Gastroesophageal reflux in infants

INTRODUCTION — 

Gastroesophageal reflux (GER) is a normal physiologic process that occurs in healthy infants, children, and adults. Most episodes are brief and do not cause symptoms or esophageal injury or result in other complications. In contrast, gastroesophageal reflux disease (GERD) occurs when the reflux episodes are associated with complications such as esophagitis or poor weight gain. The range of symptoms and complications of GERD in children vary with the age of the child.

The diagnosis and management of GER in infants will be reviewed here. Reflux in premature infants, and the clinical manifestations, diagnosis, and pathophysiology of GERD in older children, are discussed separately. (See "Gastroesophageal reflux disease in children and adolescents: Clinical manifestations and diagnosis" and "Gastroesophageal reflux in premature infants" and "Gastroesophageal reflux disease in children and adolescents: Management".)

DEFINITIONS — 

Several terms related to gastroesophageal reflux are used inconsistently in the literature and in clinical practice. In this topic review, we will use the terms as follows:

●Gastroesophageal reflux (GER) – Refers to the passage of gastric contents into the esophagus.

●Uncomplicated GER – Specifies that the reflux is the normal physiologic process of frequent regurgitation and does not have pathologic consequences; this is sometimes called "simple" reflux.

●Gastroesophageal reflux disease (GERD) – Refers to reflux that has pathologic consequences, such as peptic esophagitis, esophageal strictures, nutritional compromise with weight loss, or respiratory complications.

●Regurgitation – Describes effortless reflux up to the oropharynx or above. We use this term to refer to obvious GER, whether or not the refluxate comes outside of the mouth; other commonly used terms are "spitting up" or "spilling."

●Vomiting – Describes forceful expulsion (engaging abdominal and respiratory muscles) of the refluxate out of the mouth but not necessarily repetitively.

●Rumination – Refers to voluntary regurgitation of stomach contents into the mouth or esophagus for self-stimulation; it may present at any age including in infants [1,2]. (See "Approach to the infant or child with nausea and vomiting", section on 'Rumination syndrome'.)

EPIDEMIOLOGY

●Natural history – GER is extremely common in healthy infants, in whom gastric contents may reflux into the esophagus 30 or more times daily [3]. Many, but not all, of these reflux episodes result in regurgitation into the oral cavity. The frequency of reflux, as well as the proportion of reflux episodes that result in regurgitation, declines with increasing age, such that physiologic regurgitation or vomiting diminishes toward the end of the first year of life and is unusual in children older than 18 months old [4-6].

Conditions such as cow's milk intolerance and functional gastrointestinal disease (colic or rumination) may present with symptoms very similar to those seen in infants with GER (figure 1) [7]. Management of the reflux includes clinical assessment for these conditions and, in some cases, empiric treatment trials. (See 'Initial evaluation' below.)

In one study of healthy infants, regurgitation at least once per day was reported in approximately 50 percent of infants younger than three months, compared with only 5 percent of those between 10 and 12 months of age [8]. Regurgitation was most common around four months (61 percent), decreasing to 21 percent between six and seven months. The description of regurgitation as a "problem" peaked at 23 percent of parents of children aged six months and decreased thereafter. In almost all children with regurgitation, the condition begins to improve after six months of age and usually resolves by the end of the first year of life [9].

●Association of infant reflux with later complications – Limited evidence suggests that frequent episodes of regurgitation during infancy may be associated with a somewhat increased likelihood of having gastroesophageal reflux disease (GERD) symptoms in later childhood. In a study of 693 children, those who had a history of frequent regurgitation (defined as >90 days of "spilling" during the first two years of life) were significantly more likely to report GERD symptoms during follow-up at approximately nine years of age (relative risk 2.3, 95% CI 1.3-4.0) [10].

GERD occasionally leads to respiratory complications (recurrent pneumonia and bronchiectasis), esophageal strictures, or Barrett esophagus. These complications occur primarily in children with underlying neurologic dysfunction, esophageal dysmotility (eg, secondary to repaired esophageal atresia), or cystic fibrosis. (See "Gastroesophageal reflux disease in children and adolescents: Clinical manifestations and diagnosis", section on 'Epidemiology and natural history'.)

The prevalence and clinical risk factors for GERD in children are discussed in a separate topic review. (See "Gastroesophageal reflux disease in children and adolescents: Clinical manifestations and diagnosis", section on 'Epidemiology and natural history'.)

INITIAL EVALUATION — 

The evaluation of an infant with frequent regurgitation involves determining if the symptom is caused by underlying pathologic disease and if the reflux is causing secondary complications. In the majority of infants, a focused history and physical examination will confirm that the reflux is uncomplicated and little further evaluation or intervention is required.

The first step in the evaluation is to determine if the infant has any alarm signs that suggest gastroesophageal reflux disease (GERD) or an underlying gastrointestinal, neurologic, or systemic disease, as outlined below [11,12].

Signs suggesting possible GERD (complicated reflux) — The following signs are nonspecific but can be presenting symptoms of GERD (as opposed to symptoms that might suggest other diseases):

●Poor growth

●Marked irritability with symptoms suggesting esophageal pain (temporal association or posturing with reflux events) and/or blood-tinged refluxate

●Respiratory symptoms (in infants with conditions that predispose to aspiration)

Infants with one or more of these presentations warrant further evaluation, tailored to the symptoms, as described below. (See 'Infants with possible GERD' below.)

Alarm signs suggesting other underlying pathology — Alarm signs suggesting another underlying pathology are listed in the table (table 1). In some cases, affected infants may also have reflux, which may be unrelated to the underlying disorder. A more extensive differential diagnosis of vomiting is outlined in this table (table 2). Refer to related UpToDate content for guidance on evaluation and diagnosis of individual disorders. (See "Approach to the infant or child with nausea and vomiting".)

