These techniques may investigate reflux for a very limited time and mainly during the postprandial period. One or more reflux episodes can be detected in up to 50% of children undergoing radiologic imaging, regardless of symptoms. An upper gastrointestinal (GI) barium contrast study is mainly helpful to detect GI malformations and it can be useful in the diagnosis of hiatal hernia, malrotation, pyloric stenosis, duodenal web, duodenal stenosis, antral web, esophageal narrowing, Schatzki's ring, achalasia, esophageal stricture, and esophageal extrinsic compression. Persistent symptoms after anti-reflux surgery are another indication [78]. Ultrasonography is not indicated for GERD diagnosis as the results are clearly investigator-dependent. The sensitivity of ultrasound in the 15 minutes post-prandial is about 95% but the specificity is only 11% in comparison to pH-metry [910]. The correlation between esophageal wall thickness and esophagitis is also poor. Regarding scintigraphy, sensitivity and specificity are only moderate, at 69% and 78%, respectively [11]. Besides demonstrating tracer that refluxes into the esophagus, scintigraphy evaluates gastric emptying and may also show pulmonary aspiration [12].

Microscopic esophagitis is defined as the presence of eosinophils, papillary lengthening, and/or basal cell hyperplasia. Erosive esophagitis is defined as visible breaks in the esophageal mucosa. There is no specific symptom of esophagitis. The sensitivity of erosive esophagitis in diagnosing GERD was reported to range from 15% up to 71% and the sensitivity of microscopic esophagitis in diagnosing GERD was between 83% and 88%. The authors found that histologic esophagitis had a negative predictive value (NPV) of 62% and 73% [1314]. If the endoscopic appearance of the mucosa in control patients was also considered, the NPV of upper endoscopy decreased to only 33% [15]. These findings indicate that a biopsy without the hallmarks of esophagitis or the absence of macroscopic lesions does not rule out the presence of GERD. In all 3 studies, if mentioned, histology and macroscopic appearance were normal in the control group, which automatically led to a reported specificity and NPV of 100% [131415]. Thus, there is insufficient evidence to support the use of endoscopy with or without biopsy for the diagnosis of GERD in infants and children. However, endoscopy of the upper GI tract is useful to evaluate the mucosa in the presence of alarm symptoms or signs, such as hematemesis, dysphagia, or failure to thrive or anemia; to detect complications of GERD, such as erosive esophagitis, strictures, and Barrett's esophagus; or to diagnose conditions that might mimic GERD, such as eosinophilic esophagitis. GERD may exist despite the normal endoscopic appearance of the esophageal mucosa and the absence of histological abnormalities. The correlation between esophagitis and acid exposure time on pH-monitoring is quite poor, particularly in infants. The area under the curve is a pH-metry parameter that considers the acidity of the reflux episodes and was shown to correlate with esophagitis but has lost appeal in recent years and is no longer reported in commercially-available pH-metry reports [16].

Biomarkers, such as salivary pepsin, have not been shown to be useful to diagnose GERD. Pepsin can be found in the mouth of almost one-third of control patients [17]. The sensitivity and specificity of pepsin in bronchoalveolar lavage (BAL) fluid to predict pathologic reflux by pH-metry and MII or endoscopy was 57% and 65%, respectively [18]. The positive predictive value (PPV) of pepsin for pathologic reflux by pH-metry, MII, or endoscopy was 50% and the NPV was 71%. The sensitivity, specificity, PPV, and NPV for the presence of pepsin in the BAL of patients with confirmed pulmonary aspiration were 80%, 100%, 100%, and 93% [19]. Pepsin was reported to be present in the BAL of 84% of patients with respiratory disease and reflux symptoms. However, 87% of children with respiratory disease but no reflux symptoms were pepsin-negative [20]. Moreover, no relation was found between salivary pepsin positivity, extra-esophageal symptoms, quality of life scores, or inflammation on bronchoscopy or esophagogastroduodenoscopy [21]. Moreover, the presence of pepsin has been shown to be between 50% and 100% in children depending on the number of positive samples considered [22]. Middle ear fluid analysis showed no association between pepsin and reflux symptoms [23]. Bile salts, pepsin, and lipid-filled macrophages in BAL fluids have been studied to demonstrate gastric aspiration secondary to reflux as a cause of chronic respiratory disease but were not useful [18212425].

