secuelas gastrointestinales después de cirugía por ... · que después de la anastomosis primaria...

Secuelas gastrointestinales después de cirugía por enterocolitis

necrotizante: revisión sistemática y meta-análisis

Eva-Maria Hau, Sarah C Meyer, Steffen Berger, Myrofora Goutaki, Marcin Kordasz, Ulf Kessler

ABSTRACT

Objetivos: Documentar qué tipos de secuelas gastrointestinales fueron descriptas después de

cirugía por ECN y analizar su frecuencia.

Diseño: Revisión sistemática y meta-análisis

Fuentes de datos: Medline, EMBASE y la Biblioteca Cochrane (CENTRAL) desde 1990 hasta

Octubre 2016.

Criterios de elegibilidad para seleccionar estudios: Incluimos estudios, que proveyeron datos

originales sobre la ocurrencia de secuelas gastrointestinales en pacientes que sobrevivieron a

cirugía por ECN. Se realizaron meta-análisis y meta-regresión para determinar heterogeneidad

para estudios que incluyeran 10 o más pacientes con estrecheces intestinales, recurrencia de

ECN, falla intestinal (FI) y adherencias por íleo.

Resultados: 58 estudios, incluyendo 4260 pacientes, cumplieron los criterios de inclusión.

Estenosis fueron reportadas en 24 % (IC 95% 17% a 31%) de los sobrevivientes, recurrencia de

ECN en 8% (IC 95% 3% a 15%), FI en 13% (IC 95% 7% a 19%) e íleo por adherencias 6% (IC 95%

4% a 9%). Las estenosis fueron más comunes luego de enterostomía (30%; IC 95% 23% a 37%)

que después de la anastomosis primaria (8%; IC 95% 0% a 23 %) y ocurrieron con mayor

frecuencia después de enterostomía sin resección intestinal que con resección intestinal.

Encontramos considerable heterogeneidad en la frecuencia promedio sopesada de todas las

secuelas (I2 rango: 38%- 90%). Los resultados intestinales fueron pobremente definidos, hubo

importantes diferencias en poblaciones y diseños de estudio y los hallazgos reportados tienen

un riesgo sustancial de sesgo.

Conclusiones: Las secuelas gastrointestinales en neonatos que sobreviven a cirugía por ECN son

frecuentes. Seguimiento a largo plazo vigilando resultados gastrointestinales definidos es

recomendado.

Qué se sabe de este tópico?

➢ No hay hasta el presente una revisión sistemática

determinando los tipos y frecuencia de las

secuelas gastrointestinales en pacientes que han

tenido cirugía por enterocolitis necrotizante

Qué agrega este estudio?

➢ Nuestra revisión sistemática representa

secuelas gastrointestinales hasta en un cuarto

de los pacientes, con variables de resultado

pobremente definidas y grandes discrepancias

entre las prevalencias.

INTRODUCCIÓN

ECN es la emergencia neonatal gastrointestinal (GI) más común y fatal, pero los datos sobre

secuelas después de ECN son escasos. Debido a los recientes avances en cuidado neonatal, y a

la asociación de mejor tasa de sobrevida, la incidencia de ECN permanece sin cambios o incluso

ha aumentado (1). Un procedimiento quirúrgico podría ser necesario durante ECN aguda para

interrumpir la progresión de la enfermedad o para resecar perforación o necrosis de segmentos

del intestino. La ECN en sí misma así como la cirugía abdominal pueden resultar en secuelas

relevantes.

Se sabe que la mitad de los sobrevivientes de ECN sufren de secuelas a largo plazo (2, 3), y,

como se mostró en una revisión sistemática, están en riesgo aumentado para déficit del

neurodesarrollo comparados con infantes sin ECN (4). Los recién nacidos que sobreviven a

cirugía por ECN con frecuencia desarrollan una variedad de secuelas GI postoperatorias; sin

embargo, estas complicaciones a largo plazo no han sido determinadas sistemáticamente hasta

ahora.

En un intento de llenar esta brecha de conocimiento, la presente revisión sistemática y meta-

análisis apunta a proveer un panorama de las secuelas GI postoperatorias en infantes que han

sobrevivido a cirugía por ECN, y describir la prevalencia con las que estas secuelas ocurrieron.

