The Journal of Pediatrics
Volume 152, Issue 3 , Pages 301-303, March 2008

Talk is Cheap, Often Effective: Symptoms in Infants Often Respond to Non-Pharmacologic Measures

  • Eric Hassall, MBChB, FRCPC, FACG

      Affiliations

    • Corresponding Author InformationReprint requests: Eric Hassall, MBChB, FRCPC, FACG, Division of Gastroenterology, BC Children’s Hospital/University of British Columbia, 4480 Oak St, Vancouver BC V6H 3V4, Canada.

Division of Gastroenterology, BC Children’s Hospital, University of British Columbia, Vancouver, British Columbia, Canada

Article Outline

Abbreviations: GER, Gastroesophageal reflux, GERD, Gastroesophageal reflux disease, PPIs, Proton pump inhibitors

 

In this issue of The Journal, Orenstein and McGowan document the results of their well-designed study of “conservative therapy” for infants presenting with symptoms suggesting infant gastroesophageal reflux.1 “Suggesting” is the operative word, as the title indicates. The infants were to be enrolled in a randomized, double-blind study of oral H2-receptor antagonist versus placebo, but before randomization, they underwent a trial of “conservative” management, meaning nonpharmacologic. This consisted of avoidance of tobacco smoke exposure and modifications of position and of feeding. Formula-fed infants were switched to a semi-elemental formula, and mothers of breast-fed infants avoided cow and soy milk in their diets. Feedings were thickened with rice cereal. The modifications were taught to parents in the primary care setting in 5 office practices. With a symptom scoring instrument used at baseline and at 2 weeks, symptom scores declined impressively—78% had some improvement in scores, 59% had improvement by at least 5 points, and 24% normalized. Scores for individual symptoms related to regurgitation, crying, and arching improved significantly. The 37 subjects had a median age of 13 weeks (range 4 to 43) at entry.

See related article, p 310

The scoring instrument used, the Infant Gastroesophageal Reflux (GER) Questionnaire-Revised, was based on a cohort of 185 infants said to have gastroesophageal reflux disease (GERD), versus control subjects.2 The subjects for this came from 16 centers in 7 countries. The diagnosis of GERD was based in 21% on an “endoscopic diagnosis,” with no details given, and another 27% had abnormal pH-metry. These are not solid criteria, a problem exacerbated by different diagnostic criteria used at different centers. The rest were diagnosed by symptoms only. Even without getting into further critique, one can conclude that at the very most, only half of the test infants had proven GERD, and the gold standard for diagnosis in the rest was symptoms. Therefore, in at least half the cases, the scoring system was measuring symptoms in the test group against symptoms in the control subjects—that is, they were not necessarily symptoms of GERD. Infants have a limited range of behaviors in response to pathologic processes, among the most common being irritability, arching, unexplained crying, and apparent discomfort. These are not specific to GERD. Although almost any pathologic process can cause these, prevalent causes are milk protein intolerance, lactose intolerance, constipation, colic, smoke exposure, and infection.3, 4, 5, 6, 7 Some even claim that milk protein allergy can cause reflux disease.8 At the very least, there is an overlap in symptoms. Use of a semielemental (hypoallergenic) formula addresses the first 3 causes.

Despite the less than perfect instrument, this study1 is of enormous value, in that the authors were measuring symptoms at baseline versus symptoms only 2 weeks later—and symptoms are primarily what we care about in clinical practice, regardless of whether we call them GERD. What the study shows us is that many symptoms will improve or resolve in most infants within just 2 weeks—because of the interventions per se, or tincture of time, or the additional support and attention given to parents, or a combination of factors. For example, half of the infants in the study were under 3 months of age—colic time—so the passing of time or withdrawal from smoke exposure may have resolved some of these. What “disease state,” if any, the symptoms represented, is not clear, but it may well not have been GERD, as we currently understand it. This is acknowledged by the word “suggesting” in the article’s title. GERD is gastroesophageal reflux disease, a condition usually defined as the presence of pathologic reflux, that is, that which causes a complication. GERD is a disorder caused by pathologic reflux—it’s not just a collection of symptoms, and pathologic reflux is highly unlikely to get better with just 2 weeks of minor measures.

In another elegantly designed study, Orenstein et al9 reported on 19 infants randomized to placebo for symptoms considered to be GERD, in association with reactive changes on esophageal suction biopsy that were compatible with GERD. Ten of the 19 became symptom-free on placebo during a year of follow-up, despite having the biopsy changes persist throughout that year. From that and other studies, we could conclude that reactive changes may not be not be specific for reflux 3, 10 and that many “irritable” or otherwise symptomatic babies get better without treatment other than parental reassurance, over a period of observation.