When pulmonary aspiration is obvious, the biomarkers are positive. Also, when GERD is obvious because of the presence of classic symptoms, such as vomiting, these biomarkers are positive. However, they are not helpful in other patient groups and cannot be recommended for children with chronic respiratory diseases without GERD symptoms. The reason for this might simply be that chronic respiratory disease caused by GERD is seldom in the absence of GER symptoms in neurologically-normal children.

Manometry or motility studies do, of course, not measure reflux, but may be useful by demonstrating the etiology of GERD. High-resolution esophageal manometry may be helpful to diagnose rumination syndrome [2627]. High-resolution manometry can also highlight esophageal motility disorders in those who present with symptoms similar to GERD.

A PPI diagnostic test is based on the hypothesis that symptoms responding to PPI administration suggest that they are (acid) GERD-induced. Since none of the trials in infants showed a better symptom reduction than placebo, regardless of the duration of the trial, the administration of PPIs cannot be recommended for infants as a diagnostic test [28]. The best improvement of symptoms in children occurs during the first 2 to 4 weeks [29303132]. According to data in adults with typical symptoms, 1 week of PPI is sufficient to observe a significant response. There are insufficient data to recommend a PPI trial in patients with extra-esophageal symptoms, possibly related to GERD.

Continuous esophageal pH monitoring was developed in the 1990s and for a long time was regarded as the best technique to measure reflux since it was the only technique available to measure GER outside the postprandial period. More recently, wireless pH recording has been proposed as an alternative to pH probe monitoring. The capsule is clipped to the esophageal mucosa and is supposed to drop off after 48 hours, although up to 5 days of recording has been reported. Pediatric studies have shown that the wireless pH recording results were comparable to the pH probe studies in patients who had both techniques performed simultaneously [33]. Complications of the device occurred in 0% to 15% of the patients and included esophageal tears, chest pain, and early detachment [3435]. Outside the USA, this capsule is hardly used, although it certainly might be helpful in patients with behavioral disorders. Of course, impedance cannot be recorded with this device. Oropharyngeal monitoring is not recommended as most studies failed to show that the technique was appropriate.

The development of MII in combination with pH monitoring has challenged pH monitoring. Indeed, MII in combination with pH-metry allows the detection of both acid and non-acid reflux. Since MII is expensive, the technique is only available in a limited number of centers. The analysis of an MII is time-consuming and requires experience. The determination of a normal value range is difficult to obtain since it is not ethically acceptable to perform such a technique in healthy asymptomatic infants and children. Reference values in different age groups have been recently proposed and cut-off values for symptom association indices have also been proposed. However, data for true asymptomatic, presumably healthy children are not available.

The indications to perform pH-MII are: 1) to measure the efficacy of acid suppression medication; 2) to differentiate NERD, hypersensitive esophagus, and functional heartburn in patients with normal endoscopies and histology; 3) to correlate persistent troublesome symptoms with acid and non-acid GER events; and 4) to establish the role of acid and non-acid reflux in the etiology of esophagitis and other signs and symptoms suggestive of GERD.

Patient education, specific methods to prevent or treat symptoms, and patient empowerment have been shown to decrease parental and patient anxiety. Management should always start with parental support.

Despite the possible benefits of positioning in the management of GER, only supine positions can be recommended for infants because the risk of sudden infant death syndrome (SIDS) is associated with all other sleeping positions. Supine sleeping is universally recommended by the National Health Service and the American Academy of Pediatrics (AAP) as the safest position to prevent the risk of SIDS. Because elevating the head of an infant's crib while the infant is supine may result in the infant rolling to the foot of the crib into a position that may comprise respiration, elevating the head of the crib is not recommended by the AAP [36]. An anti-regurgitation (AR) bed was developed and is available in some European countries. However, limited data hamper a global recommendation.

There is no evidence that reduced feeding volume, more frequent feedings, or extensively hydrolyzed or amino-acid based formula is effective for the treatment of infants presenting with troublesome GER symptoms. However, there is a consensus that overfeeding is a risk factor for GER and regurgitation. Although the overall quality of studies is low to very low, there is a consensus that thickened formula reduces regurgitation. There is no evidence to suggest that 1 thickening agent is more effective than another [37]. The impact of thickened formula on non-regurgitation symptoms is not clear.

