Gastroesophageal reflux (GER), the involuntary passage of ingested material from the stomach into the esophagus, is a common event in infants. Most reflux episodes are asymptomatic, brief, and limited to the distal esophagus. Regurgitation is defined as passage of refluxed gastric contents into the oral pharynx. Vomiting is a coordinated reflex and is defined as expulsion of the refluxed gastric contents from the mouth. The difference between regurgitation and vomiting is not always clear-cut. GER disease is a condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications such as pain, poor growth, and esophagitis.
According to epidemiological data, about 20% of the parents of formula-fed infants seek medical help because of infant regurgitation (1). Dietary management has been recommended in infants with frequent regurgitation and/or vomiting by the North American and European societies for pediatric gastroenterology, hepatology, and nutrition (2,3). In some parts of western Europe, up to 20% of the formula that is sold is thickened. We performed a prospective, randomised, and blinded trial to compare the evolution of regurgitation and vomiting in infants fed standard formula or formula thickened with rice cereal or bean gum.
PATIENTS AND METHODS
Healthy term-born, formula-fed infants (ages 1–3 months) presenting with frequent regurgitation and/or vomiting (≥4 times/day since at least 1 week before inclusion) were included in a 4-week interventional trial to evaluate the evolution of regurgitation and vomiting and the clinical effect on both of a standard formula thickened with 5 g rice cereal (Rice Cereal Nestlé, Vevey, Switzerland) per 100 mL or an “antiregurgitation” formula manufactured with bean gum as a thickening agent (Nutrilon1-AR, Royal Numico, Zoetermeer, The Netherlands). The bean gum–thickened formula is a nutritionally balanced formula with increased viscosity (Table 1). At baseline, body weight for height ratio was in all children >90% by Centers for Disease Control and Prevention 2000 guidelines. According to the inclusion criteria, all of the infants were at baseline exclusively fed with standard infant formula at normal concentration. Mechanical obstruction such as infantile hypertrophic pyloric stenosis and malrotation were excluded before inclusion. Exclusion criteria were atopic symptoms such as eczema, watery rhinorrhea or diarrhea (suspected cow's milk allergy), congenital abnormalities, feeding refusal, hematemesis, melena, use of antireflux medication, or previous use of thickened formula.
All of the patients were randomly assigned to 1 of the 3 groups. Randomisation was performed according to an automated randomisation. All of the participating parents were reassured in the same way, explaining the natural evolution of infant regurgitation and the benign nature of the condition (2–4). Group A was continued on standard infant formula, group B was switched to standard formula thickened with the rice cereal, and group C received the bean gum–thickened formula. In all of the groups, infants were fed ad libitum. Parents recorded the frequency of regurgitation during the entire 4-week intervention period in a diary. Parents also were asked to record volume intake for each feeding, and periods of sleep disturbances caused by irritability, feeding refusal, stool aspects (watery or hard), or back arching. At baseline, there were no differences between the 3 groups (Table 2). Weight gain was evaluated at the beginning and the end of the 1-month intervention.
Results are expressed as the mean ± 1 standard deviation. Analyses are performed with SPSS version 15.0 (SPSS, Chicago, IL). Repeated measures analysis of variance was used to test for differences between subgroups and paired Student t test or Wilcoxon rank test for changes within subgroups. The level of significance was set at P < 0.05. The study protocol was approved by the local ethical committee; written informed consent was obtained before inclusion.
All 60 included infants completed the study; each group consisted of 20 infants. The 3 groups were comparable at inclusion (Table 2). Table 3 shows a progressive reduction in frequency of regurgitation and vomiting during the 4 intervention weeks in all 3 groups, demonstrating a statistically significant natural decrease in regurgitation frequency (group A: −2.7 ± 2.4 episodes/day; P < 0.005). Regurgitation decreased mostly in the group that received the bean gum–thickened formula (group C: −4.2 ± 2.1; P < 0.005), but the difference was not statistically significant (P = 0.14).
Table 4 summarises the evolution of the intake of formula in each group, which was comparable at every evaluation (baseline and weeks 1, 2, 3, and 4). Although not significantly different, intake in the cereal-thickened group remained stable for 2 to 3 weeks. The stool characteristics (consistency, frequency) did not differ between the groups during the intervention period with a majority of children that had normal soft stools. Similarly, there was no difference in sleeping disturbance.
