“Medicalizing Normality”: Potent Acid Reflux Drugs Overused in Infants

The use of proton pump inhibitors (PPIs) to treat acid reflux symptoms in infants is at an all-time high. According to a 2007 study of private health insurance databases, PPI use for infants rose more than sevenfold from 1999 through 2004[1] and 11-fold between 2002 and 2009. By 2009, a total of 404,000 prescriptions were dispensed to 145,000 U.S. infants, according to a recent analysis by the Food and Drug Administration (FDA).[2]

These drugs present serious safety risks to adults and young children, and the staggering increase in PPI use comes despite the fact that until 2011, no drug from this class had been approved by the FDA for use in children younger than 1 year old.

Overview of PPIs and reflux

PPIs represent the most potent class of medications used to treat acid reflux and have long been one of the most commonly prescribed classes of drugs to treat reflux symptoms in adults. There are currently eight different prescription PPI medications and three over-the-counter PPI medications available on the U.S. market. (See the table below.)

Most of the prescriptions written for PPIs for infants between 1999 and 2004 were for gastroesophageal reflux (GER),[3] a common condition of infancy that involves regurgitation of food from the stomach into the esophagus, often accompanied by spitting up following feeding.[4] In a 2013 commentary concerning GER, published in the journal Pediatrics, Dr. William Carey pointed out that “about half of normal, healthy infants in the first 6 months of life have enough daily regurgitation to be annoying to parents.”[5] While bothersome and potentially anxiety-provoking to parents, Dr. Carey notes that these GER symptoms are most often mild and typically resolve without treatment between 6 and 12 months of age.[6]

Some infants with more severe reflux symptoms, such as excessive vomiting, which do not resolve with slight changes in feeding routines, can be diagnosed with the more serious gastroesophageal reflux disease, or GERD. However, the line between GER and GERD has traditionally not been well-defined, and treatment decisions can often depend on factors as subtle as the level of a parent’s distress or, according to a study published in the May 2013 edition of the journal Pediatrics and discussed below, how the physician chooses to label the condition.

Perhaps because of this diagnostic uncertainty (and a number of other factors), the prevalence of so-called GERD diagnoses in U.S. children younger than a year old tripled from 3.4 percent to 12.3 percent of all infants from 2000 to 2005, according to a study of privately insured children.[7]

PPIs Available in the U.S.

*Do Not Use
**VIMOVO is a combination of the PPI esomeprazole and the nonsteroidal anti-inflammatory drug (NSAID) naproxen.

GER or GERD?

In 2009, “… in response to evidence that the diagnosis of GERD is applied excessively to healthy infants with bothersome but harmless symptoms of physiologic GER …”, the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHN) released joint guidelines intended to assist pediatricians in distinguishing between the usual symptoms of GER and the more severe disease, GERD.[8]

The guidelines’ authors emphasized that in most infants, GER symptoms do not rise to the level of GERD[9] and that clinicians and parents should first try behavioral or lifestyle approaches to attempt to decrease GER symptoms.[10] Options discussed included maternal dietary changes (such as cutting out cow’s milk and eggs) and introduction of slightly smaller but more frequent feedings.[11] In a 2008 study of 50 infants with GERD, feeding modifications, positional changes and avoidance of tobacco smoke improved reflux symptoms in 78 percent of infants, including complete resolution of GERD in 24 percent of the cases.[12]

Although the NASPGHN/ESPGHN guidelines recommended pharmacologic therapy in confirmed cases of GERD, the authors stressed that evidence on the effectiveness of pharmacologic therapies in infants is limited or nonexistent, and they detailed the myriad risks of the drugs.[13]

Drug risks without proven benefits

In 2011, the FDA’s approval of esomeprazole (NEXIUM) for the treatment of erosive esophagitis in children from 1 month to 1 year of age represented the first — and so far only — approval of a PPI for any indication in children under 1 year of age.[14] The approval was based not on a clinical study conducted in infants for this indication, but rather on questionably inferring safety and effectiveness from studies in adults and children older than 1 year old.[15] The only randomized trial evaluating esomeprazole’s effectiveness in infants showed the drug to be no more effective than a placebo. To this day, no PPI has been shown to be effective for GERD in infants.[16]

By contrast, it is now well-established that long-term PPI use causes a number of life-threatening side effects in adults, including community-acquired pneumonia, a severe form of diarrhea caused by the bacterium Clostridium difficile, dangerously low blood magnesium and vitamin B12 levels, bone fractures, a kidney disease known as acute interstitial nephritis, and various drug interactions.[17] In 2011, Public Citizen filed a petition with the FDA calling for a black box warning on all PPI labels alerting patients and doctors to some of these life-threatening side effects.[18]

Many of these dangers, and others, extend to children and infants given the drugs.

