Reducing the use of proton pump inhibitors in infants with gastroesophageal reflux symptoms

Clinical question

How should infants with suspected gastroesophageal reflux be managed?

Bottom line

Regurgitation, often referred to as gastroesophageal reflux, is a physiological phenomenon. Most infants younger than 1 year of age regurgitate 2 or more times daily in the first months of life; this normal behaviour should be differentiated from gastroesophageal reflux disease (GERD) or other worrisome diagnoses. There should be a suspicion of GERD when infants fail to grow due to feeding difficulties. Infants’ refluxate is less acidic due to lower gastric acid output and the buffering effects of frequent milk feeds, which differs from older age groups. Despite many randomized trials, proton pump inhibitors (PPIs) have not proven to reduce the symptoms of suspected reflux disease in infants. Therefore, infants should not be prescribed PPIs unless careful investigation by specialists concludes a diagnosis of GERD.

Evidence

Several reports point to an increase in prescriptions of PPIs in infants. Over 5% of all infants in New Zealand were prescribed PPIs in 2012, more than double the number in 2005.¹ Of these infants, a minority had a specialist’s diagnosis of GERD. A marked increase in infant PPI prescriptions was also seen in France and in Scandinavia, despite efforts to inform prescribers about current guidelines.^2,3

Between 2003 and 2015, 6 randomized controlled trials of PPIs included infants with regurgitation, 2 of which also studied preterm infants with suspected GERD.⁴ Meta-analyses and reviews of these 6 trials conclude that PPIs in this age category, compared with placebo, do not provide substantial symptom reduction.^5-7 The first trial concluded that crying and fussiness decreased over time, regardless of treatment allocation.⁸ Another study included the assessment of acid and non-acid reflux; while PPIs were shown to reduce the acidity of the esophagus, the total number of reflux episodes and concomitant symptoms did not differ from placebo treatment.⁹ The spontaneous reduction in regurgitation over time may be a reason for clinicians to overestimate the benefit of any intervention, which cannot be reproduced in controlled trials.⁴ The Pediatric Gastroesophageal Reflux Clinical Practice Guidelines from 2018 give clear recommendations to avoid the use of PPIs in otherwise healthy infants with visible regurgitation, crying, or distress, due to the lack of evidence.¹⁰

While PPIs are well tolerated in the short term, there are increasing concerns of side effects due to long-term use.¹¹ An increased risk of infection was demonstrated in a recent register-based, nationwide study from France, comprising children followed from birth to a median age of 3.8 years.¹² Further, a prospective study of 186 children (median age 10 months) found a higher risk of gastrointestinal infections compared with controls, and gastrointestinal and respiratory tract infections were more frequent during interventions with PPIs compared with the preceding 4-month period.¹³ An additional concern is reduced vitamin and mineral absorption, which may lead to nutrient deficiencies including reduction in bone mineral density and risk of fractures, according to a pediatric review.¹⁴ Intestinal dysbiosis and small intestinal bacterial overgrowth are well-known side effects from adult studies, but have not been well studied in infants, likely due to limited access to duodenal aspirates.^15,16 Small intestinal bacterial overgrowth may cause gastrointestinal symptoms such as pain, diarrhea, and bloating, and intestinal dysbiosis is associated with chronic immune-mediated diseases.^17,18

Approach to patients

Separating the normal development of gastrointestinal motility from pathology is a key challenge. The volume of food required relative to the body size, liquid feeds, recumbent positioning, and the anatomy of the lower esophageal sphincter in infants contribute to regurgitation. In one review, up to one-quarter of infants had 2 or more daily episodes.¹⁹ Consequently, regurgitation itself does not help to distinguish normal physiological gastroesophageal reflux from GERD.

