Laxantes osmóticos y estimulantes para el tratamiento del estreñimiento en niños
Resumen
Antecedentes
El estreñimiento en la niñez es un problema sumamente común. A pesar del uso generalizado de laxantes osmóticos y estimulantes por parte de los profesionales de la salud para controlar el estreñimiento en los niños, ha habido una escasez prolongada de pruebas de alta calidad para apoyar esta práctica.
Objetivos
Se propuso evaluar la eficacia y la seguridad de los laxantes osmóticos y estimulantes usados para tratar el estreñimiento funcional en los niños.
Métodos de búsqueda
Se hicieron búsquedas en MEDLINE, EMBASE, Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials) y en el registro de ensayos del Grupo Cochrane de Enfermedad Inflamatoria Intestinal y Trastornos Funcionales del Intestino (EII/TFI) (Cochrane IBD Group Specialized Trials Register) desde su inicio hasta el 10 marzo 2016. No hubo restricciones de idioma. También se buscaron las referencias de todos los estudios incluidos, los contactos personales y las compañías farmacéuticas para identificar estudios.
Criterios de selección
Se consideró la inclusión de los ensayos controlados aleatorios (ECA) que compararan los laxantes osmóticos o estimulantes con placebo u otra intervención, en pacientes de hasta 18 años de edad. El resultado primario fue la frecuencia de defecación. Las variables secundarias de evaluación incluyeron la incontinencia fecal, la desimpactación, la necesidad de tratamiento adicional y los eventos adversos.
Obtención y análisis de los datos
Se identificaron los artículos pertinentes y dos autores de la revisión evaluaron de forma independiente la elegibilidad de los ensayos, extrajeron los datos y evaluaron la calidad metodológica mediante la herramienta Cochrane del riesgo de sesgo. El resultado primario fue la frecuencia de defecación. Las variables secundarias de evaluación incluyeron la incontinencia fecal, la desimpactación, la necesidad de tratamiento adicional y los eventos adversos. Para los resultados continuos se calculó la diferencia de medias (DM) y el intervalo de confianza (IC) del 95% mediante un modelo de efectos fijos. Para los resultados dicotómicos se calculó el cociente de riesgos (CR) y el IC del 95% mediante un modelo de efectos fijos. Se utilizaron las estadísticas Ji2 e I2 para evaluar la heterogeneidad estadística. Se utilizó un modelo de efectos aleatorios en las situaciones de heterogeneidad no explicada. La calidad general de las pruebas que apoyaron los resultados primarios y secundarios se evaluó mediante los criterios GRADE.
Resultados principales
En la revisión, se incluyeron 25 ECA (2310 participantes). Catorce estudios se consideraron con riesgo alto de sesgo debido a la falta de cegamiento, los datos de resultado incompletos y el informe selectivo. El metanálisis de dos estudios (101 pacientes) que compararon el polietilenglicol (PEG) con placebo mostró un aumento significativo en el número de deposiciones por semana con PEG (DM 2,61 deposiciones por semana, IC del 95%: 1,15 a 4,08). Los eventos adversos comunes en los estudios controlados con placebo incluyeron flatulencia, dolor abdominal, náuseas, diarrea y cefaleas. Los participantes que recibieron PEG a dosis altas (0,7 g/kg) tuvieron significativamente más deposiciones por semana que los participantes que recibieron PEG a dosis baja (0,3 g/kg) (un estudio, 90 participantes, DM 1,30; 95%: 0,76 a 1,84). El metanálisis de seis estudios con 465 participantes que compararon PEG con lactulosa mostró un aumento significativo de las deposiciones por semana con PEG (DM 0,70; IC del 95%: 0,10 a 1,31), aunque el seguimiento fue corto. Los pacientes que recibieron PEG presentaron significativamente menos probabilidades de requerir tratamientos con laxantes adicionales. El 18% (27 de 154) de los pacientes que recibieron PEG necesitaron tratamientos adicionales en comparación con el 31% (47 de 150) de los pacientes que recibieron lactulosa (CR 0,55; IC del 95%: 0,36 a 0,83). No se informaron eventos adversos graves con ninguno de los agentes. Los eventos adversos comunes en estos estudios incluyeron diarrea, dolor abdominal, náuseas, vómitos y prurito anal. El metanálisis de tres estudios con 211 participantes que compararon PEG con leche de magnesia mostró un aumento significativo de las deposiciones por semana con PEG (DM 0,69; IC del 95%: 0,48 a 0,89). Sin embargo, la magnitud de esta diferencia fue muy pequeña y puede no ser clínicamente significativa. Se observó una reacción alérgica al PEG en un niño, aunque no se informó ningún otro evento adverso grave. Un estudio encontró una diferencia significativa en las deposiciones por semana que favoreció a la leche de magnesia sobre la lactulosa (DM ‐1,51; IC del 95%: ‐2,63 a ‐0,39; 50 pacientes). El metanálisis de dos estudios con 287 pacientes que compararon parafina líquida (aceite mineral) con lactulosa mostró una diferencia estadísticamente significativa relativamente grande en el número de deposiciones por semana que favoreció a la parafina líquida (DM 4,94; IC del 95%: 4,28 a 5,61). No se informaron eventos adversos graves. Los eventos adversos incluyeron dolor abdominal, distensión y deposiciones acuosas. No se encontraron diferencias estadísticamente significativas en el número de deposiciones por semana entre el PEG y los enemas (un estudio, 90 pacientes, DM 1,00; IC del 95%: ‐1,58 a 3,58), la mezcla de fibra dietética y la lactulosa (un estudio, 125 pacientes, p = 0,481), el sen y la lactulosa (un estudio, 21 pacientes, p > 0,05), el lactitol y la lactulosa (un estudio, 51 pacientes, DM ‐0,80; IC del 95%: ‐2,63 a 1,03), la goma guar hidrolizada y la lactulosa (un estudio, 61 pacientes, DM 1,00; IC del 95%: ‐1,80 a 3,80), el PEG y hierba de Santa Sofía (un estudio, 109 pacientes, DM 0,00; IC del 95%: ‐0,33 a 0,33), el PEG y la fibra dietética (un estudio, 83 pacientes, DM 0,20; IC del 95%: ‐0,64 a 1,04) y el PEG y la parafina líquida (dos estudios, 261 pacientes, DM 0,35; IC del 95%: ‐0,24 a 0,95).
Conclusiones de los autores
Los análisis agrupados sugieren que los preparados con PEG pueden ser superiores al placebo, la lactulosa y la leche de magnesia para el estreñimiento en los niños. Los análisis de GRADE indicaron que la calidad general de las pruebas para el resultado primario (número de deposiciones por semana) fue baja o muy baja debido a los datos escasos, la inconsistencia (heterogeneidad) y el riesgo alto de sesgo de los estudios en los análisis agrupados. Por lo tanto, los resultados de los análisis agrupados se deben interpretar con cuidado debido a los problemas metodológicos y de calidad, así como a la heterogeneidad clínica y el seguimiento corto. También hay pruebas que indican la eficacia de la parafina líquida (aceite mineral). No existen pruebas para demostrar la superioridad de la lactulosa en comparación con los otros agentes estudiado, aunque existe una falta de estudios controlados con placebo. Se necesita investigación adicional para examinar el uso a largo plazo de PEG para el estreñimiento en los niños, así como la función de la parafina líquida. La dosis óptima de PEG también merece estudios de investigación adicionales.
PICO
Resumen en términos sencillos
Laxantes para el tratamiento del estreñimiento en niños
¿Qué es el estreñimiento en la niñez?
El estreñimiento funcional en la niñez es un problema frecuente. El término estreñimiento funcional se utiliza cuando no se puede identificar una causa orgánica subyacente para los síntomas. Habitualmente los síntomas incluyen la reducción en la frecuencia de evacuaciones intestinales, la incontinencia fecal y un cambio en la consistencia de las heces. A pesar del uso generalizado de laxantes por parte de los profesionales de la salud para controlar el estreñimiento en los niños, durante largo tiempo ha habido una escasez de pruebas para apoyar esta práctica.
Pregunta de la revisión
El objetivo primario fue evaluar la efectividad y los efectos secundarios de los laxantes osmóticos y estimulantes utilizados para el tratamiento del estreñimiento funcional en los niños.
¿Cuáles son los laxantes osmóticos y estimulantes?
Los laxantes osmóticos son fármacos que incorporan agua a las heces, lo que da lugar a heces más blandas, y hace que las evacuaciones intestinales sean más fáciles y más frecuentes. Algunos laxantes osmóticos utilizados con frecuencia incluyen polietilenglicol (PEG), leche de magnesia y lactulosa. Los laxantes estimulantes inducen las evacuaciones intestinales al aumentar la contracción de los músculos en los intestinos. Ejemplos de laxantes estimulantes incluyen áloe, cascara, compuestos de sen, bisacodilo y aceite de ricino.
¿Qué examinaron los investigadores?
Los investigadores estudiaron si los laxantes osmóticos y estimulantes son efectivos para el tratamiento del estreñimiento en los niños y si estos fármacos provocan algún daño (efectos secundarios). Los investigadores buscaron ampliamente en la bibliografía médica hasta el 10 junio de marzo de 2016.
¿Qué encontraron los investigadores?
Esta revisión incluyó 25 estudios con 2310 niños que compararon diez agentes diferentes con placebo (fármacos inactivos) o entre sí. Muchos de los estudios fueron de tamaño pequeño y se consideraron de calidad deficiente o incierta. Los resultados de esta revisión indican que las preparaciones con polietilenglicol pueden aumentar la frecuencia de los movimientos intestinales en los niños con estreñimiento. Hay pruebas de un estudio que indica que PEG a dosis alta (0,7 g/kg) puede ser superior a PEG a dosis baja (0,3 g/kg) para aumentar la frecuencia de las evacuaciones intestinales en los niños con estreñimiento. Las tasas de efectos secundarios leves generalmente fueron menores en comparación con otros agentes. Los efectos secundarios comunes incluyeron flatulencia, dolor abdominal, náuseas, diarrea y cefaleas. También hubo algunas pruebas de que la parafina líquida (aceite mineral) aumentó la frecuencia de los movimientos intestinales en los niños con estreñimiento. Los efectos secundarios comunes de la parafina líquida incluyeron dolor abdominal, distensión y deposiciones acuosas. No hubo pruebas que indicaran que la lactulosa es superior a los otros agentes estudiados, aunque no hubo ensayos que la comparan con placebo (una medicina falsa como una pastilla de azúcar). Estos estudios fueron relativamente breves y, por lo tanto, es difícil evaluar la efectividad a largo plazo de estos agentes para el tratamiento del estreñimiento en los niños. La efectividad a largo plazo es importante, debido a la naturaleza a menudo crónica de este problema en los niños.
