Definitions

Gastroesophageal reflux (GER) is the physiologic retrograde passage of fluid from the stomach to the esophagus. Gastroesophageal reflux events occur in healthy infants multiple times per day. Gastroesophageal reflux disease (GERD) is the pathologic condition wherein such retrograde flow into the esophagus causes medical complications.¹ Regurgitation and vomiting are common and often nonpathologic complications of GER.² A definitive determination of GERD in infants is often elusive. Esophageal complications of GERD are often indirectly suggested because of difficulty in directly visualizing the esophagus in very small patients; for instance, infants who have arching, discomfort, or fussiness may be suspected of having esophagitis. Putative extraesophageal GERD-defining complications in infants such as apnea or worsening of respiratory disease are controversial, in large part, owing to lack of strong evidence in the literature.³ In most cases, no single test can diagnose or exclude GERD, and a comprehensive approach including testing and clinical assessments over time is needed to make the diagnosis.

By as early as 26 weeks’ gestational age, esophageal motor function is well developed in infants.4,5 In both term and preterm infants, swallowing triggers coordinated esophageal peristalsis and lower esophageal sphincter (LES) relaxation.⁴ However, the velocity of propagation is significantly slower in preterm compared with term infants.⁶ Esophageal activity unrelated to swallowing often takes the form of incomplete or asynchronous waves; this type of non-peristaltic motor activity occurs more frequently in preterm infants than in adults.⁴ Infants with functional or anatomic esophageal abnormalities, such as those with repaired esophageal atresia or neuropathy affecting smooth muscle, are at risk for impaired esophageal clearance of fluid.

Gastroesophageal reflux events are part of the normal functioning of the upper gastrointestinal tract. The lower esophageal sphincter, which limits the retrograde passage of air and fluids from the stomach to the esophagus, is made up of intrinsic esophageal smooth muscle and diaphragmatic skeletal muscle.⁷ Several manometry studies have documented good LES tone, even in extremely low birth weight infants.^4,8,9 In both preterm and term infants, just as in more mature patients, transient lower esophageal sphincter relaxations (TLESRs) unrelated to swallowing are the major mechanism allowing GER by dropping lower esophageal pressure below gastric pressure, thereby promoting the retrograde passage of fluid.^4,9,10 Transient lower esophageal sphincter relaxations are frequent in preterm infants, occurring several times per hour, although the majority of TLESR events are not associated with GER.¹⁰ A similar frequency of TLESRs is seen in infants with and without GERD, but a higher percentage of acid GER events during TLESRs occurs in infants with GERD.¹⁰ It has been hypothesized that increased intraabdominal pressure during a TLESR, for instance due to straining, may increase the likelihood of a GER event. Although LES relaxations also occur during normal swallowing, these are less often associated with GER events than isolated TLESR events,¹⁰ presumably owing to the coordinated waves of esophageal muscular activity propelling fluid antegrade during a swallow. The number of GER events and the height the fluid bolus reaches in the esophagus are increased after feeding; refluxate after feeding is less acidic than fluid refluxed before feeding.¹¹ Other factors also promote GER in infants, particularly patients in a neonatal intensive care unit (NICU). For instance, infants ingest a much higher volume per kilogram of body weight, approximately 180 mL/kg per day, than older children and adults.¹² In the NICU population, preterm and term patients with nasogastric or orogastric feeding tubes may experience more reflux episodes because of mechanical impairment of the competence of the LES.^13,14 Infants with anatomic abnormalities of the structures that comprise the LES, such as infants with congenital diaphragmatic hernia, are at risk for experiencing a higher-than-normal frequency of GER events.

