Chronic abdominal pain (CAP) or recurrent abdominal pain (RAP) is a frequent problem in children that has major implications for their well-being and the use of health care systems (1,2). Apley and Naish (1958) were the first to study children with this pain syndrome (3). They introduced the term “RAP” for clinically apparent nonorganic chronic or recurrent abdominal pain in children. RAP was defined as 3 or more episodes of abdominal pain that occur for 3 months and that are severe enough to interfere with the child's daily activities. Because the term “RAP” was simply a description of a pattern of symptoms without etiologic assumptions, this definition did not exclude children with organic causes of the pain. Because serious organic pathological changes would have become manifest within the time limits set, these workers assumed that the risk for organic abnormalities was low (3).
History, clinical examination, and the presence of red flags or alarm symptoms help the discrimination between organic and nonorganic causes of the pain and provide indications for further testing. However, over time and with advances in medical technology, new biochemical abnormalities have been identified in children with CAP. Nowadays, in as many as 30% of children with clinically apparent CAP can organic abnormalities be detected (4), including esophagitis, Helicobacter pylori gastritis, lactase deficiency, and celiac disease. It still needs to be established, however, whether there is a causal relation between these organic abnormalities and the abdominal pain (5–8).
At the same time, further classifications of the symptom complex of CAP have been developed, and the updated Rome criteria (Rome III) have recently been published (9). The Rome criteria classify nonorganic CAP into 5 functional gastrointestinal disorders (FGIDs): childhood functional abdominal pain, childhood functional abdominal pain syndrome, irritable bowel syndrome, functional dyspepsia, and abdominal migraine. Structural biochemical abnormalities should be absent. The extent of medical testing to exclude underlying organic pathological changes is at the discretion of the clinician, the setting of care, and the medical possibilities available.
The publication of the Rome criteria and the discovery of new organic abnormalities resulted in an explosion of clinical research. The clinical relevance and consequences for prognosis of this fine-tuning of CAP are not yet clear and need to be studied. To be able to do so, one needs a reference of the overall prognosis of CAP. Because, to our knowledge, there is no overview of the current literature on the prognosis of CAP, we performed a systematic review on cohort studies of children with CAP.
In this study, our primary focus was to investigate how often abdominal pain persisted in children with CAP or with a subtype of CAP. Our secondary interest was to investigate whether extensive medical testing (ie, laboratory tests, imaging, and endoscopy) had additive prognostic value after history taking and clinical examination.
MATERIALS AND METHODS
The MEDLINE database was searched from 1965 to October 2005, PsycINFO from 1970 to October 2005, and EMBASE from 1980 to October 2005. In MEDLINE we searched with a sensitive PubMed clinical query to identify prognostic studies (10–12). For EMBASE we used the search strategy for detecting prognostic studies recommended by Wilczynski and Haynes (13). For PsycINFO we used the search strategy (incidence or mortality or follow-up or prognosis or predict* or course* or epidemiol*). To describe the abdominal pain, the following key words were used: “abdominal pain” and “chronic or recurrent abdominal pain.” We limited by age, but no language restriction was used. The reference lists of the relevant retrieved studies were checked to identify additional published research.
Two reviewers (M.J.G. and M.Y.B.) screened all of the abstracts of the identified published articles for eligibility. Full articles were retrieved if the abstract provided insufficient information to enable selection or if the article had passed the first eligibility screening. An article was eligible if it met all of the following criteria: the study population concerned children or adolescents 4 to 18 years of age; the abdominal pain was described according to the criteria defined by Apley and Naish (3), by von Baeyer and Walker (14), or by Rasquin-Weber et al (Rome II) (15) or by using words like “nonorganic abdominal pain,” “recurrent abdominal pain,” or “functional abdominal pain”; the article determined the prognosis of CAP and the prognosis was given as the percentage of children with CAP who had abdominal pain after follow-up; and the outcome was determined prospectively. Decisions regarding the inclusion of studies were made independently, and any disagreements were resolved through consensus or by arbitration of a third person (S.M.A.B.-Z).
