Gastroesophageal reflux (GER), the passage of gastric contents into the esophagus, is common and normal in neonates and infants. Regurgitation with clinically significant sequelae constitutes a diagnosis of gastroesophageal reflux disease (GERD). Therefore, it is essential that trials of therapies for GERD assess GERD-defining symptoms, not only physiologic measures of GER. The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition jointly recommend nonpharmacologic treatment approaches for GERD in neonates.1 The six studies reviewed in this newsletter continue to support earlier literature recommending conservative nonpharmacologic interventions.|
Three recent studies examine potential strategies for nonpharmacologic treatment in these infants. Corvaglia, et al. investigated the effect of extensively hydrolyzed protein formula to reduce GER in preterm infants. This pilot study in preterm infants used multichannel intraluminal impedance (MII) with pH probe to show a reduction in gastric pH and acid reflux episodes without a reduction in total reflux amount or frequency; symptoms were not assessed. Indrio, et al. conducted a randomized, double-blind, placebo-controlled trial of effectiveness of treatment with probiotic to establish a beneficial intestinal microbiota on functional gastrointestinal disorders in normal newborns. Less regurgitation was reported by parents in the treatment group at three months, although it is not clear how much of this represented GERD. Lasekan, et al., in a randomized, double-blind, placebo-controlled trial, assessed the efficacy of a low-lactose rice starch-thickened formula at reducing spitting frequency in healthy, full-term neonates and infants. Both groups had decreased spitting over time, with a benefit shown in the treatment group, along with high parental satisfaction with the thickened formula. This is an important benefit, as much of the treatment for physiologic GER is driven by parental distress and discomfort rather than harmful sequelae in the infant. While these studies all show promise, an important distinction must be made about all three: while they found a reduction in gastric acidity or regurgitation, none of them directly measured diagnosed GERD.
Recent studies of proton pump inhibitor (PPI) treatment in neonates support existing data on their ineffectiveness for treating GERD in infants.2 Despite the current recommendations, PPIs continue to be prescribed off-label to neonates for nonspecific symptoms of GER and GERD.3 Esomeprazole, a PPI, is currently recommended only as treatment for erosive esophagitis in infants. Davidson, et al. conducted a randomized, double-blind, placebo-controlled phase III efficacy study using esomeprazole in preterm and term neonates who had GERD. This study was novel in including preterm infants and using simultaneous video, cardiorespiratory monitoring, and MII with pH probe to correlate physiologic reflux episodes with signs and symptoms of GERD. No difference was shown in GERD-related signs and symptoms with esomeprazole treatment, while increased gastric pH was shown, consistent with the drug's mechanism of action. Hussain, et al. conducted a randomized, double-blind withdrawal, placebo-controlled phase III efficacy study of rabeprazole, a PPI, in infants 1-11 months with GERD. That study used validated parent questionnaires to assess GERD symptoms. Again, no benefit was found with treatment with rabeprazole, while improvement was shown in both groups over time. This study was novel in selecting only patients who first showed parent-reported improvement during an open-label treatment phase, selecting for patients who have perceived benefit of PPI. Both of these studies use validated measures to evaluate GERD and show no benefit to PPI treatment for preterm and term GERD in neonates and infants, further iterating the growing body of evidence against pharmacologic treatment in this group.
The final study included in this review answers an important question about prophylactic surgical treatment of GERD in infants at high risk for GERD-related complications. Surgical treatment with fundoplication is considered an alternate treatment option for severe GERD and historically has been used prophylactically in patients considered to be at high risk for complications related to GERD.4 Fundoplication is a highly variable practice between centers and pediatric surgeons. Barnhart, et al. address the use of prophylactic gastric fundoplication at the time of gastrostomy tube (G-tube) placement for enteral feeding in neurologically impaired infants, who are at high risk for GERD because of disordered swallowing and abnormal muscle tone. This study was a retrospective observational cohort study aimed to determine whether a benefit of fundoplication exists. No difference was found in the first year after surgery in reflux-related hospitalization diagnoses, including pneumonia, aspiration pneumonia, esophagitis, GERD, and requirement for mechanical ventilation. No distinction was made between subjects on the basis of GERD diagnosis, so these results do not show whether the procedure is effective at treating GERD; rather, it shows that there is no clear benefit to performing this procedure prophylactically in this population.
Current research in neonatal and infant GERD continues to support the practice of non-pharmacologic treatment of GERD over medication. Corvaglia, et al. showed a possible benefit to extensively hydrolyzed protein formula, Lasekan, et al. demonstrated a reduction in physiologic GER with a low-lactose formula thickened with rice starch, and Indrio, et al. suggest benefit of probiotic treatment of healthy, term newborns. Davidson, et al. and Hussain, et al. continue to show no benefit to pharmacologic treatment of GERD in term and preterm neonates with validated measures of GERD signs and symptoms. Finally, prophylactic fundoplication to prevent GERD in infants at high risk was shown by Barnhart, et al. not to be beneficial. An important pattern, seen in many GERD treatment trials, was shown by Hussain, et al. and Lasekan, et al. of symptomatic improvement over time, regardless of treatment. The overwhelming trend of the literature continues to support the current recommendation of nonpharmacologic, nonsurgical treatment of physiologic GER and GERD in neonates and infants while awaiting physical maturation and the natural resolution of GER and GERD.
1. Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr. Gastroenterol Nutr. 2009;49:498-547.
2. Van der Pol RJ, Smits MJ, van Wijk MP, et al. Efficacy of proton-pump inhibitors in children with gastroesophageal reflux disease: a systematic review. Pediatrics. 2011;127:925-935.
3. Barron JJ, Tan H, Spalding J, et al. Proton pump inhibitor utilization patterns in infants. J Pediatr. Gastroenterol Nutr. 2007;45:421-427.Trends in resource utilization by children with neurological impairment in the United States inpatient health care system: a repeat cross-sectional study.PLoS Med. 2012;9(1):e1001158.