CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 26;4:67 72 Longitudinal Follow-up of Children With Functional Nonretentive Fecal Incontinence WIEGER P. VOSKUIJL,* JOHANNES B. REITSMA, RIJK VAN GINKEL,* HANS A. BÜLLER, JAN A. J. M. TAMINIAU,* and MARC A. BENNINGA* *Department of Pediatric Gastroenterology and Nutrition, Emma Children s Hospital, Amsterdam; Department of Clinical Epidemiology and Biostatistics, Academic Medical Centre, Amsterdam; and Department of Pediatrics, Sophia Children s Hospital, Rotterdam, the Netherlands Background & Aims: Functional nonretentive fecal incontinence (FNRFI), incontinence in the absence of signs of fecal retention, is a frustrating phenomenon in children. No data on long-term outcome are available. The aim was to investigate the long-term outcome of FNRFI patients after intensive medical treatment. Methods: Between 199 and 1999, 119 patients (96 boys) with FNRFI were enrolled in 2 prospective, randomized trials investigating the effect of biofeedback training and/or laxative treatment. Follow-up (FU) was performed at 6 months, 1 year, and thereafter annually until September 24. A standardized questionnaire was used to evaluate symptoms. Success was defined as a fecal incontinence frequency <1 per 2 weeks. Results: Median age was 9.2 years (range, 7.9 11.6 years). A 9% FU was achieved at all stages of the study. After 2 years of intensive therapy, 33 of (29.5%) patients were successfully treated. The cumulative success percentage after 7 years of FU was 8%. At the biologic ages of 12 and 18 years, 49.4% (/81) and 15.5% (9/58), respectively, of the patients still had fecal incontinence. Duration of fecal incontinence, with 4 years of age as the starting age for fecal incontinence (when a child should be toilet trained), was not related to successful outcome or relapse. Relapse occurred in 37% of patients. Conclusions: Only 29% of the patients with FNRFI were successfully treated after 2 years of intensive treatment. Despite recovery in the majority of patients beyond puberty, at age 18 years, 15% continued to have fecal incontinence. The involuntary loss of feces in the underwear after the age of 4 years is a frustrating symptom. Despite its high prevalence, 1% 2% in otherwise healthy schoolchildren, a first visit to the pediatrician is frequently delayed because of shame and cultural taboos concerning fecal incontinence. 1 In more than 8% of the patients, fecal incontinence is the result of constipation. Prolonged fecal stasis results in the involuntarily loss of feces in the underwear several times per day and in severe constipation even during the night. These patients are best treated with oral and/or rectal laxatives. 2 In approximately 2% of the children with incontinence, the fecal loss exists without any sign of fecal retention, and these patients are classified as having functional nonretentive fecal incontinence (FNRFI). 3 5 These children defecate 3 times per week on the toilet and have no other symptoms of constipation. More importantly, and in contrast with children with retentive fecal incontinence, they have no fecal retention on abdominal and rectal examination. Furthermore, these children have normal colonic transit times and normal anorectal manometry results. 6,7 9 Recently, a prospective long-term follow-up (FU) study in children with constipation showed that, in contrast to general belief, constipation continued beyond puberty in 3% of the constipated children. 1 To date, no data exist concerning the long-term prognosis of patients with FNRFI. Since 199 we yearly have contacted our cohort of children with FNRFI who participated in 2 randomized controlled trials evaluating the effect of biofeedback training and/or laxatives. In the present study we aimed to investigate (1) whether FNRFI resolved during puberty, and (2) whether there are clinical factors associated with the achievement of clinical success and with relapse after an initial successful period. Methods All FNRFI-patients enrolled in the present study participated in 2 randomized trials performed in our department between 199 and 1999. The first study compared the effect of laxatives and additional biofeedback training with laxative treatment alone. 7 During a 6-week treatment program all patients (N 71) received lactitol (5 g/1 kg body weight), and half of the children were randomly assigned to receive 5 additional sessions of biofeedback. Abbreviations used in this paper: FNRFI, functional nonretentive fecal incontinence; FU, follow-up. 26 by the American Gastroenterological Association 1542-3565/6/$32. doi:1.116/j.cgh.25.1.1
