Probiotics for treatment of chronic constipation in children

Chris Wallace<sup>a</sup>; Vassiliki Sinopoulou<sup>a</sup>; Morris Gordon; Anthony K Akobeng; Alejandro Llanos-Chea; Gregory Hungria; Liz Febo-Rodriguez; Amanda Fifi; Lilibet Fernandez Valdes; Amber Langshaw; Miguel Saps

doi:10.1002/14651858.CD014257.pub2

Probióticos para el tratamiento del estreñimiento crónico en niños

Declaraciones de intereses de los autores

Versión publicada: 29 marzo 2022 Historial de versiones

https://doi.org/10.1002/14651858.CD014257.pub2

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Resumen

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Antecedentes

El estreñimiento funcional se define como un estreñimiento crónico sin causa subyacente identificable. Es una causa importante de morbilidad en los niños, y representa hasta el 25% de las consultas a los gastroenterólogos pediátricos. Los preparados farmacéuticos probióticos podrían alterar suficientemente el microbioma intestinal y promover la fisiología normal del intestino de manera que ayude a aliviar el estreñimiento funcional. Varios estudios han tratado de abordar esta hipótesis, así como la función de los probióticos en otros trastornos funcionales del intestino. Por lo tanto, es importante realizar una revisión centrada en la evaluación de la evidencia hasta la fecha.

Objetivos

Evaluar la eficacia y seguridad de los probióticos para el tratamiento del estreñimiento crónico sin explicación física en niños.

Métodos de búsqueda

El 28 de junio de 2021, se realizaron búsquedas en CENTRAL, MEDLINE, Embase, CINAHL, AMED, la ICTR de la OMS y ClinicalTrials.gov, sin limitaciones de idioma, fecha, estado de publicación ni tipo de documento.

Criterios de selección

Se incluyeron ensayos controlados aleatorizados (ECA) que evaluaron los preparados farmacéuticos probióticos (incluidos los simbióticos) en comparación con placebo, ningún tratamiento o cualquier otro preparado farmacéutico de intervención en personas entre cero y 18 años de edad con un diagnóstico de estreñimiento funcional según los criterios de consenso (como Roma IV).

Obtención y análisis de los datos

Se utilizaron los procedimientos metodológicos estándar previstos por Cochrane.

Resultados principales

Se incluyeron 14 estudios con 1127 participantes asignados al azar: 12 estudios evaluaron los probióticos en el tratamiento del estreñimiento funcional, mientras que dos estudios investigaron los preparados farmacéuticos simbióticos.

Tres estudios compararon los probióticos con el placebo en relación con la frecuencia de defecación al final del estudio, pero no se agruparon porque había una heterogeneidad inexplicable muy significativa. Cuatro estudios compararon los probióticos con el placebo en relación con el éxito del tratamiento. Podría no haber ninguna diferencia en el éxito del tratamiento/la mejoría global (razón de riesgos [RR] 1,29; intervalo de confianza [IC] del 95%: 0,73 a 2,26; 313 participantes; evidencia de certeza baja). Cinco estudios compararon los probióticos con el placebo en relación con los retiros por eventos adversos, y el efecto agrupado indica que podría no haber diferencias (RR 0,64; IC del 95%: 0,21 a 1,95; 357 participantes; evidencia de certeza baja).

La estimación agrupada de tres estudios que compararon probióticos más un laxante osmótico con un laxante osmótico solo encontró que podría no haber diferencias en la frecuencia de defecación (diferencia de medias [DM] ‐0,01; IC del 95%: ‐0,57 a 0,56; 268 participantes; evidencia de certeza baja). Dos estudios compararon los probióticos más un laxante osmótico con el laxante osmótico solo en relación con el éxito del tratamiento/la mejoría global y encontraron que podría no haber diferencias entre los tratamientos (RR 0,95; IC del 95%: 0,79 a 1,15; 139 participantes; evidencia de certeza baja). Tres estudios compararon los probióticos más un laxante osmótico con el laxante osmótico solo en relación con los retiros por eventos adversos, pero no está claro si existe una diferencia entre estas comparaciones (RR 2,86; IC del 95%: 0,12 a 68,35; 268 participantes; evidencia de certeza muy baja).

Dos estudios compararon los probióticos con el óxido de magnesio. No está claro si existe una diferencia en la frecuencia de defecación (DM 0,28; IC del 95%: ‐0,58 a 1,14; 36 participantes), en el éxito del tratamiento (RR 1,08; IC del 95%: 0,74 a 1,57; 36 participantes) o en los retiros por eventos adversos (RR 0,50; IC del 95%: 0,05 a 5,04; 77 participantes). La certeza de la evidencia es muy baja para estos desenlaces.

Un estudio evaluó la función de un preparado farmacéutico simbiótico en comparación con un placebo. Podría haber un mayor éxito del tratamiento a favor de los simbióticos en comparación con el placebo (RR 2,32; IC del 95%: 1,54 a 3,47; 155 participantes; evidencia de certeza baja). El estudio informó que no se produjeron retiros por efectos adversos en ninguno de los grupos.

Un estudio evaluó un simbiótico más parafina en comparación con la parafina sola. No se sabe si hay alguna diferencia en la frecuencia de defecación (DM 0,74; IC del 95%: ‐0,96 a 2,44; 66 participantes; evidencia de certeza muy baja) o en el éxito del tratamiento (RR 0,91; IC del 95%: 0,71 a 1,17; 66 participantes; evidencia de certeza muy baja). El estudio informó que no se produjeron retiros por efectos adversos en ninguno de los grupos.

Un estudio comparó un preparado farmacéutico simbiótico con la parafina. No se sabe si hay alguna diferencia en la frecuencia de defecación (DM ‐1,53; IC del 95%: ‐3,00 a ‐0,06; 60 participantes; evidencia de certeza muy baja) o en el éxito del tratamiento (RR 0,86; IC del 95%: 0,65 a 1,13; 60 participantes; evidencia de certeza muy baja). El estudio informó que no se produjeron retiros por efectos adversos en ninguno de los grupos.

Los desenlaces secundarios o no se comunicaron o se comunicaron de manera que no permitía realizar un análisis.

Conclusiones de los autores

No hay evidencia suficiente para concluir si los probióticos son eficaces para tratar con éxito el estreñimiento crónico sin una explicación física en niños o para cambiar la frecuencia de la defecación, ni si hay una diferencia en los retiros por eventos adversos en comparación con el placebo. Existe evidencia limitada de un estudio que indica que un preparado farmacéutico simbiótico podría tener más probabilidades que el placebo de llevar al éxito del tratamiento, sin diferencias en los retiros por eventos adversos.

No hay evidencia suficiente para establecer conclusiones acerca de la eficacia o la seguridad del uso de probióticos en combinación con cualquiera de las otras intervenciones analizadas o en comparación con estas. La mayoría de los estudios que presentaron datos sobre los eventos adversos graves informaron de que no se produjeron. Dos estudios no informaron sobre este desenlace.

Se necesitan estudios futuros para confirmar la eficacia, pero la comunidad de investigación necesita orientación sobre el mejor contexto para los probióticos en dichos estudios, que tenga en cuenta en qué lugar de una posible jerarquía de tratamientos deben considerarse mejor y deben alinearse con conjuntos de desenlaces básicos para apoyar la futura interpretación de los resultados.

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Resumen en términos sencillos

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Probióticos para el tratamiento del estreñimiento crónico en niños

¿Cuál es el objetivo de esta revisión?

El objetivo de esta revisión Cochrane fue averiguar si los probióticos pueden utilizarse para tratar el estreñimiento crónico sin una explicación física en niños (de 0 a 18 años).

Para responder esta pregunta se analizaron los datos de 14 estudios.

Mensajes clave

No se pudieron establecer conclusiones al comparar los probióticos con el placebo para la frecuencia de defecación en niños tratados por estreñimiento crónico sin una explicación física. Podría no haber diferencias en el éxito del tratamiento entre los dos grupos.

Es posible que no haya una diferencia en la frecuencia de defecación ni en el éxito del tratamiento cuando se comparan los probióticos y los laxantes con el uso de laxantes solos.

No se pudieron establecer conclusiones al comparar los probióticos con el óxido de magnesio en cuanto a la frecuencia de defecación o el éxito del tratamiento.

Podría haber una mayor frecuencia de defecación en los niños tratados con preparados farmacéuticos simbióticos en comparación con el placebo.

Es posible que no haya una diferencia en los participantes que abandonan los estudios debido a episodios adversos cuando se comparan los preparados farmacéuticos probióticos con el placebo.

No fue posible establecer conclusiones sobre la seguridad de ninguna de las otras comparaciones debido al escaso número de personas que se retiraron de los estudios.

¿Qué se estudió en la revisión?

Los niños suelen padecer estreñimiento durante largos periodos de tiempo, y cuando no hay una causa física subyacente que pueda encontrarse, se le conoce como "estreñimiento funcional".

Se ha sugerido que los preparados farmacéuticos probióticos y simbióticos podrían ayudar a mejorar los síntomas en estos niños. Los probióticos son preparados farmacéuticos que contienen bacterias vivas que se han propuesto como beneficiosas para el sistema digestivo. Los preparados simbióticos también incluyen sustancias alimentarias que favorecen el crecimiento de estas bacterias.

Actualmente no existe un consenso sobre si esto es así, ni sobre la mejor manera de utilizar estos preparados farmacéuticos.

¿Cuáles son los resultados principales de la revisión?

Se buscaron los ensayos controlados aleatorizados (estudios en los que los participantes se asignan a uno de dos o más grupos de tratamiento mediante un método aleatorio) que compararon cualquier tratamiento probiótico o simbiótico con cualquier otro tratamiento (como tratamientos simulados/placebo) en niños con estreñimiento crónico sin explicación física. Se encontraron 14 ensayos que incluyeron en total 1127 participantes de menos de 18 años de edad. Se establecieron las siguientes conclusiones.
• Podría no haber diferencias en el éxito del tratamiento cuando se comparan los probióticos con el placebo.
• No fue posible establecer conclusiones sobre si existe una diferencia en la frecuencia de defecación.
• Podría no haber diferencias en el éxito del tratamiento cuando se comparan los probióticos y los laxantes con los laxantes solos.
• No fue posible establecer conclusiones en cuanto a la frecuencia de defecación o el éxito del tratamiento cuando se compararon los probióticos con el óxido de magnesio.
• Los simbióticos podrían ser mejores que el placebo para mejorar la frecuencia de defecación.
• Es posible que no existan diferencias en el número de personas que se retiraron de los ensayos debido a los efectos secundarios al comparar los probióticos con el placebo, o los probióticos y el laxante con el laxante solo.
• La confianza en las pruebas es limitada porque los estudios solo incluyeron un pequeño número de niños y debido a la falta de información sobre algunos de los métodos utilizados.

Todos los análisis estuvieron limitados por las diferencias entre los probióticos específicos o entre los tratamientos con los que se compararon, el escaso número de niños incluidos en los estudios y, lo que es más importante, el uso de un abanico de diferentes medidas de éxito. Esto significó que la combinación de estudios fue difícil, por lo que la capacidad general de esta revisión para responder a las preguntas principales fue limitada.

¿Qué se debe hacer a continuación?

Se necesitan estudios futuros para averiguar la utilidad de los probióticos en el estreñimiento infantil. Los investigadores deben ponerse de acuerdo sobre si los probióticos deberían ser un tratamiento de primera elección, un complemento de otros tratamientos, una segunda opción después de que otros tratamientos hayan fracasado o una combinación de todas las anteriores.

Las investigaciones futuras deberán medir los mismos elementos (conocidos como conjunto de desenlaces básicos) para garantizar que estos resultados puedan documentar las futuras revisiones.

¿Cuál es el grado de actualización de esta revisión?

Esta revisión está actualizada hasta junio de 2021.

Authors' conclusions

Implications for practice

There is insufficient evidence to draw conclusions as to whether probiotics are effective in changing the frequency of defecation or achieving global treatment success, or whether there is any difference in withdrawals due to adverse events compared with placebo. Limited evidence from one study suggests synbiotics may be efficacious in enhancing global treatment success when compared to placebo, with no difference in withdrawals due to adverse events.

There is insufficient evidence to make efficacy or safety conclusions about the use of probiotics in combination with osmotic laxatives compared with laxatives alone, probiotics compared with magnesium oxide, synbiotics and paraffin compared with paraffin alone or synbiotics compared with paraffin.

The majority of the studies that presented data on serious adverse events reported that no events occurred. Two studies did not report this outcome.

Implications for research

Research is still needed to confirm efficacy, but key issues must be considered by the research community prior to such trials. It is important for a consensus to be reached as to the potential practical role for probiotics. It is not clear whether this is as a primary first‐line therapy, an add‐on therapy to enhance efficacy, a second‐line therapy after primary treatment failure, or a combination. It is important for the research community to get a clear position view from stakeholders in the international community, as this will directly impact the design of future trials.

Consistent alignment with the Rome criteria is key moving forward, but as this does not address chronicity or resistance to treatment of the condition, future studies need to consider, report or even stratify for such characteristics. Additionally, the role for these medications in more than just the short term is of interest, given the chronic nature of the underlying condition.

The use of outcome measures consistently through studies is also key to support the completeness of the evidence base. The use of a recently published core outcome set should be considered (Kuizenga‐Wessel 2017).

Safety will always be a real priority in paediatric populations when considering any interventions. Reporting of total adverse events, events needing treatment withdrawal, serious adverse events and particularly long‐term safety follow‐up are vital to move the evidence base forward.

Summary of findings

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Summary of findings 1. Probiotic compared to placebo for treatment of chronic constipation in children

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Probiotic compared to placebo for treatment of chronic constipation in children
Patient or population: children with chronic constipation without a physical explanation Setting: outpatient Intervention: probiotic Comparison: placebo
Outcomes	Risk with placebo	Risk with probiotic	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Frequency of defecation, stools/week	‐	‐	Not estimable	280 (3 studies)	‐	Very significant inconsistency due to unexplained heterogeneity, so no analysis performed.
Global improvement/treatment success as defined by primary study Follow‐up: 3 to 12 weeks	Study population		RR 1.29 (0.73 to 2.26	313 (4 studies)	⊕⊕⊝⊝ Low^a,b	‐
	342 per 1000	441 per 1000 (250 to 773)	RR 1.29 (0.73 to 2.26	313 (4 studies)	⊕⊕⊝⊝ Low^a,b	‐
Withdrawals due to adverse events Follow‐up: 3 to 12 weeks	Study population		RR 0.64 (0.21 to 1.95)	357 (5 studies)	⊕⊕⊝⊝ Low ^c	‐
Withdrawals due to adverse events Follow‐up: 3 to 12 weeks	40 per 1000	26 per 1000 (8 to 78)	RR 0.64 (0.21 to 1.95)	357 (5 studies)	⊕⊕⊝⊝ Low ^c	‐
Serious adverse events	‐	‐	Not estimable	198 (4 studies)	‐	All studies reported 0 serious adverse events
*The risk in the intervention group (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). CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect.
^aDowngraded one level due to imprecision from low participant numbers. ^bDowngraded one level due to inconsistency (I² = 71%). ^cDowngraded two levels due to serious imprecision from very low event numbers.

