Gastroesophageal Reflux in the Preterm Neonate

Abstract

After completing this article, readers should be able to: Gastroesophageal reflux (GER) is a normal physiologic event occurring across the age spectrum. It may contribute to a variety of disorders, including esophagitis, feeding problems, and airway disease in all age groups. (1) A large number of symptoms and signs have been purported to be caused by GER despite a lack of data showing a clear association between a specific symptom and GER. In preterm infants, empiric therapy often is administered using agents of unproven efficacy and safety to treat symptoms that likely are unrelated to GER. In a survey on management practices for GER in preterm infants, common treatment strategies included positioning (98%) and slopes (96%), histamine 2 (H 2) receptor antagonists (100%), feed thickeners (98%), antacids (96%), prokinetics (79%), proton pump inhibitors (PPIs) (65%), and dopamine receptor antagonists (53%). (2)(3) The safety, efficacy, and appropriate dosing recommendations for most medical therapies remain uncertain in neonates. In this review, we attempt to summarize the current literature regarding physiology, pathophysiology, and diagnostic and management strategies for GER pertinent to the neonate, with an emphasis on the preterm infant.GER describes the retrograde movement of stomach contents (air or feeding, liquid or semisolid, acid or alkaline, enzymes or bile salts) into the esophagus. GER disease (GERD) occurs when GER causes symptoms or signs such as pain, poor weight gain, esophagitis, hematemesis, and airway symptoms, including apnea, aspiration, recurrent pneumonia, chronic lung disease (CLD), or large airway inflammation. However, any of these symptoms or signs may be independent of GER.The true incidence and prevalence of GER in preterm infants is unknown. It is estimated that about three to five GER events occur each hour in healthy infants. (4)(5) Using esophageal pH monitoring methodologies, Newell and associates (6)(7) found that episodes of acid GER are relatively common in asymptomatic healthy preterm infants, although the total time with acid in the esophagus was not abnormally high, indicating that refluxed gastric contents were cleared effectively from the esophagus. In another recent study using pH-metry, preterm infants had fewer episodes of acid GER when they attained full term postmenstrual age (PMA) than did healthy term-born controls. (8)The prevalence of abnormal pH-metry findings in sick preterm infants has not been studied. However, in a more recent observation, GERD with symptoms of reflux-associated apnea, bradycardia, or exacerbated bronchopulmonary dysplasia (BPD) were noted in 3% to 10% of infants of very low birthweight. (9) We recently noted a 60% incidence of GER in term neonates who underwent extracorporeal membrane oxygenation for life-threatening respiratory disease. (10) One retrospective study reviewed the outcomes of 137 infants born at 32 weeks’ gestation who underwent esophageal pH studies to evaluate such symptoms as apnea, bradycardia, emesis, poor oral intake, and irritability. (11) Although GER was observed in 63% of these “symptomatic” infants, their outcomes were similar to “asymptomatic” infants in terms of length of stay and complications from lung disease at 28 days (BPD) and at 36 weeks PMA (CLD). A meaningful determination of the actual prevalence or incidence of GERD in preterm or term infants requires further studies that carefully define symptoms and evaluate symptom improvement in response to therapy using controlled trials.The lower esophageal sphincter (LES) forms a pressure barrier that prevents stomach contents from entering the esophagus. It is composed of specialized smooth muscle cells that manifest continuous electrical spike activity, causing tonic contraction. Newell and associates (6)(7) found that LES pressure rose from 3.8 mm Hg in preterm infants (<29 weeks’ gestation) to 18.1 mm Hg in term infants. This has led to a generally accepted belief that the LES is incompetent in preterm infants. However, more recent, technically superior studies show that the LES generates tonic pressures in preterm infants that are sufficiently higher than intragastric pressure to maintain effective esophagogastric competence (5 to 10 mm Hg) and that there are no major changes in LES pressure during maturation in the healthy preterm infant. (12)(13)(14)(15)(16)Episodes of GER may occur during LES relaxation, which may be triggered by a variety of mechanisms, including transient LES relaxations (TLESR) that occur in the absence of swallowing, swallow-related LES relaxation, or prolonged inhibition of LES tone. TLESR is by far the most common mechanism of LES relaxation, triggering GER