Safety concerns regarding rice cereals were raised because of high levels of inorganic arsenic, which may cause neurotoxicity and long-term cancer risk. Despite an Food and Drug Administration warning, rice cereal does have some advantages over other cereals, including its ability to dissolve easily, its low cost, and it has been used for a long time. Bean gum has the advantage of adding no calories. It is important to realize that breast milk cannot be used to thicken with cereal because of the amylases present. Troublesome regurgitation and GERD are (almost) never a good reason to stop breastfeeding. Commercially-prepared thickened formula is preferred over adding thickeners to formula because the effect of the thickener on the composition of the formula has been taken into account in commercially-prepared formula. Most of the infant formula companies have developed AR and Comfort formula. While the first is positioned to reduce regurgitation in the "happy spitter", the second is positioned in the management of the infant presenting with regurgitation and distress. These comfort formulas are thickened, often the proteins are partially hydrolyzed, and lactose is reduced. In some infants, the differential diagnosis between troublesome GER-symptoms, GERD, and cow's milk protein allergy may be hard to make. Extensively hydrolyzed formula reduces GER-symptoms in cases where the symptoms are due to an allergy or delayed gastric emptying. A thickened extensive hydrolysate will be effective, independent of the cause of the symptoms, but does not make a precise diagnosis.

Limited data suggest that Lactobacillus reuteri DSM 17938 given as drops daily may be effective in reducing episodes of regurgitation, and may prevent future episodes [2].

Obese children are at increased risk of developing GER symptoms [3839]. There is insufficient evidence to recommend lifestyle modifications, such as avoidance of alcohol and tobacco, massage therapy, complementary therapy (hypnotherapy, homeopathy, acupuncture, and herbal medicine), and specific dietary modifications for the reduction of GERD symptoms.

Antacids and alginates neutralize acid and contain sodium/potassium bicarbonate, or aluminum, magnesium, or calcium salts. Alginates are reported to reduce reflux symptoms and the number of episodes of regurgitation and vomiting [4041]. Alginates were also shown to reduce the number of reflux episodes measured by pH-MII [42]. The same study confirmed the reduction of symptoms [42]. Some studies failed to show efficacy of alginate. This may be due to the design of those studies, alternating a feeding without and with alginate [42]. The National Institute for Health and Care Excellence guidelines recommend alginates as an alternative treatment to feed thickening agents in breastfed infants or as a trial in infants whose symptoms persist despite conservative measures [43]. On-demand and short-term administration of alginate have no significant adverse effects. Aluminum-containing antacids should not be used in infants and children with renal dysfunction.

Over the last decade, the efficacy of different PPIs, including lansoprazole, esomeprazole, rabeprazole, pantoprazole, and omeprazole, has been evaluated although no study compared different PPIs [44]. All studies in infants failed to show that PPIs were any better than placebos to decrease crying, fussiness, cough, arching back, regurgitation, and vomiting. PPI adverse effects received recently a lot of attention when about 25% of patients developed small intestinal bowel bacterial overgrowth [45]. An increase in upper and lower respiratory tract infections, GI infections, and eczema were reported. PPIs are a risk factor for Clostridium difficile infections [464748]. Since histamine 2 receptor antagonists (H²RAs), such as ranitidine are less effective in reducing gastric acidity than PPIs, PPIs are the first choice. However, certainly, when PPIs are not available, H²RAs can still be used to treat acid-related diseases. The choice of administering PPIs versus H²RAs should also consider the ease of administration and medication cost since reliable evidence regarding its efficacy is limited. There is no evidence for the superiority of any PPI or H²RAs in comparison with a drug from the same class. Lansoprazole at 7.5 or 15 mg twice daily for 2 weeks improved symptoms, defined as a decrease in Revised Infant Gastroesophageal Reflux Questionnaire scores, more than an extensively hydrolyzed formula [49].

Baclofen was reported to reduce transient lower esophageal sphincter (LES) relaxations, reflux episodes, and to accelerate gastric emptying, but there have been no randomized trials for GERD in children [50]. Baclofen may be used for the management of GERD, but not as a first-choice drug because of the reported side effects, including dyspeptic symptoms, drowsiness, dizziness, fatigue, and a lowered threshold for seizures [51].

There is no evidence that domperidone or metoclopramide reduces visible regurgitation or vomiting in comparison with placebo but they cause more adverse effects [5253]. The most common adverse effects are extrapyramidal symptoms (9%), diarrhea (6%), and sedation (6%) [54]. Prolongation of the corrected QT interval is the most important adverse effect of domperidone [55]. Domperidone is not available in the United States. Cisapride, a mixed serotonergic agent that facilitates the release of acetylcholine at synapses in the myenteric plexus, increased the risk of sudden death, resulting in limited access programs [12].

