INTRODUCTION — Gastroesophageal reflux (GER), the passage of gastric contents into the esophagus, occurs commonly in newborn infants and is especially common in those born prematurely. Physiologic GER typically is a developmental process that resolves with maturation. GER generally resolves on its own by one year of age. In infants who have no symptoms other than regurgitation, no further evaluation or intervention is typically required.
In contrast, gastroesophageal reflux disease (GERD) is clinically significant GER that causes morbidity . Putative morbidities of GERD in preterm infants include frequent vomiting, aspiration pneumonia, irritability, failure to thrive, and exacerbation of respiratory symptoms, including chronic lung disease. However, it is likely that in many infants with these symptoms, the GER is not the underlying cause.
GER in preterm infants will be reviewed here. GER in infants, children, and adolescents is discussed separately. (See "Gastroesophageal reflux in infants" and "Clinical manifestations and diagnosis of gastroesophageal reflux disease in children and adolescents" and "Management of gastroesophageal reflux disease in children and adolescents".)
MECHANISMS — GER is extremely common in healthy infants in whom gastric fluids reflux into the esophagus 30 or more times daily. It appears that GER is more common in healthy preterm compared with term infants. The pathogenesis of GER in preterm infants appears to be multifactorial due in part to immature or impaired anatomic and physiologic factors that typically limit reflux.
Relaxation of lower esophageal sphincter — The most important mechanism of GER in preterm infants (similar to older infants and adults) is transient relaxation of the lower esophageal sphincter (LES) [2,3]. The LES is comprised of intrinsic smooth muscle of the esophagus and skeletal muscle of the crural diaphragm .
Transient LES relaxation is defined as an abrupt decrease in LES pressure below the intragastric pressure, which is unrelated to swallowing and allows regurgitation of stomach contents into the esophagus. Normally, the LES relaxes with the onset of esophageal contractions triggered by swallowing as food passes down the esophagus, and contracts when swallowing ceases in order to prevent reflux by maintaining a lower esophageal pressure that is higher than the intragastric pressure.
The frequency of transient LES relaxation is the same in preterm infants with and without gastroesophageal reflux disease (GERD). However, infants with GERD are more likely to experience acid regurgitation during LES relaxation than those without GERD .
Gastric emptying — Premature infants have slower gastric emptying compared with mature newborns. This was illustrated in a study of preterm infants born between 25 to 30 weeks gestation that demonstrated emptying time decreased linearly with advancing gestational age at birth when emptying time was measured by breath tests using isotope labeled feeds .
The delay in gastric emptying in preterm infants may provide a greater gastric volume of liquid available for reflux. However, there are no data that show a delay in gastric emptying in preterm infants with symptomatic GER compared with asymptomatic patients .
Esophageal motility — In the preterm infant, esophageal motility may be immature and contribute to GER . In one study that evaluated esophageal function during swallowing, increasing gestational age was correlated with increasing completion of secondary esophageal peristalsis, shortening of proximal esophageal sphincter contraction, and faster propagation velocity for liquids . Another study that utilized high-resolution manometry confirmed that preterm compared with term infants were more likely to have incomplete esophageal peristalsis during swallowing . Differences in swallow propagation during active sleep between preterm and term infants have also been reported . However, there are no data showing differences in motility maturation directly correlating with an increased risk of symptomatic GER in preterm infants .
Respiratory disorders — GER may occur more frequently in infants who have respiratory disorders, such as bronchopulmonary dysplasia. One possible mechanism contributing to increased reflux in infants with respiratory disorders may be that increased work of breathing results in a relative increase of intraabdominal versus intrathoracic pressures, which facilitates GER.
Gastric tube — The presence of nasogastric or orogastric tubes, which are commonly used in preterm infants, may increase GER because they may cause greater LES relaxation and/or decreased gastric emptying [11,12].