MÉTODOS

Nuestro estudio fue realizado en concordancia con las guías de Ítems preferidos para Reportar

para Revisiones Sistemáticas y Meta-análisis y Refuerzo de los Reportes de Estudios

Observacionales en Epidemiología (PRISMA por sus siglas en inglés) (5,6). Todos los datos

publicados que cumplieron los criterios de inclusión, independientemente del diseño del

estudio, fueron tenidos en cuenta. Este estudio está registrado con PROSPERO, Nº

CRD42018091293 (www.crd.york.ac.uk/prospero/).

Criterios de elegibilidad

Incluimos todos los estudios que presentaran datos originales sobre prevalencia de secuelas

intestinales observadas después del período perioperatorio (que se definió como 14 días).

Criterios de exclusión fueron: 1) no relacionados con ECN; 2) no mención de secuelas GI en

pacientes tratados quirúrgicamente por ECN aguda; 3) reporte de caso; 4) publicación antes de

1990; 5) estudio animal; y 6) no publicados en inglés.

Fuentes de información y estrategia de búsqueda

Buscamos en las siguientes bases de datos: Medline vía PubMed, Ovid EMBASE, y la biblioteca

Cochrane (CENTRAL). Utilizamos una combinación de términos de búsqueda para ECN y sus

secuelas, así como cirugía, problemas de crecimiento, calidad de vida y estado de salud en el

título y abstract (ver suplemento online apéndice A). También examinamos las listas de

referencia de las publicaciones seleccionadas para encontrar estudios adicionales. Los términos

http://www.crd.york.ac.uk/prospero/

de búsqueda para estado de salud empleados en la búsqueda en PubMed no se emplearon

para la búsqueda en EMBASE y biblioteca Cochrane porque dejaron de ser considerados

relevantes. Limitamos nuestra búsqueda a artículos publicados en inglés. Publicaciones

duplicadas fueron excluidas empleando el gestor de citas Endnote X7 (Thomson Reuters,

Philadelphia, PA, USA)- o los seleccionamos a mano. En caso de poblaciones de estudio

superpuestas, incluimos el estudio publicado más recientemente o el estudio que proveyó la

mayor información sobre subgrupos.

Nuestra búsqueda en la literatura y selección de trabajos fue conducida de acuerdo a un

protocolo de revisión predefinido. La última actualización de nuestra búsqueda fue realizada el

21 de Octubre de 2016.

Selección de estudios

Tres autores (EMH, SCM, UK) tamizaron independientemente publicaciones elegibles que fueron

previamente identificadas sobre la base de títulos y abstracts; una tasa de acuerdo de 90% se

logró y en caso de desacuerdo, y el texto completo fue examinado por dos cirujanos pediátricos

(SB, UK), y luego discutidos para lograr una decisión de consenso.

Proceso de recolección de datos

Tres autores (EMH, SCM, UK) extrajeron independientemente información relevante de los

estudios incluidos. Extrajimos el número de los sobrevivientes de ECN quirúrgica presentados

con cada complicación. Estos números fueron adicionalmente extraídos para cada técnica

quirúrgica. Los desacuerdos se resolvieron a través de discusión.

Medición de resultados

Los resultados primarios medidos fueron la prevalencia de las siguientes cuatro secuelas:

estrecheces, recurrencia de ECN, fallo intestinal (FI) e íleo por adherencia. Estrechez y estenosis

fueron consideradas una misma patología. Por lo tanto sólo mencionamos estrecheces. El

achicamiento de la apertura del estoma intestinal (estenosis del estoma) no fue considerado

estrechez intestinal. Incluimos las estrecheces de anastomosis como estrechez intestinal. Dado

que la mayoría de los estudios no dan una definición de síndrome de intestino corto (SIC) o FI,

extrajimos FI cuando los autores mencionaron “síndrome de intestino corto”, “falla intestinal” o

“NPT prolongada”. La “adhesión” por sí sola no fue considerada íleo por adherencia.

Los resultados secundarios o menos frecuentes medidos tales como complicaciones del estoma,

complicaciones hepatobiliares, secuelas anastomóticas y otros problemas digestivos fueron

descriptos en detalle en el Apéndice B suplementario online.