Los resultados de la revisión deben interpretarse con precaución debido a problemas de calidad en los estudios incluidos. Como tal, la fuerza de las conclusiones es muy limitada y se necesitan más estudios de investigación. Las preguntas clave que es necesario analizar incluyen la seguridad de la parafina líquida, debido a que su efectividad es evidente pero los estudios de investigación son limitados. En particular los estudios de investigación futuros deben comparar la parafina líquida con el PEG. La dosis óptima de PEG justifica la realización de estudios de investigación adicionales. La función del PEG para el tratamiento a largo plazo del estreñimiento crónico también necesita estudios de investigación adicionales para permitir un mejor informe a la práctica clínica real. Hay una falta de estudios que comparen lactulosa con placebo.
Authors' conclusions
Summary of findings
| PEG versus placebo for the management of childhood constipation | ||||||
| Patient or population: patients aged 0 to 18 years with a diagnosis of functional constipation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | PEG versus placebo | |||||
| Frequency of defecation (mean number of bowel movements per week) | The mean number of bowel movements ranged across the placebo groups from 1.6 to 2.4 per week | The mean number of bowel movements in the PEG group was on average 2.61 higher per week (95% CI 1.15 to 4.08) | 101 | ⊕⊕⊝⊝ | ||
| Serious adverse events | 83 per 10003 | 1 5 per 1000 (2 to 126) | RR 0 .18 (0.02 to 1.51) | 101 | ⊕⊕⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to sparse data (101 patients). | ||||||
| PEG versus lactulose for the management of childhood constipation | ||||||
| Patient or population: patients aged 0 to 18 years with a diagnosis of functional constipation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | PEG versus lactulose | |||||
| Frequency of defecation (mean number of bowel movements per week) | The mean number of bowel movements ranged across the lactulose groups from 0.8 to 13.5 per week | The mean number of bowel movements in the PEG group was on average 0.70 higher per week (95% CI 0.10 to 1.31) | 465 | ⊕⊝⊝⊝ | ||
| Need for additional therapies | 3 13 per 10003 | 1 72 per 1000 (113 to 260) | RR 0.5 5 (0.36 to 0.83) | 304 | ⊕⊕⊝⊝ | |
| Successful disimpaction | 800 per 10006 | 9 92 per 1000 (808 to 1000) | RR 0.55 (0.36 to 0.83) | 50 | ⊕⊕⊝⊝ | |
| Adverse events | 4 54 per 10003 | 3 95 per 1000 (309 to 504) | RR 0.8 7 (0.68 to 1.11) | 242 | ⊕⊕⊕⊝ | |
| Serious adverse events | 1 4 per 10003 | 3 3 per 1000 (5 to 216) | RR 2 .43 (0.37 to 15.96) | 145 | ⊕⊕⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded two levels due to serious Inconsistency (high statistical heterogeneity I2 = 69%; P = 0.007). | ||||||
| PEG versus milk of magnesia (MOM) for the management of childhood constipation | ||||||
| Patient or population: patients aged 0 to 18 years with a diagnosis of functional constipation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | PEG versus MOM | |||||
| Frequency of defecation (mean number of bowel movements per week) | The mean number of bowel movements ranged across the MOM groups from 4.3 to 9.7 per week | The mean number of bowel movements in the PEG group was on average 0.69 higher per week (95% CI 0.48 to 0.89) | 211 | ⊕⊕⊝⊝ | ||
| Successful disimpaction | 960 per 10003 | 9 98 per 1000 (893 to 1000) | RR 1 .04 (0.93 to 1.16) | 50 | ⊕⊕⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to sparse data (211 patients). | ||||||
| PEG versus enema for the management of childhood constipation | ||||||
| Patient or population: patients aged 0 to 18 years with a diagnosis of functional constipation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | PEG versus enema | |||||
| Frequency of defecation (mean number of bowel movements per week) | The mean number of bowel movements in the enema group was 7.7 per week | The mean number of bowel movements in the PEG group was on average 1.0 higher per week (95% CI ‐1.58 to 3.58) | 80 | ⊕⊕⊝⊝ | ||
| S uccessful disimpaction | 8 04 per 10003 | 6 84 per 1000 (531 to 877) | RR 0 .85 (0.66 to 1.51) | 90 | ⊕⊕⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to sparse data (80 patients). | ||||||
| PEG versus paraffin for the management of childhood constipation | ||||||
| Patient or population: patients aged 0 to 18 years with a diagnosis of functional constipation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | PEG versus paraffin | |||||
| Frequency of defecation (mean number of bowel movements per week) | The mean number of bowel movements ranged across the paraffin groups from 4.5 to 6.3 per week | The mean number of bowel movements in the PEG group was on average 0.35 higher per week (95% CI ‐0.24 to 0.95) | 261 | ⊕⊝⊝⊝ | ||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to sparse data (261 patients). | ||||||
| PEG versus flixweed for the management of childhood constipation | ||||||
| Patient or population: patients aged 0 to 18 years with a diagnosis of functional constipation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | PEG versus flixweed | |||||
| Frequency of defecation (mean number of bowel movements per week) | The mean number of bowel movements in the flixweed group was 5 per week | The mean number of bowel movements in the PEG group was on average 0.00 higher per week (95% CI ‐0.33 to 0.33) | 109 | ⊕⊕⊝⊝ | ||
| Need for additional therapies | 5 4 per 10003 | 1 89 per 1000 (55 to 648) | RR 3 .52 (1.03 to 12.10) | 109 | ⊕⊝⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to sparse data (109 patients). | ||||||
| PEG versus dietary fibre for the management of childhood constipation | ||||||
| Patient or population: patients aged 0 to 18 years with a diagnosis of functional constipation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | PEG versus dietary fibre | |||||
| Frequency of defecation (mean number of bowel movements per week) | The mean number of bowel movements in the dietary fibre group was 5.6 per week | The mean number of bowel movements in the PEG group was on average 0.20 higher per week (95% CI ‐0.64 to 1.04) | 83 | ⊕⊕⊝⊝ | ||
| Need for additional therapies | 4 0 per 10003 | 2 0 per 1000 (2 to 214) | RR 0 .50 (0.05 to 5.34) | 100 | ⊕⊕⊝⊝ | |
| Frequency of faecal incontinence | The mean number of faecal incontinence episodes in the dietary fibre group was 0.3 per week | The mean number of faecal incontinence episodes in the PEG group was on average ‐0.10 lower per week (95% CI ‐0.62 to 0.42) | 83 | ⊕⊕⊝⊝ | ||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to sparse data (83 patients). | ||||||
| High dose PEG versus low dose PEG for the management of childhood constipation | ||||||
| Patient or population: patients aged 0 to 18 years with a diagnosis of functional constipation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | High dose PEG versus low dose PEG | |||||
| Frequency of defecation (mean number of bowel movements per week) | The mean number of bowel movements in the low dose PEG group was 5.2 per week | The mean number of bowel movements in the high dose PEG group was on average 1.3 higher per week (95% CI 0.76 to 1.84) | 90 | ⊕⊕⊝⊝ | ||
| Need for additional therapy | 3 70 per 10003 | 1 81 per 1000 (89 to 377) | RR 0 .49 (0.24 to 1.02) | 90 | ⊕⊝⊝⊝ | |
| Faecal incontinence | 130 per 10003 | 22 per 1000 (3 to 181) | RR 0.17 (0.02 to 1.39) | 90 | ⊕⊝⊝⊝ | |
| Adverse events | 65 per 10003 | 9 1 per 1000 (22 to 383) | RR 1 .39 (0.33 to 5.88) | 90 | ⊕⊝⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to sparse data (90 patients). | ||||||
| Liquid paraffin (mineral oil) versus lactulose for the management of childhood constipation | ||||||
| Patient or population: patients aged 0 to 18 years with a diagnosis of functional constipation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Liquid paraffin versus lactulose | |||||
| Frequency of defecation (mean number of bowel movements per week) | The mean number of bowel movements ranged across the lactulose groups from 8.1 to 12.3 per week | The mean number of bowel movements in the liquid paraffin group was on average 4.94 higher per week (95% CI 4.28 to 5.61) | 287 | ⊕⊕⊝⊝ | ||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to sparse data (287 patients). | ||||||
| Lactulose versus lactitol for the management of childhood constipation | ||||||
| Patient or population: patients aged 0 to 18 years with a diagnosis of functional constipation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Lactulose versus lactitol | |||||
| Frequency of defecation (mean number of bowel movements per week) | The mean number of bowel movements in the lactitol group was 5.6 per week | The mean number of bowel movements in the lactulose group was on average 0.8 lower per week (95% CI ‐2.63 to 1.03) | 42 | ⊕⊕⊝⊝ | ||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to sparse data (42 patients). | ||||||
| Lactulose versus milk of magnesia (MOM) for the management of childhood constipation | ||||||
| Patient or population: patients aged 0 to 18 years with a diagnosis of functional constipation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Lactulose versus MOM | |||||
| Frequency of defecation (mean number of bowel movements per week) | The mean number of bowel movements in the MOM group was 4.7 per week | The mean number of bowel movements in the lactulose group was on average 1.51 lower per week (95% CI ‐2.63 to ‐0.39) | 50 | ⊕⊕⊝⊝ | ||
| Successful disimpaction | 960 per 10003 | 797 per 1000 (643 to 989) | RR 0.83 (0.67 to 1.03) | 50 | ⊕⊕⊝⊝ | |
| Need for additional therapies | 200 per 10003 | 400 per 1000 (160 to 1000) | RR 2.00 (0.80 to 5.02) | 50 | ⊕⊝⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to sparse data (50 patients). | ||||||
| Lactulose versus partially hydrolyzed guar gum (PHGG) for the management of childhood constipation | ||||||
| Patient or population: patients aged 0 to 18 years with a diagnosis of functional constipation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Lactulose versus PHGG | |||||
| Frequency of defecation (mean number of bowel movements per week) | The mean number of bowel movements in the PHGG group was 5.0 per week | The mean number of bowel movements in the lactulose group was on average 1.0 higher per week (95% CI ‐1.80 to 3.80) | 61 | ⊕⊕⊝⊝ | ||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to sparse data (61 patients). | ||||||
Background
Description of the condition
Constipation within childhood is an extremely common problem (Van den Berg 2006), representing the chief complaint in 3% of visits to general paediatric clinics and as many as 30% of visits to paediatric gastroenterologists (Partin 1992). The term functional constipation is used when no underlying organic cause can be identified for the symptoms. Creating a workable diagnostic classification for functional constipation has proven difficult. Criteria vary, but are mostly based on a variety of symptoms, including decreased frequency of bowel movements, faecal incontinence and a change in consistency of stools (Pijpers 2008).
