Gastroesophageal reflux (GER) is a physiological condition that occurs several times per day in healthy infants, because it can be promoted by a number of physiological factors. GER in healthy infants, children, and adults can cause few or no symptoms (1,2). In infants, the most common symptoms associated with GER are irritability, cough, anorexia/food refusal, regurgitation, and vomiting (3–6). This condition tends to resolve spontaneously in 95% of infants within 12 to 14 months of life (7,8). Parents are more likely to be worried when vomiting is frequent, or when the infant cries constantly, and often seek medical help because of regular regurgitation.
According to the guidelines of the North American and the European Societies for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN and ESPGHAN), the therapeutic management of GER can be achieved by using nonpharmacological interventions such as body positioning, modification of feeding methods, or milk thickening, limiting drug administration to those infants who do not benefit from conservative measures or those with clinical complications of GER (1,2,9); however, widespread use of empirical antireflux medications in infants, both during hospital recovery and after discharge, has been reported (10). Most of these drugs have been reported to cause adverse effects (11,12).
The American management guidance for pediatricians suggests the use of alginate in physiological GER but does not recommend the use of surface agents where there are serious symptoms or with gastroesophageal reflux disease (GERD) complications (2); however, in the literature, there are conflicting results regarding the effect of alginate on GER symptoms in infants (1,2). Clinical studies showed that sodium alginate significantly decreases the mean frequency and severity of vomiting in infants compared with placebo (13,14). Moreover, it has been reported that sodium alginate, associated with bicarbonates, reduces the frequency, height, and acidity of reflux, showing the same efficacy as acid suppressors, with no systemic effects (15). The addition of sodium bicarbonate to the formulation contributes to the formation of a gel, converting it into carbon dioxide, which is entrapped within the forming foam. It then floats on the gastric content and preferentially enters the esophagus during reflux episodes (16). Recently, a new formulation containing magnesium alginate has been developed (Gastrotuss Baby, DMG Italia SRL, Pomezia, Italy). Magnesium alginate should offer the advantages of a 3-fold higher viscosity compared with sodium alginate (1000–1800 mPa vs 300–700 mPa) and reduce the sodium uptake for the patients. Nevertheless, the formulation has not yet been evaluated in clinical trials, either in adults or in children.
On the contrary, a placebo-controlled study with alginate in infants showed that although symptoms improved with therapy, the only objective change on combined multichannel intraluminal impedance/pH metry (pH/MII) evaluation was a minimal decrease in reflux height in the esophagus (17).
The aim of the present randomized, open-label, controlled trial was to evaluate the efficacy of 3 different treatments (reassurance with lifestyle changes and a magnesium alginate aluminum-free formulation plus simethicone, reassurance with lifestyle changes and thickened formula, and reassurance with lifestyle changes alone) on GER symptom score. Our secondary aim was to evaluate the safety and tolerability of magnesium alginate plus simethicone.
The present prospective randomized, open-label, controlled trial was conducted from September 2012 to September 2013, in consecutive full-term, formula-fed infants, ages 1 to 12 months, affected by symptoms suggestive of GER. Infants were enrolled by 6 general pediatricians from the Italian National Health System. Each pediatrician enrolled consecutive patients with infant regurgitation defined according to the Rome III criteria (18). Evidence of chronic diseases, hepatic, renal, or cardiac diseases, metabolic or central nervous system diseases, or use of acid suppressor treatment (H2-receptor antagonists or proton pump inhibitors [PPIs]), thickened formula, or a history of prematurity or atopy was considered an exclusion criterion.
A validated questionnaire (19) (Infant Gastroesophageal Reflux Questionnaire [I-GERQ], modified) was completed at enrollment and during the follow-up visits. The I-GERQ Revised is a 35-item questionnaire based on the characteristics of regurgitation (quantity and frequency), feeding, bowel habits, crying, hiccups, respiratory symptoms, weight gain, stool alteration, family history of GER and allergy, and parental suspicion of GERD. Each question gives a score of 0 to 1 to give a maximum score of 35. Patients with a symptomatic score ≥7 were considered affected by GER (19). The parents were asked to complete the questionnaire.
