The true prevalence of regurgitation syndrome in children remains unknown. According to various authors, regurgitation occurs in 60-90% of infants during their first year of life [1, 2]. For diagnosing gastrointestinal (GI) conditions not associated with any structural or biochemical changes, the Rome IV Criteria (2016) [3] and the Russian clinical guidelines "Functional Gastrointestinal Disorders" (2020), developed by national gastroenterologists based on the former, are used [4].

The main criteria for classifying regurgitation as a functional condition are: child's age from 3 weeks to 12 months, the presence of two or more episodes of regurgitation per day, troubling the infant for three or more weeks. Furthermore, alarm symptoms ("red flags") indicating organic pathology must be absent. These include [3, 4, 5, 6, 7]:

The etiology of regurgitation, like other functional GI disorders, is multifaceted; perinatal hypoxia is one contributing factor. It is known that prolonged fetoplacental insufficiency, accompanying many pregnancy complications, alters gene expression in the intestine, particularly in cells responsible for synthesizing tight junction proteins, inflammatory mediators, and immune defense factors. As a result of this transformation, the integrity of the intestinal barrier is compromised, including reduced alpha-diversity of the gut microbiota and antimicrobial activity, leading to chronic low-grade inflammation. This inflammation serves as a background for numerous pathologies, ranging from digestive and immune system disorders to metabolic disturbances and central nervous system diseases.

Furthermore, hypoxia adversely affects the nervous system. Typically, the balance of excitatory and inhibitory neurotransmitters is disrupted [8], and brain structures responsible for coordinating GI motor function can be impaired [9]. All this, against the backdrop of the relative immaturity and insufficient adaptation of the infant's body to external and internal stimuli, leads to dysfunction of the gut-brain axis, which is considered the primary pathogenetic mechanism for the development of functional GI disorders, including infantile regurgitation.

The basis of functional regurgitation in infants may involve:

In most cases, these mechanisms are combined and result from the immaturity of neurovegetative, intramural, and hormonal regulatory systems of motor function.

The common belief that regurgitation in infants decreases or disappears with age has lost its relevance. Longitudinal follow-up of children with persistent regurgitation in the first year of life has shown that by the age of 2-3 years, these children suffered from frequent respiratory diseases, ENT pathology, had restless sleep, increased excitability, and reflux-associated apnea with sudden death syndrome; during school years, they were significantly more likely to be diagnosed with GERD and chronic Helicobacter pylori-associated gastroduodenitis.

Given the long-term consequences of regurgitation syndrome, identifying the underlying perinatal factors is a necessary preventive measure.

To assess the influence of pregnancy characteristics and the nature of delivery on the risk of development and intensity of regurgitation syndrome in infants during their first year of life.

A retrospective survey was conducted, and questionnaires were completed based on parental reports for children treated in the infectious diseases department of Filatov Children's City Clinical Hospital No. 5 in St. Petersburg between October and December 2024. The questionnaires were specifically designed and included several sections: data on pregnancy characteristics, delivery, feeding patterns, child development in the first year of life, and the presence of functional GI disorders, specifically regurgitation syndrome. Parents of 88 children, predominantly mothers, participated in the study. The gender distribution of the children was: boys – 47 (53.4%), girls – 41 (46.6%). The mean age of the children at the time of inclusion was 1 year ± 9 months. All children were born in maternity hospitals to socially stable, relatively young parents, no earlier than 37 weeks of gestation, in satisfactory condition, with an Apgar score of at least 7, and with average physical development parameters.

Considering the study's objective, post facto, we divided the questionnaires into two groups. The first group consisted of 49 (56%) questionnaires containing information about the presence of regurgitation in the infant during the first year of life. The second group consisted of 39 (44%) questionnaires where mothers did not report that the child regurgitated. In both groups, a comparative analysis was conducted based on the questionnaires regarding pregnancy characteristics, delivery, neonatal and infant period, feeding patterns, physical development, and past illnesses.

