Prospective Pediatric Study of the Persistence and Progression of Recurrent Abdominal Pain

J Sjolund et al. Clin Gastroenterol Hepatol 2021; 19: 930-938. Prevalence and Progression of Recurrent Abdominal Pain, From Early Childhood to Adolescence

Using a prospective, population-based Swedish cohort (1994-1996) (BAMSE project), the authors analyzed data from 2455 children with complete follow-up evaluation at ages 1, 2, 12, and 16 years.

Key findings:

  • RAP was reported by 26.2% of children on at least 1 of 3 assessment points, of which 11.3% reported symptoms more than once
  • Children with RAP at 12 years had persistent symptoms at 16 years in 45% of cases and increased risks for RAP (relative risk, 2.2; 95% CI, 1.7–2.8), any AP-FGID (relative risk, 2.6; 95% CI, 1.9–3.6), and IBS (relative risk, 3.2; 95% CI, 2.0–5.1) at 16 years
  • Figure 3 summarizes the overlap of RAP at different time points:
  • **In early childhood (1-2 years of age), 149 (6%) had RAP per parental reports. Only 27 in this group, had RAP noted at 16 years of age which accounted for 7% of the total 16 year old cohort with RAP
  • **At 12 years of age, 98 (4%) had RAP. 44 (45%) of this group continued with pain at 16 years which accounted for 11% of the total 16 year old cohort with RAP

My take: Most children (84%) with RAP at 16 years of age did NOT report RAP at younger ages; however, in children with RAP at 12 years of age, 45% continued to have RAP at 16 years of age.

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Narrowing the Workup for Chronic Abdominal Pain –Carlo DiLorenzo Was Right!

In the good old days when we could have large meetings, Carlo DiLorenzo gave a terrific summary of recurrent abdominal pain (#NASPGHAN19 Postgraduate Course -part 3).  One of the slides, shown below, is supported by a new study (J Zeevenhooven et al. J Pediatr 2020; 219: 76-82)

In this recent reterospective study, the authors examined 853 patients, of whom 102 (12%) had an organic disorder; all had abdominal pain >2 months. The authors compared two diagnostic strategies:

  • Group 1: anti-TTG IgA, fecal calprotectin, Giardia, along with blood tests (hemoglobin, CRP, ESR)
  • Group 2: anti-TTG IgA, fecal calprotectin, and Giardia (if diarrhea)

Calprotectin was considered normal if <50 mcg/g,  “gray zone” if 51-250, mildly elevated if 251-1000, and elevated/active inflammation if >1000.

Key findings:

  • Sensitivity of the strategies was 90% and 88% for Group 1 and Group 2 respectively
  • In the presence of 1 or more alarm symptoms, the sensitivity was 92% for both strategies.
  • The sensitivity/specificity of calprotectin varied based on the cutoff value.
    • For >50, the sensitivity 75%, specificity 87%, PPV 44%, and NPV 96%
    • For >250, the sensitivity 48%, specificity 99%, PPV 82%, and NPV 93%
    • For >1000, the sensitivity 38%, specificity 100%, PPV 98%, and NPV 92%

Alarm symptoms

  • Alarm symptoms that were statistically different in the organic group included the following:
    • Chronic diarrhea (P <.001), occurred in 32% organic compared to 6% functional
    • GI blood loss (P <.001) , occurred in 35% organic compared to 5% functional
    • Recurrent vomiting (P=.029), occurred in 10% organic compared to 5% functional
    • Perianal complications (P=.001), occurred in 6% organic compared to 1% functional
    • Impaired growth (P=.023), occurred in 4% organic compared to 1% functional
  • Interestingly, the study found that having a positive family history of IBD/celiac/FMF did not differentiate functional and organic patients, occuring in 12% and 15% respectively.
  • Pain in RUQ or lower region also did not differentiate functional and organic patients, occuring in 3% and 4% respectively.
  • The authors note that 30 (29%) patients with organic disease did not have an identified alarm symptom -this compares to 479 (64%) patients with functional disease did not have an identified alarm symptom

From my experience with our recent study (Digestive Diseases (Full Text): Diagnostic Yield Variation with Colonoscopy among Pediatric Endoscopists) which focused on diagnostic yield with colonoscopy, it is clear that there are significant limitations with data collection in a retrospective study regarding recurrent abdominal pain.  Even the definition of chronic diarrhea may vary considerably among practitioners.  At the same time, we did find that an abnormal calprotectin had the highest diagnostic yield (See related blog post for summary: Our Study: Provider Level Variability in Colonoscopy Yield)

It is surprising to me that only 10 patients (1%) in their cohort were identified as having impaired growth.

