Gastroesophageal Reflux in the Preterm Neonate

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 medical or GER suggesting that chronic GER may cause disease. In addition, patients who have also have suggesting that even small episodes of of gastric contents may it reasonable to that GER may disease in preterm infants who have airway protective and associates the relationship of GER and in preterm infants and found less reflux into the esophagus in those who had compared with those who did and (11) outcomes in infants born 32 weeks’ 137 symptomatic infants underwent esophageal pH monitoring with abnormal findings reported in more than in the incidence of GER was observed in infants who had as at 28 compared with those The observed a incidence of as an at 36 weeks found no between infants with or GER. In another retrospective and noted that GER was and treated more in preterm infants who had compared with other infants. However, the for were on a clinical of GER and response to GER did not growth or the suggested that the observed association of GER and was likely due to an increased diagnostic of GER in infants who had and associates (17) showed that the mechanisms of GER were similar in healthy infants and those who had with of GER events being due to Thus, the current data do not show a clear causal relationship of GER and disease in preterm infants. study in preterm infants has or improvement of with any treatment for GER. However, because treatment often is because of a of it is possible that GER may be a in some and associates have the associated with GER events in infants and often is a symptom of GER in infants, a recent study showed no in symptom improvement in infants treated with a to esophageal acid compared with infants. Furthermore, and observed that common behavioral characteristics observed in older infants, such as and were not specific for acid GER events in healthy preterm infants. and associates the GERD for older infants and changes in behavioral following cisapride versus in preterm infants who had increased gastric and were for GER and gastric The symptoms in this were poor weight gain, apnea or choking, or were no in the behavioral symptom or in gastric with cisapride therapy compared with these findings showed no of symptoms as a of GER and no response to medical indicating that of purported GER symptoms is not for GER in preterm in a retrospective study compared preterm infants with GER and infants who were for gestational and of was no in in or between the groups. However, the time for full oral length of and PMA at were significantly in the GER another infants who underwent a pH study to GER were into three normal of GER of to and GER is the of time the esophagus is to a pH of less than during a period. The or treatment including gestational or between the groups were who had and GER had significantly more clinical GER. who had reflux of more than also had more respiratory a lower and length of it is not clear that GER caused these symptoms or the infants had acid showing in are to support a causal healthy infants and have episodes of GER. It is to for GER complications should be to evaluate the relationship of a specific and It also is to and infants at increased for GERD due to underlying an healthy infant who to feed and has no respiratory regurgitation should be as a normal that with maturation any This is the for most preterm infants. the other infants who recurrent or regurgitation associated with feeding, or may have GERD to these However, as noted the association of GERD with any symptom in preterm infants is and all symptoms of GER may result from other disorders, it to other diagnostic and must be (1) and such as esophageal or or hiatus diaphragmatic and of acid and abnormalities of the also should be of diagnostic is to the of GER being the cause of disease. The diagnostic the that GER is causing a specific symptom or and the of in most no a of and the of a to treatment response in preterm infants has not been in any for the evaluation of possible GERD in the period and are in the pH monitoring is by a pH into the esophagus and the time of acid in the esophagus. Episodes of GER decrease the pH in the esophagus when gastric contents the In preterm infants, frequent feeding gastric and of acid GER may be less the LES and esophageal the is not in The esophageal length may be estimated using The is into the stomach and the pH is not and the is with However, all such also result in an and the of the measured the of the infant during the of in the stomach and to feeding or feeding or of the esophagus on when the is and when normal are not in preterm infants. the temporal is the from a study to may the of reflux events during physiologic such as feeding, and as well as changes in of and it is to the physiologic for a meaningful of the Furthermore, postprandial feeding of or may the gastric pH therefore, or reflux esophageal pH study reflux frequency reflux or the of the that the esophageal pH is less than of each reflux number of episodes than and of the It is to that normal are for term infants and that these to preterm infants has not been Furthermore, the upper of normal for the reflux in term infants is higher than the normal for of esophageal pH monitoring studies in older and on the number of episodes than and the of the episode esophageal clearance esophageal clearance the infant at for to be a higher of complications of GERD in older infants and esophageal pH monitoring results are apnea is to GER is when using esophageal pH monitoring because of the response time of the In addition, the infant should not be or 2 receptor antagonists for at to the The of esophageal pH monitoring as a of treatment response or has to be in preterm impedance monitoring a that through the esophagus. It allows of acid and nonacid GER events with no time requires and is very which makes clinical in most have not been in preterm or term infants. when nonacid reflux episodes are a temporal relationship between nonacid reflux and apnea be in preterm infants. (4) In older infants, of all apnea episodes within or after an episode of a relationship was not The of this to treatment response to GER therapies is not and a meaningful role in clinical has to be including esophageal or upper have been to and swallowing problems, and the presence of reflux. This has no role in the evaluation of GERD to other that may cause symptoms similar to those due to studies evaluation of events, and their with feeding may to the mechanism of GER or esophageal clearance and esophageal studies the characteristics of esophageal peristalsis, of sphincter to and reflux events, and mechanism of GER. These studies specialized and who are with the evaluation and The has no role in the evaluation of GERD in clinical with allows and evaluation of esophageal This requires and or and is of for the of It be in preterm infants by using that have of less than in