A team of paediatricians met in 1997 in Rome to standardize the diagnostic criteria for various functional gastroenterological disorders in children. The first paediatric Rome II criteria were published in 1999 (Rasquin‐Weber 1999) and were updated during the Rome III process in 2006, producing guidance for functional constipation for neonates, toddlers and children (Hyman 2006; Rasquin 2006).
To diagnose constipation using the Rome III criteria, at least two of the symptoms below must be present for at least one month in infants and children up to age four and at least two months in children over four, with insufficient criteria for the diagnosis of irritable bowel syndrome:
-
Two or fewer defecations per week;
-
At least one episode per week of incontinence after the acquisition of toileting skills;
-
History of retentive posturing or excessive voluntary stool retention (over 4 years) or excessive stool retention (under 4 years);
-
History of painful or hard bowel movements;
-
Presence of a large faecal mass in the rectum; and
-
History of large diameter stools which may obstruct the toilet.
Effective management of childhood functional constipation depends on securing a therapeutic alliance with the parents, particularly through the first years when children cannot accurately report symptoms. Clinicians depend on the reports and interpretations of the parents, who know their child best, and their own training and experience to differentiate between health and illness (Hyman 2006).
Description of the intervention
Laxative therapies are often the mainstay of medical therapy used in children suffering with functional constipation, alongside adjuvant therapies such as dietary and behavioural modification. Osmotic laxatives, such as lactulose, milk of magnesia and polyethylene glycol (PEG), are usually supplied as solutions or powders to be dissolved in water and are therefore relatively easy to administer to young children. Stimulant laxatives, such as Senna and Bisacodyl, come in a variety of forms, including tablets, liquids, and suppositories.
How the intervention might work
Osmotic laxatives are poorly absorbed in the gut. They act as hyperosmolar agents, increasing water content of stool and therefore making stool softer and easier to pass, as well as increasing colonic peristalsis. Stimulant laxatives act on the intestinal mucosa, increasing water and electrolyte secretion. They also stimulate peristaltic action.
Why it is important to do this review
Despite the widespread use of these medications by health professionals to manage constipation in children, there has been a long standing paucity of high quality evidence to support this practice. Previous efforts have been made to produce guidance on this topic (Baker 1999; Anonymous 2006), most recently by the National Institute for Health and Clinical Excellence in the UK (Anonymous 2010).
In recent years, the widespread introduction of PEG to paediatric practice has led to a resurgence in research on paediatric constipation. Some studies have suggested that PEG has greater efficacy when compared with placebo (Thomson 2007), as well as when compared to lactulose (Voskujl 2004; Candy 2006).
A recently published Cochrane review investigated the specific comparison of PEG versus lactulose in children and adults (Lee‐Robichaud 2010). There currently exists no other systematic review using the Cochrane collaboration format for the use of osmotic laxatives in children. A previous Cochrane review evaluating the effect of stimulant laxatives on constipation in children found no studies of sufficient quality to allow evaluation (Price 2001). An up to date systematic review using the Cochrane Collaboration format is indicated to summarise the current evidence on the use of osmotic and stimulant laxatives for the management of constipation in children. This systematic review is an update of a previously published Cochrane review (Gordon 2012; Gordon 2013).
Objectives
The primary objectives are to evaluate the efficacy and safety of osmotic and stimulant laxatives used to treat functional childhood constipation.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials were considered for inclusion.
Types of participants
Patients aged 0 to 18 years with a diagnosis of functional constipation, with or without incontinence were considered for inclusion. The diagnosis of constipation was patient self‐reported, physician diagnosed, or by consensus criteria (e.g. Rome III). Studies with patients suffering from any underlying pathology, such as thyroid abnormalities, Hirschsprung’s disease or having undergone previous bowel surgery at study entry, were excluded.
Types of interventions
Studies comparing osmotic or stimulant laxatives with another intervention or placebo were considered for inclusion. All preparations and dosing regimes were considered. Studies using multiple osmotic or stimulant laxative combinations or combinations of both as their intervention were also considered for inclusion.
Types of outcome measures
Primary outcomes
The primary outcome measure was the frequency of defecation (number of stools per week).
Secondary outcomes
Secondary outcomes included:
1) Faecal incontinence;
2) Disimpaction;
4) Need for additional therapies; and
5) Adverse events.
Search methods for identification of studies
Electronic searches
A computer‐assisted search for relevant studies (from database inception to 10 March 2016) was performed using MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials and the Cochrane IBD Group Specialized Register (Appendix 1). References from published articles and conference proceedings were searched to identify additional citations.
There is some evidence that data from abstracts can be inconsistent with data in published articles (Pitkin 1999), therefore abstract publications were not included in this review.
Searching other resources
B. Reference searching
The references of all identified studies were inspected for more trials.
C. Personal contacts
Leaders in the field were contacted to try to identify other studies.
D. Drug companies
The manufacturers of osmotic and stimulant laxative agents were contacted for additional data.
Data collection and analysis
All identified abstracts and results from searches were reviewed by two authors (MG and KN). If the reference appeared relevant, a full copy of the study was obtained.
Selection of studies
Two authors (MG and KN), after reading the full texts, independently assessed the eligibility of all trials identified based on the inclusion criteria above. Disagreement among authors was discussed and agreement reached by consensus.
Data extraction and management
A data extraction form was developed and piloted to extract information on relevant features and results of included studies. The two reviewers separately extracted and recorded data on the predefined checklist.
Extracted data included the following items:
a. characteristics of patients: age, sex, duration of symptoms;
b. study methods, total number of patients originally assigned to each treatment group;
c. intervention: preparations, dose, administration regime;
d. control: placebo, other drugs;
e. concurrent medications;
f. outcomes (time of assessment, length of follow‐up, frequency of defecation, pain on defecation and/or straining, faecal incontinence, stool consistency, need for additional therapies, number and type of adverse events associated with treatment, adverse events); and
g. withdrawals and reasons for withdrawals.
Assessment of risk of bias in included studies
The methodological quality of selected trials was assessed independently by two authors using the Cochrane risk of bias tool (Higgins 2011a). Factors assessed included:
-
sequence generation (i.e. was the allocation sequence adequately generated?);
-
allocation sequence concealment (i.e. was allocation adequately concealed?);
-
blinding (i.e. was knowledge of the allocated intervention adequately prevented during the study?);
-
incomplete outcome data (i.e. were incomplete outcome data adequately addressed?);
-
selective outcome reporting (i.e. are reports of the study free of suggestion of selective outcome reporting?); and
-
other potential sources of bias (i.e. was the study apparently free of other problems that could put it at a high risk of bias?).
A judgement of 'Yes' indicates low risk of bias, 'No' indicates high risk of bias, and 'Unclear' indicates unclear or unknown risk of bias. Disagreements was resolved by consensus. Study authors were contacted for further information when insufficient information was provided to determine the risk of bias.
We used the GRADE approach for rating the overall quality of evidence for the primary outcome. Randomised trials start as high quality evidence, but may be downgraded due to: (1) risk of bias, (2) indirectness of evidence, (3) inconsistency (unexplained heterogeneity), (4) imprecision (sparse data), and (5) reporting bias (publication bias). The overall quality of evidence for each outcome was determined after considering each of these elements, and categorized as high quality (i.e. further research is very unlikely to change our confidence in the estimate of effect); moderate quality (i.e. further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate); low quality (i.e. further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate); or very low quality (i.e. we are very uncertain about the estimate) (Guyatt 2008; Schünemann 2011).
Measures of treatment effect
For the primary outcome, frequency of defecation, we calculated the mean difference (MD) and corresponding 95% confidence interval (CI). For the secondary dichotomous outcomes we calculated the risk ratio (RR) and corresponding 95% CI.
Dealing with missing data
The authors of included studies were contacted to supply any missing data.
Assessment of heterogeneity
Heterogeneity among trial results was assessed by visual inspection of forest plots and by calculating the Chi2 square test for heterogeneity (a P value of 0.10 was regarded as statistically significant). We also used the I2 statistic to quantity the effect of heterogeneity (Higgins 2003). A random‐effects model was used in situations of unexplained heterogeneity. We aimed to further investigate potential sources of heterogeneity.
Assessment of reporting biases
If an appropriate number of studies was found, we aimed to investigate the possibility of a publication bias through the construction of funnel plots (trial effects versus trial size).
Data synthesis
For outcomes that were sufficiently homogenous, meta‐analysis was carried out using a fixed‐effect model. A random‐effects model was used in situations of unexplained heterogeneity.