in all age groups from 26 weeks’ gestation preterm infants through adults. (13) TLESRs are stimulated in response to gastric distention following a meal. They are most common in the early postprandial period and decrease in frequency after the first postprandial hour. (17) TLESRs occur via a vagovagal reflex initiated by stretch-sensitive receptors located in the smooth muscle of the stomach wall, particularly in the cardia of the stomach. TLESRs have the same characteristics (duration, nadir pressure) in preterm infants as described in adults, indicating that the mechanisms underlying TLESR are well developed in this age group.The LES mechanism is enhanced by sling fibers of the diaphragmatic crus that wrap around the lower esophagus. (18)(19)(20) During inspiration, the measured LES pressure increases, corresponding with the increased thoracoabdominal pressure gradient and contraction of crural diaphragm, which tends to decrease the tendency for GER. In addition, a segment of intra-abdominal esophagus aids in preventing GER during straining because it is extrinsically compressed, providing a further seal against GER. These mechanisms are both absent in the presence of a hiatus hernia and may be absent in the neonate because the intra-abdominal esophagus is short or the cardia often extends through the diaphragmatic hiatus.The relatively small volume of the esophagus compared with the gastric volume plus supine positioning results in rapid filling of the esophagus following an episode of GER in infants. This makes infants more prone to reflux to the upper esophagus. It is possible that regurgitation episodes may become less frequent with growth simply due to an improvement in the first tier of the protective barrier (LES volume) as esophageal length and diameter increase. Following GER to the upper esophagus, the upper esophageal sphincter relaxes via a vagal reflex, which allows gastric contents to enter the pharynx, resulting in a swallow-mediated primary peristalsis. These mechanisms are intact in the healthy preterm infant. (21)The preterm infant secretes gastric acid shortly after birth. (22)(23)(24) Episodes of GER into the esophagus and pharynx, therefore, contain caustic contents and must be cleared to prevent mucosal damage. In adults, GER into the pharynx or esophagus triggers swallowing and/or esophageal peristalsis, which clears most of the refluxed material. Subsequent swallows of saliva neutralize the residual acid. (25) These mechanisms appear to be intact in healthy preterm infants because clearance time for both acid and nonacid GER are similar to those for adults. (4)(26)Most of the mechanisms that protect the esophagus against damage from GER appear to be present in the healthy preterm infant. (21) Theoretically, GERD could result from failure of these mechanisms manifested by a(n): Abnormalities of all of these reflexes is unlikely in physiologically healthy infants, which is why most healthy infants are asymptomatic despite having frequent episodes of reflux. In one investigation, older preterm infants (36 weeks PMA) referred for evaluation of GER had an increased incidence of symptoms, including apnea, choking, or behavioral events, compared with healthy infants. (17) However, the infants had other associated comorbid abnormalities that may have contributed independently to the reported GER symptom frequency. The mechanisms of GER were similar in both groups, and 80% of the symptomatic group remained symptomatic even at 3 months after study completion, suggesting that the GER symptoms were not due simply to prematurity.Because few data describe clinical patterns of GER in preterm neonates, diagnostic and treatment strategies have been extrapolated from older infants. This lack of data also has resulted in the “practice of myths and anecdotal beliefs.” The following section reviews the data supporting a causal relationship of GER and each purported GER symptom as well as treatment approaches.It is commonly believed that apnea in preterm infants is the result of GER. This belief stems from apnea events occurring more commonly during and after feeding and GER events also being frequent in the postprandial period. (27)(28) Furthermore, studies in sleeping preterm infants at full term PMA showed that laryngeal stimulation with saline or water evoked apnea and bradycardia. (29) Thus, it seemed reasonable that the apneic laryngeal chemoreflex observed in preterm infants would result in apnea during episodes of GER. (30)(31) However, numerous studies have failed to show a temporal or causal relationship of acid (32) or nonacid GER events and apnea in preterm infants. (4)(26)(33) Recently, studies employing concurrent esophageal impedance and cardiorespiratory recordings in 19 