Randomized, Controlled Trials Andrea Horvath, Piotr Dziechciarz and Hania Szajewska Pediatrics 2008;122;e1268-e1277; originally published online Nov 10, 2008; DOI: 10.1542/peds.2008-1900
Updated Information & Services References including high-resolution figures, can be found at: http://www.pediatrics.org/cgi/content/full/122/6/e1268 This article cites 31 articles, 6 of which you can access for free at: http://www.pediatrics.org/cgi/content/full/122/6/e1268#BIBL This article has been cited by 1 HighWire-hosted articles: http://www.pediatrics.org/cgi/content/full/122/6/e1268#otherarti cles This article, along with others on similar topics, appears in the following collection(s): Gastrointestinal Tract http://www.pediatrics.org/cgi/collection/gastrointestinal_tract An erratum has been published regarding this article. Please see next page or: http://www.pediatrics.org/cgi/content/full/123/4/1254-a Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.pediatrics.org/misc/Permissions.shtml Information about ordering reprints can be found online: http://www.pediatrics.org/misc/reprints.shtml

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ERRATA

Hoilette LK, Clark SJ, Gebremariam A, Davis MM. Usual Source of Care and Unmet Need Among Vulnerable Children: 1998 2006. 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:

TABLE 1 Age and Race of Uninsured Children, and Children Reporting no Usual Source of Care, NHIS 1998 & 2006
Demographics Age (years) Uninsured 1998 Proportion (95% CI) N 8 746 854 n 1993 30.1 (27.732.7) 34.7 (32.037.5) 35.2 (32.837.7) 46.0 (42.849.2) 15.3 (13.117.) 33.0 (30.236.0) 5.7 (4.18.0) Uninsured 2006 Proportion (95% CI) N 7 250 542 n 1080 25.9 (22.729.5) 34.7 (31.038.7) 39.3 (35.743.1) 39.2 (35.043.6) 12.7 (10.415.5) 42.5 (38.2 -46.8) 5.6 (4.07.7) No USC 1998 Proportion (95% CI) N 2 208 722 n 552 16.5 (13.120.5) 34.0 (28.839.5) 49.6 (44.354.9) 37.0 (31.642.7) 13.7 (10.318.0) 41.6 (36.347.2) 7.7 (5.211.2) No USC 2006 Proportion (95% CI) N 2 358 232 n 345 17.8 (13.323.6) 28.2 (21.935.5) 54.0 (47.060.8) 32.7 (25.540.8) 11.1 (7.116.8) 50.9 (43.558.4) 5.0 (2.69.4)

05 611 1217 Race/Ethnicity White Black Hispanic Asian

doi:10.1542/peds.2009-0360

Horvath A, Dziechciarz P, Szajewska H. The Effect of ThickenedFeed Interventions on Gastroesophageal Reux in Infants: Systematic Review and Meta-analysis of Randomized, Controlled Trials. 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 and Strabismus, American Academy of Ophthalmology, and American Association of Certied Orthoptists. Red Reex Examination in Neonates, Infants, and Children. PEDIATRICS 2008;122(6): 1401 1404 An error occurred in the AAP policy statement Red Reex 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

1254

ERRATA

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