Gastric emptying also plays a strategic role in upper gastrointestinal tract function. Between 25 and 30 weeks’ gestational age, gastric emptying time seems to be inversely and linearly correlated with gestational age at birth. Simultaneously decreasing the osmolality and increasing the volume of feeds may accelerate gastric emptying, although changes in osmolality or volume alone did not seem to have a significant effect.¹⁵ Human milk also promotes gastric emptying, but fortification may increase emptying time.¹⁶ In formula-fed infants, several small studies suggest that prebiotics, probiotics, and hydrolyzed formulas may speed gastric emptying time.^17–19 However, although it seems logical that slower gastric emptying would promote GER because of increased fluid and possibly pressure in the stomach, a study of the relationship between gastric emptying and GER in preterm infants found no association.²⁰

Gastroesophageal reflux events are frequent in healthy preterm and term infants. Among 509 healthy asymptomatic infants age 3 to 365 days, the mean number of acid reflux episodes in 24 hours was 31.28, with a standard deviation of 20.68.²¹ The reflux index, the percent of time the esophageal pH was less than 4, ranged from less than 1% to 23%, with the median and 95th percentile being 4% and 10%, respectively. Among the neonates in this study, the 95th percentile for the reflux index was as high as 13%. In a smaller study of 21 asymptomatic preterm infants, continuous combined esophageal pH and impedance monitoring detected refluxed fluid in the esophagus by impedance for a median of 0.73% (range, 0.3%-1.22%) of the recording time, and acid exposure detected by pH monitoring for a median of 5.59% (range, 0.04%-20.69%) of the recording time. These studies make it clear that GER events occur frequently in asymptomatic infants, and a wide range of reflux measurements may be seen in healthy preterm infants without GERD.

In a study of infants in general pediatric practice, half of all parents reported at least daily regurgitation at 0 to 3 months of age.²² The peak prevalence occurred at 4 months, with 67% reporting regurgitation. Thus benign regurgitation was the norm in the first few months of life. Parents reported regurgitation to be a problem when it was associated with increased crying or fussiness, perceived pain, or back arching. The prevalence of regurgitation perceived as a problem peaked at 23% at 6 months, and was down to 14% by 7 months. The majority of these children did not receive treatment for GERD from their pediatrician. Infants who did and did not experience frequent regurgitation between 6 and 12 months of age were followed up a year later.²³ At this time, none of the parents described regurgitation as a current problem. Infants with frequent spitting at 6 to 12 months of age did not experience more infections of the ear, sinuses, or upper respiratory tract, nor did they experience more wheezing.

It is also important to remember that regurgitation and vomiting are not necessarily caused by GER or GERD. Clinical correlation is needed to determine whether other pathologic processes are present. The differential diagnosis includes gastrointestinal obstruction, motility abnormalities, infection, inborn errors of metabolism, adrenal insufficiency and other hormonal abnormalities, and neurologic abnormalities, including increased intracerebral pressure. Commonly, milk protein allergy may mimic GERD.²

The distinction between GER and GERD is important when communicating with families. One study showed that in infants with a label of GERD, families were more likely than those with a GER label to be interested in medications, even when they were told that those medications were likely ineffective.²⁴

Identifying whether troublesome symptoms are in fact caused by reflux can be challenging in infants.25,26 Symptoms frequently attributed to GERD in infants include regurgitation, Sandifer posturing, worsening of lung disease, food refusal or intolerance, apnea, bradycardia, crying or fussiness, and stridor. Regurgitation may be a symptom of GERD in infants, but in itself is neither necessary nor sufficient to make a diagnosis.²⁶ Clustering regurgitation with other symptoms may increase the accuracy of diagnosis, as demonstrated by the I-GERQ-R infant reflux questionnaire.^26,27 However, the validity of such questionnaires has not been established in the NICU population, which includes preterm infants and sick term neonates who have multiple competing causes for the symptoms frequently attributed to GERD.