Blood-tinged stools are a relatively common finding in infants and are usually associated with diagnoses unrelated to GERD. In particular, food protein intolerance (usually related to milk and/or soy) typically presents with mild rectal bleeding (caused by proctocolitis); it is somewhat more likely in infants with eczema or a strong family history of atopic disease. Some affected infants also have reflux, but, in most cases, the reflux is uncomplicated and does not warrant specific intervention (see 'Infants with uncomplicated reflux' below). Management of suspected food protein-induced proctocolitis generally includes a cow's milk-free diet, as described separately. (See "Food protein-induced allergic proctocolitis of infancy".)

An anal fissure is another common cause of rectal bleeding in infants. Assessment of the stool and careful examination of the rectum can help to distinguish between an anal fissure and food protein-induced proctocolitis. In food protein-induced proctocolitis, the stool often has mucus, along with a "string-like" appearance, unlike the bright red blood seen with a fissure or ulceration. To look for an anal fissure, careful inspection of the anal canal with good lighting is necessary.

Diarrhea and/or very bloody stools suggest a more severe colitis and warrant evaluation for infectious causes, immune dysregulation, or very early-onset inflammatory bowel disease. (See "Lower gastrointestinal bleeding in children: Causes and diagnostic approach".)

DIAGNOSTIC TESTS FOR SELECTED PATIENTS — 

The diagnosis of uncomplicated GER is generally based on clinical evaluation and does not require specific testing (algorithm 1). Similarly, a provisional diagnosis of gastroesophageal reflux disease (GERD) usually can be made based on presenting symptoms and excluding other causes.

For a minority of infants with suspected GERD, one or more of the following tests may be needed to clarify the diagnosis, either during the initial evaluation or if the diagnosis remains unclear after a trial of empiric acid suppression. (See 'Management' below.)

Esophageal pH and impedance monitoring — Esophageal reflux can be quantified by an esophageal pH and multichannel intraluminal impedance (pH-MII) monitoring study.

●Indications – These studies rarely are useful in evaluating GER or establishing the diagnosis of GERD in infants. This is because physiologic reflux is very common in infants and there is only a weak association between abnormal results of esophageal monitoring and the presence of reflux complications (ie, GERD) in this age group [13-15]. Moreover, there are no established pH and MII criteria for diagnosing GERD in infants or children. Furthermore, clinical symptoms sometimes attributed to GER in young infants, such as irritability, apnea, bradycardia, or episodes of oxygen desaturation, correlate poorly with reflux events [14].

Despite these limitations, these studies may be useful in selected situations, such as infants with discrete episodes of severe symptoms (eg, apnea, bradycardia, cough, oxygen desaturation). In this context, they are used in conjunction with monitoring of respirations, heart rate, or oxygen saturation to determine whether there is a temporal relationship between episodes of reflux and these specific events [15] (see 'Irritability with symptoms suggesting esophageal pain' below). Esophageal pH-MII monitoring can also be used to assess the adequacy of acid suppression therapy, eg, in patients with a history of GERD who have persistent symptoms.

●Technique – To monitor esophageal reflux, the ideal technique is to measure both esophageal pH and MII on a single device and record for 24 hours [15]. While pH monitoring alone is able to detect the presence of acidic refluxate in the esophagus, the addition of MII can detect reflux events regardless of pH and also measures the proximal extent of each reflux event. Infants and children with wheezing or coughing that occurs during sleep or when lying down may have nonacid reflux that can be identified by MII. (See "Gastroesophageal reflux disease in children and adolescents: Clinical manifestations and diagnosis", section on 'Esophageal pH monitoring or impedance monitoring'.)

Alternative forms of pH monitoring, such as wireless pH testing, are not approved for use children under the age of four years.

Imaging

●Abdominal ultrasound – Infants with persistent forceful vomiting developing during the first few months of life should be evaluated first with an abdominal ultrasound to look for pyloric stenosis, anatomic abnormalities, and other causes of vomiting including ureteropelvic junction obstruction. (See "Infantile hypertrophic pyloric stenosis".)

●Contrast study – An upper gastrointestinal contrast study ("upper GI series") is not necessary or helpful for the routine evaluation of infants with GER [11,12]. This is because the study does not reflect the frequency of reflux under physiologic conditions and infants with and without GERD may have reflux episodes observed during the study.

In selected cases, such as infants with bilious vomiting, feeding difficulties, or poor weight gain, an upper gastrointestinal contrast study may be helpful to identify anatomic abnormalities such as esophageal stenosis or achalasia, malrotation, antral web, annular pancreas, or ectopic pancreatic tissue (which is typically found in the distal stomach) [16].

●Conventional radiograph – A conventional plain abdominal radiograph has no role in the routine evaluation of an infant with reflux. However, it is an appropriate first step for an infant with signs or symptoms of intestinal obstruction, including abdominal distention or bilious vomiting.

Endoscopy — Upper endoscopy may be helpful for the evaluation of infants who have not responded to empiric treatment trials for GERD and/or those who are suspected of having dietary protein intolerance that remains problematic despite a trial of eliminating cow's milk and soy proteins from the diet.

When endoscopy is performed, biopsies of the esophagus, stomach, or duodenum should be taken because they can reveal clinically significant diseases even when the gross appearance of the mucosa is normal. In addition to providing evidence about GERD, biopsies also may reveal inflammation characteristic of dietary protein intolerance (often termed "allergy") or other systemic disorders.

The results of the biopsies must be interpreted in the context of the infant's clinical presentation, and mild histologic abnormalities may not be clinically significant. Approximately 25 percent of infants undergoing endoscopy have some evidence of esophageal inflammation [17], and the histologic findings are poorly correlated with symptoms. As an example, in a study of 19 infants with histologic abnormalities including basal cell layer hyperplasia who were treated with placebo for one year as part of a randomized trial, over one-half displayed improvement or resolution of symptoms during the placebo treatment, despite the lack of improvement in the histology [18].