General symptoms — Because of the nonspecific nature of the symptoms associated with gastroesophageal reflux disease (GERD), there is a wide variation among clinicians regarding their beliefs about the presenting signs and symptoms . Signs or symptoms that are often attributed to GER include irritability, nonspecific behaviors suggesting discomfort such as posturing or grimacing, frequent bouts of emesis, worsening of lung disease, and failure to thrive. However, it is likely that in many cases the GER is not the underlying cause of these symptoms, as outlined in the following sections .
GER episodes tend to occur more frequently after feeding . Reflux that occurs after feeds tends to be less acidic and rises higher in the esophagus compared with reflux episodes that are not temporally related to feeds.
Relationship to apnea — Accumulating evidence suggests that GER is not a common trigger or mechanism for pathologic apnea of prematurity, although in selected cases a causal relationship may exist .
The possibility of a causal association was suggested in the past because several studies performed in the 1970s and 1980s linked GER with apnea or respiratory arrest in neonates born at term and in older infants [17-20]. A proposed mechanism is that GER elicits reflexes that protect the airway and interrupt normal respiratory patterns . As an example, evidence from animal models demonstrated fluid stimulation of the laryngeal mucosa inhibited normal respiratory patterns .
However, subsequent studies in preterm infants have mostly failed to demonstrate a temporal relationship between GER and apnea [22-29]. The lack of a temporal relationship between these two conditions has been demonstrated in studies that utilized cardiorespiratory monitoring, including respiratory inductance plethysmography, heart rate monitoring, oxygen saturation, and esophageal pH testing to detect acidic GER [23-26]. This is illustrated by the following studies:
●A study of 119 premature infants with a mean gestational age of 28 weeks used 12-hour cardiorespiratory monitoring to record 6255 acidic GER episodes . Apnea ≥15 seconds was associated with only 1 percent of the GER episodes. There was no difference in the rate of apnea ≥15 seconds before, during, or after GER episodes. GER did not prolong apnea duration.
●Similar findings were shown in a subsequent study from the same tertiary center, in which less than 3 percent of all cardiorespiratory events (defined as apnea ≥10 seconds in duration, bradycardia ≤80 beats per minute, and oxygen desaturation ≤85 percent) were preceded by GER . GER did not increase the duration or severity of the event.
●Studies measuring nonacidic GER using multichannel intraluminal impedance (MII) monitors have mixed results, but generally suggest that a minority of events precede apnea. In most studies, there was no association between respiratory pauses and reflux episodes in the majority of infants [27,28], although there may be a modest temporal association in certain infants [31,32].
A few studies suggest that apnea may precipitate GER, rather than the opposite relationship of GER causing apnea. As an example, motility studies in premature infants (postmenstrual age range from 34 to 37 weeks) demonstrated that apneic episodes were associated with a reduction in lower esophageal sphincter (LES) tone, which is the key mechanism for GER (see 'Relaxation of lower esophageal sphincter' above) . Similar results have been reported in a study of newborn piglets .
Failure to thrive — Although GER is common in infants with poor weight gain, there is little evidence that the association is causal . In a small, match-controlled retrospective study of 23 preterm infants with clinically significant GER, there were no differences in the average weekly weight gain, caloric intake, and growth parameters between patients and matched controls. However, infants with GER took longer to achieve full oral feedings (32 versus 19 days) and had a longer length of hospital stay (99 versus 70 days) .
Relationship to bronchopulmonary dysplasia — There is no evidence that GER contributes to bronchopulmonary dysplasia, although infants with bronchopulmonary dysplasia may be more susceptible to GER [14,36-38].
DIAGNOSTIC EVALUATION — The diagnosis of gastroesophageal reflux disease (GERD) is challenging in preterm infants because symptoms are nonspecific and diagnostic testing is limited due to technical problems and difficulties of interpreting results in the newborn. In most cases, the diagnosis rests on the clinician's clinical suspicion that a pathologic problem in an individual infant is likely to be caused by GER, based on a global assessment and exclusion of other causes of the symptoms. Because the pathologic problems of poor growth, apnea of prematurity, or chronic lung disease probably are not caused by GER in the majority of infants, invasive testing for GER usually is not appropriate except in selected cases.