There is no evidence for the efficiency of bethanechol, which has a high incidence of side effects [5657]. Erythromycin and azithromycin, motilin agonists, may be of benefit in patients with gastroparesis [12]. However, these drugs have not been shown to reduce GER [58].

As always, optimal diagnosis and management start with taking a complete history and performing a complete physical examination. The healthcare provider is supposed to know the “red flags” or “alarm signs” and the most frequent differential diagnoses that may present with similar histories, symptoms, and signs. One example is the differential diagnosis in infants between GER, GERD, and cow's milk protein allergy.

In infants with overt regurgitation, in the absence of alarm symptoms, explaining the reasons why infants regurgitate (proportional large feeding volume, liquid feeding, supine position) and the natural evolution of the symptoms (spontaneous improvement between six and 18 months in the vast majority), to the parents is recommended. In general, regurgitation does not start before the age of 1 week or after the age of 6 months. Regurgitation and reflux are almost never reasons to stop breastfeeding. Frequency and the volume of feedings should be checked and adapted according to the age because overfeeding with large volumes occurs frequently in this age group. A trial with a thickened AR formula will decrease regurgitation and, thus, decrease parental anxiousness. Commercially-prepared thickened formula is preferable to formula thickened at home because the effect of the thickener on the composition of the formula is taken into account in commercial formula preparation. Some thickeners, such as bean gum may hamper iron absorption therefore, this micronutrient content is increased in the AR-formula. If the AR-formula does not successfully treat the symptoms after 1 to 2 weeks, an extensive hydrolysate trial for 2 to 4 weeks is recommended, certainly in cases where the infant presents with other symptoms indicative of atopic diseases, such as atopic dermatitis. Regarding all nutritional interventions, there is a consensus that a lack of improvement after 2 weeks is very unlikely to bring symptom relief afterward. In case of sufficient improvement, the AR-formula can be continued up to the age of 6 months, or until 12 months of age if symptoms relapse with a non-thickened formula. If an extensive hydrolysate was started, management of cow's milk protein allergy should be followed, with a challenge after 2 to 4 weeks, and continuation of the extensively hydrolyzed formula up to the age of 12 months or at least for 6 months, whichever is reached first. Many infant formula companies commercialized “comfort formula.” This type of formula is very often thickened, has a reduced lactose content, and contains a partially hydrolyzed protein. The efficacy of many of these formulas is poorly documented. In case the infant is also distressed, a trial with alginate for 2 to 4 weeks is recommended. Positional treatment is not recommended because the positions that decrease GER are positions with increased risk for SIDS. Although there are some data, evidence for the routine use of prebiotics, probiotics, massage, or herbal medications to treat GERD is too insufficient for their recommendation.

If nutritional management also remains unsuccessful, referral to a pediatric gastroenterologist is advised. In the case where referral is not possible, a 2 to 4 weeks trial of antacid medication (PPI and H²RA) is acceptable, although as stated, it is not recommended without an objective diagnosis of GERD. However, if the trial of antacid medication also fails, an appropriate referral is recommended. In the absence of alarm symptoms, diagnostic investigations are not recommended at the primary healthcare level.

The older the child, the closer the recommended approach is to the management in adults. Of course, at any age, the recommended approach starts with a complete history and physical examination. The healthcare provider should be aware of the alarm signs and most relevant differential diagnoses and act accordingly (Tables 2 and 3). In the absence of red flags, parent and child education and lifestyle modifications are the recommended first approaches. If there is insufficient improvement, a diagnostic trial with antacid medication for 2 to 4 weeks is recommended in children that are old enough to express themselves in a reliable way (>8–12 years). Again, if there is no improvement starts after 1 month, it is very unlikely that improvement will occur later. If there is sufficient improvement, the antacid medication should be continued and the necessity of continuation should be checked regularly, e.g., every 3 to 6 months. In the case of insufficient improvement, the patient should be referred for a diagnostic upper GI tract endoscopy with biopsies. In the case of abnormalities, appropriate management should be started. If the endoscopy and histology are normal, a pH-MII recording is recommended. If the result is abnormal, a diagnosis of NERD is established and management should be determined accordingly. If the result of the pH-MII is normal, but there is a positive symptom association, the patient suffers from a hypersensitive esophagus. In the case where there is also a negative symptom association, the conclusion is that the patient suffers from a functional GI disorder. Appropriate management is recommended for each of these situations.