Medical management of gastro-esophageal reflux in healthy infants

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Gastroesophageal reflux (GER), which is the passage of gastric contents from the stomach to the esophagus, with or without regurgitation or vomiting, is common in healthy infants. Regurgitation or vomiting following most feeds has been reported in 20% of healthy infants at 1 month of age. This can increase to 41% between 3 and 4 months of age, then subsequently decreases, becoming rare after 1 year of age ^[1]. Gastroesophageal reflux disease (GERD) occurs when GER leads to symptoms that affect daily functioning or to complications ^[2]. This definition is problematic in infants because many symptoms attributed to GERD are non-specific. Crying, fussiness, and back arching with or without regurgitation may be normal behaviours or caused by other etiologies. Correlation between these symptoms and the acidity of esophageal secretions or endoscopic findings is weak ^[3][4]_. In the infant who is growing well, symptoms are unlikely to be improved by therapy aimed at GERD. The incorrect attribution of symptoms leads to frequent overtreatment of GERD by physicians ^[5][6]_.

This practice point presents the evidence-base for management of symptoms attributed to GERD in healthy term infants younger than one year of age and discourages the over-prescription of medications in this population. The management of severe disease or GERD associated with comorbidities is beyond the scope of this document.

Non-pharmacological therapies for healthy infants with suspected GERD

Non-pharmacological therapies to be considered for healthy infants with suspected GERD include thickened feeds, avoiding cow’s milk protein, and infant positioning.

Thickened feeds

Evidence for thickened feeds was summarized in a systematic review that included 14 randomized controlled trials (RCTs) comparing thickened with regular feeds ^[7]. Thickening agents included carob-bean gum (seven trials), cornstarch (three), rice starch (two), cereal (one), and soy fiber (one). Thickened feeds did not improve acidity scores measured via pH-probe. They did decrease the daily number of episodes of vomiting and regurgitation, and weight gain improved in four studies. The impact of thickened feeds on other symptoms attributed to GERD, such as crying or fussiness, is unclear ^[2]. Recent international guidelines state that a 2-week trial of thickened feeds may be attempted for infants with GERD who display significant vomiting ^[2]. One recent review article summarized options for thickening feeds and may be used as a treatment reference ^[8]. Unless commercial thickened formula is used, consulting a dietician or speech therapist can be useful to establish the desired consistency and infant tolerance.

Avoiding cow’s milk protein

Avoiding cow’s milk does not treat GERD, although a subset of children who have cow’s milk protein allergy may experience symptoms similar to GERD and could benefit from this approach. Symptoms in these children will usually improve within 2 weeks of cow’s milk protein removal, and re-introduction typically results in symptom return. A 2- to 4-week trial of cow’s milk protein avoidance can be tried when other non-pharmacological measures to treat symptoms attributed to GERD have failed ^[2]. For the breastfed infant, breastfeeding should be continued, with maternal dietary elimination of cow’s milk protein. For the formula-fed infant, a formula with extensively hydrolyzed protein is recommended. For more information about cow’s milk protein allergy in this clinical context, see the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHN) guidelines for 2018 ^[2].

Infant positioning

Small studies have suggested that left lateral positioning or head elevation after feeding may improve acid reflux parameters measured by pH probe ^[9]. However, there is little evidence either way for assessing whether infant positioning improves symptoms attributed to GERD ^[10]. The Canadian Paediatric Society (CPS) recommends placing infants in a supine position for sleep, on a flat surface, based on strong evidence that this position helps prevent sudden infant death syndrome (SIDS) ^[11]. Comparing the weak evidence for improved GERD symptoms via infant positioning with strong evidence for “back to sleep” positioning to prevent SIDS, the use of positional therapy to treat GERD should be discouraged ^[2][11]_.

Pharmacological therapies for healthy infants with suspected GERD

Pharmacological agents to treat GERD in infants include acid-suppressive medications (H2 receptor antagonists (H2RAs), proton pump inhibitors (PPIs)) and prokinetics.

Acid-suppressive medications

Data supporting the efficacy of H2RAs for infants with GERD symptoms are limited ^[2][12]. While the endoscopic evaluation of infants with esophagitis who have been treated with H2RAs appears to show histological improvement, it remains uncertain whether H2RAs can improve symptoms of GERD, such as crying and fussiness, when compared with placebo or PPIs.

Several systematic reviews have assessed the effectiveness of PPIs in relieving GERD symptoms in infants ^[2][13][14]. PPIs decrease acid secretion in the stomach ^[15], but it remains unclear whether they have any effect in reducing symptoms, compared with placebo, hydrolyzed formula, or H2RAs ^[13][14]. One multicentre double-blind RCT randomized 162 infants (mean age 4 months) with persistent GERD symptoms to lansoprazole or placebo for 4 weeks. Most infants in both groups (54%) showed a greater than 50% improvement in crying ^[16]. More infants in the lansoprazole group experienced adverse events (62% versus 46%), including increased risk for infection.

In infants and young children, acid-suppressive therapy increases risk for pulmonary and gastrointestinal infections ^[17]. An increase in neonatal infections, necrotizing enterocolitis, and death has also been reported with H2RA use in very low birth weight infants ^[18]. Changes in the acidity of gastric secretions from acid-suppressive therapy may modify flora in the host, suggesting a mechanism for the increased risk of infection observed and associated with acid-suppressive medication use ^[19]. An increased risk of fracture in children treated with acid-suppressive therapy in their first year post-birth has also been recently described ^[15][20]. Risk factors include longer duration of use and earlier age at initiation.

