Toxicity of reflux medications in infancy

Before I leave the topic for at least a few days, I thought I would discuss data about the toxicity of reflux medications in older children. Most of my ‘toxic placebo’ comments have been about studies in preterm infants, and one of the major secondary effects of anti-acid medications in preterm infants is an increase in necrotizing enterocolitis and in systemic sepsis, neither of which are likely to be very common in older children. But there is in fact, also good evidence that anti-acid medications increase infections, at least respiratory infections, in older children.

Orenstein SR, et al. 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.  160 infants less than a year of age were randomized to lansoprazole or placebo if they had “symptoms of GERD”. There was no improvement in symptoms or any of the primary or secondary outcomes. There was however, an increase in serious adverse effects from 2% to 12%, the most common of which were lower respiratory infections.

Writing Committee for the American Lung Association Asthma Clinical Research Centers. Lansoprazole for children with poorly controlled asthma: a randomized controlled trial. JAMA. 2012;307(4):373-81. This multicenter trial was performed because of a widespread belief that acid reflux was responsible for triggering episodes of asthma, and anti-acid medications were frequently prescribed. Over 300 children were randomized (aged 6 to 17), and the proton pump inhibitor did absolutely nothing good. There was no improvement in any symptom, or any primary or secondary outcome. In contrast the children on the active drug had more respiratory infections (number needed to harm = 7) had more sore throats and had more than twice as many episodes of bronchitis (NNH=14).

The data from these 2 RCTs confirm  a prospective non-randomized study in 100 infants started on anti-acid drugs by pediatric gastroenterologists, both ranitidine and omeprazole were studied. There were significant increases in both gastroenteritis (from 20% to 47%) and pneumonia during the 4 months of treatment compared to the period before, and compared to the (non-randomized) controls. An observational study in adults also showed an increased risk of community acquired pneumonia.

So acid suppression doesn’t work for symptoms attributed to GERD  in older infants either, and the medications increase risks of infectious disease in infants, children and adults.

Metoclopramide has a poor safety profile with dystonic reactions, oculogyric crisis, irritability, drowsiness, emesis and apnoea occuring in 9 to 15% of patients, it also has not been shown to improve reflux, and indeed in a neonatal mammalian model, didn’t even have prokinetic effects.

Domperidone worsens GE reflux in newborns and has no beneficial effect in older children, it may prolong the QT interval; it is not thought to cross the blood brain barrier in older children, but the relatively ‘leaky’ BBB in babies might be another matter entirely.

So the data about efficacy and safety are very similar in older infants as in preterm babies: no good evidence of any benefit of any of the medications, and reliable evidence of harm.

They are still toxic placebos after hospital discharge.



About Keith Barrington

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.

2 Responses to Toxicity of reflux medications in infancy

  1. Saleh Al-Alaiyan says:

    I totally agree, so what do you recommend if other measures fail?

    • There is some evidence of a minor effect of thickening milk, but some thickeners have been associated with an increase in NEC. Alginate suspensions are now aluminium free and there is some reasonable evidence of a decrease in symptoms. The main treatments though are reassurance and time. Once the kid is toddling and mostly upright the reflux goes away, Usually.

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