
Functional constipation (FC) in children affects neonates to adolescents, has a high prevalence, and tends to become chronic, accounting for a relatively high health care burden. Its prevalence varies from 0.7% to 29.6%, depending on the diagnostic criteria and age.1
Recent advances in 16S recombinant DNA gene sequencing have led to active research on the association between the gut microbiome and gastrointestinal diseases, including constipation, inflammatory bowel disease, and other allergic diseases, type 2 diabetes, and behavioral disorders.2-4 A survey of pediatricians and pediatric gastroenterologists in the Netherlands revealed that the prescription rates of prebiotics or probiotics for the treatment of childhood FC were remarkably higher than those among United States physicians (32.0%). Both general pediatricians (27.0%) and pediatric gastroenterologists (19.0%) frequently prescribed prebiotics or probiotics.5 According to a recent nationwide survey of the Korean Society of Pediatric Gastroenterology, Hepatology, and Nutrition, children with FC aged > 1 year were most commonly prescribed lactulose (59.1%), followed by polyethylene glycol (PEG) 4000 (17.7%), and 11.8% of respondents prescribed probiotics as the first-line maintenance treatment for these children.6
Although it is unclear how probiotics affect FC, some adult studies have reported that probiotics modulate colonic transit time and reduce functional gastrointestinal symptoms.7,8 However, the effectiveness of probiotics in the treatment of childhood constipation remains controversial. Two recent systematic reviews of probiotics for childhood FC reported different conclusions.9,10 One study showed no difference in treatment success between the probiotic and control groups,9 while the other concluded that probiotics increased stool frequency and had other beneficial effects in Asian children.10 In addition, most probiotic species used to treat FC belong to the genera
This study aims to investigate the effectiveness of
This randomized, open-label, multicenter study was conducted between July 2019 and November 2020. Pediatric gastroenterologists from 10 academic tertiary hospitals participated in this study. Patients aged 6 months to 10 years who were diagnosed with FC using the Rome IV criteria were eligible for inclusion. According to the Rome IV criteria, FC is defined as the presence of at least 2 of the following symptoms or signs for at least 1 month without an organic cause: ≤ 2 defecations per week, history of excessive stool retention, painful or hard bowel movements, presence of a large fecal mass in the rectum, history of large-diameter stools that could obstruct the toilet, and for toilet-trained children, ≥ 1 episode of incontinence per week.17,18
We excluded patients with organic causes of constipation such as Hirschsprung’s disease, spina bifida, hypothyroidism, metabolic disorder, intellectual disability, or other gastrointestinal diseases, as well as those taking medications that could affect the gastrointestinal system, including oral laxatives or probiotics, for more than 2 weeks. The institutional review board of each hospital approved this study (2019GR0184). Written informed consent was obtained from the parents of each patient. This clinical trial was registered with the Clinical Research Information Service of the Korea Center for Disease Control and Prevention (KCT0004155).
The study was conducted over a treatment period of 12 weeks with 4 visits (baseline, 2 ± 1, 6 ± 2, and 12 ± 3 weeks). At the baseline visit, we included patients who met the inclusion criteria. We randomly assigned the patients to the lactulose monotherapy, combination therapy, or
All patients received glycerin enemas for disimpaction before the intervention. Their parents were encouraged to keep stool diaries to enable the estimation of treatment effects, side effects, and interventional compliance. The stool diary included information on stool frequency per day, fecal incontinence frequency, stool consistency in terms of Bristol Stool Form Scale scores (7-point scale, 1 for separate hard lumps to 7 for watery stool),19 frequency of painful bowel movements, and side effects such as abdominal pain, vomiting, abdominal distension, and diarrhea. During each visit, the physician checked patient compliance and the dosage of lactulose or
Since there are no previous studies using a study regimen, data using
Randomization was implemented automatically using Random Allocation Software 2.0 (Informer Technologies, Inc, Dallas, TX, USA) with a random block size. Stratification was performed between the institutes.
Treatment success was defined as ≥ 3 defecations per week (and in toilet-trained children, no incontinence episodes) was calculated at each visit, and the treatment success rate at 12 weeks was considered as the primary outcome.
A drug change was defined as discontinuation of the administration of lactulose or
We investigated cumulative treatment outcomes throughout the study period using Cox regression analysis. The “cumulative successful maintenance rate” was defined as the success rate during the study period considering censored cases, and the “cumulative drug maintenance rate” was the maintenance rate of the original drug during the study period regardless of treatment success.