Weight gain was significantly higher in the group with bean gum–thickened formula (965 ± 166 g) compared with the standard formula group (828 ± 160 g; P < 0.05) or compared with the cereal-thickened formula (575 ± 97 g; P < 0.00001). The percent weight changes were, respectively, 16.4 ± 1.09% (group A), 11.5 ± 0.9% (group B), and 19.9 ± 0.8% (group C) (P < 0.0001). This may be related to the (nonsignificant) smaller intake in group B in comparison with the other groups.
Knowledge of the natural history of regurgitation and vomiting is relatively poor because of the limited description and identification of the infants. In an Italian observational study in which 2879 infants were followed from birth to 6 months, regurgitation was reported in 23.1% of all infants (5). Formula was changed in 60% of all infants (5). The frequency of regurgitation varies largely in relation to age. Martin et al (4) showed that about 40% of all 3- to 4-month-old infants regurgitate, whereas at 12 months of age, only 5% of infants regurgitate. A prospective follow-up of 63 regurgitating infants reported a remission in all before 1 year old (1). Even thereafter, feeding refusal, duration of a meal, and parental feeding-related distress were significantly prolonged or increased in the group with regurgitation if compared with a control group (1,6). This observation suggests a decreased quality of life in regurgitating infants and their parents, even if the regurgitation has disappeared. Infants spitting up during 90 days or more during their first 2 years of life have a greater risk for developing GER symptoms at 9 years old (4). This may point to the fact that some of these children who frequently spit up may have undiagnosed GER disease (7). Conversely, a history of GER is the most frequent underlying cause of feeding disorders in young children (6).
Parental reassurance has been strongly recommended by the European Society of Paediatric Gastroenterology, Hepatology, and Nutrition as the first step in the therapeutic approach (2). Avoiding overfeeding also has been shown to reduce regurgitation (8). Volume reduction may be helpful in clearly overfed infants, but is of no or limited interest in infants who are fed with a normal frequency and volumes according to weight and age. In this trial, there was no difference in volume intake among the 3 groups. Milk-thickening agents have been shown to further reduce regurgitation (8). In the United States, thickening is usually achieved with the addition of rice cereal to formula (3,9). When thickening an infant formula with an energy density of 20 kcal/oz, the addition of 1 tablespoon of rice cereal per ounce of formula increases the energy density to approximately 34 kcal/oz, whereas the addition of 1 tablespoonful of rice cereal per 2 oz of formula increases the energy density to approximately 27 kcal/oz (3). Thickening agents—such as rice cereal, gelatin, and various polysaccharides such as carob bean gum or galactomannan—have been successfully administered for the treatment of regurgitation in infants (9–13). Adding rice starch to formula may provide additional buffering of acid, which may alleviate irritability. Moreover, rice cereals have an excellent digestibility in infants as young as 1 to 3 months (13,14). Theoretically, increase of the energy density in this manner may be an appropriate strategy for infants who fail to thrive because of inadequate intake or excessive loss because of regurgitation. When formula is thickened, it is necessary to cross-cut the nipple to allow for adequate flow. All of the infants participating in this study had a normal nutritional status at inclusion. It is not clear why weight gain was smaller in the group with rice cereal than the other 2 groups. However, weight gain was significantly greater in the group fed the bean gum–thickened formula than the standard formula. The strong trend in reduction of episodes of regurgitation could have facilitated this observation, given that intake was similar in all of the groups. Because increased weight gain in infants may be a risk factor for obesity during adulthood, these nutritional aspects need further evaluation.
Many commercial antiregurgitation formulas are available in European countries that contain potato, rice, or corn starch, locust bean gum (prepared from St John bread, a galactomannan), or carboxymethylcellulose (a combination of pectin and cellulose) as thickening agents. There are as many different compositions of antiregurgitation formulas as there are companies: Some formulas are casein predominant, whereas others contain protein hydrolysates. These formulas have been reported to decrease regurgitation, vomiting, and esophageal acid exposure when compared with unthickened formula and formula thickened with rice cereal (15). This benefit, although cosmetic, is welcome to parents of children who frequently spit up. Decrease of the incidence of regurgitation does reassure the parents. In the first randomised trial, parental reassurance without formula change was shown to not decrease regurgitation more significantly than bean gum–thickened formula (identical to that used in this trial) (16).
