Gastroesophageal reflux (GER) occurs in greater than one-third of healthy infants with a peak incidence around age 4 months, which decreases by age 1 year to less than 5%.1 GER is defined as “the involuntary retrograde passage of gastric contents into the esophagus with or without regurgitation and/or vomiting.”2 It is generally considered a normal physiologic process, with physiologic reflux events occurring around 70 times per day in many neonates.3 Neonates at particularly high risk for GER include those with neurologic impairment, bronchopulmonary dysplasia, repaired esophageal atresia, and preterm infants.4 Infants with physiologic GER are commonly referred to as “happy spitters” and continue to grow and develop appropriately despite their reflux.
Unlike physiologic reflux, pathologic gastroesophageal reflux disease (GERD) is associated with a subset of symptoms and/or complications that denote a pathologic process. GERD is defined as the regurgitation of gastric contents into the esophagus accompanied by symptoms such as vomiting, weight loss, poor weight gain, irritability, or dysphagia.5 Pathologic complications of persistent GER include esophagitis, nutritional compromise with poor growth or growth failure, or respiratory complications such as recurrent pneumonia, stridor, and cough. This pathologic GERD may require more extensive clinical evaluation, and potentially treatment. GERD is often classified into primary or secondary disease, where secondary GERD is associated with a separate underlying disease process such as a genetic syndrome, chromosomal abnormality, hiatal hernia, esophageal atresia, or neurologic anomaly. Preterm infants who are diagnosed with GERD have longer hospital stays and hospital costs approximately $70,000 higher than infants without this diagnosis.6
The Joint Committees of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) recently released new guidelines regarding the diagnosis and management of both GER and GERD in 2018.2 This review provides a discussion of those guidelines in the context of current literature and clinical guidelines.
Pathophysiology of Gastroesophageal Reflux Disease
Newborn infants have several unique features that make them more prone to GER and GERD. These include anatomic factors, immaturity, feeding methods, position, esophageal clearance mechanisms, and presence of inflammation or anomalies. From an anatomic perspective, newborn infants have a short, narrow esophagus resulting in a lower esophageal sphincter that lies proximal to the diaphragm and is, therefore, less effective at protecting the esophagus from passive regurgitation of stomach contents into the esophagus. During the first 6 to 12 months of life, the esophagus lengthens, resulting in the lower esophageal sphincter (LES) moving to a more distal location in the abdomen. Specifically, this process resulting in an intra-abdominal esophagus develops around 6 months corrected age, making preterm infants more susceptible to GER.7
The physiology of GER in infants is not fully understood. Although some evidence suggests that delayed gastric emptying leading to gastric distention may play a role in GER, other evidence suggests that transient LES relaxation is the primary etiology.8 The normal resting tone of the LES is approximately 12 to 25 mm Hg, and when there is a peristaltic wave the LES relaxes for a short period of time. The LES also has long periods of relaxation, but they are not associated with swallowing activity and are termed transient lower esophageal sphincter relaxation (TLESR). These periods generally last 5 to 30 seconds, during which the esophageal pressure is the same as that of the stomach. As the LES functionally matures, it generates increased esophageal pressures and decreased TLESR. In infants who receive tube feedings, the presence of a feeding tube may lead to increased episodes of GER because of incomplete closure of the LES, although several studies have suggested that the presence of a tube alone does not affect the number of GER episodes or acid exposure in preterm infants.9,10
Several feeding characteristics also may influence GER, including the volume, frequency, and rate of feeds as well as the infant's position. Higher volume and higher frequency feeds result in greater stomach distension and may, therefore, cause regurgitation for the infant to relieve gastric strain and prevent discomfort. Additionally, higher flow rates were found to be associated with GER events. No strong correlation has been established between GER and the type of milk (breast milk vs formula) or caloric density.11 Lastly, supine position places the stomach at the level of the posterior gastroesophageal junction, which increases the risk for GER when LES relaxation takes place. Further discussion regarding alterations in feeding and positioning are included in the management section.