Las técnicas quirúrgicas fueron definidas como drenaje peritoneal (DP), resección y anastomosis

primaria (AP), enterostomía (E) incluyendo enterostomía con resección intestinal, enterostomía

sin resección intestinal, o enterostomía sin otra especificación, y otras técnicas (O), que

incluyeron: laparotomía abierta y cerrada, técnica de clip y soltar, resección no especificada,

debridamiento y cierre de perforación, y laparotomía no especificada. El primer procedimiento

quirúrgico sobre un paciente fue considerado el tipo de tratamiento para ese paciente, esto es,

cuando un paciente que fue inicialmente tratado con DP por ECN aguda, luego desarrolló

secuelas que requirieron laparotomía, clasificamos a este paciente como habiendo tenido DP.

Análisis estadístico

Utilizamos un modelo de efectos aleatorios (DerSimonian y Laird) para los datos binarios para

nuestro meta-análisis, que da cuenta del hecho de que puede existir heterogeneidad entre los

estudios agrupados (7). Este modelo se empleó para realizar un meta-análisis de la prevalencia

transformada (Freeman-Tukey transformación de doble arco) de secuelas GI (8-10). Hicimos un

meta-análisis para las medidas de resultado primarios: 1) estenosis, 2) recurrencia de ECN, 3) FI,

4) íleo por adherencia. Las otras secuelas incluidas en los estudios seleccionados fueron

demasiado heterogéneas o muy raramente mencionadas para un meta-análisis. Por lo tanto,

sólo el rango de prevalencia fue extraido para las otras secuelas. Incluimos en nuestro meta-

análisis estudios con un número total de sobrevivientes de ECN quirúrgica de 10 o más. Hicimos

análisis de sub-grupo para cada uno de los cuatro resultados primarios, dividiendo los estudios

entre los que realizaron enterostomía o DP. Estos análisis fueron sólo realizados si el número

total de estudios fue cinco o más. El análisis de sub-grupo sólo incluyó estudios que reportaron

datos completos referidos al número de sobrevivientes con tratamiento y el número de secuelas

resultantes de ese particular tratamiento.

Determinamos la heterogeneidad entre-estudios calculando la estadística I2 (11). Ajustamos

modelos de meta-regresión para efectos mixtos lineares univariados (DerSimonian y Laird) para

la recurrencia de ECN, estrechez, estrechez luego de enterostomía, FI e íleo por adherencias para

examinar si aplicaban los siguientes factores de explicación: período de estudio (1995 y anterior,

1996-2004, desde 2005); resección antes de enterostomía (sí, no); y tipo de tratamiento

quirúrgico (enterostomía, AP, o DP) (7). Calculamos el coeficiente de regresión transformada

(transformación de doble arco) y realizamos un test QE para heterogeneidad residual para

determinar si la heterogeneidad podría ser explicada por el posible factor explicatorio y el test

QM de moderadores para mostrar si hay en la prevalencia de los resultados examinados entre

las categorías del factor de explicación. Significancia estadística p<0.05. Hicimos el análisis

estadístico usando el software R V.3.2 con el meta paquete V.4.2 (especialmente comandos

“metaprop” y “metareg”). Evaluamos la calidad de estudio y riesgo de sesgo utilizando un

análisis GRADEpro (GRADEpro GDT: GRADEpro Guide Development Tool (Software). McMaster

University, 2015 (desarrollado por Evidence Prime. Disponible en grade.pro).

RESULTADOS

Selección de estudio

Nuestro tamizaje inicial identificó 9601 artículos (ver Apéndice C suplementario). Excluimos 3249

duplicados y 6078 estudios sobre la base de títulos y abstracts. Un total de 219 artículos fueron

agregados escaneando la lista de referencias, resultando en 58 artículos elegibles.

Determinación de características y de calidad del estudio

Nosotros excluimos varios estudios de nuestro meta-análisis debido a superposición de

poblaciones (2, 12-16). Algunos estudios (17-25) mostraron superposición parcial de

poblaciones de estudio con Autmizguine et al (26), sin embargo describían diferentes resultados

GI. Thyoka et al publicaron dos estudios con una población de estudio grandemente

superpuesta, pero reportaron diferentes resultados (27, 28). Los estudios de Hall et al/Thyoka et

al (28, 29) y Autmizguine et al/O´Connor y Sawin (18, 26) mostraron sólo una pequeña parcial

superposición y proveyó mayormente información única. Por lo tanto, incluimos cuatro estudios

(ver online Suplemento apéndice D).

