List of Abbreviations
AR – anti-reflux (formula)
GER – gastroesophageal reflux
GERD – gastroesophageal reflux disease
GI – gastrointestinal tract
PPI – proton pump inhibitors
RI – reflux index
ABDS – acid-base balance status
LES – lower esophageal sphincter
NICU – neonatal intensive care unit
HH – hiatal hernia
MM – mucous membrane
TLESR – transient lower esophageal sphincter relaxation
Terms and Definitions
Gastroesophageal reflux – retrograde reflux of gastric contents into the esophagus, accompanied by regurgitation and/or vomiting.
Gastroesophageal reflux disease – a pathological condition developing when the reflux of gastric contents into the esophagus (gastroesophageal reflux) leads to troublesome symptoms and/or the development of complications.
Hematemesis – vomiting containing fresh blood, blood clots, or "coffee grounds".
Esophageal clearance – restoration of pH in the distal esophagus after each episode of gastroesophageal reflux.
Regurgitation (symptom) – the passage of gastric contents due to reflux into the lower pharynx, oral cavity, and/or beyond the oral cavity.
Refractory GERD – in the absence of convincing clinical and endoscopic remission within 4–8 weeks of therapy.
Transient lower esophageal sphincter relaxation – a sharp decrease in lower esophageal sphincter (LES) pressure to the level of intragastric pressure, unrelated to swallowing and having a relatively longer duration than relaxation induced by swallowing.
1. Brief information on the disease or condition
1.1 Definition of the disease or condition
Gastroesophageal reflux disease – a pathological condition that develops when the reflux of gastric contents into the esophagus leads to troublesome symptoms and/or the development of complications [1].
1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)
GERD is a multifactorial disease based on the passage of gastric contents into the esophagus – gastroesophageal reflux (GER) [2,3], characterized by a pathologically high frequency and/or duration of episodes, resulting in impaired integrity of the esophageal mucosa (EM) or the esophageal barrier. In most cases, GER is not accompanied by clinical symptoms and is considered physiological in newborns [4].
Maintaining the integrity of the esophageal mucosa is determined by the balance between aggressive factors and the ability of the mucosa to withstand the damaging effects of gastric contents refluxed during GER.
Traditional "aggressive" factors include: hydrochloric acid, and in the case of duodenogastric reflux – lysolecithin, bile acids, and pancreatic juice enzymes. However, in the neonatal period, these factors do not play the same role as in subsequent age periods due to anatomical and physiological features [4].
Protective factors are represented by: the antireflux barrier (lower esophageal sphincter and crura of the diaphragm), esophageal mucosal resistance (pre-epithelial, epithelial, and post-epithelial levels), esophageal clearance (restoration of pH in the distal esophagus after each reflux episode), and timely gastric emptying [5].
The neonatal period is characterized by a decrease in the effectiveness of "protective factors" with an unchanged level of aggressive factors [3,6].
Risk factors for the development of GERD in newborns are presented in Table 1 [3].
Table 1. Risk factors for GERD development in the neonatal period
Craniofacial anomalies | Cleft lip (cheiloschisis) |
|---|---|
Airway anomalies | Tracheoesophageal fistula |
Diaphragmatic anomalies | Congenital diaphragmatic hernia Hiatal hernia |
Anomalies of the anterior abdominal wall | Abdominal wall defects |
Gastrointestinal anomalies | Esophageal atresia Intestinal rotation anomalies Pyloric stenosis Duodenal and other small bowel atresia Intestinal strictures Annular pancreas |
Nervous system pathology | Intraventricular hemorrhages Periventricular leukomalacia Hypoxic-ischemic encephalopathy |
Main mechanisms in the pathogenesis of GERD:
1. Pathological transient LES relaxation, impairing the function of the antireflux barrier.
Periodic relaxations of the lower esophageal sphincter (LES) occurring during swallowing are a physiological phenomenon and generally do not impair esophageal clearance. Pathological transient LES relaxation (TLESR), unrelated to swallowing and characterized by a high frequency and/or duration of LES relaxation episodes, underlies the development of neonatal GERD [7]. Triggers of pathological LES relaxation are [7,8]:
▪ abdominal distension;
▪ tension of the anterior abdominal wall;
▪ respiratory distress syndrome;
▪ therapy with xanthine derivatives (ATC code N06BC).