Currently, there are no gold standard diagnostic tools for the diagnosis of GERD in infants and children. Often, the symptoms of GER and GERD in newborn infants are nonspecific, which may lead to overdiagnosis and overtreatment. Symptoms are usually mild, resulting in increased fussiness or decreased nocturnal sleeping. In the inpatient setting, GER events are commonly blamed for cardiorespiratory events, especially in preterm infants. A temporal association between GER and cardiorespiratory events has been demonstrated in some studies,12,13 but several others have shown no association.14,15 In addition, what constitutes “troublesome” symptoms, thus shifting GER to GERD, is difficult to define and is often subjective based on an infant's age and the interpretation of their caregivers and health care professionals.
Clinical History and Examination
In infants, symptoms are classified as being either esophageal or extra-esophageal. Esophageal symptoms include vomiting, poor weight gain, dysphagia, and esophagitis. Extra-esophageal symptoms include those that either have established associations with GERD, such as cough and laryngitis or wheezing, as well as those that have been proposed as having associations, which include pharyngitis and recurrent otitis media.
The evaluation of an infant with GERD must include a focused history and physical examination to help determine if the symptoms are physiologic or are caused by underlying pathologic disease, as well as to identify secondary complications from GERD. A specific history of the nature of the vomiting should also be obtained, such as the presence of bile or blood, association with irritability, forceful or projectile character, or if the emesis is associated with other symptoms such as fever or lethargy. A detailed feeding history should include volume and frequency of feedings, type of formula, preparation of formula, and positioning of the infant during the feeds. Important details of the past medical history include inquiring about birth history and prematurity, neurologic problems, growth or developmental issues, past surgeries or hospitalizations and allergies. Pertinent family history includes inquiring about gastrointestinal disorders (including GERD) and atopic disease.
The timing of onset of regurgitation or vomiting may allow for targeted evaluation. If symptoms present during the first 2 weeks of life, infections, anatomical anomalies, and metabolic disorders should be excluded based on history provided and severity of illness. If the onset is after age 6 months or if symptoms persist after age 1 year, referral to a pediatric gastroenterologist should be considered for evaluation of other underlying etiologies.
Much of the initial evaluation in GERD is targeted at assessing for underlying pathophysiology that may need urgent intervention. For instance, although an upper gastrointestinal series is not necessary for the routine evaluation of infants with GERD, it should be considered in infants with bilious vomiting to exclude anatomic abnormalities such as malrotation, antral web, or annular pancreas. Similarly, infants with persistent forceful vomiting developing during the first few months of life may benefit from pyloric ultrasonography to assess for the possibility of pyloric stenosis. Upper endoscopy is only indicated in infants who have not responded to empiric clinical trials and/or including those infants with potential continued protein intolerance despite dietary elimination. It is important that results of the biopsies be interpreted in the context of the infant's clinical presentation, so mild histologic abnormalities may not be clinically significant.
The methods most commonly used to specifically evaluate GER in the neonate include pH monitoring and multichannel intra-esophageal impedance (MII) monitoring. The pH monitoring method can assess for acidic reflux into the esophagus and may be used to assess the adequacy of acid suppression therapy. It has limited clinical utility in preterm neonates; however, because compared to adults, their stomach spends much less time with pH <4 due to frequent milk feedings and a higher baseline pH.16,17
GERD can also be assessed using MII, which detects reflux events regardless of pH. MII uses an esophageal catheter equipped with several electrodes along its length. By measuring changes in electrical impedance between the electrodes, MII can detect the path of fluid, solid, and air movement within the esophagus. It can also be used to discern whether a fluid bolus is traveling antegrade (swallow) or retrograde (reflux) in the esophagus as well as the distance that the retrograde fluid travels. It is a reliable and reproducible technique for diagnosing GER in preterm infants. Despite its accuracy in diagnosing reflux events, many healthy newborn infants demonstrate physiologic episodes of GER, and the association between abnormal results of esophageal monitoring and the presence of GERD is weak in neonates.