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Summary of findings 2. Probiotics and osmotic laxative compared to osmotic laxative for treatment of chronic constipation in children

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Probiotics and osmotic laxative compared to osmotic laxative for treatment of chronic constipation in children
Patient or population: children with chronic constipation without a physical explanation Setting: outpatient Intervention: probiotics and osmotic laxative Comparison: osmotic laxative
Outcomes	Risk with Osmotic laxative	Risk with Probiotics and osmotic laxative	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Frequency of defecation (number of stools/week) Follow‐up: 8 to 12 weeks	Mean number of stools per week ranged from 6.3 to 6.9	MD 0.01 lower (0.57 lower to 0.56 higher)	‐	268 (3 studies)	⊕⊕⊝⊝ Low ^a,b	‐
Global improvement or treatment success, as defined by primary studies Follow‐up: 8 to 12 weeks	Study population		RR 0.95 (0.79 to 1.15)	139 (2 studies)	⊕⊕⊝⊝ Low ^a,b	‐
	739 per 1000	702 per 1000 (584 to 850)	RR 0.95 (0.79 to 1.15)	139 (2 studies)	⊕⊕⊝⊝ Low ^a,b	‐
Withdrawal due to adverse events Follow‐up: 8 to 12 weeks	Study population		RR 2.86 (0.12 to 68.35)	268 (3 studies)	⊕⊝⊝⊝ Very low ^a,c	‐
Withdrawal due to adverse events Follow‐up: 8 to 12 weeks	0 per 1000	0 per 1000 (0 to 0)	RR 2.86 (0.12 to 68.35)	268 (3 studies)	⊕⊝⊝⊝ Very low ^a,c	‐
Serious adverse events Follow‐up: 8 to 12 weeks	Study population		‐	308 (4 studies)	‐	All studies reported 0 serious adverse events.
Serious adverse events Follow‐up: 8 to 12 weeks	0 per 1000	0 per 1000 (0 to 0)	‐	308 (4 studies)	‐	All studies reported 0 serious adverse events.
*The risk in the intervention group (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). CI: confidence interval; MD: mean difference; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect.
^aDowngraded one level due to risk of bias for allocation concealment and blinding. ^bDowngraded one level due to imprecision from low participant numbers. ^cDowngraded two levels due to serious imprecision from low event numbers.

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Summary of findings 3. Probiotics compared to magnesium oxide for treatment of chronic constipation in children

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Probiotics compared to magnesium oxide for treatment of chronic constipation in children
Patient or population: children with chronic constipation without a physical explanation Setting: outpatients Intervention: probiotics Comparison: magnesium oxide
Outcomes	Risk with magnesium oxide	Risk with probiotics	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Frequency of defecation (number of stools/week) Follow‐up: 4 weeks	The mean number of stools per week was 4.75	MD 0.28 higher (0.58 lower to 1.14 higher)	‐	36 (1 study)	⊕⊝⊝⊝ Very low ^a
Global improvement/treatment success, as defined by the primary study Follow‐up: 4 weeks	Study population		RR 1.08 (0.74 to 1.57)	36 (1 study)	⊕⊝⊝⊝ Very low ^a
	722 per 1000	780 per 1000 (534 to 1000)	RR 1.08 (0.74 to 1.57)	36 (1 study)	⊕⊝⊝⊝ Very low ^a
Withdrawals due to adverse events Follow‐up: 4 weeks	Study population		RR 0.50 (0.05 to 5.04)	77 (2 studies)	⊕⊝⊝⊝ Very low ^a
Withdrawals due to adverse events Follow‐up: 4 weeks	51 per 1000	26 per 1000 (3 to 257)	RR 0.50 (0.05 to 5.04)	77 (2 studies)	⊕⊝⊝⊝ Very low ^a
Serious adverse events Follow‐up: 4 weeks	Study population		not estimable	77 (2 studies)	‐	The studies reported 0 serious adverse events.
Serious adverse events Follow‐up: 4 weeks	0 per 1000	0 per 1000 (0 to 0)	not estimable	77 (2 studies)	‐	The studies reported 0 serious adverse events.
*The risk in the intervention group (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). CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect.
^a Downgraded twice due to high imprecision from very low participant numbers and once more due to risk of bias for allocation concealment

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Summary of findings 4. Synbiotics compared to placebo for treatment of chronic constipation in children

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Synbiotics compared to placebo for treatment of chronic constipation in children
Patient or population: children with chronic constipation without a physical explanation Setting: outpatient Intervention: synbiotics Comparison: placebo
Outcomes	Risk with placebo	Risk with synbiotics	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Frequency of defecation (number of stools/week at end of study)	‐	‐	‐	‐	‐
Global improvement or treatment success, as defined by primary study Follow‐up: 4 weeks	Study population		RR 2.32 (1.54 to 3.47)	155 (1 study)	⊕⊕⊝⊝ Low ^a
	269 per 1000	633 per 1000 (414 to 933)	RR 2.32 (1.54 to 3.47)	155 (1 study)	⊕⊕⊝⊝ Low ^a
Withdrawals due to adverse events Follow‐up: 4 weeks	Study population		Not estimable	155 (1 study)	‐	The study reported 0 withdrawals due to adverse events.
Withdrawals due to adverse events Follow‐up: 4 weeks	0 per 1000	0 per 1000 (0 to 0)	Not estimable	155 (1 study)	‐	The study reported 0 withdrawals due to adverse events.
Serious adverse events Follow‐up: 4 weeks	Study population		Not estimable	155 (1 study)	‐	The study reported 0 serious adverse events.
Serious adverse events Follow‐up: 4 weeks	0 per 1000	0 per 1000 (0 to 0)	Not estimable	155 (1 study)	‐	The study reported 0 serious adverse events.
*The risk in the intervention group (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). CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect.
^aDowngraded two levels due to serious imprecision from low participant numbers

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Summary of findings 5. Synbiotics and paraffin compared to paraffin for treatment of chronic constipation in children

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Synbiotics and paraffin compared to paraffin for treatment of chronic constipation in children
Patient or population: children with chronic constipation without a physical explanation Setting: outpatient Intervention: synbiotics and paraffin Comparison: paraffin
Outcomes	Risk with paraffin	Risk with synbiotics and paraffin	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Frequency of defecation (number of stools/week) Follow‐up: 4 weeks	The mean number of stools per week was 6.75.	MD 0.74 higher (0.96 lower to 2.44 higher)	‐	66 (1 study)	⊕⊝⊝⊝ Very low ^{a, b}
Global improvement or treatment success, as defined by primary studies Follow‐up: 4 weeks	Study population		RR 0.91 (0.71 to 1.17)	66 (1 study)	⊕⊝⊝⊝ Very low ^{a, b}
	774 per 1000	705 per 1000 (580 to 983)	RR 0.91 (0.71 to 1.17)	66 (1 study)	⊕⊝⊝⊝ Very low ^{a, b}
Withdrawals due to adverse events Follow‐up: 4 weeks	Study population		not estimable	66 (1 study)	‐	The study reported 0 withdrawals due to adverse events.
Withdrawals due to adverse events Follow‐up: 4 weeks	0 per 1000	0 per 1000 (0 to 0)	not estimable	66 (1 study)	‐	The study reported 0 withdrawals due to adverse events.
Serious adverse events Follow‐up: 4 weeks	Study population		not estimable	66 (1 study)	‐	The study reported 0 serious adverse events.
Serious adverse events Follow‐up: 4 weeks	0 per 1000	0 per 1000 (0 to 0)	not estimable	66 (1 study)	‐	The study reported 0 serious adverse events.
*The risk in the intervention group (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). CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect.
^aDowngraded two levels due to serious imprecision from very low participant numbers. ^bDowngraded one level due to risk of bias for randomisation method.

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Summary of findings 6. Synbiotics compared to paraffin for treatment of chronic constipation in children

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Synbiotics compared to paraffin for treatment of chronic constipation in children
Patient or population: children with chronic constipation without a physical explanation Setting: outpatient Intervention: synbiotics Comparison: paraffin
Outcomes	Risk with paraffin	Risk with synbiotics	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Frequency of defecation (number of stools/week) Follow‐up: 4 weeks	The mean number of stools per week was 6.75.	MD 1.53 lower (3.00 lower to 0.06 lower)	‐	60 (1 study)	⊕⊝⊝⊝ Very low ^{a, b}
Global improvement or treatment success, as defined by primary studies Follow‐up: 4 weeks	Study population		RR 0.86 (0.65 to 1.13)	60 (1 study)	⊕⊝⊝⊝ Very low ^{a, b}
	774 per 1000	967 per 1000 (789 to 1000)	RR 0.86 (0.65 to 1.13)	60 (1 study)	⊕⊝⊝⊝ Very low ^{a, b}
Withdrawals due to adverse events Follow‐up: 4 weeks	Study population		not estimable	60 (1 study)	‐	The study reported 0 withdrawals due to adverse events
Withdrawals due to adverse events Follow‐up: 4 weeks	0 per 1000	0 per 1000 (0 to 0)	not estimable	60 (1 study)	‐	The study reported 0 withdrawals due to adverse events
Serious adverse events Follow‐up: 4 weeks	Study population		not estimable	60 (1 study)	‐	The study reported 0 serious adverse events
Serious adverse events Follow‐up: 4 weeks	0 per 1000	0 per 1000 (0 to 0)	not estimable	60 (1 study)	‐	The study reported 0 serious adverse events
*The risk in the intervention group (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). CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect.
^aDowngraded two levels due to serious imprecision from low participant numbers. ^bDowngraded one level due to risk of bias for randomisation method.

Background

Description of the condition

Childhood constipation is a very common problem in paediatrics (Kubota 2020), with a reported pooled prevalence of 9.5% in a recent study (Koppen 2018). It accounts for 3% of all visits to general paediatric clinics and up to 25% of visits to paediatric gastroenterologists (Banaszkiewicz 2005). The Rome criteria III for functional gastrointestinal disorders were published in 2006 (Hyman 2006; Rasquin 2006). They were updated to Rome IV in 2016, to include definitions for functional constipation and other functional disorders (Hyams 2016). According to the Rome IV criteria, functional constipation, which is chronic constipation without physical causation, is diagnosed when the symptoms below are met (and no other pathological cause exists) (Hyams 2016). Criteria do vary, but are mostly based on key symptoms, including decreased frequency of defecations, hard or painful bowel movements, faecal incontinence, and large diameter stools (Hyams 2016).

To diagnose constipation in children over four years old, using the Rome IV criteria, at least two of these symptoms must be present at least once per week for one month, with insufficient criteria for the diagnosis of irritable bowel syndrome (Hyams 2016):

two or fewer defecations in the toilet per week;
history of painful or hard bowel movements;
history of retentive posturing (standing or sitting with legs straight or stiff), or excessive volitional stool retention (withholding from passing stool);
history of large diameter stools that can obstruct the toilet;
presence of a large faecal mass in the rectum;
one or more episodes of faecal incontinence per week.

These criteria were amended for infants and toddlers in Rome IV, excluding reference to incontinence or large diameter stools until the child is toilet trained (Zeevenhooven 2017).

Effective management of childhood functional constipation requires a partnership between clinicians and parents, particularly for younger children who cannot accurately report symptoms. The North American and European societies for Paediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN and ESPGHAN) published a consensus international guideline to support these decisions (Tabbers 2014). Informed by parents' reports and interpretations, since they know their child best, clinicians use their training and experience to differentiate between health and illness (Hyams 2016). To successfully treat functional constipation, clinicians must manage the constipation and its causes, and also the psychological impact that functional childhood constipation can have on children and their families.

Description of the intervention

Probiotics are micro‐organisms that, when ingested, are thought to have beneficial effects on a person’s health. Research is ongoing into the use of probiotics in the treatment of various gastrointestinal illnesses, including inflammatory and pathological disorders, functional disorders, and chronic non‐pathological disorders. In infants, it has been proposed that supplying probiotic bacteria can redress this balance and provide a healthier intestinal microbiota landscape, with impact on transit through the gut (Savino 2013). In the context of constipation, it has been proposed that these mechanisms enhance colonic peristalsis and shorten the transit time through the whole gut (Waller 2011).

How the intervention might work

Experimental studies have shown that constipation is often associated with gut microbiota dysbiosis, which consists of the modified abundance of certain taxa of the colonic microbiome, i.e. the natural balance of gut bacteria has been lost (Attaluri 2010). The use of micro‐organisms might change the composition of bacterial colonies in the bowel, reduce inflammation, and promote normal gut physiology, thereby reducing functional symptoms. Some probiotics may influence colonic motility by softening the stool; changing secretion or absorption of water and electrolytes, or both; modifying smooth muscle cell contractions; increasing the production of lactate and short‐chain fatty acids; and lowering intraluminal pH (Waller 2011). In addition, since they are essentially a food supplement, probiotics are generally perceived as having a good safety profile, particularly compared with other treatments.

Why it is important to do this review

The management of functional childhood constipation varies internationally, and also between centres within the same region. This reflects the lack of a good evidence base for many current treatment strategies (Gordon 2016; Tabbers 2014).

Until recently, there had only been minimal research on the use of these agents (Tabbers 2010), with published studies showing conflicting results (Banaszkewicz 2005; Sadeghzadeh 2014).

A number of recent systematic reviews in the wider fields of probiotics and childhood constipation have demonstrated a rapid rise in published trials in this context (Horvath 2013; Tabbers 2010; Tabbers 2015). To date, there is not a Cochrane Review that examines the role of probiotics for chronic constipation in children. Therefore, it is important to synthesise the evidence, using Cochrane methodology.

International guidelines do not list probiotics as therapy; however, it is clear they are of interest to researchers (Tabbers 2014). In addition, as many probiotics are available without a prescription, clear evidence‐based guidelines are key for policymakers and parents, to empower them to make appropriate choices for their children.

Objectives

To evaluate the efficacy and safety of probiotics for the management of chronic constipation without a physical explanation in children.

Methods

Criteria for considering studies for this review

Types of studies

A protocol for this review has been previously published (Wallace 2021).

We included randomised controlled trials (RCTs) that compared probiotics to no intervention, placebo, or any other intervention. If identified, we planned to include cross‐over trials and cluster‐RCTs.

Types of participants

We included trials with children and adolescents between the ages of 0 and 18 years, who have been diagnosed with functional constipation, with or without incontinence. The diagnosis of constipation was based on consensus criteria (e.g. Rome IV). We excluded studies with children suffering from any underlying pathology, such as thyroid abnormalities, Hirschsprung’s disease, or those who underwent previous bowel surgery at study entry.

Types of interventions

Eligible interventions were probiotics administered in any form (powder, liquid, capsule), through any route (oral or rectal), as a single species or as a cocktail of multiple species (including combination with other agents, e.g. synbiotics), compared to no treatment, placebo, or any other intervention. Studies could use probiotics at any dosage, and for any duration deemed appropriate by the primary study. We planned to consider studies that used probiotics as adjunct therapy, and meta‐analyse their results where they could be appropriately grouped per main therapy.

Types of outcome measures

The outcome measures are noted below. We included the primary outcomes in summary of findings tables.

Primary outcomes

The frequency of defecation (number of stools per week), measured at end of study
Global improvement or treatment success, as defined by primary studies, measured at end of study
Withdrawal due to adverse events

Secondary outcomes

Faecal incontinence, or encopresis, measured at end of study
Successful disimpaction, as defined by study, measured at end of study
Need for additional therapies during the study period
Serious adverse events
Adverse events

Search methods for identification of studies

Electronic searches

On 28 June 2021, the Information Specialist searched the following sources:

CENTRAL via the Cochrane Library (Cochrane Central Register of Controlled Trials; until 28 June 2021; Appendix 1);
MEDLINE via Ovid SP (1946 to 28 June 2021; Appendix 2);
Embase via Ovid SP (1974 to 2021, Week 25; Appendix 3);
CINAHL via EBSCOhost (Cumulative Index to Nursing and Allied Health Literature; 1937 until 28 June 2021; Appendix 4);
AMED via Ovid SP (Allied and Complementary Medicine; 1985 to 28 June 2021; Appendix 5);
World Health Organization's International Clinical Trials Registry Platform (ICTRP) (until search date; Appendix 6);
ClinicalTrials.gov (28 June 2021; Appendix 7).

We adapted the MEDLINE search strategy for the other sources. We also used Cochrane's sensitivity‐maximising RCT filter for Ovid MEDLINE (Lefebvre 2019), Cochrane's RCT filter for Embase (Glanville 2019a), and RCT filter for CINAHL (Glanville 2019b).

For studies published in a non‐English language we planned to have them professionally translated in full. We collated references and removed any duplicates. We did not impose any date, language, publication status, or document type restrictions on the searches.

Searching other resources

Reference Searching

We inspected the references of all identified studies for more trials.

Personal contacts

We contacted leaders in the field to try to identify other studies.

Manufacturers

We contacted manufacturers of probiotic agents to try to identify other studies.

Grey Literature

We searched Google, Google Scholar, and OpenGrey, using the main search terms. To identify other potentially relevant studies that may not have been published in full, we handsearched conference proceedings from the Digestive Disease Week (DDW), United European Gastroenterology Week (UEGW), and European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) annual scientific meetings from 2019 to 2021. We only included studies from the grey literature if they presented sufficient data to enable an inclusion decision.