preterm infants (24 to 34 weeks’ gestational age) treated for apnea of prematurity showed no relationship of apneic episodes and GER episodes. (4) The frequency of apnea within 20 sec of a reflux episode was not significantly different from that during reflux-free epochs (0.19 versus 0.25/min), and results were similar for desaturations and bradycardic events as well. Pharmacologic treatment of GER with prokinetic agents, including cisapride or metoclopramide, also failed to decrease the incidence of apnea in preterm infants. (34)(35) Thus, these data do not support a role for GER as a cause of apnea in preterm infants, although some studies have suggested this relationship.Older pediatric patients who have recurrent pneumonia and GER improve after receiving medical or surgical GER therapy, suggesting that chronic GER may cause pulmonary disease. (36)(37) In addition, many patients who have idiopathic pulmonary fibrosis also have GER, suggesting that even repeated small episodes of aspiration of gastric contents may compromise pulmonary function severely. Therefore, it seems reasonable to suspect that GER may exacerbate pulmonary disease in preterm infants who have inadequate airway protective mechanisms.Sindel and associates (38) studied the relationship of GER and BPD in preterm infants and found less reflux into the proximal esophagus in those who had BPD compared with those who did not. Akinola and colleagues (11) retrospectively evaluated outcomes in 629 infants born before 32 weeks’ gestation. Of these, 137 symptomatic infants underwent esophageal pH monitoring studies, with abnormal findings reported in more than 60%. No difference in the incidence of GER was observed in infants who had BPD (defined as oxygen requirement at 28 days) compared with those without BPD (65%). The investigators observed a high incidence of CLD (defined as an oxygen requirement at 36 weeks PMA), but found no difference between infants with or without GER. In another retrospective study, Fuloria and coworkers (39) noted that GER was diagnosed and treated more frequently in preterm infants who had CLD compared with other infants. However, the criteria for diagnosis were based on a clinical suspicion of GER and response to subsequent treatment. GER history did not alter growth or development. Further, the authors suggested that the observed association of GER and CLD was likely due to an increased diagnostic suspicion of GER in infants who had CLD. Omari and associates (17) showed that the mechanisms of GER were similar in healthy infants and those who had BPD, with 85% of GER events being due to TLESR. Thus, the current data do not show a clear causal relationship of GER and pulmonary disease in preterm infants. No study in preterm infants has demonstrated prevention or improvement of CLD with any treatment regimen for GER. However, because treatment often is instituted because of a suspicion of GER, it is possible that GER may be a contributing factor in some infants.Orenstein and associates (40)(41) have characterized the behaviors associated with GER events in infants and children. Irritability often is considered a symptom of GER in infants, but a recent double-blind, placebo-controlled study showed no difference in symptom improvement in infants treated with a PPI (at doses documented essentially to eliminate esophageal acid exposure) compared with placebo-treated infants. (42) Furthermore, Snel and colleagues (43) observed that common behavioral characteristics observed in older infants, such as discomfort, head retraction, and mouthing, were not specific for acid GER events in healthy preterm infants. Barnett and associates (44) modified the Infant–Gastro-Esophageal Reflux Questionnaire GERD score for older infants and studied changes in behavioral responses following cisapride versus placebo in feeding-intolerant preterm infants who had increased gastric residuals and were evaluated for GER and gastric emptying problems. The cardinal symptoms scored in this questionnaire were vomiting, poor weight gain, irritability, apnea or choking, posturing, or grimacing. There were no significant differences in the behavioral symptom scores or in gastric emptying with cisapride therapy compared with control. Overall, these findings showed no predictive value of symptoms as a determinant of GER and no response to medical therapies, indicating that observation of purported GER symptoms is not useful for diagnosing GER in preterm infants.Investigators in a retrospective study compared preterm infants diagnosed with GER and control infants (n=23 each) who were matched for gestational age, birthweight, and severity of BPD. (45) There was no difference in average weekly increase in weight, length, or head circumference between