Approach to Management of Gastroesophageal Reflux in Newborn Infants
The main goal of GERD treatment is to relieve symptoms and prevent long-term secondary effects of reflux. Treatment strategies can be nonpharmacologic, pharmacologic, or surgical. Providers must weigh the risks and benefits to choose the optimal intervention for each patient using a multidisciplinary and thoughtful approach, particularly for sick and/or premature infants. When treating GERD, emphasis must first be placed on optimal growth and nutrition, feeding methods, and reassurance.
GER is an almost universal phenomenon in newborn infants and in most healthy infants with frequent regurgitation, education and reassurance of the infant's parents is usually the only intervention necessary, combined with periodic reevaluation of the neonate for the appearance of warning signals. If the infant's regurgitation affects the family's quality of life, or if the infant has difficulty sleeping because of regurgitation while supine, conservative measures should be trialed before pharmacologic or surgical therapies.
Nonpharmacologic strategies for decreasing the symptoms of GER or GERD include environmental and nutritional alterations. One of the most significant environmental changes that can be made for GER is tobacco smoke avoidance. Tobacco smoke has been shown to lower the esophageal sphincter tone and promote GER in adults and may have similar effects in infants.18 Because of this, as well as the other significant adverse effects of second-hand smoke exposure, providers should counsel all families to avoid exposing the infant to tobacco smoke.
Positioning of the infant after feeds may also affect GER symptoms. Studies using MII and pH probes have demonstrated that prone and left lateral positioning tend to produce the lowest number of TLESR episodes.19,20 Despite widespread use, elevation of the head of the bed has not demonstrated benefit in reducing GER in infants,21 and placing an infant in a chair or car seat may increase GER events.22 Therapeutic positioning using prone or left lateral positions should only be used in the neonatal intensive care unit while the infant is undergoing cardiorespiratory monitoring, and units should model safe sleep practices for as long as possible prior to discharge home. Once home, all infants younger than age 1 year should be placed supine for sleep, regardless of whether they demonstrate GER symptoms. Clinicians commonly recommend that parents hold infants with GER upright for at least 30 minutes after feeds—a practice that is safe but its effectiveness on decreasing GER symptoms has not been evaluated.
Avoidance of overfeeding and providing smaller feedings are helpful in reducing the frequency or quantity of reflux, as they both decrease gastric distention. Additionally, the type of nutrition provided may have some effect on GER symptoms. For infants who are breast-fed, continuation of breast-feeding should be encouraged when possible due to known immune and maternal-infant bonding benefits associated with breast-feeding. Additionally, some studies have demonstrated decreased regurgitation events after the administration of probiotics, although these data are limited.23
A trial of thickened feeds has been demonstrated to have moderate effectiveness in meta-analyses,24 and may therefore be worthwhile for most infants with problematic reflux. Standard formulas or expressed breast milk usually are thickened by adding oat infant cereal, up to one tablespoon of dry cereal per ounce of formula. Although rice cereal has traditionally been used for this purpose, oat cereal is now preferred because of concerns about possible contamination of rice cereal with arsenic. It may be necessary to adjust the nipple of the bottle to permit adequate flow of the thickened formula. Premixed formulas thickened with rice starch are available in some countries including the United States, and formulas thickened with carob flour or locust bean gum are also available in some countries. The efficacy of such pre-thickened formulas to decrease regurgitation and esophageal acid exposure has not been extensively evaluated. If thickened feeds are unable to provide adequate symptom relief after 1 to 2 weeks, the current NASPGHAN guidelines suggest that the next step should be a hypoallergenic diet for 2 to 4 weeks prior to considering pharmacologic therapy for GERD.