INFANTS WITH UNCOMPLICATED REFLUX

Clinical manifestations and diagnosis — In most infants, reflux occurs frequently but is physiologic and has no serious consequences. This is known as "uncomplicated" or "simple" reflux. Uncomplicated GER can be diagnosed in infants who have no alarm signs, have good growth and weight gain, are feeding well, are not unusually irritable, and have appropriate development and a normal physical examination [12,15]. Most infants presenting with frequent GER will fall into this category; they are sometimes referred to as "happy spitters." The history and physical examination usually are sufficient for establishing the diagnosis, and specific laboratory testing is not necessary.

Features that often concern parents and caregivers but are usually consistent with uncomplicated reflux include:

●Frequent and high-volume reflux – These features are generally benign as long as the infant has maintained normal growth and hydration status.

●"Vomiting" – It can be difficult for a parent or caregiver to distinguish between high-volume reflux and true vomiting (forceful expulsion that engages the abdominal and respiratory muscles). A clinician may be able to determine whether the infant has true vomiting by observing a feed and any related reflux events. True vomiting is also more likely in an infant who is ill-appearing and/or has poor weight gain, bilious vomiting, or features of pyloric stenosis (persistent and progressive forceful vomiting developing during the first few months of life).

●Irritability and/or sleep problems – Reflux often cooccurs with intermittent irritability or sleep problems because these are all common during infancy. Both problems can be stressful to parents or caregivers. In most infants, reflux is not painful and is not causing the irritability or sleep problems. Signs that warrant further investigation include severe irritability, poor weight gain, feeding refusal, or repetitive arching or turning of the neck (also known as Sandifer syndrome). If these signs are not present, management includes reassurance, monitoring, and counseling for handling the irritability and sleep complaints; changing the formula is not usually helpful. Following the patient will also help support the diagnosis of uncomplicated reflux because symptoms should improve over time.

●Choking or gagging – Occasionally, large-volume reflux can cause gagging, coughing, or laryngospasm. In most cases, these events are infrequent and resolve spontaneously. Rarely, this may cause an acute event with apnea and/or cyanosis (color change), which is categorized as a "brief resolved unexplained event" (BRUE). A BRUE can be frightening to the parent or caregiver and warrants an urgent evaluation; however, in most cases these events have no long-term consequences. While these events have been historically thought to be triggered by an episode of physiologic reflux, there is some evidence suggesting that oropharyngeal dysphagia with associated aspiration may be an alternative explanatory diagnosis [19,20]. (See "Acute events in infancy including brief resolved unexplained event (BRUE)".)

Management — For infants with uncomplicated reflux (no alarm signs), education and reassurance of the infant's parent(s) are appropriate. Lifestyle measures that may be helpful include breast milk feeds if possible, avoiding exposure to tobacco smoke, and avoiding overfeeding [5,15]. The clinician should specifically counsel the caregivers that all infants should be placed in the supine position for sleep, even if they have reflux. (See 'Measures for all infants' below and 'Information for patients' below.)

If the family's quality of life is affected by the infant's regurgitation, or if the infant has nasal congestion or difficulty sleeping because of regurgitation while supine, conservative measures to improve the symptoms may be worthwhile. These include a trial of thickened feeds, upright positioning after feeds, or a limited two-week trial of eliminating cow's milk and soy proteins from the diet (because intolerance of these proteins may cause reflux). (See 'Additional options for infants with GERD or problematic reflux' below.)

Infants with uncomplicated reflux should be reevaluated periodically for the evolution of other new symptoms or alarm signs. The regurgitation usually resolves by one year of age. It is not uncommon for children who have GER to consume additional calories to compensate for losses. As reflux resolves, the compensated eating habits may persist, resulting in increased weight gain. For this reason, monitoring weight and growth is important to avoid excessive weight gain. If the symptoms worsen or do not improve by the time the child is 18 to 24 months of age, they should be reevaluated for a comorbid condition, and, if possible, a pediatric gastroenterologist should be consulted. (See "Gastroesophageal reflux disease in children and adolescents: Clinical manifestations and diagnosis".)

INFANTS WITH POSSIBLE GERD

Clinical manifestations and differential diagnosis — For infants with signs of possible gastroesophageal reflux disease (GERD; poor weight gain, severe irritability, or blood-tinged refluxate) but without alarm signs suggesting other underlying pathology (table 1), the next step is a more focused evaluation to determine if the symptoms are caused by a disorder other than GERD. The initial evaluation, management, and differential diagnosis depend on the type and severity of associated symptoms, as shown in the algorithm (algorithm 1) and detailed below.

Poor growth — Poor growth due to insufficient caloric intake typically presents with poor weight gain and low weight for height. Evaluation of an infant with poor growth is discussed separately. (See "Poor weight gain in children younger than two years in resource-abundant settings: Etiology and evaluation", section on 'Definitions'.)

Poor weight gain is occasionally caused by GERD, if the reflux is high volume and the infant is unable to retain sufficient nutrition for growth. Such infants typically have large reflux events after every meal. Because estimates of the regurgitated volume are inherently imprecise, this is a diagnosis of exclusion. Hence, these infants should have a focused evaluation to determine if something other than reflux is causing (or contributing to) the poor weight gain. Key considerations include:

●Pyloric stenosis – Presents with persistent forceful vomiting in a young infant.

●Food protein-induced gastrointestinal disease – Food protein-induced enterocolitis syndrome (FPIES) or enteropathy typically present with vomiting, diarrhea, and poor weight gain.

●Insufficient intake – This can be due to breastfeeding problems (eg, insufficient milk production), food insecurity (eg, insufficient or improper formula preparation), or other family stressors that interfere with feeding.