For all infants with GER, nonpharmacologic management should be the mainstay of therapy (see 'Management' below). However, if nonpharmacologic measures have failed and there is a strong clinical suspicion that GER is causing complications, some clinicians do an empiric time-limited trial of acid suppression. (See 'Acid suppression' below.)
History and examination — The nonspecific signs associated with GER include regurgitation of milk, vomiting, irritability, arching, grimacing, desaturation, and respiratory symptoms. In contrast, bilious vomiting, gastrointestinal bleeding, diarrhea, constipation, fever, lethargy, abdominal tenderness and distension, hepatosplenomegaly or the presence of blood in the stools suggest a diagnosis other than GER .
Diagnostic testing — Esophageal monitoring tests are sometimes used in the evaluation of GER. The diagnostic value of these tests is limited due to difficulties of interpreting results, especially in the newborn. These tests can document the presence of GER but rarely establish a causal association between GER and pathologic consequences .
In addition, the postconceptional age at which preterm infants can safely undergo procedures may be a limiting factor for diagnostic testing. Small, medically unstable infants may not be able to tolerate being transported for radiologic testing or placement of a pH or multiple intraluminal impedance probe in the nostril, because it may compromise respiratory status or increase the risk of esophageal perforation from probe placement in the smallest infants, although this has not been reported in the literature. The size at which the diagnostic procedures may be safely accomplished will depend on institutional comfort and familiarity. In our institution, for instance, we rarely place a multiple intraluminal impedance probe, which is stiffer than a pH probe, in infants with a weight less than 1600 g.
Esophageal pH probe — Esophageal pH measurement to detect reflux of acidic gastric contents in the distal esophagus has been the most widely employed diagnostic test for GER in preterm infants, but the diagnostic value is limited. The test, which may last up to 24 hours, is performed by the transnasal passage of a microelectrode containing a pH sensor into the lower one-third of the esophagus. The wide spectrum of size of preterm infants makes placement of the catheter challenging. However, placement is crucial, as misplacement may result in under- or overestimation of acid reflux, especially in the smallest infants in whom a small error in positioning could give rise to a potentially large error in the results . The catheter is placed using the Strobel formula that correlates the patient's length to his/her esophageal length . Placement is confirmed radiographically.
Intraluminal impedance — Multichannel intraluminal impedance (MII) can detect acid and nonacid esophageal reflux.
MII uses an esophageal catheter designed to measure impedance from multiple intraluminal recording sensors . The method allows detection of GER based on changes in electrical resistance to electrical current flow between two electrodes when a liquid and/or gas bolus moves between them. Impedance detects GER if there is a sequential drop in impedance to less than 50 percent of baseline values, starting distally above the lower esophageal sphincter (LES) and propagating retrograde to at least the next two more proximal measuring segments. Therefore, anterograde swallows can be differentiated from retrograde boluses (GER). This emerging technology is being employed as both a clinical and research tool in preterm infants.
The obvious advantage of MII compared with esophageal pH monitoring is the ability to assess postprandial reflux, which may be masked by milk neutralizing the acid content of the refluxate when only a pH probe is used. This was illustrated in one study of preterm infants (gestational age of 23 to 37 weeks, tested at a postconceptional age between 34 to 48 weeks) that showed more episodes of reflux and less acidic reflux contents after versus before a feed .