Subgroup analysis and investigation of heterogeneity
Subgroup analyses were to be carried out to further study the effects of a number of variables on the outcomes including:
a. whether patients were being inducted in to ‘remission’ from constipation or whether this was a study of ‘maintenance’ therapy;
b. the effect of length of therapy / follow‐up; and
c. specifically what, if any agents, were initially allowed in the protocol to clear any impaction (such as enemas).
Sensitivity analysis
Sensitivity analyses was conducted based on the following:
a. only including patients’ whose outcome is known i.e. number of patients who completed the study used as denominator; and
b. random‐effects versus fixed‐effect models.
We also planned to consider the effect of:
c. allocation concealment;
d. type of agent;
e. dose of agent; and
f. concurrent medications.
Results
Description of studies
A literature search conducted on 10 March 2016 identified 763 studies. Four additional studies were identified through searching of references. After duplicates were removed a total of 668 reports remained for review of titles and abstracts. Two authors independently reviewed the titles and abstracts of these studies 49 studies were selected for full text review (See Figure 1). Nineteen reports of 18 studies were excluded (See Characteristics of excluded studies). Thirty reports of 25 studies involving a total of 2310 patients were selected for inclusion (Bekkali 2009; Candy 2006; Dupont 2005; Dziechciarz 2015; Farahmand 2007; Gomes 2011; Gremse 2002; Karami 2009; Kokke 2008; Loening‐Baucke 2006; Nimrouzi 2015; Nurko 2008; Perkin 1977; Pitzalis 1995; Quitadamo 2012; Rafati 2011; Ratanamongkol 2009; Saneian 2012; Thomson 2007; Tolia 1993; Treepongkaruna 2014; Urganci 2005; Ustundag 2010; Voskujl 2004; Wang 2007) (See Characteristics of included studies).
Study flow diagram.
Eighteen studies were excluded for various reasons. Five studies were not randomised controlled trials (Dupont 2005; Hardikar 2007; Hejl 1990; Shevtsov 2005; Sonheimer 1982), two studies included adult patients (Corazziari 1996; Ferguson 1999), one study included adult and paediatric participants without reporting separate results for children (Connolly 1974), one study was of children with soiling (Berg 1983), two studies focused on the treatment of children with faecal impaction rather than functional constipation (Miller 2012; Youssef 2002); one study was of children with underlying bowel pathology (Kazak 1999); three studies looked at combination therapy with PEG compared to PEG by itself ( Bongers 2009; Dehghani 2014; Khoshoo 2006); one study compared one formulation of PEG to another (Savino 2012), and two studies were abstract publications (Bekkali 2009; Ormarsson 2013).
Two studies compared PEG to placebo (Thomson 2007; Nurko 2008), five compared PEG with lactulose (Gremse 2002; Voskujl 2004; Dupont 2005; Candy 2006; Wang 2007), three compared PEG with milk of magnesia (magnesium oxide) (Loening‐Baucke 2006, Gomes 2011, Ratanamongkol 2009), two compared liquid paraffin with lactulose (Urganci 2005; Farahmand 2007) two compared liquid paraffin with PEG (Tolia 1993; Rafati 2011), one compared PEG with enemas (Bekkali 2009), one compared a dietary fibre mix with lactulose (Kokke 2008), one lactulose with senna (Perkin 1977) and one lactitol with lactulose (Pitzalis 1995).
The age of participants ranged from 6 months up to 16 years. The duration of the studies varied from 2 weeks to 12 months. The specific criteria for a diagnosis of constipation also varied between studies, as did the minimum length of symptoms. All studies excluded children with organic causes for their pathology (see characteristics of included studies).
Risk of bias in included studies
The risk of bias analysis for the included studies is summarised in Figure 2 and Figure 3.
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
Allocation
In nine of the included studies, the method of random allocation of participants to intervention groups was described and was judged to be adequate (Tolia 1993; Loening‐Baucke 2006; Thomson 2007; Wang 2007; Kokke 2008; Ratanamongkol 2009; Saneian 2012; Treepongkaruna 2014; Dziechciarz 2015). These studies were rated as low risk of bias for sequence generation. For one study (Candy 2006), the sponsor responded to a request for more details and confirmed adequate sequence generation. This study was rated as low risk of bias for sequence generation. Allocation was described as random in the 15 remaining studies, although the method of randomisation was not described. These studies were rated as unclear risk of bias for sequence generation. Allocation concealment was rated as low risk of bias in six studies (Perkin 1977; Loening‐Baucke 2006; Thomson 2007; Kokke 2008; Ratanamongkol 2009; Dziechciarz 2015), and as unclear risk of bias for the other studies.
Blinding
Methods for blinding were described and judged to be adequate in seven studies. These studies were rated as low risk of bias for blinding (Voskujl 2004; Dupont 2005; Candy 2006; Thomson 2007; Kokke 2008; Nurko 2008; Treepongkaruna 2014). In six studies, the use of blinding was reported but not described clearly. These studies were rated as unclear risk of bias for blinding (Perkin 1977; Pitzalis 1995; Wang 2007; Ratanamongkol 2009; Ustundag 2010; Rafati 2011). Saneian 2012 did not describe the use of blinding but clearly reported that no patients received placebo. This study was rated as high risk of bias for blinding. The remaining 11 studies were described as open label or single‐blind and were rated as high risk of bias for blinding (Tolia 1993; Gremse 2002; Urganci 2005; Loening‐Baucke 2006; Farahmand 2007; Bekkali 2009; Karami 2009; Gomes 2011; Quitadamo 2012; Dziechciarz 2015; Nimrouzi 2015).
Incomplete outcome data
Three studies were judged to be at high risk of bias for incomplete outcome data (Karami 2009; Gomes 2011, Rafati 2011). Four studies were rated as unclear risk of bias because drop outs were no adequately described (Wang 2007; Quitadamo 2012; Saneian 2012; Nimrouzi 2015). The remaining studies were judged to be at low risk of bias because drop outs were balanced across treatment groups with similar reasons for withdrawal or there were few drop outs..
Selective reporting
In five studies, the authors did not report on adverse event outcomes and therefore these studies were judged to be at risk of bias for selective reporting (Pitzalis 1995; Gremse 2002; Bekkali 2009; Gomes 2011; Rafati 2011). One study was judged to be at unclear risk of bias because adverse events were not adequately reported. The remaining studies were judged to be at low risk of bias for selective reporting.
Other potential sources of bias
None of the studies appeared to have any other potential sources of bias other than industry funding. All of the studies were rated as low risk of bias for other potential sources of bias. One study stated that they were supported by a pharmaceutical company, but details of the extent of involvement were unclear (Candy 2006). Two studies were sponsored by pharmaceutical companies, but confirmation was received that industry had no involvement in the conduct of the studies or the writing up of the results (Thomson 2007; Nurko 2008).
Effects of interventions
See: Summary of findings for the main comparison PEG versus placebo for the management of childhood constipation; Summary of findings 2 PEG versus lactulose for the management of childhood constipation; Summary of findings 3 PEG versus milk of magnesia (MOM) for the management of childhood constipation; Summary of findings 4 PEG versus enema for the management of childhood constipation; Summary of findings 5 PEG versus paraffin for the management of childhood constipation; Summary of findings 6 PEG versus flixweed for the management of childhood constipation; Summary of findings 7 PEG versus dietary fibre for the management of childhood constipation; Summary of findings 8 High dose PEG versus low dose PEG for the management of childhood constipation; Summary of findings 9 Liquid paraffin (mineral oil) versus lactulose for the management of childhood constipation; Summary of findings 10 Lactulose versus lactitol for the management of childhood constipation; Summary of findings 11 Lactulose versus milk of magnesia (MOM) for the management of childhood constipation; Summary of findings 12 Lactulose versus partially hydrolyzed guar gum (PHGG) for the management of childhood constipation
For the analyses, we used the total number of patients randomised as the denominator. In all analyses, the frequency of defecation was measured as stools per week.
PEG versus Placebo
The published results for the two studies concerning 101 patients were inadequate to allow pooling for meta‐analysis. The authors were contacted and directed us to the study sponsors who supplied unpublished data to allow analysis for outcomes at two weeks. One of the studies used multiple dosing regimens, but data were obtained for the dose of 0.8 g/kg (Nurko 2008).
Efficacy
Frequency of defecation
Heterogeneity was noted to be moderate (P = 0.12, I2 = 58%) and using a random‐effects model, the MD was 2.61 stools per week (95% CI 1.15 to 4.08), favouring PEG over placebo, see Analysis 1.1 and Figure 4. The GRADE analysis indicated that the overall quality of the evidence for the primary outcome (frequency of defecation) was low due to sparse data (101 patients) and inconsistency (statistical heterogeneity I2 = 58%) in the pooled analysis (See summary of findings Table for the main comparison).
Forest plot of comparison: 1 PEG versus Placebo, outcome: 1.1 Frequency of defecation.
Episodes of faecal incontinence
At two weeks, both studies reported higher rates of faecal incontinence in the PEG group. As there was some discrepancy in baseline data between groups in one study (Nurko 2008), and the difference before and after treatment was not reported, meta‐analysis for this outcome was not completed.
Safety
Serious adverse events were not reported in the PEG groups in either study, but were seen in the placebo groups (8% of placebo patients experienced a serious adverse event). However, there was no statistically significant difference in the incidence of serious adverse events using a fixed‐effect model (RR 0.18, 95% CI 0.02 to 1.51). A sensitivity analysis using a random‐effects model did not have any impact on the results (RR 0.19, 95% 0.02 to 1.63). Minor adverse events were common and included flatulence, abdominal pain, nausea, diarrhoea and headache. However, data were not reported to allow meta‐analysis. The studies both stated that no difference in the incidence of adverse events appeared to exist between the groups.
PEG versus Lactulose
One of the seven studies did not report data that could be used for meta‐analysis (Wang 2007). The authors were contacted, but no response was received and so the remaining 6 studies including 465 patients were analysed. One study reported separate results for babies and toddlers (Dupont 2005). Using the method described in the Cochrane handbook (Higgins 2011b), the mean and standard deviation for the entire sample were estimated.