Patients with infant regurgitation defined according to the Rome III criteria and with a positive symptom score were randomly assigned to 3 groups. The parents of all of the enrolled infants were reassured on the benign nature of the condition and were advised to apply lifestyle changes, provided by means of oral and written instructions. In particular, parents were explained that GER is a functional disorder in the absence of any organic cause and were invited to follow modifications in feeding practices (20), with a reduction in the quantity and an increase in the frequency of the feedings, and to keep the infant in a supine position during sleep (21) (see Appendix, http://links.lww.com/MPG/A359). In addition to reassurance and lifestyle changes, the first group (group A) was treated with magnesium alginate aluminum-free formulation plus simethicone, at a dose of 2.5 mL 3 times per day for infants weighing <5 kg or 5 mL 3 times per day for those weighing >5 kg, to be given 10 minutes after feeding. In addition to reassurance and lifestyle changes, the second group (group B) was treated with a formula thickened with rice starch. The amount of rice starch in the formula was 14.3 g per 100 mL of milk (14.3%) for infants younger than 6 months and 14.2 g per 100 mL of milk (14.2%) for older infants. The formula was milk-based and nonhydrolyzed. The third group (control group—group C) was instructed to continue with lifestyle changes, and parents were reassured on the benign nature of the condition. All of the patients were treated for 8 weeks. Parents of the patients were counseled by one of the authors (F.C.) before starting, during, and at the end of the study period regarding any adverse effects of the treatments. In addition, all of the parents were asked to report any possible adverse effects in a daily diary. Compliance was assessed by counting returned bottles for group A and questioning the parents for group B and for group C.
Each pediatrician reevaluated the enrolled infants after 4 weeks (T1) and after 8 weeks (T2) of treatment. Patients with a symptom score <7 points in the questionnaire were considered clinically free of symptoms. The clinician who evaluated the questionnaire results at enrollment and at the follow-up visits was blind to the infants’ treatments. Excellent compliance was defined as no violation of the protocol with respect to the study treatments. None of the patients underwent invasive evaluations such as MII and upper endoscopy. The manufacturer had no role in the conception, design, or conduct of the study, or in the analysis or interpretation of the data. The study proposal was approved by the ethics committee of the University of Naples “Federico II.” Informed consent was obtained at enrollment from the parents of all of the enrolled infants.
Statistical analysis was performed using Statistical Package for the Social Sciences (SPSS 21.0, IBM SPSS Statistics, Armonk, NY). The required sample size (75 infants) was calculated at a 2-tailed significance level of 5% and with a power of 80% to detect a 30% decrease in symptom score. A randomization list was generated using Microsoft Excel 11.0. The randomization list was based on the random extraction of numbers (1–75) in the 3 groups. Variables were screened for their distribution, and appropriate parametric or nonparametric tests were adopted as required. The Student t test, Mann-Whitney U test, and analysis of variance were used for non-normally distributed variables, whereas χ2 and Fisher exact test were used for categorical variables where appropriate. A value of P < 0.05 was considered statistically significant.
A total of 75 consecutive infants (boys/girls 41/34; median age 5 months; range 1–10) with symptoms suggestive of GER were enrolled in the study. According to the randomization list, 25 patients were treated with Mg alginate plus simethicone (group A), 25 infants were treated with thickened formula (group B), and 25 patients were enrolled in reassurance with lifestyle changes (group C).
Demographic data at enrollment are shown in Table 1. Symptom score was not statistically different between the 3 groups at enrollment (P < 0.2) (Table 1). In our population, we found that all of the patients (100%) showed regurgitation and vomiting with different grades (Table 1), whereas 25 of 75 patients (33.3%) showed mild respiratory symptoms, such as coughing, hoarseness, hiccups, and stridor (Table 1).
During the treatment, 11 of 75 infants (14.6%) dropped out of the study. A flow diagram showing the progress of infants through the study with the corresponding reason for dropping out is presented in Figure 1.