According to the NASPGHAN-ESPGHAN guidelines, refractory GERD is defined as that which does not respond, or responds insufficiently, to at least 8 weeks of optimal treatment. If nutritional management and conservative efforts remain unsuccessful, referral to a pediatric gastroenterologist may be warranted. While waiting for the consultation, initiation of a trial of pharmacologic therapy for 2 to 4 weeks may be reasonable.
The most common pharmacologic approach to treating GERD in infants is through stomach acid suppression by either histamine 2 (H2) antagonists or protein pump inhibitors (PPIs). Other medications that were previously attempted to treat GERD, such as promotility agents like cisapride and metoclopramide, have been removed from the market due to concerns for associated cardiac and neurologic problems. Some centers have used erythromycin, a motilin agonist that improves antral contractility; however, the benefit needs to be weighed against the risk of pyloric stenosis that has been associated with macrolide administration. Buffering agents such as alginate and sucralfate have been used in older patients but are generally contraindicated in infants due to the potential for electrolyte and acid-base disturbances.
Although PPIs may be effective at increasing the stomach pH,25 several randomized trials of H2 antagonists and PPIs have failed to demonstrate significant symptom relief in infants with GERD.26,27 In addition to a lack of clear benefit, there are several concerns that have been raised regarding the use of H2 blockers or PPIs in infants. These medications have been associated with increased risk of gastrointestinal, respiratory, and systemic infections and altered small bowel microbiome resulting in bacterial overgrowth and altered motility. One of the most concerning associations is the increased incidence of necrotizing enterocolitis with PPIs, which is also thought to be due in part to the changes in the gut microbiome with changes in stomach pH. Due to these risks and the lack of clear benefit, national guidelines and campaigns such as Choosing Wisely have strongly cautioned against their overuse, especially in preterm infants.28,29
The US Food and Drug Administration suggests against the use of PPIs in otherwise healthy infants without clear evidence of acid-induced disease. Although routine use of these medications is not supported by the current literature, a brief (2 week) trial of acid suppression may be considered in severe cases.
Surgical interventions for reflux include fundoplication or post-pyloric feeds. The use of surgical fundoplication for GERD has been controversial and tends to be offered in cases of severe refractory GER with comorbidities, especially in neurologically impaired children.30 Retrospective studies on the effectiveness of fundoplication have demonstrated mixed results, with no significant decrease in reflux-related hospitalizations after fundoplication. Gastrojejunal feeding tubes can be used as an alternative approach to improve reflux by decreasing the fluid volume in the stomach.
GER is common in neonates and infants and, if symptoms develop, most can be managed conservatively. Due to its association with nonspecific symptoms and a lack of a gold standard test, GERD remains a difficult entity to define and manage. Additional studies to aid in the clinical diagnosis and management are needed to avoid overdiagnosis and overtreatment, especially in preterm infants.
- Martin AJ, Pratt N, Kennedy JD, et al. Natural history and familial relationships of infant spilling to 9 years of age. Pediatrics. 2002;109(6):1061–1067. doi:10.1542/peds.109.6.1061 [CrossRef] PMID:12042543
- Rosen R, Vandenplas Y, Singendonk M, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr. 2018;66(3):516–554. doi:10.1097/MPG.0000000000001889 [CrossRef] PMID:29470322
- López-Alonso M, Moya MJ, Cabo JA, et al. Twenty-four-hour esophageal impedance-pH monitoring in healthy preterm neonates: rate and characteristics of acid, weakly acidic, and weakly alkaline gastroesophageal reflux. Pediatrics. 2006;118(2):e299–e308. doi:10.1542/peds.2005-3140 [CrossRef] PMID:16831894