2. Alteration of the abdominal cavity – thoracic cavity pressure gradient.
Lower pressure in the thoracic cavity compared to the abdominal cavity creates a pressure gradient that promotes the retrograde flow of gastric contents from the stomach into the esophagus. Any conditions that lead to an increase in this gradient increase the likelihood of GER [7,9].
Among the conditions associated with GERD in the neonatal period as triggers are:
1) apnea of prematurity [10,11];
2) bronchopulmonary dysplasia [12,13].
The reasons for this relationship may be caused by chronic aspiration of gastric contents and an increase in intra-abdominal pressure as a result of respiratory distress, which, in turn, can lead to increased reflux. However, existing studies aimed at identifying the relationship between these conditions have a low level of evidence [3].
1.3 Epidemiology of the Disease or Condition
The true incidence of GERD in newborns is unknown, as in most cases the disease is mild and masked as infant regurgitation, which belongs to functional gastrointestinal (GI) disorders [3]. At the same time, GERD is detected with a frequency of 1 in 10 newborns admitted to the neonatal intensive care unit (NICU). A confirmed diagnosis of GERD leads to an increased length and cost of hospitalization [3].
1.4 Features of Coding the Disease or Condition
P78.8 Other specified perinatal digestive disorders
1.5 Classification of the disease or condition
There is no generally accepted classification of GERD in newborns. It is recommended to use the classification of GERD in children based on esophageal mucosal changes detected during esophagogastroduodenoscopy [14].
Based on the severity of endoscopic changes in the esophageal mucosa, grades I–IV of GERD with esophagitis are distinguished:
Grade I – mild focal erythema and/or friability of the mucosa of the abdominal esophagus.
Grade II – total hyperemia of the abdominal esophagus with focal fibrinous exudate and possible single superficial, non-confluent erosions within the abdominal esophagus.
Grade III – spread of inflammation and erosions (non-confluent or confluent, but not circular) to the thoracic esophagus. Increased mucosal friability upon contact is possible.
Grade IV – esophageal ulcer(s). Esophageal stricture.
1.6 Clinical presentation of the disease or condition
The clinical presentation is variable and nonspecific. Most suspected symptoms of GERD in the neonatal period are unreliable, making GERD a diagnosis of exclusion. The following symptoms help suspect the disease [3,15]:
General manifestations: prolonged episodes of crying and restlessness, including at night, poor weight gain;
Digestive system: regurgitation, vomiting, irritability during feeding, hematemesis, food refusal [2];
Respiratory system: cough worsening during feeding, stridor, wheezing, or episodes of aspiration;
Cardiovascular system: apnea, bradycardia, decreased blood oxygen saturation.
In most cases, symptoms are mild to moderate, manifesting as episodes of restlessness, crying, and impaired night sleep quality [3,15].
2. Diagnostics, medical indications and contraindications for diagnostic methods
Criteria for Establishing the Diagnosis/Condition
To establish a diagnosis, the following data are taken into account:
Identification of risk factors for GERD development.
Nature of complaints – attention is paid to the time of onset of regurgitation/vomiting, frequency, relation to feeding, other complaints, and the additional presence of bile or blood in the contents, as well as the rate of changes in physical development parameters.
Physical examination – assessment of physical development, identification of red flag symptoms.
Instrumental examination (esophagogastroduodenoscopy [EGD], 24-hour esophageal pH monitoring, pH-impedance monitoring).
Due to the lack of specific symptoms characteristic of GERD, attention should be paid to the presence of red flag symptoms for differential diagnosis and detection of diseases with a clinical presentation similar to GERD (Table 2).
Table 2. Complaints and red flag symptoms, the presence of which requires the exclusion of diseases with a clinical presentation similar to GERD [2]:
Complaints | Symptoms identified during examination |
|---|---|
Onset of regurgitation: < 2 weeks of life | Abnormalities identified during general physical examination of the digestive, respiratory, and nervous systems (visual therapeutic examination). |
Bile-stained vomiting, nocturnal or persistent vomiting | Marked abdominal distension |
Chronic diarrhea or bloody diarrhea | Fever |
Hematemesis | Lethargy or increased irritability |
Dysuria | Poor weight gain or failure to thrive |
Seizures | Bulging fontanelle, rapid head circumference growth, or micro-/macrocephaly |
Recurrent pneumonia | Pathological changes in muscle tone |
Dysphagia | Psychomotor development abnormalities |
Notes. The onset of regurgitation at 1–2 weeks of life requires the exclusion of infectious diseases, anatomical anomalies, and metabolic disorders.