The effect of thickened feeding on GER documented by milk scintigraphy, 24-hour esophageal pH monitoring, or impedancemetry remains controversial, although the reduction in the incidence of regurgitation was confirmed in most studies. Gastroesophageal scintigraphy is a sensitive and noninvasive test for the detection of GER. In the study by Chao and Vandenplas (17), the number of infants with more than 3 postprandial reflux episodes was significantly reduced in the group receiving rice cereal–thickened formula. Cereal-thickened formula was significantly more efficacious than postural therapy in decreasing the frequency of regurgitation in regurgitating infants. Treatment of regurgitation with cereal-thickened formula resulted in an increased energy intake (approximately 25%), related to increased gain in weight and length, in comparison with regular formula and positioning therapy (17). Esophageal pH monitoring showed that milk thickened with rice starch or carob bean gum decreased the number of acid reflux episodes, but the total duration of acid exposure remained unchanged, presumably because of the slower clearance of the thickened acid reflux from the esophagus (9,16). A controlled trial that evaluated the use of formula thickened with 4% rice starch in infants with GER showed decreased regurgitation and crying and increased sleeping time, even though the number of reflux episodes documented by scintigraphy did not decrease (13).
Vandenplas et al (16) previously reported that milk thickened with carob bean gum (the same content as the already thickened formula in this trial) decreased the number of acid reflux episodes, but the total duration of acid exposure remained unchanged, presumably because of slower clearance of the thickened acid refluxate from the esophagus. Wenzl et al (18) confirmed (for the same formula) a significant decrease in regurgitation, although the height of the reflux episodes as measured with impedance was not different. However, a recent multicentre trial found that a casein-dominant formula thickened with a specifically treated corn starch reduced esophageal acid exposure, reduced reflux as detected by scintigraphy, and reduced clinical symptoms (19,20).
Few studies have compared the impact of feeding with standard versus thickened formula on the frequency of infant regurgitation. The findings of this trial confirm the data reported in the first article on the efficacy of commercial antiregurgitation formula (16). The 1994 report and this study used the same prethickened formula. Also, in the first trial, parental reassurance was shown to reduce regurgitation and vomiting significantly (16). The difference in decrease of regurgitation between standard and unthickened formulas was not significant (16).
Some thickening agents have potential side effects. Thickening agents may mask symptoms and delay correct diagnosis and other therapeutic interventions. Orenstein et al (10) indicated that thickened formulas were associated with significantly more coughing, which led to the hypothesis that thickened formulas worsen nonregurgitant reflux. According to in vitro models, bean gum may be associated with malabsorption of minerals and micronutrients. Studies of various thickening agents (including guar gum, carob bean gum, and soybean polysaccharides) indicate the potential for decreased intestinal absorption of carbohydrates, fats, calcium, iron, zinc, and copper (21–23). Abdominal pain, colic, and diarrhea may ensue from fermentation of bean gum and undigested starch derivatives in the colon. In some animal studies, although not all, the addition of carob bean gum to the diet decreased growth. Although they are rare, serious complications of bean gum consumption such as acute intestinal obstruction, gastric bezoar, and necrotizing enterocolitis have been reported in preterms and newborns. Allergic reactions to carob bean gum have been reported in adults exposed to it at their workplaces. However, only a few infants have been reported with carob bean gum allergy after exposure to thickened formula. No data are available on whether the addition of starch of different sources (rice, corn) with protein contamination may put the young, regurgitating infant at risk for developing allergies to these foods.
A Cochrane review concluded that thickened feeds reduce the regurgitation severity score (95% confidence interval [CI] −1.35 to −0.52) as well as the frequency of emesis (95% CI −1.22 to −0.61), but that acid reflux, expressed as reflux index, was not reduced (95% CI −3.27–4.23) (24). In this trial, there was no statistically significant difference among the groups in the incidence of regurgitation, although the incidence of regurgitation was smallest in the bean gum–thickened group. In poor socioeconomic conditions, more expensive antiregurgitation formula should not be recommended. Parental reassurance remains the cornerstone in the approach to infant regurgitation. Although volume intake was similar in the 3 groups, short-term weight gain was significantly higher in the bean gum–thickened group. Whether this increased weight gain is beneficial needs further evaluation.
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