In keeping with recent international recommendations and a CPS recommendation made for the Choosing Wisely Canada campaign in 2017, acid-suppressive therapy should not be routinely used for the treatment of crying, fussing, arching, or regurgitation in otherwise well infants ^[2][21]. There is no evidence that these medications improve GERD symptoms in infants, and their side-effect profile is significant. Because the natural history of GERD symptoms is to resolve over time, trials of therapy with acid-suppressive agents to establish a diagnosis of GERD are not recommended ^[2]. 

Acid-suppressive therapy can be useful for children with GERD showing signs of erosive esophagitis (e.g., hematemesis, failure to feed, or failure to thrive). Depending on clinical severity, they may also benefit from a referral to a paediatric gastroenterologist. When trialling acid-suppressive therapy, it is wise to use the lowest effective dose for the shortest possible time (typically a period of 4 to 8 weeks) before re-assessing the need to continue use (Table 1) ^[2].

Table 1. Dose for acid-suppressive medications
Medication	Dose
Proton pump inhibitors
Lansoprazole*	1 to 2 mg/kg/day
Omeprazole*	Weight 3 to 5 kg: 2.5 mg daily Weight 5 to 10 kg: 5 mg daily Weight 10 to 20 kg: 10 mg daily
Esomeprazole*	Weight 3 to 5 kg: 2 mg daily Weight 5 to 7.5 kg: 5 mg daily Weight 7.5 to 20 kg: 10 mg daily
H2-receptor antagonists (H2RAs)
Ranitidine*	4 to 10 mg/kg/day, divided in two to three doses
Famotidine*	0.5 mg/kg/dose Infant <3 months of age: Give daily Infant ≥3 months of age: Give 2 times/day (maximum dose = 40 mg)
* These medications are used off-label for children younger than 1 year of age

Prokinetics for healthy infants with GERD

Several systematic reviews have assessed the efficacy of domperidone ^[22][23]and metoclopramide ^[2][24] for reducing GERD symptoms in infants. Few RCTs were identified for each medication, and the studies they included were both small and flawed. 

There is no robust evidence supporting the use of domperidone to treat paediatric GERD ^[22][23]. There have been reports that domperidone can prolong the QTc interval in children ^[25][26]. In 2012 and 2015, Health Canada issued warnings about domperidone based on increased risk for sudden death.

Study results for metoclopramide do not support its effectiveness in treating paediatric GERD ^[2][24]. The side effects of metoclopramide include extrapyramidal symptoms, tardive dyskinesia, diarrhea, and sedation ^[27]. Since 2015, Health Canada has counselled against use of metoclopramide in infants younger than 1 year of age.

The efficacy of cisapride was evaluated in one Cochrane meta-analysis. No clear evidence that cisapride improves symptoms of GER in children was found ^[28]. Based on reports that it can prolong the QTc interval, leading to fatal cardiac arrhythmias and sudden death, cisapride has only been available in Canada through a limited access federal program since 2000 ^[4]_.

Scant evidence to support the efficacy of prokinetics and accumulating evidence for their significant negative side-effects both indicate they should not be used routinely to treat otherwise healthy infants with symptoms of GERD.

Best practice points

• Most importantly, diagnosing GERD in infants whose symptoms are non-specific and overlap with normal feeding behaviours should be avoided. 
• Non-pharmacological therapies, such as a 2- to 4-week trial of thickened feeds or cow’s milk protein avoidance, are preferred strategies for symptom improvement.
• The natural history of symptom resolution in GER, the limited evidence that pharmacological management of GERD in infants improves symptoms, and the serious side-effect profile of medications, all indicate that their routine use in infants who are otherwise healthy should be avoided.
• Anticipatory guidance, especially reassuring parents and caregivers about the natural resolution of reflux symptoms in otherwise healthy babies, often negates the need for therapy.

Acknowledgements

The authors wish to thank Mrs. Stéphanie Tremblay and Mr. Christopher Marquis, pharmacists at CHU Sainte Justine, for their help reviewing Table 1. This practice point was reviewed by the Drug Therapy and Hazardous Substances, and Nutrition and Gastroenterology Committees of the Canadian Paediatric Society.

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CANADIAN PAEDIATRIC SOCIETY ACUTE CARE COMMITTEE (2020-2021)

Members: Carolyn E Beck MD, MSc, Kevin Chan MD (Chair), Kimberly Dow MD (Board Representative), Karen Gripp MD, Kristina Krmpotic MD, Marie-Pier Lirette MD (Resident Member), Evelyne D. Trottier MD

Liaisons: Laurel Chauvin-Kimoff MD (Past Chair 2012-2019), CPS Paediatric Emergency Medicine Section; Sidd Thakore MD, CPS Hospital Paediatrics Section

CANADIAN PAEDIATRIC SOCIETY COMMUNITY PAEDIATRICS COMMITTEE (2020-2021)

Members: Tara Chobotuk MD, Carl Cummings MD (Past Chair), Michael Hill MD, Audrey Lafontaine MD, Alisa Lipson MD, Marianne McKenna MD (Board Representative), Julia Orkin MD MSc (Chair)

Liaison: Peter Wong MD (CPS Community Paediatrics Section)

Principal authors: Isabelle Chevalier, MDCM, MSc, (Department of Pediatrics, CHU Sainte Justine, Université de Montréal), Carolyn E Beck, MD, MSc, Marie-Joëlle Dore-Bergeron, MD, Julia Orkin, MD, MSc

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References

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Disclaimer: The recommendations in this position statement do not indicate an exclusive course of treatment or procedure to be followed. Variations, taking into account individual circumstances, may be appropriate. Internet addresses are current at time of publication.