Methodological Quality Assessment
Two reviewers (M.J.G. and S.M.A.B.-Z.) independently scored the quality of the studies. The instrument used was a modified version of an established criteria list used in systematic reviews of prognostic studies (16,17). We modified the criteria list on the basis of the framework for assessing internal validity of studies of prognosis as described by Altman (18). The final list consisted of 11 items (Table 1), each having an answer option of “yes”/“no”/“don't know.” The operationalization of the criteria list is available from the first author. A positive score indicated sufficient information and a positive assessment. A negative score indicated sufficient information but potential bias due to inadequate design or conduct. If an item was scored as unclear it meant that the article provided insufficient information about these criteria. A score of 1 point was given only to a criterion that was assessed with “yes”; the criteria assessed as “no” or “?” did not receive any points. Equal weights were applied to all of the items. This resulted in a maximum score of 11 points. Disagreement was resolved through consensus or by arbitration of a third person (M.Y.B.).
M.J.G. extracted the information regarding study population, inclusion and exclusion criteria, the study setting, follow-up period, numbers lost to follow-up, and outcome measures on a standardized form. A second observer (M.Y.B.) verified the data.
The interassessor agreement on the methodological quality was calculated by use of κ scores (>0.7 = a high level of agreement between assessors; 0.5–0.7 = a moderate level of agreement; <0.5 = a poor level of agreement) (21). The prognosis was measured as abdominal pain after follow-up and was given as the percentage of patients who had not recovered from CAP, with corresponding 95% confidence intervals (exact binominal). To take into account the large variation in group size, a weighted pooled percentage was calculated. Each reported percentage was weighted by dividing it through its squared standard error. A sensitivity analysis was performed to estimate the effect of the number of patients lost to follow-up.
The influence on prognosis of the following variables was studied by stratifying 3 factors: inclusion and exclusion criteria (as a result of the shift of the definition of CAP over time), the setting of care (inpatients/outpatients and secondary/tertiary based), and the duration of follow-up (1 to <5 years, 5 to <10 years, and ≥10 years).
The influence of different inclusion and exclusion criteria was studied by comparing studies with a clinical diagnosis of CAP—that is, without alarm symptoms (“red flags”) with studies that diagnosed CAP after extensive testing—and studies conducted before and after 1980. We compared studies before and after 1980 because we hypothesized that with the introduction of, for example, fiberoptic endoscopy and the detection of H pylori more organic abnormalities could be detected. The percentages of CAP patients with abdominal pain after follow-up of the strata were compared with the χ2 test.
The search strategy resulted in 2620 citations (MEDLINE 1071, EMBASE 1517, PsycINFO 32), of which 60 full publications were evaluated. Two publications from Czechoslovakia were excluded from further evaluation because of the inability to translate the manuscripts. In total, 17 studies fulfilled the inclusion criteria. One study defined CAP after follow-up as at least 1 episode of abdominal pain in 6 months (22). This frequency was low in comparison with the frequency of abdominal pain presented at baseline and with the frequency used in the other selected studies. We decided that this outcome was not comparable with the outcome used in the other studies, and we excluded the study from further analysis. Two additional studies (23,24) were detected by screening the reference lists of the studies and of 2 recently published reviews of RAP (2,25). Finally, 18 articles were included (23,24,26–41).
Table 2 shows the results of the methodological quality assessment. The reviewers agreed on 92.5% of the quality items. The interobserver reliability of the methodological quality assessment (κ = 0.85) was good.
Studies that scored 0 on item D retrospectively identified the patients by using medical records, but the outcome was determined prospectively (27–30,35,36,38,39,41). The most important methodological shortcomings concerned the following items: None of the studies identified the cohort at a unique point in the course of the disease (item A). In more than 50% of the studies, the study population was not clearly defined (items B, C). Only 4 studies compared the patients lost to follow-up with those who were followed up (item G) (27,32,36,41). Only 6 studies described the treatments that the patients received (item H) (23,28,35,38–40).
The main characteristics of the studies are given in Table 3. In total, the 18 studies were of 1747 patients ages 4 to 18 years with CAP. The sample sizes ranged from N = 22 (36) to N = 356 (30). For 1331 patients, follow-up data were given (23.8% lost to follow-up). The follow-up periods ranged from a minimum of 1 year (27) to a maximum of 29 years (39) (median 5 years, SD 7 years 2 months).
In 9 studies, CAP was diagnosed after additional medical testing before patients were included in the study (tested nonorganic) (27–29,31,32,35,36,39,41). In the remaining 9 studies, CAP was clinically diagnosed (clinically nonorganic) (23,24,26,30,33,34,37,38,40). In 4 of the latter 9 studies, children were additionally tested after inclusion in the study, and the authors described the abnormalities found (23,26,30,33).