Concerns have been raised previously regarding the accuracy of data presented in abstract publications (Pitkin 1999). Therefore, we planned that if we identified references for relevant unpublished or ongoing studies, we would attempt to collect sufficient information to incorporate them in this review. If data were incomplete, we planned to contact the authors to verify the eligibility of the study, and only include it if they provided suitable data to enable us to assess quality and outcomes.

Data collection and analysis

We carried out data collection and analysis according to the methods recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2020).

Selection of studies

Two review authors (CW and VS) independently screened titles, abstracts, and full reports for eligibility against the inclusion criteria. The authors discussed and resolved disagreement by consensus, or with resolution by a third review author (MG).

At the stage of screening abstracts and titles, the two review authors identified reports that appeared to be potentially relevant. We obtained the full‐text reports of those that appeared to be potentially relevant. After reading the full texts, the two review authors independently assessed the eligibility of trials, based on the inclusion criteria above, and develop a PRISMA flowchart (Page 2021).

Data extraction and management

We developed data extraction forms a priori, as per the recommendations in the Cochrane Handbook for Systematic Reviews (Higgins 2020), to extract information on relevant features and results of included studies. Eight review authors extracted and recorded data on the data extraction form (two authors extracted data independently and a third author checked the exactions). We extracted the following data:

characteristics of children: age, sex, duration of symptoms;
inclusion and exclusion criteria;
study methods;
total number of children originally assigned to each treatment group;
intervention: preparations, dose, administration regimen;
control: placebo, other drugs;
concurrent medications;
outcomes (time of assessment, length of follow‐up, frequency of defecation, pain or straining on defecation, faecal incontinence, stool consistency, need for additional therapies, number and type of adverse events associated with treatment, adverse events); and
withdrawals and reasons for withdrawals.

After data extraction, the review authors compared the extracted data and discussed and resolved discrepancies before the data were transferred into the 'Characteristics of included studies' table.

Assessment of risk of bias in included studies

Eight review authors independently assessed all studies meeting the inclusion criteria for their risk of bias, using criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (Higgins 2011). The domains were:

sequence generation (selection bias);
allocation concealment (selection bias);
blinding of participants and personnel (performance bias);
blinding of outcome assessment (detection bias);
incomplete outcome data (attrition bias);
selective reporting (reporting bias);
other bias, such as imbalance in participants' baseline characteristics.

We judged the studies to be at low, high, or unclear risk of bias for each domain assessed, based on the guidance in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (Higgins 2011).

For cluster‐RCTs, we intended to judge risk of bias as prescribed in Section 16.3.2 of the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (Higgins 2011)

Measures of treatment effect

Dichotomous outcomes

We assessed all dichotomous outcomes by calculating the risk ratio (RR) and 95% confidence interval (CI).

Continuous outcomes

We assessed all continuous outcomes by calculating the mean difference (MD) and 95% CI, when using the same units. When studies had used different scales to evaluate the same outcome, we calculated the standardised mean difference (SMD) and 95% CI.

Unit of analysis issues

The participant was the unit of analysis. For studies comparing more than two intervention groups, we made multiple pair‐wise comparisons between all possible pairs of intervention groups. To avoid double‐counting if it had been necessary to include multiple arms within the same forest plot, we planned to divide shared intervention groups evenly among the comparisons. For dichotomous outcomes, we planned to divide both the number of events and the total number of participants. For continuous outcomes, we planned to only divide the total number of participants and leave the means and standard deviations unchanged.

We planned to include cross‐over studies, but only pool data if they were separately reported before and after the cross over; we planned to only use data from the pre‐cross‐over phase.

Dealing with missing data

We contacted authors when there were missing data, or where studies did not report data in sufficient detail. We planned to estimate missing standard deviations using relevant statistical tools and calculators available in Review Manager 5 if studies reported standard errors (Review Manager 2020). We judged studies that failed to report measures of variance to be at high risk of selective reporting bias.

Assessment of heterogeneity

We scrutinised studies to ensure that they were clinically homogeneous in terms of participants, interventions, comparators, and outcomes. To test for statistical heterogeneity, we used a Chi² test and interpreted a P value of less than 0.1 to give an indication of the presence of heterogeneity. We quantified consistency as represented by the I² statistic. We interpreted the thresholds as follows (Higgins 2020):

0% to 40%: might not be important;
30% to 60%: may represent moderate heterogeneity;
50% to 90%; may represent substantial heterogeneity;
75% to 100%: considerable heterogeneity.

We planned to examine possible explanations for heterogeneity when sufficient data were available, exploring factors such as participant characteristics (e.g. age, sex), condition severity, healthcare system, and country.

We planned to avoid pooling data in a meta‐analysis if we detected a considerable degree of statistical heterogeneity (I² > 75%). In cases of considerable statistical heterogeneity, we planned to investigate whether this could be explained on clinical, methodological, or risk of bias grounds, in which case, we planned to perform sensitivity analyses excluding identified studies, with reasons. If we could not find any such reasons for the considerable statistical heterogeneity, we planned to present the results narratively, in detail.

Assessment of reporting biases

An inclusive search strategy minimised most reporting biases. We planned to investigate publication bias using a funnel plot if there were 10 or more studies. We planned to determine the magnitude of publication bias by visual inspection of the asymmetry of the funnel plot. In addition, we planned to test funnel plot asymmetry by conducting a linear regression of intervention effect estimate against its standard error, weighted by the inverse of the variance of the intervention effect estimate (Egger 1997).

Data synthesis

We combined data from individual trials into a meta‐analysis if the interventions, participant groups, and outcomes were sufficiently similar (determined by consensus). We calculated the pooled RR and corresponding 95% CI for dichotomous outcomes, and MD or SMD and corresponding 95% CI for continuous outcomes. We used a random‐effects model for meta‐analysis. We did not pool data in meta‐analysis if we detected considerable heterogeneity (i.e. I² > 75%).

We used RevMan Web 2022 for data analysis. We analysed data according to the intention‐to‐treat principle. We assumed that participants with missing final outcomes had failed treatment.

Subgroup analysis and investigation of heterogeneity

We planned to conduct subgroup analyses to study the effects of a number of variables on the outcomes, including:

specific probiotic preparation;
the effect of length of therapy and follow‐up;
what, if anything, was initially allowed in the protocol to clear any impaction (such as enemas);|
age of participants (infants, non‐toilet trained toddlers, older children and adolescents, as per Rome IV criteria (Hyams 2016)).

Sensitivity analysis

Where possible, we planned to undertake a sensitivity analysis on the primary outcomes to assess whether the findings of the review are robust, based on the decisions made during the review process. In particular, we planned to exclude studies at high or unclear risk of selection bias due to allocation bias and performance bias, from analyses that include studies with different risk of bias judgements.

Where data analyses included studies with reported and estimated standard deviations, we planned to exclude those with estimated standard deviations, to assess whether this affected the findings of the review. We planned to investigate whether the choice of model (fixed‐effect versus random‐effects) affected results, as well as studies published in full versus abstract format.

Summary of findings and assessment of the certainty of the evidence

We presented the main results in summary of findings tables. We exported data for each comparison and primary outcome from RevMan Web (RevMan Web 2022) to GRADEpro GDT software to assess the certainty of the evidence (GRADEpro GDT).

We planned to present two summary of findings tables in the following hierarchy:

probiotics versus placebo;
probiotics and osmotic laxative versus osmotic laxative.

We added summary of findings tables for other comparisons identified during the review, including comparisons with magnesium oxide (summary of findings Table 3), synbiotics compared with placebo (summary of findings Table 4), synbiotics and paraffin compared with paraffin (summary of findings Table 5), and synbiotics compared with paraffin (summary of findings Table 6).

We planned to include all three primary outcomes and the secondary outcome 'serious adverse events'.

We did not conduct GRADE assessments for outcomes for which meta‐analysis was not conducted.

Based on risk of bias, inconsistency, imprecision, indirectness, and publication bias, we graded the certainty of the evidence for each outcome as high, moderate, low, or very low (described below). We justified all decisions to downgrade the certainty of studies using footnotes, and we made comments to aid the reader's understanding of the review where necessary.

GRADE Working Group grades of evidence

High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Results

Description of studies

Key characteristics of the included studies can be found in Characteristics of included studies, Table 1 and Table 2.

Open in table viewer

Table 1. Included studies further details ‐ diagnosis, participants, length of treatment, time point of outcome measurements

Study ID	Methods of diagnosis	Age range	Number randomised (IG/CG)	Number analysed (IG/CG)	Length of intervention	Time points of outcome measurements
Banaszkiewicz 2005	< 3 BMs per week for > 12 weeks	2 to 16 y	43/41	43/41	12 weeks	Weeks 4, 8, 12, 24
Basturk 2017	Rome III	4 to 18 y	77/78	72/74	4 weeks	End of intervention
Bu 2007	< 3 BMs per week for > 2 months	< 10 y	18/18/9	18/18/9	4 weeks	End of intervention
Chao 2016	Rome III	6m to 10 y	41/40	41/40	12 weeks	Weeks 4 and 12
Coccorullo 2010	Rome III	6 to 12 m	22/22	22/22	8 weeks	Weeks 4 and 8
Guerra 2011	Rome III	5 to 15 y	30/30	30/29	5 weeks	Weeks 1, 3, 5
Jadresin 2018	Rome III	2 to 18 y	18/15	18/15	12 weeks	4 weeks after the end of the intervention
Khodadad 2010	Rome III	4 to 12 y	29/31/37	29/31/37	4 weeks	Weekly and at the end
Kubota 2020	Rome IV	6 m to 6 y	20/19/21	20/19/21	4 weeks	End of intervention
Russo 2017	Rome III	4 to 12 y	27/28	25/25	8 weeks	2, 4, 8 weeks
Tabbers 2011	Rome III	3 to 16 y	79/80	74/74	3 weeks	1, 2, 3 weeks
Wegner 2018	Rome III	3 to 7 y	65/64	59/61	8 weeks	Weeks 4 and 8
Wojtyniak 2017	Rome III	< 5 y	46/48	41/40	4 weeks	Weeks 1, 2, 3, 4
Zaja 2021	Rome III	10 to 18 y	15/16	15/16	12 weeks	End of intervention

BM: bowel movement; CG: control group; IG: intervention group

Open in table viewer

Table 2. Included studies further details ‐ interventions and trial registrations

Study ID	Interventional Agent	Intervention dosage (amount and frequency)	Control	Control dosage (amount and frequency)	Trial registration(prospective/ retrospective/none)	Do the trial registration outcomes match those published?
Banaszkiewicz 2005	Lactobacillusrhamnosus GG (LGG) + lactulose	10⁹ CFU twice daily orally + 1mL/kg/day of 70% lactulose (in two divided doses)	"comparable" placebo + lactulose	placebo twice daily orally + 1 mL/kg/day of 70% lactulose (in two divided doses)	None	NR
Basturk 2017	Probiotic mixture containing: Lactobacillus casei; L rhamnosus; L plantarum; Bifidobacterium lactis and prebiotic mixture (fibre, polydextrose, fructo‐oligosaccharides, and galacto‐oligosaccharides)	4 x 10⁹ CFU of probiotics and prebiotics at a dose of 1996.57 mg as a sachet once a day	Placebo which had the same properties of colour, odour, taste	Sachet once a day	None	NR
Bu 2007	Group 1: Lactobacillus casei rhamnosus (Lcr 35) Group 2: magnesium oxide (MgO)	Group 1: 8 × 10⁸ CFU/day, two capsules twice daily Group 2: 50 mg/kg per day, twice daily (both were administered in identical looking capsules)	placebo ("starch in content") similar in appearance and administered in identical capsules	NR	None	NR
Chao 2016	Clostridium butyricum miyairi + MgO	NR	MgO	NR	None	NR
Coccorullo 2010	Lactobacillus reuteri (DSM 17938)	10⁸ CFU in 5 drops of oil suspension	Unidentified placebo	5 drops once daily	None	NR
Guerra 2011	Bifidobacterium longum + commercial goat yogurt (The goat yogurt contained the two classical yogurt starters, Lactobacillus delbrueckii subspecies bulgaricus and Streptococcus thermophilus)	1 ml of 10⁹ CFU/mL (1mL) + 9 mL of commercial goat yogurt	Peptoned water + commercial goat yogurt	1 mL of peptoned water + 9 mL of goat yogurt	None	NR
Jadresin 2018	Lactobacillus reuteri DSM 17938	1 x 10⁸CFU in citrus flavoured 450 mg chewable tablet (containing isomalt, xylitol, sucrose distearate, hydrogenated palm oil, lemon‐lime flavouring, and anhydrous citric acid), dosage not reported + lactulose treatment in a dose of 1 to 3 mL/kg per day.	Placebo (identical tablets as in the active study product in all respects but live bacteria)	Dosage not reported + lactulose treatment in a dose of 1 to 3 mL/kg per day.	Prospective	Yes
Khodadad 2010	Group B: synbiotic (L casei, L rhamnosus, S hermophilus, B breve, L acidophilus, B infantis and fructo‐oligosaccharide as prebiotic) + placebo (n = 29) Group C: synbiotic ((L casei, L rhamnosus, S hermophilus, B breve, L acidophilus, B infantis and fructo‐oligosaccharide as prebiotic) +paraffin (n = 37)	Group B: 1 x 10⁹ CFU/sachet, 1 sachet per day Group C: 1.5ml/kg/day oral liquid paraffin and 1 sachet synbiotic per day	Group A: paraffin plus placebo (n = 31)	Group A: 1.5 ml/kg/day oral liquid paraffin plus placebo	Prospective	Yes
Kubota 2020	Group A received L reuteri DSM 17938 and lactose hydrate Group B received L reuteri DSM 17938 and MgO and lactose hydrate	L reuterii DSM 17938 was administered at a dose of 10⁸ CFU in 5 drops, twice daily. MgO was administered at a dose of 30 mg/kg of body weight per day. Placebo dosage not reported	Group C received a placebo and MgO and lactose hydrate	MgO was administered at a dose of 30 mg/kg of body weight per day Placebo dosage not reported	None	NR
Russo 2017	Polyethylene glycol (PEG) and probiotic mixture (PM) (including Bifidobacteria breve, infantis and longum)	1 sachet of PEG (3.6 g) and 1 sachet (3g) of probiotics daily	PEG	1 sachet (3.6 g) daily	None	NR
Tabbers 2011	The intervention product was the milk drink Activia containing B lactis and yogurt starter cultures (Lactobacillus delbrueckii ssp. bulgaricus, Streptococcus thermophilus, Lactococcus cremoris)	4.25 x 10⁹ CFU of B lactis, and L bulgaricus at least 1.2 x 10⁹ CFU per pot, twice daily	Placebo which consisted of a milk‐based, nonfermented dairy product (125‐g pot) without probiotics and with a low content of lactose (2.5 g per pot).	Twice daily	Prospective	Yes
Wegner 2018	L reuteri DSM 17938 and macrogol therapy	L reuteri: 1 tablet containing 10⁸ CFU Macrogol: 10 g per day	Matching placebo and macrogol	Macrogol (10 g per day)	Prospective	Yes
Wojtyniak 2017	Lcr35	8x10⁸ CFU, twice daily orally	comparable placebo (containing 99% milk powder and 1% magnesium stearate), twice daily orally	99% milk powder and 1% magnesium stearate	Prospective	Yes
Zaja 2021	L reuteri DSM 17938 (the tablet also contained isomalt, xylitol, sucrose distearate, hydrogenated palm oil, lemon‐lime flavouring and anhydrous citric acid)	1 x 10⁸ CFU/tablet, twice daily	Identical placebo without the probiotic (isomalt, xylitol, sucrose distearate, hydrogenated palm oil, lemon‐lime flavouring and anhydrous citric acid)	One tablet, twice daily	Prospective	Yes

CFU: colony forming units; NR: not reported

Results of the search

The search conducted on 28 June 2021 identified 941 records. After duplicates were removed, a total of 618 records entered the title and abstracts screening stage. Two authors independently reviewed titles and abstracts, and identified 29 reports full‐text review (Figure 1). Of those, we excluded four records, classified two under awaiting classification, and included 23 records.