A total of 67 of 75 patients (89.3%) completed 1 month of treatment. Patients treated with Mg alginate plus simethicone (group A) and those treated with the thickened formula (group B) showed a significant reduction of symptoms (P < 0.005, <0.02, respectively), whereas the median symptom score in group C decreased with a trend toward statistical significance (P < 0.07) (Fig. 2). A total of 12 of 25 patients (48%) treated with Mg alginate plus simethicone were free of symptoms compared with 4 of 25 patients (16%) treated with the thickened formula (P < 0.03). None of the patients in group C showed a negative symptom score after 4 weeks of treatment. At T1 (after 4 weeks), Mg alginate plus simethicone was more effective on GER symptoms than reassurance (P < 0.0001), whereas no statistical difference was found when we compared the thickened formula with the reassurance alone (P < 0.1). After 4 weeks, patients treated with Mg alginate plus simethicone showed a median symptom score not significantly different from that shown by patients treated with the thickened formula (7, 1–20 vs 10, 5–16 [median, range, respectively]; P < 0.1) (Table 1; Fig. 2).
A total of 64 of 75 patients (85.3%) completed 2 months of treatment. At the end of the treatment period, 3 groups of patients, irrespective of the management, showed a reduction of symptom score (P < 0.002, <0.038, <0.03, respectively) (Fig. 2). A total of 20 of 24 infants (83.3%) treated with Mg alginate were free of symptoms compared with 15 of 23 patients (65.2%) treated with the thickened formula (P < 0.2). Two of 17 patients (11.76%) treated with parents’ reassurance and lifestyle changes were free of symptoms. Both Mg alginate plus simethicone and thickened formula–treated infants showed a significant reduction in symptom score if compared with patients treated with reassurance (P < 0.0001, <0.001, respectively). In addition, patients treated with Mg alginate plus simethicone showed a median symptomatic score lower than that of patients treated with the thickened formula (1, 0–19 vs 5, 0–15 [median, range, respectively]; P < 0.02) (Table 1; Fig. 2).
No severe adverse effects were recorded for any of the 3 different treatments. One patient treated with Mg alginate plus simethicone presented with constipation. Compliance with the study treatments and control was 96% in group A, 92% in group B, and 68% in group C. None of the patients enrolled in group B changed the prescribed milk-based formula.
Our study shows that Mg alginate plus simethicone significantly improved symptom score after 8 weeks of treatment in infants with GER. The efficacy of the treatment was evident on all of the evaluated symptoms, including respiratory symptoms, hiccups, irritability, projective vomiting, and feeding compliance.
In some patients, GER can cause a wide spectrum of symptoms, which can stress the infants and their parents. In an infant with uncomplicated recurrent regurgitation, it may be important to recognize physiological GER, which is effortless, painless, and not affecting growth. In some patients, this condition can result in an inappropriate use of acid suppressive therapy (2–22). Barron et al reported a significant increase in PPI prescription in infancy, without any increase in GERD diagnosis. Between 1999 and 2004, the number of prescriptions increased by approximately 800% (23). In this situation, pediatricians should focus on minimal testing and conservative management. The last published NASPGHAN/ESPGHAN report recommends that GER should be treated with nonpharmacological interventions such as body positioning, modification of feeding methods, or milk thickening (1); however, recently Quitadamo et al clearly showed that the NASPGHAN/ESPGHAN guidelines are poorly adhered to by European general pediatricians (24). In detail, only 1.8% of them showed complete compliance with the guidelines, with 39% of general pediatricians prescribing PPIs in infants with unexplained crying and/or distressed behavior and 36% of them prescribing PPIs in infants with uncomplicated recurrent regurgitation and vomiting. These findings confirm the difficulties with operating solely within the above guidelines in day-to-day practice, highlighting the need for harmless, efficacious symptomatic therapies in the management of infant GER. Indeed, an additional aim of our study was to suggest an efficacious treatment for symptoms suggestive of GER in infants, without a systemic effect, to reduce the dramatic increase in PPI prescriptions. Our data suggest that Mg alginate plus simethicone could be a valuable and harmless option to be used in those patients in whom conservative therapies have failed. In addition, despite little difference in terms of cost, Mg alginate plus simethicone certainly has a significantly lower incidence of adverse effects when compared with PPIs.