2.1 Complaints and Anamnesis
In newborns with suspected GERD, it is recommended to:
– review the course of the early neonatal period to identify risk factors for GERD development;
– note the time of onset and dynamics of complaints [1-3,5,14].
LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)
Comments: see Section 1.2 "Etiology and Pathogenesis of the Disease". When taking the history of a newborn with suspected GERD, it should be noted that GERD is more frequently detected in certain patient groups (Table 1) [3]. The most characteristic complaints include frequent regurgitation/vomiting accompanied by severe anxiety, sleep disturbance, and poor weight gain.
2.2 Physical Examination
A newborn infant with suspected GERD is recommended to undergo a visual therapeutic examination [3].
LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)
Comments: see Section 1.6 "Clinical Presentation of the Disease". Due to the absence of pathognomonic symptoms, primary attention should be paid to the presence of red flag symptoms (Table 2); if identified, differential diagnosis with other pathological conditions presenting with similar symptoms to GERD should be performed.
2.3 Laboratory Diagnostics
It is recommended that all newborn infants with suspected GERD presenting with vomiting and poor weight gain undergo a complete blood count (CBC) with differential to rule out an infectious origin of the symptoms and to identify comorbid conditions/complications, such as anemia [16,31].
GCR CLEL 4Grade of Recommendation C (Level of Evidence - 4)
Comments: ruling out infectious diseases is necessary when symptoms characteristic of GERD debut within the first week of the child's life [2].
It is recommended that newborn infants with suspected GERD presenting with severe vomiting and poor weight gain undergo an acid-base balance (ABB) and blood gas test, blood lactate level, and blood ammonia level assessment to detect signs of metabolic disorders indicating systemic errors of metabolism for further diagnostic workup [16,31].
GCR CLEL 4Grade of Recommendation C (Level of Evidence - 4)
Comments: ruling out metabolic disorders is required when complaints characteristic of GERD debut within the first week of the child's life [2].
2.4 Instrumental Diagnostics
It is recommended that newborns with suspected GERD undergo esophagogastroduodenoscopy to determine the severity of esophageal mucosal damage, detect complications, and perform differential diagnosis [17].
LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)
Comments: the procedure assesses the condition of the esophageal mucosa, which is especially important in the presence of alarming symptoms such as hematemesis, dysphagia, failure to thrive, or anemia, as well as for detecting GERD complications such as erosive esophagitis [2,17].
The procedure allows for the diagnosis of a range of congenital anomalies of esophageal development (atresia, stenosis, "short esophagus", etc.), as well as acquired inflammatory and non-inflammatory diseases.
It is recommended that newborns with GERD undergo endoscopic esophageal biopsy followed by pathoanatomical examination of the esophageal biopsy (surgical) material in cases of treatment failure, in order to rule out rare esophageal diseases, particularly eosinophilic esophagitis [2,3].
LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)
Comments: it is important to note that even minor deviations in biopsy technique affect the reliability of histology as a diagnostic method in determining reflux esophagitis. For reliable diagnosis, at least two biopsy specimens (preferably 4) should be taken at a distance of two centimeters or more above the Z-line [18].
The diagnostic value of biopsy increases in the presence of red flag symptoms such as hematemesis, swallowing disorders, and anemia, for detecting GERD complications such as erosive esophagitis or strictures, or for diagnosing conditions that may mimic GERD, such as eosinophilic esophagitis [2,17].
It is recommended that newborns with GERD undergo 24-hour esophageal pH monitoring in cases of treatment failure to clarify the diagnosis and adjust treatment taking into account existing indications [2,3,6,14,19].
LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)
Comments: this method allows for high-precision detection of gastric acid reflux into the esophagus and assessment of its duration. The study typically lasts from several hours to several days, after which the reflux index (RI) is calculated. The reflux index is defined as the percentage of time with pH recording below 4 relative to the total study time (in %) [14,19]. Limitations of pH monitoring in newborns include the lack of reference pH values in this age group and the inability to detect weakly acidic refluxate, which constitutes the majority of refluxate in infants (up to 73% of reflux episodes are weakly acidic and alkaline, with a pH ranging from 4 to 7, largely determined by feeding characteristics – the alkaline pH of breast milk) [4,6].
