Preterm Infants with Increased Infections Following Acid Suppression Therapy

A recent study (P Manzoni et al. J Pediatr 2018; 193: 62-7) provide more data on the detrimental effects of gastric acid inhibitors (eg. proton pump inhibitors, histamine-2 receptor antagonists).  This study was a secondary analysis using prospectively collected data from 235 preterm very low birth weight infants. Key findings:

  • “After multivariate analysis, exposure to inhibitors of gastric acidity remained significantly and independently associated with LOS [late-onset sepsis] (OR 1.03); each day of inhibitors of gastric acidity exposure conferred an additional 3.7% odds of developing LOS.”
  • Acid suppression therapy was associated with gram-negative (P<.001) and fungal pathogens (P=.001)
  • The study showed an association between acid blockers and with necrotizing enterocolitis, which was mitigated in those who received bovine lactoferrin

My take (borrowed, in part, from authors): This data “confirm, strengthen, and expand on previous reports describing an association between inhibitors of gastric acidity and infections.”  Thus, the risks of these medications is likely greater than the benefits in the majority of preterm infants.

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#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.


AGA Blog: What are the complications of PPI Therapy?

AGA Journals Blog: What are the complications of proton pump inhibitor (PPI) Therapy?

The blog post reviews a recent article on PPIs and potential complications.

An excerpt:

review article from Michael F. Vaezi et al discusses potential adverse consequences of proton-pump inhibitor (PPI) therapy in the July issue of Gastroenterology…(2017; 153: 35-48). The authors discuss overzealous conclusions based on weak associations that have caused widespread alarm, leading to inappropriate discontinuation of a medicine that is needed for an established disease process. They present absolute and relative risks for adverse effects associated with long-term use of PPIs…

Vaezi et al review the consistency of proposed associations with PPI use and the time period between the PPI exposure and outcome, and the effects of different doses. They provide guidance for methodologies of future studies.

The review article concludes that PPIs have revolutionized the management of patients with GERD and patients at risk of upper gastrointestinal ulceration and bleeding from aspirin or NSAIDs. However, many patients receive PPIs unnecessarily for conditions or symptoms for which they would not have been expected to provide benefit… Vaezi et al state that, as always, PPIs should be given in the lowest effective dose, for the shortest possible time.

They add that much of the evidence linking PPI use to serious long-term adverse consequences is weak and insubstantial. It should not deter prescribers from using appropriate doses of PPIs for appropriate indications.

Full text of original article: Complications of Proton Pump Inhibitor Therapy

Table 6 lists the strengths of the findings along with other Hill Criteria to assess all of the proposed complications.  The vast majority of potential complications have “weak” proof; the exceptions include bacterieal enteric infections/Clostridium difficile infection which have moderate strength of evidence and and fundic gland polyps which have high strength of evidence.

My take: This study and the associated AGA Journals blog post indicate that most of the reports of complications associated with PPI remain unproven and are based on weak evidence.


Recent Study Did NOT Find Dementia Risk with PPIs

When performing retrospective studies, many times a potential association can be found with medications or diet and specific problems.  When these risks/associations are low (i.e. relative risks <2), often, these findings do not hold up, particularly with prospective studies which are much more able to control for confounding variables.

For proton pump inhibitors (PPIs), many potential complications have been suggested at  low relative risk findings in poorly-controlled studies.  A recent study has contradicted previous findings suggesting that PPIs increase the risk of dementia.

Goldstein FC, et al. J Am Geriatr Soc. 2017;doi:10.1111/jgs.14956. (Thanks to Ben Gold for this reference)

A link and an excerpt from a summary of this study from Healio Gastroenterology:

Link: Study finds no link between PPIs, dementia, Alzheimer’s risk


They evaluated 10,486 volunteers within the NIH-supported Alzheimer’s Disease Centers who were aged 50 years and older and had either normal cognition or mild cognitive impairment at baseline. Participants underwent neuropsychological evaluations and self-reported PPI use at two to six annual visits between 2005 and 2015.