We compared other clinical outcomes such as stool frequency, consistency (Bristol Stool Form Scale score), frequency of fecal incontinence, and frequency of painful defecation at 2 weeks. We also compared the side effects, lactulose dosage, drug change rate, and follow-up loss rate.
Categorical variables, such as treatment success, were compared using the χ2 test or Fisher’s exact test. An analysis of variance was used to compare continuous variables such as defecation frequency, incontinence frequency, painful defecation frequency, and stool consistency. Repeated-measures analysis of variance was also performed to evaluate within-subject factors, treatment group factors, and between-subject factors. We used a
Since the proportion of missing data was large, and higher drug change rates (up to 46.0%) were observed in the S. bouradii group, a simple treatment success rate at 12 weeks or imputation method could have bias. Therefore, we used the complete case analysis method for missing data.21 We analyzed the cumulative successful maintenance rate and drug maintenance rate by Cox regression test to reflect follow-up loss and drug change during the study period. We adjusted for sex for the Cox regression analysis because there were sex differences among the 3 groups. The effect of the intervention on treatment failure and drug change through week 12 is expressed as a hazard ratio with 95% confidence interval (CI) derived from Cox regression. Treatment failure or drug change was coded as an event, and the final follow-up duration was used as the time period. Data were presented as the mean and standard deviation. The data were analyzed using SPSS version 21.0 software (IBM Corp, Armonk, NY, USA). Intergroup differences were considered to be significant at
A total of 187 children with FC were randomly assigned to the lactulose monotherapy (n = 69 [36.9%]), combination therapy (n = 68 [36.4%]), and
Table 1 . Patients’ Baseline Characteristics
Clinical characteristics | Lactulose (n = 69) | Combination (n = 68) | ||
---|---|---|---|---|
Male | 33 (47.8) | 24 (35.3) | 29 (58.0) | 0.047a |
Female | 36 (52.2) | 44 (64.7) | 21 (42.0) | |
Age (mo) | 42.3 ± 23.7 | 44.4 ± 23.6 | 38.6 ± 23.7 | 0.176 |
Disease duration (mo) | 11.4 ± 11.3 | 7.6 ± 9.4 | 9.1 ± 11.2 | 0.109 |
Previous use of laxatives | 9 (13.2) | 17 (25.0) | 7 (14.0) | 0.178 |
Previous use of probiotics | 27 (39.1) | 28 (41.2) | 21 (42.0) | 0.970 |
Stool frequency/week | 2.7 ± 1.8 | 2.9 ± 2.7 | 2.7 ± 2.2 | 0.883 |
Incontinency/week | 1.2 ± 6.0 | 0.9 ± 3.0 | 3.0 ± 8.7 | 0.153 |
Stool consistency | 1.7 ± 0.7 | 1.6 ± 0.8 | 1.9 ± 0.8 | 0.055 |
Painful defecation | 66 (95.7) | 63 (92.6) | 49 (98.0) | 0.396 |
Painful defecation/week | 2.6 ± 1.8 | 2.3 ± 2.6 | 2.1 ± 1.3 | 0.484 |
aGender differences was observed between combination therapy group and
Values are shown as n (%) or mean ± SD.
The treatment success rate at week 12 was significantly higher in the lactulose monotherapy group (26.1%) or combination therapy group (41.2%) than in the
Table 2 . Study Outcomes
Treatment outcomes | Analysis | Lactulose (n = 69) | Combination (n = 68) | ||||
---|---|---|---|---|---|---|---|
Lactulose vs Combination | Lactulose vs | Combination vs | |||||
Treatment success rates at each visit | |||||||
Week 12 | ITT | 18/69 (26.1) | 28/68 (41.2) | 4/50 (8.0) | 0.086 | 0.019 | < 0.001 |
Week 6 | ITT | 40/69 (58.0) | 36/68 (52.9) | 12/50 (24.0) | 0.576 | < 0.001 | < 0.001 |
Week 2 | ITT | 39/69 (56.5) | 42/68 (61.8) | 19/50 (38.0) | 0.799 | 0.087 | 0.018 |
PP | 39/60 (65.0) | 42/61 (68.9) | 19/37 (51.4) | 0.702 | 0.206 | 0.091 | |
Clinical outcomes at week 2 | Lactulose(n = 60) | Combination(n = 61) | |||||
Stool frequency/week | PP | 4.05 ± 2.49 | 4.57 ± 2.91 | 3.69 ± 2.60 | 0.264 | ||
Incontinency/week | PP | 0.53 ± 1.69 | 0.56 ± 1.66 | 0.96 ± 3.63 | 0.627 | ||
Stool consistency | PP | 3.38 ± 1.23 | 3.54 ± 1.32 | 2.92 ± 1.04 | 0.051 | ||
Painful defecations/week | PP | 0.48 ± 0.5 | 0.64 ± 0.97 | 0.68 ± 0.75 | 0.359 | ||
Follow-up loss rate | ITT | 9/69 (13.0) | 7/68 (10.3) | 13/50 (26.0) | 0.616 | 0.072 | 0.025 |
Drug change rate during study period | ITT | 3/69 (4.3) | 7/68 (10.3) | 23/50 (46.0) | 0.511 | < 0.001 | < 0.001 |
Values are shown as n (%) or mean ± SD.
