Not so long ago when an infant showed signs of gastroesophageal reflux (GER), popularly known as spitting up, the treatment was a good burp and a ready towel. After all, the condition is common: Up to 65% of all babies do it and most grow out of it by their first birthday as their digestive tracts functionally mature.
But in recent years, physicians have been increasingly prescribing powerful stomach-acid suppressors, such as proton pump inhibitors (PPIs) and histamine2 receptor antagonists (H2-blockers), to otherwise healthy infants with GER. However, evidence suggests these drugs don’t reduce symptoms of even more serious reflux conditions in infants or crying and irritability in infants that is often presumed to be a sign of reflux. Safety concerns have also recently emerged with new findings that suggest giving the drugs to infants younger than 6 months of age is associated with a higher risk of bone fractures later in childhood.
The number of children potentially affected is not likely to be small. Proton pump inhibitor prescriptions among infants younger than 1 year increased 4-fold from 1999 to 2003, and 7.5-fold from 1999 to 2004 when partial data from 2004 were included, according to a 2007 study. This despite the fact that, at the time, no PPI was approved by the US Food and Drug Administration (FDA) for any use in children younger than 1 year. More recently, esomeprazole and omeprazole have been approved by the FDA for use in infants aged 1 month to 1 year but only for erosive esophagitis due to acid-mediated gastroesophageal reflux disease (GERD), a far more serious condition than GER.
The evidence tying acid suppressors to bone deficiency comes from the first-of-its-kind retrospective cohort study of 874 447 children without diagnosed GERD born within the Military Health Care System (MHS) from 2001 to 2013. All had received follow-up MHS care for 2 or more years, with a median of 5.8 years and a range of 3.6 to 9.1 years. Outpatient pharmacy data from the first 6 months of life identified prescriptions for PPIs in 6943 infants, H2 blockers in 67 096, and both in 10 777, or about 10% of the entire cohort. The researchers used the International Classification of Disease, Ninth Revision, codes to identify fractures after 6 months of age and calculated hazard ratios adjusting for confounding factors including sex, prematurity, and low birth rate.
The study, which was presented as an abstract at the Pediatric Academic Societies (PAS) meeting this past May in San Francisco (the full study was in peer review as of this writing), found that children who received PPIs in the first 6 months of life had a 22% increased likelihood of fractures at a median 5.8 years following PPI use. When the drugs were used in combination with H2-blockers, the hazard climbed to 31%. The H2 blockers alone were not associated with a statistically significant hazard, according to the study’s lead author, US Air Force Capt Laura Malchodi, MD.
There was a dose-response relationship between fracture hazard and duration of treatment with PPIs. Those taking them for a month or less were at a 19% greater hazard of bone breakage than infants who did not take the suppressors. Those taking the drugs for 60 days to 150 days were at 23% greater hazard and those taking them longer than 150 days were at 42% increased hazard.
Malchodi told PAS conferees that the drugs may seem benign, since most are easily available over the counter. “However, our study adds to a growing body of evidence suggesting [acid-reducing] medications are not safe for children, especially very young children,” she said. She cautioned that they “should only be prescribed to treat confirmed serious cases of more severe, symptomatic, gastroesophageal reflux disease (GERD), and for the shortest length of time needed.”
Proton pump inhibitors are widely acknowledged as effective in treating adults with GERD and other conditions, including peptic ulcers and Barrett esophagus. But the drugs, which are prescribed for about 7.8% of the US population, have hit a rough patch recently.
In 2010-2011, they were linked to a heightened susceptibility to hip and other fractures in the elderly, prompting the FDA to issue a warning. This July, a report suggested that they may contribute to early death among adults, based on an analysis of 350 000 people in the US Veterans Affairs database.
Such negatives make it all the more worrisome to pediatricians that the drugs are being used to suppress something as natural in infants as GER.
The findings are “very bad news,” said Eric Hassall, MD, a pediatric gastroenterologist and emeritus professor at the University of British Columbia in Vancouver, who was not involved in the study.
“It’s a cautionary tale about a serious problem. When you are a physician and you prescribe a drug that triggers an allergic response, you know about the adverse effect right away and you can take the child off it or diminish the dose. But when the adverse effect is months or years away, you can’t necessarily connect it with the drug,” he said.
Jenifer Lightdale, MD, division chief for pediatric gastroenterology at the University of Massachusetts Memorial Children’s Medical Center, who was not involved in the study, thinks the increased use of acid reducers has resulted, in part, from the belief among some physicians that GER could be related to other conditions like excess crying or colic. However, “treating with a PPI doesn’t help that,” she said.
It is important to distinguish between GER and the much more corrosive GERD, which needs treatment with acid reducers, at least in the short-term, she explained. “If you use an endoscope on a baby with classic GERD markers, you can see esophagitis. There is erosion, changes in the lining. There may be blood in the spit. They may stop wanting to eat and then lose weight. Swallowing becomes hard. So it can cause problems. But less than 5% of babies have GERD.”
Lightdale admits she is taking a wait-and-see attitude about the MHS study. “This is just one more association study. Causality remains elusive,” she said, referring to previous observational studies linking PPI use to bone fracture in adults and the elderly. “But that doesn’t mean you should ignore the drumbeat. It is possible that the era of considering these to be scot-free medications where you need not worry about side effects is over,” she said.
Craig Langman, MD, who heads the Division of Pediatric Nephrology and Mineral Metabolism at Lurie Children’s Hospital in Chicago and has studied bone disease in children for 3 decades, said he is also reserving judgment on the study until the full article is published.
Nevertheless, he said that the study “confirms what I’ve been thinking for a long time. I was concerned that bone modeling would be affected by these drugs, and I think that’s the mechanism behind these early fractures.”
While the exact process is not well understood, many experts believe that by inhibiting gastric acid secretion in the gut, PPIs and other acid reducers limit calcium absorption. If the body doesn’t absorb enough calcium, it compensates by increasing parathyroid hormone, which results in bone resorption that releases calcium out of bone and into the bloodstream.
“It’s not rocket science,” said Langman, who was not involved in the study. “There isn’t enough calcium.”
Whether the study findings will change prescribing habits remains uncertain. But for the moment, physicians in doubt can refer to the 2013 AAP management guidelines covering GER and GERD in infants, which advocate lifestyle changes, such as positioning therapy and feeding adjustments as “first-line therapy,” noting that the “overuse of PPIs in infants with reflux is a matter of great concern.”
Note: The print version excludes source references. Please go online to jama.com.
Lyon J. Study Questions Use of Acid Suppressors To Curb Mild Infant Reflux. JAMA. Published online September 29, 2017. doi:10.1001/jama.2017.12160