It is recommended that newborns with GERD undergo 24-hour pH-impedance monitoring in cases of treatment failure for treatment adjustment taking into account existing indications [3,19].
LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)
Comments: pH-impedance monitoring overcomes the limitations of 24-hour pH monitoring by detecting both acidic and non-acidic reflux. Additionally, the method allows determining the height of refluxate ascent into the esophagus and predicting the risk of refluxate aspiration. Combined pH-impedance monitoring holds promise as an objective diagnostic method for GERD; however, more normative data are needed before this method can be considered the "gold standard" test [3,19].
It is recommended that newborn infants with GERD and suspected hiatal hernia, diaphragmatic hernia, or refractory GERD (absence of convincing clinical and endoscopic remission within 4–8 weeks of therapy) undergo contrast esophagography for differential diagnosis and exclusion of anatomical anomalies [2,17].
LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)
Comments: barium swallow examination of the esophagus and stomach is performed in anteroposterior and lateral projections and in the Trendelenburg position with mild abdominal compression. The study evaluates suspension transit, esophageal diameter, contours, wall elasticity, pathological strictures, ampullary dilations, peristalsis, and mucosal relief. In overt reflux, the esophagus and stomach radiologically form an "elephant with raised trunk" figure, and contrast medium reappears in the esophagus on delayed radiographs, confirming the fact of reflux. The method is of great importance in diagnosing sliding hiatal hernia (SHH), esophageal developmental anomalies, evaluating the consequences of trauma and surgical interventions, and is indispensable in diagnosing functional esophageal diseases. The specificity of X-ray examination in diagnosing SHH, according to literature data, is 94% [17].
Disadvantages of the method include the fact that esophageal radiography does not always detect small hernias and also entails a high radiation dose [2,17].
2.5 Other Procedures
Diagnostics of diseases associated with GERD is performed according to indications [3].
3. Treatment, including drug and non-drug therapies, diet therapy, and pain management
Given the multi-component nature of this pathophysiological phenomenon, treatment of gastroesophageal reflux disease is comprehensive. It includes dietary therapy, postural therapy, drug therapy, non-pharmacological therapy, and surgical correction ("step-up therapy"). The choice of treatment method or their combination depends on the causes of reflux, its severity, and the spectrum of complications [2,14].
Treatment measures for GERD are based on three main pillars:
1) a set of non-pharmacological interventions, mainly normalization of lifestyle, daily routine, and diet;
2) conservative therapy;
3) surgical correction.
3.1 Conservative Treatment
3.1.1 Diet Therapy
It is recommended to use postural therapy or body position changes in newborns with GERD—holding the baby at a 45–60° angle during feeding, which prevents regurgitation and aerophagia. At night, it is advisable to elevate the head of the crib by 10–15 cm [20]. Overfeeding infants with GERD is unacceptable [21].
GCR CLEL 4Grade of Recommendation C (Level of Evidence - 4)
Comments: prone and left lateral positions are not recommended for home use, as they increase the risk of sudden infant death syndrome [14, 22].
It is recommended to use dietary correction with anti-regurgitation (AR) infant formulas in newborns with GERD when postural therapy is ineffective; the viscosity of these formulas is increased by adding thickeners to reduce the frequency of regurgitation and vomiting [23].
LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)
Comments: the use of specialized products enriched with complex carbohydrates, which help prevent the backflow of gastric contents and improve gastric emptying, is a fundamental approach to the diet therapy of GERD in children. For infants with mild regurgitation and adequate or slightly slowed weight gain rates, this nutritional approach is highly effective. Its efficacy combined with postural therapy is 90–95% [14, 23].
The best effect is achieved when AR formulas are introduced at the earliest stages of the disease.
When prescribing formulas that use indigestible polysaccharides (PS) (locust bean gum) as a thickener, it should be kept in mind that:
○ these formulas are therapeutic and must be prescribed by a physician;
○ they require precise selection of the volume in the child's daily diet (1/2, 1/3, or 1/4);
○ they are prescribed for a limited period;
○ they are not recommended for healthy children who do not suffer from regurgitation;
○ they are only one of the components of the treatment program.
Options for prescribing anti-regurgitation formulas:
– At the end of each feeding with breast milk/adapted formula, an anti-regurgitation (AR) formula is prescribed in an amount of 1/2 to 1/4 of the feeding volume.
