Protein pump inhibitors cause coeliac disease and asthma, and they are unnecessary.

OK, that title is perhaps slightly too definite, the publications that I wanted to discuss are observational studies, which can only prove associations, but it would be hard to perform the prospective controlled trials that would be necessary to prove (or disprove) causality. A trial for PPIs and coeliac disease would need an RCT of about 2400 per group, which will clearly never be done; for asthma the sample sizes I calculated were even larger, around 5000 per group.

So what this first study shows (Boechler M, et al. Acid Suppression and Antibiotics Administered During Infancy Are Associated with Celiac Disease. The Journal of Pediatrics. 2022) is that from a huge database, the military healthcare system database, the Hazard Ratio of having coeliac disease was 3.37, and after adjustment was 2.23, for infants who had a prescription for a PPI prior to 6 months of age; a risk that was also shown for histamine receptor blockers (adjusted HR 1.94) and antibiotics (1.14). Having all 3 was the worst risk (adjusted HR 5.43). They also showed that the longer the infant received a prescription for acid suppression, the higher the risk. In this database about 2% of all the babies got a prescription for a PPI during the 1st 6 months of life.

The other article is also from an administrative database and shows, using propensity score matching, an increase in the frequency of asthma diagnoses and of prescriptions for asthma medications among children who had a PPI prescription. (Wang YH, et al. Association Between Proton Pump Inhibitor Use and Risk of Asthma in Children. JAMA Pediatr. 2021;175(4):394-403), with the hazard ratio being about 1.5 for the various drugs, being highest in the first 6 moths after prescription and then decreasing.

In a recent study from Scandinavia rates of PPI prescriptions were given to up to 8% of all infants under 1 year of age in Denmark in 2017. There must be a global epidemic of hyperacidity. (Lyamouri M, et al. Proton pump inhibitors for infants in three Scandinavian countries increased from 2007 to 2020 despite international recommendations. Acta Paediatr. 2022;111(11):2222-8).

Why on earth are so many babies and infants receiving a PPI? We seem to have become intolerant of babies spitting up, or being irritable, or having colic, all of which can be rather disturbing things for new parents, but which do not usually need, or respond to, any medication!

In the NICU this is usually done because someone thinks a baby has pathological reflux, and gets a label of Gastro-Oesophageal Reflux Disease, which then leads to treatment with a protein pump inhibitor and/or other medications. A recent review article (Sawyer C, et al. Neonatal gastroesophageal reflux. Early Hum Dev. 2022;171:105600) is generally well done, I thought, but it is not intended just for the NICU or for preterm and former preterm infants.

Overall, available evidence does not support the routine use of PPIs or H2RAs to treat classically associated GERD symptoms in post-term infants, although some sub-populations may benefit from treatment. Outside of proven acid-reflux, treatment with a PPI should be time limited and all caregivers should be aware of possible side-effects. Acid-suppression therapy should not be used in preterm infants given the risk of severe side effect.

To put it simply, I think of this as follows:

  1. The only reliable clinical sign of reflux in the newborn is regurgitation, but having regurgitation does not mean that a baby has significant reflux, most babies regurgitate. No other clinical sign discriminates between babies with more or less reflux, either the total number of episodes, or the number of acid reflux episodes. When the nurse tells you they think the baby has significant reflux, either based on using a clinical score, or based on their personal evaluation, there is no correlation with objective measures of reflux.
  2. You cannot diagnose reflux with a laryngoscope.
  3. Diagnosis of abnormally frequent reflux requires objective evaluation, using multi-luminal impedance with pH monitoring.
  4. Most reflux in newborn infants is not acidic, as shown by such studies.
  5. Diagnosis of GOR DISEASE requires evidence, in addition, that the reflux is actually causing clinical problems; this is rarely due to acid in the newborn.
  6. Apnoea spells are not triggered by reflux, for the great majority of cases, but sometimes reflux may be triggered by apnoeas, especially obstructive apnoeas.
  7. Bronchopulmonary dysplasia is not clearly worsened or caused by reflux.
  8. Blocking gastric acid production does not decrease reflux, it just changes it from being majority non-acid to being a very large majority non-acid. It is possible that PPI use actually increases reflux, in several animal models they cause relaxation of the lower oesophageal sphincter.
  9. Gastric acid is there for a reason. Blocking it changes the intestinal microbiome, and increases the risk of respiratory infections, systemic sepsis and NEC. PPIs reduce calcium, magnesium, and iron absorption, and seem to cause coeliac disease, asthma, and increase the risk of fractures.

In summary, only prescribe acid blocking medications if there is some clear evidence that the baby will be improved with less gastric acid production. A rare occurrence.

The review article that I mentioned and linked to also discusses the evidence against using prokinetics, which I totally agree with:

None of the[prokinetic agents] have been shown to reduce GERD symptoms in preterm infants. Similar to other medical therapies for GERD, most are not well studied in neonates and are associated with significant and concerning side effects. Side effects of metoclopramide and domperidone are primarily neurologic including irritability, drowsiness, apnea, and possible irreversible tardive dyskinesia. Erythromycin is associated with infantile pyloric stenosis and cardiac arrythmias. Given the lack of evidence for efficacy and the potential for significant side effects, the use of prokinetic agents to treat neonatal GERD is not recommended.

The review does discuss the idea that bovine protein intolerance is a factor in GOR; in my evaluation there is some soft evidence for this in older infants, and as a result a therapeutic trial of elimination of cow’s milk protein is sometimes included in treatment guidelines, but, as far as I know, there is no such evidence in the newborn, especially in the preterm newborn.

An article I discussed previously noted that lansoprazole was a drug with a major decrease in use between 2010 and 2018, but over the whole period covered by that study about 5% of all the ELBW babies received at least one course of treatment. There were also about 10% of the ELBW infants received ranitidine, which was taken off the market towards the end of that study, let’s hope its use wasn’t replaced by more PPIs!

About Keith Barrington

I am a neonatologist and clinical researcher at Sainte Justine University Health Center in Montréal
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