●Celiac disease – Develops in older infants after introduction of gluten-containing foods.

The differential diagnosis and evaluation of an infant with poor weight gain are discussed in detail separately. (See "Poor weight gain in children younger than two years in resource-abundant settings: Etiology and evaluation".)

If other causes are initially excluded, the infant can be given a provisional diagnosis of GERD and managed accordingly with treatment trials (see 'Management' below). However, they should be followed closely and may warrant further evaluation if symptoms and weight gain do not improve.

Irritability with symptoms suggesting esophageal pain — Irritability and disturbed sleep in infants are nonspecific symptoms that can be caused by a variety of nonpathologic and pathologic conditions. In general, irritability is unlikely to be related to reflux unless there are additional symptoms:

●Isolated irritability – Even in an infant with frequent regurgitation, there is little evidence suggesting that the reflux causes esophageal pain; the common belief that reflux causes pain in infants is largely extrapolated from studies in adults. A few studies have shown an association between reflux, as documented by esophageal pH monitoring or esophagitis, and measures of apparent discomfort [21]. However, multiple other studies have failed to demonstrate an association between irritability and acid reflux in infants [12,22]. In several placebo-controlled trials of infants presenting with irritability, acid suppression had no effect on symptoms [23-25]. (See 'No role for most infants' below.)

●Possible signs of esophageal pain – Irritability is more likely to be caused by GERD if the symptom consistently occurs when the infant is regurgitating (ideally documented with esophageal pH and multichannel intraluminal impedance [pH-MII] monitoring). Particularly suggestive is the symptom complex of arching of the back, torsion of the neck, and lifting up of the chin, known as Sandifer syndrome; this posturing can be confused with torticollis or seizures. In infants presenting with these symptoms, a careful history should be taken to exclude causes other than reflux. (See "Acquired torticollis in children".)

Feeding refusal is occasionally, but not commonly, caused by GERD. A variety of other disorders, including eosinophilic esophagitis (also rare in infants), can cause feeding refusal, and diagnostic testing should depend on associated symptoms. A distal ring or web causing esophageal narrowing also could cause feeding refusal (see 'Diagnostic tests for selected patients' above). If a strong suspicion for GERD remains, the evaluation and treatment are similar to that for an infant with reflux and Sandifer syndrome.

Blood-tinged refluxate (hematemesis) can be a symptom of esophagitis [26]. In a series of 113 infants, hematemesis was the only sign that significantly correlated with histologic esophagitis [27]. Hematemesis also may occur with pyloric stenosis and cow's milk allergy.

●Sleep disturbance – If sleep disturbance is a prominent complaint, the family may benefit from counseling about establishing healthy sleep patterns in the infant. (See "Behavioral sleep problems in children", section on 'Young children with behavioral insomnia'.)

Respiratory symptoms (in infants with predisposing conditions)

●Infants without predisposing conditions – In healthy infants, respiratory symptoms, including recurrent stridor, chronic cough, recurrent pneumonia, and recurrent wheezing, are unlikely to be caused by GERD and should prompt an evaluation for other causes. (See "Assessment of stridor in children" and "Approach to chronic cough in children" and "Approach to the child with recurrent infections".)

In particular, persistent wheezing in an otherwise healthy infant is unlikely to be caused by GERD. Associations between persistent wheezing and GERD have been demonstrated in adults and in some groups of children, but there is little evidence for this association in infants, except for a few nonrandomized studies [28,29]. Acute or intermittent wheezing is usually caused by a viral infection. Persistent wheezing is more likely to be related to a congenital airway anomaly, hypogammaglobulinemia, or cystic fibrosis. Foreign body aspiration should be considered if the symptoms had abrupt onset. (See "Evaluation of wheezing in infants and children".)

●Infants with predisposing conditions – By contrast, respiratory symptoms (persistent wheezing, chronic cough, or recurrent pneumonia) are more likely to be related to GERD in infants with predisposing conditions, including neurologic problems that cause swallowing dysfunction, anatomic anomalies that cause aspiration (eg, laryngotracheal cleft or tracheoesophageal fistula), and/or esophageal dysmotility. For these infants, the evaluation focuses on identifying the underlying condition; whether it is causing aspiration; and whether the aspiration is antegrade (upon swallowing), retrograde (upon reflux), or both. Once that is known, management is tailored to the infant's specific problem and may include thickened feeds and/or other antireflux measures, outlined below. (See "Aspiration due to swallowing dysfunction in children".)

Management

Overview — For infants with suspected GERD, management typically involves one or more of the following interventions (algorithm 1):

●All infants – Human milk feeding if possible; avoid tobacco smoke exposure and avoid overfeeding; pause feeding to "burp" the infant to eliminate intragastric gas. (See 'Measures for all infants' below.)

●Selected infants – Treatment trials selected by presenting symptoms (see 'Additional options for infants with GERD or problematic reflux' below):

•Thickening feeds and upright positioning after feeds. (See 'Thickening feeds' below and 'Positioning therapy' below.)

•Increasing the caloric density of the expressed milk or formula – For infants with poor weight gain. (See "Poor weight gain in children younger than two years in resource-abundant settings: Management", section on 'Strategies to increase intake'.)

•Cow's milk- and soy-free diet – Especially appropriate for infants with blood-tinged stools, eczema, or family history of atopic disease but can be trialed in any infant with suspected GERD. (See 'Avoidance of cow's milk and soy protein' below.)

•Limited trial of acid-suppressing medication – This intervention should be reserved for infants with problematic reflux who do not respond to the above conservative measures, especially if they have posturing suggesting esophageal pain. (See 'Treatment for selected infants' below.)

If an infant fails to respond to these treatment trials or is ill-appearing, evaluation with upper endoscopy or imaging may be appropriate. Further treatment depends on the findings. (See 'Endoscopy' above and 'Imaging' above.)