Figure 1

Study flow diagram.

Included studies

We included 14 RCTs (in 23 reports) involving a total of 1127 participants (Banaszkiewicz 2005; Basturk 2017; Bu 2007; Chao 2016; Coccorullo 2010; Guerra 2011; Jadresin 2018; Khodadad 2010; Kubota 2020; Russo 2017; Tabbers 2011; Wegner 2018; Wojtyniak 2017; Zaja 2021).

Participants

Age

In the studies that reported age ranges, participants were between the ages of six months and 18 years old. Bu 2007 and Wojtyniak 2017 did not specify a lower age limit for the children randomised in their studies. However, the inclusion criteria for the Wojtyniak 2017 study required children to be under five years old, and the mean age of children in the Bu 2007 study was approximately three years old.

Diagnosis/definition of chronic constipation

Twelve studies based diagnosis of chronic constipation on Rome criteria, 11 of them on Rome III (Basturk 2017; Chao 2016; Coccorullo 2010; Guerra 2011; Jadresin 2018; Khodadad 2010; Russo 2017; Tabbers 2011; Wegner 2018; Wojtyniak 2017; Zaja 2021), and one on Rome IV (Kubota 2020). Banaszkiewicz 2005 defined chronic constipation as three or fewer bowel movement per week for at least three months, and Bu 2007 as three or fewer bowel movement per week for at least two months.

The participants in the Zaja 2021 RCT were children and adolescents with anorexia nervosa who also had chronic constipation.

Interventions

Length of the interventions and time points of outcome measurements

The interventions of the included RCTs lasted from three weeks (Tabbers 2011), up to 12 weeks (Banaszkiewicz 2005; Chao 2016; Jadresin 2018; Zaja 2021).

Four studies measured their outcomes only at the end of the intervention (Basturk 2017; Bu 2007; Kubota 2020 Zaja 2021). Eight studies measured outcomes at both the end of the intervention and various time points in between (Chao 2016; Coccorullo 2010; Guerra 2011; Khodadad 2010; Russo 2017; Tabbers 2011; Wegner 2018; Wojtyniak 2017). Banaszkiewicz 2005 measured outcomes at the end of the intervention, at various time points in between, and followed up their participants 12 weeks after the end of the intervention. Jadresin 2018 measured their outcomes four weeks after the end of their 12‐week intervention.

Interventions

Intervention arms

Three studies had three intervention arms (Bu 2007; Khodadad 2010; Kubota 2020), and the others had two intervention arms. Guerra 2011 was a cross‐over RCT.

Intervention and placebo agents

Seven studies compared probiotics to placebo (Bu 2007; Coccorullo 2010; Guerra 2011; Jadresin 2018; Tabbers 2011; Wojtyniak 2017; Zaja 2021).
Five studies compared probiotics and osmotic laxatives to osmotic laxatives (Banaszkiewicz 2005; Chao 2016; Kubota 2020; Russo 2017; Wegner 2018).
Two studies compared probiotics to magnesium oxide (Bu 2007; Kubota 2020).
One study compared synbiotics to placebo (Basturk 2017).
One study compared synbiotics and paraffin to paraffin (Khodadad 2010).
One study compared synbiotics to paraffin (Khodadad 2010).

All agents were taken orally. Information on the interventional agents, strains and dosages can be found in Table 2.

Reporting of outcomes

Primary outcomes

Six studies reported our primary continuous outcome of frequency of defecation (Banaszkiewicz 2005; Bu 2007; Khodadad 2010; Russo 2017; Wegner 2018; Wojtyniak 2017). In the other studies, the outcome was either unclear or not reported.

Nine studies reported our primary dichotomous outcome of global improvement/treatment success (Banaszkiewicz 2005; Basturk 2017; Bu 2007; Jadresin 2018; Khodadad 2010; Russo 2017; Tabbers 2011; Wojtyniak 2017; Zaja 2021). In the other studies, the outcome was either unclear or not reported.

Twelve studies reported out primary dichotomous outcome of withdrawals due to adverse events (Banaszkiewicz 2005; Basturk 2017; Bu 2007; Coccorullo 2010; Jadresin 2018; Khodadad 2010; Kubota 2020; Russo 2017; Tabbers 2011; Wegner 2018; Wojtyniak 2017; Zaja 2021). The remaining two studies did not report this outcome.

Reporting of secondary outcomes

Four studies reported faecal incontinence/encopresis as a continuous outcome (Banaszkiewicz 2005; Bu 2007; Khodadad 2010; Wojtyniak 2017), and four reported it as a dichotomous outcome (Basturk 2017; Russo 2017; Tabbers 2011; Wegner 2018). The other studies either did not report the outcome or reported it unclearly.

None of the studies reported our secondary outcome of successful disimpaction.

Eight studies reported our secondary outcome of need for additional therapies (Banaszkiewicz 2005; Basturk 2017; Bu 2007; Jadresin 2018; Russo 2017; Tabbers 2011; Wegner 2018; Wojtyniak 2017).

Eleven studies reported serious adverse events as an outcome (Banaszkiewicz 2005; Basturk 2017; Bu 2007; Jadresin 2018; Khodadad 2010; Kubota 2020; Russo 2017; Tabbers 2011; Wegner 2018; Wojtyniak 2017; Zaja 2021). The remaining three studies did not report this outcome.

Twelve studies reported total adverse events as an outcome (Banaszkiewicz 2005; Basturk 2017; Bu 2007; Coccorullo 2010; Jadresin 2018; Khodadad 2010; Kubota 2020; Russo 2017; Tabbers 2011; Wegner 2018; Wojtyniak 2017; Zaja 2021).

Excluded studies

We excluded four records (Figure 1). Three studies were not RCTs (Bekkali 2007; Olgac 2013; Szajewska 2011), and one had an ineligible study population (Magro 2014).

Risk of bias in included studies

Figure 2 and Figure 3 provide a graph and a summary for the risk of bias of the included studies.

Figure 2

Risk of bias graph

Figure 3

Risk of bias summary

Allocation

Random sequence generation

All included studies were described as randomised trials.

Twelve of the fourteen studies adequately described their method of random sequence generation, so we deemed these to be at low risk of bias (Banaszkiewicz 2005; Basturk 2017; Bu 2007; Coccorullo 2010; Guerra 2011; Jadresin 2018; Kubota 2020; Russo 2017; Tabbers 2011; Wegner 2018; Wojtyniak 2017; Zaja 2021).

Chao 2016 and Khodadad 2010 described participants as being randomised into intervention or control groups, but did not give information on how this random sequence was obtained, so we deemed these to be at unclear risk of bias.

Allocation concealment

We rated five studies as having a low risk of bias, as they adequately described a method of allocation concealment (Basturk 2017; Jadresin 2018; Khodadad 2010; Tabbers 2011; Wojtyniak 2017).

The remaining nine studies either did not mention allocation concealment, or had a description of allocation concealment that did not adequately describe the process in order to be deemed low risk of bias. We contacted these authors for clarification but they did not provide further details, so we rated these with an unclear risk of bias for allocation concealment (Banaszkiewicz 2005; Bu 2007; Chao 2016; Coccorullo 2010; Guerra 2011; Kubota 2020; Russo 2017; Wegner 2018; Zaja 2021).

Blinding

Blinding of participants and personnel

Twelve of the fourteen studies adequately described their methods of blinding of study participants and personnel ‐ including the matching of placebo in taste, look and packaging ‐ in order to be rated as low risk of bias (Banaszkiewicz 2005; Basturk 2017; Bu 2007; Coccorullo 2010; Guerra 2011; Jadresin 2018; Khodadad 2010; Kubota 2020; Tabbers 2011; Wegner 2018; Wojtyniak 2017; Zaja 2021). Chao 2016 was described as being a controlled trial, but did not describe the method or means of blinding of participants and personnel, so we deemed it to be at unclear risk of bias. Russo 2017 was an open‐label trial, and as such we deemed it to be at high risk for blinding of participants and personnel.

Blinding of outcome assessors

Twelve of the fourteen studies adequately described their methods of blinding for those assessing the study outcomes in order to be rated as low risk of bias (Banaszkiewicz 2005; Basturk 2017; Bu 2007; Coccorullo 2010; Guerra 2011; Jadresin 2018; Khodadad 2010; Kubota 2020; Tabbers 2011; Wegner 2018; Wojtyniak 2017; Zaja 2021). Chao 2016 did not describe the method or means of blinding of those assessing the outcomes, so we deemed it to be at unclear risk of bias. Russo 2017 was an open‐label trial, so we considered it to be at high risk for blinding of outcome assessors.

Incomplete outcome data

Thirteen of the fourteen studies described their study flow in sufficient detail and with balanced withdrawals in order to be deemed at low risk for attrition bias (Banaszkiewicz 2005; Basturk 2017; Bu 2007; Coccorullo 2010; Guerra 2011; Jadresin 2018; Khodadad 2010; Kubota 2020; Russo 2017; Tabbers 2011; Wegner 2018; Wojtyniak 2017; Zaja 2021). It was not possible to assess the study flow or withdrawals from the Chao 2016 study based on the information provided, so we deemed this to be at unclear risk of attrition bias.

Selective reporting

Twelve of the fourteen studies reported all the outcomes described in their methods in sufficient detail to be deemed at low risk of reporting bias (Banaszkiewicz 2005; Basturk 2017; Bu 2007; Coccorullo 2010; Jadresin 2018; Khodadad 2010; Kubota 2020; Russo 2017; Tabbers 2011; Wegner 2018; Wojtyniak 2017; Zaja 2021).

Chao 2016 did not provide sufficient detail in the methods or results section for us to assess against this domain, and so we rated it as having an unclear risk of bias. Guerra 2011 reported their primary outcomes, but only in graphical form with insufficient detail on the graphs to extract data from them. We contacted the authors for further clarification, but having received no response we deemed this study to be at high risk of reporting bias.

Other potential sources of bias

Thirteen of the fourteen studies had no other sources of bias of note that we could see, and had balanced baseline characteristics for the intervention and control groups. As such, we rated them at low risk for other sources of bias (Banaszkiewicz 2005; Basturk 2017; Bu 2007; Coccorullo 2010; Guerra 2011; Jadresin 2018; Khodadad 2010; Kubota 2020; Russo 2017; Tabbers 2011; Wegner 2018; Wojtyniak 2017; Zaja 2021). As Chao 2016 was presented in abstract form, without information on baseline characteristics, we were unable to assess this study and so rated it as having an unclear risk of bias.

Effects of interventions

See: Summary of findings 1 Probiotic compared to placebo for treatment of chronic constipation in children; Summary of findings 2 Probiotics and osmotic laxative compared to osmotic laxative for treatment of chronic constipation in children; Summary of findings 3 Probiotics compared to magnesium oxide for treatment of chronic constipation in children; Summary of findings 4 Synbiotics compared to placebo for treatment of chronic constipation in children; Summary of findings 5 Synbiotics and paraffin compared to paraffin for treatment of chronic constipation in children; Summary of findings 6 Synbiotics compared to paraffin for treatment of chronic constipation in children

Details on the outcome data can be found in Table 3.

Open in table viewer

Table 3. Included studies further details ‐ outcome data

Study ID	Intervention grouping	1a. Frequency of defecation	1b. Global improvement/treatment success	1c. Withdrawals due to adverse events	2a. Faecal incontinence/encopresis	2b. Successful disimpaction	2c. Need for additional therapies	2d. Serious adverse events	2e. Adverse events
Banaszkiewicz 2005	Probiotic plus lactulose vs lactulose	Stools/week 4 weeks IG: 5.9 ± 2.3 CG: 7.7 ± 5.4 8 weeks IG: 6.1 ± 2.3 CG: 7.2 ± 3.8 12 weeks IG: 6.1 ± 1.8 CG: 6.8 ± 3.1	12 weeks IG: 31/43 CG: 28/41 24 weeks IG: 27/43 CG: 27/41	IG:1 CG: 0	Episodes/week 4 weeks IG: 0.9 ± 2.1 CG: 0.7 ± 1.5 8 weeks IG: 0.8 ± 2.2 CG: 0.3 ± 0.8 12 weeks IG: 0.8 ± 1.8 CG: 0.3 ± 0.9	NR	IG: 19/43 CG: 18/41	IG:0 CG:0	IG: 4/43 (9%) IG:3/4 (abdominal pain) IG: 1/4 (vomiting) CG: 6/41 (14.68%) CG:5/6 (abdominal pain) CG: 1/6 (headache)
Basturk 2017	Synbiotic vs placebo	Not provided as continuous data by study	4 Weeks: IG: 48/72 CG: 21/74	IG: 0 CG: 0	Episodes of incontinence 4 weeks IG: 17/72 CG: 19/74	NR	IG:5/72 CG:4/74	IG:0 CG:0	Fleet enema was performed due to complaints of abdominal distention and pain. IG: 5/72 CG: 4/74
Bu 2007	MgO vs probiotic vs placebo	Stools/week MgO: 4.75 ± 1.11 Probiotic: 5.03 ± 1.50 Placebo: 2.60 ± 0.71	MgO = 13/18 (72.2%) Probiotic = 14/18 (77.8%) Placebo = 1/9 (11.1%)	MgO = 2 Probiotic = 1 Placebo = 1	Episodes/week MgO = 2.7 ± 5.1 Probiotic = 2.1 ± 3.8 Placebo = 2.7 ± 1.4	NR	Number of times glycerin enemas was used, as reported in the diary MgO = 1.3 ± 1.9 Probiotic = 1.6 ± 1.9 Placebo = 4.0 ± 2.1	MgO = 0 Probiotic =0 Placebo =0	MgO = 1 Probiotic =0 Placebo =0
Chao 2016	Probiotic vs placebo	Data presented as change in frequency with no SD	NR	NR	NR	NR	NR	NR	NR
Coccorullo 2010	Probiotic vs placebo	Data not presented in format suitable for meta‐analysis	NR	IG: 0 CG: 0	NR	NR	NR	IG: 0 CG: 0	IG: 0 CG: 0
Guerra 2011	Probiotic vs placebo	Data not presented in format suitable for meta‐analysis	NR	NR	Excluded if incontinent	NR	NR	NR	NR
Jadresin 2018	Probiotic vs Placebo	NR	Absence of symptoms at the end of study (number of children): IG: 7/18 CG: 6/15	IG: 0 CG: 0	Data presented as median and range, unable to convert to suitable format for meta‐analysis	NR	IG: 14/18 CG: 12/15	IG: 0 CG: 0	IG: 0 CG: 0
Khodadad 2010	Synbiotics plus paraffin vs Synbiotic vs Paraffin	Stools/week Group A (paraffin + placebo): 6.75 (± 2.6) Group B (synbiotics + placebo): 5.22 (± 3.2) Group C (paraffin + synbiotics): 7.49 (± 4.4)	Group A (paraffin + placebo): 24/29 Group B (synbiotics + placebo): 22/31 Group C (paraffin + synbiotics): 28/37	Group A: 0 Group B: 0 Group C: 0	Episodes/week Group A (paraffin + placebo): 0.24 (± 1.3) Group B (synbiotics + placebo): 0.06 (± 0.25) Group C (paraffin + synbiotics): 0.0 (± 0.0)	NR	NR	Group A: 0 Group B: 0 Group C: 0	Group A (paraffin + placebo): 18 Group B (synbiotics + placebo): 0 Group C (paraffin + synbiotics): 21
Kubota 2020	Probiotic vs probiotic + MgO vs MgO	Data presented as change in stool frequency	NR	IGA: 0 IGB: 0 CG: 0	NR	NR	NR	IGA: 0 IGB: 0 CG: 0	IGA: 0 IGB: 0 CG: 0
Russo 2017	Probiotic plus macrogol vs macrogol	Stools/week 2 weeks IG: 5.4 ± 1.4 CG: 5.9 ± 1.3 4 weeks IG: 6.0 ± 1.2 CG: 6.3 ± 0.9 8 weeks IG: 6.3 ± 1.0 CG: 6.3 ± 0.9	2 weeks IG: 59% (n=16) CG: 72% (n=20) 4 weeks IG: 63.6% (n=17) CG: 80% (n=22) 8 weeks IG: 81.8% (n=22) CG: 88% (n=24)	IG: 0 CG: 0	Episodes of incontinence 2 weeks IG: 8% (n = 2) CG: 12% (n = 2) 4 weeks IG: 4% (n = 1) CG: 8% (n = 2) 8 weeks IG: 4% (n = 1) CG: 6% (n = 2)	NR	IG: 0 CG: 0	IG: 0 CG: 0	IG: 0 CG: 0
Tabbers 2011	Probiotic vs placebo	Reported as change in stool frequency, and end of follow‐up. Data not presented with SD for meta‐analysis	IG: 27/71 CG: 17/72	IG: 6/74 CG: 4/74	Episodes of incontinence IG: = 27 (reported as 36.6%; n = 74) CG: = 36 (reported as 48.6%; n=74)	NR	Use of bisacodyl IG: = 23.6% (n = 19) CG: = 30.6% (n = 24)	2 serious adverse events, not specified in which group (the authors conclude these were probably unrelated to the intervention as one child broke his arm, and one developed gynecological pain, which was caused by a gynecological cyst)	IG: 4 CG: 6
Wegner 2018	Probiotic plus macrogol vs macrogol	Stools/week Week 4 IG: 7.69 ± 4.3 CG: 7.74 ± 3.6 Week 8 IG: 7.5 ± 3.3 CG: 6.9 ± 2.5	NR	0	Episodes of incontinence Week 4 IG 23/59; CG 26/61 Week 8 IG 17/59; CG 11/61	NR	Rescue enema: Week 4 IG 4; CG 5 Weeks 4 to 8: IG 3; CG 3	0	IG: 2 (abdominal pain – did not cause withdrawal) CG: 0
Wojtyniak 2017	Probiotic vs placebo	Presented as median and IQR, converted to mean and SD for analysis using Cochrane Handbook formulae. Stools/week Week 1 CG: 6 (5 to 8.2) IG: 5 (3 to 6) Week 2 CG: 6 (4 to 7) IG: 4 (3 to 6) Week 3 CG: 6 (3 to 8) IG: 4 (3 to 5) Week 4 CG: 6 (4 to 9) IG: 4 (3 to 5)	IG: 24/41 CG: 28/40	0	Presented as median and IQR, converted to mean and SD for analysis using Cochrane Handbook formulae. episodes/week Week 1 CG: 0 (0) IG: 0 (1.35) Week 2 CG: 0 (0.27) IG: 0 (0) Week 3 CG: 0 (0) IG: 0 (1.35) Week 4 CG: 0 (0) IG: 0 (0)	NR	IG: 18/41 CG: 10/40	0	IG: 0 CG: 3
Zaja 2021	Probiotic vs placebo	NR	IG: 13/15 CG: 10/16	0	NR	NR	NR	0	0