My take: This study shows that anti-TTG testing and calprotectin are the most useful tests in children with persistent abdominal pain.  The addition of hemoglobin, CRP, and ESR “can be left out in the clinical evaluation of chronic abdominal pain in children.”  The authors advocate, as well, for a prospective cohort study to confirm their observations.

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Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition

Probiotics and Recurrent Abdominal Pain

Numerous articles have questioned the effectiveness of probiotics for many of the conditions for which they have been promoted.  A recent systematic review (T Newlover-Delgado, et al. JAMA PediatrPublished online December 28, 2018. doi:10.1001/jamapediatrics.2018.4575) concludes that probiotics “may be effective in the shorter term in improving pain in children with” recurrent abdominal pain (RAP). Thanks to Ben Gold for this reference.

This study extended findings from a 2009 Cochrane review (Huertas-Ceballos AA, et al Cochrane Database Syst Rev 2009; (1):CD003019).  In total, the authors identified 19 eligible studies; of these 15 were not included in the previous review. The most common probiotic studied was Lactobacillus rhamnosus GG in 5 trials.

Key findings:

  • At 0 to 3 months postintervention, ‘based on moderate-quality evidence (odds ratio [OR], 1.63, 95% CI 1.07-2.47; 7 studies, 772 children). The number needed to treat for an additional beneficial outcome was 8.” 
  • There were only 2 studies with results extending 3 to 6 months.  These studies also found reduction in pain in the probiotic-treated children, OR 1.94 (CI 1.10-3.43). 
  • Interestingly, the authors note that fiber-based treatments were not considered more effective than placebo, despite a similar OR of 1.83.  Due to the small number of children in these studies with fiber (n=136), the CI were wide: 0.92-3.65.

The authors discuss some of the limitations such as variations in definitions, choice of probiotic and dosage, and short-term duration.  There is not a discussion of selection bias.  It is quite possible that some negative studies were completed which were not published which could further lower or eliminate the potential benefit.

My take: Probiotics may be helpful for children with recurrent abdominal pain; it is certainly not a panacea.

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Moon over Zabriskie Point, Death Valley -just before sunrise

Almost sunrise at Zabriskie Point, Death Valley


Why Stomach Pain Improves in the Summer

A recent small study (published online: KL Pollard et al. JPGN  doi: 10.1097/MPG.0000000000001886) indicates that the well-recognized phenomenon of improvement in functional abdominal pain during the summer months is associated with lower anxiety.  Here is a link to abstract: Seasonal Association of Pediatric Functional Abdominal Pain Disorders and Anxiety



In a sample of 34 participants who completed both questionnaires, 22 reported improvements during the summer months. These participants reported a significantly higher seasonal decrease in anxiety than participants whose children’s symptoms did not improve from spring to summer (mean decrease 2.21 vs 0.08, P = 0.017). Both groups reported equal improvements in sleep and decreased stress from spring to summer. Neither group experienced statistically significant seasonal change in physical activity or fruit, vegetables, dairy, or caffeine consumption.


This study suggests that amelioration of gastrointestinal symptoms in pediatric patients with AP-FGID during summer months is associated with amelioration of anxiety in the same time period. It is not yet clear whether decreased anxiety is the cause or effect of decreased AP-FGID symptom

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#NASPGHAN17 Selected Abstracts

Some of the abstracts that were presented at this year’s meeting –see below.  For a listing of the titles/authors presented, use this link: NASPGHAN Annual Mtg 2017

For complete abstracts: NASPGHAN 2017 Scientific Abstracts

Using a standardized approach along with a protocol for oral cleanouts and saline enemas if needed, the authors showed a marked decline in admissions for fecal impaction:

In this study, the authors found that low risk patients had a 91% likelihood of a negative scope.  However, on closer inspection, this rate OVERESTIMATES the likelihood of finding anything significant.  Most findings in the low risk group had questionable benefit from being identified on endoscopy including “acute colitis,” and H pylori.

The following abstract showed that in patients with EoE and not PPI-REE that topical steroids alone were as effective as PPI with topical steroids.

The following slides indicate the development of A4250, a bile acid transporter, which reduces pruritus. The presenter stated that this drug essentially is a chemical diversion which could replace biliary diversion for pruritic conditions like PFIC and Alagille syndrome.