However, several reservations associated with the use of MII in preterm infants remain, particularly the lack of validated normative standards in neonates [44,45]. When compared with pH measurement, MII detects more frequent and shorter duration episodes, which are of uncertain clinical significance. Finally, it is important not to measure impedance-based reflux alone, as there is a high incidence of acid reflux events detected by pH monitoring that is not identified by MII . Acid reflux events missed by MII occurred most often in the least mature infants, possibly due to delayed esophageal fluid clearance in this immature population. To address this issue, MII has been combined with esophageal pH into a single probe [44,47]. In a study of newborns with symptoms suggesting GERD, the frequency of reflux events and percent of time with bolus reflux exposure, as measured by MII, were predictive of GERD symptoms in later infancy .
Other techniques — Techniques used to detect GER in older infants and children, including endoscopy and esophageal manometry, are rarely employed in neonates because of size limitation. In addition, endoscopy is rarely indicated because its primary indication is to diagnose esophagitis, which is exceedingly rare in preterm infants.
Other studies that may be performed in neonates include:
●Upper gastrointestinal contrast study — An upper gastrointestinal (UGI) contrast study with small bowel follow-through should be performed in infants with severe GER. This study is used to evaluate esophageal, gastric, and intestinal anatomy because congenital anomalies in these structures may cause reflux or vomiting.
However, UGI is a poor method to demonstrate GER because the procedure is performed under nonphysiologic conditions that may provoke reflux that is not clinically important. Also, a UGI may not detect clinically significant GER, because the period of fluoroscopic monitoring is brief, typically less than five minutes.
●Technetium scintigraphy — A nuclear medicine scintigraphy study, often commonly referred to as a milk scan, allows detection of esophageal reflux events and detection of aspirated gastric contents in the lungs. However, this technique is more likely to miss reflux events than continuous pH or MII monitoring.
MANAGEMENT — The initial treatment for GER is conservative and consists of dietary changes and parental education . Pharmacologic therapy is reserved for infants who fail conservative management and who have symptoms or diagnostic test results strongly suspicious for gastroesophageal reflux disease (GERD). Infants without GER-related morbidity ("happy spitters") should not be treated with medications, as recommended by expert panels [1,50]. However, these recommendations do not specifically address preterm infants, in whom it is often difficult to distinguish between GER and GERD, especially when deciding to initiate treatment and evaluate the efficacy of different therapies. Therefore, the following discussion reflects our practice, informed by available evidence.
Nonpharmacologic therapy — Initial nonpharmacologic therapy includes dietary changes and parental education . We assure the parents that reflux is a common physiologic occurrence in preterm infants that will resolve on its own and generally does not need intervention. Approximately one-half of all infants between zero and four months of age regurgitate at least once per day, with symptoms peaking at four months of age when the majority of infants have clinical GER. The use of a pacifier ("dummy") does not increase GER .
Diet — In term and older infants with presumed symptomatic GER, several dietary manipulations appear to have some efficacy, including smaller more frequent feeds and thickened feeds. For preterm infants with GER, these dietary modifications have not been adequately studied to determine whether they are effective. In particular, it remains unclear whether thickening of feeds with infant cereal is effective in preterm infants, as the available limited data report conflicting results [52,53]. Moreover, the use of feeds thickened by infant cereal may be challenging in preterm infants with weak oromotor skills or who are fed by tube feeds, and the cereals also increase the osmolality of the formula .
If cereal is used to thicken feeds, rice- or oat-based cereal are options. Due to concerns about possible contamination of rice with arsenic in 2014, the American Academy of Pediatrics (AAP) recommended oat cereal as a preferable thickening agent [55,56]. However, in 2020, the US Food and Drug Administration (FDA) finalized an AAP-supported limit on arsenic concentration in rice cereal . Although safe arsenic levels in preterm infants are not well established, with the new regulations, rice may be considered as a thickening agent when needed. (See "Gastroesophageal reflux in infants", section on 'Lifestyle changes'.)
The use of the commercial thickener that is based on xanthan gum (SimplyThick), should not be used in preterm infants, because of a possible link with necrotizing enterocolitis [58,59]. Since June 2011, the FDA has warned against use of this product in infants . Similar concerns exist for other commercial thickening agents, and these should also be avoided.