Pediatric reflux has had a lot of press in the last few years, much of it for good reason. However, to read some medical and especially lay literature, one could get the impression that reflux is a major scourge and the cause of most troublesome symptoms in infants. This has occurred largely because of blurring of the line between what’s normal and abnormal in infancy.11, 12 What is “normal?” Some 40% to 70% of healthy, thriving infants effortlessly “spit up” in North America, “spill” in Australia, or “regurgitate” or “posset” in the United Kingdom (other countries’ synonyms omitted) 1 to 4 times per day. Some 20% spit up more than 4 times per day. The prevalence peaks at 3 to 4 months, falling to 15% by 7 to 8 months, and less than 5% by 12 to 15 months.13, 14 Clearly, for most infants, recurrent effortless regurgitation is squarely in the realm of physiological normality—that is, “life” (GER), not “disease” (GERD).11 Nevertheless, in a common scenario, when there’s regurgitation, and the infant also is “irritable,” a diagnosis of GERD is often made, and pharmacotherapy instituted. However, it may be a case of “true-true-unrelated”—true, there’s regurgitation; true, there are other symptoms; but they may not be related.

As evidence for the rush to diagnosis of GERD, a recent retrospective analysis of data from 4 US health care plans showed an enormous rise in the use of proton pump inhibitors (PPIs) in infants.15 In the 6 years 1999 through 2004, PPI prescriptions showed an overall 7.5-fold increase, and one PPI, available in a child-friendly liquid formulation, saw a 16-fold increase. If these were appropriate prescriptions, one would have to propose that there’s been a 7.5-fold increase in pathologic reflux in infancy—talk of an epidemic that’s not! From this and the coding details, it’s not hard to infer that many infants were being treated for physiological regurgitation, as well as other non-GERD symptoms. This is addressed in more detail elsewhere.12

The association between acid reflux and irritability was seriously challenged by Moore et al16 in an elegant double-blind randomized placebo-controlled trial with 2-week crossover of infants with irritability and frequent “spilling.” Patients had failed treatment with histamine-2–receptor antagonist or cisapride. They had a similar improvement in irritability while taking placebo or omeprazole, despite documented reduction of esophageal acidification in the PPI group. In another double-blind randomized placebo-controlled trial of omeprazole in premature infants, there was a similar lack of improvement in the drug or placebo groups.17 Short duration or low dose of therapy may have obscured symptom response in these studies, but what they likely show is that the cause of irritability was not reflux at all, or at least that it was not acid reflux.

Nonacid reflux is a burgeoning area of investigation. In a study using multichannel intraesophageal impedance monitoring,18 which can measure acid and nonacid (“volume”) reflux, approximately half the reflux episodes in symptomatic infants were found to be nonacid. In this study, the most frequently reported symptom was fussiness/pain, which correlated with nonacid reflux events in 25% and acid reflux in 25%. The proximal height of a reflux episode was predictive for symptoms of fussiness/pain, arching, and burping. At present, impedance is primarily used as a research tool in children because normal values are not available, and interpretation is time consuming and somewhat operator specific. A problem is that even when a prokinetic agent might be indicated, we don’t have an effective one.

Acid suppression with histamine-2–receptor antagonist or PPI is not without infectious or nutritional complications in some patients. These data are summarized elsewhere.12, 19 They require corroboration and may be specific to certain ages, durations of treatment, or other qualifiers, but they serve as reminders that even very safe drugs have some adverse effects that are not necessarily apparent in the individual patient.

In the assault on overprescription, let’s not forget that for children who have bona fide, proven chronic GERD, the benefits of PPI therapy considerably outweigh the known risks, including the risks and high failure rates of antireflux surgery in certain patients.20, 21 However, the great majority of patients with proven chronic or severe GERD are well beyond the first year of life. In other words, the primary problem with overdiagnosis and overprescription appears to be in infancy.

This is where the study by Orenstein and MacGowan1 shows its value. The symptoms that were improved with this approach were regurgitation, crying, and arching—among the most common that bring infants to medical attention. The nonpharmacologic approach is first-line therapy that can be taught to parents at a primary care level and will help patients, hopefully lessen unnecessary drug treatment, and decrease subspecialty referrals.

Because the symptoms in most otherwise healthy infants aren’t those of a severe or chronic disease, it’s a fair bet that this therapy would sustain and increase the response rate. Chronic disease has to begin some time, but those infants with something more serious or chronic will declare themselves—they’ll either fail to respond, relapse after initial improvement, or will have presented with symptoms that are so severe as to warrant early investigation. Therefore there’s little to lose in most patients by implementing nonpharmacologic therapy at the outset. After the infant has been symptom free for some months, milk protein can be carefully reintroduced into the diet, because the prevalence of milk protein intolerance diminishes significantly during the first year of life.22

As it happens, the institution of these specific nonpharmacologic measures for 2 weeks is also the first-line course of action recommended by the GERD Guidelines from the North American Society for Pediatric Gastroenterology and Nutrition.23 For those infants who do not respond or who relapse, a trial of acid suppression therapy is warranted, but it should be a time-limited trial, because even when GERD is present, it is often not chronic.24