La Tabla 1(verla en el original) lista las características del estudio, secuelas reportadas e

intervenciones realizadas. Los artículos elegibles describieron un total de 4260 pacientes con

intervención quirúrgica por ECN, de los cuales 2996 (70%) sobrevivieron la fase aguda (2, 12, 13,

15-69). La mayoría de las cohortes de pacientes fueron pequeñas (mediana de ECN quirúrgica

44 pacientes por estudio, rango 7-706, ver Tabla 2). Sólo 6 estudios fueron prospectivos (19, 21,

25, 42, 57, 60) de los cuales sólo cuatro estudios involucraban múltiples centros (19, 21, 25, 57).

La calidad de los estudios incluidos en el análisis para resultados principales basada en el

análisis GRADEpro fue muy pobre (ver suplemento online apéndice P).

Síntesis de resultados

La Figura 1 muestra una generalidad de las secuelas gastrointestinales descriptas después de

cirugía por ECN identificadas por nuestra revisión.

La Tabla 3 ilustra la generalidad de las secuelas, que ocurrieron en sobrevivientes de ECN

quirúrgica examinadas en los estudios elegidos para el meta-análisis. Encontramos considerable

heterogeneidad para la prevalencia media sopesada de todas las secuelas (rango I2: 38 %- 90%)

y una falta de aplicación de nomenclaturas estandarizadas de los diferentes resultados.

Recurrencia de ECN

La recurrencia de ECN fue reportada en n= 10 estudios (2, 12, 27, 29, 31-34, 36, 60). Su

prevalencia general fue desde 0 % hasta 23 % (prevalencia media sopesada 8 %; IC 95 % 3% a

15 %, rango I2 = 68 %) (ver apéndice E en el suplemento online).

La recurrencia de ECN fue más común después de enterostomía (rango 5 %- 40 %) que después

de AP (rango 0 %- 26 %; media sopesada 6 %; IC 95 % 0 % a 18 %, ver apéndice F en el

suplemento online).

Fallo intestinal

FI fue reportado en 33 estudios (2, 12, 16, 18-24, 28, 31-34, 38, 39, 44, 47-50, 53, 54, 56-64). La

prevalencia media sopesada fue 13 % (IC 95 % 7 % a 19 %, I2 = 90 %). FI fue más común

siguiendo a enterostomía (11 %; IC 95 % 3% a 23 %) que después de AP (rango 0%- 8 %) ( ver

Tabla 3 y suplemento online apéndices G y H).

Estrecheces

De los 34 estudios que explícitamente reportaron estrecheces 2, 12, 13, 15, 16, 18, 26, 28-38, 41-

55, 69) siete estudios no fueron incluidos en el meta-análisis. Las estrecheces ocurrieron en 24 %

(IC 95 % 17 % a 31 %). Las estrecheces fueron más comunes siguiendo a resección intestinal y

enterostomía que después de AP, y ocurrieron con más frecuencia después de enterostomía sin

resección intestinal que después de enterostomía con resección intestinal ( ver figura 2 y

apéndice I-K en el suplemento online).

Íleo por adherencias

Íleo por adherencia fue reportada en 20 estudios (2, 15, 16, 18, 28, 31, 32, 36-38, 44, 47, 48, 50,

58, 60, 61, 65, 67, 69). La prevalencia media sopesada fue 6 % (IC 95 % , 4% a 9 %). Su ocurrencia

fue similar después de enterostomía y AP (ver suplemento online apéndices L y M).

Complicaciones del ostoma

Las complicaciones del ostoma fueron reportadas en 20 estudios y la prevalencia reportada de

complicaciones fue desde 4 % hasta 71 % de todos los ostomas realizados y entre 5 % y 71 %

en sobrevivientes después de enterostomía (15, 16, 18, 22, 29, 33-37, 44, 47, 49, 58, 61).

Los problemas reportados fueron prolapso del ostoma (% de ostomas realizados: rango 4 %-17

% y % de sobrevivientes con ostoma: rango 5 %- 33 %), estenosis del ostoma (3 %- 15 % y 5 %-

8 %, respectivamente), problemas de piel (5 %- 23 % y no reportado, respectivamente), necrosis

(3 %- 10 % y 5 % respectivamente), retracción (5 % y 7 %, respectivamente) y hernia para-

ostoma (3 %- 17 % y 5 %- 25 %, respectivamente).