Trial of formula changes should not routinely be used and is very unlikely to be effective. There are very limited data to support the use of amino acid based or similar formulas in preterm infants with an intact intestine.
Position — Preterm infants who are approaching hospital discharge should be placed in the supine position for sleep even if they have reflux . The supine sleeping position is important to reduce the risk of sudden infant death syndrome, and available data do not identify a preferred position to reduce GER that outweighs the recommendation for supine position. It is important to model supine positioning prior to discharge in the hospital and to educate families to use the supine sleeping position at home. (See "Sudden infant death syndrome: Risk factors and risk reduction strategies".)
The protective benefits of supine positioning in preventing sudden infant death outweigh the possible benefits of other positions on GER . Studies that compared supine positioning to prone positioning [61-63] or lateral positioning [63,64] yielded mixed results regarding outcomes for GER, as measured by pH or impedance monitoring. Similarly, studies in term and older infants found that elevation of the head is not beneficial [65,66] and that infant-seat positioning worsens GER .
Pharmacologic therapy — Pharmacologic therapy has a limited role in infants with GER, as outlined in a position statement from the AAP . The AAP also targeted decreasing the frequency of antireflux medications in infants for a "Choosing Wisely in Newborn Medicine" initiative . This initiative is in response to observations that antireflux therapies are among the most commonly prescribed drugs in the neonatal intensive care unit , despite little evidence for benefit. Indeed, one study from the United States reported that 25 percent of extremely low birth weight (ELBW) infants (birth weight below 1000 g) were discharged from the hospital on antireflux medications . Moreover, antireflux medications are often initiated after neonatal intensive care unit discharge, and prolonged courses and combination therapy are common, despite limited evidence for efficacy . These findings underscore the need for informed and judicious use of these medications by outpatient providers.
When antireflux therapy is used, the most appropriate type is acid-suppressing medications. These drugs increase gastric pH, and thereby reduce esophageal acid exposure during episodes of reflux. However, they do not reduce the frequency of nonacid reflux. (See 'Acid suppression' below.)
Prokinetic agents, such as metoclopramide or cisapride, have an even more limited role in the treatment of GER in infants. These agents improve gastric emptying and/or esophageal sphincter tone, but they do not reduce the occurrence of transient lower esophageal relaxations. They are not recommended for management of GER in infants, due to safety concerns and low efficacy, as discussed below. (See 'Prokinetic agents' below.)
Acid suppression — Acid-suppressing medications have a limited role in the treatment of infants with GER because of limited evidence of short- or long-term benefit and mounting concerns about potential adverse effects, and because GER typically improves as the infant matures.
Indications — Acid-suppressing medications should not be used for infants with uncomplicated GER (ie, those without pathologic problems that are directly attributable to GER). They also should not be routinely used for treatment of apnea and episodes of oxygen desaturation in premature infants; this perspective is supported by expert consensus [1,14,50]. There is no evidence that acid suppression is effective in this population, and observational data suggests that acid-suppressing medications may be associated with an increased risk of necrotizing enterocolitis and sepsis as well as a long-term risk of allergy, asthma, and fracture. (See "Neonatal necrotizing enterocolitis: Prevention", section on 'Avoid gastric acid suppression'.)
Whether there is a role for acid-suppressing medication for selected preterm infants remains unclear. No specific indications or selection criteria have been established. In our practice, we occasionally perform a time-limited trial of acid suppression (eg, one week) for selected infants for whom there is a strong clinical suspicion that GER is causing complications and if nonpharmacologic measures have failed. If there is no clear improvement in the symptom over several days, we stop the medication. If there is a clear clinical improvement in the symptom, we continue treatment for several more weeks. The need for intervention should be reassessed every two to three weeks as the infant matures. It should be recognized that such empiric trials are rarely definitive because of the nonspecific nature of the symptoms attributed to GER and because GER typically improves as the infant matures.