CG: control group; IG: intervention group; NR: not reported

Probiotics vs placebo

Key outcomes for this comparison are summarised in summary of findings Table 1.

Of the seven studies that looked at this comparison, one study with 31 participants was conducted in a population of people with chronic constipation who had anorexia nervosa (Zaja 2021). We have reported the available results from their study separately below, and not as part of our meta‐analyses on the general population of children with chronic constipation.

Primary outcomes

Frequency of defecation

Three studies with 280 participants provided data for a meta‐analysis of this outcome (Bu 2007; Tabbers 2011; Wojtyniak 2017). We performed meta‐analysis, but this had very serious inconsistency with two studies not overlapping visually on opposing sides of the forest plot and an I² of 95%. Exploration of this was not possible due to there only being three studies; therefore, in line with the planned methods, we have not presented this analysis. One study found a mean frequency of defecation at study end greater in the probiotic group (Bu 2007 probiotics mean 5.03 stools per week, SD 1.5; placebo mean 2.6 stools per week, SD 0.71), one found no difference between groups on change scores (Tabbers 2011 probiotics mean 2.9 stools per week, SD 3.2; placebo mean 2.6 stools per week, SD 2.6), and in the other (Wojtyniak 2017), the placebo group had greater frequency of defecation at study end (probiotics mean 4 stools per week, SD 1.48; placebo mean 6 stools per week, SD 3.7).

Global improvement/treatment success

Four studies with 313 participants provided data for a meta‐analysis of this outcome (Bu 2007; Jadresin 2018; Tabbers 2011; Wojtyniak 2017). There may be no difference in global improvement/treatment success in childhood chronic constipation (RR 1.29, 95% CI 0.73 to 2.26; Analysis 1.1) when probiotics (72/161) are compared to placebo (52/152). The certainty of the results is low due to imprecision and inconsistency (I² = 63%). A sensitivity analysis using a fixed‐effect model did not change the result (Analysis 1.2).

Zaja 2021 reported global improvement/treatment success in 13/15 patients in their probiotics group and 10/16 patients in their placebo group.

Withdrawals due to adverse events

Five studies with 357 participants provided data for a meta‐analysis of this outcome (Bu 2007; Coccorullo 2010; Jadresin 2018; Tabbers 2011; Wojtyniak 2017). There may be no difference in withdrawals due to adverse events (RR 0.64, 95% CI 0.21 to 1.95; Analysis 1.3) when probiotics (5/183) are compared to placebo (7/174). Three of the studies in the meta‐analysis reported zero withdrawals due to adverse events; therefore, the analysis is only based on data from two studies (Bu 2007; Tabbers 2011). The certainty of the results is low due to serious imprecision (summary of findings Table 1). A sensitivity analysis using the fixed effect model found no difference in this result (Analysis 1.4).

Zaja 2021 reported zero withdrawals due to adverse events in their study.

Secondary outcomes

Faecal incontinence/encopresis

Two studies with 121 participants provided continuous data for a meta‐analysis of this outcome (Bu 2007; Wojtyniak 2017). There may be no difference in faecal incontinence/encopresis episodes per week (MD ‐0.60, 95% CI ‐2.58 to 1.38; Analysis 1.5) when probiotics (n = 64) are compared to placebo (n = 57). The certainty of the results is low due to serious imprecision.

One study with 159 participants provided dichotomous data for this outcome (Tabbers 2011). It is uncertain if there is a difference in faecal incontinence/encopresis (RR 0.76, 95% CI 0.51 to 1.12; Analysis 1.6) when probiotics (27/79) are compared to placebo (36/80). The certainty of the results is low due to serious imprecision.

Successful disimpaction

No studies reported this outcome.

Need for additional therapies

Four studies with 380 participants provided data for a meta‐analysis of this outcome (Banaszkiewicz 2005; Jadresin 2018; Tabbers 2011; Wojtyniak 2017). There probably is no difference in need for additional therapies (RR 1.04, 95% CI 0.78 to 1.39; Analysis 1.7) when probiotics (70/186) are compared to placebo (64/184). The certainty of the results is moderate due to imprecision.

Serious adverse events

Four studies with 198 participants provided data for a meta‐analysis of this outcome (Bu 2007; Coccorullo 2010; Jadresin 2018; Wegner 2018; Wojtyniak 2017). There was no estimable effect for this meta‐analysis as all studies reported zero serious adverse events for their participants.

Zaja 2021 reported zero serious adverse events in their study.

Total adverse events

Zaja 2021 reported zero total adverse events in their study.

Probiotics and osmotic laxative vs osmotic laxative

Primary outcomes

Frequency of defecation

Three studies with 268 participants provided data for a meta‐analysis of this outcome (Banaszkiewicz 2005; Russo 2017; Wegner 2018). There may be no difference in frequency of defecation, measured in stools per week (MD ‐0.01, 95% CI ‐0.57 to 0.56; Analysis 2.1) when probiotics and osmotic laxative (n = 135) are compared to osmotic laxative (n = 133). The certainty of the results is low due to risk of bias and imprecision (summary of findings Table 2). A sensitivity analysis using a fixed‐effect model led to no change in the result (Analysis 2.2).

Global improvement/treatment success

Two studies with 139 participants provided data for a meta‐analysis of this outcome (Banaszkiewicz 2005; Russo 2017). There may be no difference in global improvement/treatment success in childhood chronic constipation (RR 0.95, 95% CI 0.79 to 1.15; Analysis 2.3) when probiotics and osmotic laxative (49/70) are compared to osmotic laxative (51/69). The certainty of the results is low due to risk of bias and imprecision (summary of findings Table 2). A sensitivity analysis using a fixed‐effect model led to no change in the result (Analysis 2.4).

Withdrawals due to adverse events

Three studies with 268 participants provided data for a meta‐analysis of this outcome (Banaszkiewicz 2005; Russo 2017; Wegner 2018). There may be no difference in withdrawals due to adverse events (RR 2.86, 95% CI 0.12 to 68.35) when probiotics and osmotic laxative (1/135) are compared to osmotic laxative (0/133). Two of the studies in the meta‐analysis reported zero withdrawals due to adverse events; this analysis is only based on data from one study (Banaszkiewicz 2005). The certainty of the results is very low due to risk of bias and serious imprecision (Analysis 2.5; summary of findings Table 2). A sensitivity analysis using a fixed‐effect model led to no change in the result (Analysis 2.6).

Secondary outcomes

Faecal incontinence/encopresis

One study with 84 participants provided continuous data for this outcome (Banaszkiewicz 2005). There may be no difference in faecal incontinence/encopresis episodes per week (MD 0.50, 95% CI ‐0.10 to 1.10; Analysis 2.7) when probiotics and osmotic laxative (n = 43) are compared to osmotic laxative (n = 41). The certainty of the results is low due to serious imprecision.

Two studies with 184 participants provided dichotomous data for a meta‐analysis of this outcome (Russo 2017; Wegner 2018). There may be no difference in faecal incontinence/encopresis (RR 1.40, 95% CI 0.73 to 2.68; Analysis 2.8) when probiotics and osmotic laxative (18/92) are compared to osmotic laxative (13/92). The certainty of the results is very low due to imprecision and risk of bias.

Successful disimpaction

No studies reported this outcome.

Need for additional therapies

Three studies with 268 participants provided data for a meta‐analysis of this outcome (Banaszkiewicz 2005; Russo 2017; Wegner 2018). There may be no difference in need for additional therapies (RR 0.98, 95% CI 0.63 to 1.50; Analysis 2.9) when probiotics and osmotic laxative (26/135) are compared to osmotic laxative (26/133). The certainty of the results is low due to imprecision and risk of bias.

Serious adverse events

Four studies with 308 participants provided data for a meta‐analysis of this outcome (Banaszkiewicz 2005; Coccorullo 2010; Russo 2017; Wegner 2018). There was no estimable effect for this meta‐analysis as all studies reported zero serious adverse events for their participants.

Total adverse events

Four studies with 308 participants provided data for a meta‐analysis of this outcome (Banaszkiewicz 2005; Coccorullo 2010; Russo 2017; Wegner 2018). There may be no difference in total adverse events (RR 1.11, 95% CI 0.18 to 6.79; Analysis 2.10) when probiotics and osmotic laxative (6/154) are compared to osmotic laxative (6/154). The certainty of the results is low due to imprecision and risk of bias.

Probiotic vs magnesium oxide

Primary outcomes

Frequency of defecation

One study with 36 participants reported this outcome (Bu 2007). It is not clear if there is a difference in frequency of defecation, measured in stools per week (MD 0.28, 95% CI ‐0.58 to 1.14; Analysis 3.1) when probiotics (n = 18) are compared to magnesium oxide (n = 18). The certainty of the results is very low due to high imprecision and risk of bias (summary of findings Table 3).

Global improvement/treatment success

One study with 36 participants reported this outcome (Bu 2007). It is not clear if there is a difference in global improvement/treatment success in childhood chronic constipation (RR 1.08, 95% CI 0.74 to 1.57; Analysis 3.2) when probiotics (14/18) are compared to magnesium oxide (13/18). The certainty of the results is very low due to high imprecision and risk of bias (summary of findings Table 3).

Withdrawals due to adverse events

Two studies with 77 participants provided data for a meta‐analysis of this outcome (Bu 2007; Kubota 2020). It is not clear if there is a difference in withdrawals due to adverse events in childhood chronic constipation (RR 0.50, 95% CI 0.05 to 5.04; Analysis 3.3) when probiotics (1/38) are compared to magnesium oxide (2/39). The certainty of the results is very low due to high imprecision and risk of bias (summary of findings Table 3).

Secondary outcomes

Faecal incontinence/encopresis

One study with 36 participants reported this outcome (Bu 2007). It is not clear if there is a difference in faecal incontinence/encopresis episodes per week in childhood chronic constipation (MD ‐0.60, 95% CI ‐3.54 to 2.34; Analysis 3.4) when probiotics (n = 18) are compared to magnesium oxide (n = 18). The certainty of the results is very low due to high imprecision and risk of bias.

Successful disimpaction

No studies reported this outcome.

Need for additional therapies

One study with 36 participants reported this outcome (Bu 2007). It is not clear if there is a difference in need for additional therapies (measured as number of times glycerin enema was used) in childhood chronic constipation (MD 0.30, 95% CI ‐0.94 to 1.54; Analysis 3.5) when probiotics (n = 18) are compared to magnesium oxide (n = 18). The certainty of the results is very low due to high imprecision and risk of bias.

Serious adverse events

Two studies with 77 participants provided data for a meta‐analysis of this outcome (Bu 2007; Kubota 2020). There was no estimable effect for this meta‐analysis as both studies reported zero serious adverse events for their participants (summary of findings Table 3).

Total adverse events

Two studies with 77 participants provided data for a meta‐analysis of this outcome (Bu 2007; Kubota 2020). It is not clear if there is a difference in total adverse events in childhood chronic constipation (RR 0.33, 95% CI 0.01 to 7.68) when probiotics (0/38) are compared to magnesium oxide (1/39). The certainty of the results is very low due to high imprecision and risk of bias (Analysis 3.6)

Synbiotics vs placebo

Primary outcomes

Frequency of defecation

No studies reported this outcome.

Global improvement/treatment success

One study with 155 participants provided data for this outcome (Basturk 2017). There may be higher global improvement/treatment success in childhood chronic constipation in favour of synbiotics (RR 2.32, 95% CI 1.54 to 3.47; Analysis 4.1) when synbiotics (48/77) are compared to placebo (21/78). The certainty of the results is low due to serious imprecision (summary of findings Table 4). A sensitivity analysis using a fixed‐effect model led to no change in the result (Analysis 4.2).

Withdrawals due to adverse events

One study with 155 participants provided data for this outcome (Basturk 2017). There was no estimable effect for this analysis as the study reported zero withdrawals due to adverse events for their participants ( summary of findings Table 4).

Secondary outcomes

Faecal incontinence/encopresis

One study with 155 participants provided dichotomous data for this outcome (Basturk 2017). There may be no difference in faecal incontinence/encopresis (RR 0.91, 95% CI 0.51 to 1.61; Analysis 4.3) when synbiotics (17/77) are compared to placebo (19/78). The certainty of the results is very low due to serious imprecision.

Successful disimpaction

The study did not report this outcome.

Need for additional therapies

One study with 155 participants provided data for this outcome (Basturk 2017). There probably is no difference in need for additional therapies (RR 1.27, 95% CI 0.35 to 4.54; Analysis 4.4) when synbiotics (5/77) are compared to placebo (4/78). The certainty of the results is low due to serious imprecision.

Serious adverse events

One study with 155 participants provided data for this outcome (Basturk 2017). There was no estimable effect for this analysis as the study reported zero serious adverse events for their participants.

Total adverse events

One study with 155 participants provided data for this outcome (Basturk 2017). There may be no difference in total adverse events (RR 1.27, 95% CI 0.35 to 4.54; Analysis 4.5) when synbiotics (5/77) are compared to placebo (4/78). The certainty of the results is low due to serious imprecision.

Synbiotics and paraffin vs paraffin

Primary outcomes

Frequency of defecation

One study with 66 participants provided data for this outcome (Khodadad 2010). It is uncertain if there is a difference in frequency of defecation, measured in stools per week (MD 0.74, 95% CI ‐0.96, 2.44; Analysis 5.1) when synbiotics and paraffin (n = 37) are compared to paraffin (n = 29). The certainty of the results is very low due to serious imprecision and risk of bias (summary of findings Table 5). A sensitivity analysis using a fixed‐effect model led to no change in the result (Analysis 5.2).