Overall, 884 reported they were taking PPIs at every visit, 1,925 reported they took PPIs intermittently, and 7,677 never reported taking PPIs.

Those who reported continuous PPI use showed a lower risk for cognitive function decline compared with those who never reported using PPIs (HR = 0.78; 95% CI, 0.66-0.93) as well as a lower risk for developing mild cognitive impairment or Alzheimer’s disease (HR = 0.82; 95% CI, 0.69-0.98).

Those who reported using PPIs intermittently also showed a lower risk for cognitive function decline (HR = 0.84; 95% CI, 0.76–0.93) and for developing mild cognitive impairment or Alzheimer’s disease (HR = 0.82; 95% CI, 0.74–0.91).

My take: This study provides reassurance that PPIs are unlikely to result in cognitive decline. Particularly when a study suggests a low risk of an association, further studies are needed to clarify the true risks.

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Long-term Effects on Bone Health of PPIs in Infancy?

A recent study –summarized by Pediatric News (MDedge): Antacid use in infants linked to increased fracture risk.

In this large study (874,447 children), more than 90% of the cohort had not received a prescription for any antacid.

An excerpt:

The large study revealed that use of proton pump inhibitors (PPIs) before age 1 year was linked to a 22% increased risk of fracture, compared with those not prescribed antacids…

The retrospective study’s cohort comprised 874,447 children born between 2001 and 2013 who had been in the U.S. Military Health System for at least 2 years…

Adjustment for preterm birth, low birth weight, sex, and a previous fracture barely reduced those risks: 22% increased risk for PPI use, 4% increased risk for H2 blocker use, and 31% increased risk for using both. The vast majority of children who took antacids had been prescribed them in their first 6 months, so the researchers calculated adjusted risk by age of exposure. 

My take: There are a lot of reasons to resist using PPIs in most infants, particularly lack of efficacy.  Potential harms of these medications, particularly at the youngest ages, should not be overlooked either.

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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

All Bleeding Stops (part 2)

Several years ago, this blog provided a summary of the guidelines for stopping upper gastrointestinal bleeding (All bleeding stops | gutsandgrowth).  Most of the recommendations are unchanged.  A nice review of this topic (L Laine. NEJM 2016; 374: 2367-76), specifically focused on peptic ulcers, provides a few new pointers.

Two areas with more data:

  1. Transfusion.  “A randomized trial showed lower rates of death (the primary outcome), rebleeding, and adverse events with a transfusion threshold of 7 g per deciliter than with a transfusion threshold of 9 g per deciliter.”
  2. Proton pump inhibitors. “A recent meta-analysis showed that intermittent oral or intravenous proton-pump inhibitor therapy results in outcomes that were non inferior to those after continuous infusion.”  (JAMA Intern Med 2014; 174: 1755-62) For adults, the suggested dosing was 80 mg followed by 40 to 80 mg twice daily for 72 hours.

As before, the author recommends preoperative (30 min prior) erythromycin (250 mg) and states that a nasogastric tube in not needed.  The author also recommends that in patients with idiopathic ulcers (not due to NSAIDs or H pylori) that ongoing (indefinite) use of once-daily maintenance therapy with a proton-pump inhibitor is recommended to prevent rebleeding.

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Proton Pump Inhibitors Webinar

For those who missed the live NASPGHAN webinar, it is also available on demand: Link: Proton Pump Inhibitors Webinar. CME credit is available too.