Drug selection — When acid suppression is undertaken, the optimal choice of drug is unclear. Both histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) have potential safety concerns for all age groups (see 'Safety concerns' below), and limited information exists on long-term outcomes after their use during infancy. The advantage of H2RAs is that they probably have fewer side effects than PPIs. On the other hand, H2RAs are somewhat less effective in suppressing acid production compared with PPIs and their efficacy decreases with chronic use (tachyphylaxis). Use of H2RAs or PPIs in infants is "off-label" (not approved by the FDA), except for short-term use of esomeprazole, omeprazole, and famotidine for infants one month and older with documented erosive esophagitis.
Efficacy — Acid-suppressing medications have low efficacy in treating symptoms attributed to GER in infants. Although they reduce gastric acidity and duration of acid exposure in the esophagus [71-73], randomized trials in infants found no advantage of PPIs (eg, lansoprazole and esomeprazole) compared with placebo in treating symptoms attributed to GER [71,74,75]. This may be in part because refluxate in this population is only weakly acidic, thus limiting any potential benefit from acid suppression. (See "Gastroesophageal reflux in infants", section on 'Pharmacotherapy'.)
Safety concerns — Safety concerns about acid-suppression medications in premature infants include a possible increased risk for necrotizing enterocolitis, which may be related to alterations in the gastric flora due to acid suppression [74,76-79]. These drugs may also increase risks for pneumonia, sepsis, and other infections, based on limited evidence in premature infants and extrapolation from older age groups . Furthermore, one study of cimetidine in very low birth weight (VLBW) infants found increased risks for death or severe intraventricular hemorrhage; these findings prompted early termination of the study . A concern has been raised that lansoprazole may be associated with heart valve injury in infants <1 year, based on nonclinical studies in animals . Ranitidine products were removed from the market by the FDA due to concerns about the contaminant N-nitrosodimethylamine, a probable carcinogen . Long-term sequelae of acid suppression may include increased risk of fracture, allergy, and asthma later in childhood [83,84]. Additional details about the safety and selection of acid-suppressing medications in older infants are discussed in a separate topic review. (See "Gastroesophageal reflux in infants", section on 'Pharmacotherapy'.)
Prokinetic agents — Prokinetic agents are not recommended for management of GER in preterm or term infants, because of the potential for significant adverse effects as well as uncertainty of benefit [85-91]:
●Metoclopramide has several reported adverse effects including hyperkalemia, irritability, rare dystonic reactions, and extrapyramidal symptoms in infants, and its efficacy in treatment of GER in infants is unclear [85,86].
●Cisapride was removed from the market in Canada and the United States because of the risk of ventricular arrhythmia due to QT segment prolongation, and efficacy for GERD has not been established [89,90,92].
●Erythromycin is associated with an increased risk for pyloric stenosis in infants [93,94]. In addition, it does not improve feeding tolerance, as shown by a meta-analysis of 10 randomized trials that demonstrated no benefit of erythromycin as a prokinetic agent . (See "Infantile hypertrophic pyloric stenosis".)
These agents are discussed in greater detail separately. (See "Management of gastroesophageal reflux disease in children and adolescents", section on 'Prokinetics'.)
A small trial in preterm infants with a mean gestational age of 29 weeks found that a combined regimen of metoclopramide and ranitidine compared with placebo did not reduce, and may have increased, the episodes of bradycardia attributed to GER . An important additional result was the observation that there was a decrease in the frequency of bradycardia episodes over time, which was unrelated to treatment. This may contribute to misleading conclusions in nonrandomized and unmasked trials, which do not take this finding into account.
Transpyloric feeding — Transpyloric placement of an enteral feeding tube in the duodenum or jejunum has the theoretical advantage of decreasing GER. However, there are technical challenges associated with correct tube placement and maintenance of position, as well as bypassing the gastric phase of digestion. A meta-analysis of this technique failed to find any advantage of transpyloric feeding with respect to growth or time to establish full oral feeds, and reported an increased incidence of gastrointestinal disturbance and possibly mortality .