– The AR formula is prescribed 1–3 times a day in the feeding volume; in other cases, an adapted formula is used.
– The AR formula is prescribed in the full daily volume for 2–4 weeks.
It is recommended to use extensively hydrolyzed protein formulas or amino acid-based formulas in newborn infants with GERD if dietary correction with anti-regurgitation formulas is ineffective for 2 weeks [2, 23].
LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)
Comments: extensively hydrolyzed protein formulas are particularly indicated in cases where the child exhibits other symptoms pointing to atopic diseases, such as atopic dermatitis [2].
The lack of improvement in clinical symptoms within 2 weeks indicates the failure of the chosen diet therapy tactics. In case of a positive effect, it is recommended to continue formula feeding up to 12 months, but for at least 6 months [2, 24, 25].
3.1.2 Pharmacotherapy
Routine prescription of pharmacotherapy is not recommended for newborns with uncomplicated GER due to insufficient efficacy and lack of safety data; in most cases, symptoms in infants disappear spontaneously after 6 months [17].
LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)
Comments: available data do not confirm the efficacy of proton pump inhibitors (ATX code A02BC) for treating characteristic GERD symptoms in newborns. Acid-suppressive therapy should not be used in premature infants due to the risk of serious side effects [26, 27].
It is recommended to administer proton pump inhibitors (ATX code A02BC) (PPIs)—#esomeprazole** (ATX code A02BC05)—to newborns with pronounced GERD symptoms (agitation, refusal to feed, poor weight gain) and moderate-to-severe esophagitis when non-pharmacological correction methods are ineffective [3, 17, 32].
LeveL of Recommendation BGrade of Evidence 2LeveL of Recommendation B (Grade of Evidence - 2)
Comments: #Esomeprazole** (ATX code A02BC05) is administered at a daily dose of 0.5 mg/kg once daily orally. The average duration of therapy is 4–6 weeks. Contraindications: individual intolerance to the drug [3, 17].
3.2 Surgical Treatment
It is recommended to perform surgical correction—fundoplication/laparoscopic fundoplication (Nissen, less commonly Thal, Dor, or Toupet operations) (open fundoplication/laparoscopic fundoplication)—in newborns with GERD who have persistently maintained endoscopic signs of grade III–IV reflux esophagitis despite repeated courses of therapy, with GERD complications (bleeding, strictures), or with GERD combined with a hiatal hernia [28, 30].
LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)
Comments: in the absence of contraindications, laparoscopic fundoplication is preferred [28].
3.3 Other Treatment
Not applicable.
4. Medical Rehabilitation and Sanatorium-Resort Treatment
Special methods of medical rehabilitation have not been developed.
5. Prevention and Dispensary Observation
For the prevention of GERD, it is recommended to limit/avoid factors provoking the development of GERD [14]:
1) avoid overfeeding;
2) apply postural therapy techniques after each feeding;
3) limit, if possible, the use of medications that relax the lower esophageal sphincter.
It is recommended that newborns diagnosed with GERD receive dispensary appointments (examinations, consultations) with a gastroenterologist [14, 29].
LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)
Comments: follow-up observation of a patient with GERD is conducted at least twice a year for 3 years from the date of the last visit [29], and is also determined by the severity of clinical symptoms and clinical-endoscopic findings.
6. Organization of Medical Care
Children with GERD are managed by a pediatrician and a gastroenterologist; in the presence of comorbid pathology, jointly with relevant specialists, including a pediatric surgeon.
Indications for hospitalization: appearance of symptoms requiring urgent intervention (dysphagia, weight loss, hematemesis, or recurrent vomiting) [30].
Indications for discharge of a patient with GERD from a medical organization: satisfactory condition, resolution of GERD symptoms, positive dynamics/normalization of the endoscopic picture.
After discharge from the hospital, children are subject to dispensary follow-up by a pediatrician and a gastroenterologist [14].
As a rule, children with GERD do not require treatment in an inpatient setting, except for complicated cases and indications for surgical intervention. To establish a diagnosis and make possible adjustments to therapy, hospitalization in a day care unit is advisable (average duration is 10–14 days).
7. Additional Information
7.1 Complications
A formidable complication of GERD is esophageal strictures, which occur upon scarring of ulcerative defects. In this case, against the background of chronic inflammation, the deep layers of the esophageal wall and perieploeic/periesophageal tissues become involved in the process, i.e., peri-esophagitis occurs. The predominance of fibrosis leads to scar formation, resulting in the development of peptic esophageal stricture.
