Published online November 10, 2008
PEDIATRICS (doi:10.1542/peds.2008-1900)
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REVIEW ARTICLE

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

Andrea Horvath, MD, Piotr Dziechciarz, MD and Hania Szajewska, MD

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


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS AND FUTURE RESEARCH
 REFERENCES
 
CONTEXT. Currently, thickened feeds are increasingly being used to treat infants with gastroesophageal reflux, driven in large part by the baby food industry. Previous meta-analyses have shown that although thickened formulas do not seem to reduce measurable 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 of gastroesophageal reflux in healthy infants.

METHODS. The Cochrane Library, Medline, Embase, and CINAHL databases and proceedings 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 reflux 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, some with methodologic limitations, were included. Use of thickened formulas compared with standard formula significantly 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 reflux index, 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 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 reflux in healthy infants.

Key Words: randomized • controlled trial • RCT • thickeners • spitting up • vomiting • children

Abbreviations: GER—gastroesophageal reflux • GERD—gastroesophageal reflux disease • RCT—randomized, controlled trial • RR—risk ratio • CI—confidence interval • MD—mean difference • WMD—weighted mean difference


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS AND FUTURE RESEARCH
 REFERENCES
 
Gastroesophageal reflux (GER) is defined as the passage of gastric contents into the esophagus, and GER disease (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 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 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, controlled trials (RCTs). This systematic review revealed that although thickened formulas do not seem to reduce measurable reflux, 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) identified 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 reflux 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 efficacy 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
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS AND FUTURE RESEARCH
 REFERENCES
 
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 identified 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 defined; 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 filter for identifying RCTs, which was combined with a topic-specific strategy using search terms. The following search terms were used: (gastro-esophageal reflux[r] or idiopathic gastro-esophageal reflux or gastro-esophageal reflux disease or GER or GERD or GORD or infantile reflux 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 reflux 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 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 insufficient 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-to-treat 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 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% confidence 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 {chi}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 fixed-effects models for the main analysis. For simplicity, if heterogeneity was not revealed, we present results of only the fixed-effects model. Although we planned to visually examine funnel plots to determine publication bias, there were too few studies to warrant their generation.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS AND FUTURE RESEARCH
 REFERENCES
 
Search Results and Description of Studies
Table 1 summarizes the characteristics of the 14 included studies involving 877 participants.13–26 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 definition varied between the trials.


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  		TABLE 1 Characteristics of Included Trials

 
Interventions
The feed thickeners used in the studies were carob-bean gum (7 trials15–18,20,23,25), cornstarch (3 trials13,19,26), rice starch (2 trials22,24), cereal (1 trial14), and soy fiber (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 used an adequate method to conceal allocation. The method used in the remaining 8 trials15–20,22,24 was unclear. Six trials21,22–26 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.15,17,18,20,23–26 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 final 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
Significant heterogeneity was found for the number of episodes of regurgitation and vomiting per day ({chi}2 = 18.13, P < .0001, I2 = 94%); the number of episodes of regurgitation per day ({chi}2 = 168, P < .00001, I2 = 96%); the number of episodes of vomiting per day ({chi}2 = 2.23, P = .13, I2 = 55%); weight gain ({chi}2 = 9.39, P = .02, I2 = 68%); the reflux index ({chi}2 = 14.2, P = .003, I2 = 79%); and the number of reflux episodes lasting >5 minutes ({chi}2 = 7.84, P = .02, I2 = 74%). Heterogeneity was not significant for 2 outcomes only (ie, the number of infants without regurgitation [{chi}2 = 1.30, P = .52, I2 = 0%] and the duration of the longest reflux episode [{chi}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 significant 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 fiber (1 RCT, n = 133, RR: 3.6 [95% CI: 1.1 to 12.4]) thickeners were effective.


Figure 1
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  		FIGURE 1 Number of infants without regurgitation.

 
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 fixed-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 fixed-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 fiber) 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 fixed-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).
  • 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-thickened formula, n = 81, RR: 0.27 [95% CI: 0.08 to 0.88]).


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

 

Figure 3
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  		FIGURE 3 Number of episodes of regurgitation per day.

 

Figure 4
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  		FIGURE 4 Number of episodes of vomiting per day.

 
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 meta-analysis. The pooled results showed that compared with controls, thickening of infant formula was associated with a statistically significant increase in weight gain (4 RCTs, 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 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 gum–thickened 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.


Figure 5
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  		FIGURE 5 Weight gain (g/day).

 
Esophageal pH Monitoring
The pooled results of 4 trials,19,22,23,26 regardless of the thickening agent used, revealed no significant difference in the reflux 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 fixed-effects model, and –1.64% [95% CI: –5.0 to 1.7], in random-effects model). However, the subgroup analysis based on the thickening agent used revealed a significant difference in infants treated with cornstarch-thickened formula compared with the control group (2 RCTs,19,26 n = 156, WMD: –3.6% [95% CI: –6 to –1.2], in both fixed- and random-effects models) but no significant 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).


Figure 6
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  		FIGURE 6 Reflux index (percentage of time during which pH was <4).

 
One RCT26 (n = 96) revealed no significant 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 reflux episodes lasting >5 minutes (WMD: –0.8 episode [95% CI: –1.7 to 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) revealed a significant reduction in the duration of the longest reflux 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]).


Figure 7
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  		FIGURE 7 Number of reflux episodes lasting >5 minutes.

 

Figure 8
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  		FIGURE 8 Duration of the longest reflux 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 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 report any adverse events, but they still found that infants who received thickened formula had a slightly higher number of bowel movements and had difficulty sucking the thickened formula.


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  		TABLE 2 Adverse Effects

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS AND FUTURE RESEARCH
 REFERENCES
 
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 significantly 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 benefit 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 significant, the reduction may be of questionable clinical significance (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, significant reduction in the duration of the longest reflux episode of pH at <4), others did not show significant differences between the groups (eg, the pooled results of 4 trials, regardless of the thickening agent used, revealed no significant reduction in the reflux index). It is noteworthy, however, that even if there was a significant 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 definitely 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 define 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 study's double-blind design, some physicians and parents may have suspected the intervention because all thickened formulas have a specific 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 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 short-term. 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.31–36 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
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS AND FUTURE RESEARCH
REFERENCES
 
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 significant, the effect may be of questionable clinical significance. More data are needed. The safety of thickening foods and the cost-effectiveness of this therapy need to be defined. 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 definitive 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 patient's preference, cost, and product availability.


   FOOTNOTES
 
Accepted 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: hania{at}ipgate.pl

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


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS AND FUTURE RESEARCH
 REFERENCES
 

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  5. Vandenplas Y, Belli DC, Benatar A, et al. The role of cisapride in the treatment of pediatric gastroesophageal reflux. The European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 1999;28 (5):518 –528[CrossRef][Web of Science][Medline]
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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics

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Thickened Formula Reduces Reflux in Infants
Journal Watch Pediatrics and Adolescent Medicine, December 24, 2008; 2008(1224): 4 - 4.
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