Which Symptom is Best for Indicating Reflux in Infants?

A recent study (CR Collins et al. J Pediatr 2019; 206; 240-7) showed that symptoms alone are not able to predict the degree/presence of reflux in infants.

Methods: The authors recruited ‘symptomatic’ infants with median 41 weeks postmenstrual age (median 29 weeks at birth) and employed a combination of 24-hour pH-impedance to determine acid reflux index (ARI) and subsequently used provocative esophageal infusions (with air, water then apple juice) to assess manometry and symptoms. In total, they analyzed 2635 separate esophageal stimula in 74 infants.

The authors considered ARI <3% as normal, 3-7% as indeterminate ARI, and >7% as abnormal ARI.

Symptoms that they recorded included arching, irritability, cough, gag, sneeze, gasp, bradycardia, desaturation, throat clearing, startle, grimace, grunting, mouthing, and yawning.

Key findings:

  • “The presence of physical symptoms (ARI <3: 80%; ARI 3-7: 77%; ARI >7: 81%; P=0.4), cardiorespiratory symptoms (ARI <3: 27%; ARI 3-7: 40%; ARI >7: 26%; P=0.4),or sensory symptoms (ARI <3: 26%; ARI 3-7: 22%; ARI >7: 35%; P=0.3) were also not significantly different by ARI groups”
  • All infants had a normal symptom index (SI) for acid, nonacid, or total reflex.
  • Accepted metrics, SI, SSI, and SAP, had higher association with nonacid events compared with acid events.
  • Cardiorespiratory symptoms are more likely to be elicited by esophageal infusions with both water and apple juice than air.  “Symptoms are indicators of esophageal dysmotility and maladaptive aerodigestive protective mechanisms.”
  • The authors in their discussion state that “GERD severity plays no role in the generation of symptoms.”

My take: All infants with and without reflux have a lot of “symptoms.”  Nonacid reflux is much more likely to provoke symptoms in this population than acid reflux reinforcing the idea that acid suppression is likely ineffective and potentially harmful.  “The findings of this study challenge the rationale for instituting anti-GERD therapies in neonates based on either symptoms alone or the existing acid-reflux indices or pH-impedance metrics.”

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Link to article cited below from The Onion: Dog Feels Like He Always Has To Be ‘On’ Around Family Thanks to Jennifer for this reference.

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  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.


How often are acid blockers used in neonates?

A recent study (JL Slaughter et al. J Pediatric 2016l 174: 63-70) shows a high rate of acid blockers in neonatal intensive care units.  This study retrospectively analyzed the Pediatric Health Information System database (PHIS) from 2006-2013.

  • Of 122,0002 infants: 23.8% received either a histamine-2-receptor antagonist (H2RA) or proton pump inhibitor (PPI).
  • 19.0% had received an H2RA
  • 10.5% had received a PPI

My take (borrowed from authors): “despite limited evidence and  increasing safety concerns, H2RAs/PPIs are frequently prescribed to extremely preterm neonates…Our findings support the need for innovative studies.”  Wouldn’t it be nice if there was proof of efficacy in this population?

Vickery Creek, Roswell

Vickery Creek, Roswell

‘Little’ Knowledge Exists Regarding Medicines for Neonates

Despite federal legislation encouraging the study of products used in the pediatric population, very little of these studies has translated into meaningful information regarding neonates (JAMA Pediatr 2014; 168: 130-36, thanks to Ben Gold for this reference).

This publication reviewed studies submitted to the FDA between 1997-2010.  The authors identified all drugs with pediatric studies that included neonates.  Subsequently, the use of these drugs was examined in a oohort of neonates admitted to 290 neonatal intensive care units (NICU) (Pediatrix Data Warehouse) in the U.S. form 2005-2010.

Key findings:

  • 28 drugs (in 41 studies) were examined in neonates. This led to 24 labeling changes.
  • 11 of 24 neonatal labeling changes included an approval for use in neonates, including 4 for HIV and 3 for anesthesia.
  • 13 of 24 labeling changes were the following: “safety and effectiveness have not been established.”  These drugs included several reflux medications: esomeprazole, lansoprazole, pantoprazole, and ranitidine.
  • In the Pediatrix database involving 446,335 hospitalized neonates, there were 399 different drugs identified that had been administered.  Of the 28 studied drugs, the gastroesophageal reflux medicines were used most frequently.  13 of the 28 studied drugs were not used at all in the NICUs.
  • Of the 11 drugs with a neonatal indication, 7 were never used in the Pediatrix neonatal population and the other 4 drugs were used infrequently.


  • Neonates are a vulnerable and an understudied population
  • Most of the exposure to drugs was off-label for neonates.
  • Most often, off-label drugs were prescribed “despite studies indicating they were not effective…For example, ranitidine, lansoprazole, and inhaled nitric oxide (for the prevention of bronchpulmonary dysplasia) were the top 3 drugs used in neonates…none have FDA labelling for the indication studied because of lack of efficacy.”
  • Furthermore, drugs like ranitidine and lansoprazole” are associated with serious adverse effects in neonates.” (Clin Perinatol 2012; 39: 99-109)

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PPIs in Neonates –Helpful?

Acid suppression in infants has not been proven to be effective in reducing gastroesophageal reflux (GER) symptoms. In a systemic review, this was thought to be either “because the symptoms are not caused by GER or if due to GER, because the symptoms are caused by volume reflux, rather than acidity.”  This quote is noted in the background information of another study which came to the same conclusion (J Pediatr 2013; 163: 692-8).

The pharmaceutical-supported study enrolled neonates (n=52) at 3 centers with gestational ages between 28-44 weeks.  Half of the participants were randomized to esomeprazole (0.5 mg/kg/day) and half placebo.  GER symptoms that were required for enrollment included any 2 of the following:

  • apnea with or without bradycardia
  • apnea with or without oxygen desaturations
  • irritability/pain
  • vomiting/gagging

Participants underwent extensive testing with video monitoring, esophageal pH & impedance testing, and cardiorespiratory monitoring.  They were followed for 14 days.


  • There were no significant differences in any GERD-related signs and symptoms.
  • The esomeprazole group had improvement in acid reflux parameters on testing at 7 days, including number of reflux episodes (35 –>23) and mean percent time with pH<4.0.  The latter change was -10.7% was statistically significant (p= .0017) compared to placebo group which had an increase in time with pH<4.0 (2.2% increase).
  • No new safety signals were identified.

Despite its widespread usage, the authors had difficulty enrolling a larger cohort.  The small sample size was one of the study’s limitations along with the 14-day study period.  This limitation also precludes conclusions regarding the safety of these medications in neonates.

Bottomline: this study adds to the growing body of evidence that proton pump inhibitors (PPIs) are not effective in infants with so-called ‘signs and symptoms of reflux.’  PPIs are effective at reducing acid exposure and could be helpful in proven mucosal disease (eg. esophagitis and gastritis).

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