Although GERD and bronchopulmonary dysplasia (BPD) seem to be associated, causality has not been determined.26,28–31 Patients with increased work of breathing may generate more negative intrathoracic pressures, thereby promoting the passage of gastric contents into the esophagus. Conversely, aspirated refluxate could injure the lungs, thereby promoting chronic lung disease. Finally, immaturity and severity of illness predispose to both conditions, and there may be no causal link in the majority of patients. In addition, part of the apparent association between BPD and GERD may be the result of an increased index of suspicion for GERD in patients with BPD, leading to increased rates of diagnosis.³⁰

A similar issue exists for apnea in premature infants. Although in animal models, esophageal stimulation may trigger airway protective reflexes,³² there is insufficient evidence in human infant patients to confirm that reflux causes apnea.^26,33 In fact, apnea may itself trigger reflux.^34,35 Finally, immature infants are simply prone to both apnea and reflux, and there may be no causal association.³⁶ In a cohort of infants referred for overnight esophageal and respiratory monitoring for suspicion of GERD-induced apnea, desaturation, or bradycardia, fewer than 3% of all cardiorespiratory events were preceded by a reflux event.³⁷ Conversely, 9.1% of reflux events were preceded by a cardiorespiratory event. Thus it was more common for a cardiorespiratory event to precede reflux than for reflux to precede a cardiorespiratory event. Even in this population referred for suspicion of GER-triggering cardiorespiratory events, only a small minority of cardiorespiratory events were in fact preceded by reflux. However, data from small or moderately sized research cohorts cannot rule out the possibility that reflux can trigger the majority of cardiorespiratory events in a small subset of patients. Because bedside recording of apnea events is known to be inaccurate, correlation of apnea with feeding or reflux events in a specific patient requires simultaneous respiratory and esophageal monitoring.

It is unclear what component of the refluxate triggers complications. Acidity is often implicated, but it is not clear which, if any, complications are triggered by acidity.²⁶ The other characteristics of the refluxate that have been postulated to be associated with symptoms include the height of the bolus in the esophagus, the volume of the bolus, or the pressure exerted on the esophagus.

Treatment

The general categories of interventions available to treat GERD are conservative nonpharmacologic, pharmacologic, and surgical. The natural history of GERD, often with improvement within a few weeks,38–40 must be remembered when interpreting the impact of an intervention. Treatment failures may result from either a failure of the medication to achieve its intended action or from the erroneous application of drugs to symptoms not caused by GERD. Apparent successes may result from either a true drug effect or from the natural resolution of symptoms with maturation (Figure 91-1). Because the goal of therapy is to treat GERD, not physiologic GER, the gold standard for gauging therapeutic success must be improvement in symptoms or complications, not simply improvement in physiologic measures. The most effective treatment for GERD is time and maturation, and so expectant conservative management is the mainstay of therapy in most cases.

Conservative Nonpharmacologic Management

Commonly used conservative interventions for GERD include positioning, thickening feeds, and decreasing the volume while increasing the frequency of feeds. When milk protein allergy is thought to be mimicking or triggering GERD, changing to a more elemental formula may also be appropriate. In the run-in period for a randomized control trial of a pharmacotherapeutic intervention for GERD, the majority of infants seemed to improve over a 2-week period with such a multipronged conservative management strategy, although this effect simply could also be attributed to time and maturation.³⁹

Although typical positioning precautions for an infant with a diagnosis of GERD include elevating the head of the bed, there is not an advantage to supine upright versus supine flat positioning.⁴¹ Prone positioning seems to be associated with fewer GER events than supine, but is generally contraindicated because of the increased risk of sudden infant death.^41,42 Lateral positioning with the right side down results in more frequent reflux events than left lateral positioning, but it is not clear whether this results in more symptoms.⁴³

Thickening feeds has been shown to decrease episodes of clinical vomiting, although it does not seem to decrease physiologic measures of GER.41,45 Feeds may be thickened by adding a thickening agent or using a prethickened commercially available formula. Common thickeners include rice, carob, cornstarch, and locust-bean gum. Rice and some prethickened rice-based formulas require gastric acidity to fully increase their viscosity, so their action may be impaired by drugs that block gastric acidity.⁴⁴ An insufficient number of large trials have been conducted to assess the safety of thickening agents in infants, and concerns have been raised about the potential for various thickening agents to cause diarrhea, increased cough, poor growth, and nutrient malabsorption.⁴⁵ The efficacy and safety of thickened feeds have not been well studied in preterm infants. A recent US Food and Drug Administration (FDA) warning cautioned against the use of one brand of commercial thickener in preterm infants because of reports of late-onset NEC.⁴⁶

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