Measures for all infants — The following measures are appropriate for all infants with reflux. These measures may have modest benefits on GER symptoms, in addition to other benefits.

●Breast milk versus formula feeding – For infants with GER who are breastfed, continuation of breastfeeding should be encouraged if practicable. In addition to other health benefits, breastfeeding may have a protective effect on regurgitation in infants, based on limited data [30,31]. As an example, breastfed neonates (age two to eight days) experience less nocturnal esophageal acid exposure compared with formula-fed neonates [30]. Mechanisms for this protective effect of breastfeeding might include differences in gastric emptying or differential exposure of infants with a cow's milk protein intolerance, but these possibilities have not been formally evaluated. Other benefits of breastfeeding are described separately. (See "Infant benefits of breastfeeding".)

●Avoid overfeeding – Because gastric distension contributes to uncomplicated reflux, providing smaller feedings often reduces the frequency or quantity of reflux. The clinician should provide advice to ensure that the infant is not overfed. In general, this is most relevant for infants who are bottle fed (with either formula or breast milk). For infants with suboptimal weight gain, it may help to provide smaller but more frequent feedings and/or to concentrate the formula.

●Avoid tobacco smoke exposure – The clinician should counsel all families/caregivers to avoid exposing the infant to tobacco smoke [5]. Tobacco smoke (specifically, nicotine) is known to lower esophageal sphincter pressure and to promote GER in adults. In addition, a study in infants found that those with perinatal exposure to tobacco smoke had significantly more frequent reflux events, as measured by esophageal impedance testing, compared with unexposed infants [32]. Avoidance of exposure to tobacco smoke has many other benefits to the infant's health. Important measures to avoid smoke exposure include smoking bans in the home and car and guidance to support smoking cessation for household members. (See "Secondhand smoke exposure: Effects in children" and "Control of secondhand smoke exposure".)

Additional options for infants with GERD or problematic reflux — Several additional interventions may be trialed for infants with GERD or for those with uncomplicated reflux if the symptoms are distressing to the family. Although the efficacy of lifestyle changes varies with the intervention and among patients, the risks are low, so empiric trials are appropriate, provided that they do not interfere with breastfeeding or unduly burden the family. In one study of 50 infants with problematic reflux, a two-week trial of combined lifestyle changes (thickened feeds, antireflux positioning, milk-free diet, and tobacco smoke avoidance) improved symptoms substantially in nearly 60 percent and resolved in nearly 25 percent [33].

Thickening feeds

●Candidates – A trial of thickening feeds is worthwhile for some infants with problematic reflux. Thickening feeds is rarely appropriate for breastfed infants because it would require expressing breast milk, the modest potential benefit may not warrant the inconvenience, and some thickeners are not effective in breast milk [34]. Breastfeeding should not be stopped for the purposes of thickening feeds. Thickening feeds also may not be appropriate for infants who are either preterm or overweight. Thickening feeds is also a key intervention for infants with swallowing dysfunction. (See "Aspiration due to swallowing dysfunction in children".)

●Efficacy – Thickening feeds appears to modestly improve some of the symptoms and objective measures of reflux frequency [35-37]. In a meta-analysis of eight studies, thickened feeds significantly reduced the frequency of emesis [37]. There is no direct evidence to suggest that this symptomatic improvement corresponds to a decreased incidence of reflux-related pathology, such as esophagitis [12].

●Thickener type – The impact of both starch- and gum-based thickeners on viscosity can be variable in both formula and breast milk. Acid in the stomach may change the composition of breast milk thickened with gum-based thickeners. Moreover, starch-based thickeners including cereal may not effectively thicken human milk [34]. Standard formulas or expressed breast milk usually are thickened by adding oat infant cereal, up to 1 tablespoon of dry cereal per ounce of formula. Although rice cereal has traditionally been used for this purpose, oat cereal is now preferred because of concerns about possible contamination of rice cereal with arsenic [38,39]. In 2020, the US Food and Drug Administration (FDA) issued an updated statement on arsenic in infant cereal [40]. It may be necessary to select an appropriate nipple for the bottle to permit adequate flow of the thickened formula [41]. Premixed formulas thickened with rice starch are available in some countries including the United States (called "antireflux" or "spit-up" formulas). The efficacy of such prethickened formulas has not been extensively evaluated, but they appear to decrease regurgitation and esophageal acid exposure [42,43].

●Dietary impact – Thickening of feeds with cereal can increase the caloric density of the formula, which may help infants who are underweight as a result of having GERD but is not desirable in those who are overweight. The caloric density of 1 ounce of formula thickened with 1 tablespoonful of oat cereal is approximately 34 kcal per ounce (1 tablespoon per 2 ounces of formula provides a caloric density of 27 kcal per ounce). The caloric densities of formulas thickened with other substances vary. Providers and families should be alert for signs of excessive weight gain in infants fed thickened formulas and should discontinue formula thickening as soon as it is no longer needed to control reflux symptoms.

●Safety – Thickening formulas with cereal appears to be safe, although one study suggested that these children may experience increased coughing during feedings [44]. In addition, concerns have been raised about the use of a thickening agent that contains xanthan gum ("SimplyThick") because of a possible association with necrotizing enterocolitis; both premature and term infants appear to be at risk. In 2011, the FDA issued a warning about the use of this thickening agent for infants [45]. (See "Gastroesophageal reflux in premature infants", section on 'Diet'.)

Positioning therapy

●Recommended positions – Keeping an infant upright (eg, on the shoulder of a caregiver who is standing or sitting) for 20 to 30 minutes after a feed seems to reduce the likelihood of regurgitation and can be attempted when practicable. For safety, the adult must be upright, awake, and alert; the infant should not sleep prone on a recumbent adult's chest.