Efficacy
Frequency of defecation
Heterogeneity was noted to be high (P = 0.007, I2 = 69%) and using a random‐effects model a statistically significant difference in favour of PEG over lactulose was seen, with a MD of 0.70 stools per week (95% CI 0.10 to 1.31), see Analysis 2.1 and Figure 5. The GRADE analysis indicated that the overall quality of the evidence for the primary outcome (frequency of defecation) was very low due to inconsistency (statistical heterogeneity I2 = 69%), and a high risk of bias (i.e. lack of blinding and selective reporting) in two studies in the pooled analysis (See summary of findings Table 2).
Forest plot of comparison: 2 PEG versus Lactulose, outcome: 2.1 Frequency of defecation.
Need for additional therapies
Using a fixed‐effect model, there was a statistically significant result favouring PEG over lactulose. For the 4 studies (304 patients) that reported this outcome (Voskujl 2004; Dupont 2005; Candy 2006; Saneian 2012), 18% (27/154) of PEG patients required additional therapy compared to 31% (47/150) of lactulose patients, (RR 0.55, 95% CI 0.36 to 0.83), see Analysis 2.2. The GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due high risk of bias (i.e. lack of blinding) and sparse data (74 events; See summary of findings Table 2). When a sensitivity analysis using a random‐effects model was calculated the results were no longer statistically significant (RR 0.59, 95% CI 0.33 to 1.04), see Analysis 2.3.
Successful disimpaction
For the one study that reported this outcome (Saneian 2012), 100% of PEG participants were successfully disimpacted compared to 80% of lactulose patients (RR 1.24, 95% CI 1.01 to 1.53; P = 0.04). The GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to high risk of bias (i.e. lack of blinding) and sparse data (45 events; See summary of findings Table 2).
Safety
Minor adverse events were seen in most studies, but were not reported in one study (Gremse 2002). Common adverse events included diarrhoea ( Saneian 2012; Wang 2007) , abdominal pain (Saneian 2012; Wang 2007), bloating (Saneian 2012), nausea, vomiting (Treepongkaruna 2014), impacted faeces (Treepongkaruna 2014), and pruritis ani (Treepongkaruna 2014). For the 3 studies (242 patients) that reported data allowing meta‐analysis (Dupont 2005; Candy 2006; Treepongkaruna 2014), there was no statistically significant difference in the proportion of patients who experienced at least one adverse event. Thirty‐seven per cent (46/123) of PEG patients experienced at least one adverse event compared to 45% (54/119) of lactulose patients (RR 0.87, 95% CI 0.68 to 1.11), see Analysis 2.5. The GRADE analysis indicated that the overall quality of the evidence supporting this outcome was moderate due to sparse data (100 events; See summary of findings Table 2).
Serious adverse events were reported in two studies (Candy 2006;Treepongkaruna 2014). Candy 2006 reported a chest infection in a patient in the PEG group, thought to be unrelated to therapy. Serious adverse events reported in the Treepongkaruna 2014 study include pneumonia and a traffic accident in the PEG 4000 group and a varicella infection in the lactulose group. None of these events were considered to be related to the study drug. There was no statistically significant difference in the proportion of patients who experienced a serious adverse event. Four per cent (3/71) of PEG participants had a serious adverse event compared to 1% (1/74) of lactulose participants (RR 2.43, 95% CI 0.37 to 15.96). The GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to very sparse data (4 events; See summary of findings Table 2).
PEG versus Milk of Magnesia
Four studies (261 participants) compared PEG to milk of magnesia (Loening‐Baucke 2006; Ratanamongkol 2009; Gomes 2011; Saneian 2012). One study reported outcomes at 1 month and 12 months (Loening‐Baucke 2006). However, data for outcomes at 4 weeks were used for meta‐analysis. Ratanamongkol 2009 reported median and interquartile ranges for results and these were used to estimate the mean and standard deviation (Hozo 2005).
Efficacy
Frequency of defecation
Using a random‐effects model, there was no statistically significant difference the frequency of defecation (MD 0.20, 95% CI ‐0.68 to 1.07). However, there was significant heterogeneity in the pooled analysis(P = 0.03, I2 = 66%). A visual inspection of the forest plot suggests that the Saneian 2012 study is the source of this heterogeneity. When this study was excluded in a sensitivity analysis there was a statistically significant result favouring PEG over milk of magnesia and the I2 value dropped to 0%. The MD was 0.69 stools per week (95% CI, 0.48 to 0.89), see Analysis 3.1. The GRADE analysis indicated that the overall quality of the evidence for the primary outcome (frequency of defecation) was low due to sparse data (211 patients) and a high risk of bias (i.e. lack of blinding in one study and lack of blinding, incomplete outcome data and selective reporting in the other study) in two studies in the pooled analysis (See summary of findings Table 3).
Succesful disimpaction
There was no statistically significant difference in the proportion of participants who were successfully disimpacted. Successful disimpaction was achieved in 100% (25/25) of PEG patients compared to 96% (24/25) of milk of magnesia patients (RR 1.04, 95% CI 0.93 to 1.16). The GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to sparse data (49 events) and a high risk of bias (i.e. lack of blinding; See summary of findings Table 3).
Safety
A serious adverse event of allergy to PEG was reported in one patient (Loening‐Baucke 2006). Minor adverse events data were not reported to allow meta‐analysis. One study (Ratanamongkol 2009) noted a statistically significant difference in proportion of patients experiencing diarrhoea. Twenty‐eight per cent of patients in the milk of magnesia group experienced diarrhoea compared to 4% of PEG patients (P = 0.002). Gomes 2011 did not explicitly report adverse event data. Common adverse events reported in the Saneian 2012 study included abdominal pain and bloating in the PEG group and abdominal pain, bloating and diarrhoea in the milk of magnesia group.
PEG versus Enemas
Bekkali 2009 compared PEG to enemas (90 participants). This study reported outcomes at four weeks.
Efficacy
Frequency of defecation
There was no statistically significant difference in the frequency of defecation between PEG and enema groups. The MD was 1.00 stools per week (95% CI ‐1.58 to 3.58). The GRADE analysis indicated that the overall quality of the evidence for the primary outcome (frequency of defecation) was low due to sparse data (80 patients) and a high risk of bias (i.e. lack of blinding and selective reporting; See summary of findings Table 4).
Succesful disimpaction
Successful disimpaction was reported in 80% (37/46) of enema patients compared to 68% (30/44) of PEG patients. However, the difference was not statistically significant (RR 0.85, 95% CI 0.66 to 1.09). The GRADE analysis indicated that the overall quality of the evidence for the primary outcome (frequency of defecation) was low due to sparse data (67 events) and a high risk of bias (i.e. lack of blinding and selective reporting; See summary of findings Table 4).
Safety
Adverse event data were not explicitly reported within this study, although the authors reported significantly higher rates of faecal incontinence and watery stools with PEG.
PEG versus Liquid paraffin
Three studies (299 participants) compared PEG to liquid paraffin (Tolia 1993; Karami 2009; Rafati 2011). The studies had varying lengths of follow‐up. Tolia 1993 followed up patients at two days. Karami 2009 followed patients every week for a month and then monthly for two to four months. Rafati 2011 followed patients weekly for the first two weeks and then monthly until 120 days. The Tolia 1993 study was not pooled with the other two studies because the primary outcome was not similar enough to allow pooling.
Efficacy
Frequency of defecation
Tolia 1993 reported on the frequency of bowel movements after treatment (scored as > 5, 1 to 5 or none). The authors reported that PEG patients had more frequent bowel movements after treatment than liquid paraffin patients (P < 0.005). Two studies reported on the frequency of defecation at 30 days and were pooled for meta‐analysis (Karami 2009; Rafati 2011). There was no statistically significant difference in the frequency of defecation (MD 0.35, 95% CI ‐0.24 to 0.95). The GRADE analysis indicated that the overall quality of the evidence for the primary outcome (frequency of defecation) was very low due to sparse data (261 patients) and a high risk of bias in both studies in the pooled analysis (i.e. lack of blinding and incomplete outcome data in one study and incomplete outcome data and selective reporting in the other study; See summary of findings Table 5).
Safety
No serious adverse events were reported. Tolia 1993 reported significantly more vomiting in the PEG group compared to liquid paraffin (P < 0.005). Karami 2009 reported that there were no adverse events. Adverse events reported in the Rafati 2011 study included nausea, vomiting, diarrhoea, flatulence, abdominal pain and dehydration. All of these outcomes, with the exception of diarrhoea, were significantly more likely to occur in children who received liquid paraffin compared to PEG.
PEG versus Flixweed
One study (109 participants) compared PEG to flixweed (Nimrouzi 2015). Participants were assessed at three and eight weeks.
Efficacy
Frequency of defecation
There was no statistically significant difference in the frequency of defecation (MD 0.00, 95% CI ‐0.33 to 0.33). The GRADE analysis indicated that the overall quality of the evidence for the primary outcome (frequency of defecation) was low due to sparse data (109 participants) and a high risk of bias (i.e. lack of blinding and random sequence generation, allocation concealment and incomplete outcome data were also rated as unclear; See summary of findings Table 6).
Need for additional therapy
There was a non‐significant trend (P = 0.05) favouring flixweed over PEG for the need for additional therapy. Nineteen per cent (10/53) of PEG participants needed additional therapy compared to 5% (3/56) of flixweed participants (RR 3.52, 95% CI 1.03 to 12.10). The GRADE analysis indicated that the overall quality of the evidence supporting this outcome was very low due to serious imprecision (13 events) and a high risk of bias (i.e. lack of blinding and random sequence generation, allocation concealment and incomplete outcome data were also rated as unclear; See summary of findings Table 6).
Safety
The authors reported no difference in the proportion of patients who experienced flatulence and abdominal pain after 8 weeks of therapy.
PEG versus dietary fibre mix
One study (83 participants) compared PEG to dietary fibre mix (Quitadamo 2012). Participants were assessed at one, two, four and eight weeks.