Another serious complication of GERD is posthemorrhagic anemia, which can occur both in sliding hiatal hernias, where the incarceration traumatizes the mucosa of the diaphragmatic "sac," and as a result of erosive and ulcerative lesions of the esophageal mucosa.
7.2 Differential diagnosis of GERD
differential diagnosis is carried out with the following diseases and conditions:
Achalasia cardia.
Esophageal strictures caused by pathological changes in adjacent organs.
Mediastinal tumors and cysts.
Posterior mediastinitis.
Pleuropulmonary fibrosis.
Aortic aneurysm.
Right-sided aorta.
Vascular anomalies.
Drug-induced effects.
Incongruous/congenital metabolic disorders:
a. organic acid metabolism disorders;
b. amino acid metabolism disorders;
c. primary lactic acidosis;
d. fatty acid oxidation disorders.
7.3 Outcomes and prognosis
The prognosis for most children with GERD is favorable. A number of complications, such as Barrett's esophagus, may develop at an older age [14, 17].
Criteria for Evaluating the Quality of Medical Care
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Appendix A1. Working Group Composition
Ekaterina N. Balashova – Candidate of Medical Sciences, Leading Researcher at the Prof. A.G. Antonov ICU of the Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after V.I. Kulakov of the Russian Ministry of Health, Associate Professor at the Department of Neonatology, Institute of Professional Education, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after V.I. Kulakov of the Russian Ministry of Health, Member of the Council of the Russian Society of Neonatologists.
Margarita M. Gurova – Doctor of Medical Sciences, Leading Researcher at the Laboratory of Medical and Social Problems in Pediatrics, National Medical Research Center, St. Petersburg State Pediatric Medical University of the Russian Ministry of Health, Professor at the Department of Propaedeutics of Children's Diseases with a Course of General Nursing, St. Petersburg State Pediatric Medical University of the Russian Ministry of Health, Member of the Russian Society of Pediatric Gastroenterologists, Hepatologists and Nutritionists, Deputy Chief Medical Officer for Medical Affairs, St. Petersburg State Budgetary Healthcare Institution Consultative and Diagnostic Center for Children.
Anna N. Zavyalova – Doctor of Medical Sciences, Professor at the Department of Propaedeutics of Children's Diseases with a Course of General Nursing, St. Petersburg State Pediatric Medical University of the Russian Ministry of Health.
Dmitry O. Ivanov – Doctor of Medical Sciences, Professor, Rector of St. Petersburg State Pediatric Medical University of the Russian Ministry of Health, Head of the Department of Neonatology with Courses of Neurology and Obstetrics and Gynecology, Faculty of Postgraduate Education, St. Petersburg State Pediatric Medical University of the Russian Ministry of Health, Chief Freelance Neonatologist of the Ministry of Health of the Russian Federation.
Valeria P. Novikova – Doctor of Medical Sciences, Professor, Head of the Department of Propaedeutics of Children's Diseases with a Course of General Nursing, St. Petersburg State Pediatric Medical University of the Russian Ministry of Health, Head of the Laboratory of Medical and Social Problems in Pediatrics, National Medical Research Center, St. Petersburg State Pediatric Medical University of the Russian Ministry of Health, Member of the Russian Society of Pediatric Gastroenterologists, Hepatologists and Nutritionists.
Aleksandra S. Panchenko – Doctor of Medical Sciences, Professor at the Department of Neonatology with Courses of Neurology and Obstetrics and Gynecology, Faculty of Postgraduate Education, St. Petersburg State Pediatric Medical University of the Russian Ministry of Health.
Valery F. Privorotsky – Doctor of Medical Sciences, Professor at the Prof. I.M. Vorontsov Department of Children's Diseases, St. Petersburg State Pediatric Medical University of the Russian Ministry of Health, Member of the Russian Society of Pediatric Gastroenterologists, Hepatologists and Nutritionists.
Larisa A. Fedorova – Candidate of Medical Sciences, Associate Professor at the Department of Neonatology with Courses of Neurology and Obstetrics and Gynecology, Faculty of Postgraduate Education, St. Petersburg State Pediatric Medical University of the Russian Ministry of Health.