Global improvement/treatment success

One study with 66 participants provided data for this outcome (Khodadad 2010). It is uncertain if there is a difference in global improvement/treatment success in childhood chronic constipation (RR 0.91, 95% CI 0.71 to 1.17; Analysis 5.3) when synbiotics and paraffin (28/37) are compared to paraffin (24/29). The certainty of the results is very low due to serious imprecision and risk of bias (summary of findings Table 5). A sensitivity analysis using a fixed‐effect model led to no change in the result (Analysis 5.4).

Withdrawals due to adverse events

One study with 66 participants provided data for a meta‐analysis of this outcome (Khodadad 2010). There was no estimable effect for this meta‐analysis as the study reported zero withdrawals due to adverse events for their participants ( summary of findings Table 5).

Secondary outcomes

Faecal incontinence/encopresis

One study with 66 participants provided continuous data for this outcome (Khodadad 2010). It is uncertain if there is a difference in faecal incontinence/encopresis episodes per week (MD ‐0.23, 95% CI ‐0.70 to 0.24; Analysis 5.5) when synbiotics and paraffin (n = 37) are compared to paraffin (n = 29). The certainty of the results is very low due to serious imprecision and risk of bias.

Successful disimpaction

The study did not report this outcome.

Need for additional therapies

The study did not report this outcome.

Serious adverse events

One study with 66 participants provided data for this outcome (Khodadad 2010). There was no estimable effect for this meta‐analysis as the study reported zero serious adverse events for their participants.

Total adverse events

One study with 68 participants provided data for this outcome (Khodadad 2010). It is uncertain if there is a difference in total adverse events (RR 0.91, 95% CI 0.61 to 1.36; Analysis 5.6) when synbiotics and paraffin (21/37) are compared to paraffin (18/29). The certainty of the results is very low due to serious imprecision and risk of bias.

Synbiotics vs paraffin

Primary outcomes

Frequency of defecation

One study with 60 participants provided data for this outcome (Khodadad 2010). It is uncertain if there is a difference in frequency of defecation in stools per week in childhood chronic constipation (MD ‐1.53, 95% CI ‐3.00 to ‐0.06; Analysis 6.1) when synbiotics (n = 31) are compared to paraffin (n = 29). The certainty of the results is very low due to serious imprecision and risk of bias (summary of findings Table 6). A sensitivity analysis using a fixed‐effect model led to no change in the result (Analysis 6.2).

Global improvement/treatment success

One study with 60 participants provided data for this outcome (Khodadad 2010). It is uncertain if there is a difference in global improvement/treatment success in childhood chronic constipation (RR 0.86, 95% CI 0.65 to 1.13; Analysis 6.3) when synbiotics (22/31) are compared to paraffin (24/29). The certainty of the results is very low due to serious imprecision and risk of bias (summary of findings Table 6). A sensitivity analysis using a fixed‐effect model led to no change in the result (Analysis 6.4).

Withdrawals due to adverse events

One study with 60 participants provided data for this outcome (Khodadad 2010). There was no estimable effect for this meta‐analysis as the study reported zero withdrawals due to adverse events for their participants (summary of findings Table 6).

Secondary outcomes

Faecal incontinence/encopresis

One study with 60 participants provided continuous data for this outcome (Khodadad 2010). It is uncertain if there is a difference in faecal incontinence/encopresis episodes per week (MD ‐0.18, 95% CI‐0.66 to 0.30; Analysis 6.5) when synbiotics (n = 31) are compared to paraffin (n = 29). The certainty of the results is very low due to serious imprecision and risk of bias.

Successful disimpaction

The study did not report this outcome.

Need for additional therapies

The study did not report this outcome.

Serious adverse events

One study with 60 participants provided data for this outcome (Khodadad 2010). There was no estimable effect as the study reported zero serious adverse events for their participants.

Total adverse events

One study with 60 participants provided data for this outcome (Khodadad 2010). It is uncertain if there is a difference in total adverse events (RR 0.03, 95% CI 0.0 to 0.40; Analysis 6.6) when synbiotics (0/31) are compared to paraffin (18/29). The certainty of the results is very low due to serious imprecision and risk of bias.

Discussion

Summary of main results

This review included 14 parallel group randomised controlled trials (three of which were multi‐arm studies that included two different comparisons): seven studies compared probiotics to placebo, five compared probiotics and osmotic laxatives to osmotic laxatives, two studies compared probiotics to magnesium oxide, one compared synbiotics to placebo, one synbiotics and paraffin to paraffin alone, and a final study compared synbiotics to paraffin for the treatment of functional constipation of childhood.

The results did not allow any conclusions to be drawn as to the effect of probiotics for functional constipation in children versus placebo on frequency of defecation at study end. There may be no difference in occurrence of treatment success or adverse events when compared with placebo (low‐certainty evidence).

Probiotics combined with osmotic laxatives may lead to no difference in frequency of defecation, occurrence of treatment success or adverse events at study end when compared with osmotic laxatives for functional constipation in children (low‐certainty evidence).

No conclusions could be drawn when probiotics were compared to magnesium oxide (very low‐certainty evidence) for frequency of defecation, treatment success, faecal incontinence, need for additional therapies or about any adverse events (leading to withdrawals, serious or total).

Synbiotics may result in increased occurrence of treatment success when compared with placebo (low‐certainty evidence), with no withdrawals due to adverse events observed in either group (low‐certainty evidence).

Synbiotics combined with paraffin may result in no difference in treatment success when compared with paraffin (low‐certainty evidence). No conclusions can be drawn for frequency of defecation (very low‐certainty evidence) and no withdrawals due to adverse events occurred in either group (low‐certainty evidence).

No conclusions can be drawn for treatment success or frequency of defecation (very low‐certainty evidence) when comparing synbiotics to paraffin, and no withdrawals due to adverse events occurred in either group (very low‐certainty evidence).

There were insufficient data to allow analysis of faecal incontinence, successful disimpaction, need for additional therapies, or total adverse events. There were insufficient data for subgroup analysis of treatment success, frequency of defecation or withdrawals due to adverse events by specific probiotic preparation, length of follow‐up, initial disimpaction or age of participants.

Overall completeness and applicability of evidence

The evidence is incomplete in a number of ways. Whilst using consensus diagnostic criteria in all studies (as a required inclusion criteria) has helped clinical homogeneity and applicability of the findings, within the context of functional constipation there is still much scope for variations in patient characteristics. The most prominent issue is the chronic nature of the constipation and previous use of therapies. It is conceivable that these trials could be considering treatment‐naive children together with those who have had years of failed interventions, and the studies do little to differentiate between the two. This is not a component of current consensus diagnostic definitions and so it is difficult to suggest this is just an issue with research design, but it remains a way in which the applicability of the evidence to individual children is limited.

The severity of the participants' constipation was not evaluated in the primary studies, which further limits interpretation of findings. There was also no assessment and relevant classification of the type of functional constipation, such as cases related to slow transit or rectal outlet dysfunction.

Multiple probiotics and synbiotics were used in the studies, therefore little can be said regarding such specific preparations; instead, the evidence can only consider the broad class of these interventions.

Additionally, the majority of studies had short follow‐up. Given the chronic nature of the condition, this raises questions about the completeness of the studies' evidence for children and their clinicians. The impact of cessation of therapy or long‐term continuation by children or young people has not been addressed at all. This must also be considered when interpreting evidence. The capricious selection of outcome measures was a major contributor to this issue, a factor limiting the completeness of the evidence, and is not in line with a recently published core outcome set (Kuizenga‐Wessel 2017).

The issues of clinical heterogeneity above have limited meta‐analysis to small groups of studies with smaller sample sizes. This may impact a number of other factors. Clearly, it impacts and reduces certainty due to imprecision and may be contributing to inconsistency. Whilst these judgements are objective and in line with guidance, it is possible that further studies could impact the results.

Finally, the reporting of adverse events is another area of concern with the evidence. It is not uncommon to experience problems related to heterogeneity of thresholds of defining serious or severe events, and as such withdrawals due to adverse events is often the most available measure for review teams. This is not necessarily the most important outcome for clinicians or children with chronic constipation, and represents a gap in the evidence that must be considered.

Quality of the evidence

We reviewed the studies' quality and assessed their risk of bias. The evidence‐base was generally at low risk of bias, as shown in Figure 2. The overall risk of bias was low for most studies, with very few items at high risk in all the studies and just one study with unclear risk of bias in all items (Chao 2016). However, allocation concealment was the most poorly‐reported risk of bias item, resulting in nine of the 14 studies to be judged at unclear risk of bias for allocation concealment, as well as two cases of unclear description of the randomisation method.

Due to an insufficient number of studies, we could not examine publication bias with a funnel plot.

In GRADE analysis, imprecision due to low participant and event numbers was pervasive in the judgements made. Additionally, there was inconsistency seen in statistical heterogeneity testing and visual inspection of forest plots, which may be related to the insufficient number of studies and low participant and event numbers.

We did not conduct GRADE assessments for outcomes for which meta‐analysis was not carried out.

Potential biases in the review process

The definition of the Rome process has changed in small ways over time. The bulk of studies used Rome III and only one used the latest Rome IV, so this must be considered when interpreting the findings.

We had fewer than the recommended number of studies required to carry out some subgroup analyses, particularly by specific probiotic preparation. The lack of data available by specific probiotic preparation is a significant issue in the primary literature, and future studies should take this into account.

The certainty of the evidence across all primary outcomes was impacted by significant imprecision as a result of the small sample sizes and event numbers.

The primary evidence for all other secondary outcomes was poorly reported, and no conclusions could be reached about them.

Agreements and disagreements with other studies or reviews

The North American and European Societies for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN and ESPGHAN) published a consensus international guideline (Tabbers 2014). They concluded that the evidence does not support the use of probiotics in the treatment of childhood constipation, which is aligned with this review.

A recent systematic review also found no evidence for benefit from the use of probiotics (Wegh 2021).

Figure 1

Study flow diagram.

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Figure 2

Risk of bias graph

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Figure 3

Risk of bias summary

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Analysis 1.1

Comparison 1: Probiotics vs placebo, Outcome 1: Global improvement or treatment success, as defined by primary studies

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Analysis 1.2

Comparison 1: Probiotics vs placebo, Outcome 2: Global improvement or treatment success, as defined by primary studies (sensitivity analysis fixed‐effect model)

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Analysis 1.3

Comparison 1: Probiotics vs placebo, Outcome 3: Withdrawals due to adverse events

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Analysis 1.4

Comparison 1: Probiotics vs placebo, Outcome 4: Withdrawals due to adverse events (sensitivity analysis fixed‐effect model)

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Analysis 1.5

Comparison 1: Probiotics vs placebo, Outcome 5: Faecal incontinence, or encopresis, measured at end of study (continuous data)

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Analysis 1.6

Comparison 1: Probiotics vs placebo, Outcome 6: Faecal incontinence, or encopresis, measured at end of study (dichotomous data)

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Analysis 1.7

Comparison 1: Probiotics vs placebo, Outcome 7: Need for additional therapies during the study period

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Analysis 1.8

Comparison 1: Probiotics vs placebo, Outcome 8: Total adverse events

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Analysis 2.1

Comparison 2: Probiotics and osmotic laxative vs osmotic laxative, Outcome 1: Frequency of defecation (number of stools/week at end of study)

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Analysis 2.2

Comparison 2: Probiotics and osmotic laxative vs osmotic laxative, Outcome 2: Frequency of defecation (number of stools/week at end of study) (sensitivity analysis fixed‐effect model)

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Analysis 2.3

Comparison 2: Probiotics and osmotic laxative vs osmotic laxative, Outcome 3: Global improvement or treatment success, as defined by primary studies

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Analysis 2.4

Comparison 2: Probiotics and osmotic laxative vs osmotic laxative, Outcome 4: Global improvement or treatment success, as defined by primary studies (sensitivity analysis fixed‐effect model)

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Analysis 2.5

Comparison 2: Probiotics and osmotic laxative vs osmotic laxative, Outcome 5: Withdrawal due to adverse events

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Analysis 2.6

Comparison 2: Probiotics and osmotic laxative vs osmotic laxative, Outcome 6: Withdrawal due to adverse events (sensitivity analysis fixed‐effect model)

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Analysis 2.7

Comparison 2: Probiotics and osmotic laxative vs osmotic laxative, Outcome 7: Faecal incontinence, or encopresis, measured at end of study (continuous)

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Analysis 2.8

Comparison 2: Probiotics and osmotic laxative vs osmotic laxative, Outcome 8: Faecal incontinence, or encopresis, measured at end of study (dichotomous)

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Analysis 2.9

Comparison 2: Probiotics and osmotic laxative vs osmotic laxative, Outcome 9: Need for additional therapies during the study period

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Analysis 2.10

Comparison 2: Probiotics and osmotic laxative vs osmotic laxative, Outcome 10: Total adverse events

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Analysis 3.1

Comparison 3: Probiotics vs magnesium oxide, Outcome 1: Frequency of defecation (number of stools/week at end of study)

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Analysis 3.2

Comparison 3: Probiotics vs magnesium oxide, Outcome 2: Global improvement or treatment success, as defined by primary studies

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Analysis 3.3

Comparison 3: Probiotics vs magnesium oxide, Outcome 3: Withdrawals due to adverse events

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Analysis 3.4

Comparison 3: Probiotics vs magnesium oxide, Outcome 4: Faecal incontinence, or encopresis, measured at end of study (continuous)

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Analysis 3.5

Comparison 3: Probiotics vs magnesium oxide, Outcome 5: Need for additional therapies during the study period (continuous data)

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Analysis 3.6

Comparison 3: Probiotics vs magnesium oxide, Outcome 6: Total adverse events

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Analysis 4.1

Comparison 4: Synbiotics vs placebo, Outcome 1: Global improvement or treatment success, as defined by primary studies

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Analysis 4.2

Comparison 4: Synbiotics vs placebo, Outcome 2: Global improvement or treatment success, as defined by primary studies (sensitivity analysis fixed‐effect model))

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Analysis 4.3

Comparison 4: Synbiotics vs placebo, Outcome 3: Faecal incontinence, or encopresis, measured at end of study (dichotomous)

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Analysis 4.4

Comparison 4: Synbiotics vs placebo, Outcome 4: Need for additional therapies during the study period

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Analysis 4.5

Comparison 4: Synbiotics vs placebo, Outcome 5: Total adverse events

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Analysis 5.1

Comparison 5: Synbiotics and paraffin vs paraffin, Outcome 1: Frequency of defecation (number of stools/week at end of study)

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Analysis 5.2

Comparison 5: Synbiotics and paraffin vs paraffin, Outcome 2: Frequency of defecation (number of stools/week at end of study) (sensitivity analysis fixed‐effect model)

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Analysis 5.3

Comparison 5: Synbiotics and paraffin vs paraffin, Outcome 3: Global improvement or treatment success, as defined by primary studies

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Analysis 5.4

Comparison 5: Synbiotics and paraffin vs paraffin, Outcome 4: Global improvement or treatment success, as defined by primary studies (sensitivity analysis fixed‐effect model)

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Analysis 5.5

Comparison 5: Synbiotics and paraffin vs paraffin, Outcome 5: Faecal incontinence, or encopresis, measured at end of study (continuous)

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Analysis 5.6

Comparison 5: Synbiotics and paraffin vs paraffin, Outcome 6: Total adverse events

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Analysis 6.1

Comparison 6: Synbiotics vs paraffin, Outcome 1: Frequency of defecation (number of stools/week at end of study)

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Analysis 6.2

Comparison 6: Synbiotics vs paraffin, Outcome 2: Frequency of defecation (number of stools/week at end of study) (sensitivity analysis fixed‐effect model)

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Analysis 6.3

Comparison 6: Synbiotics vs paraffin, Outcome 3: Global improvement or treatment success, as defined by primary studies

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Analysis 6.4

Comparison 6: Synbiotics vs paraffin, Outcome 4: Global improvement or treatment success, as defined by primary studies (sensitivity analysis fixed‐effect model)

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Analysis 6.5

Comparison 6: Synbiotics vs paraffin, Outcome 5: Faecal incontinence, or encopresis, measured at end of study (continuous)

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Analysis 6.6

Comparison 6: Synbiotics vs paraffin, Outcome 6: Total adverse events

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Summary of findings 1. Probiotic compared to placebo for treatment of chronic constipation in children

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Probiotic compared to placebo for treatment of chronic constipation in children
Patient or population: children with chronic constipation without a physical explanation Setting: outpatient Intervention: probiotic Comparison: placebo
Outcomes	Risk with placebo	Risk with probiotic	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Frequency of defecation, stools/week	‐	‐	Not estimable	280 (3 studies)	‐	Very significant inconsistency due to unexplained heterogeneity, so no analysis performed.
Global improvement/treatment success as defined by primary study Follow‐up: 3 to 12 weeks	Study population		RR 1.29 (0.73 to 2.26	313 (4 studies)	⊕⊕⊝⊝ Low^a,b	‐
	342 per 1000	441 per 1000 (250 to 773)	RR 1.29 (0.73 to 2.26	313 (4 studies)	⊕⊕⊝⊝ Low^a,b	‐
Withdrawals due to adverse events Follow‐up: 3 to 12 weeks	Study population		RR 0.64 (0.21 to 1.95)	357 (5 studies)	⊕⊕⊝⊝ Low ^c	‐
Withdrawals due to adverse events Follow‐up: 3 to 12 weeks	40 per 1000	26 per 1000 (8 to 78)	RR 0.64 (0.21 to 1.95)	357 (5 studies)	⊕⊕⊝⊝ Low ^c	‐
Serious adverse events	‐	‐	Not estimable	198 (4 studies)	‐	All studies reported 0 serious adverse events
*The risk in the intervention group (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). CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect.
^aDowngraded one level due to imprecision from low participant numbers. ^bDowngraded one level due to inconsistency (I² = 71%). ^cDowngraded two levels due to serious imprecision from very low event numbers.

