Gastroesophageal Reflux and Gastrointestinal Manifestations of Cow’s Milk Protein Allergy

Gastroesophageal Reflux and Gastrointestinal Manifestations of Cow’s Milk Protein Allergy

Gastroesophageal reflux (GER) and cow milk allergy (CMA) occur frequently in infants younger than 1 year. In recent years, the relation between these 2 entities has been investigated and some important conclusions have been reached: in up to half of the cases of GER in infants younger than 1 year, there may be an association with CMA. In a high proportion of cases, GER is not only CMA associated but also CMA induced.

The frequency of this association should induce pediatricians to screen for possible concomitant CMA in all infants who have GER and are younger than 1 year. With the exception of some patients with mild typical CMA manifestations (diarrhea, dermatitis, or rhinitis), the symptoms of GER associated with CMA are the same as those observed in primary GER. Immunologic tests and esophageal pH monitoring (with a typical pH pattern characterized by a progressive, slow decrease in esophageal pH between feedings) may be helpful if an association between GER and CMA is suspected, although the clinical response to an elimination diet and challenge is the only clue to the diagnosis.

Gastrointestinal motility

Cow’s milk protein allergy (CMPA) may cause gastrointestinal motility disorders. Symptoms of both conditions overlap and diagnostic tests do not reliably differentiate between both. A decrease of symptoms with an extensive hydrolysate and relapse during challenge is not a proof of allergy, because hydrolysates enhance gastric emptying, a pathophysiologic mechanism of gastro-oesophageal reflux (GER). Thickened formula reduces regurgitation, and failure to do so suggests CMPA. A thickened extensive hydrolysate may induce more rapid improvement, but does not always differentiate between CMPA and GER. Different hypotheses are discussed: is the overlap between CMPA and functional disorders coincidence, or do both entities present with identical symptoms, or does the fact that symptoms are identical indicates that there is only one entity involved? Studies on the prevention of CMPA focused on ‘at-risk families’, and resulted in a decrease of CMPA and atopic dermatitis, but did not provide data on the incidence of GER. Conclusion:  As long as there are no objective diagnostic tools to separate GER from CMPA, the physician has two options: first treat the most likely diagnosis, and switch if after 2-4 weeks there is no improvement, or treat both conditions with one intervention, what will not result in a diagnosis.

Gastrooesephageal Refluks

Gastroesophageal reflux (GER) is one of the most frequent symptomatic clinical disorders affecting the gastrointestinal tract of infants and children. During the past 2 decades, GER has been recognized more frequently because of an increased awareness of the condition and also because of the more sophisticated diagnostic techniques that have been developed for both identifying and quantifying the disorder. Gastroesophageal fundoplication is currently one of the three most common major operations performed on infants and children by pediatric surgeons in the United States. Normal gastroesophageal function is a complex mechanism that depends on effective esophageal motility, timely relaxation and contractility of the lower esophageal sphincter, the mean intraluminal pressure in the stomach, the effectiveness of contractility in emptying of the stomach, and the ease of gastric outflow. More than one of these factors are often abnormal in the same child with symptomatic GER. In addition, in patients with GER disease, and particularly in those patients with neurologic disorders, there appears to be a high prevalence of autonomic neuropathy in which esophagogastric transit and gastric emptying are frequently delayed, producing a somewhat complex foregut motility disorder. GER has a different course and prognosis depending on the age of onset. The incompetent lower esophageal sphincter mechanism present in most newborn infants combined with the increased intraabdominal pressure from crying or straining commonly becomes much less frequent as a cause of vomiting after the age of 4 months. Chalasia and rumination of infancy are self-limited and should be carefully separated from symptomatic GER, which requires treatment.
The most frequent complications of recurrent GER in childhood are failure to thrive as a result of caloric deprivation and recurrent bronchitis or pneumonia caused by repeated pulmonary aspiration of gastric fluid. Children with GER disease commonly have more refluxing episodes when in the supine position, particularly during sleep. The reflux of acid into the mid or upper esophagus may stimulate vagal reflexes and produce reflex laryngospasm, bronchospasm, or both, which may accentuate the symptoms of asthma. Reflux may also be a cause of obstructive apnea in infants and possibly a cause of recurrent stridor, acute hypoxia, and even the sudden infant death syndrome. Premature infants with respiratory distress syndrome have a high incidence of GER. Esophagitis and severe dental carries are common manifestations of GER in childhood.