A recent 2013 guidance by the American Academy of Pediatrics reaffirming the importance of the 2009 NASPGHN/ESPGHN guidelines warned that “a growing body of evidence suggests that acid suppression, in general, with either H2RAs [another class of reflux medications] or PPIs, may be a risk factor for pediatric community-acquired pneumonia, gastroenteritis, candidemia, and necrotizing enterocolitis in preterm infants.”[19]

As of 2004, lansoprazole (PREVACID), although unapproved for this age group, was the most commonly used PPI in infants.[20] A 2009 randomized controlled trial of infants between 1 and 12 months of age — sponsored by the drug’s manufacturer— found that lansoprazole was no better than a placebo in relieving infants’ reflux symptoms but did cause severe harms.[21] Five times as many infants on lansoprazole suffered serious adverse events resulting in hospitalization as those on placebo, most commonly for lower respiratory tract and lung infections (e.g., bronchitis and pneumonia). Though none of these infections were deemed to be “treatment-related” by the company-sponsored study investigators, pneumonia has been identified as a side effect of PPI use in adults in several studies.[22]

Disease label prompts overtreatment

The serious risks of these therapies should make physicians and parents cautious when diagnosing an infant with GERD. A study published in the May 2013 issue of the journal Pediatrics highlighted the pitfalls of medicalizing common and largely harmless symptoms during the first year of a child’s life.[23]

In the study, 175 parents of children of all ages visiting a primary care pediatrics clinic were presented with a hypothetical vignette of an infant displaying “excessive crying and regurgitation.”[24] Half of the parents received a vignette in which the hypothetical doctor labeled the baby’s condition as GERD, while the symptoms in the other group’s vignette were described simply as “this problem” with no disease label. All vignettes presented medication as an option to treat the baby’s condition, but half described available medications as ineffective while the other half did not. The infant was described as otherwise healthy and gaining weight appropriately, but with symptoms not effectively treated by behavioral interventions, such as being positioned upright after a meal. The doctor in the vignette emphasized that “most infants grow out of [GERD/this problem] on their own.”[25]

Results indicated that parents were more likely to opt for medications if the infant’s condition was labeled as GERD. Interestingly, these parents were more likely to choose drug therapy, even when told that the medications were ineffective. By contrast, parents not given a disease label for the child’s condition chose drug therapy less often and were far less likely to favor medications described as ineffective.

In an interview with the Reuters news agency on the significance of her team’s findings, Dr. Laura Scherer, the lead author of the Pediatrics study, concluded that, “It’s really becoming pretty clear that GERD in infants is overdiagnosed and overtreated. One reason for this could be that doctors’ use of this GERD label could unintentionally increase people’s (desire) for medications.”[26]

“We are medicalizing normality,” noted pediatrician Dr. Eric Hassall, eloquently encapsulating the phenomenon underlying the overdiagnosis of infant GERD. “In most infants, these symptoms are ‘life,’ not a disease, and do not warrant treatment with drugs, which can have significant adverse effects.”[27]

Unfortunately, too many doctors continue to resort to unnecessary and risky drugs for what is a normal condition of infancy. The quick fix of a prescription may be more appealing to a busy pediatrician than a careful counseling session with a caregiver distressed by a baby’s frequent spitting up. In addition, many pediatricians may not be aware of the dangers of the medications, such as PPIs, that have historically been perceived as relatively harmless, though this will hopefully change in the face of steadily accumulating evidence on their myriad risks.

What You Can Do

If you have an infant or know someone who does, remember that mild reflux symptoms after feeding are completely normal. Try the following slight changes in diet and feeding patterns first to help keep the baby’s food down.

Breastfeeding mothers can try reducing their intake of cow’s milk or eggs as the baby could have an allergy to proteins in these foods. Do not discontinue breastfeeding in favor of formula feeding unless the reflux becomes severe and unresponsive to these dietary changes. Though breastfeeding is best whenever possible, caregivers who opt for formula feeding may find that thickening the formula with rice cereal reduces the frequency of regurgitation episodes.[28]

Caregivers also can avoid large-volume feedings and try slightly smaller and more frequent feedings (while ensuring the baby continues to gain weight normally) to reduce the amount of food an infant must digest at a time.[29]

While lying infants on their stomachs rather than their backs was previously recommended as a way of reducing reflux, this is no longer recommended, as lying a baby on his or her stomach may increase the risk of sudden infant death syndrome (SIDS).[30] After feeding, infants should always be placed in a fully upright position or, if about to fall asleep, on their back.[31]

If the infant’s reflux and/or vomiting symptoms are severe or do not improve with these lifestyle changes, caregivers should see their pediatrician to look for any serious underlying causes of their infant’s symptoms. Once these causes are ruled out, other therapies can be explored, which may include acid-suppressing medications.

If a medication is recommended, the lowest possible dose and shortest possible duration of therapy should be prescribed. Histamine-2 receptor antagonists (H2RAs) should be tried first, as these are often effective and less dangerous than PPIs. No acid-suppressing medication should be taken on a chronic basis for GERD.