Best Tweets from Postgraduate Course: #NASPGHAN15

Since I am not at this year’s national meeting, I have followed some of the information on social media.  Here are some of the best tweets:

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UTI in Infancy–New Risk Factor for Chronic Abdominal Pain?

A recent study (Rosen JM, et al. JPGN 2015; 60: 214-16) identifies a history of a urinary tract infection (UTI) in infancy as a risk factor for development of chronic abdominal pain.

The authors identified 57 patients with a history of UTI during the first year of life and compared them to 58 sibling controls.  Mean age of UTI was 4.8 months and mean time since UTI was 9.3 years.

Key finding:

  • Chronic abdominal pain was noted in 10 (17.5%) of patients with prior UTI compared with 2 (3.4%) of controls (P=0.02)

The authors state that this is the first study showing an infection outside the GI tract could increase the risk of chronic abdominal pain.  It is not clear to me if the UTI would truly be a sensitizing factor or whether other factors like the administration of antibiotics could play a role.

Bottomline: While this is a small study and the incidence of chronic abdominal pain was fairly low in both groups, it suggests that a history of a UTI may be a risk factor for recurrent abdominal pain; a bigger study is needed to validate these findings.

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From Twitter

Trending on Twitter -CampWeeKanEatIt Shoutout

Brave New World: Psychotropic Manipulation & Pediatric Functional GI Disorders

A recent review (JPGN 2014; 59: 280-87) provides helpful advice for the use of psychotropic medications in pediatric functional GI disorders.  That being said, a couple key caveats need to be stated first and foremost:

  • “A minority of psychotropic drugs has been studied in children and safety data remain inadequate.  Psychotropic drugs used for gastrointestinal symptoms in pediatric patients will be off-label for the foreseeable future.”
  • “Descriptions of individual drugs in the present review are too brief to provide accurate guidance to someone who is not already familiar with them.”

Given the limited data, the authors, in my opinion, bravely state recommendations regarding these medications.  Despite their common usage, providing explicit recommendations is quite uncommon.  The title of the blog references Aldous Huxley’s book which discusses psychological manipulation.  This book in turn is titled after a line from Shakespeare’s The Tempest, Act V, Scene I (from Wikipedia):

“O wonder!
How many goodly creatures are there here!
How beauteous mankind is! O brave new world,
That has such people in’s.”

Back to the review of psychotropic medications, the authors provide a rationale/pathophysiologic mechanism for the use of these drugs mainly for recurrent abdominal pain and chronic nausea/dyspepsia.  Table 1 lists the authors’ specific suggestions regarding first to fourth choices:

  • For abdominal pain, first choice was amitriptyline, followed by gabapentin, clonidine patch, and SSRI.
  • For nausea/dyspepsia,  first choice was amitriptyline, followed by mirtazapine, buspirone, and clonazepam.
  • For d-IBS,  first choice was amitriptyline, followed by alosetron [not a psychotropic], clonidine patch, and SSRI.
  • For c-IBS (along with polyethylene glycol),  first choice was imipramine, followed by lubiprostone [not a psychotropic], gabapentin, and SSRI.

Table 2 provides dosing suggestions, and common adverse effects.  For example, with amitriptyline, suggested dose is 10-50 mg qhs and “best to begin low dose…titrate up by response.” Other suggestions:

  • SSRIs: “should begin with low dose; titrate up by response.  With SSRIs, benefit is usually apparent after 4 to 6 wk.  Most GI adverse effects disappear in 1 to 2 wk.”
  • Mirtazapine: 7.5 mg dosing for sleep, 15-30 mg qAM for nausea/dyspepsia (higher dose is usually not sedating.  “Few drug interactions; safer than TCAs.” Weight gain is common.
  • Buspirone: 10-60 mg/day, divided twice daily; “may start with half dose in the morning.” Avoid grapefruit juice. Can “used alone or in combination with SSRIs or TCAs.”
  • Gabapentin (100 mg BID to 800 mg TID). “Rare adverse effects include drowsiness and blurred vision…Safe but only effective in about one-third of patients.”
  • Recommends that second-generation antipsychotics (quetiapine, risperidone, and olanzapine) be used only in collaboration with child psychiatry (Figure 2)

Additional pointers:

TCAs:“In RCTs, among children with functional abdominal pain, both amitriptyline and placebo were associated with an excellent therapeutic response.”  It is interesting to note the authors lack of critical comments regarding this statement.  “The usual dose of amitriptyline for chronic functional pain is 1 mg/kg/day up to a maximum of 50 mg/day.”