68 VOSKUIJL ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 1 The second study investigated the effect of biofeedback training with additional laxative treatment compared with biofeedback alone. 8 During a 7-week program all patients (N 48) underwent 5 biofeedback sessions, and half of the children received additional lactulose (5 g/1 kg body weight). In addition to laxative therapy and/or biofeedback training, therapy in both studies consisted of a protocol including education about incontinence, a high fiber diet, toilet training, and the fill in of a bowel diary. Motivation was enhanced by praise and small gifts. After the intensive treatment period, patients were seen once every month to once every 2 months during a period of at least 2 years, depending on the severity of the complaints. Thereafter, if necessary, patients were seen once every 3 6 months. Patients in both studies (N 119) were referred to our tertiary gastrointestinal motility center by general practitioners, pediatricians, psychologists, psychiatrists, and school doctors. At intake all patients fulfilled the criteria for FNRFI, defined as 2 or more episodes of fecal incontinence (the voluntary or involuntary loss of loose stool in the underwear after the age of 4 years 2 ) per week during the preceding 8 weeks, with no signs of constipation; a defecation frequency of 3 per week; no periodic passage of very large amounts of stool at least once every 7 3 days; and no palpable abdominal or rectal mass on physical examination. 2 All children included in both treatment studies were older than 4 years of age so they could understand the biofeedback procedure. Children with functional constipation and patients with organic causes of fecal incontinence such as Hirschsprung s disease, muscle disorders, prior rectoanal surgery, spina bifida (occulta), and mental retardation were excluded. The 2 treatment studies were approved by the medical ethical committee of the Academic Medical Centre. All subjects and/or parents gave informed consent. Data Collection and Follow-up After the end of the 2 randomized trials, all patients were enrolled in our long-term registry of FU. In this longterm outcome registry we actively contacted our former patient cohort to monitor success and relapse. Children were contacted 6, 12, and 18 months after the end of the initial studies and thereafter annually until September 24. A standardized questionnaire was used for FU to evaluate symptoms during an outpatient visit or by telephone when the patient had been discharged. Data about frequency of defecation, frequency of fecal incontinence, and the use of medication were collected. Children who still had fecal incontinence were seen regularly at our outpatient clinic. Successful outcome (clinical success) was defined as having less than 1 incontinence episode in 2 weeks while not using medication, such as loperamide, for at least 1 month. 1,11 Statistical Analysis Baseline characteristics of the cohort were analyzed in a descriptive way. The frequency and timing of first success and relapse were presented in a Kaplan Meier curve without Table 1. Patient Characteristics at Intake Number of patients in study 114 (9 male) Median age at intake, 9.2 (7.9 11.6) Median years of symptoms before intake 4.4 (3. 6.7) Median incontinence frequency/wk 8. (5. 14.) Median defecation frequency/wk on toilet 7. (7. 1.) Primary incontinence (never toilet trained at 32% intake) Daytime enuresis 28% Night-time enuresis 26% Median months of treatment before intake 5.5 (2. 24.) Psychological treatment before intake 28% Positive family history 2% adjustment for the discrete nature of the FU. To gain insight into the clinical characteristics that are associated with clinical outcome during FU, we set up 2 different analyses. Data are shown with 95% confidence intervals. A P value.5 was considered significant. Prognostic Factors for Success and Relapse After Initial Success In the first model, prognostic factors for the occurrence of first success were analyzed (success model). We used a complementary log-log regression model to examine the relation between predefined baseline characteristics and the probability of a successful outcome. 12 This regression model assumes that a continuous time, proportional hazards model has generated the underlying observations, but because we observed only data grouped by 6 monthly or yearly intervals, we used a discrete hazard model to estimate the contributions of the independent variables to the hazard. It has been shown that the discrete hazard model generates unbiased estimates of the coefficients of a continuous time proportional hazards model. 12 A limited set of predefined baseline factors was entered. These factors were selected on the basis of previous research findings and own interest. The following factors at intake were examined: gender, frequency of incontinence, family history positive for fecal incontinence during childhood, and earlier psychological treatment. Duration of fecal incontinence was defined as the time between the starting age of fecal incontinence (with 4 years of age as starting point, ie, when a child should be toilet trained) and the time of intake. Frequency of incontinence at intake was dichotomized into 7 times of incontinence per week or less versus more than 7 times per week. Because of the low number of events, we analyzed all relapses during the 2 years after initial success combined rather than in a discrete time model. A standard logistic regression model was used to examine predictive factors for relapse after an initial success. The same factors were examined as in the success model. Analyses were performed with SAS (SAS Institute, Inc, Cary, NC) software version 8.2 and SPSS (SPSS Inc, Chicago, IL) version 11..