Two studies explicitly stated that no organic diseases had been diagnosed during follow-up (mean duration of follow-up 8 years 5 months, number followed up 118) (26,35). Three studies reported the organic diseases that were diagnosed during follow-up. In 1 study (duration of follow-up ≥5 years, number followed up 161) 3 patients had Crohn disease, 2 patients underwent appendectomy, 1 underwent adhesiolysis, and 1 underwent ovariocystectomy (41). In the second study (mean duration of follow-up 29 years, number followed up 34) duodenal ulcers developed in 2 patients (39). In the third study (duration of follow-up 8–20 years, number followed up 60), 1 patient experienced duodenal cancer and 1 patient had dermoid cysts in her ovaries (38). The remaining 13 studies did not describe whether organic diseases had been diagnosed during follow-up.
In total, 9 studies were conducted in tertiary care facilities (pediatric gastroenterology) (23,27–31,33,36,40), 5 were conducted in secondary care clinics (26,34,35,37,39), and 1 was population based (24). In 3 studies, the setting was not clearly reported (32,38,41). Ten studies were conducted in outpatients (23,26,30,31,33–35,38,40,41) and 5 studies in hospitalized patients (27–29,36,39); in the remaining 3 studies, it was not clear whether inpatients or outpatients were involved (24,32,37).
The studies were performed during a wide time span. In 1 study the diagnosis of CAP was made in the 1940s (39) and in 5 other studies in the 1960s (32,36–38,41), and 2 studies were performed in 2005 (26,27).
In 6 studies (24,26,29,31,32,39), the authors performed a nested case-control study; they described a prevalence of abdominal pain at follow-up of formerly well patients and compared this percentage with the percentage of CAP children with abdominal pain at follow-up.
Prognosis of Abdominal Pain
Of the 1331 children with CAP who were followed up for a median of 5 years (range 1–29, SD 7 years 2 months), 415 had abdominal pain after follow-up. The mean pooled percentage of children with abdominal pain after follow-up was 29.1% (95% CI 28.1%–30.2%, range 13.5%–54.2%).
If all the patients who were lost to follow-up had recovered, the crude percentage of CAP patients with abdominal pain after follow-up would have been 23.7% (95% CI 21.7%–25.8%). If all of the patients who were lost to follow-up had persistence of their abdominal pain after follow-up, this would have been 47.6% (95% CI 45.2%–49.9%).
Five studies described the percentages of children with abdominal pain after follow-up of subtypes of CAP (23,26,27,30,33). These results are shown in Table 4.
Factors That Influenced the Prognosis of CAP
Table 5 shows the prognosis of abdominal pain stratified according to inclusion criteria, setting of care, and duration of follow-up. CAP that was clinically diagnosed after history taking and physical examination had a prognosis comparable to that of CAP diagnosed after additional medical testing. CAP studied before and after 1980 had comparable prognoses. Inpatients had a statistical significantly worse prognosis than did outpatients. There were no differences in prognoses between studies performed in secondary and tertiary care. The longer the duration of follow-up, the worse was the prognosis.
Four studies additionally tested a group of patients in whom CAP was clinically diagnosed (23,26,30,33). In 137 of the 378 (36.2%) patients, organic abnormalities were found; 38 of these 137 patients had abdominal pain after follow-up (27.7%) (95% CI 20.4–36.0), in comparison with 76 of the 241 patients in whom no organic abnormalities were found (31.5%) (95% CI 25.7–37.8) (χ2 test NS, P = 0.4). The organic abnormalities were poorly defined and included gastroesophageal reflux disease, gastritis, H pylori gastritis, esophagitis, constipation, lactose intolerance, celiac disease, and urinary tract abnormalities (Table 3). All of the studies reported that the children received treatment, although the type of treatment was not specified.
The prognosis of 278 patients with former CAP was compared with the prognosis of 2901 formerly well patients (24,26,29,31,32,39). Formerly well patients and patients with former CAP had the same duration of follow-up (mean 12 years 8 months, range 5–19 years). At follow-up, 41.3% (95% CI 35.5–47.4) of the patients with former CAP had abdominal pain, compared with 10.1% (95% CI 9.0–11.2) of the formerly well patients (RR = 4.1, 95% CI 3.43–4.89).
To our knowledge, this is the first systematic review of the prognosis of CAP in children. The systematic literature search yielded 18 follow-up studies. In total, 1331 children 4 to 18 years of age were followed up for 5 years (median, range 1–29 years; SD 7 years 2 months).