Efficacy
Frequency of defecation
There was no statistically significant difference in the frequency of defecation (MD 0.20, 95% CI ‐0.64 to 1.04). The GRADE analysis indicated that the overall quality of the evidence for the primary outcome (frequency of defecation) was low due to sparse data (83 participants) and a high risk of bias (i.e. lack of blinding and random sequence generation, allocation concealment and incomplete outcome data were also rated as unclear; See summary of findings Table 7).
Need for additional therapy
There was no statistically significant difference in the proportion of participants who required additional therapy for their constipation. Two per cent (1/50) of PEG participants required additional therapy compared to 4% (2/50) of dietary fibre participants (RR 0.50, 95% CI 0.05 to 5.34). The GRADE analysis indicated that the overall quality of the evidence supporting this outcome was very low due to serious imprecision (3 events) and a high risk of bias (i.e. lack of blinding and random sequence generation, allocation concealment and incomplete outcome data were also rated as unclear; See summary of findings Table 7).
Faecal incontinence
There was no statistically significant difference in the frequency of faecal incontinence (MD ‐0.10, 95% CI ‐0.62 to 0.42). The GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to sparse data (83 participants) and a high risk of bias (i.e. lack of blinding and random sequence generation, allocation concealment and incomplete outcome data were also rated as unclear; See summary of findings Table 7).
High dose PEG versus low dose PEG
One study (90 participants) compared high dose PEG (0.7 g/kg) to low dose PEG (0.3 g/kg) (Dziechciarz 2015). Participants were assessed six weeks.
Efficacy
Frequency of defecation
There was a statistically significant difference in the frequency of defecation favouring high dose over low dose PEG (MD 1.30, 95% CI 0.76 to 1.84). The GRADE analysis indicated that the overall quality of the evidence supporting the primary outcome (frequency of defecation) was low due to sparse data (90 participants) and a high risk of bias (i.e. lack of blinding; See summary of findings Table 8).
Need for additional therapy
There was a non‐significant trend (P = 0.06) favouring high dose PEG over low dose PEG for the need for additional therapy. Eighteen per cent (8/44) of high dose PEG participants needed additional therapy compared to 37% (17/46) of low dose PEG participants (RR 0.49, 95% CI 0.24 to 1.02). The GRADE analysis indicated that the overall quality of the evidence supporting this outcome was very low due to serious imprecision (25 events) and a high risk of bias (i.e. lack of blinding; See summary of findings Table 8).
Faecal incontinence
There was no statistically significant difference in the proportion of patients who experienced faecal incontinence. Two per cent (1/44) of high dose PEG participants had faecal incontinence compared to 13% (6/46) of low dose PEG participants (RR 0.17, 95% CI 0.02 to 1.39). The GRADE analysis indicated that the overall quality of the evidence supporting this outcome was very low due to serious imprecision (7 events) and a high risk of bias (i.e. lack of blinding; See summary of findings Table 8).
Safety
Adverse events
There was no statistically significant difference in the proportion of patients who experienced an adverse event. Nine per cent (4/44) of high dose PEG participants had an adverse event compared to 6% (3/46) of low dose PEG participants (RR 1.39, 95% CI 0.33 to 5.88). The GRADE analysis indicated that the overall quality of the evidence supporting this outcome was very low due to serious imprecision (7 events) and a high risk of bias (i.e. lack of blinding; See summary of findings Table 8). Adverse events in the high dose PEG group included loose stools (n = 3) and refusal of PEG (n = 1). Adverse events in the low dose group included
Liquid Paraffin versus Lactulose
Two studies (287 participants) compared liquid paraffin to lactulose (Urganci 2005; Farahmand 2007). These studies reported outcomes at eight weeks.
Efficacy
Frequency of defecation
Using a fixed‐effect model, there was a statistically significant result favouring liquid paraffin over lactulose. The MD was 4.94 stools per week (95% CI 4.28 to 5.61) see Analysis 9.1 and Figure 6. There was no evidence of heterogeneity in the pooled analysis (P = 0.45, I2 = 0%). The GRADE analysis indicated that the overall quality of the evidence for the primary outcome (frequency of defecation) was low due to sparse data (287 patients) and a high risk of bias (i.e. lack of blinding in both studies) (See summary of findings Table 9).
Forest plot of comparison: 4 Liquid Paraffin versus Lactulose, outcome: 4.1 Frequency of defecation.
Safety
No serious adverse events were reported in either study. Minor adverse events such as abdominal pain, distention and watery stools were reported with both agents, but data were not presented in a manner to allow meta‐analysis.
Lactulose versus Lactitol
Pitzalis 1995 compared lactulose to lactitol (51 participants), This study reported outcomes at 30 days.
Efficacy
Frequency of defecation
There was no statistically significant difference between the two agents in the frequency of defecation. The MD was ‐0.80 stools per week (95% CI ‐2.63 to 1.03). The GRADE analysis indicated that the overall quality of the evidence for the primary outcome (frequency of defecation) was low due to sparse data (42 participants) and a high risk of bias (i.e. selective reporting, random sequence generation, allocation concealment and blinding were also rated as unclear; See summary of findings Table 10).
Safety
Adverse events were not reported.
Lactulose versus Milk of Magnesia
One study (50 participants) also compared lactulose to milk of magnesia (Saneian 2012). Outcomes were measured at five weeks.
Efficacy
Frequency of defecation
There was a statistically significant difference in the frequency of defecation favouring milk of magnesia over lactulose (MD ‐1.51, 95% CI ‐2.63 to ‐0.39). The GRADE analysis indicated that the overall quality of the evidence supporting the primary outcome (frequency of defecation) was low due to sparse data (50 participants) and a high risk of bias (i.e. lack of blinding, allocation concealment and incomplete outcome data were also rated as unclear; See summary of findings Table 11).
Successful disimpaction
There was no statistically significant difference in the proportion of participants who were successfully disimpacted. Eighty per cent (20/25) of participants in the lactulose group were successfully disimpacted compared to 96% (24/25) of milk of magnesia patients (RR 0.83, 95% CI 0.67 to 1.03). The GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to sparse data (44 events) and a high risk of bias (i.e. lack of blinding, allocation concealment and incomplete outcome data were also rated as unclear; See summary of findings Table 11).
Need for additional therapy
There was no statistically significant difference in the proportion of participants who needed additional therapy for their constipation. Forty per cent (10/25) of participants in the lactulose group required additional therapy compared to 20% (5/25) of milk of magnesia patients (RR 2.00, 95% CI 0.80 to 5.02). The GRADE analysis indicated that the overall quality of the evidence supporting this outcome was very low due to sparse data (15 events) and a high risk of bias (i.e. lack of blinding: See summary of findings Table 11).
Safety
Adverse events
Common adverse events reported in the Saneian 2012 study included abdominal pain, bloating and diarrhoea in the milk of magnesia group and abdominal pain and bloating in the lactulose group.
Lactulose versus Partially Hydrolyzed Guar Gum
One study (61 participants) compared lactulose to partially hydrolyzed guar gum (Ustundag 2010). Outcomes were measured at four weeks.
Efficacy
Frequency of defecation
There was no statistically significant difference in the frequency of defecation (MD 1.00, 95% CI ‐1.80 to 3.80). The GRADE analysis indicated that the overall quality of the evidence supporting the primary outcome (frequency of defecation) was low due to sparse data (61 participants) and an unclear risk of bias (i.e. random sequence generation, allocation concealment, blinding and selective reporting were rated as unclear; See summary of findings Table 12).
Safety
Adverse events
Flatulence was reported in the lactulose group (Ustundag 2010).
Dietary fibre mix versus Lactulose
Kokke 2008 compared dietary fibre to lactulose (125 participants). This study reported outcomes at eight weeks.
Efficacy
Frequency of defecation
Kokke 2008 reported that there was no statistically significant difference in the frequency of defecation between the two agents at eight weeks (mean 7 stools per week in the fibre group versus 6 stools per week in the lactulose group; P = 0.481).
Safety
The authors reported no serious or significant adverse effects. There were three cases of diarrhoea (one in the fibre mixture group and two in the lactulose group).
Senna versus Lactulose
One crossover study (Perkin 1977), compared senna with lactulose (21 participants),
Efficacy
Passage of stool
There was no statistically significant difference between the two agents in the number of patients passing stools of any kind each day.
Safety
No serious or significant adverse effects were reported in the two study groups. Minor adverse events such as colic or diarrhoea, were more commonly seen in the senna group.
Subgroup and sensitivity analyses
GIven the heterogenous nature of the included studies, further subgroup or sensitivity analyses were not completed.
Publication Bias
Publication bias was not investigated as there were not enough studies in any of the pooled analyses to construct a reliable funnel plot.
Discussion
Summary of main results
Lactulose was compared to liquid paraffin (Urganci 2005; Farahmand 2007), lactitol (Pitzalis 1995), milk of magnesia (Saneian 2012) , dietary fibre (Kokke 2008), and partially hydrolyzed guar gum (Ustundag 2010) and senna (Perkin 1977). Despite the many agents that it was compared to, no trial found superiority of lactulose in terms of efficacy. Lactulose was found to be inferior to liquid paraffin and milk of magnesia. There were no studies comparing lactulose to placebo. In addition, the occurrence of minor adverse events, such abdominal cramps and flatus, were more common in the lactulose groups.
PEG was frequently studied, with trials comparing its efficacy for constipation with lactulose (Gremse 2002; Voskujl 2004; Dupont 2005; Candy 2006; Wang 2007; Saneian 2012; Treepongkaruna 2014), milk of magnesia (Loening‐Baucke 2006; Ratanamongkol 2009; Gomes 2011; Saneian 2012), enema (Bekkali 2009) , liquid paraffin (Tolia 1993; Karami 2009; Rafati 2011), flixweed (Nimrouzi 2015), dietary fibre (Quitadamo 2012) and placebo (Thomson 2007; Nurko 2008). Dziechciarz 2015 compared high dose PEG (0.7 g/kg) to low dose PEG (0.3 g/kg). PEG was found to be superior to placebo, lactulose, and milk of magnesia. However, the effect size was modest in these analyses, particularly for the pooled analysis of PEG versus milk of magnesia and PEG versus lactulose. Although PEG was superior to milk of magnesia and lactulose the magnitude of this difference was quite small and may not be clinically significant. One study (N = 90) found high dose PEG (0.7 g/kg) to be superior to low dose PEG (0.3 g/kg) (Dziechciarz 2015). With the exception of one case of allergy to PEG, no significant adverse events were associated with the use of PEG and the limited evidence reported suggests that minor adverse events occur with a similar or reduced frequency.