Anatoly I. Khavkin – Doctor of Medical Sciences, Professor, Head of the A.V. Mazurin Department of Gastroenterology and Dietetics, Head of the Moscow Regional Center for Pediatric Gastroenterology and Hepatology at the Research Clinical Institute of Childhood of the Ministry of Health of the Moscow Region; Professor at the Department of Pediatrics with a Course of Pediatric Surgical Diseases, Medical Institute, Belgorod State National Research University, Chairman of the Russian Society of Pediatric Gastroenterologists, Hepatologists and Nutritionists, Member of the Union of Pediatricians of Russia.
There is no conflict of interest.
Appendix A2. Methodology for Developing Clinical Guidelines
Methods used for evidence collection/selection: electronic database search.
Description of methods used for evidence collection/selection: the evidence base for the guidelines included publications from the Cochrane Library, PubMed, EMBASE and MEDLINE, Scopus, Web of Science, eLIBRARY, clinicaltrials.gov, electronic libraries, and clinical guidelines published by The National Institute for Health and Care Excellence, The European Association of Perinatal Medicine, The European Society for Pediatric Research, The European Foundation for the Care of Newborn Infants, and The European Society for Neonatology. The search depth was 32 years.
Methods used to assess the quality and strength of evidence:
- expert consensus;
- grading of significance according to the rating scheme.
Scales for assessing Levels of Evidence (LoE) (Tables 3, 4) for diagnostic, preventive, therapeutic, and rehabilitation methods (diagnostic, preventive, therapeutic, rehabilitation interventions) with definitions, and the scale for assessing Grades of Recommendation (GoR) (Table 5) for preventive, diagnostic, therapeutic, and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions).
Methods used for evidence analysis:
reviews of published meta-analyses;
systematic reviews with evidence tables.
Description of methods used for evidence analysis.
When selecting publications as potential sources of evidence, the methodology used in each study was reviewed to ensure its validity. Methodological evaluation was based on questions focused on study design features that significantly affect the validity of the results and conclusions.
To minimize potential subjective errors, each study was evaluated independently by at least two members of the working group. Any discrepancies in assessments were discussed by the full working group. If consensus could not be reached, an independent expert was involved.
Economic analysis:
Cost analysis was not performed, and pharmacoeconomic publications were not reviewed.
Method of recommendation validation:
external expert review;
internal expert review.
Description of the guideline validation method:
The preliminary version of these guidelines was reviewed by independent experts who were asked to comment primarily on whether the interpretation of the evidence underlying the recommendations was accessible and understandable.
Comments were received from primary care physicians and district pediatricians regarding the clarity of the presentation of the guidelines and their assessment of the importance of the guidelines as a working tool in daily practice.
The draft version was also sent to a non-medically trained reviewer to obtain comments from a patient perspective.
Comments received from experts were carefully systematized and discussed by the chair and members of the working group. Each point was discussed, and resulting modifications to the guidelines were recorded. If no changes were made, the reasons for declining the changes were recorded.
Consultation and peer review:
Recent changes in these guidelines are presented for discussion in a preliminary version. The updated version for wide discussion was posted on the website of the Russian Society of Neonatologists (RSN) www.neonatology.pro and https://portalcr.minzdrav.gov.ru/ so that all interested parties could take part in the discussion and improvement of the guidelines.
The draft guidelines were reviewed by independent experts who were asked to comment primarily on the clarity and accuracy of the interpretation of the evidence base underlying the recommendations.
For the final revision and quality control, the recommendations were re-evaluated by the members of the working group, who concluded that all comments and feedback from the experts had been taken into account and the risk of bias in the development of the recommendations was minimized.