Barrett’s columnar mucosal changes in the lower esophagus are not infrequent in adolescent children with chronic GER, particularly when Heliobacter pylori is present in the gastric mucosa. Associated disorders include esophageal dysmotility, which has been recognized in approximately one third of children with severe GER.

Symptomatic GER is estimated to occur in 30% to 80% of infants who have undergone repair of esophageal atresia malformations. Neurologically impaired children are at high risk for having symptomatic GER, particularly if nasogastric or gastrostomy feedings are necessary. Delayed gastric emptying (DGE) has been documented with increasing frequency in infants and children who have symptoms of GER, particularly those with neurologic disorders. DGE may also be a cause of gas bloat, gagging, and breakdown or slippage of a well-constructed gastroesophageal fundoplication.

The most helpful test for diagnosing and quantifying GER in childhood is the 24-hour esophageal pH monitoring study. Miniaturized probes that are small enough to use easily in the newborn infant are available.

Gastroesophageal reflux (GER) in infants can be secondary to food allergy. We have evaluated the frequency with which GER is associated with cow’s milk protein allergy (CMPA) in infants < 1 yr old and tried to indicate the laboratory and instrumental examinations useful in diagnosing GER + CMPA. The studies of 140 infants, After 24-h esophageal pH-metry, esophageal endoscopy, and elimination diet, followed by a double-blind challenge, the patients were divided into four groups: primary GER, GER secondary to CMPA, CMPA without GER, and a control group with subjects suffering from neither GER nor CMPA. Thirty of 72 patients with GER were also suffering from CMPA. No differences were observed as regards age, sex, symptoms, and clinical or family history between patients with GER only and those with GER + CMPA.

The immunological test most useful for GER + CMPA diagnosis was the IgG anti-beta-lactoglobulin assay: positive in 27/30 subjects with GER + CMPA and in 4/42 patients with GER only. We also observed a characteristic pattern of the pH-monitoring tracing in 26/30 patients with GER + CMPA but in none of the 42 patients with GER only. This consisted of a progressive, constant reduction in esophageal pH at the end of a feed, which continued up to the following feed, when pH rose steeply. The evidence of this characteristic tracing and of a high IgG anti-beta-lactoglobulin value are specific and sensitive tests for GER + CMPA diagnosis.

Vomiting and gastric motility in infants with cow’s milk allergy.

Regurgitation and vomiting are common manifestations of cow’s milk protein allergy (CMPA) in infants and are usually ascribed to gastroesophageal reflux (GER). Gastric anaphylaxis can induce antral dysmotility in the rat, and therefore the hypothesis for the current study was that cow’s milk in sensitized infants may impair antral motility, thereby promoting GER and reflex vomiting.

Seven vomiting infants with CMPA and nine with primary GER underwent a challenge with cow’s milk formula. Electrogastrography (EGG) was used to measure the spectral frequency (bradygastria = 1.5-2.4 cycles per minute [cpm], normogastria = 2.5-3.9 cpm, tachygastria = 4.0-9.0 cpm) and the postprandial-to-fasting power ratio of gastric electrical activity, whereas gastric half-emptying time (T1/2) was measured by electrical impedance tomography (EIT). In CMPA and GER, respectively, during fasting, the frequency distribution of the EGG was as follows: normogastria, bradygastria, and tachygastria . In contrast, after the cow’s milk challenge, the difference between the two groups was statistically significant: normogastria. bradygastria and tachygastria. The postprandial/ fasting power ratio in CMPA and in GER. Gastric T1/2 of the cow’s milk meal was 89.0+/-26.3 minutes versus 54.0+/-12.6 minutes. In infants with GER all EGG parameters and gastric T1/2 were similar to that in 10 healthy control infants.

