The lower esophageal sphincter (LES) and crural diaphragm play a major role in GER. A ring of thickened and tonically contracted smooth muscle that generates high pressure constitutes the LES. Additionally, the right crus of the diaphragm circumscribes the LES and provides extra muscular support. The LES in conjunction with the diaphragm creates a high-pressure zone in the distal esophagus that prevents reflux of gastric contents into the esophagus. Fig. 1 shows physiological reasoning of GERD in neonates. Presence of an indwelling feeding tube across the LES increases GER. This effect is most prominent during the first post prandial hour. Feeding tubes may impair competence of LES, thereby causing reflux [4]. Mechanical and chemical stimulation of acid production accounts for the majority of acid production. This begins with distension of the stomach that follows ingestion of food, which stimulates the stretch receptors, resulting in gastrin release by G cells [5].

Fig. 1 Mechanism of Gastroesophageal Reflux.

Symptoms of GERD occur due to regurgitation of acid and related esophagitis. The most common clinical manifestation of GERD is related to regurgitation ranging from drooling and spitting to overt projectile vomiting. Regurgitation and vomiting can lead to loss of nutrients and calories, and, subsequently lead to inadequate weight gain, weight loss, and failure to thrive [6]. Symptoms like aspiration, apnea, and bradycardia are a result of the physical presence of refluxate, and vary with the nature of reflux contents. The presence of acid in combination with pepsin is most likely to result in mucosal injury. Prolonged exposure of acidic gastric contents can lead to mucosal inflammation, excoriation and ulceration leading to painful esophagitis. Symptoms of esophagitis include increased crying and irritability, feeding difficulties, hematemesis, and failure to thrive [1,7]. Sleep disturbance and swallowing dysfunction also occur more frequently in infants with GERD [8,9].

There is no gold standard investigation for diagnosing GERD in infants. Often the diagnosis is inferred from a positive response to a therapeutic trial in children, but the same is not true for infants or neonates. In neonates, detailed history and examination are useful tools in diagnosing GERD. There are several methods to diagnose GER in the preterm infants: contrast fluoroscopy, pH monitoring and multi-channel intra-esophageal impedance (MII) monitoring [1]. However, none of these diagnostic tools are routinely used in clinical practice. Contrast fluoroscopy can be used to detect GER, but has a poor sensitivity, and pH probe monitoring will calculate the reflux index (RI) determining abnormal versus normal reflux. Reflux index is defined as percent of time the gastric pH is <4.0 for more than 10% of time in infants <1 year of age [10]. However, measurement of pH is not an accurate method to diagnose GER in premature infants because their stomach pH is rarely below 4.0 owing to frequent milk feedings and higher baseline pH [1]. Presently, combining MII with the pH probe method has a better accuracy to detect GER. MII can be used to estimate the movement of fluids, solids and air in the esophagus by alterations in electric impedance between multiple electrodes [1].

The diagnostic approach and treatment of GERD should be based on evidence-informed guidelines such as those developed by the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) [11]. Infants with uncomplicated GER do not require any treatment. Management of GERD should include non-pharmacological approaches aimed to prevent and alleviate symptoms, promote normal growth, and resolve inflammatory changes in the esophagus [12]. A stepwise approach to treatment is used. Firstly, non-pharmacological therapies such as post-feeding positioning and dietary modifications, including feed thickeners and a trial of hypoallergenic formula are used. Pharmacological management is attempted only after non-pharmacological therapies fail (Fig. 2). Finally surgical intervention is reserved for severe cases of proven and severe GERD not responding to medical therapies [13,14].

Fig. 2 Approach to treatment of gastroesophageal reflux disease in infants.

Non-pharmacological management mainly involves infant positioning, feed thickeners, altering feed volumes and feed duration, and avoidance of cow’s milk protein based feeding formulas. Reduction of feeding volume is often employed for symptomatic relief of reflux; however, there is no evidence in the literature to support this intervention. Hydrolyzed milk formulas have been reported to reduce GER by reducing gastric transit time [15]. Non-pharmacological strategies for GERD are often the first line of management in the treatment of reflux.

The main focus of the pharmacotherapy of GERD is reducing the esophageal exposure to gastric acid. This is achieved either by buffering secreted acid or reducing acid production. Oral antacids are effective in neutralizing gastric acid, but their use is poorly studied in preterm infants. The drawback to using antacids is that they contain heavy metals like aluminum, which can lead to encephalopathy, anemia, and osteomalacia [13]. Therefore, antacid use in preterm infants is not recommended [12]. Prokinetics agents – metoclopramide, domperidone, and erythromycin – also have a limited role in the treatment of GERD in infants. These drugs appear to increase gastric emptying, reduces the regurgitation episodes, and increase the LES tone. There is little evidence to support the use of metoclopramide and other prokinetics agents [1,7]. Using either domperidone or cisapride is not recommended due to various cardiac side effects, especially prolonged QTc and arrhythmia. Erythromycin increases antral contractility, and is used in preterm infants for gastric emptying. However, its use is associated with hypertrophic pyloric stenosis and cardiac arrhythmias [16]. In a recent randomized controlled trial, erythromycin did not decrease GER events in 24 hours pH-MII, and its role remained ineffective in the treatment of GERD in premature neonates [17]. Baclofen, a GABA agonist, reduces the frequency of lower esophageal sphincter relaxation, decreases acid reflux, and accelerates gastric emptying. However, its use is associated with significant central nervous system adverse effects [1,7]. Therefore, the mainstay of treatment for GERD has remained acid suppression.

There is a lack of evidence supporting efficacy of acid-reducing drugs for GERD symptoms in the neonatal population. Currently there are no established guidelines for using acid reducing drugs in neonates. Despite the fact that none of the currently available PPIs are approved for use in children less than 1 year of age, they continue to be used in the treatment of GERD [22]. Efficacy, dosing, and duration of PPI in infants is not well studied and unclear [7]. The duration of the treatment must be between 4 and 6 weeks following which a trial off medications must be undertaken. Since these medications reach maximal effect close to 4 days after initiation, PPIs must be tried for a longer duration (at least 1 week) before being deemed ineffective. We recommend that utmost caution be exercised when using these medications to suppress acid production, because they are not always effective and they are associated with several adverse effects.

There are some potential adverse effects associated with these medications. Exposure to ranitidine was associated with a seven-fold increase in late-onset sepsis in infants, especially from gram-negative infections, and included death [1,3,7]. The proposed mechanism is loss of gastric acidity leading to increased gastrointestinal colonization. A retrospective study linked ranitidine use to a 6.6-fold increase in necrotizing enterocolitis and a higher mortality rate [1,3,7]. Acid suppression has been associated with increased risk of acute gastroenteritis, community-acquired pneumonia, and Clostridium difficile, Salmonella and Campylobacter infections [1,3,7]. There are no studies that have looked at long-term effects, especially with respect to calcium turnover and bone loss in neonates.

Contributors: PM: drafted and revised the manuscript, AKL: conceptualized the manuscript, drafted, reviewed, and revised the final manuscript, PM, AD, AKL: revised and reviewed the final draft before submission

Funding: None; Competing interests: None stated.

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