- Lightdale JR, Gremse DASection on Gastroenterology, Hepatology, and Nutrition. Gastroesophageal reflux: management guidance for the pediatrician. Pediatrics. 2013;131(5):e1684–e1695. doi:10.1542/peds.2013-0421 [CrossRef] PMID:23629618
- Davies I, Burman-Roy S, Murphy MSGuideline Development Group. Gastro-oesophageal reflux disease in children: NICE guidance. BMJ. 2015;350:g7703. doi:10.1136/bmj.g7703 [CrossRef] PMID:25591811
- Jadcherla SR, Slaughter JL, Stenger MR, Klebanoff M, Kelleher K, Gardner W. Practice variance, prevalence, and economic burden of premature infants diagnosed with GERD. Hosp Pediatr. 2013;3(4):335–341. doi:10.1542/hpeds.2013-0036 [CrossRef] PMID:24435191
- Gupta A, Jadcherla SR. The relationship between somatic growth and in vivo esophageal segmental and sphincteric growth in human neonates. J Pediatr Gastroenterol Nutr. 2006;43(1):35–41. doi:10.1097/01.mpg.0000226368.24332.50 [CrossRef] PMID:16819375
- Omari TI, Miki K, Davidson G, et al. Characterisation of relaxation of the lower oesophageal sphincter in healthy premature infants. Gut. 1997;40(3):370–375. doi:10.1136/gut.40.3.370 [CrossRef] PMID:9135527
- Funderburk A, Nawab U, Abraham S, et al. Temporal association between reflux-like behaviors and gastroesophageal reflux in preterm and term infants. J Pediatr Gastroenterol Nutr. 2016;62(4):556–561. doi:10.1097/MPG.0000000000000968 [CrossRef] PMID:26334254
- Murthy SV, Funderburk A, Abraham S, Epstein M, DiPalma J, Aghai ZH. Nasogastric feeding tubes may not contribute to gastroesophageal reflux in preterm infants. Am J Perinatol. 2018;35(7):643–647. doi:10.1055/s-0037-1608875 [CrossRef] PMID:29190845
- Jadcherla SR, Chan CY, Moore R, Malkar M, Timan CJ, Valentine CJ. Impact of feeding strategies on the frequency and clearance of acid and nonacid gastroesophageal reflux events in dysphagic neonates. JPEN J Parenter Enteral Nutr. 2012;36(4):449–455. doi:10.1177/0148607111415980 [CrossRef] PMID:22038208
- Cresi F, Martinelli D, Maggiora E, et al. Cardiorespiratory events in infants with gastroesophageal reflux symptoms: is there any association?Neurogastroenterol Motil. 2018;30(5):e13278. doi:10.1111/nmo.13278 [CrossRef] PMID:29266638
- Corvaglia L, Zama D, Gualdi S, Ferlini M, Aceti A, Faldella G. Gastro-oesophageal reflux increases the number of apnoeas in very preterm infants. Arch Dis Child Fetal Neonatal Ed. 2009;94(3):F188–F192. doi:10.1136/adc.2008.143198 [CrossRef] PMID:18786960
- Rossor T, Andradi G, Ali K, Bhat R, Greenough A. Gastrooesophageal reflux and apnoea: is there a temporal relationship?Neonatology. 2018;113(3):206–211. doi:10.1159/000485173 [CrossRef] PMID:29262418
- Di Fiore J, Arko M, Herynk B, Martin R, Hibbs AM. Characterization of cardiorespiratory events following gastroesophageal reflux in preterm infants. J Perinatol. 2010;30(10):683–687. doi:10.1038/jp.2010.27 [CrossRef] PMID:20220760
- Omari TI, Davidson GP. Multipoint measurement of intragastric pH in healthy preterm infants. Arch Dis Child Fetal Neonatal Ed. 2003;88(6):F517–F520. doi:10.1136/fn.88.6.F517 [CrossRef] PMID:14602702
- Sondheimer JM, Clark DA, Gervaise EP. Continuous gastric pH measurement in young and older healthy preterm infants receiving formula and clear liq--uid feedings. J Pediatr Gastroenterol Nutr. 1985;4(3):352–355. doi:10.1097/00005176-198506000-00005 [CrossRef] PMID:4020567
- Djeddi D, Stephan-Blanchard E, Léké A, et al. Effects of smoking exposure in infants on gastroesophageal reflux as a function of the sleep-wakefulness state. J Pediatr. 2018;201:147–153. doi:10.1016/j.jpeds.2018.05.057 [CrossRef] PMID:30041936
- Omari TI, Rommel N, Staunton E, et al. Paradoxical impact of body positioning on gastroesophageal reflux and gastric emptying in the premature neonate. J Pediatr. 2004;145(2):194–200. doi:10.1016/j.jpeds.2004.05.026 [CrossRef] PMID:15289766
- Bhat RY, Rafferty GF, Hannam S, Greenough A. Acid gastroesophageal reflux in convalescent preterm infants: effect of posture and relationship to apnea. Pediatr Res. 2007;62(5):620–623. doi:10.1203/PDR.0b013e3181568123 [CrossRef] PMID:17805196
- Bagucka B, De Schepper J, Peelman M, Van de Maele K, Vandenplas Y. Acid gastro-esophageal reflux in the 10 degrees-reversed-Trendelenburg-position in supine sleeping infants. Acta Paediatr Taiwan. 1999;40(5):298–301. PMID:10910536.