In sensitized infants, cow’s milk induces severe gastric dysrhythmia and delayed gastric emptying, which in turn may exacerbate GER and induce reflex vomiting. Electrogastrography and EIT can be useful in the assessment of vomiting, GER, and CMPA in infants.

Acid gastroesophageal reflux and intensity of symptoms in children with gastroesophageal reflux disease.

The ability to differentiate between primary and secondary causes of gastroesophageal reflux (GER) is extremely important during the diagnostic procedure. At the same time, the quality of symptoms and the intensity of the course of gastroesophageal reflux disease (GERD) should be estimated. Acid GER is assessed using 24-hour esophageal pH monitoring; the results of this diagnostic test should always be interpreted alongside the clinical picture.

The interdependence between the intensity of the clinical symptoms and the acid reflux index in children with primary GER and GER secondary to cow’s milk protein allergy (CMA) and/or other food allergies (FA).

Primary GERD was diagnosed and GERD secondary to CMA/FA was confirmed. The most important pH-metric parameter analyzed in study groups 1 and 2 was the GER index: total and supine. An assessment of the intensity of symptoms and a comparative analysis of intensity was evaluated against the GER index: total and supine. It was estimated that the higher the GER result in both total and supine positions (for both leads), the higher the level of symptoms noted. This interdependence was demonstrated for both groups.

In seeking to determine any etiopathogenetic connection between primary GER or GER secondary to CMA/FA and their clinical consequences, 24-hour esophageal pH monitoring with a 2-channel probe is recommended, since it provides for better clinical control of GERD and its appropriate treatment.

Vomiting and gastroesophageal motor activity in children with disorders of the central nervous system.

Vomiting is common in children with disorders of the central nervous system (CNS) and is usually ascribed to gastroesophageal reflux (GER). However, recent acquisitions on the pathophysiology of vomiting suggest that the dysmotility of the foregut may be more widespread.

Fifty-five children with CNS disorders, 50 of whom suffered from retching and/or vomiting (18 following fundoplication) were studied. The study assessed GER by 24 hour pH monitoring and endoscopy, gastric electrical activity by electrogastrography, and gastric half-emptying time (T1/2) of a milk meal be electrical impedance tomography. Of the 50 vomiting patients, 29 had GER and 31 had gastric dysrhythmias, 4 bradyarrhythmia, 15 unstable electrical activity; controls; 2.2-4.0 cpm). Sixteen patients had GER and gastric dysrhythmias. Gastric T1/2 was delayed in patients with gastric dysrhythmia, versus 2 of 5 with GER alone. No abnormalities were detected in the 5 patients who did not suffer from vomiting.

Children with CNS disorders who vomit have abnormal gastric motility as often as GER. Following fundoplication, many patients continue to have symptoms possibly related to gastric dysrhythmias, the effects of which may be unmasked by fundoplication. Foregut dysmotility may be related to abnormal modulation of the enteric nervous system by the CNS or to involvement of the enteric nervous system by the same process affecting the brain.


  • Vandenplas Y, et al. Gastrointestinal manifestations of cow’s milk protein allergy and gastrointestinal motility. Acta Paediatr. 2012 Aug 7.
  • Ravelli AM, et al. Vomiting and gastric motility in infants with cow’s milk allergy. J Pediatr Gastroenterol Nutr. 2001 Jan;32(1):59-64.
  • Ravelli AM, et al. Vomiting and gastroesophageal motor activity in children with disorders of the central nervous system. J Pediatr Gastroenterol Nutr. 1998 Jan;26(1):56-63.
  • Cavataio F, et al. Gastroesophageal reflux associated with cow’s milk allergy in infants: which diagnostic examinations are useful? Am J Gastroenterol. 1996 Jun;91(6):1215-20.
  • Salvatore S, et al. Gastroesophageal reflux and cow milk allergy: is there a link? Pediatrics. 2002 Nov;110(5):972-84.
  • Semeniuk J, et al. Acid gastroesophageal reflux and intensity of symptoms in children with gastroesophageal reflux disease. Comparison of primary gastroesophageal reflux and gastroesophageal reflux secondary to food allergy. Adv Med Sci. 2008;53(2):293-9.
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