Regarding lifestyle changes, mild symptoms of reflux without complications are often well managed with modification in nutrition, feeding practices, and positioning. Large-volume feeds can promote regurgitation in infants because of gastric distention and increased transient lower esophageal sphincter relaxation (21); however, restricting volume can result in an insufficient energy intake. Thus, increasing the caloric content of feeds while decreasing the total volume of feeds can relieve GER (1,25). Alternatively, adding rice cereal, starch, or carob bean gum, or other thickening agents, to the formula can decrease the amount of regurgitation. At present, thickened feeds are increasingly being used to treat infants with GER/GERD driven to a large extent by the baby food industry (21,25). On the contrary, in the literature, it has been demonstrated that thickened formulas increase the caloric intake and may predispose infants for later obesity (26).
Alginate-based raft-forming formulations have been marketed worldwide for >30 years under various brand names. Several studies evaluated the role and the importance of alginate in the treatment of GER; however, the efficacy of alginate has not been adequately studied in pediatric populations, and the use of alginate in the treatment of severe symptoms of GERD or esophagitis is not recommended (2). This consideration is because of the controversial results of the effect of alginate in various pediatric studies.
Several studies evaluated the effects of alginate on the characteristics of reflux in infants through objective instrumental evaluation, such as pH metry or pH/MII, and the effect on symptoms reported by the parents. It has been reported that alginate is superior to placebo in reducing the frequency and quantity of reflux and symptoms (13–15).
In contrast, Del Buono et al did not find any difference in acid GER indices between an alginate formula and placebo, except for the lower esophageal peaks reached by the refluxate. This result could be influenced with the use of powder formulations not containing bicarbonate (17). In another study, Corvaglia et al evaluated the effect of alginate in preterm infants. They concluded that the effect of alginate was most evident on acid reflux and on total acid exposure, whereas alginate had no effect on nonacid reflux (27). In the literature, it is clear that the addition of sodium bicarbonate improves the capacity of the formulation to precipitate in gel form and reduce gastric content flow.
In our study, Mg alginate plus simethicone, thickened formula, and reassurance with lifestyle changes demonstrated efficacy on GER symptoms; however, Mg alginate was shown to be more efficacious in reducing symptom scores with a higher number of patients free of symptoms at both 4 and 8 weeks. The formulation of magnesium alginate used in the present study also contains simethicone. We speculate that, as previously reported (28), this component may contribute toward improving gastric distension with a synergistic reduction of transient lower esophageal sphincter relaxation.
In the present study, we also studied the adverse effects and patient acceptance of the different treatments. Both Mg alginate and thickened formula were not associated with significant clinical adverse effects. Adult studies demonstrated that sodium alginate can cause electrolyte disorders (29), whereas in pediatric populations it has been demonstrated that precipitation of alginate in the stomach can form a bezoar, responsible for a possible increase in reflux frequency (30–32).
The limitations of our study include a relatively high dropout rate, because of refusal of medication and loss to follow-up monitoring. Although the dropout rate may have partially influenced the significance of our results, these data once more underline the poor compliance with conservative treatments, such as reassurance and lifestyle changes. Another limitation is that we did not evaluate the characteristics of the reflux with an objective diagnostic test, such as pH/MII.
In conclusion, magnesium alginate was shown to be more rapid and more effective on all of the GER symptom scores compared with thickened formula. It is well defined that physiological GER has a tendency to resolve spontaneously in 95% of patients within 12 to 14 months of life (7,8). Nevertheless, a nonsystemic treatment can be used to improve symptoms that are distressing for infants and their family, to minimize the impact of spontaneous evolution. Mg alginate has been demonstrated to be more effective on symptoms with no systemic mode of action and to have a favorable safety profile. Further well-designed studies on the effect of magnesium alginate on the characteristics of reflux are needed.
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