the two groups. However, the time required for achieving full oral feedings, length of stay, and PMA at discharge were significantly longer in the GER group, thus increasing resource utilization.In another study, 150 neonatal intensive care unit infants who underwent a pH study to exclude GER were divided into three groups: normal (reflux index of <6), mild GER (reflux index of 6 to 14), and severe GER (reflux index >14). (34) Reflux index is the percentage of time the esophagus is exposed to a pH of less than 4 during a 24-hour recording period. The demographic, disease, or treatment characteristics, including birthweight, gestational age, patent ductus arteriosus, intraventricular hemorrhage, necrotizing enterocolitis, BPD, or xanthine use, between the groups were similar. Infants who had mild and severe GER had significantly more clinical GER. Infants who had reflux indexes of more than 14 also had more respiratory disease, a lower hematocrit, and longer length of stay, but it is not clear that GER caused these symptoms or if the sicker infants had poorer acid clearance. Treatment trials showing improvements in outcome are required to support a causal relationship.All healthy infants and adults have episodes of GER. It is unnecessary to consider therapeutic interventions for GER unless complications ensue. Diagnostic testing should be undertaken to evaluate the potential relationship of a specific presentation and GERD. It also is helpful to recognize and identify infants at increased risk for GERD due to underlying disorders.In an otherwise healthy infant who continues to feed well, gains weight, and has no respiratory illness, regurgitation should be considered as a normal variant that resolves with maturation without any complications. This is the case for most preterm infants. On the other hand, infants who experience recurrent vomiting or regurgitation associated with apparent irritability, difficulty feeding, pulmonary disease, or hematemesis may have GERD contributing to these symptoms. However, as noted previously, the association of GERD with any symptom presentation in preterm infants is poorly substantiated, and all symptoms of GER may result from other disorders, making it obligatory to consider other diagnostic possibilities.Predisposing risk factors and alternate diagnoses must be excluded. (1) Risk factors include anatomic malformations and congenital foregut anomalies, such as esophageal atresia or tracheoesophageal fistula, omphalocele, gastroschisis, duodenal atresia or web, hiatus hernia, diaphragmatic hernia, malrotation, and pyloric stenosis. Sepsis, metabolic diseases (disorders of amino acid metabolism, urea cycle defects, galactosemia, congenital adrenal hyperplasia), and structural abnormalities of the brain also should be ruled out.The purpose of diagnostic testing is to determine the likelihood of GER being the cause of disease. The ideal diagnostic test delineates the probability that GER is causing a specific symptom or sign and predicts the success of treatment. Unfortunately, in most cases, no single test provides a definitive diagnosis of GERD, and the ability of a test to predict treatment response in preterm infants has not been demonstrated in any setting. Investigations used for the evaluation of possible GERD in the neonatal period and infancy are summarized in the TableT1.Esophageal pH monitoring is performed by placing a pH sensor into the distal esophagus and measuring the time of acid exposure in the esophagus. Episodes of GER decrease the pH in the esophagus when acidic gastric contents encounter the sensor. In preterm infants, frequent feeding buffers gastric acidity, and detection of acid GER may be less likely.Although manometry accurately localizes the LES position and esophageal length, the technique is not feasible in many centers. The naso-lower esophageal length may be estimated using Strobel’s formula. (46) The probe is placed into the stomach and gradually withdrawn until the pH is not acidic, and the position is confirmed with radiographically. However, all such measurements also can result in an incorrect location (47) and depend on: the accuracy of the measured length, the position of the infant during chest radiograph, the degree of acidity in the stomach and its relation to feeding or feeding methods, lengthening or shortening of the esophagus based on peristalsis when the chest radiograph is obtained, and structural problems. Even when placed correctly, normal values are not well-established in preterm infants. If the temporal correlation is documented correctly, the information obtained from a long study (18 to 24 hr) may include the occurrence of reflux events during daily physiologic activities, such as feeding, voiding, stooling, abdominal