More about reflux: anti-acid medications may also be toxic placebos

While I am still finalizing my long overdue chapter on gastro-esophageal reflux (sorry Sanjay if you are reading this, it is on its way, honestly) I have been reviewing the data on acid blockade as a potential treatment.

Probably the biggest problem with GERD (that is, disease caused by gastro-esophageal reflux) in the newborn, is that it is impossible to diagnose. There is no validated scoring system, and systems used in older children do not transpose to babies. When there have been studies performing objective recordings of esophageal impedance and pH at the same time as recording “symptoms” (this is another of my many peeves, newborn babies do not have symptoms as they can’t tell you how they feel, they have clinical signs), there has been no correlation, babies have just as many clinical signs when they are not having reflux as when they are. So any diagnosis of GERD in a newborn is nothing more than a guess. 

(All the references are below).

One thing that could theoretically cause GERD in a newborn is the acidity of the gastric contents, just like in adults where the reflux causes pain, it is entirely possible that in some preterm or term babies reflux causes pain. Unfortunately we don’t know how to differentiate GER discomfort from other causes of fussiness in babies, and anti-acid therapies do not reduce fussiness.

So do anti-acid therapies do anything? They can be divided into 3 groups, histamine receptor blockers (such as ranitidine), proton pump inhibitors, and others. The histamine H2 blockers (H2RB) have been widely used for years, so we have accumulated a lot of observational data, but unfortunately very little scientific useful data, as usual. The observational data show that H2RB use is associated with more infections, more NEC, and higher mortality; not very encouraging then. So do H2RB at least improve clinical symptoms? Well, no. Controlled trials show that GER symptoms improve over time, whether you get H2RB or not. Why might acid blockers infections? We all swallow billions of bugs every day, this includes babies. The stomach contents are usually very acidic, which kills most of the bugs. If you block the acid, you let more bugs through and increase infections. This is even true in older kids with asthma, a really nice large multi-center RCT in children with asthma was published in JAMA this year, the authors were investigating the common assumption that reflux is an important risk factor for asthmatic episodes, so the idea was that blocking gastric acid should prevent asthma spells, and make the kids better. What they actually found was that there was no improvement in asthma at all, but there were more chest infections in the group that had acid blockade. The same thing seems to happen with babies that have a clinical diagnosis of GER, when you reduce their acid production, you don’t affect their symptoms, but you do risk an increase in infections.

One thing that I was reminded about while reviewing the literature for this chapter is some of the other physiological roles of gastric acid, and potential adverse consequences of blocking it: gastric acid is important in the absorption of calcium, magnesium, iron and vitamin B12. So, if you block it, you might well worsen bone mineralization and anemia. Adults who are on PPIs have more osteoporotic bone fractures; so it is reasonable to think that babies on acid blockers might have more osteopenia as well. As far as I know this has not been studied; if anyone has a database that could answer the question please go ahead (and acknowledge my seminal influence in the eventual PNEJM publication! (the prestigious NEJM)) H2 receptor blockers also have behavioral side effects, and interact with other medications.

So to summarize: if you think that a baby has clinical signs due to acid reflux you are as likely to be wrong as right; even if you are right you need to be aware of the toxicities, which include potentially, osteopenia, iron deficiency, and  an increase in infections and NEC; and even if you are right reducing acid output doesn’t improve symptoms any better than placebo, and also has toxicities, so that causing the risk of getting more troubles like in the prilosec lawsuit settlement case.

Is GER of any importance at all in the newborn? I think it would be a mistake to completely dismiss it. Gastric acid does indeed injure the esophageal mucosa after a while, and causes symptoms in older patients. I think it is likely that there are some newborn babies who have clinical signs as a result of acid reflux, and perhaps as a result of non-acid reflux. We need to find out how to identify those babies, and then find evidence based therapies to help them.

Snel A, Barnett CP, Cresp TL, et al. Behavior and gastroesophageal reflux in the premature neonate. Journal of Pediatric Gastroenterology and Nutrition 2000; 30: 18-21.

Moore DJ, Tao BS-K, Lines DR, Hirte C, Heddle ML, Davidson GP. Double-blind placebo-controlled trial of omeprazole in irritable infants with gastroesophageal reflux. The Journal of Pediatrics 2003; 143(2): 219-23.