All infants younger than 12 months of age should be placed in the supine position for sleep, on a flat surface, even if they have reflux. Elevation of the head of the crib is not recommended, because it has no effect on reflux for infants placed in the supine position [46-48] and also risks the infant sliding into an unsafe sleep position [49]. (See "Sudden infant death syndrome: Risk factors and risk reduction strategies", section on 'Sleep position'.)

●Not recommended – The following positions are not recommended for managing reflux in infants:

•Semisupine (infant seat) – Semisupine positioning is unlikely to be helpful because it increases reflux for some infants; moreover, it is also associated with oxygen desaturations in young infants and risk for sudden infant death syndrome (SIDS). For these reasons, car seats should not be routinely used for sleep outside of a car, although they are strongly recommended for car travel [49]. (See "Sudden infant death syndrome: Risk factors and risk reduction strategies", section on 'Sleep environment'.)

•Prone – Although the prone position tends to reduce reflux [50-52], it is also associated with a substantially higher risk for SIDS, and this risk outweighs the small possible beneficial effect of prone sleeping on reflux [11,12,53].

•Side – Lateral positioning for sleep is not recommended to treat reflux in infants, primarily because side positioning is associated with an increased risk for SIDS [49,54]. Moreover, studies in young infants are inconsistent about the effect of side positioning on reflux [50,55].

Avoidance of cow's milk and soy protein

●Candidates – We suggest an empiric trial of removing all cow's milk (and possibly soy) from the diet for infants with problematic GER, especially if there are additional symptoms suggesting cow's milk protein intolerance, such as gross or occult blood in the stool, eczema, a strong family history of atopy, or poor weight gain. This is because the symptoms of food protein intolerance (typically to cow's milk) sometimes mimic GERD [12]. As an example, some studies report that up to 40 percent of infants with problematic GER have a food protein intolerance [56-58]. The majority of these infants will be sensitive to cow's milk protein alone, but a substantial number are also sensitive to soy proteins.

●Implementation in breastfed infants – Breastfed infants can be treated with careful elimination of all cow's milk proteins from the mother's diet. Major sources of soy protein may need to be eliminated as well. The response to this change is often more delayed than in formula-fed infants because it takes some time to eliminate the offending protein from breast milk and small amounts of milk protein may be found in other foods. These diets are difficult, and adherence to the diet may become a burden over time. Some families may have improved compliance if a partner or close family member commits to taking the same diet, for convenience and to provide support. (See "Food protein-induced allergic proctocolitis of infancy", section on 'Management'.)

●Implementation in formula-fed infants – In formula-fed infants, we suggest switching to an extensively hydrolyzed formula (often marketed as "hypoallergenic") (table 3). Because a significant number of affected infants are sensitive to soy instead of or in addition to cow's milk, substitution of soy-based formulas is not recommended. Similarly, lactose-free cow's milk-based formulas contain intact cow's milk protein and are not helpful [59]. Some infants may react to corn protein, which is found in some formulas. If there is a strong suspicion of a food protein intolerance (because of bloody stools or atopic symptoms) and the infant does not respond to a fully hydrolyzed formula, a trial of an amino acid-based ("elemental") formula or elimination of other dietary proteins may be necessary.

●Follow-up – Infants who respond to the dietary change are typically maintained on a milk-free diet until one year of age, at which time many (although not all) infants will have become tolerant to the protein. However, the condition often resolves before one year of age and earlier reintroduction should be considered for those with mild symptoms because there are concerns that unnecessary restriction of foods may result in less tolerance later in life [60,61]. Infants who do not respond to dietary restriction initially may respond to a trial of other lifestyle changes, as outlined below.

Pharmacotherapy — Acid-suppressing medications have a limited role in the treatment of infants with regurgitation. They are not valuable in treating children under one year of age with uncomplicated GER ("happy spitters") [11,12,15,62].

No role for most infants — Pharmacotherapy is not indicated for infants with uncomplicated reflux, based on lack of efficacy and modest safety concerns and because the symptoms typically resolve without treatment in many infants. This is also the case for premature infants, as discussed separately. (See "Gastroesophageal reflux in premature infants".)

In most infants with reflux who are managed with conservative measures alone, symptoms will improve over time with advancing age, growth, and development. This is the case for many infants with symptoms suggestive of GERD, including parent-reported discomfort and irritability during episodes of reflux or feeding. In an observational study, over 50 percent of such infants demonstrated clinically significant improvement or resolution of symptoms with conservative measures alone, including thickened feeds, avoidance of exposure to tobacco smoke, and/or elimination of cow's milk proteins from their diet (by switching to a hypoallergenic formula, or restriction of milk from the mother's diet if the infant is breastfed) [33]. (See 'Additional options for infants with GERD or problematic reflux' above.)

The available clinical trial data suggest that, for most infants with symptoms of GERD such as regurgitation and/or irritability (eg, colic), empiric treatment with acid-suppressing therapy does not improve symptoms [12,23,24,63,64]. In addition, acid suppression is unlikely to be effective because most reflux episodes are not acidic and because infant distress may be more related to the volume of refluxate [65].

Safety concerns about proton pump inhibitors (PPIs) and other drugs are outlined below. (See 'Treatment for selected infants' below.)

Treatment for selected infants

●Indications – Acid-suppressing medications are indicated in the following situations:

•We suggest a limited trial of acid suppression (eg, two weeks) for patients with the following characteristics:

-Infants with significant symptoms suspected to be caused by GERD, such as marked irritability in a pattern that suggests esophageal pain (consistently occurs when the infant is regurgitating or associated with posturing), feeding refusal, or poor weight gain, and in whom conservative measures including a milk-free diet have failed [15]. If these infants have a clear improvement in symptoms, acid suppression may be continued for three to six months, then reevaluated.