strain, and crying, as well as changes in posture, state of arousal, vital signs, and diurnal variation. Therefore, it is important to document the physiologic state for a meaningful interpretation of the study. Furthermore, postprandial states, feeding periods, type of feedings, or medication use (eg, antacids, antibiotics, prokinetics) may affect the gastric pH and, therefore, under- or overestimate reflux episodes.A properly performed esophageal pH study provides: reflux frequency per 24-hour period, reflux index or the percentage of the day that the esophageal pH is less than 4, mean duration of each reflux episode, number of episodes longer than 5 minutes, and duration of the longest episode. It is important to recognize that normal values are established for term infants only and that applying these norms to preterm infants has not been validated. Furthermore, the upper limit of normal for the reflux index in term infants (>12%) is substantially higher than the normal values used for interpretation of esophageal pH monitoring studies in older children and adults (>6%). Information on the number of episodes longer than 5 minutes and the duration of the longest episode reflects esophageal clearance abilities. Poor esophageal clearance places the infant at risk for peptic esophagitis. There appears to be a higher risk of pulmonary complications of GERD in older infants and children if esophageal pH monitoring results are abnormal. Determining if apnea is related to GER is problematic when using standard esophageal pH monitoring equipment because of the slow response time of the sensors. In addition, the infant should not be receiving antacids, PPIs, or H 2 receptor antagonists for at least 48 hours prior to the study. The predictive value of esophageal pH monitoring as a determinant of either treatment response or outcome has yet to be established in preterm infants.Esophageal impedance monitoring applies a new technology that evaluates bolus transit through the esophagus. (5)(48) It allows detection of acid and nonacid GER events with no time delay. Analysis requires experience and is very time-consuming, which makes clinical application unrealistic in most settings. Normal values have not been established in preterm or term infants. Even when nonacid reflux episodes are measured, a temporal relationship between nonacid reflux and apnea cannot be demonstrated in preterm infants. (4) In older infants, only 30% of all apnea episodes occurred within 30 seconds before or after an episode of GER, (5) but a cause-and-effect relationship was not documented clearly. The predictive value of this test to determine treatment response to GER therapies is not established, and a meaningful role in clinical care has yet to be established.Radiographic fluoroscopy studies, including video swallow studies, esophageal fluoroscopy, or upper gastrointestinal barium swallow studies, have been used to identify sucking and swallowing problems, anatomic detail, and the momentary presence of reflux. This test has no role in the evaluation of GERD except to exclude other disorders that may cause symptoms similar to those potentially due to GER.Esophageal manometry studies permit evaluation of motility events, and their correlation with feeding state may help to identify the pathophysiologic mechanism of GER or esophageal clearance mechanisms. When performed patiently and carefully, esophageal manometry studies can identify the pathophysiologic characteristics of esophageal peristalsis, velocity of propagation, sphincter responses to swallow and reflux events, and mechanism of GER. These studies require specialized equipment and highly skilled personnel who are familiar with the tedious evaluation and analysis. The test has no role in the evaluation of GERD in typical clinical practice.Endoscopy with biopsy allows direct visualization and histopathologic evaluation of esophageal mucosa. This technique requires skilled personnel and sedation or anesthesia and is of value for the identification of esophagitis. It can be performed safely in preterm infants by experienced individuals using newer endoscopes that have diameters of less than 5 mm. Endoscopy can aid in discriminating between different causes of esophageal inflammation, including GERD and infectious or allergic (eosinophilic) esophagitis. All of these may occur in preterm infants, and the treatment approach varies, depending upon diagnosis.Empiric therapy frequently is administered to infants in whom GERD is suspected. Although this approach avoids risks associated with diagnostic testing, it is associated with other potential risks. Interpretation of the response to treatment is problematic because there is a large “placebo” (or chance) effect. In