A pooled analysis of two studies (n = 261 participants) found no difference in efficacy between PEG and liquid paraffin. One study (n = 80) found no difference between PEG and rectal enemas in efficacy for treating faecal impaction. Nimrouzi 2015 found no difference in efficacy between PEG and flixweed and Quitadamo 2012 found no difference between PEG and dietary fibre. However, no firm conclusions regarding efficacy can be drawn from these studies. None of these studies were designed to be formal equivalence of non‐inferiority studies.
The largest treatment effect in terms of the frequency of defecation (i.e. number of stools per week), was seen with liquid paraffin (mineral oil) when compared to lactulose. While a number of case reports have been made that raise safety concerns about liquid paraffin in terms of the risk of aspiration pneumonia (Zanetti 2007), no cases of liquid paraffin‐related pneumonia were reported in the trials in this review.
Overall completeness and applicability of evidence
While there are a large number of studies included in this review, it is clear that these studies are extremely heterogenous, with nine different study agents and a variety of specific treatment regimens reported. As such, despite the common nature of the problem, it is difficult to draw particularly strong conclusions for any of the investigated agents. The scope of this study was osmotic and stimulant laxatives, but the vast majority of studies investigated osmotic laxatives.
If we consider PEG, while this was the most studied agent in 19 different trials, with a total of 1757participants, these studies compared PEG to seven different agents, as well as its use for constipation or faecal impaction. However, there was wide variation in study length and the time at which outcomes were assessed. Clearly, given the modest effect sizes and small sample sizes, coupled with these variations in treatment protocols (i.e. time of outcome assessment, use of additional therapies, specific form of interventional laxative used), the ability to use these findings to inform clinical practice is modest at best. These factors have certainly contributed to the statistical evidence of heterogeneity in intervention effects observed in meta‐analyses comparing PEG to placebo or lactulose.
As constipation is a chronic problem, outcomes really need to be assessed in the medium to long term. However, only one study assessed outcomes beyond three months and half of the studies measured outcomes at one month or less. If management of chronic constipation is considered in terms of induction (disimpaction) and maintenance of remission, the limitation in the application of these results becomes apparent. It is difficult to comment on the ability of PEG or lactulose to maintain a child's normal bowel habits over the long term, when the studies have such short follow‐up periods. In addition, outcomes such as frequency of defecation are inherently limited in relation to the realities of clinical practice. While there may be a statistically significant increase in rates of defecation between study groups, this does not give any information as to whether the patient or their parents feel that there has been a functional improvement.
Quality of the evidence
There were no studies that were judged to be fully free of risk of bias. While the majority of studies described themselves as randomised, only 10 studies provided enough detail to be judged as low risk of bias. The other studies were rated as unclear for random sequence generation. This was also the case for allocation concealment, again with the majority of studies giving insufficient detail to be judged as low risk of bias. Ten studies were open label (high risk of bias) or reported insufficient information to be judged as low risk of bias for blinding. Three studies were judged to be at high risk of bias for incomplete outcome data and five studies were judged to be at high risk of bias due to selective reporting. This has to be considered when judging the conclusions of this review. Furthermore, GRADE analyses indicated that the overall quality of the evidence for the primary outcome (number of stools per week) was low or very low due to sparse data, inconsistency (heterogeneity), and high risk of bias in the studies in the pooled analyses. Thus, given these concerns the results of the pooled analyses should be interpreted with caution.
Study flow diagram.
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
Forest plot of comparison: 1 PEG versus Placebo, outcome: 1.1 Frequency of defecation.
Forest plot of comparison: 2 PEG versus Lactulose, outcome: 2.1 Frequency of defecation.
Forest plot of comparison: 4 Liquid Paraffin versus Lactulose, outcome: 4.1 Frequency of defecation.
Comparison 1 PEG versus placebo, Outcome 1 Frequency of defecation.
Comparison 1 PEG versus placebo, Outcome 2 Serious adverse events.
Comparison 2 PEG versus Lactulose, Outcome 1 Frequency of defecation.
Comparison 2 PEG versus Lactulose, Outcome 2 Need for additional therapies.
Comparison 2 PEG versus Lactulose, Outcome 3 Need for additional therapies (sensitivity analysis).
Comparison 2 PEG versus Lactulose, Outcome 4 Successful disimpaction.
Comparison 2 PEG versus Lactulose, Outcome 5 Adverse events.
Comparison 2 PEG versus Lactulose, Outcome 6 Serious adverse events.
Comparison 3 PEG versus Milk of Magnesia, Outcome 1 Frequency of defecation.
Comparison 3 PEG versus Milk of Magnesia, Outcome 2 Frequency of defecation (sensitivity analysis excluding outlier).
Comparison 3 PEG versus Milk of Magnesia, Outcome 3 Successful disimpaction.
Comparison 4 PEG versus Enema, Outcome 1 Frequency of defecation.
Comparison 4 PEG versus Enema, Outcome 2 Successful disimpaction.
Comparison 5 PEG versus Liquid Paraffin, Outcome 1 Frequency of defecation.
Comparison 6 PEG versus Flixweed, Outcome 1 Frequency of defecation.
Comparison 6 PEG versus Flixweed, Outcome 2 Need for additional therapies.
Comparison 7 PEG versus Dietary fibre mix, Outcome 1 Frequency of defecation.
Comparison 7 PEG versus Dietary fibre mix, Outcome 2 Need for additional therapy.
Comparison 7 PEG versus Dietary fibre mix, Outcome 3 Frequency of faecal incontinence.
Comparison 8 High dose PEG versus low dose PEG, Outcome 1 Frequency of defecation.
Comparison 8 High dose PEG versus low dose PEG, Outcome 2 Need for additional therapy.
Comparison 8 High dose PEG versus low dose PEG, Outcome 3 Faecal incontinence.
Comparison 8 High dose PEG versus low dose PEG, Outcome 4 Adverse events.
Comparison 9 Liquid Paraffin versus Lactulose, Outcome 1 Frequency of defecation.
Comparison 10 Lactulose versus Lactitol, Outcome 1 Frequency of defecation.
Comparison 11 Lactulose versus Milk of Magnesia, Outcome 1 Frequency of defecation.
Comparison 11 Lactulose versus Milk of Magnesia, Outcome 2 Need for additional therapy.
Comparison 11 Lactulose versus Milk of Magnesia, Outcome 3 Successful disimpaction.
Comparison 12 Lactulose versus Partially Hydrolyzed Guar Gum, Outcome 1 Frequency of defecation.
| PEG versus placebo for the management of childhood constipation | ||||||
| Patient or population: patients aged 0 to 18 years with a diagnosis of functional constipation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | PEG versus placebo | |||||
| Frequency of defecation (mean number of bowel movements per week) | The mean number of bowel movements ranged across the placebo groups from 1.6 to 2.4 per week | The mean number of bowel movements in the PEG group was on average 2.61 higher per week (95% CI 1.15 to 4.08) | 101 | ⊕⊕⊝⊝ | ||
| Serious adverse events | 83 per 10003 | 1 5 per 1000 (2 to 126) | RR 0 .18 (0.02 to 1.51) | 101 | ⊕⊕⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to sparse data (101 patients). | ||||||
| PEG versus lactulose for the management of childhood constipation | ||||||
| Patient or population: patients aged 0 to 18 years with a diagnosis of functional constipation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | PEG versus lactulose | |||||
| Frequency of defecation (mean number of bowel movements per week) | The mean number of bowel movements ranged across the lactulose groups from 0.8 to 13.5 per week | The mean number of bowel movements in the PEG group was on average 0.70 higher per week (95% CI 0.10 to 1.31) | 465 | ⊕⊝⊝⊝ | ||
| Need for additional therapies | 3 13 per 10003 | 1 72 per 1000 (113 to 260) | RR 0.5 5 (0.36 to 0.83) | 304 | ⊕⊕⊝⊝ | |
| Successful disimpaction | 800 per 10006 | 9 92 per 1000 (808 to 1000) | RR 0.55 (0.36 to 0.83) | 50 | ⊕⊕⊝⊝ | |
| Adverse events | 4 54 per 10003 | 3 95 per 1000 (309 to 504) | RR 0.8 7 (0.68 to 1.11) | 242 | ⊕⊕⊕⊝ | |
| Serious adverse events | 1 4 per 10003 | 3 3 per 1000 (5 to 216) | RR 2 .43 (0.37 to 15.96) | 145 | ⊕⊕⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded two levels due to serious Inconsistency (high statistical heterogeneity I2 = 69%; P = 0.007). | ||||||
| PEG versus milk of magnesia (MOM) for the management of childhood constipation | ||||||
| Patient or population: patients aged 0 to 18 years with a diagnosis of functional constipation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | PEG versus MOM | |||||
| Frequency of defecation (mean number of bowel movements per week) | The mean number of bowel movements ranged across the MOM groups from 4.3 to 9.7 per week | The mean number of bowel movements in the PEG group was on average 0.69 higher per week (95% CI 0.48 to 0.89) | 211 | ⊕⊕⊝⊝ | ||
| Successful disimpaction | 960 per 10003 | 9 98 per 1000 (893 to 1000) | RR 1 .04 (0.93 to 1.16) | 50 | ⊕⊕⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to sparse data (211 patients). | ||||||
| PEG versus enema for the management of childhood constipation | ||||||
| Patient or population: patients aged 0 to 18 years with a diagnosis of functional constipation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | PEG versus enema | |||||
| Frequency of defecation (mean number of bowel movements per week) | The mean number of bowel movements in the enema group was 7.7 per week | The mean number of bowel movements in the PEG group was on average 1.0 higher per week (95% CI ‐1.58 to 3.58) | 80 | ⊕⊕⊝⊝ | ||
| S uccessful disimpaction | 8 04 per 10003 | 6 84 per 1000 (531 to 877) | RR 0 .85 (0.66 to 1.51) | 90 | ⊕⊕⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to sparse data (80 patients). | ||||||