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References 

  1. Orenstein S, MacGowan JD. Efficacy of conservative therapy as taught in the primary care setting for symptoms suggesting infant gastroesophageal reflux. J Pediatr. 2008;152:310–314
  2. Kleinman L, Rothman M, Strauss R, Orenstein SR, Nelson S, Vandenplas Y, et al. The infant gastroesophageal reflux questionnaire revised: development and validation as an evaluative instrument. Clin Gastroenterol Hepatol. 2006;4:588–596
  3. Hill DJ, Heine RG, Cameron DJ, Catto-Smith AG, Chow CW, Francis DE, et al. Role of food protein intolerance in infants with persistent distress attributed to reflux esophagitis. J Pediatr. 2000;136:641–647
  4. Hiscock H, Jordan B. Problem crying in infancy. Med J Aust. 2004;181:507–512
  5. Iacono G, Cavataio F, Montalto G, Florena A, Tumminello M, Soresi M, et al. Intolerance of cow’s milk and chronic constipation in children. N Engl J Med. 1998;339:1100–1104
  6. Barr RG. Colic and crying syndromes in infants. Pediatrics. 1998;102:1282–1286
  7. Shenassa ED, Brown MJ. Maternal smoking and infantile gastrointestinal dysregulation: the case of colic. Pediatrics. 2004;114:e497–e505
  8. Cavataio F, Carroccio A, Iacono G. Milk-induced reflux in infants less than one year of age. J Pediatr Gastroenterol Nutr. 2000;30(Suppl):S36–S44
  9. Orenstein SR, Shalaby TM, Kelsey SF, Frankel E. Natural history of infant reflux esophagitis: symptoms and morphometric histology during one year without pharmacotherapy. Am J Gastroenterol. 2006;101:628–640
  10. Dahms BB. Reflux esophagitis: sequelae and differential diagnosis in infants and children including eosinophilic esophagitis. Pediatr Dev Pathol. 2004;7:5–16
  11. Hassall E. Mistaking “life” (as we know it) for “disease.”. Am J Gastroenterol. 2006;101:2434–2435
  12. Orenstein SR, Hassall E. Infants and proton pump inhibitors: tribulations, no trials. J Pediatr Gastroenterol Nutr. 2007;45:395–398
  13. Nelson SP, Chen EH, Syniar GM, Christoffel KK. Prevalence of symptoms of gastroesophageal reflux during infancy (A pediatric practice-based survey. Pediatric Practice Research Group). Arch Pediatr Adolesc Med. 1997;151:569–572
  14. Martin AJ, Pratt N, Kennedy JD, et al. Natural history and familial relationships of infant spilling to 9 years of age. Pediatrics. 2002;109:1061–1067
  15. Barron JJ, Tan H, Spalding J, Bakst A, Singer J. Proton pump inhibitor utilization patterns in infants. J Pediatr Gastroenterol Nutr. 2007;45:421–427
  16. Moore DJ, Tao BS, Lines DR, Hirte C, Heddle ML, Davidson GP. Double-blind placebo-controlled trial of omeprazole in irritable infants with gastroesophageal reflux. J Pediatr. 2003;143:219–223
  17. 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. J Pediatr Gastroenterol Nutr. 2007;44:41–44
  18. Condino AA, Sondheimer J, Pan Z, Gralla J, Perry D, O’Connor JA. Evaluation of infantile acid and nonacid gastroesophageal reflux using combined pH monitoring and impedance measurement. J Pediatr Gastroenterol Nutr. 2006;42:16–21
  19. Leonard J, Marshall JK, Moayyedi P. Systematic review of the risk of enteric infection in patients taking acid suppression. Am J Gastroenterol. 2007;102:2047–2056quiz 2057
  20. Hassall E, Kerr W, El-Serag HB. Characteristics of children receiving proton pump inhibitors continuously for up to 11 years duration. J Pediatr. 2007;150:262–267267e1
  21. Hassall E. Outcomes of fundoplication: causes for concern, newer options. Arch Dis Child. 2005;90:1047–1052
  22. Fiocchi A, Assa’ad A, Bahna S. Food allergy and the introduction of solid foods to infants: a consensus document (Adverse Reactions to Foods Committee, American College of Allergy, Asthma and Immunology). Ann Allergy Asthma Immunol. 2006;97:10–20
  23. Rudolph CD, Mazur LJ, Liptak GS, Baker RD, Boyle JT, Colletti RB, et al. Guidelines for evaluation and treatment of gastroesophageal reflux in infants and children: recommendations of the North American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr. 2001;32(suppl 2):S1–S31
  24. Hassall E. Treatment interruptus: the need for withdrawal. Am J Gastroenterol. 2007;102:2108–2109

PII: S0022-3476(07)00978-X

doi:10.1016/j.jpeds.2007.10.014

Refers to article:

  • Efficacy of Conservative Therapy as Taught in the Primary Care Setting for Symptoms Suggesting Infant Gastroesophageal Reflux , 09 November 2007

    Susan R. Orenstein, John D. McGowan
    The Journal of Pediatrics March 2008 (Vol. 152, Issue 3, Pages 310-314.e1)

The Journal of Pediatrics
Volume 152, Issue 3 , Pages 301-303, March 2008

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