Infants who have feeding difficulties and poor growth as additional symptoms require follow-up and investigation, with GERD being one of several differential diagnoses (Table 1).¹⁰ Warning signs that suggest alternate diagnoses include forceful or bilious vomiting, abdominal distension or diarrhea, or symptoms of increased intracranial pressure such as a bulging fontanelle or a rapid increase in head circumference. Red flags that should prompt referral to pediatric follow-up are detailed in Table 1, and in select cases supplementary investigations would be necessary. While upper endoscopy is invasive for infants with suspected GERD, it is the recommended investigation for a diagnosis of GERD and to rule out similarly presenting conditions.¹⁰ The macroscopic findings of upper endoscopy are usually unremarkable, but biopsies will identify reflux esophagitis and important differential diagnoses such as eosinophilic esophagitis. Endoscopy may be supported by esophageal pH–impedance monitoring in select cases. Upper gastrointestinal radiology examinations are neither sensitive nor specific for identifying GERD, but serve to exclude obstructions such as pyloric stenosis, malrotation, or duodenal webs.

Implementation

Parents are often concerned about frequent regurgitation episodes in their infant. Explaining the expected resolution of symptoms over time, regardless of prescribed medications, is key, aiming to separate gastrointestinal immaturity and physiological reflux from GERD. This should include the review of reassuring factors (eg, thriving baby with appropriate weight gain, meeting developmental milestones), and a plan for more thorough investigation in the case of continued or more worrisome symptoms over time. Written parental information and online tools such as AboutKidsHealth (SickKids, Canada)²⁰ and JAMA Pediatrics²¹ are helpful and trustworthy sources (Box 1).

Cow’s milk protein allergy (CMPA) may cause reflux symptoms, making the 2 diagnoses difficult to distinguish. In infants with suspected CMPA, the first therapeutic step would be to eliminate cow’s milk protein from the diet. In formula-fed infants, a 2-week trial of hydrolyzed formula is recommended.^10,22 In breastfed infants, maternal elimination of cow’s milk for 2 to 4 weeks is an option. In both cases, a clear reduction in symptoms may be due to the natural history of regurgitation resolution or CMPA itself. Therefore, the reintroduction of cow’s milk protein is preferred to assess ongoing symptoms and to avoid unnecessary elimination diets.⁴ When a diagnosis of CMPA is made, there is usually no need for additional therapies.

Given the evidence against the use of antacid therapies and the limited role of esophageal acid exposure in infants, the term volume reflux (as opposed to acid reflux) is appropriate. In some cases, overfeeding may increase the regurgitation and can be addressed. In the context of normal weight gain, excess milk volume may result in increased regurgitation. Similarly, evacuation of swallowed air (ie, burping) is recommended.

Feed thickeners have been shown to reduce the frequency of regurgitation by an average of 2 daily episodes, as indicated in a Cochrane review that included 8 randomized controlled trials.²³ The effect on other symptoms and on reducing esophageal acid exposure is less clear. Breast milk may be thickened with gum-based thickeners, while either infant cereals (eg, rice cereal) or gum-based thickeners may be used to thicken formula. The amount of thickener will depend on the infant’s needs, being mindful that a nipple with a larger hole may be required for thicker consistencies. Constipation and slowed gastric emptying (which may, in turn, worsen regurgitation) are potential side effects of some feed thickeners. The introduction of solid feeds may reduce the frequency of regurgitation and may be considered after the age of 4 months. In breastfed babies who are not candidates for feed thickeners, aluminum-free or magnesium alginates may be an option but are not well supported by evidence. Only a single randomized trial (n=43 infants) has been conducted, though with substantial reductions in symptoms and esophageal acidity.²⁴ However, it is important to remember that acid reduction should not be a treatment goal for infant regurgitation in the absence of GERD or reflux esophagitis. International guidelines differ in their recommendations for use of alginates in infants; the National Institute for Health and Care Excellence guidelines suggest a therapeutic trial for 1 to 2 weeks,²⁵ whereas the Pediatric Gastroesophageal Reflux Clinical Practice Guidelines advocate against long-term treatment due to lack of evidence.¹⁰