| PEG versus paraffin for the management of childhood constipation | ||||||
| Patient or population: patients aged 0 to 18 years with a diagnosis of functional constipation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | PEG versus paraffin | |||||
| Frequency of defecation (mean number of bowel movements per week) | The mean number of bowel movements ranged across the paraffin groups from 4.5 to 6.3 per week | The mean number of bowel movements in the PEG group was on average 0.35 higher per week (95% CI ‐0.24 to 0.95) | 261 | ⊕⊝⊝⊝ | ||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to sparse data (261 patients). | ||||||
| PEG versus flixweed for the management of childhood constipation | ||||||
| Patient or population: patients aged 0 to 18 years with a diagnosis of functional constipation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | PEG versus flixweed | |||||
| Frequency of defecation (mean number of bowel movements per week) | The mean number of bowel movements in the flixweed group was 5 per week | The mean number of bowel movements in the PEG group was on average 0.00 higher per week (95% CI ‐0.33 to 0.33) | 109 | ⊕⊕⊝⊝ | ||
| Need for additional therapies | 5 4 per 10003 | 1 89 per 1000 (55 to 648) | RR 3 .52 (1.03 to 12.10) | 109 | ⊕⊝⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to sparse data (109 patients). | ||||||
| PEG versus dietary fibre for the management of childhood constipation | ||||||
| Patient or population: patients aged 0 to 18 years with a diagnosis of functional constipation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | PEG versus dietary fibre | |||||
| Frequency of defecation (mean number of bowel movements per week) | The mean number of bowel movements in the dietary fibre group was 5.6 per week | The mean number of bowel movements in the PEG group was on average 0.20 higher per week (95% CI ‐0.64 to 1.04) | 83 | ⊕⊕⊝⊝ | ||
| Need for additional therapies | 4 0 per 10003 | 2 0 per 1000 (2 to 214) | RR 0 .50 (0.05 to 5.34) | 100 | ⊕⊕⊝⊝ | |
| Frequency of faecal incontinence | The mean number of faecal incontinence episodes in the dietary fibre group was 0.3 per week | The mean number of faecal incontinence episodes in the PEG group was on average ‐0.10 lower per week (95% CI ‐0.62 to 0.42) | 83 | ⊕⊕⊝⊝ | ||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to sparse data (83 patients). | ||||||
| High dose PEG versus low dose PEG for the management of childhood constipation | ||||||
| Patient or population: patients aged 0 to 18 years with a diagnosis of functional constipation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | High dose PEG versus low dose PEG | |||||
| Frequency of defecation (mean number of bowel movements per week) | The mean number of bowel movements in the low dose PEG group was 5.2 per week | The mean number of bowel movements in the high dose PEG group was on average 1.3 higher per week (95% CI 0.76 to 1.84) | 90 | ⊕⊕⊝⊝ | ||
| Need for additional therapy | 3 70 per 10003 | 1 81 per 1000 (89 to 377) | RR 0 .49 (0.24 to 1.02) | 90 | ⊕⊝⊝⊝ | |
| Faecal incontinence | 130 per 10003 | 22 per 1000 (3 to 181) | RR 0.17 (0.02 to 1.39) | 90 | ⊕⊝⊝⊝ | |
| Adverse events | 65 per 10003 | 9 1 per 1000 (22 to 383) | RR 1 .39 (0.33 to 5.88) | 90 | ⊕⊝⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to sparse data (90 patients). | ||||||
| Liquid paraffin (mineral oil) versus lactulose for the management of childhood constipation | ||||||
| Patient or population: patients aged 0 to 18 years with a diagnosis of functional constipation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Liquid paraffin versus lactulose | |||||
| Frequency of defecation (mean number of bowel movements per week) | The mean number of bowel movements ranged across the lactulose groups from 8.1 to 12.3 per week | The mean number of bowel movements in the liquid paraffin group was on average 4.94 higher per week (95% CI 4.28 to 5.61) | 287 | ⊕⊕⊝⊝ | ||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to sparse data (287 patients). | ||||||
| Lactulose versus lactitol for the management of childhood constipation | ||||||
| Patient or population: patients aged 0 to 18 years with a diagnosis of functional constipation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Lactulose versus lactitol | |||||
| Frequency of defecation (mean number of bowel movements per week) | The mean number of bowel movements in the lactitol group was 5.6 per week | The mean number of bowel movements in the lactulose group was on average 0.8 lower per week (95% CI ‐2.63 to 1.03) | 42 | ⊕⊕⊝⊝ | ||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to sparse data (42 patients). | ||||||
| Lactulose versus milk of magnesia (MOM) for the management of childhood constipation | ||||||
| Patient or population: patients aged 0 to 18 years with a diagnosis of functional constipation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Lactulose versus MOM | |||||
| Frequency of defecation (mean number of bowel movements per week) | The mean number of bowel movements in the MOM group was 4.7 per week | The mean number of bowel movements in the lactulose group was on average 1.51 lower per week (95% CI ‐2.63 to ‐0.39) | 50 | ⊕⊕⊝⊝ | ||
| Successful disimpaction | 960 per 10003 | 797 per 1000 (643 to 989) | RR 0.83 (0.67 to 1.03) | 50 | ⊕⊕⊝⊝ | |
| Need for additional therapies | 200 per 10003 | 400 per 1000 (160 to 1000) | RR 2.00 (0.80 to 5.02) | 50 | ⊕⊝⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to sparse data (50 patients). | ||||||
| Lactulose versus partially hydrolyzed guar gum (PHGG) for the management of childhood constipation | ||||||
| Patient or population: patients aged 0 to 18 years with a diagnosis of functional constipation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Lactulose versus PHGG | |||||
| Frequency of defecation (mean number of bowel movements per week) | The mean number of bowel movements in the PHGG group was 5.0 per week | The mean number of bowel movements in the lactulose group was on average 1.0 higher per week (95% CI ‐1.80 to 3.80) | 61 | ⊕⊕⊝⊝ | ||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded one level due to sparse data (61 patients). | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Frequency of defecation Show forest plot | 2 | 101 | Mean Difference (IV, Random, 95% CI) | 2.61 [1.15, 4.08] |
| 2 Serious adverse events Show forest plot | 2 | 101 | Risk Ratio (M‐H, Random, 95% CI) | 0.19 [0.02, 1.63] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Frequency of defecation Show forest plot | 6 | 465 | Mean Difference (IV, Random, 95% CI) | 0.70 [0.10, 1.31] |
| 2 Need for additional therapies Show forest plot | 4 | 304 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.55 [0.36, 0.83] |
| 3 Need for additional therapies (sensitivity analysis) Show forest plot | 4 | 304 | Risk Ratio (M‐H, Random, 95% CI) | 0.59 [0.33, 1.04] |
| 4 Successful disimpaction Show forest plot | 1 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.24 [1.01, 1.53] |
| 5 Adverse events Show forest plot | 3 | 242 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.87 [0.68, 1.11] |
| 6 Serious adverse events Show forest plot | 2 | 145 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.43 [0.37, 15.96] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Frequency of defecation Show forest plot | 4 | 261 | Mean Difference (IV, Random, 95% CI) | 0.20 [‐0.68, 1.07] |
| 2 Frequency of defecation (sensitivity analysis excluding outlier) Show forest plot | 3 | 211 | Mean Difference (IV, Fixed, 95% CI) | 0.69 [0.48, 0.89] |
| 3 Successful disimpaction Show forest plot | 1 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.04 [0.93, 1.16] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Frequency of defecation Show forest plot | 1 | 80 | Mean Difference (IV, Fixed, 95% CI) | 1.00 [‐1.58, 3.58] |
| 2 Successful disimpaction Show forest plot | 1 | 90 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.85 [0.66, 1.09] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Frequency of defecation Show forest plot | 2 | 261 | Mean Difference (IV, Fixed, 95% CI) | 0.35 [‐0.24, 0.95] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Frequency of defecation Show forest plot | 1 | 109 | Mean Difference (IV, Random, 95% CI) | 0.0 [‐0.33, 0.33] |
| 2 Need for additional therapies Show forest plot | 1 | 109 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.52 [1.03, 12.10] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Frequency of defecation Show forest plot | 1 | 83 | Mean Difference (IV, Fixed, 95% CI) | 0.20 [‐0.64, 1.04] |
| 2 Need for additional therapy Show forest plot | 1 | 100 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.5 [0.05, 5.34] |
| 3 Frequency of faecal incontinence Show forest plot | 1 | 83 | Mean Difference (IV, Fixed, 95% CI) | ‐0.10 [‐0.62, 0.42] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Frequency of defecation Show forest plot | 1 | 90 | Mean Difference (IV, Fixed, 95% CI) | 1.30 [0.76, 1.84] |
| 2 Need for additional therapy Show forest plot | 1 | 90 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.49 [0.24, 1.02] |
| 3 Faecal incontinence Show forest plot | 1 | 90 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.17 [0.02, 1.39] |
| 4 Adverse events Show forest plot | 1 | 90 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.39 [0.33, 5.88] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Frequency of defecation Show forest plot | 2 | 287 | Mean Difference (IV, Fixed, 95% CI) | 4.94 [4.28, 5.61] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Frequency of defecation Show forest plot | 1 | 42 | Mean Difference (IV, Fixed, 95% CI) | ‐0.80 [‐2.63, 1.03] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Frequency of defecation Show forest plot | 1 | 50 | Mean Difference (IV, Fixed, 95% CI) | ‐1.51 [‐2.63, ‐0.39] |
| 2 Need for additional therapy Show forest plot | 1 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.0 [0.80, 5.02] |
| 3 Successful disimpaction Show forest plot | 1 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.83 [0.67, 1.03] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Frequency of defecation Show forest plot | 1 | 61 | Mean Difference (IV, Fixed, 95% CI) | 1.0 [‐1.80, 3.80] |