Target audience for these clinical guidelines:
1. Neonatologists
2. Gastroenterologists
3. Pediatricians
Table 1. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)
LoE | Definition |
|---|---|
1 | Systematic reviews of studies with reference standard control or systematic reviews of randomized controlled trials with meta-analysis |
2 | Individual studies with reference standard control or individual randomized controlled trials and systematic reviews of studies of any design, except randomized controlled trials, with meta-analysis |
3 | Studies without consecutive reference standard control or studies with a reference standard not independent of the test method, or non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case report |
5 | Only justification of mechanism of action or expert opinion is available |
Table 2. Scale for assessing the levels of evidence (LE) for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitation interventions)
LoE | Definition |
|---|---|
1 | Systematic review of RCTs with meta-analysis |
2 | Individual RCTs and systematic reviews of studies of any design except RCTs, with meta-analysis |
3 | Non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case reports or case series, case-control studies |
5 | Only justification of the mechanism of action of the intervention (preclinical studies) or expert opinion is available |
Table 3. Scale for assessing the grades of recommendation (GR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitation interventions)
GoR | Definition |
|---|---|
A | Strong recommendation (all considered efficacy criteria (outcomes) are important, all studies are of high or acceptable methodological quality, and their conclusions on the outcomes of interest are consistent) |
B | Conditional recommendation (not all considered efficacy criteria (outcomes) are important, not all studies are of high or acceptable methodological quality, and/or their conclusions on the outcomes of interest are inconsistent) |
C | Weak recommendation (lack of adequate quality evidence (all considered efficacy criteria (outcomes) are unimportant, all studies are of low methodological quality, and their conclusions on the outcomes of interest are inconsistent) |
Procedure for updating clinical guidelines.
The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.
Appendix A3. Reference Materials
Appendix A3.1 Related Documents
Federal Law No. 323-FZ of November 21, 2011 "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation" (with amendments and additions, effective July 1, 2025).
Order of the Ministry of Health of Russia No. 203n dated May 10, 2017, "On Approval of Criteria for Assessing the Quality of Medical Care" (Registered with the Ministry of Justice of Russia on May 17, 2017, No. 46740).
International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) (https://nsi.rosminzdrav.ru/dictionaries/1.2.643.5.1.13.13.11.1005/passport/2.27).
Order of the Ministry of Health of the Russian Federation No. 804n of October 13, 2017 "On Approval of the Nomenclature of Medical Services" (Registered with the Ministry of Justice of Russia on November 7, 2017, No. 48808).
<Letter> of the Ministry of Health of the Russian Federation No. 15-4/I/2-2570 dated March 4, 2020 <On sending the methodical letter "Resuscitation and stabilization of newborns in the delivery room">.
Order of the Ministry of Health of the Russian Federation No. 222n of April 17, 2025 "On Approval of the Procedure for Providing Medical Care in the Profile 'Neonatology'" (Registered with the Ministry of Justice of Russia on June 2, 2025, No. 82516).
Decree of the Government of the Russian Federation No. 2406-r of October 12, 2019 <On approval of the list of vital and essential medicines, as well as lists of medicines for medical use and the minimum assortment of medicines required for medical care>.
Appendix B. Physician Action Algorithms
Appendix C. Patient Information
Gastroesophageal reflux disease, or GERD, can occur not only in adults, but also in children, starting from the neonatal period. GERD is based on the backflow or entry of gastric contents into the esophagus – gastroesophageal reflux (GER). Distinguishing between GER and GERD is important, as reflux is frequently detected in healthy children and is caused by immaturity of the lower esophageal sphincter (the barrier separating the stomach and esophagus). In addition, reflux is protective, preventing gastric overdistension if a child consumes a larger volume of food. In this case, regurgitation causes no concern, and the child's well-being is not impaired. If regurgitation becomes frequent and prolonged, the esophageal mucosa reacts, an inflammatory process develops, and mucosal defects – erosions – may appear. The child's well-being deteriorates – they become restless, appetite decreases, and weight gain may slow down. When symptoms appear, we are already talking about the development of a disease – GERD.
Suspecting the development of GERD is aided by alarm symptoms or "red flags". These include: persistent regurgitation, marked infant distress during feeding, poor weight gain, and the appearance of new symptoms – fever, diarrhea, abdominal distension. In this case, the child needs to be examined to identify the cause of the deterioration. Diagnosing GERD requires several research methods, as only a comprehensive examination helps obtain a complete picture: during esophagogastroduodenoscopy, we can assess the condition of the mucosa, identify signs of inflammation and defects. During 24-hour esophageal pH-metry/pH-impedance monitoring, we assess whether the contents in the esophageal lumen are acidic or alkaline, which is important for choosing treatment tactics. In newborns, non-pharmacological treatment methods are primarily used: positional therapy and dietary therapy – the use of specialized formulas with thickeners, or, in the absence of an effect, whey protein hydrolysate-based formulas. The prognosis is generally favorable. Children recover, but for up to 3 years after recovery, they are followed up by a pediatrician and a gastroenterologist (once every 6–12 months).
Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools
Not applicable.