Overall, this is a terrific review and intended for a high level audience. Here are a couple of key points from the talk:

  • Dr. Jennifer Lightdale introduced the webinar.  She noted that there has been a tremendous rise in the use of proton pump inhibitors (PPIs) in children over the past 15 years, including in infants.
  • Preponderance of evidence does not support use of PPIs for reducing GER symptoms or crying in infants.
  • PPIs are extremely effective at acid suppression.
  • Excellent discussion by Dr. Rachel Rosen on Nonerosive Reflux Disease (NERD) and distinguishing this entity from erosive reflux disease, hypersensitive esophagus, and functional heartburn.
  • On a microscopic level, NERD is similar to erosive reflux with microscopic inflammation and dilated intracellular spaces.
  • With regard to testing, it is recommended that for impedance studies, that acid suppression be stopped prior due to improved sensitivity/accuracy.
  • For those at odds with their pulmonologists and ENT colleagues, Dr. Ben Gold reviewed the literature on asthma, cough, and laryngeal-pharyngeal pathology related to reflux. The sensitivity of laryngoscopic findings to identify reflux is poor.  “There is insufficient evidence to recommend for OR against the use of acid suppression therapy.”
  • Dr. Jose Garza reviewed the indications for PPI use which include eosinophilic esophagitis/PPI-REE, erosive esophagitis, NSAID prophylaxis, Upper GI bleeding, and H pylori therapy.
  • Dr. Carlo DiLorenzo provided an in-depth discussion of the potential risks of PPI therapy and explained some of the context as well as absolute risks.  He noted that besides the risk of infection, particularly C difficile, other risks demonstrated in adults have not yet been confirmed in children.
  • “Prolonged acid suppression should be used only when indicated.”  Thus, management should include strategies for treatment discontinuation in the majority of those receiving PPI therapy.

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Isla Verde, San Juan

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PPIs Alter the Microbiome

A couple of comments –today’s blog (below) and yesterday’s blog both point out potential concerns with proton pump inhibitors (PPIs).  There is a danger that when publications emphasize the potential consequences of PPI use (including NPR’s recent piece on kidney disease and PPIs) that physicians and families will overlook the value of these medications.

With regard to the benefits of PPIs, there are a large number of studies supporting the effectiveness of PPIs for various GI conditions.  As a result, there is little being published on drug effectiveness at this time.  On a daily basis, these medications prevent a great deal of suffering, heal esophagitis, heal ulcers and contribute to improved health.  If one looks only at the negative side of the ledger, this could create harm.

My personal belief is that when PPIs are used, that it is important to consider both the advantages and the disadvantages.  If the benefits are unclear, this increases the necessity of evaluating the risks, especially in vulnerable populations.  In addition, when the benefits are unclear, determining the length of therapy and/or performing appropriate diagnostic workup becomes essential.

Also, for pediatric gastroenterologists reading this blog, it is important to realize that my blog’s following is tiny in comparison to the circulation of the Journal of Pediatrics and news organizations like NPR.  Therefore, we need to engage our pediatrician/family medicine colleagues to help make sure that PPIs are used effectively.  I am looking forward to the January 26 NASPGHAN webinar on this topic.


The degree to which proton pump inhibitors (PPIs) affect the gut microbiome is unclear.  A recent study of 12 healthy volunteers (DE Freedberg et al. Gastroenterol 2015; 149: 883-85, Clearing Out My Desk | gutsandgrowth) indicated that this was not much; however, an even more recent study (F Imhann et al. Gut 2015 December 9 (Gut doi:10.1136/gutjnl-2015-310376)suggests otherwise (abstract below) -their conclusion: “On a population level, the effects of PPI are more prominent than the effects of antibiotics or other commonly used drugs.”  

Link: Proton pump inhibitors affect the gut microbiome


BACKGROUND AND AIMS: Proton pump inhibitors (PPIs) are among the top 10 most widely used drugs in the world. PPI use has been associated with an increased risk of enteric infections, most notably Clostridium difficile. The gut microbiome plays an important role in enteric infections, by resisting or promoting colonisation by pathogens. In this study, we investigated the influence of PPI use on the gut microbiome.

METHODS: The gut microbiome composition of 1815 individuals, spanning three cohorts, was assessed by tag sequencing of the 16S rRNA gene. The difference in microbiota composition in PPI users versus non-users was analysed separately in each cohort, followed by a meta-analysis.