The Cox regression analysis showed significant differences in cumulative successful maintenance and drug maintenance rates during the follow-up period after sex adjustment (Fig. 2). The
There were no differences in the frequencies of defecation, incontinence, or painful defecation or stool consistency among the 3 groups at week 2 (Table 2). The follow-up loss rate at week 2 was significantly higher in the
Repeated-measures analysis of variance showed that treatment efficacy for these outcomes over time did not differ among the 3 groups: fecal incontinence (
Although the combination therapy group showed significantly lower successful doses of lactulose at week 2 compared to the lactulose monotherapy group (0.97 vs 1.11 mL/kg/day,
Abdominal pain was the most common adverse event (20.9%, 11.3%, and 1.8% at weeks 2, 6, and 12, respectively), followed by diarrhea (6.3% and 4.7% at weeks 2 and 6, respectively), abdominal distension (4.4% at week 2), and vomiting (1.3% at week 2). The frequency of adverse effects decreased from week 2 to week 12; no vomiting or distension was observed at week 6; and no vomiting, distension, or diarrhea was observed at week 12. There were no intergroup differences in the adverse events.
To the best of our knowledge, this is the first study to evaluate the effectiveness of
We report significantly different treatment outcomes between the
Unfortunately, a large amount of missing data occurred in our study, so we could not provide PP analysis at week 6 and week 12. Although the PP analysis provides a clear efficacy of a treatment intervention, this result does not reflect the real-world situation and usually shows overestimated treatment effects.28,29
In our study, missing data were caused by several complex factors. A previous pediatric study also had a very low recruitment rate (23.8%) compared to the estimated sample size because pediatric FC is not a severe disease.12 However, this may be a characteristic of childhood FC treatment in real-world practice. Furthermore, the coronavirus disease was a pandemic on March 11 2020,30 and the Korean government declared social distancing rules. This situation made it difficult for our patients to visit our clinics. Lastly, the low efficacy of the study medication could be a reason for follow-up loss. Even considering the high follow-up loss rate, the sample size of our study was similar to or greater than that of other probiotic randomized controlled trials for childhood FC.12,13,20,31,32
We used Cox regression analysis to reflect missing data, which also showed inferior results for
A randomized study reported that children who consumed yogurt with
Therefore, the effects of probiotics on pediatric constipation remain controversial.9,10
The European Society for Paediatric Gastroenterology, Hepatology and Nutrition, and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition have developed guidelines for the evaluation and treatment of FC in children.35 The guidelines recommended PEG as the first-line treatment for childhood FC with fecal impaction. Lactulose is also recommended if PEG is not available. However, they did not support the use of pre- or probiotics for the treatment of childhood constipation because of a lack of evidence. Many previous studies have reported the infectiveness of probiotics for treating childhood FC.35
The main limitation of our study was the high follow-up loss rate. We described parallel results of the ITT and PP analyses in addition to Cox regression analysis to allow readers to interpret the effect of our intervention. We also declare the pitfalls of the complete case analysis for dealing with missing data. Second, this was an open-label study, which may have biased the effects of the intervention.
The strength of our study is its prospective randomized design and appropriate sample size. We also conducted this study using
In conclusion,
The statistical analysis reported in this paper was supported by the Division of Biostatistics, Hallym Institute for Clinical Medicine of Hallym University Medical Center and Hyun Jin Choi. An abstract of this work was presented at the 6th World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition in June 2021.
None.
None.
Kyung Jae Lee and Jung Ok Shim contributed to the study conception and design, and wrote and critically reviewed the manuscript; Ju Young Chung contributed to the study design and review; and Eell Ryoo, Yoo Min Lee, Jung Min Yoon, Hyo-Jeong Jang, So Yoon Choi, You Jin Choi, and Hyun Jin Kim collected data, discussed the results, and contributed to the final manuscript. All authors agree with submission of the final manuscript.