Surgery — Surgical intervention (typically fundoplication) is generally reserved for infants with severe GERD who have failed maximal medical management. These patients often have central nervous system dysfunction and respiratory morbidity, or have suffered a severe life-threatening event associated with reflux. However, it is important to note that infants, and in particular those with medical comorbidities, are at high risk for morbidity and mortality associated with fundoplication; recurrence of GERD symptoms after fundoplication is also common. In neurologically impaired infants who require gastrostomy tube placement for feeding, there is no evidence that adjunctive fundoplication is beneficial, compared with gastrostomy placement alone [97-101]. (See "Management of gastroesophageal reflux disease in children and adolescents", section on 'Surgery'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Gastroesophageal reflux in children".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
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SUMMARY AND RECOMMENDATIONS
●Mechanisms – Gastroesophageal reflux (GER) is common during infancy, especially in preterm infants. The increased risk of GER in preterm infants is thought to be due to immature or impaired anatomic and physiologic factors. Most infants have no complications from their GER and do not require further evaluation or intervention, because GER usually resolves without intervention by one year of age. (See 'Introduction' above and 'Mechanisms' above.)
●Clinical manifestations and possible complications – Gastroesophageal reflux disease (GERD) is defined as GER that causes morbidity. Signs or symptoms that are often attributed to GER include irritability, nonspecific behaviors suggesting discomfort such as posturing or grimacing, frequent bouts of emesis, worsening of lung disease, and failure to thrive. However, it is likely that in many cases, GER is not the underlying cause of these symptoms. In addition, GER is probably not a common trigger or mechanism for pathologic apnea of prematurity, although in selected cases, a causal relationship may exist. (See 'Clinical manifestations' above.)
●Diagnosis – The diagnosis of GERD is challenging in preterm infants because symptoms are nonspecific and diagnostic testing (esophageal pH and multiple intraluminal impedance monitoring) is limited due to technical problems and difficulties of interpreting results in the newborn. Moreover, esophageal monitoring rarely establishes a causal association between GER and pathologic consequences. As a result, the diagnosis of GERD usually depends on the clinician's clinical suspicion that a pathologic problem in an individual (eg, poor growth, apnea of prematurity, or chronic lung disease) is likely to be caused by GER, based on a global assessment and exclusion of other causes of the symptoms. (See 'Diagnostic evaluation' above and 'Acid suppression' above.)
•Treatment should be reserved for infants in whom there is concern that reflux may cause harmful sequelae. Management initially is begun with nonpharmacologic measures that include dietary changes (eg, smaller, frequent feeds and thickened feeds), based upon evidence from term and older infants and parental education. (See 'Nonpharmacologic therapy' above and "Gastroesophageal reflux in infants", section on 'Lifestyle changes'.)
•Pharmacologic therapy should not be used for infants with uncomplicated GER or episodes of apnea and oxygen desaturation, as it has not been demonstrated to be safe or effective in this population. For selected infants who have failed nonpharmacologic measures and for whom there is a strong clinical suspicion that GER is causing complications, it is reasonable to perform a time-limited trial of acid suppression (eg, one week). If there is no clear improvement in the symptom over several days, the medication should be stopped. (See 'Indications' above.)
•When pharmacologic therapy is used, the most appropriate type is acid-suppressing medication, either histamine-2 receptor antagonists (H2RAs) or proton pump inhibitors (PPIs). However, these drugs should be used cautiously and on a time-limited basis because they have not been shown to be effective in improving symptoms and may be associated with adverse sequelae. Prokinetic agents generally are not recommended for management of GER in preterm or term infants, because of the potential for significant adverse effects as well as uncertainty of benefit. (See 'Pharmacologic therapy' above.)
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