Summary of findings 1. Probiotic compared to placebo for treatment of chronic constipation in children

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Summary of findings 2. Probiotics and osmotic laxative compared to osmotic laxative for treatment of chronic constipation in children

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Probiotics and osmotic laxative compared to osmotic laxative for treatment of chronic constipation in children
Patient or population: children with chronic constipation without a physical explanation Setting: outpatient Intervention: probiotics and osmotic laxative Comparison: osmotic laxative
Outcomes	Risk with Osmotic laxative	Risk with Probiotics and osmotic laxative	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Frequency of defecation (number of stools/week) Follow‐up: 8 to 12 weeks	Mean number of stools per week ranged from 6.3 to 6.9	MD 0.01 lower (0.57 lower to 0.56 higher)	‐	268 (3 studies)	⊕⊕⊝⊝ Low ^a,b	‐
Global improvement or treatment success, as defined by primary studies Follow‐up: 8 to 12 weeks	Study population		RR 0.95 (0.79 to 1.15)	139 (2 studies)	⊕⊕⊝⊝ Low ^a,b	‐
	739 per 1000	702 per 1000 (584 to 850)	RR 0.95 (0.79 to 1.15)	139 (2 studies)	⊕⊕⊝⊝ Low ^a,b	‐
Withdrawal due to adverse events Follow‐up: 8 to 12 weeks	Study population		RR 2.86 (0.12 to 68.35)	268 (3 studies)	⊕⊝⊝⊝ Very low ^a,c	‐
Withdrawal due to adverse events Follow‐up: 8 to 12 weeks	0 per 1000	0 per 1000 (0 to 0)	RR 2.86 (0.12 to 68.35)	268 (3 studies)	⊕⊝⊝⊝ Very low ^a,c	‐
Serious adverse events Follow‐up: 8 to 12 weeks	Study population		‐	308 (4 studies)	‐	All studies reported 0 serious adverse events.
Serious adverse events Follow‐up: 8 to 12 weeks	0 per 1000	0 per 1000 (0 to 0)	‐	308 (4 studies)	‐	All studies reported 0 serious adverse events.
*The risk in the intervention group (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). CI: confidence interval; MD: mean difference; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect.
^aDowngraded one level due to risk of bias for allocation concealment and blinding. ^bDowngraded one level due to imprecision from low participant numbers. ^cDowngraded two levels due to serious imprecision from low event numbers.

Summary of findings 2. Probiotics and osmotic laxative compared to osmotic laxative for treatment of chronic constipation in children

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Summary of findings 3. Probiotics compared to magnesium oxide for treatment of chronic constipation in children

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Probiotics compared to magnesium oxide for treatment of chronic constipation in children
Patient or population: children with chronic constipation without a physical explanation Setting: outpatients Intervention: probiotics Comparison: magnesium oxide
Outcomes	Risk with magnesium oxide	Risk with probiotics	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Frequency of defecation (number of stools/week) Follow‐up: 4 weeks	The mean number of stools per week was 4.75	MD 0.28 higher (0.58 lower to 1.14 higher)	‐	36 (1 study)	⊕⊝⊝⊝ Very low ^a
Global improvement/treatment success, as defined by the primary study Follow‐up: 4 weeks	Study population		RR 1.08 (0.74 to 1.57)	36 (1 study)	⊕⊝⊝⊝ Very low ^a
	722 per 1000	780 per 1000 (534 to 1000)	RR 1.08 (0.74 to 1.57)	36 (1 study)	⊕⊝⊝⊝ Very low ^a
Withdrawals due to adverse events Follow‐up: 4 weeks	Study population		RR 0.50 (0.05 to 5.04)	77 (2 studies)	⊕⊝⊝⊝ Very low ^a
Withdrawals due to adverse events Follow‐up: 4 weeks	51 per 1000	26 per 1000 (3 to 257)	RR 0.50 (0.05 to 5.04)	77 (2 studies)	⊕⊝⊝⊝ Very low ^a
Serious adverse events Follow‐up: 4 weeks	Study population		not estimable	77 (2 studies)	‐	The studies reported 0 serious adverse events.
Serious adverse events Follow‐up: 4 weeks	0 per 1000	0 per 1000 (0 to 0)	not estimable	77 (2 studies)	‐	The studies reported 0 serious adverse events.
*The risk in the intervention group (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). CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect.
^a Downgraded twice due to high imprecision from very low participant numbers and once more due to risk of bias for allocation concealment

Summary of findings 3. Probiotics compared to magnesium oxide for treatment of chronic constipation in children

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Summary of findings 4. Synbiotics compared to placebo for treatment of chronic constipation in children

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Synbiotics compared to placebo for treatment of chronic constipation in children
Patient or population: children with chronic constipation without a physical explanation Setting: outpatient Intervention: synbiotics Comparison: placebo
Outcomes	Risk with placebo	Risk with synbiotics	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Frequency of defecation (number of stools/week at end of study)	‐	‐	‐	‐	‐
Global improvement or treatment success, as defined by primary study Follow‐up: 4 weeks	Study population		RR 2.32 (1.54 to 3.47)	155 (1 study)	⊕⊕⊝⊝ Low ^a
	269 per 1000	633 per 1000 (414 to 933)	RR 2.32 (1.54 to 3.47)	155 (1 study)	⊕⊕⊝⊝ Low ^a
Withdrawals due to adverse events Follow‐up: 4 weeks	Study population		Not estimable	155 (1 study)	‐	The study reported 0 withdrawals due to adverse events.
Withdrawals due to adverse events Follow‐up: 4 weeks	0 per 1000	0 per 1000 (0 to 0)	Not estimable	155 (1 study)	‐	The study reported 0 withdrawals due to adverse events.
Serious adverse events Follow‐up: 4 weeks	Study population		Not estimable	155 (1 study)	‐	The study reported 0 serious adverse events.
Serious adverse events Follow‐up: 4 weeks	0 per 1000	0 per 1000 (0 to 0)	Not estimable	155 (1 study)	‐	The study reported 0 serious adverse events.
*The risk in the intervention group (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). CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect.
^aDowngraded two levels due to serious imprecision from low participant numbers

Summary of findings 4. Synbiotics compared to placebo for treatment of chronic constipation in children

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Summary of findings 5. Synbiotics and paraffin compared to paraffin for treatment of chronic constipation in children

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Synbiotics and paraffin compared to paraffin for treatment of chronic constipation in children
Patient or population: children with chronic constipation without a physical explanation Setting: outpatient Intervention: synbiotics and paraffin Comparison: paraffin
Outcomes	Risk with paraffin	Risk with synbiotics and paraffin	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Frequency of defecation (number of stools/week) Follow‐up: 4 weeks	The mean number of stools per week was 6.75.	MD 0.74 higher (0.96 lower to 2.44 higher)	‐	66 (1 study)	⊕⊝⊝⊝ Very low ^{a, b}
Global improvement or treatment success, as defined by primary studies Follow‐up: 4 weeks	Study population		RR 0.91 (0.71 to 1.17)	66 (1 study)	⊕⊝⊝⊝ Very low ^{a, b}
	774 per 1000	705 per 1000 (580 to 983)	RR 0.91 (0.71 to 1.17)	66 (1 study)	⊕⊝⊝⊝ Very low ^{a, b}
Withdrawals due to adverse events Follow‐up: 4 weeks	Study population		not estimable	66 (1 study)	‐	The study reported 0 withdrawals due to adverse events.
Withdrawals due to adverse events Follow‐up: 4 weeks	0 per 1000	0 per 1000 (0 to 0)	not estimable	66 (1 study)	‐	The study reported 0 withdrawals due to adverse events.
Serious adverse events Follow‐up: 4 weeks	Study population		not estimable	66 (1 study)	‐	The study reported 0 serious adverse events.
Serious adverse events Follow‐up: 4 weeks	0 per 1000	0 per 1000 (0 to 0)	not estimable	66 (1 study)	‐	The study reported 0 serious adverse events.
*The risk in the intervention group (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). CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect.
^aDowngraded two levels due to serious imprecision from very low participant numbers. ^bDowngraded one level due to risk of bias for randomisation method.

Summary of findings 5. Synbiotics and paraffin compared to paraffin for treatment of chronic constipation in children

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Summary of findings 6. Synbiotics compared to paraffin for treatment of chronic constipation in children

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Synbiotics compared to paraffin for treatment of chronic constipation in children
Patient or population: children with chronic constipation without a physical explanation Setting: outpatient Intervention: synbiotics Comparison: paraffin
Outcomes	Risk with paraffin	Risk with synbiotics	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Frequency of defecation (number of stools/week) Follow‐up: 4 weeks	The mean number of stools per week was 6.75.	MD 1.53 lower (3.00 lower to 0.06 lower)	‐	60 (1 study)	⊕⊝⊝⊝ Very low ^{a, b}
Global improvement or treatment success, as defined by primary studies Follow‐up: 4 weeks	Study population		RR 0.86 (0.65 to 1.13)	60 (1 study)	⊕⊝⊝⊝ Very low ^{a, b}
	774 per 1000	967 per 1000 (789 to 1000)	RR 0.86 (0.65 to 1.13)	60 (1 study)	⊕⊝⊝⊝ Very low ^{a, b}
Withdrawals due to adverse events Follow‐up: 4 weeks	Study population		not estimable	60 (1 study)	‐	The study reported 0 withdrawals due to adverse events
Withdrawals due to adverse events Follow‐up: 4 weeks	0 per 1000	0 per 1000 (0 to 0)	not estimable	60 (1 study)	‐	The study reported 0 withdrawals due to adverse events
Serious adverse events Follow‐up: 4 weeks	Study population		not estimable	60 (1 study)	‐	The study reported 0 serious adverse events
Serious adverse events Follow‐up: 4 weeks	0 per 1000	0 per 1000 (0 to 0)	not estimable	60 (1 study)	‐	The study reported 0 serious adverse events
*The risk in the intervention group (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). CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect.
^aDowngraded two levels due to serious imprecision from low participant numbers. ^bDowngraded one level due to risk of bias for randomisation method.

Summary of findings 6. Synbiotics compared to paraffin for treatment of chronic constipation in children

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Table 1. Included studies further details ‐ diagnosis, participants, length of treatment, time point of outcome measurements

Study ID	Methods of diagnosis	Age range	Number randomised (IG/CG)	Number analysed (IG/CG)	Length of intervention	Time points of outcome measurements
Banaszkiewicz 2005	< 3 BMs per week for > 12 weeks	2 to 16 y	43/41	43/41	12 weeks	Weeks 4, 8, 12, 24
Basturk 2017	Rome III	4 to 18 y	77/78	72/74	4 weeks	End of intervention
Bu 2007	< 3 BMs per week for > 2 months	< 10 y	18/18/9	18/18/9	4 weeks	End of intervention
Chao 2016	Rome III	6m to 10 y	41/40	41/40	12 weeks	Weeks 4 and 12
Coccorullo 2010	Rome III	6 to 12 m	22/22	22/22	8 weeks	Weeks 4 and 8
Guerra 2011	Rome III	5 to 15 y	30/30	30/29	5 weeks	Weeks 1, 3, 5
Jadresin 2018	Rome III	2 to 18 y	18/15	18/15	12 weeks	4 weeks after the end of the intervention
Khodadad 2010	Rome III	4 to 12 y	29/31/37	29/31/37	4 weeks	Weekly and at the end
Kubota 2020	Rome IV	6 m to 6 y	20/19/21	20/19/21	4 weeks	End of intervention
Russo 2017	Rome III	4 to 12 y	27/28	25/25	8 weeks	2, 4, 8 weeks
Tabbers 2011	Rome III	3 to 16 y	79/80	74/74	3 weeks	1, 2, 3 weeks
Wegner 2018	Rome III	3 to 7 y	65/64	59/61	8 weeks	Weeks 4 and 8
Wojtyniak 2017	Rome III	< 5 y	46/48	41/40	4 weeks	Weeks 1, 2, 3, 4
Zaja 2021	Rome III	10 to 18 y	15/16	15/16	12 weeks	End of intervention
BM: bowel movement; CG: control group; IG: intervention group

Table 1. Included studies further details ‐ diagnosis, participants, length of treatment, time point of outcome measurements

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Table 2. Included studies further details ‐ interventions and trial registrations