Secuelas hepatobiliares

Complicaciones hepatobiliares fueron reportadas en 12 estudios (2, 23-25, 34, 37, 39, 40, 59, 65,

66, 68). Se reportó estasis biliar en 5 % (1/21) (37) y en 33 % (51/153) (59), cálculos biliares en

1% (1/90) (39) y en 23 % (4/17) (40), histología hepática anormal en 100 % (24/24) (68) y

enfermedad hepática en 5 % (8/153) (66) de los pacientes con ECN quirúrgica recibieran NPT o

no.

Entre los pacientes recibiendo NPT, las siguientes complicaciones hepatobiliares fueron

descriptas: estasis biliar en 14 % (21/147) (24), 15 % (4/26) (2), 34 % (10/29) (65) y 35 % (13/37)

(66); enfermedad hepática en 15 % (4/26) (2), 35 % (13/37) (66), 58 % (37/64) (23) y 71 %

(89/127) (25).

Secuelas anastomóticas

Complicaciones anastomóticas fueron reportadas en nueve estudios (rango 0 %- 7 % en general

y 0 %- 12 % en sobrevivientes) (18, 29, 32, 36, 38, 43, 44, 49, 60). Los problemas fueron

mayormente pérdidas por la anastomosis (0 %- 8 % general) (18, 32, 36, 38, 43, 44, 49, 60) y

estrecheces (0 %- 8 % general) (18, 32, 36, 38, 43, 44).

Otros problemas digestivos

Diarrea y heces flojas frecuentes fueron reportadas en cinco estudios (rango 5 %- 24 % general)

(34, 39, 40, 48, 62). Chardot y otros encontraron problemas digestivos en 32 % de los

participantes del estudio (39). Constipación fue descripta con una frecuencia de 6 % (38, 40). Un

estudio de seguimiento a largo plazo (mediana 36 meses) encontró que los problemas GI más

comunes fueron constipación, encopresis, enfermedad por reflujo gastroesofágico y obstrucción

intestinal subaguda (38).

Heterogeneidad de los resultados

La meta-regresión mostró que la heterogeneidad observada podía sólo parcialmente ser

explicada por los factores explicativos examinados (ver online el suplemento apéndice N). El tipo

de tratamiento quirúrgico explicó algo de la heterogeneidad para estrechez, así como hubo una

tendencia a una baja prevalencia de estrechez en pacientes que tuvieron AP (p= 0.073) y una

significativa mayor prevalencia en pacientes que tuvieron enterostomía sin resección (p= 0.002).

DISCUSIÓN

En nuestra revisión sistemática y meta-análisis, que incluyó 4260 pacientes después de cirugía

por ECN en 58 estudios, encontramos un amplio rango de secuelas intestinales con

complicaciones únicas, ocurriendo tanto como en un cuarto de los pacientes. Las estrecheces

intestinales fueron la complicación más frecuentemente observada (25 %). Estas estrecheces

ocurrieron con mayor frecuencia siguiendo a la creación de un ostoma (30 %) que después de

AP (8%), y más frecuente si la enterostomía no estuvo combinada con resección intestinal (72 %)

que si asociada con resección (30 %).

Fortalezas y debilidades del estudio

Esta es la primera revisión sistemática investigando secuelas somáticas después de ECN. La

principal fortaleza de esta revisión fue la estrategia de búsqueda liberal y amplia. Permitió

identificar un gran número de estudios, intentando incluir todos los estudios mencionados y el

tipo de complicación siguiendo a cirugía por ECN aguda.

La generalización de nuestros resultados es limitada por la gran heterogeneidad de la

prevalencia de complicación, periodos de estudio, diseños de estudio, ubicaciones, tamaños

poblacionales de estudio y definiciones de los estudios que incluimos. Todos estos factores por

tanto resultan en una baja certeza de resultados.

Hay áreas de potencial sesgo en esta revisión sistemática, incluyendo sesgo de la publicación,

sesgo de lenguaje, sesgo de reporte de resultados, y sesgo de selección.

Dado que sólo se incluyeron artículos publicados, un sesgo de publicación es muy probable.

Otro potencial sesgo podría resultar del hecho de que ningún estudio publicado antes de 1990

fue incluido. Dentro del período de estudio incluido, la meta-regresión no mostró una influencia

del año de estudio sobre la heterogeneidad de resultados.