Subsequently, when identifying any adverse event during pregnancy and/or delivery, we formed comparison groups for each specific case.

Information on regurgitation included its intensity, assessed using the Y. Vandenplas scale [7]. We modified it slightly considering our questionnaire structure:

A database was created in Microsoft Excel based on the completed questionnaires; the STATISTICA 6.0 software package was used for statistical analysis. Statistical patterns were studied using Pearson's χ2 test; differences between group indicators were considered significant at p ≤ 0.05.

Questionnaire analysis revealed that slightly more than half of the women (57.8%) had various symptoms of toxemia/preeclampsia in a relatively mild form, manifested as nausea and vomiting (83.7% and 76.9% in the first and second groups, respectively), edema (20.4% and 23%), hypertension (8.2% and 10.3%), nephropathy (6.1% – only in the first group); anemia without specified etiology was noted in 38.8% of women in the first group and 28.2% in the second group; gestational diabetes was present in 17.9% and 14.3%, respectively.

Regarding delivery characteristics, we found that almost every fourth child was born via cesarean section (24.5% and 23.1%, respectively), and every eighth child was born as a result of precipitous labor (in 12.24% and 12.82%, respectively). Statistical analysis did not reveal significant differences in the development of regurgitation syndrome between the groups.

Conversely, we identified a significant association between maternal toxemia and the development of regurgitation in their child (p=0.002, n=40). Among children whose mothers had symptoms of toxemia/preeclampsia, regurgitation was observed in 57.75% of cases, compared to 40% in the control group (without toxemia) (p ≤ 0.05). However, no influence was found for individual manifestations of preeclampsia, such as hypertension (p=0.253, n=8), edema (p=0.539, n=19), as well as for gestational diabetes (p=0.253, n=14), anemia (p=0.123, n=30), precipitous labor (p=0.819, n=11), and cesarean section (p=0.769, n=21) on the presence of regurgitation in the child.

Although it is worth noting that regurgitation was 11.6% more frequent in children whose mothers received treatment for anemia during pregnancy compared to children whose mothers did not have anemia. Also, regurgitation troubled children delivered by cesarean section slightly more often than those born vaginally. However, this association did not reach statistical significance in either case.

Additionally, we found a significant correlation between the timing of toxemia/preeclampsia onset and the intensity of regurgitation. Notably, 85.7% of children from mothers with toxemia/preeclampsia in the third trimester had minimal regurgitation intensity, whereas among children from mothers with toxemia/preeclampsia in the 1st-2nd trimesters, such minimal intensity was recorded in 64.7% of cases (p ≤ 0.05). Similar results were obtained for gestational diabetes: in the group of mothers with gestational diabetes, children had regurgitation scoring 1-2 points in 85.7% of cases, while in the control group (mothers without gestational diabetes), 64.7% of children demonstrated minimal regurgitation intensity (p ≤ 0.05).

No statistically significant association was found between regurgitation intensity and the presence of edema (p=0.668, n=10), hypertension (p=0.133, n=4), or anemia (p=0.223, n=19) during pregnancy.

The influence of precipitous labor on regurgitation intensity was significant (p=0.00011, n=6). In the group with precipitous labor, regurgitation scoring 4 and 5 points was recorded in 50% of cases, whereas with physiological delivery, low-intensity regurgitation was more common – 70% (p ≤ 0.05). The mode of delivery did not affect regurgitation intensity (p=0.133, n=12).

Analysis of the neonatal period, feeding patterns, physical development level, and morbidity during the first year of life did not reveal statistically significant differences between the groups.

Regurgitation syndrome is a functional digestive disorder determined not only by the anatomical and physiological characteristics of the infant's lower esophageal sphincter (LES) but also by disturbances in the autonomic and humoral regulation of esophageal motility.