TCAs and EKGs: “at doses <1 mg/kg/day used to treat chronic pain and nausea, there have been no reports of death or cardiac arrhythmias in >60 years.  An EKG before starting a TCA is unnecessary in otherwise healthy children and adolescents, but may be advisable in those with a personal or family history of corrected QT interval prolongation or heart disease, or in children requiring a dose >50 mg/day.”

TCAs: some tricyclics may be less sedating and constipating including imipramine, doxepin, and nortriptyline.  The later two also come in liquid formulations.

SSRIs: “may be used in combination with TCAs in teens and adolescents…using them simultaneously may increase serum concentrations of both.” “In children there was a single RCT showing citalopram superior to placebo in IBS. Some clinicians obtain an EKG assessing corrected QT interval before initiating citalopram doses >20 mg daily.”

Clonidine has “improved diarrhea-predominant IBS…Common adverse effects include dry mouth, drowsiness, dizziness, and tiredness…checking blood pressure at each clinic visit [is recommended].” It is available as a patch (0.1-0.3 mg/wk).

Melatonin: dosed 3- to 10-mg at bedtime can promote sleep.

Take-home message: This article provides practical advice for the use of these agents.  Discussion with patients and parents regarding the role of these medications in targeting CNS arousal which perpetuates disabling chronic symptoms is crucial as well.  More studies are needed to determine conclusively their effectiveness.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.


Change the Name: “Functional” is Lousy

A recent commentary explains why “functional” pain is such a lousy term (JAMA Pediatr. Published online June 02, 2014. doi:10.1001/jamapediatrics.2014.530 –thanks to Ben Gold for this reference).  In pediatric GI practice, functional gastrointestinal disorders (FGIDs) constitute a large part of clinical work.

The author, Neil Schechter from the Chronic Pain Program in Boston, makes several important observations:

  • “There is general dissatisfaction with the terminology.”  This stems from the fact that “in common parlance today, functional disorders are typically assumed to be a product of psychological distress.” Yet, parents/patients are “not ready to accept a strictly psychological explanation.”
  • The idea that functional pain is solely a psychological disturbance is inaccurate.  Though, anxiety and depression are common associated problems which often contribute to symptoms.  He states that “hyperexcitability” of the nervous system is “the core biological link and final common pathway for the creation of functional pain disorders.”
  • This category should be labeled dysfunctional pain.  “In effect, calling pain ‘functional’ is like calling disease, ‘ease.'”
  • These disorders frequently respond to centrally acting therapies including antidepressants, anticonvulsants, exercise, cognitive behavioral therapy, and acupuncture.
  • “The search for an appropriate term for these pain problems is far more than semantic…[a patient’s] understanding of their illness is clearly linked to their compliance with medical advice…it may stem their desire for additional costly investigation.”
  • Dr. Schechter proposes the term “primary pain disorder.”  “Unlike Shakespeare’s rose, functional pain would benefit from a new name.”

Take-home message: I wish I had written this commentary.  Explaining “functional” pain and “irritable bowel syndrome” are Sisyphean tasks.  Better nomenclature could ease the burden.  Join me in abandoning the use of the word “functional.”

In the same issue, an editorial on the “Role of Celiac Disease Screening for Children with Functional Gastrointestinal Disorders” (JAMA Pediatr. 2014;168(6):514-515. doi:10.1001/jamapediatrics.2013.5418) comments on a study (JAMA Pediatr. 2014; 168(6):555-60) in the same issue which reports a 4-fold higher prevalence of celiac disease among children who meet clinical criteria for irritable bowel syndrome.  The study reports the results from a cohort of 992 children identified with recurrent abdominal pain in a primary care setting.  In the editorial, the authors note:  “When grouped together, the prevalence rate of celiac disease among all children with FGIDs (IBS included) approaches 2%.  Celiac disease screening in this population would result in a positive tTG-IgA test result in 4%…However, 53% of all positive test results would be falsely elevated.”  As such the editorial advocates in favor of screening for celiac disease in children with IBS but not all FGIDs.

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“If all you have is a hammer…”

In my training, one of my mentors would be critical of the mentality “scope first, think second.”  He was concerned that too many gastroenterologists/pediatric gastroenterologists used endoscopy as a tool simply “because if all you have is a hammer, the world looks like a nail.”