The abdominal pain persisted in 29.1% (95% CI 28.1–30.2) of children with CAP. Children with a history of CAP had a 4 times higher risk of persistent abdominal pain than did children who presented for the first time with CAP. Because of the high dropout rate of 23.8%, we performed a sensitivity analysis. The analysis showed that even if all of the children dropping out were assumed to have become free of abdominal pain, almost one fourth of CAP patients would still have abdominal pain after follow-up (23.7%, 95% CI 21.7–25.8).
The prognoses of specific subtypes of CAP were addressed in only 5 studies. The numbers of patients studied were too small to enable reliable conclusions to be drawn about the prognosis of discrete FGIDs.
In studies of children with clinically diagnosed CAP, an organic abnormality was found in 2% of the children during follow-up. This finding is in accordance with a recent systematic review of the literature in which it was observed that additional diagnostic testing of children with CAP without alarming symptoms did not yield relevant organic disease (25).
We examined whether extensive medical testing had additive prognostic value above history taking and clinical examination. No differences were found between the prognosis of CAP diagnosed clinically and that of CAP diagnosed after extensive investigations. In addition, we found no differences in the prognosis of CAP between studies performed at the time of limited diagnostic possibilities and those performed more recently.
We found that the persistence of CAP in children without alarming symptoms was not influenced by the detection of abnormalities, such as gastroesophageal reflux disease, gastritis, H pylori gastritis, esophagitis, constipation, lactose malabsorption, celiac disease, and urinary tract abnormalities.
This may indicate that the prognosis would have been worse if these children had not received adequate diagnosis and treatment. From this perspective, it is important to detect these abnormalities to minimize persistent abdominal pain. One may argue, however, that the prognosis of the patient with an abnormality should have been better in case of a causal relation between the abnormality and the abdominal pain, given an effective treatment. From this perspective, a causal relation between the abnormality and CAP is unlikely, and thus it is not useful to test for these abnormalities in children with CAP to influence the prognosis of CAP. This interpretation is supported by others. Until now an etiologic relation between CAP and H pylori gastritis, lactose malabsorption, or celiac disease could not be demonstrated (5–7,43–45).
From a psychological point of view it should be kept in mind that negative test results do not reassure the child's parents; rather, tests reinforce the parents' fear of an unknown organic disease, which makes it harder to introduce the concept of a functional disorder afterwards. This brings us to the conclusion that testing children with CAP without alarming symptoms is not useful and should be avoided. Our findings endorse the removal of the recommendation for endoscopy in children with CAP without alarming symptoms, as recently described in the Rome III criteria for FGIDs (9).
The results of our study showed that almost twice as many inpatients as outpatients did not improve from CAP. Hospitalization may reflect the severity of the abdominal pain, existing comorbidity, or inability of patients and their families to deal with the disorder.
Another finding was that almost 1.5 as many patients who were followed up for more than 10 years had persistent abdominal pain, compared to those followed up for 1 to 5 years. CAP in children may progress to irritable bowel syndrome in adults (31–46). The persistence of abdominal pain is a complex multifactorial mechanism that urgently needs further investigation to recognize children at risk for a prolonged course of this disabling condition.
The following limitations should be taken into account when interpreting the results of this review. In a literature search there is always a risk of missing studies. This risk may be higher for diseases that lack a clear definition, such as CAP. We tried to avoid this problem by using a sensitive search strategy that included all available words and all known definitions of this pain syndrome. Most studies defined the abdominal pain at follow-up as a pain that resembled baseline pain. However, not all of the studies clearly defined this pain. The outcome measure, therefore, may be heterogeneous with respect to the frequency and the severity of pain.
The presented prognosis for childhood CAP is an overall estimate. Many factors determine a patient's prognosis. We found that inpatients had different prognoses than did outpatients and that the duration of follow-up influenced prognosis. Other factors that may influence prognoses are treatment, duration of the pain at baseline, and psychological factors. The identification of these prognostic factors, however, was outside the scope of this study.
There is a need for prognostic research of good methodological quality on CAP in children, in a broad range of settings. To establish the clinical utility of a classification system of CAP, the course of disease of the different FGIDs defined should be studied. To grasp the full context of functional disorders, one should add functional disability as an outcome measure for prognosis (47).
CAP persisted in 29.1% (95% CI 28.1–30.2) of children. In the absence of alarm symptoms, additional diagnostic testing did not influence prognosis. There is a need for prognostic research in a broad range of settings on CAP in children.
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