January 26 LONGITUDINAL FOLLOW-UP OF CHILDREN WITH FNRFI 69 Success at different years of FU Figure 1. Percentage of clinically successful patients at different years of FU. The number on top of each bar indicates the number of patients available to FU in that year. The number between parentheses below the figure indicates the number of patients who were lost to FU during that specific year. Percentage 1 9 8 7 6 5 3 2 1 13 64 53 36 76 89 98 19 19 11,5 1 1,5 2 3 4 5 6 7 8 9 1 11 12 (2) (2) (2) (1) (1) (1) (1) Duration of FU in years Results Patient Characteristics Between 199 and 1999 a total of 114 patients were enrolled in this long-term FU study of which 9 were boys (79%). Median age at intake was 9.2 years, and the median age of onset of defecation problems was 4 years. The mean time of FU was 8.8 2.4 years (range, 2 12 years). There were no significant differences between boys and girls with regard to patient characteristics at intake (Table 1). Clinical Outcome During Follow-up A total of 119 consecutive children with FNRFI took part in 2 previous randomized, large biofeedback studies. 7,8 Five patients did not complete these treatment studies; consequently 114 children were enrolled in the present FU study. During the 12-year period of the current FU study, 1 of the 114 patients were lost to FU, in all cases as a result of a change to a new and unknown address. Despite all efforts, we were unable to trace the new addresses of these subjects. No differences were found between the baseline characteristics of those individuals in the trial and those individuals who were lost to FU. The overall FU percentage throughout the study was therefore 9%. Figure 1 shows the percentages of clinically successful patients at different years of FU. At 2 years of FU, only 29.5% of the patients (FU percentage, 98%) were successfully treated, despite intensive treatment and regular FU. Figure 1 shows a steady increase in success from 3 years of FU and further on. At 5 years of FU, 71 of 19 patients (65%) (FU percentage, 97%) were successfully treated according to the strict criteria. Only 13 patients of the total patient sample reached 12 years of FU at the time of this report; they were all clinically successful. Figure 2 shows the FU results according to biologic age. A steady increase in percentage of successfully treated patients can be observed from the age of 7 years. However, at the age of 12 years, still 49% of the patients were not successfully treated and had at least 1 incontinence episode per 2 weeks. At 18 years of age, 85% of the FNRFI patients were clinically successful. At this age, 81% of patients had no incontinence any more. Frequency and Prognostic Factors for First Success Success model. Figure 3 shows the cumulative percentage of FNRFI patients achieving at least 1 successful outcome somewhere during the course of FU. Cumulative success percentages were not significantly Success at different age Percentage 1 9 8 7 6 5 3 2 1 66 58 75 91 87 88 81 65 78 49 5 3 17 6 7 8 9 1 11 12 13 14 15 16 17 18 Biological age in years Figure 2. Success percentages at different (biologic) ages. The number of patients who reached distinct biologic age during FU is noted above each bar.
7 VOSKUIJL ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 1 Cumulative % success 1 8 6 2 Girls Boys 1 2 3 4 5 6 7 Follow-up (years) Figure 3. Cumulative percentage of children who achieved successful outcome. different between boys and girls during all FU time points (P.67, log-rank test) (Figure 3). Within 1 year after the initial treatment period of 6 7 weeks, clinical success was obtained at least once in 36% of patients. After 5 years of FU this percentage was 75%. After 7 years of FU the cumulative percentage of children who did experience at least 1 successful outcome was 8%. In other words, after 7 years of FU 2% of children had not once experienced successful treatment outcome. The different variables associated with first success after treatment in the patient sample are depicted in Table 2 (univariate and multivariate analysis); none were associated with a lower chance on achieving a first success somewhere during FU. We found duration of fecal incontinence with 4 years of age as the starting age of fecal incontinence not to be related to successful outcome or relapse after an initial successful outcome. A trend was observed toward a diminished number of clinically successful children who had received prior psychological treatment (hazard ratio,.6; 95% confidence interval,.35 1.1; P.6). Frequency and Prognostic Factors for Relapse After Initial Successful Treatment Relapse. Figure 4 (Kaplan Meier curve) shows the cumulative percentage of relapses during FU after achievement of initial success. Cumulative relapse percentages were not significantly different between boys and girls during all FU time points (P.41, log-rank test). Within the first 2 years after initial success, relapses occurred most frequently, 29% after 1 year, and 2 years Table 2. Factors Predicting First Treatment Success (Hazard Ratios and 95% Confidence Intervals [CIs]) after their original successful treatment, 34% of patients experienced a relapse. After 7 years of FU the cumulative percentage of children who experienced a relapse at least once after initial success was 37%. Multivariate analysis (Table 3) showed that no single factor could be significantly related to relapse after an initial successful treatment outcome. Discussion This is the first study describing the long-term FU of patients with FNRFI. After 2 years of intensive medical and behavioral treatment, only 29% of the children were successfully treated. At the age of 12 years, almost 5% of the children still suffered from fecal incontinence. Although a steady increase in success was observed over the years and even during puberty, in 15% of the FNRFI patients, fecal incontinence persisted into young adulthood. Relapses were frequent (cumulative percentage, 37%), occurring most likely within the first 2 years after an initial success. Cumulative % relapse 1 8 6 2 Hazard ratio (95% CI), univariate analysis Hazard ratio (95% CI), multivariate analysis Male sex 1.6 (.65 1.74) 1.24 (.72 2.14) Incontinence more than 7/wk.65 (.42.99).77 (.49 1.22) Family history positive.93 (.56 1.54).91 (.53 1.54) Psychological treatment.62 (.39.98).6 (.35 1.1) Girls Boys 1 2 3 4 5 Time since first success (years) Figure 4. Cumulative percentage of children who relapsed after initial successful treatment.