- Orenstein SR, Whitington PF, Orenstein DM. The infant seat as treatment for gastroesophageal reflux. N Engl J Med. 1983;309(13):760–763. doi:10.1056/NEJM198309293091304 [CrossRef] PMID:6350877
- Indrio F, Riezzo G, Raimondi F, et al. Lactobacillus reuteri accelerates gastric emptying and improves regurgitation in infants. Eur J Clin Invest. 2011;41(4):417–422. doi:10.1111/j.1365-2362.2010.02425.x [CrossRef] PMID:21114493
- Horvath A, Dziechciarz P, Szajewska H. The effect of thickened-feed interventions on gastroesophageal reflux in infants: systematic review and meta-analysis of randomized, controlled trials. Pediatrics. 2008;122(6):e1268–e1277. doi:10.1542/peds.2008-1900 [CrossRef] PMID:19001038
- Omari TI, Haslam RR, Lundborg P, Davidson GP. Effect of omeprazole on acid gastroesophageal reflux and gastric acidity in preterm infants with pathological acid reflux. J Pediatr Gastroenterol Nutr. 2007;44(1):41–44. doi:10.1097/01.mpg.0000252190.97545.07 [CrossRef] PMID:17204951
- Moore DJ, Tao BS-K, Lines DR, Hirte C, Heddle ML, Davidson GP. Double-blind placebo-controlled trial of omeprazole in irritable infants with gastroesophageal reflux. J Pediatr. 2003;143(2):219–223. doi:10.1067/S0022-3476(03)00207-5 [CrossRef] PMID:12970637
- Orenstein SR, Hassall E, Furmaga-Jablonska W, Atkinson S, Raanan M. Multicenter, double-blind, randomized, placebo-controlled trial assessing the efficacy and safety of proton pump inhibitor lansoprazole in infants with symptoms of gastroesophageal reflux disease. J Pediatrics. 2009;154(4):514–520.e514. doi:10.1016/j.jpeds.2008.09.054 [CrossRef]
- Eichenwald ECCommittee on Fetus and Newborn. Diagnosis and management of gastroesophageal reflux in preterm infants. Pediatrics. 2018;142(1):e20181061. doi:10.1542/peds.2018-1061 [CrossRef] PMID:29915158
- Ho T, Dukhovny D, Zupancic JA, Goldmann DA, Horbar JD, Pursley DM. Choosing wisely in newborn medicine: five opportunities to increase value. Pediatrics. 2015;136(2):e482–e489. doi:10.1542/peds.2015-0737 [CrossRef] PMID:26195536
- Rothenberg SS. Two decades of experience with laparoscopic nissen fundoplication in infants and children: a critical evaluation of indications, technique, and results. J Laparoendosc Adv Surg Tech A. 2013;23(9):791–794. doi:10.1089/lap.2013.0299 [CrossRef] PMID:23941587