All medications come with risks, and caregivers must monitor their baby for signs of infection, diarrhea, vitamin or mineral deficiency, or other potential side effects of acid-suppressing drugs. Caregivers should ask for a copy of the label of the prescribed drug from their doctor to know the signs and symptoms of these health concerns.

References

[1]  Barron JJ, Tan H, Spalding J, et al. Proton pump inhibitor utilization patterns in infants. J Pediatr Gastroenterol Nutr. 2007 Oct;45(4):421-7.

[2]  Chen IL et al. Proton pump inhibitor use in infants: FDA reviewer experience. J Pediatr Gastroenterol Nutr. 2012 Jan;54(1):8-14.

[3]  Barron JJ, Tan H, Spalding J, et al. Proton pump inhibitor utilization patterns in infants. J Pediatr Gastroenterol Nutr. 2007 Oct;45(4):421-7.

[4]  Vandenplas Y et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroenterol Nutr. 2009 Oct;49(4):498-547.

[5]  Carey WB. The Hazards of Medicalizing Variants of Normal. Pediatrics 2013;131;991.

[6]  Ibid.

[7]  Nelson SP et al. Pediatric gastroesophageal reflux disease and acid-related conditions: trends in incidence of diagnosis and acid suppression therapy. J Med Econ. 2009;12(4):348-55.

[8]  Vandenplas Y et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroenterol Nutr. 2009 Oct;49(4):498-547.

[9]  Ibid.

[10]  Ibid.

[11]  Ibid.

[12]  Orenstein SR et al. Efficacy of conservative therapy as taught in the primary care setting for symptoms suggesting infant gastroesophageal reflux. J Pediatr. 2008 Mar;152(3):310-4.

[13]  Vandenplas Y et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroenterol Nutr. 2009 Oct;49(4):498-547.

[14]  Labels (Indications and Usage section) of:
Nexium (Nov 2012 – Indication in 1.1 added 12/2011) http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021153s044,021957s014,022101s011lbl.pdf, Prilosec (May 2013) http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019810s097,022056s013lbl.pdf
Zegerid (Nov 2012) http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021636s012,021849s007lbl.pdf
Vimovo (Oct 2012)
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022511s008lbl.pdf
Protonix (Oct 2012)
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020987s043,022020s006lbl.pdf          
Prevacid (Sept 2012)
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020406s078-021428s025lbl.pdf
Dexilant (Sept 2012)
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022287s014lbl.pdf
Aciphex (April 2013)
http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020973s032lbl.pdf

[15]  Nexium label. Nov 2012. Section 8.4.

[16]  Chen IL et al. Proton pump inhibitor use in infants: FDA reviewer experience. J Pediatr Gastroenterol Nutr. 2012 Jan;54(1):8-14.

[17]  Proton pump inhibitors: Dangerous and habit-forming heartburn drugs. Worst Pills, Best Pills News. November 2011.

[18]  Public Citizen petition to the FDA, http://www.citizen.org/petition-asking-fda-to-add-warnings-to-ppis. August 2011. Accessed August 19, 2013.

[19]  Lightdale JR, Gremse DA; Section on Gastroenterology, Hepatology, and Nutrition. Gastroesophageal reflux: management guidance for the pediatrician. Pediatrics. 2013 May;131(5):e1684-95.

[20]  Barron JJ, Tan H, Spalding J, et al. Proton pump inhibitor utilization patterns in infants. J Pediatr Gastroenterol Nutr. 2007 Oct;45(4):421-7.

[21]  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. J Pediatr. 2009 Apr;154(4):514-520.e4.

[22]  Proton pump inhibitors: Dangerous and habit-forming heartburn drugs. Worst Pills, Best Pills News. November 2011.

[23]  Scherer LD, et al. Influence of ‘GERD’ label on parents' decision to medicate infants. Pediatrics 2013; 131: 1–7.

[24]  Ibid.

[25]  Ibid.

[26]  Reuters. GERD label makes parents more likely to want medicine. Pittman G. April 1, 2013.  http://www.reuters.com/article/2013/04/01/us-gerd-label-idUSBRE93002120130401

[27]  ScienceDaily. Are Acid-Suppressing Drugs Prescribed Too Often in Infants? Oct. 21, 2011. http://www.sciencedaily.com/releases/2011/10/111020024127.htm. Accessed on July 23, 2013.  

[28]  Vandenplas Y et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroenterol Nutr. 2009 Oct;49(4):498-547.

[29]  Ibid.

[30]  Ibid.

[31]  Lightdale JR, Gremse DA; Section on Gastroenterology, Hepatology, and Nutrition. Gastroesophageal reflux: management guidance for the pediatrician. Pediatrics. 2013 May;131(5):e1684-95.