Debido al hecho de que sólo se incluyeron estudios en inglés, hay un potencial sesgo de

lenguaje. Sin embargo, una investigación de Jûni et al propuso que la exclusión de estudios no

publicados en inglés podría sólo representar un efecto menor en los resultados agrupados (70).

Hay potencial de sesgo de reporte en esta revisión sistemática, dado que no pudimos incluir

datos si los estudios no documentaban separadamente el número de secuelas que ocurrieron

en sus pacientes tratados médica y quirúrgicamente. Nuestro meta-análisis no incluyó estudios

donde el número de sobrevivientes a ECN quirúrgica fue menor de 10 resultando en posible

sesgo de reporte de resultado.

El hecho de que muchos autores no proveyeran definiciones o usara nomenclatura inconsistente

para sus resultados puede haber llevado a un sesgo de clasificación.

Finalmente, debido a que el tipo de tratamiento quirúrgico realizado en cada estudio fue a

discreción del médico tratante, puede haber sesgo de selección.

Fortalezas y debilidades en relación a otros estudios

Nuestro hallazgo de menos estrecheces después de AP comparado con enterostomía es un

argumento contra el concepto de que la anastomosis directa debería ser evitada durante un

proceso inflamatorio como ECN. Sin embargo, no se puede argumentar que la AP es

básicamente la técnica más segura debido a que las decisiones intraoperatorias estuvieron a la

discreción de los cirujanos asistentes,

El hallazgo de que las estructuras ocurrieron con menos frecuencia en pacientes con

enterostomía que tuvieron resección antes de la creación del ostoma comparados con aquellos

que no tuvieron resección intestinal podría ser debido a la inflamación continuada y

cicatrización del intestino afectado y no removido. Sin embargo, los reportes sobre la tasa de

estricturas después de enterostomía sin resección varía entre tasas de estrecheces de 90 % (45,

49) y 9 % (28). En el estudio de Thyoka et al la proporción de pacientes que murieron antes de

evaluar el resultado podría haber dado resultados defectuosos (28).

Una preocupación mayor de este estudio es la gran heterogeneidad de la prevalencia reportada.

Casi no hubo correlación entre la heterogeneidad observada y las posibles razones para la

heterogeneidad en nuestro análisis de meta-regresión. La severidad de la enfermedad y la

extensión intestinal de la enfermedad pueden haber influenciado grandemente las variables de

resultado reportadas. Concordantemente, Fasoli et al describieron una elevada tasa de estrechez

en asociación con pan ECN (31). La heterogeneidad de la prevalencia de enfermedad podría

haber sido influenciada por definiciones de caso inconsistentes. En lo que se refiere a FI, SIC y

NPT prolongada, las diferencias entre términos fueron con frecuencia no suficientemente claras.

Un gran número de publicaciones definió SIC como la “dependencia de NPT por más de 90

días” sin indicar la longitud del intestino delgado. La Asociación Canadiense de Cirujanos

Pediátricos define FI como la necesidad de NPT por más de 42 días después de la cirugía o tener

una longitud de intestino delgado residual <25 % (59).

Implicancias para la práctica clínica, preguntas no respondidas y futura investigación

Nuestros resultados revelan por primera vez, que las secuelas intestinales de ECN quirúrgica son

frecuentes y heterogéneas, y por lo tanto, merecen mayor atención. Los infantes prematuros son

generalmente seguidos para evaluación del neurodesarrollo. La estandarización de los

procedimientos quirúrgicos, indicaciones y nomenclaturas, el establecimiento de registros de

enfermedad con un seguimiento a largo plazo así como estudios prospectivos de tratamiento

bien conducidos son necesarios para caracterizar mejor o reducir las secuelas GI a largo plazo

de ECN.

CONCLUSIONES

Concluimos que las secuelas GI en neonatos que sobreviven a cirugía por ECN son frecuentes;

sin embargo, en los estudios la prevalencia difiere considerablemente. Debido a serias

limitaciones de los estudios incluidos en esta revisión sistemática, las conclusiones deben ser

interpretadas con precaución. Pese a la creciente preocupación de las consecuencias de ECN,

hay todavía insuficientes datos disponibles sobre las implicancias a largo plazo de la

enfermedad.

