Is Reflux Really a Disease in Premature Infants?

From Atlanta Botanical Garden

Z Sultana et al. Gastro Hep Advances 2022; 1: 869-881: Open Access! Symptom Scores and pH-Impedance: Secondary Analysis of a Randomized Controlled Trial in Infants Treated for Gastroesophageal Reflux

In the introduction, the authors note: “Gastroesophageal reflux (GER) is a physiological process defined as the passage of gastric contents into the esophagus with or without regurgitation and vomiting, while GER disease (GERD) is pathophysiologic and occurs when GER is associated with troublesome symptoms and/or complications.”

“This distinction between GER and GERD remains enigmatic among survivors in the neonatal intensive care unit (NICU). Reflux-type symptoms (arching, irritability, acute life-threatening events, coughing, failure to thrive, and swallowing difficulties) in this high-risk infant population can be troublesome to the parent and provider, and empiric management using pharmacological and dietary changes are common albeit with consequences.”

Methods: “Infant Gastroesophageal Reflux Questionnaire Revised (I-GERQ-R) and 24-hour pH-impedance data were analyzed from 94 infants…[and] Longitudinal data from 40 infants that received randomized GER therapy (proton pump inhibitor [PPI] with or without feeding modifications) for 4 weeks followed by 1-week washout were analyzed. Relationships between I-GERQ-R and pH-impedance metrics (acid reflux index, acid and bolus GER events, distal baseline impedance, and symptoms) were examined and effects of treatments compared.”

Key findings:

  • Acid-suppressive therapy with feeding modifications had no effect on symptom scores or pH-impedance metrics. Clearance of refluxate worsened despite PPI therapy.
  • Correlations between I-GERQ-R and pH-impedance metrics were weak or non-existent, indicating that physicians cannot depend only on the questionnaire to diagnose and treat GERD in premature infants.

My take: This study shows that reflux symptoms are unreliable in establishing a diagnosis of reflux disease in infants. In addition, medical treatments were not beneficial in infants with abnormal pH-impedance metrics. Perhaps, it is time to acknowledge that we cannot even agree what reflux “disease” is in (premature) infants.

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Selected Slides from NASPGHAN 2022 Postgraduate Course (Part 2)

See previous post for lecturers

Oral small molecultes in IBD. Anne Griffiths, MD
Judith Kelsen, Very early onset IBD
VEO Evaluation
VEO Treatments
Jeremy Adler and Treat to Target for IBD
Jeremy Adler and Treat to Target for IBD
Jeremy Adler and Treat to Target for IBD
Jeremy Adler and Treat to Target for IBD
Jeremy Adler and Treat to Target for IBD
Timothy Sentongo and Growth and Nutrition Issues in the NICU
Maureen Leonard and Gluten-Related Disorders Update
Maureen Leonard and Gluten-Related Disorders Update
Maureen Leonard and Gluten-Related Disorders Update
Maureen Leonard and Gluten-Related Disorders Update
Rachel Rosen and Esophageal Motor Disorders
Katja Kovacic and Functional Nausea
This study was 20 yrs ago -we can do better today

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

My Favorite Posts from the Past Year

Recently, I listed the posts that had the most views in the past year –some dating back to 2012.  The following list includes less viewed but some of my favorite posts from 2018:





Flowers in Calgary

Clinical Practice Update: Extraesophageal Symptoms Attribute to Gastroesophageal Reflux Disease

A recent practice update (MF Vaezi, D Katzka, F Zerbib. Clin Gastroenterol Hepatol 2018; 16: 1018-29) reviews the data and provides up-to-date recommendations for extraesophageal symptoms attributed to gastroesophageal reflux disease (GERD) in adults.

Extraesophageal symptoms attributed to GERD could include cough, asthma, hoarseness, sore throat, sinusitis, dental erosions, and ear pain.

