Pharmacological treatment of children with gastro-oesophageal reflux

For the current issue of the Journal, we asked Dr Sanjay Mahant to comment on and put into context the recent Cochrane Review on pharmacological treatment of children with gastro-oesophageal reflux. Gastro-oesophageal reflux (GOR) is a common disorder, characterized by regurgitation of gastric contents into the oesophagus. GOR is a very common presentation in infancy in both primary and secondary care settings. GOR can affect approximately 50% of infants younger than 3 months old (1). The natural history of GOR in infancy is generally that of a functional, self-limiting condition that improves with age; <5% of children with vomiting or regurgitation continue to have symptoms after infancy (2). Older children and children with co-existing medical conditions can have a more protracted course. The definition of gastro-oesophageal reflux disease (GORD) and its precise distinction from GOR are debated, but consensus guidelines from the North American Society of Gastroenterology, Hepatology, and Nutrition (3) define GORD as “troublesome symptoms or complications of GOR.” Abstracts were reviewed by two review authors, and relevant randomized controlled trials (RCTs) on study participants (birth to 16 years) with GOR receiving a pharmacological treatment were selected. Subgroup analysis was considered for children up to 12 months of age, for children 12 months to 16 years of age, and for those with neurological impairment. Trials were critically appraised and data collected by two review authors. Risk of bias was assessed. Meta-analysis data were independently extracted by two review authors, and suitable outcome data were analyzed using RevMan. A total of 24 studies (1201 participants) contributed data to the review. The review authors had several concerns regarding the studies. Pharmaceutical company support for manuscript preparation was a common feature; also, because common endpoints were lacking, study populations were heterogenous and variations in study design were noted, individual drug meta-analysis was not possible. Moderate-quality evidence from individual studies suggests that proton pump inhibitors (PPIs) can reduce GOR symptoms in children with confirmed erosive oesophagitis. It was not possible to demonstrate statistical superiority of one PPI agent over another. Some evidence indicates that H₂antagonists are effective in treating children with GORD. Methodological differences precluded performance of meta-analysis on individual agents or on these agents as a class, in comparison with placebo or head-to-head versus PPIs, and additional studies are required. RCT evidence is insufficient to permit assessment of the efficacy of prokinetics. Given the diversity of study designs and the heterogeneity of outcomes, it was not possible to perform a meta-analysis of the efficacy of domperidone. In younger children, the largest RCT of 80 children (1–18 months of age) with GOR showed no evidence of improvement in symptoms and 24-hour pH probe, but improvement in symptoms and reflux index was noted in a subgroup treated with domperidone and co-magaldrox (Maalox). In another RCT of 17 children, after 8 weeks of therapy, 33% of participants treated with domperidone noted an improvement in symptoms (P value was not significant). In neonates, the evidence is even weaker; one RCT of 26 neonates treated with domperidone over 24 hours showed that although reflux frequency was significantly increased, reflux duration was significantly improved. Diversity of RCT evidence was found regarding efficacy of compound alginate preparations (Gaviscon Infant) in infants, although as a result of these studies, Gaviscon Infant was changed to become aluminium-free and has been assessed in its current form in only two studies since 1999. Given the diversity of study designs and the heterogeneity of outcomes, as well as the evolution in formulation, it was not possible to perform a meta-analysis on the efficacy of Gaviscon Infant. Moderate evidence indicates that Gaviscon Infant improves symptoms in infants, including those with functional reflux; the largest study of the current formulation showed improvement in symptom control but was limited by length of follow-up. No serious side effects were reported. No RCTs on pharmacological treatments for children with neurodisability were identified. Moderate evidence was found to support the use of PPIs, along with some evidence to support the use of H₂ antagonists in older children with GORD, based on improvement in symptom scores, pH indices and endoscopic/histological appearances. However, lack of independent placebo-controlled and head-to-head trials makes conclusions as to relative efficacy difficult to determine. Further RCTs are recommended. No robust RCT evidence is