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F1Hau E-M, et al. Arch Dis Child Fetal Neonatal Ed 2018;0:F1–F9. doi:10.1136/archdischild-2017-314435

Original article

Gastrointestinal sequelae after surgery for necrotising enterocolitis: a systematic review and meta-analysisEva-Maria Hau,1,2 Sarah C Meyer,1 Steffen Berger,1 Myrofora Goutaki,3,4 Marcin Kordasz,1 Ulf Kessler1,5

To cite: Hau E-M, Meyer SC, Berger S, et al. Arch Dis Child Fetal Neonatal Ed Epub ahead of print: [please include Day Month Year]. doi:10.1136/archdischild-2017-314435

► Additional material is published online only. To view please visit the journal online (http:// dx. doi. org/ 10. 1136/ archdischild- 2017- 314435).

1Department of Pediatric Surgery, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland2Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland3Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland4Paediatric Respiratory Medicine, Bern University Hospital, University of Bern, Bern, Switzerland5Center of Visceral Surgery, Klinik Beau-Site, Hirslanden, Bern, Switzerland

Correspondence toDr Ulf Kessler, Department of Pediatric Surgery, Inselspital, Bern University Hospital, University of Bern, Bern 3012, Switzerland; ulf- kessler@ hotmail. com

E-MH and SCM contributed equally.

Received 7 November 2017Revised 26 May 2018Accepted 28 May 2018

AbsTrACTObjectives To document what types of gastrointestinal sequelae were described after surgery for necrotising enterocolitis (NEC) and to analyse their frequency.Design Systematic review and meta-analysis.Data sources Medline, EMBASE and the Cochrane library (CENTRAL) from 1990 to October 2016.Eligibility criteria for selecting studies We included studies, which provided original data on the occurrence of gastrointestinal sequelae in patients surviving surgery for NEC. Meta-analysis and metaregression to assess heterogeneity were performed for studies including 10 or more patients with gastrointestinal strictures, recurrence of NEC, intestinal failure (IF) and adhesion ileus.results Altogether 58 studies, including 4260 patients, met the inclusion criteria. Strictures were reported to occur in 24% (95% CI 17% to 31%) of surviving patients, recurrence of NEC in 8% (95% CI 3% to 15%), IF in 13% (95% CI 7% to 19%) and adhesion ileus in 6% (95% CI 4% to 9%). Strictures were more common following enterostomy (30%; 95% CI 23% to 37%) than after primary anastomosis (8%; 95% CI 0% to 23%) and occurred more often after enterostomy without bowel resection than with bowel resection. We found considerable heterogeneity in the weighted average frequency of all sequelae (I2 range: 38%–90%). Intestinal outcomes were poorly defined, there were important differences in study populations and designs, and the reported findings bear a substantial risk of bias.Conclusions Gastrointestinal sequelae in neonates surviving surgery for NEC are frequent. Long-term follow-up assessing defined gastrointestinal outcomes is warranted.

InTrODuCTIOnNecrotising enterocolitis (NEC) is the most common and fatal neonatal gastrointestinal (GI) emergency, but data on sequelae following NEC are scarce. Due to recent advances in neonatal care, and the associ-ated improved survival rate, the incidence of NEC has remained unchanged or even increased.1 A surgical procedure might become necessary during acute NEC in order to interrupt disease progres-sion or to resect perforation or necrosis of bowel segments. NEC itself as well as abdominal surgery may result in relevant sequelae.

Half of NEC survivors are known to suffer from long-term sequelae,2 3 and, as shown in a system-atic review, are at an increased risk for neurode-velopmental impairment as compared with infants without NEC.4 Newborns who survive NEC

surgery often develop a variety of postoperative GI sequelae; however, these long-term complica-tions have not been systematically assessed until now.

As an attempt to fill this knowledge gap, the present systematic review and meta-analysis aims to provide an overview of the postoperative GI sequelae in infants who survived surgery for NEC, and to describe the prevalence at which these sequelae occurred.

METhODsOur study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Strengthening the Reporting of Observational Studies in Epidemiology reporting guidelines.5 6 All published data that met inclusion criteria, regardless of the study design, were consid-ered. This study is registered with PROSPERO, No CRD42018091293 (www. crd. york. ac. uk/ prospero/).