between different causes of esophageal including GERD and or of these may occur in preterm infants, and the treatment therapy is administered to infants in GERD is Although this associated with diagnostic it is associated with other of the response to treatment is because there is a large In addition, appropriate and the of empiric medical therapy are not in the preterm is to that there is no to evaluate reflux in the preterm Furthermore, it is to GER events are physiologic or in preterm infants, the The pH study reflux by not nonacid events, and results with and infant all the of in the neonate or and no infants at for of GERD may on the specific symptom or the underlying the of the of infant GER also management the very prevalence of of GER therapy in preterm infants, no data support the efficacy of such therapy for any of GER. In addition, data about or dosing of any of the agents to acid or are neonates and infants, such as frequent and supine positioning have been associated with increased reflux episodes. The of and agents may LES therefore, reflux although most studies have not in GER in symptomatic infants these It is reasonable to attempt to lower of these agents when of the infant in the infant in a reflux prone with a and are associated with fewer episodes of GER. A recent study of 10 healthy preterm infants at to weeks PMA that infants in a had significantly more a higher of liquid and gastric compared with infants in the Although both prone and positioning are for infant preterm infants in the are or positioning may be a therapy for any of GER with in the in the feeding and of may be for treatment of is that may present in term infants with that is from a of a be in infants who or other of a improvement is noted within However, no or for to the preterm infant are The of using the must be with any of a of versus has been to to in the of GER with neonates having less esophageal acid than neonates versus no data have an of for treatment of GER. of that the stomach more could decrease gastric the number of TLESR and the number of GER episodes. However, there is no that the of such as those or those that have of which are for treatment of GERD in episodes also may be in term infants by with or However, these have not been in preterm infants. The increased with and swallowing, with the for and other of these therapies on other these less for in preterm infants or sick infants they have been In some simply the to or may decrease gastric which the of GER that contain that in the stomach are for in term infants. could GER they have not been for efficacy or safety in preterm infants, and they are not for in preterm of also may a for some infants who have The tendency for regurgitation and is in older infants are administered by than by This has been as a to growth in infants who have GER and growth failure the of GER Furthermore, feeding the of feeding in infants who have symptoms from swallowing and GER. However, because a the number of episodes of GER in preterm infants, of chronic or could GER events and such as for with and after may GER are no data on the and of or in symptoms in preterm agents have been carefully for the treatment of GERD in the preterm infant. The of changes in and in may the efficacy, appropriate and safety of these agents at different data are to of these agents in the preterm and their in preterm infants that GER is causing symptoms must be carefully with The agents agents, and and of a through the esophagus. They also may esophageal clearance reflexes and would be to decrease the volume and frequency of refluxed gastric of these agents has been for efficacy of GER therapy in preterm infants. has study in infants of weeks’ gestational cisapride had to be effective in GER symptoms in term and older infants, (1) a recent that for this has no on the esophageal or on the it may improve in preterm infants older than weeks PMA and improve gastric in older However, it has been associated with an increased incidence of of and have been in older infants. has been from in most of the due to about In of the lack of efficacy of any of these agents and the associated with be for the treatment of term or preterm infants with GERD that GER is the cause of clinical 2 (H and are both effective by the 2 the of histamine from the A recent of therapy in to infants who had GER showed of regurgitation episodes and time in infants treated with of infants including increased and and associates and and the of in preterm infants. The of a in preterm infants than in term infants. The time for gastric pH was significantly in preterm than in term infants. The of with the of increased gastric pH was in both preterm and term infants. The of for preterm infants is of weight and for term infants is of weight and associates found that a hour of was to a gastric pH higher than and prevent or in infants who had findings of in infant and older are reported for studies have not been in preterm infants. Although the of have been in the preterm no data efficacy for GERD in preterm is to that of gastric pH would be for therapy of esophagitis, symptoms are not a for the possible for esophageal pH monitoring increased esophageal acid or and due to would be a reasonable of these agents to treat airway symptoms, or feeding any agents have become for GERD therapy because of their superior during and by in the the has been the most in infants. are by the by the A in this results in of to three and The incidence of in patients treated for may the efficacy of treatment or with resulting clinical for the of Although there was no association between and of the of these agents in preterm infants has not been and increased in is in these infants. studies have the safety, or efficacy of any in the preterm gastric acid could have in the preterm infant. These may of small because clearance by the is about 36 weeks 2) an increased of due to increased and due to of gastric and These with a lack of data on the efficacy, safety, and safety of in preterm infants against their in to be due to GERD that are not to should be in preterm neonates because of complications such as and or and particularly with which is no or about the or appropriate for in infants. for GER often is for neonates and infants when and medical therapy and and complications from GER are In the preterm infant who is likely to be at of GER complications with maturation and it is reasonable to when complications of may of the small and The and of must be with the of medical the of or feeding an that prevents the for early GER may be a that infants of GERD in neonates and infants remain particularly the true incidence of meaningful disease and the to which infants from The safety, efficacy, and appropriate of the therapy for each specific GERD remain Although most infants improve with some from GER to define GER is causing disease in a specific are to prevent the of unproven therapies for GER in the preterm infant.