January 26 LONGITUDINAL FOLLOW-UP OF CHILDREN WITH FNRFI 71 Table 3. Factors Predicting Relapse After an Initial Success (Odds Ratios and 95% Confidence Intervals [CIs]) Odds ratio (95% CI), univariate analysis Multivariate odds ratio (95% CI) Male sex 1.54 (.53 4.48) 1.78 (.58 5.54) Incontinence more than 7/wk 1.5 (.44 2.48) 1.4 (.41 2.62) Family history positive.87 (.31 2.44).91 (.31 2.69) Psychological treatment.89 (.34 2.3).89 (.31 2.6) Patients with FNRFI differ substantially from constipated children with respect to patient characteristics and success percentage. FNRFI patients are mainly boys (79% in this sample), whereas in children with constipation, the male:female ratio is 3:2. Compared with constipated children participating in our long-term FU study, 1 FNRFI patients had less therapy before intake (5.5 vs 15 months), had more daytime and night-time enuresis (28%/26% vs 8%/18%, respectively), and were more likely to have a positive family history (2% vs 13%). Another important difference was the delay in presentation; FNRFI patients presented to our outpatient clinic at the age of 9.2 years, whereas constipated children were seen at the age of 6.5 years. 13 We hypothesize that parents of children with FNRFI are ashamed of failing to toilet train their child successfully and therefore postpone a visit to the doctor. In contrast, children with constipation complain of infrequent, painful defecation, which is a good reason for the parents to visit a doctor earlier, whereas in FNRFI patients the absence of accompanying symptoms such as painful or infrequent defecation will often not alarm parents. Moreover, fecal incontinence in the absence of constipation will often not be recognized as a separate clinical entity by general physicians and pediatricians and might cause a delay in referral after unsuccessful therapy. Clinical success, ie, less than 1 fecal incontinence episode in 2 weeks without the use of medication influencing motility for 1 month, was achieved in only 29% of FNRFI patients at 2 years of FU. Thereafter, a steady increase in success was observed. Of all young adults with FNRFI (aged 18 years), 85% were free of incontinence. In contrast, we reported a significantly higher percentage of success after 1 year of treatment, 59% (P.1), but a significantly lower success percentage at the age of 18 years (7%) (P.5) in children with chronic constipation. 1 We can only speculate about the difference in success between nonretentive and retentive children. Van Ginkel et al 8 clearly showed that laxatives were not helpful and even worsened the frequency of incontinence episodes in patients with FNRFI. We now know that behavioral therapy consisting of structured toilet training 3 times daily after meals and keeping a bowel diary together with education is the only effective therapy in FNRFI, whereas children with constipation need additional long-lasting laxative treatment. As stated, a strict toilet training program is the cornerstone of FNRFI treatment. Thus, motivation to adhere to this intensive program is of paramount importance in children with FNRFI. During puberty, the increase in success percentage might be the result of peer pressure. During this critical period, influences of the social environment of the young adolescent could persuade him or her to sustain toilet training 3 times daily. The influence of behavioral or psychological factors cannot be fully assessed in this study because we did not collect data for all patients on these factors. Approximately 3% of this patient sample were initially seen by the psychologist instead of a pediatrician. However, none of these children were classified as having attention deficit hyperactivity disorder, oppositional defiant disorder, or a pervasive developmental disorder. We hypothesize that many of these caregivers are convinced that fecal incontinence is the result of behavioral problems, and that therefore these patients should be seen by a mental health professional. Van der Plas et al 7 showed that approximately 3% of the patients with FNRFI indeed had significantly more behavioral problems than healthy control