available to support the use of domperidone, and further studies on prokinetics are recommended, including assessments of erythromycin. Pharmacological treatment of infants with reflux symptoms is problematic, as many infants have GOR, and little correlation has been noted between reported symptoms and endoscopic and pH findings. Better evidence has been found to support the use of PPIs in infants with GORD, but heterogeneity in outcomes and in study design impairs interpretation of placebo-controlled data regarding efficacy. Some evidence is available to support the use of Gaviscon Infant, but further studies with longer follow-up times are recommended. Studies of omeprazole and lansoprazole in infants with functional GOR have demonstrated variable benefit, probably because of differences in inclusion criteria. No robust RCT evidence has been found regarding treatment of preterm babies with GOR/GORD or children with neurodisabilities. Initiation of RCTs with common endpoints is recommended, given the frequency of treatment and the use of multiple antireflux agents in these children. The full text of the Cochrane Review is available in The Cochrane Library: Tighe M, Afzal NA, Bevan A, Hayen A, Munro A, Beattie RM. Pharmacological treatment of children with gastro-oesophageal reflux. Cochrane Database of Systematic Reviews 2014, Issue 11. Art. No.: CD008550. DOI: 10.1002/14651858.CD008550.pub2. Gastroesophageal reflux (GER) is common in infancy, most prevalent at 4 months of life and resolves by about a year of life (i.e., “the happy spitter”). It is a common point of anticipatory guidance in well infant health care visits (4). Gastroesophageal reflux disease (GERD) occurs when GER results in troublesome symptoms and/or complications (4). GERD is much less common in the otherwise healthy infant and child, but is a frequently encountered health issue in specialized paediatric hospital care (4,5). As a hospital based General Paediatrician, I have seen how practice has turned the tide over the past two decades: first, the dramatic rise in the use of medications to treat GERD and now, calls to reign in this practice. This recent Cochrane review highlights the weak randomized control trial evidence base supporting the widespread use of these medications. It is important to distinguish GER from GERD in order to guide management and judicious use of medications (4,6). The clinical assessment is key to distinguishing the two and excluding other worrisome disorders that present with vomiting. It is useful to think about the presentation of GERD in age categories (infants < 1 years, 1–5 years, and 5–18 years), by high-risk populations (e.g., neurologic impairment, obesity, chronic respiratory disorders, repaired esophageal atresia) and by location (esophageal or extresophageal). Infants with GERD will experience regurgitation or vomiting associated with irritability, feeding refusal, poor weight gain, and/or arching of the back during feeding. The distinction between GER and GERD may be complicated in this age group because of the co-existence of unrelated regurgitation, crying and irritability. However, with follow-up the presence of concerning signs is usually more obvious. In the older child, the troublesome symptoms are more localized including regurgitation, vomiting, abdominal pain, anorexia, and/or feeding refusal. Growth may or may not be affected. Older adolescents resemble adults and may complain of heartburn, chest pain, pain on swallowing, and sour tasting burps. Diagnostic studies are not needed for the diagnosis of GER. Clinical assessment may be also sufficient to make the diagnosis of GERD. The use of diagnostic tests must be undertaken with thoughtfulness, as there is no one test that can rule in or out GERD. The value in undertaking diagnostic tests (e.g., upper GI series, esophageal manometry, endoscopy) is often to rule out other conditions that maybe important to consider based on the clinical assessment. Prescription of acid suppressant medications, such as PPIs and histamine2-receptor antagonists (H2RAs), and pro-motility agents has rapidly increased over the past several decades. There are several postulated reasons for this: the over diagnosis of GERD due to lack of diagnostic clarity around GER and GERD, promotion of the use of these medications by drug manufacturers, a perception that these medications are safe, and previous guideline recommendations which suggested an empiric medication trial for suspected GERD even in young infants (6). Accumulating data has changed thinking about the benefits and risk of using acid suppressant and pro-motility agents (7). First, as reported in this review, the effectiveness of these medications in certain populations is not compelling. This Cochrane review found a lack of effectiveness of PPIs in infants with crying. For