-Infants with mild esophagitis on endoscopic biopsies. This is because mild abnormalities seen on biopsy may not be clinically significant (see 'Endoscopy' above). If the patient has a clear clinical response to treatment, the course may be extended. Infants with esophageal atresia, chronic neuromuscular diseases (eg, developmental delay), chronic respiratory disease (eg, cystic fibrosis), or diaphragmatic hiatal defects are more likely to develop erosive esophageal disease over time and may benefit from early and prolonged treatment if clinically indicated [66,67].

•For infants with moderate or severe esophagitis documented by endoscopic biopsies, we recommend a three- to six-month course of acid suppression, in addition to the lifestyle changes described above [11]. Those with erosive esophagitis should undergo a repeat endoscopy to demonstrate healing after three to six months.

All patients treated with chronic PPIs should be periodically evaluated to determine whether ongoing treatment is necessary. (See 'Monitoring and follow-up' below.)

●Drug selection – If the decision is made to initiate pharmacotherapy, a PPI is generally preferred. However, if only a limited trial is planned, a histamine 2 receptor antagonist (H2RA) is an acceptable alternative.

•PPIs – Randomized trials in adults show that PPIs lead to more rapid healing of esophagitis compared with H2RAs [68]. There are no similar comparative, randomized trials in children, but several case series report that PPIs have healed severe esophagitis that had been unresponsive to H2RA therapy [69,70]. Metabolism of PPIs through CYP2C19 of the cytochrome p450 system varies among individuals and also varies throughout infancy and childhood due to changes in enzyme maturity. As a result, the optimal dose may vary between individuals and also varies with age [71,72].

To be most effective, the PPI should be taken 30 minutes prior to the first meal/feeding of the day. Unlike H2RAs, PPIs do not lose efficacy with prolonged use. The PPIs omeprazole, lansoprazole, esomeprazole, and pantoprazole have all been studied in young children, and some have formulations that facilitate administration to infants and young children. Omeprazole and esomeprazole are approved by the FDA for use in infants older than one month of age with erosive esophagitis [73,74]. Approval updates and labeling changes are available on the FDA website.

There are also safety concerns about the use of PPIs in children. These include short-term acid rebound after stopping the drug and increased risks for diarrhea [75-77], possibly pneumonia [75,78], and changes to the microbiome [79]. A nationwide cohort study of nearly 1.3 million infants in France (median age three months) reported an association between PPI use and many types of bacterial and viral infections, affecting multiple sites (digestive tract, ears/nose/throat, upper respiratory tract, urinary tract, and nervous system), with adjusted hazard ratios ranging from 1.2 to 1.5 and greater effects in children with comorbidities [80]. Although the analysis was adjusted for multiple factors including sociodemographic characteristics and maternal and child comorbidities, the possibility of residual confounding could not be excluded. In addition, a large study found an association between use of acid-suppressing medications (H2RAs or PPIs) in young infants less than six months old and later development of allergic disease [81]. Moreover, there are theoretical reasons that long-term use of PPIs might predispose to B12 and iron deficiency. Finally, studies in adults have raised theoretical concerns that long-term use of PPIs may be associated with increased risk for osteoporosis. (See "Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorders", section on 'Adverse effects'.)

•H2RAs – H2RAs are a reasonable alternative to PPIs for a short-term trial of acid suppression. They are less effective compared with PPIs in reducing gastric acidity but are more effective than placebo [82]. Their long-term use is limited by tachyphylaxis (tolerance), which usually develops within a few weeks of chronic use. (See "Physiology of gastric acid secretion", section on 'Tolerance'.)

•Antacids – Antacids are not generally useful in the treatment of GER in infants. These drugs directly buffer gastric acid in the esophagus or stomach and may provide short-term relief of acid-related symptoms in older children and adults. However, in most infants with frequent regurgitation, there is little evidence suggesting that the reflux causes esophageal injury or pain. Those few infants with esophagitis should be treated with longer-acting agents (PPIs or H2RAs). Moreover, chronic use of antacids should be avoided in infants because of risks of aluminum toxicity, milk-alkali syndrome, or rickets [83]. Similar considerations apply to mucosal protective agents such as sucralfate or alginate-based products, which have not been adequately studied in infants.

•Prokinetic agents – Prokinetic agents have a minimal role in the treatment of GER in this age group [12,15]. The few prokinetic agents with any established efficacy also have significant safety concerns, including central nervous system side effects for metoclopramide and cardiac arrhythmias for cisapride, which resulted in its removal from the market in the United States and Canada, and lack of evidence for efficacy and possible safety concerns for domperidone (primarily prolonged QTc interval and related drug interactions) [84].

A more detailed discussion of pharmacologic therapy for the pediatric age group, including safety considerations, is provided separately. Specific issues related to premature infants are discussed in a separate topic review. (See "Gastroesophageal reflux disease in children and adolescents: Management", section on 'Pharmacotherapy' and "Gastroesophageal reflux in premature infants", section on 'Pharmacologic therapy'.)

Monitoring and follow-up — Because of safety concerns, patients treated with PPIs should be reevaluated on a regular basis to determine if ongoing use is necessary. In our practice, we attempt to wean patients from PPIs after six months of treatment and then periodically thereafter, depending on symptom control. When stopping therapy after six months, one might consider alternate-day dosing of the PPI for two weeks or transitioning to an H2RA for two weeks, followed by tapering, to avoid acid rebound.

Surgery — Surgical procedures to treat reflux, such as fundoplication, are rarely indicated in infants younger than one year of age. However, some children who present with reflux during infancy may ultimately require surgical management later in childhood. (See "Gastroesophageal reflux disease in children and adolescents: Management", 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 infants and 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 5^th to 6^th 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 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Spitting up and GERD in babies (The Basics)")

●Beyond the Basics topic (see "Patient education: Acid reflux (gastroesophageal reflux) in babies (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definitions – Gastroesophageal reflux (GER) and regurgitation are extremely common during infancy and typically resolve on their own by one year of age. The term gastroesophageal reflux disease (GERD) is used when the reflux has pathologic consequences, such as esophagitis, nutritional compromise, or respiratory complications. (See 'Definitions' above.)