Key recommendations:

  • Non-GI evaluations by ENT, pulmonary and/or allergy are essential and often should be performed initially in most patients.
  • “Abnormalities seen on endoscopy have poor predictive value for determination of GERD as the cause of extraesophageal symptoms”
  • “Ambulatory pH/impedance monitoring…have limited ability to establish GERD as the cause of an extraesophageal symptom.  The main role of testing is to document the absence of GERD.”
  • Empiric therapy with ‘aggressive’ acid suppression for 6-8 weeks can help in assessing association between reflux and extraesophageal symptoms.
  • Testing for reflux on therapy should be considered mainly in those with high probability of baseline reflux (eg. previous esophagitis, Barrett’s esophagus, or prior abnormal pH study).
  • Surgical treatment is discouraged in those with extraesophageal reflux symptoms unresponsive to aggressive PPI therapy

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Breathing (Diaphragmatic) Helps Belching and Reflux Symptoms

A recent prospective study (A M-L Ong et al. Clin Gastroenterol Hepatol 2018; 16: 407-16) of 36 patients (median age 45) showed that diaphragmatic breathing was helpful for PPI-refractory GERD symptoms/belching.  Patients enrolled all had “troublesome belching” for 6 months and GERD. Patients underwent high resolution manometry and pH-impedance study.

Key findings:

  • 9 of 15 (60%) in the diaphragmatic treatment group reduced their belching visual analog score by ≥50%, whereas none of the control group achieved the primary outcome
  • Treatment also resulted in lower GERD symptoms based on reflux disease questionnaire score -decrease of 12.2 vs 3.1 in the control group (P=.01)
  • Treatment improved QOL scores, based on Reflux-Qual Short form (15.7 increase for treatment group compared to 2.4 decrease in control group)
  • Treatment effects were sustained at 4 months after treatment

My take: Diaphragmatic breathing can be a useful adjunct in GERD, particularly in patients with belching.

Related blog post: Treatment for rumination and belching


Foggy Morning in Sandy Springs

Esophageal Diseases Special

Gastroenterology published a ‘special issue’ in January 2018 (volume 154; pages 263-451) which reviewed several esophageal diseases in-depth: gastroesophageal reflux disease (GERD), eosinophilic esophagitis (EoE), and esophageal cancer. For me, this issue served as a good review on GERD and EoE.

A couple of items that I picked up:

  • For both GERD and functional dyspepsia, “estimated prevalence values are approximately 20% for each.” (pg 269)
  • “15% of healthy individuals may have microscopic esophagitis” (pg 291)
  • For pH-impedance, the current view of non-acid reflux is unchanged: “unknown clinical relevance of non-acid reflux in the setting of aggressive acid suppression.” (pg 291)
  • Treatment algorithm for EoE (pg 353):
    • Induction treatment with any of the three approaches:  high dose topical corticosteroids, double dose proton pump inhibitor (PPI) or elimination diet “because no comparative studies have shown any of these to be superior to the others.”
    • Then, re-evaluation after 2-3 months (clinical, endoscopic, and histologic).  Responders should continue on therapy but maintenance treatment suggests low dose topical corticosteroid, lowering PPI to single dose, or continuing elimination diet.  For nonresponders, switching to one of the other two treatment approaches is recommended.
    • The algorithm indicates that followup evaluation of responders to insure ongoing response should be considered 1 year later
  • As for dilatation, the authors note that this does not control the underlying inflammation and thus should not be used as monotherapy. Also, “after dilatation, 75% of patients have considerable chest pain that may last several days.” (pg 354)

Unrelated twitter post below -IgG allergy testing is NOT a good idea:

#NASPGHAN17 Annual Meeting Notes (Part 2): Year in Review

This blog entry has abbreviated/summarized this presentation. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.

This first slide shows the growth in NASPGHAN membership:

Year in Review

Melvin Heyman  Editor, JPGN

This lecture reviewed a number of influential studies that have been published in the past year.  After brief review of the study, Dr. Heyman summarized the key take-home point.


Update on Chronic Cough

It is not uncommon for a pediatric gastroenterologist to see a patient with a chronic cough due to concerns about potential gastroesophageal reflux disease (GERD).  As such, a recent clinical practice article (JA Smith, A Woodcock. NEJM 2016; 375: 1544-51) by lung specialists was of interest, even though this article was not targeted to the pediatric population.

Key points:

  • The authors define a chronic cough as lasting more than 8 weeks and note that it common with respiratory conditions (eg. chronic obstructive pulmonary disease, asthma, and bronchiectasis) and some non-respiratory conditions (eg. gastroesophageal reflux and rhinosinusitis).  Medications, particularly ACE inhibitors, can trigger a chronic cough as well.
  • Steps in evaluation: 1. H&P, CXR, spirometry. 2. Consider metacholine challenge, ENT evaluation, consider empiric treatment (eg. inhaled glucocorticoids, PPI), and consider GERD evaluation. 3. High-resolution CT and bronchoscopy.
  • For many patients, there is likely to be an abnormality in neuronal pathways controlling cough and the term “cough hypersensitivity syndrome” has been coined.  Figure 2 (below) illustrates the neuronal pathways.
  • For refractory patients, potential therapies would include low-dose morphine, gabapentin or pregabalin, and speech language therapy.