subjects. These problems disappeared, however, after these patients were successfully treated, which suggests that fecal incontinence has to be interpreted as an important factor in the occurrence and maintenance of behavioral problems in children with FNRFI. Future prospective studies in these children should include psychiatric testing by using standardized questionnaires to evaluate comorbid disease. This might take away the assumption that children with FNRFI have abnormal behavior. The high percentage of relapse within the first 2 years after an initial success has consequences for the management of FNRFI patients. It underscores that these children should be closely monitored for at least 2 years after initial success. On the basis of our clinical experience we suggest continuing toilet training and keeping the bowel diary in combination with regular outpatient visits. A limitation of this study is that it might not be an epidemiologic view of the natural history of FNRFI, but it is more likely an FU of the most severely affected patients. Not only have these patients sought medical consultation at a tertiary care medical center, but they also were participants in a treatment trial and were also willing to be contacted during a longitudinal period.
72 VOSKUIJL ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 1 Thus, it is unlikely that this cohort of patients represents most patients seen in primary care. In conclusion, in children with FNRFI a cumulative success percentage of 8% is found after 12 years of FU. However, in those reaching the age of 18 years, 15% still have incontinence. Relapse after an initial success occurs frequently and is most likely during the first 2 years after successful treatment. This high percentage of relapse stresses the importance of intensive monitoring and FU of FNRFI patients. References 1. Rappaport LA, Levine MD. The prevention of constipation and encopresis: a developmental model and approach. Pediatr Clin North Am 1986;33:859 869. 2. Benninga MA, Voskuijl WP, Taminiau JA. Childhood constipation: is there new light in the tunnel? J Pediatr Gastroenterol Nutr 24;39:448 464. 3. Benninga M, Candy DC, Catto-Smith AG, et al. The Paris Consensus on Childhood Constipation Terminology (PACCT) Group. J Pediatr Gastroenterol Nutr 25;:273 275. 4. Rasquin-Weber A, Hyman PE, Cucchiara S, et al. Childhood functional gastrointestinal disorders. Gut 1999;45:6 68. 5. Voskuijl WP, Heijmans J, Heymans HS, et al. Use of Rome II criteria in childhood defecation disorders: applicability in clinical and research practice. J Pediatr 24;145:213 217. 6. Benninga MA, Büller HA, Heymans HS, et al. Is encopresis always the result of constipation? Arch Dis Child 1994;71:186 193. 7. van der Plas RN, Benninga MA, Redekop WK, et al. Randomised trial of biofeedback training for encopresis. Arch Dis Child 1996; 75:367 374. 8. van Ginkel R, Benninga MA, Blommaart PJ, et al. Lack of benefit of laxatives as adjunctive therapy for functional non-retentive fecal incontinence in children. J Pediatr 2;137:88 813. 9. Benninga MA, Voskuijl WP, Akkerhuis GW, et al. Colonic transit times and behaviour profiles in children with defecation disorders. Arch Dis Child 24;89:13 16. 1. van Ginkel R, Reitsma JB, Büller HA, et al. Childhood constipation: longitudinal follow-up beyond puberty. Gastroenterology 23;125:357 363. 11. van der Plas RN, Benninga MA, Büller HA, et al. Biofeedback training in treatment of childhood constipation: a randomised controlled study. Lancet 1996;348:776 78. 12. Prentice RL, Gloeckler LA. Regression analysis of grouped survival data with application to breast cancer data. Biometrics 1978;34:57 67. 13. Voskuijl W, de Lorijn F, Verwijs W, et al. PEG 335 (Transipeg) versus lactulose in the treatment of childhood functional constipation: a double blind, randomised, controlled, multicentre trial. Gut 24;53:159 1594. Address requests for reprints to: Wieger P. Voskuijl, MD, Department of Pediatric Gastroenterology and Nutrition, Room C2-312, Academic Medical Centre, Meibergdreef 9, 115 AZ Amsterdam, The Netherlands. e-mail: w.p.voskuijl@amc.nl; fax: 31-2-691733.