Study ID	Interventional Agent	Intervention dosage (amount and frequency)	Control	Control dosage (amount and frequency)	Trial registration(prospective/ retrospective/none)	Do the trial registration outcomes match those published?
Banaszkiewicz 2005	Lactobacillusrhamnosus GG (LGG) + lactulose	10⁹ CFU twice daily orally + 1mL/kg/day of 70% lactulose (in two divided doses)	"comparable" placebo + lactulose	placebo twice daily orally + 1 mL/kg/day of 70% lactulose (in two divided doses)	None	NR
Basturk 2017	Probiotic mixture containing: Lactobacillus casei; L rhamnosus; L plantarum; Bifidobacterium lactis and prebiotic mixture (fibre, polydextrose, fructo‐oligosaccharides, and galacto‐oligosaccharides)	4 x 10⁹ CFU of probiotics and prebiotics at a dose of 1996.57 mg as a sachet once a day	Placebo which had the same properties of colour, odour, taste	Sachet once a day	None	NR
Bu 2007	Group 1: Lactobacillus casei rhamnosus (Lcr 35) Group 2: magnesium oxide (MgO)	Group 1: 8 × 10⁸ CFU/day, two capsules twice daily Group 2: 50 mg/kg per day, twice daily (both were administered in identical looking capsules)	placebo ("starch in content") similar in appearance and administered in identical capsules	NR	None	NR
Chao 2016	Clostridium butyricum miyairi + MgO	NR	MgO	NR	None	NR
Coccorullo 2010	Lactobacillus reuteri (DSM 17938)	10⁸ CFU in 5 drops of oil suspension	Unidentified placebo	5 drops once daily	None	NR
Guerra 2011	Bifidobacterium longum + commercial goat yogurt (The goat yogurt contained the two classical yogurt starters, Lactobacillus delbrueckii subspecies bulgaricus and Streptococcus thermophilus)	1 ml of 10⁹ CFU/mL (1mL) + 9 mL of commercial goat yogurt	Peptoned water + commercial goat yogurt	1 mL of peptoned water + 9 mL of goat yogurt	None	NR
Jadresin 2018	Lactobacillus reuteri DSM 17938	1 x 10⁸CFU in citrus flavoured 450 mg chewable tablet (containing isomalt, xylitol, sucrose distearate, hydrogenated palm oil, lemon‐lime flavouring, and anhydrous citric acid), dosage not reported + lactulose treatment in a dose of 1 to 3 mL/kg per day.	Placebo (identical tablets as in the active study product in all respects but live bacteria)	Dosage not reported + lactulose treatment in a dose of 1 to 3 mL/kg per day.	Prospective	Yes
Khodadad 2010	Group B: synbiotic (L casei, L rhamnosus, S hermophilus, B breve, L acidophilus, B infantis and fructo‐oligosaccharide as prebiotic) + placebo (n = 29) Group C: synbiotic ((L casei, L rhamnosus, S hermophilus, B breve, L acidophilus, B infantis and fructo‐oligosaccharide as prebiotic) +paraffin (n = 37)	Group B: 1 x 10⁹ CFU/sachet, 1 sachet per day Group C: 1.5ml/kg/day oral liquid paraffin and 1 sachet synbiotic per day	Group A: paraffin plus placebo (n = 31)	Group A: 1.5 ml/kg/day oral liquid paraffin plus placebo	Prospective	Yes
Kubota 2020	Group A received L reuteri DSM 17938 and lactose hydrate Group B received L reuteri DSM 17938 and MgO and lactose hydrate	L reuterii DSM 17938 was administered at a dose of 10⁸ CFU in 5 drops, twice daily. MgO was administered at a dose of 30 mg/kg of body weight per day. Placebo dosage not reported	Group C received a placebo and MgO and lactose hydrate	MgO was administered at a dose of 30 mg/kg of body weight per day Placebo dosage not reported	None	NR
Russo 2017	Polyethylene glycol (PEG) and probiotic mixture (PM) (including Bifidobacteria breve, infantis and longum)	1 sachet of PEG (3.6 g) and 1 sachet (3g) of probiotics daily	PEG	1 sachet (3.6 g) daily	None	NR
Tabbers 2011	The intervention product was the milk drink Activia containing B lactis and yogurt starter cultures (Lactobacillus delbrueckii ssp. bulgaricus, Streptococcus thermophilus, Lactococcus cremoris)	4.25 x 10⁹ CFU of B lactis, and L bulgaricus at least 1.2 x 10⁹ CFU per pot, twice daily	Placebo which consisted of a milk‐based, nonfermented dairy product (125‐g pot) without probiotics and with a low content of lactose (2.5 g per pot).	Twice daily	Prospective	Yes
Wegner 2018	L reuteri DSM 17938 and macrogol therapy	L reuteri: 1 tablet containing 10⁸ CFU Macrogol: 10 g per day	Matching placebo and macrogol	Macrogol (10 g per day)	Prospective	Yes
Wojtyniak 2017	Lcr35	8x10⁸ CFU, twice daily orally	comparable placebo (containing 99% milk powder and 1% magnesium stearate), twice daily orally	99% milk powder and 1% magnesium stearate	Prospective	Yes
Zaja 2021	L reuteri DSM 17938 (the tablet also contained isomalt, xylitol, sucrose distearate, hydrogenated palm oil, lemon‐lime flavouring and anhydrous citric acid)	1 x 10⁸ CFU/tablet, twice daily	Identical placebo without the probiotic (isomalt, xylitol, sucrose distearate, hydrogenated palm oil, lemon‐lime flavouring and anhydrous citric acid)	One tablet, twice daily	Prospective	Yes
CFU: colony forming units; NR: not reported

Table 2. Included studies further details ‐ interventions and trial registrations

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Table 3. Included studies further details ‐ outcome data

Study ID	Intervention grouping	1a. Frequency of defecation	1b. Global improvement/treatment success	1c. Withdrawals due to adverse events	2a. Faecal incontinence/encopresis	2b. Successful disimpaction	2c. Need for additional therapies	2d. Serious adverse events	2e. Adverse events
Banaszkiewicz 2005	Probiotic plus lactulose vs lactulose	Stools/week 4 weeks IG: 5.9 ± 2.3 CG: 7.7 ± 5.4 8 weeks IG: 6.1 ± 2.3 CG: 7.2 ± 3.8 12 weeks IG: 6.1 ± 1.8 CG: 6.8 ± 3.1	12 weeks IG: 31/43 CG: 28/41 24 weeks IG: 27/43 CG: 27/41	IG:1 CG: 0	Episodes/week 4 weeks IG: 0.9 ± 2.1 CG: 0.7 ± 1.5 8 weeks IG: 0.8 ± 2.2 CG: 0.3 ± 0.8 12 weeks IG: 0.8 ± 1.8 CG: 0.3 ± 0.9	NR	IG: 19/43 CG: 18/41	IG:0 CG:0	IG: 4/43 (9%) IG:3/4 (abdominal pain) IG: 1/4 (vomiting) CG: 6/41 (14.68%) CG:5/6 (abdominal pain) CG: 1/6 (headache)
Basturk 2017	Synbiotic vs placebo	Not provided as continuous data by study	4 Weeks: IG: 48/72 CG: 21/74	IG: 0 CG: 0	Episodes of incontinence 4 weeks IG: 17/72 CG: 19/74	NR	IG:5/72 CG:4/74	IG:0 CG:0	Fleet enema was performed due to complaints of abdominal distention and pain. IG: 5/72 CG: 4/74
Bu 2007	MgO vs probiotic vs placebo	Stools/week MgO: 4.75 ± 1.11 Probiotic: 5.03 ± 1.50 Placebo: 2.60 ± 0.71	MgO = 13/18 (72.2%) Probiotic = 14/18 (77.8%) Placebo = 1/9 (11.1%)	MgO = 2 Probiotic = 1 Placebo = 1	Episodes/week MgO = 2.7 ± 5.1 Probiotic = 2.1 ± 3.8 Placebo = 2.7 ± 1.4	NR	Number of times glycerin enemas was used, as reported in the diary MgO = 1.3 ± 1.9 Probiotic = 1.6 ± 1.9 Placebo = 4.0 ± 2.1	MgO = 0 Probiotic =0 Placebo =0	MgO = 1 Probiotic =0 Placebo =0
Chao 2016	Probiotic vs placebo	Data presented as change in frequency with no SD	NR	NR	NR	NR	NR	NR	NR
Coccorullo 2010	Probiotic vs placebo	Data not presented in format suitable for meta‐analysis	NR	IG: 0 CG: 0	NR	NR	NR	IG: 0 CG: 0	IG: 0 CG: 0
Guerra 2011	Probiotic vs placebo	Data not presented in format suitable for meta‐analysis	NR	NR	Excluded if incontinent	NR	NR	NR	NR
Jadresin 2018	Probiotic vs Placebo	NR	Absence of symptoms at the end of study (number of children): IG: 7/18 CG: 6/15	IG: 0 CG: 0	Data presented as median and range, unable to convert to suitable format for meta‐analysis	NR	IG: 14/18 CG: 12/15	IG: 0 CG: 0	IG: 0 CG: 0
Khodadad 2010	Synbiotics plus paraffin vs Synbiotic vs Paraffin	Stools/week Group A (paraffin + placebo): 6.75 (± 2.6) Group B (synbiotics + placebo): 5.22 (± 3.2) Group C (paraffin + synbiotics): 7.49 (± 4.4)	Group A (paraffin + placebo): 24/29 Group B (synbiotics + placebo): 22/31 Group C (paraffin + synbiotics): 28/37	Group A: 0 Group B: 0 Group C: 0	Episodes/week Group A (paraffin + placebo): 0.24 (± 1.3) Group B (synbiotics + placebo): 0.06 (± 0.25) Group C (paraffin + synbiotics): 0.0 (± 0.0)	NR	NR	Group A: 0 Group B: 0 Group C: 0	Group A (paraffin + placebo): 18 Group B (synbiotics + placebo): 0 Group C (paraffin + synbiotics): 21
Kubota 2020	Probiotic vs probiotic + MgO vs MgO	Data presented as change in stool frequency	NR	IGA: 0 IGB: 0 CG: 0	NR	NR	NR	IGA: 0 IGB: 0 CG: 0	IGA: 0 IGB: 0 CG: 0
Russo 2017	Probiotic plus macrogol vs macrogol	Stools/week 2 weeks IG: 5.4 ± 1.4 CG: 5.9 ± 1.3 4 weeks IG: 6.0 ± 1.2 CG: 6.3 ± 0.9 8 weeks IG: 6.3 ± 1.0 CG: 6.3 ± 0.9	2 weeks IG: 59% (n=16) CG: 72% (n=20) 4 weeks IG: 63.6% (n=17) CG: 80% (n=22) 8 weeks IG: 81.8% (n=22) CG: 88% (n=24)	IG: 0 CG: 0	Episodes of incontinence 2 weeks IG: 8% (n = 2) CG: 12% (n = 2) 4 weeks IG: 4% (n = 1) CG: 8% (n = 2) 8 weeks IG: 4% (n = 1) CG: 6% (n = 2)	NR	IG: 0 CG: 0	IG: 0 CG: 0	IG: 0 CG: 0
Tabbers 2011	Probiotic vs placebo	Reported as change in stool frequency, and end of follow‐up. Data not presented with SD for meta‐analysis	IG: 27/71 CG: 17/72	IG: 6/74 CG: 4/74	Episodes of incontinence IG: = 27 (reported as 36.6%; n = 74) CG: = 36 (reported as 48.6%; n=74)	NR	Use of bisacodyl IG: = 23.6% (n = 19) CG: = 30.6% (n = 24)	2 serious adverse events, not specified in which group (the authors conclude these were probably unrelated to the intervention as one child broke his arm, and one developed gynecological pain, which was caused by a gynecological cyst)	IG: 4 CG: 6
Wegner 2018	Probiotic plus macrogol vs macrogol	Stools/week Week 4 IG: 7.69 ± 4.3 CG: 7.74 ± 3.6 Week 8 IG: 7.5 ± 3.3 CG: 6.9 ± 2.5	NR	0	Episodes of incontinence Week 4 IG 23/59; CG 26/61 Week 8 IG 17/59; CG 11/61	NR	Rescue enema: Week 4 IG 4; CG 5 Weeks 4 to 8: IG 3; CG 3	0	IG: 2 (abdominal pain – did not cause withdrawal) CG: 0
Wojtyniak 2017	Probiotic vs placebo	Presented as median and IQR, converted to mean and SD for analysis using Cochrane Handbook formulae. Stools/week Week 1 CG: 6 (5 to 8.2) IG: 5 (3 to 6) Week 2 CG: 6 (4 to 7) IG: 4 (3 to 6) Week 3 CG: 6 (3 to 8) IG: 4 (3 to 5) Week 4 CG: 6 (4 to 9) IG: 4 (3 to 5)	IG: 24/41 CG: 28/40	0	Presented as median and IQR, converted to mean and SD for analysis using Cochrane Handbook formulae. episodes/week Week 1 CG: 0 (0) IG: 0 (1.35) Week 2 CG: 0 (0.27) IG: 0 (0) Week 3 CG: 0 (0) IG: 0 (1.35) Week 4 CG: 0 (0) IG: 0 (0)	NR	IG: 18/41 CG: 10/40	0	IG: 0 CG: 3
Zaja 2021	Probiotic vs placebo	NR	IG: 13/15 CG: 10/16	0	NR	NR	NR	0	0
CG: control group; IG: intervention group; NR: not reported

Table 3. Included studies further details ‐ outcome data

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Comparison 1. Probiotics vs placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Global improvement or treatment success, as defined by primary studies Show forest plot	4	313	Risk Ratio (M‐H, Random, 95% CI)	1.29 [0.73, 2.26]

1.2 Global improvement or treatment success, as defined by primary studies (sensitivity analysis fixed‐effect model) Show forest plot	4	313	Risk Ratio (M‐H, Fixed, 95% CI)	1.29 [0.97, 1.72]

1.3 Withdrawals due to adverse events Show forest plot	5	357	Risk Ratio (M‐H, Random, 95% CI)	0.64 [0.21, 1.95]

1.4 Withdrawals due to adverse events (sensitivity analysis fixed‐effect model) Show forest plot	5	357	Risk Ratio (M‐H, Fixed, 95% CI)	0.64 [0.21, 1.96]

1.5 Faecal incontinence, or encopresis, measured at end of study (continuous data) Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

1.6 Faecal incontinence, or encopresis, measured at end of study (dichotomous data) Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Subtotals only

1.7 Need for additional therapies during the study period Show forest plot	4	370	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.78, 1.39]

1.8 Total adverse events Show forest plot	5	357	Risk Ratio (M‐H, Random, 95% CI)	0.54 [0.17, 1.67]

Comparison 1. Probiotics vs placebo

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Comparison 2. Probiotics and osmotic laxative vs osmotic laxative

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Frequency of defecation (number of stools/week at end of study) Show forest plot	3	268	Mean Difference (IV, Random, 95% CI)	‐0.01 [‐0.57, 0.56]

2.2 Frequency of defecation (number of stools/week at end of study) (sensitivity analysis fixed‐effect model) Show forest plot	3	263	Mean Difference (IV, Fixed, 95% CI)	0.00 [‐0.43, 0.43]

2.3 Global improvement or treatment success, as defined by primary studies Show forest plot	2	139	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.79, 1.15]

2.4 Global improvement or treatment success, as defined by primary studies (sensitivity analysis fixed‐effect model) Show forest plot	2	139	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.78, 1.17]

2.5 Withdrawal due to adverse events Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2.6 Withdrawal due to adverse events (sensitivity analysis fixed‐effect model) Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2.7 Faecal incontinence, or encopresis, measured at end of study (continuous) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

2.8 Faecal incontinence, or encopresis, measured at end of study (dichotomous) Show forest plot	2	184	Risk Ratio (M‐H, Random, 95% CI)	1.40 [0.73, 2.68]

2.9 Need for additional therapies during the study period Show forest plot	3	268	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.63, 1.50]

2.10 Total adverse events Show forest plot	4	308	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.18, 6.79]

Comparison 2. Probiotics and osmotic laxative vs osmotic laxative

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Comparison 3. Probiotics vs magnesium oxide

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Frequency of defecation (number of stools/week at end of study) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

3.2 Global improvement or treatment success, as defined by primary studies Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.3 Withdrawals due to adverse events Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.4 Faecal incontinence, or encopresis, measured at end of study (continuous) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

3.5 Need for additional therapies during the study period (continuous data) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

3.6 Total adverse events Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

Comparison 3. Probiotics vs magnesium oxide

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Comparison 4. Synbiotics vs placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Global improvement or treatment success, as defined by primary studies Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4.2 Global improvement or treatment success, as defined by primary studies (sensitivity analysis fixed‐effect model)) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.3 Faecal incontinence, or encopresis, measured at end of study (dichotomous) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4.4 Need for additional therapies during the study period Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4.5 Total adverse events Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

Comparison 4. Synbiotics vs placebo

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Comparison 5. Synbiotics and paraffin vs paraffin

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Frequency of defecation (number of stools/week at end of study) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

5.2 Frequency of defecation (number of stools/week at end of study) (sensitivity analysis fixed‐effect model) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

5.3 Global improvement or treatment success, as defined by primary studies Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

5.4 Global improvement or treatment success, as defined by primary studies (sensitivity analysis fixed‐effect model) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.5 Faecal incontinence, or encopresis, measured at end of study (continuous) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

5.6 Total adverse events Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

Comparison 5. Synbiotics and paraffin vs paraffin

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Comparison 6. Synbiotics vs paraffin

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Frequency of defecation (number of stools/week at end of study) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

6.2 Frequency of defecation (number of stools/week at end of study) (sensitivity analysis fixed‐effect model) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

6.3 Global improvement or treatment success, as defined by primary studies Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

6.4 Global improvement or treatment success, as defined by primary studies (sensitivity analysis fixed‐effect model) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

6.5 Faecal incontinence, or encopresis, measured at end of study (continuous) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

6.6 Total adverse events Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

Comparison 6. Synbiotics vs paraffin

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