  • Guidelines “suggest a trial of treatment with acid-suppression therapy” (eg. twice-daily PPIs for up to 3 months).
  • “Most randomized, controlled trials of reflux treatment for cough have not shown a significant improvement in association with this type of treatment.”
  • Subgroups of patients with heartburn, regurgitation, or excessive acid reflux on esophageal pH monitoring “appeared marginally more likely to have a response to PPI treatment.”  pH or impedance tests “are poorly predictive of a response of cough to acid suppression.”

My take: In the absence of clinical reflux, reflux therapy is unlikely to help with chronic cough.  However, in patients with an adequate workup, an empiric course of a PPI is likely more preferable than empiric morphine or gabapentin.

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Does Reflux Lead to Increased Aspiration Pneumonia?

This post’s title question turns out to be quite tricky.  According to a recent study (RL Rosen et al. JPGN 2016; 63: 210-17), reflux burden, even in children that aspirate did not correlate with increased hospitalization.

Here are the details:

Methods: Prospectively recruited cohort of 116 children who had both pH-impedance testing along with modified barium swallow. The authors considered pathologic reflux to have at least 73 episodes on pH-impedance or if pH<4 for >6% of study period.

Key findings:

  • There was no statistical correlation between pH-impedance study results and total number of admissions even with or without adjusting for aspiration status (and neurologic complications).

When the authors tried to reconcile these findings, they offered three competing potential explanations for these results:

  • Reflux has little impact on hospitalziations
  • Our methods for measuring reflux are not good
  • Even “normal” reflux can be a problem for those prone to complications; therefore, reflux burden is not consequential.

What is clear is that pH-impedance studies cannot predict which patients are at risk for increased complications.  This is supported by data showing that ‘reflux-related’ hospitalizations may not improve after fundoplication (Pediatrics 2006; 118: 2326-33; J Pediatr Surg 2008; 43: 59-63).  One particularly important limitation was that the cause of hospitalizations was determined by medical record review.

My take: A simple algorithm for preventing aspiration pneumonia does not exist.  Even the role of reflux testing is uncertain.

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The accompanying article guaranteed that the pizza would pass through the body within 30 minutes.

The accompanying article guaranteed that the pizza would pass through the body within 30 minutes!!!


More advice on Proton Pump Inhibitors

L Laine, A Nagar. Am J Gastroenterol 2016; 111: 913-15.

This reference explains how these clinicians discuss the long-term use of proton-pump inhibitors with their adult patients.  Thanks to Ben Gold for this reference.  Here are a couple pointers:

  • “The recent studies about CKD (chronic kidney disease) and dementia, similar to many prior studies assessing PPI risk, are retrospective observational studies…This results in differences between PPI users and non-users in factors that may impact study outcomes and confound results.”
  • Gastroesophageal reflux disease: The authors suggest that PPIs for GERD can be stopped >2 weeks after symptoms resolve.  For infrequent symptoms, H2RAs, lifestyle modifications and intermittent PPIs often suffice.
  • Barrett’s esophagus: “observational sutdies suggest that PPIs may decrease progression to neoplastic Barrett’s esophagus”

WHAT WE TELL PATIENTS: “Because of inherent risk of bias and low effect sizes we cannot conclude that associations of PPIs and adverse outcomes such as dementia and CKD in recent observational studies are vailid…Nevertheless, we cannot conclude that risks do not exist…we need to ensure that benefits outweigh potential risk.  If PPIs are indicated, using the lowest effective dose and, if possible, intermittent rather than daily therapy..should decrease the risk of potential side effects.”

On the same topic, Paul Moayyedi (in Gastroenterology and Endoscopy News, August 2016): “Every study has shown that sicker patients tend to be prescribed PPIs…Sick patients tend to develop other illnesses so PPIs will be associated with about any disease you can imagine in a database.”  As such, he asserts that weak associations (OR <2) are usually due to cofounding factors.  “The only benefit [these studies]..have is that it is another opportunity to discuss with the patients about stopping their PPI therapy, as there are a significant proportion…on these drugs unnecessarily.”

purple flowers