A recent publication (Clin Gastroenterol Hepatol 2014; 12: 963-69) on first glance, however, provides ammunition to the “scope first” gastroenterologists and undermines the concept that “functional” GI disorders vastly outnumber “organic” GI disorders.  The key finding was that esophagogastroduodenoscopy (EGD) provided an “accurate” diagnosis in 38%.  This included reflux esophagitis in 21%, eosinophilic esophagitis (EoE) in 5%, eosinophilic gastroenteritis (EGE) in 4%, H pylori in 2%, celiac disease 0.6%, and Crohn’s disease 0.4%. This finding is dramatically higher than previous studies.  In fact, in a recent published study (Understanding Idiopathic Nausea | gutsandgrowth) on idiopathic nausea, a control group of patients with chronic abdominal pain had a normal endoscopy in 100%!

In this prospective study of 290 children (ages 4-18 years with a mean age of 11.9 years), the primary indication for upper endoscopy was chronic abdominal pain.  Of this 290, 216 had at least 1 alarm feature and 125 had at least 2 alarm features.  Alarm features were considered to be the following:

  • Nighttime awakening 33.3%
  • Weight loss 15.6%
  • Family history of IBD 8.4%
  • Vomiting 7.8%
  • Dysphagia 6.9%
  • Nocturnal diarrhea 6.7%
  • Gastrointestinal bleed 5.8%
  • Chronic diarrhea 5.8%
  • Unexplained fever 4.4%
  • Arthralgia 4.0%
  • Growth failure 2.4%
  • Perirectal disease 0.7%
  • Delayed puberty 0.2%

There is little debate that abdominal pain in combination with true alarm symptoms (True red flags in recurrent abdominal pain | gutsandgrowth) merits further evaluation.  The aspect of this report that is worthy of close inspection is the diagnostic yield in the 74 patients without alarm symptoms.  The authors note that 25 (33.7%) had a diagnosis established with EGD including 16 with reflux esophagitis, 4 with EGE, 2 with EoE, 1 with erosive esophagitis, 1 with celiac and 1 with H pylori.  The diagnostic criteria for EGE included ≥10 eosinophils per hpf in the stomach and ≥20 eosinophils per hpf in the duodenum.

The authors note that the diagnostic yield was based on gross endoscopic findings in procedure notes or histologic changes in biopsy reports; “final pathology report on biopsies provided the data source for histologic diagnosis.”

In my opinion there are multiple flaws of this prospective study.

1. There is a very high rate of reflux esophagitis in both the alarm group and the non-alarm group patients with chronic abdominal pain.  Of the entire cohort (n=290), the authors identified reflux esophagitis in 21% and this was “primarily histologic esophagitis.”  Furthermore, the authors state that “the presence or response to PPI therapy was not predictive of esophagitis or GERD.”  So, the obvious problems:

  • Presence of histologic reflux esophagitis varies widely based on the interpreting pathologist.  In a prospective study, more than one pathologist interpreting the histology would be useful.
  • Presence of histologic reflux esophagitis does not exclude the likelihood of coexisting functional disorders (related blog post: Why didn’t patient with documented reflux get better with PPI …).  As a practical matter, “slight” or “focal” esophagitis on histology has questionable real-world relevance in pediatric gastroenterology.
  • The authors acknowledge, “current expert consensus indicates that histology has limited value in evaluating pediatric GERD.”  Yet this diagnostic finding is one of the reasons why the authors claim that EGD is so valuable.

2. In the entire cohort, the authors try to validate their findings by indicating that identification of a diagnosis led to medical therapy that was “effective in approximately 67%” of children with short-term followup. (Only 81% had short-term followup outcomes available).  Yet, there is no control group.  How many children with chronic abdominal pain will improve for a short period without an EGD-based diagnosis?  The answer: a lot of them.

3. Limitations include selection bias toward those with more severe symptoms or alarm symptoms.  In addition, this study included only a small number who were considered to have no alarm symptoms.  Finally, the short-term followup makes conclusions about the response to therapy questionable.

This study will be a useful reference for any pediatric gastroenterologist who wants to justify the need for an endoscopy.  The authors note “the majority of children in our study (93%) met criteria for functional gastrointestinal disorders, and a significant proportion (38%) still had significant histologic findings.  Therefore, we conclude the Rome III criteria alone are not sufficient to identify children who require upper endoscopy, and screening for alarm symptoms has limited utility.”

In my opinion, the reliance on histology as well as selection bias weaken the findings of this study.  If a patient with a histologic diagnosis of reflux (or several other entities) and a presentation of chronic abdominal pain does not improve, the pediatric gastroenterologist should remember that only “a poor carpenter blames his tools.”

Bottomline: EGD remains an important tool in evaluating abdominal pain.  However, I think this study substantially overestimates its utility.

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