Neonatal Gastroesophageal Reflux

Epidemiology

Gastroesophageal reflux (GER) is defined as the retrograde movement of gastric contents into the esophagus with or without regurgitation. Uncomplicated GER is a normal physiologic process in infants, in part due to relatively large liquid volumes ingested during feedings and supine positioning which places the gastroesophageal junction in a liquid environment. Preterm infants are at particular risk for reflux due to gastrointestinal dysmotility and delayed gastric emptying affected by immaturity. Uncomplicated GER should not prompt further investigation or treatment. However, when reflux of gastric contents is associated with troublesome clinical symptoms or signs, it is called gastroesophageal reflux disease (GERD). In clinical practice, since “troublesome signs” in neonatal patients are most often nonspecific and subjective, it is difficult to differentiate GER from GERD in the neonatal intensive care unit (NICU); as a result, these terms are frequently used interchangeably by medical professionals and parents alike.

The difficulty in making a diagnosis of GERD in neonatal patients can lead to its overdiagnosis and treatment, as well as significant practice variation. In one study of 33 academic children’s hospital NICUs, there was a 13-fold variation (2% to 26%) in the diagnosis and treatment of GERD in NICU patients. In this study, patients with a GERD diagnosis had longer hospital stays and higher costs than infants without this diagnosis. In addition, infants discharged from the NICU on antireflux medications frequently remain on treatment for many months after discharge, making it an important clinical entity in the NICU and beyond. This chapter will discuss the physiology, diagnosis, and therapy of GER in nonsurgical patients in the NICU.

Pathophysiology

There are many pathophysiologic mechanisms which increase the risk of GER in the neonatal period ( Fig. 63.1 ). The lower end of the esophagus is defined anatomically by the junction of the esophagus with the stomach, and functionally by the junction of the inferior border of the high-pressure area of the lower esophageal sphincter (LES) with the lower pressure in the stomach. The LES is comprised of smooth muscles organized in two layers, with circular and longitudinal muscle fibers separated by a myenteric plexus. The gastroesophageal junction is functionally augmented by the diaphragmatic crural fibers, the intra-abdominal esophagus, and sling fibers of the stomach, which together form the principal barrier to GER. Extrinsic innervation of the esophagus involves neurons in both the brainstem and spinal cord. The LES is innervated by both parasympathetic (vagus) and sympathetic (primarily splanchnic) nerves. The LES is tonically active and functionally closed. The vagal pathways are the central neural pathway for reflex relaxation of the LES. Parasympathetic vagal nerve pathways, coordinated through the dorsal motor nucleus and nucleus tractus solitarius, trigger periodic reflex relaxation induced by swallows and esophageal dilatation to facilitate bolus transit from the upper esophagus. These mechanisms of swallow-related relaxation of the LES and tonic activity of the LES to maintain esophagogastric competence are present even in extremely preterm infants.

In addition to reflex relaxation of the LES related to swallowing, the LES also spontaneously relaxes without stimulation. These events are termed “transient lower esophageal sphincter relaxation” events, or TLESR. TLESR is an abrupt reflex decrease in LES pressure to levels at or below intragastric pressure unrelated to swallowing and is the primary mechanism for GER in infants. TLESR appears to use the same efferent neural pathway as the swallow reflex, whereas afferent pathways may originate in the pharynx, larynx, or stomach. In contrast to swallow-related LES relaxation, TLESRs are generally longer in duration and at lower LES pressures.

The normal function of TLESR is to prevent gastric bloating by periodically releasing gas from the stomach. As such, gastric distention after a meal stimulates stretch receptors in smooth muscle in the stomach wall, stimulating a vasovagal response with resultant TLESR. The number of TLESR events per day in neonates appears to decrease with maturity, so that preterm infants have dozens of episodes per day, many of which are associated with GER. GER and regurgitation is very common in neonates, induced by a reflex TLESR associated with gastric distention after a feeding. As such, physiologically, some degree of subclinical or clinically apparent reflux is a normal phenomenon in neonates. In neonates, GER is exacerbated by a pure liquid diet and age-specific body positioning. Newborns spend most of their sleeping time in the supine position because of its known protective effect on the incidence of sudden infant death syndrome (SIDS).

Infants positioned supine and in the right-side-down lateral position have more episodes of TLESR and GER compared with the left-side-down lateral position, despite more rapid gastric emptying in the right lateral position. Prone position decreased episodes of GER versus the supine position, likely due to a more optimal positioning of the LES relative to the liquid-filled stomach rather than a decrease in TLESR events.

Impaired gastric motility and delayed emptying do not appear to play a contributory role in GER in infancy, in that infants with symptomatic GER do not have delayed gastric emptying compared with other infants. However, the composition of gastric contents does affect the rate of gastric emptying, which may influence the frequency of GER. Increased caloric density feeding, especially with fats, frequently fed to preterm infants, slows gastric emptying, whereas expressed breast milk empties at almost double the rate of formula.

Preterm infants, especially those with intrauterine growth restriction, are at a higher risk for gut dysmotility, causing feeding intolerance which may be assessed as a sign of GER. The motility of the small intestine is less organized in preterm compared with term infants, due in part to intrinsic immaturity of the enteric nervous system that slows intestinal transit. In growth-restricted infants, prolonged periods of intrauterine hypoxia can produce injury to the bowel, which modulates the development of motor, secretory, and mucosal functions after birth, and may result in a higher risk for dysmotility and stasis.

Mechanisms to protect the esophagus and airway from GER appear to be intact even in the most preterm infants. These include reflex antegrade peristalsis of the esophagus in response to esophageal dilatation with gastric contents, and closure of the upper esophageal sphincter to prevent refluxate from reaching the pharynx. Despite this, if refluxed material does reach the upper esophagus, the upper esophageal sphincter will reflexively open to allow the material into the pharynx to protect the laryngeal structures, resulting in episodes of “spitting” or emesis frequently seen in infants.