It is now widely accepted that discoordination of esophageal and gastric motor activity is due to several aspects. Firstly, traumatic-hypoxic damage to the brain and spinal cord of perinatal origin, namely, pregnancy pathology (toxemia, preeclampsia, threatened abortion, anemia, preeclampsia, exacerbation of chronic conditions, insulin-dependent gestational diabetes, smoking, etc.) and delivery (precipitous labor, labor dystocia, operative delivery, preterm birth, etc.) [9, 10, 11]. For instance, it has been noted that functional gastric disorders in infants are significantly more frequently associated with a diagnosis of autonomic-visceral dysfunction syndrome. The leading mechanism for this syndrome is damage to the diencephalic brain structures, limbic system, medulla oblongata, and subsequent disruption of neuroendocrine regulation [12].

Secondly, an imbalance of gastrointestinal hormones (gastrin, secretin, cholecystokinin, motilin, vasoactive intestinal peptide), as well as increased intra-abdominal and intragastric pressure, which can also be caused by hypoxia, exacerbate LES incompetence and gastroesophageal reflux (GER).

Thirdly, considering the GI tract as a unified system, it has been suggested that a failure in central regulatory mechanisms is unlikely to characterize only an isolated lesion of its upper parts. According to research findings, qualitative and quantitative changes in the gut microbiota structure were found in more than half of children with functional GI disorders and were accompanied by motor-sphincteric impairments. The obtained research data can possibly be explained by deviations along the brain-gut-microbiota axis.

During the statistical analysis of the questionnaire data, we identified an association between regurgitation and its intensity with maternal toxemia/preeclampsia, despite the sample characteristics, which included relatively healthy children with a relatively favorable perinatal history. The literature, however, primarily emphasizes that severe toxemia (preeclampsia), manifesting as increased blood pressure, preeclampsia, eclampsia, edema, nephropathy, leads to impaired maturation of cortical and subcortical centers regulating digestive tract motility [9, 12].

When assessing regurgitation intensity, we discovered a paradoxical situation: children from mothers with preeclampsia in the third trimester, which manifested as nephropathy and mild edema, significantly more often had low-intensity regurgitation. Most likely, this contradictory finding can be explained by the fact that although preeclampsia presented with serious symptoms, it did not reach severe forms like eclampsia. Also, the expected positive correlation between gestational diabetes and regurgitation intensity was not found. On the contrary, children from mothers with gestational diabetes more frequently had non-intense regurgitation, which is likely due to its mild course, compensated by diet.

It has been described that symptoms of preeclampsia such as nausea, vomiting, hypertension, preeclampsia, eclampsia, edema, nephropathy, as well as gestational diabetes, are associated with translocation of the maternal gut microbiome composition and reduced its alpha-diversity [13]. However, it remains unclear whether these changes are a cause or consequence of preeclampsia, as well as gestational diabetes [14, 15]. There is evidence that gut microbes and their metabolites influence the development of the fetal immune, endocrine, general, and enteric nervous systems, determining the neurohumoral regulation of the digestive tube in the postnatal period [16]. It has been noted that children whose mothers suffered from preeclampsia had an aberrant gut microbiota composition [17] and impaired GI motor function [10].

Based on our questionnaire analysis, we established that precipitous labor is associated with the development of intense regurgitation. This fact has been repeatedly confirmed by domestic and international studies [9, 10, 11]. One of the causes of excessively strong labor is considered to be fetoplacental insufficiency, which develops during pathological pregnancy, in our case – toxemia/preeclampsia and gestational diabetes. The consequences of precipitous labor include the release of stress hormones, acute hypoxia, and birth trauma, including injury to the cervical spine with compression of the vertebral arteries and the occurrence of brain ischemia areas in the projection zone of the lower esophageal sphincter [18].

This retrospective study identified an association between minor pregnancy characteristics, specific features of delivery, and the development of regurgitation syndrome of varying intensity in infants.

The results of our study emphasize the importance of considering even mild forms of preeclampsia and gestational diabetes as potential predictors for the development of regurgitation syndrome in infants. Their detection will allow for timely preventive measures and help avoid the subsequent development of chronic respiratory and digestive pathologies in these children. Further studies with a larger number of participants are needed to clarify the identified associations.