addition, appropriate doses and the risks of empiric medical therapy are not established in the preterm infant.It is important to understand that there is no gold standard test to evaluate reflux in the preterm neonate. Furthermore, it is difficult to ascertain if GER events are physiologic or pathologic in preterm infants, given the associations discussed previously. The so-called gold standard pH probe study underestimates reflux by not considering nonacid events, and results vary with probe position and infant position. No single test can ascertain all the elements of investigation in the neonate or infant, and no test can predict infants at risk for pathologic GER.Treatment of GERD may vary, depending on the specific symptom or sign requiring therapy. Understanding the underlying pathophysiology directs the selection of potential interventions. Recognizing the natural history of infant GER also alters management approaches. Despite the very high prevalence of administration of GER therapy in preterm infants, no good data support the efficacy of such therapy for any manifestation of GER. In addition, data about drug metabolism, adverse effects, or dosing range of any of the pharmacologic agents employed to manage acid suppression or promote motility are lacking.In neonates and high-risk infants, provoking factors such as frequent suctioning, chest physical therapy, and supine positioning have been associated with increased reflux episodes. The use of xanthines and beta mimetic agents may increase LES relaxation and, therefore, increase reflux episodes, (49) although most studies have not shown substantial differences in GER parameters in symptomatic infants receiving these agents. (34)(50) It is reasonable to attempt to use lower doses of these agents when required.Placement of the infant in the supine, right lateral, infant car seat position (upright position in a car seat) increases reflux frequency; prone position with a 30-degree elevation and left lateral position are associated with fewer episodes of GER. (3)(51)(52) A recent study of 10 healthy preterm infants at 35 to 37 weeks PMA confirmed that infants in a right lateral position had significantly more GER, a higher proportion of liquid GER, and faster gastric emptying compared with infants studied in the left lateral position. (53) Although both prone and left-lateral positioning are recognized risk factors for sudden infant death syndrome, (54) preterm infants in the nursery usually are monitored. Prone or left-lateral positioning may be a useful therapy for any manifestation of GER with minimal risk in the monitored infant.Changes in the feeding composition, viscosity, and method of administration may be useful for treatment of GERD. There is evidence that cow’s milk allergy may present in term infants with vomiting that is indistinguishable from GERD. (55)(56) Therefore, a trial of a hydrolyzed formula can be considered in infants who exhibit irritability, vomiting, or other potential manifestations of GERD. Generally, a dramatic improvement is noted within 1 week. However, no elemental or semi-elemental formulas appropriately formulated for administration to the preterm infant are available. The potential nutritional consequences of using the available formulas must be balanced with any potential benefit of a time-limited formula trial. Administration of human versus formula milk has been shown to lead to subtle differences in the nature of GER episodes, with breastfed neonates having less esophageal acid exposure than formula-fed neonates (3.0 versus 8.3 min/hr), but no data have documented an advantage of human milk over formula for treatment of GER. (57)The use of formulas that the stomach empties more rapidly theoretically could decrease gastric distention, the number of TLESR episodes, and the number of GER episodes. However, there is no evidence that the use of formulas such as those containing medium-chain triglycerides or those that have decreased caloric density (both of which increase emptying rate) are useful for treatment of GERD in infants.GER episodes also may be reduced in term infants by increasing formula viscosity with added rice cereal, carob flour, or sodium alginate. (58)(59)(60)(61) However, these therapeutic approaches have not been evaluated systematically in preterm infants. The increased difficulties encountered with sucking and swallowing, combined with the potential for bezoar formation and other (unknown) effects of these therapies on other nutritional parameters make these approaches less attractive for use in preterm infants or sick infants until they have been studied carefully. In some cases, simply concentrating the formula to 24 or 27 kcal/oz may decrease gastric distention, which decreases the likelihood