Terrin G, Passariello A, De Curtis M, et al. Ranitidine is associated with infections, necrotizing enterocolitis, and fatal outcome in newborns. Pediatrics 2012; 129(1): e40-5.

Graham PL, Begg MD, Larson E, Della-Latta P, Allen A, Saiman L. Risk factors for late onset gram-negative sepsis in low birth weight infants hospitalized in the neonatal intensive care unit. Pediatr Infect Dis J 2006; 25(2): 113-7.

Writing Committee for the American Lung Association Asthma Clinical Research C, Holbrook JT, Wise RA, et al. Lansoprazole for children with poorly controlled asthma: a randomized controlled trial. JAMA : the journal of the American Medical Association 2012; 307(4): 373-81.

Orenstein SR, Shalaby TM, Devandry SN, et al. Famotidine for infant gastro-oesophageal reflux: a multi-centre, randomized, placebo-controlled, withdrawal trial. Alimentary Pharmacology & Therapeutics 2003; 17(9): 1097-107.

Yang YX. Chronic proton pump inihibitor therapy and calcium metabolism. Curr Gastroenterol Rep 2012; 14(6): 473-9.

Ito T, Jensen RT. Association of long-term proton pump inhibitor therapy with bone fractures and effects on absorption of calcium, vitamin B12, iron, and magnesium. Curr Gastroenterol Rep 2010; 12(6): 448-57.

Orenstein SR, Hassall E, Furmaga-Jablonska W, Atkinson S, Raanan M. Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial Assessing the Efficacy and Safety of Proton Pump Inhibitor Lansoprazole in Infants with Symptoms of Gastroesophageal Reflux Disease. The Journal of Pediatrics 2009; 154(4): 514-20.e4.

Tham SY, Rogers IM, Samuel KF, Singh A, Ong KK. Does oral lansoprazole really reduce gastric acidity in VLBW premature neonates? The Medical journal of Malaysia 2012; 67(3): 284-8.

Omari TI, Haslam RR, Lundborg P, Davidson GP. Effect of Omeprazole on Acid Gastroesophageal Reflux and Gastric Acidity in Preterm Infants With Pathological Acid Reflux. Journal of Pediatric Gastroenterology & Nutrition 2007; 44(1): 41-4.

About keithbarrington

I am a neonatologist and clinical researcher at Sainte Justine University Health Center in Montréal
This entry was posted in Neonatal Research and tagged , , , . Bookmark the permalink.

4 Responses to More about reflux: anti-acid medications may also be toxic placebos

  1. M Assaad says:

    Thank you for info, just out of curiosity how long (which year exactly) have we been using these drugs?

  2. I’m not certain, exactly, we have been using cimetidine and then ranitidine for many years, since the late 1980’s at least. As for PPI’s they have been a more recent introduction to the NICU, over the last 10 to 12 years I think, intravenous versions have been available for a relatively short time.

  3. Charlene Crichton MD says:

    Have you found anything in your review of the literature that supports ( or doesn’t support ) the use of thickened feeds treat reflux “clinical signs” in the growing preterm infant?

    • I recently wrote a chapter for a textbook about GER. The section on thickening feeds is reproduced below: (to put it briefly, there is very little data in growing preterm infants of efficacy, and some evidence of toxicity).

      Feeds can be thickened in a number of different ways, with gums, cereals, starches or other agents. The efficacy of this approach is limited, some studies in infants show no effect, some show a reduction in obvious regurgitation but not esophageal acid exposure, and some show a reduction in many indices of reflux, both the number and duration of episodes. Whether these different results are due to different thickeners, patient population, or monitoring methodology is not clear. Few studies have been performed in a specifically neonatal population, but one study showed that thickening feeds with starch was ineffective in a sample of preterm infants. There is also no evidence of enhanced healing or other clinically important effects of thickeners in the setting of newborn infants with GERD. Thickening feeds may not be innocuous. There are reports of interference with the absorption of various nutrients, increases in cough, and even GI obstruction. Recent case reports suggest that some thickeners at least (specifically xanthan gum) may be associated with the development of necrotizing enterocolitis. These reports reinforce the importance of performing studies in preterm infants, in whom clinical responses and potential toxicities are unique.

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