RESULTS: 211 of the participants were using PPIs at the moment of stool sampling. PPI use is associated with a significant decrease in Shannon’s diversity and with changes in 20% of the bacterial taxa (false discovery rate <0.05). Multiple oral bacteria were over-represented in the faecal microbiome of PPI-users, including the genus Rothia (p=9.8×10(-38)). In PPI users we observed a significant increase in bacteria: genera Enterococcus, Streptococcus, Staphylococcus and the potentially pathogenic species Escherichia coli.

CONCLUSIONS: The differences between PPI users and non-users observed in this study are consistently associated with changes towards a less healthy gut microbiome. These differences are in line with known changes that predispose to C. difficile infections and can potentially explain the increased risk of enteric infections in PPI users. On a population level, the effects of PPI are more prominent than the effects of antibiotics or other commonly used drugs.

My take: It is likely that the effects on the microbiome are even more notable in infants/younger children; in neonates, the changes in the microbiome could increase the risk of serious diseases like necrotizing enterocolitis.

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The Prosecution Rests…PPIs on Trial

For physicians who use proton pump inhibitors in a cavalier manner, a recent review (CM Stark, CM Nylund. J Pediatr 168: 16-22) provides a sobering reassessment of the potential side effects and potential complications of proton pump inhibitors (PPIs).  After finishing the article, the impression left was of a lawyer putting these medications on trial for high crimes and misdemeanors.

Here were the key points:

Infectious disease: PPI-induced hypochloridia is known to alter the gastrointestinal bacteria motif, allowing certain normally absent or depleted pathogenetic microorganisms to survive and proliferate.  This can lead to all of the following:

  • small bowel bacterial overgrowth
  • increased gastrointestinal infections (including Clostridium difficile, Salmonella, Campylobacter, and acute viral gastroenteritis)
  • pneumonia (particularly community acquired pneumonia and hospital acquired pneumonia)
  • upper respiratory infections
  • spontaneous bacterial peritonitis.

The magnitude of these associations is discussed in detail in the review.

Gastrointestinal disease: Use of PPIs has been associated with an increased incidence of the following:

  •  celiac disease which persisted after excluding prescriptions in the year preceding diagnosis (association does not prove causation)
  • benign gastric fundic polyps
  • rebound acid hypersecretion

Malabsorption: PPIs can affect absorption of multiple nutrients, though more studies are needed, particularly in the pediatric age group.

  • calcium: “there is significant evidence to suggest that PPI use can alter calcium and bone metabolism…associated with an increased risk of hip fractures in older adults….It is reasonable to hypothesize that PPI administration during adolescence and early adulthood could decrease an individual’s peak bone density.”
  • magnesium: PPI have been hypothesized to affect magnesium absorption.  “A study of 366 Canadian patients hospitalized with hypomagnesemia…found PPIs [were] associated with a 43% increased risk of hospitalization.”  More studies are needed to determine the whether this risk is truly significant.
  • iron, vitamin B12, and vitamin C absorption may be affected by PPI use.


  • Cardiac: In adults, PPI use has been associated with adverse cardiac events.  The pathophysiology could have been pediatric implications.  PPIs can increase asymmetrical dimethylarginine (ADMA) which is an endogenous inhibitor of nitric oxide synthase.
  • Renal: PPIs have been associated with cases of acute interstitial nephritis
  • Microbiome: “PPIs alter the microbiome.”  Decreased diversity of the microbiome has been associated with a large number of medical conditions, including irritable bowel syndrome, inflammatory bowel disease, nonalcoholic fatty liver disease, necrotizing enterocolitis as well as many non-gastrointestinal conditions.  “The temporality of dysbiosis and subsequent disease development has  not been explored fully for most conditions.”

My take: PPIs can be life-saving and disease-altering medications.  At the same time, (per authors) “PPIs should not be prescribed without consideration for all short- and long-term side effects.”

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This Webinar Will Review Issues with Regard to Optimal PPI Usage and Includes My Esteemed Colleagues (Dr. Gold and Dr. Garza)

This NASPGHAN Webinar Will Review Issues with Regard to Optimal PPI Usage and Includes My Esteemed Partners (Dr. Gold and Dr. Garza)