of GER while allowing adequate calorie delivery. Newer antiregurgitant formulas that contain starches that thicken upon acidification in the stomach are available for use in term infants. Such formulas could reduce GER episodes, but they have not been evaluated for efficacy or safety in preterm infants, and they are not formulated appropriately for routine use in preterm infants.The mode of formula delivery also may provide a therapeutic option for some infants who have GERD. The tendency for regurgitation and vomiting is reduced in older infants if feedings are administered by continual drip rather than by bolus. This technique has been used as a short-term bridge to promote growth in infants who have GER and growth failure until the problems of GER lessen. (62) Furthermore, continual jejunal tube feeding markedly reduces the risk of feeding aspiration in infants who have pulmonary symptoms from swallowing dysfunction and GER. (63) However, because a nasogastric tube increases the number of episodes of GER in preterm infants, use of chronic indwelling nasogastric or nasojejunal tubes actually could increase GER events and worsen problems such as esophagitis. (64) Strategies for intermittent orogastric tube placement with feedings and its removal after feedings may minimize GER events. There are no data on the relative risks and benefits of continual drip nasogastric or transpyloric feedings in reducing GER-associated symptoms in preterm infants.No pharmacologic agents have been evaluated carefully for the treatment of GERD in the preterm infant. The impact of known developmental changes in drug metabolism and potential differences in therapeutic targets may alter the therapeutic efficacy, appropriate dose, and safety profiles of these agents at different postgestational ages. No good data are available to guide prescription of these agents in the preterm infant, and their use in preterm infants without good evidence that GER is causing symptoms must be carefully balanced with unknown risks. The potential pharmacologic agents include: prokinetics, acid-suppression agents, and acid-neutralizing agents.Prokinetics increase gastrointestinal motility and favor aboral transit of a bolus through the esophagus. They also may increase esophageal clearance reflexes and theoretically would be useful to decrease the volume and frequency of refluxed gastric contents. None of these agents has been evaluated for efficacy of GER therapy in preterm infants. Metoclopramide has undergone pharmacokinetic study in infants of 31 weeks’ gestational age. (65) Only cisapride had appeared to be somewhat effective in reducing GER symptoms in term and older infants, (1) but a recent review suggests that publication bias accounted for this interpretation. (66) Erythromycin has no effect on the esophageal motility or on the LES, but it may improve gastroduodenal contractility in preterm infants older than 33 weeks PMA (67) and improve gastric emptying in selected cases among older children. (68) However, it has been associated with an increased incidence of infantile hypertrophic pyloric stenosis. (69)(70) Neurologic adverse effects of bethanechol (71) and metoclopramide (72)(73) have been demonstrated in older infants. Cisapride has been withdrawn from distribution in most of the world due to concerns about cardiac arrhythmia risks. In view of the lack of proven efficacy of any of these agents and the proven risks associated with each, none can be recommended for the treatment of term or preterm infants with GERD without direct evidence that GER is the cause of clinical manifestations.H 2 receptor-antagonists (H 2-RAs) and PPIs are both effective acid-reducing agents. H 2-RAs act by inhibiting the H 2 receptors, thus limiting the interaction of histamine released from the histamine-secreting mast cells. A recent double-blind, placebo-controlled trial of famotidine therapy in 1- to 11-month-old infants who had GER showed reduced numbers of regurgitation episodes and decreased crying time in infants treated with doses of 1 mg/kg per day, but many infants experienced neurologic adverse effects, including increased irritability, anorexia, and somnolence. (74)Kelly and associates (24) and Kuusela and colleagues (75) studied the pharmacokinetics of ranitidine in preterm infants. The effect of a single dose lasted longer in preterm infants than in term infants. The time needed for reaching maximum gastric pH was significantly longer in preterm than in term infants. The correlation of ranitidine dose with the duration of increased gastric pH was dose-dependent in both preterm and term infants. The optimal dose of ranitidine for preterm infants is 0.5 mg/kg of body weight BID and for term infants is 1.5 mg/kg of body weight