●Alarm signs – Infants presenting with frequent regurgitation should be evaluated for the presence of alarm signs suggestive of underlying pathologic disease (table 1 and table 2). In most cases, a careful history and physical examination is adequate to identify these alarm signs. Blood-tinged stools are a relatively common sign and are often caused by milk protein intolerance or anal fissures. Affected infants also may have reflux, but this should be evaluated and managed similarly to other infants. (See 'Signs suggesting possible GERD (complicated reflux)' above.)

●Uncomplicated reflux (infants without alarm signs or signs of pathologic GERD) – For infants with reflux who have no alarm signs and who feed well without unusual irritability, we suggest not using acid-suppressing or other drugs (Grade 2B). These infants have simple reflux rather than GERD; acid suppression has no benefits, and chronic treatment is potentially harmful. (See 'No role for most infants' above.)

Education and reassurance without any other specific intervention are usually sufficient for infants with uncomplicated reflux. Education of parents/caregivers includes encouraging breast milk feeding if possible, avoiding tobacco smoke, and avoiding overfeeding. (See 'Measures for all infants' above.)

If the reflux symptoms are problematic for the family, it is reasonable to trial one or more of the conservative measures used for management of presumed GERD, as described below (eg, thickening of the formula or expressed breast milk, or a trial of eliminating cow's milk from the diet). (See 'Additional options for infants with GERD or problematic reflux' above.)

●Possible GERD – Symptoms that are sometimes associated with GERD in infants include:

•Poor weight gain – Very large amounts of reflux can cause poor weight gain but should also prompt evaluation for other causes.

•Irritability or feeing refusal – Generally only suspicious for GERD if there are specific signs suggesting esophageal pain, such as Sandifer syndrome, a strong temporal association between reflux events and irritability, and/or blood-tinged refluxate.

•Respiratory symptoms – Generally only in infants with underlying conditions that predispose to aspiration.

Each of these symptom patterns has multiple possible causes other than GERD, and a focused evaluation and close follow-up are warranted. (See 'Infants with possible GERD' above.)

●Management of presumed GERD – For infants with significant symptoms suspected to be caused by GERD (poor weight gain, feeding refusal, or marked irritability in a pattern that suggests esophageal pain) without evidence of another underlying cause, we use a stepwise management approach (algorithm 1):

•Initial conservative measures – For most infants with presumed GERD, we suggest initial conservative measures (including avoidance of tobacco smoke, avoiding overfeeding, thickening of feeds, or positioning therapy) rather than upfront acid-suppressing drug therapy (Grade 2C). (See 'Additional options for infants with GERD or problematic reflux' above.)

-Thickening feeds – A trial of thickening feeds is worthwhile for some infants with problematic reflux (but generally not for breastfed infants). (See 'Thickening feeds' above.)

-Positioning – Antireflux positioning consists of keeping an infant upright (eg, on the shoulder of a caregiver who is standing or sitting) for 20 to 30 minutes after a feed. Infants with reflux, like all infants, should be positioned supine for sleep. Although prone positioning tends to decrease reflux, it also is a significant risk factor for sudden infant death syndrome (SIDS). Semisupine positioning (eg, in an infant seat) is unlikely to be helpful and may exacerbate reflux. Lateral positioning is associated with an increased risk for SIDS and may or may not affect reflux. (See 'Positioning therapy' above and "Sudden infant death syndrome: Risk factors and risk reduction strategies".)

-Milk-free diet – If symptoms persist despite implementing the above measures, it is reasonable to do a trial of a milk-free diet (and possibly also a soy-free diet). This is because symptoms of food protein intolerance (typically to cow's milk) sometimes mimic GERD. The trial is particularly important for (but not limited to) infants with gross or occult blood in the stool, eczema, or a strong family history of atopic disease. Other diagnoses and treatments should be explored if there is not a clear response to the diet change within a few weeks. Empiric dietary management of food protein intolerance in infancy is discussed in detail separately. (See 'Avoidance of cow's milk and soy protein' above and "Food protein-induced allergic proctocolitis of infancy", section on 'Management'.)

•Persistent GERD symptoms despite conservative measures – For infants with persistent GERD-related symptoms (poor weight gain, feeding refusal, or marked irritability in a pattern that suggests esophageal pain) despite a trial of conservative measures outlined above, we suggest a limited trial of acid-suppressing medication (Grade 2C). We generally use a proton pump inhibitor (PPI), but a histamine 2 receptor antagonist (H2RA) is an acceptable alternative for a short-term trial; a typical trial is two weeks. If there is a clear improvement in symptoms, acid suppression may be continued using a PPI for three to six months, then reevaluated. (See 'Treatment for selected infants' above and 'Monitoring and follow-up' above.)

●Management of biopsy-proven GERD – For infants who undergo endoscopy and have evidence of esophagitis on biopsy, the choice and duration of acid-suppressing therapy depends on disease severity:

•Mild esophagitis – For infants with mild esophagitis documented by endoscopic biopsies, we suggest a two-week trial with either a PPI or H2RA rather than conservative measures alone (Grade 2C). If the patient has a clear clinical response to treatment, the course may be extended. (See 'Treatment for selected infants' above and 'Monitoring and follow-up' above.)

•Moderate to severe esophagitis – For infants with moderate or severe esophagitis documented by endoscopic biopsies, we suggest three to six months of PPI therapy rather than shorter courses or treatment with an H2RA (Grade 2C). All patients treated chronically with PPIs should be periodically evaluated to determine whether ongoing treatment is necessary. (See 'Treatment for selected infants' above and 'Monitoring and follow-up' above.)