example, the trials by Moore and Ornstein do not show any benefit to PPIs in a group of young infants with GER symptoms and crying and/or irritability (8,9). It is also important to note that in these trials, the symptoms resolved in both treatment and placebo groups over time. It is likely that many of these infants did not have GERD and had crying and/or irritability that was associated with GER symptoms but not as a result of disease. Furthermore, this Cochrane review found no trials addressing the effectiveness of pro-motility agents such as domperidone. Second, an emerging body of evidence from observational studies have reported on the potential harms of these medications (10,11). These studies have shown an increased risk of infections such as pneumonia and gastroenteritis in children on PPIs and H2Ras (10,11,12). This is biologically plausible, based on the role of stomach acid as a line of defense against microorganisms. More recently, domperidone use has been reported in association with life threatening cardiac arrhythmias in adults resulting in a Health Canada warning for all ages (13). This Cochrane review also examined the evidence on the use of alginate salt medications, (such as Gaviscon Infant, which is not available in Canada) which are postulated to work by reacting with gastric acid to form a viscous gel and then thicken the stomach contents to reduce GER. The two studies in the review that examined the effectiveness of the aluminum free preparation of this agent in infants with GER showed marginal, if any benefit, and had significant limitations including a very short follow-up. Their use is not recommended (6). Given the shifting balance between the benefits and risks of medications for GER and GERD, and their increased use, an emphasis has been placed on reducing their overuse. For example, the Canadian Paediatric Society’s Choosing Wisely recommendations include a statement on not routinely using acid blockers and motility agents for the treatment of GER in infants (14). Education, guidance, and support are recommended here. The most recent North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHN) guidelines emphasize a step up approach to management of GERD (6). For treatment of GERD in infants, the guidelines suggest the use of lifestyle modifications as the first step in management, such as thickening of feeds, and a 2–4 week trial of a hypoallergenic formula (or maternal restriction of cow’s milk protein for breast fed infants). Prone positioning is suggested only in infants greater than 12 months of age due to the risk of SIDS in younger infants. In older children and teenagers, lifestyle modifications might include weight loss in those who are overweight, cessation of smoking, and avoiding alcohol use. When symptoms are severe or lifestyle modifications ineffective (or are not relevant), then the addition of H2RAs or PPIs are warranted. This Cochrane review also highlights the lack of paediatric trials that have compared these classes of medications head-to-head. Based largely on adult studies, PPIs have been found to be more effective resulting in higher and faster healing rates for erosive esophagitis. Furthermore, tachyphylaxis may occur with H2RAs, which limits their effectiveness when treatment is required for longer term (15). For chronic heartburn in older children and adolescents a 2–4 week trial of a PPI is suggested, and then, based on response, either continuation of treatment or further evaluation. For those with erosive esophagitis, PPIs are recommended as initial therapy. In children who are not at risk of longer-term or recurrent disease, GERD treatment should be limited to 8–12 weeks in order to avoid unnecessary treatment and side effects. This Cochrane review found no trials in children with neurologic disability. Cohort studies, not included in this systematic review, have demonstrated the effectiveness of PPIs in the management of erosive esophagitis and for disease maintenance in this population (16,17). Children in this high-risk GERD population may warrant longer-term treatment. However, it is still important to regularly consider whether continued acid suppression is necessary and if so, the minimal dose that will adequately control symptoms. After reading this Cochrane review and considering the state of affairs in GER and GERD management (especially in infants), I was reminded of the wisdom of Dr Richard Goldbloom, who wrote in an article in this journal: “two enduring lessons we can learn in paediatrics are that not every symptom must be treated, especially with medication, and that no ‘condition’ should be treated before its natural history is clearly documented. And on that same note, learn to be an ultraconservative prescription writer (18).”

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