TID. (75) Kelly and associates (24) found that a 0.0625-mg/kg per hour infusion of ranitidine was sufficient to ensure a gastric pH higher than 4 and prevent stress ulcers or bowel perforation in dexamethasone-treated infants who had BPD. Similar findings of differences in infant and older child pharmacokinetics are reported for famotidine, (76) but studies have not been performed in preterm infants. Although the pharmacokinetics of ranitidine have been studied in the preterm infant, no data demonstrate its efficacy for GERD in preterm infants.It is logical to assume that reduction of gastric pH would be useful for therapy of esophagitis, but symptoms are not a reliable method for determining the possible risk for esophagitis. If esophageal pH monitoring shows increased esophageal acid exposure or if esophagoscopy and biopsy suggest esophagitis due to GERD, ranitidine would be a reasonable therapeutic option. Use of these agents to treat airway symptoms, irritability, or feeding intolerance lacks any supportive data.These agents have become increasingly popular for GERD therapy because of their superior acid-reducing effect during short- and long-term therapy. PPIs act by irreversibly inhibiting H +/K +-ATPase in the parietal cell. Of the PPIs, omeprazole has been studied the most in infants. (77)(78) PPIs are metabolized by the cytochrome P450 (CYP) pathway, primarily by the CYP 2C19 enzyme. A genetically determined defect in this pathway results in impaired metabolism of PPIs, giving rise to three distinct phenotypes: fast, medium, and slow metabolizers. The incidence of mutant alleles in patients treated for acid-related disorders may influence the efficacy of treatment or toxicity, with resulting clinical implications for the prescribers of PPIs. Although there was no association between genotype and pharmacokinetics of omeprazole, the metabolism of these agents in preterm infants has not been studied, and increased variability in metabolism is expected in these infants. (79)(80)(81) No studies have evaluated the pharmacokinetics, safety, or efficacy of any PPI agent in the preterm infant.Profound gastric acid reduction theoretically could have negative consequences in the preterm infant. These may include: 1) promotion of small bowel bacterial overgrowth because bacterial clearance by the migrating motor complex is deficient until about 36 weeks PMA, 2) an increased risk of hypertrophic pyloric stenosis due to increased serum gastrin, and 3) altered digestion due to decreased activity of acid-dependent gastric and lingual lipases. These theoretical negative consequences combined with a lack of data on the efficacy, safety, dosing, pharmacokinetics, metabolism, and long-term safety of PPIs in preterm infants argues against their use except in cases clearly demonstrated to be due to GERD that are not responsive to H 2-RA therapy.No antacid medication should be used routinely in preterm neonates because of complications such as constipation (calcium- and aluminum-containing antacids) or diarrhea (magnesium-containing antacids) and metabolic bone disease, particularly with aluminum-containing antacids, which bind phosphate. (82)There is no general consensus among neonatologists, gastroenterologists, or surgeons about the indications or appropriate timing for antireflux surgery in infants. Surgery for pathologic GER often is considered for neonates and young infants when conservative and medical therapy fails and sequelae and complications from GER are anticipated. In the preterm infant who is likely to be at reduced risk of GER complications with maturation and growth, it is reasonable to avoid surgical intervention except when severe complications ensue. Consequences of fundoplication may include breakdown of the wrap, small bowel obstruction, gas bloat syndrome, and dumping syndrome. The potential risks and long-term consequences of surgery must be balanced with the risks of medical therapy. Often, the use of nasogastric or nasojejunal feeding provides an alternative approach that prevents the need for early surgical intervention.Physiologic GER may be a maturational phenomenon that infants outgrow over time. Many aspects of GERD in neonates and young infants remain incompletely understood, particularly the true incidence of meaningful disease and the approach to delineating which infants benefit from therapy. The safety, efficacy, and appropriate selection of the best therapy for each specific GERD presentation remain unclear. Although most infants improve with conservative therapy, some clearly benefit from GER therapy. New methods to define whether GER is causing disease in a specific patient are needed to prevent the continued use of untested, unproven therapies for GER in the preterm infant.