Eligibility criteriaWe included all studies presenting original data on prevalence of intestinal sequelae observed after the acute perioperative period (which we defined as 14 days). Exclusion criteria were: (1) not related to NEC; (2) no GI sequelae in patients surgically treated for acute NEC mentioned; (3) case report; (4) published before 1990; (5) animal study; and (6) not published in English.

Information sources and search strategyWe searched the following databases: Medline via PubMed, the Ovid EMBASE and the Cochrane library (CENTRAL). We used a combination of

What is already known on this topic?

► There is at present no systematic review addressing the types and the frequency of gastrointestinal sequelae in patients who have undergone surgery for necrotising enterocolitis.

What this study adds?

► Our systematic review features gastrointestinal sequelae in up to one-quarter of patients, with poorly defined outcome variables and large discrepancies in prevalence.

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F2 Hau E-M, et al. Arch Dis Child Fetal Neonatal Ed 2018;0:F1–F9. doi:10.1136/archdischild-2017-314435

Original article

search terms for NEC and its sequelae, as well as surgery, growth problems, quality of life and health status in the title and abstract (see online supplementary appendix A). We also examined the reference lists of the selected publications in order to find addi-tional studies. The search terms for health status used in the PubMed search were not used for the EMBASE and Cochrane library search because they were no longer deemed relevant. We limited our search to articles published in English. Duplicate publications were excluded using Endnote X7 citation manager (Thomson Reuters, Philadelphia, PA, USA)—or we sorted them out by hand. In case of overlapping study populations, we included the study that was published most recently or the study which provided most information about subgroups.

Our literature search and trial selection were carried out according to a predefined review protocol. The latest update of our literature search was performed on 21 October 2016.

study selectionThree authors (EMH, SCM, UK) independently screened eligible publications that were previously identified on the basis of titles and abstracts; a 90% agreement rate was achieved and in case of disagreement, the full text was assessed by two paedi-atric surgeons (SB, UK), and then discussed in order to reach a consensus decision.

Data collection processThree authors (EMH, SCM, UK) independently extracted rele-vant information from the included studies. We extracted the number of surgical NEC survivors presenting with each compli-cation. These numbers were additionally extracted for each surgical technique. Disagreements were solved by discussion.

OutcomesPrimary outcome measures were the prevalence of the following four sequelae: stricture, recurrence of NEC, intestinal failure (IF) and adhesion ileus. Stricture and stenosis were considered to describe the same pathology. We therefore only mentioned strictures throughout. Narrowing at the opening of an intes-tinal stoma (stomal stenosis) was not considered an intestinal stricture. We included anastomotic strictures as strictures. Since the majority of studies did not provide a definition for short bowel syndrome (SBS) or IF, we extracted IF when the authors mentioned ‘short bowel syndrome’, ‘intestinal failure’ or ‘prolonged parenteral nutrition’. ‘Adhesion’ alone was not considered to be adhesion ileus.

Secondary or less frequent outcome measures such as stoma complications, hepatobiliary complications, anastomotic sequelae and other digestive problems were described in detail in the online supplementary appendix B.

Surgical techniques were defined as peritoneal drainage (PD), resection and primary anastomosis (PA), enterostomy (E) including enterostomy with intestinal resection, enterostomy without intestinal resection, or enterostomy not otherwise spec-ified, and other techniques (O), which included: open and close laparotomy, clip and drop technique, resection not otherwise specified, debridement and closure of perforation, and lapa-rotomy not otherwise specified. The first surgical procedure on a patient was considered the type of surgical treatment for that patient, that is, when a patient, who was initially treated with PD for acute NEC, later developed sequelae requiring laparotomy, we classified this patient as having undergone PD.

statistical analysisWe used a random effects model (DerSimonian and Laird) for binomial data for our meta-analysis, which accounts for the fact that heterogeneity may exist between the pooled studies.7 This model was used to perform a meta-analysis on the trans-formed prevalence (Freeman-Tukey double arcsine transfor-mation) of GI sequelae.8–10 We performed a meta-analysis for the primary outcome measures: (1) stricture, (2) recurrence of NEC, (3) IF, and (4) adhesion ileus. The other sequelae included in the selected studies were either too heterogeneous or too rarely mentioned for a meta-analysis. Therefore, only the range of prevalence was extracted for the other sequelae. We only included studies with a total number of surgical NEC survivors of 10 or more in our meta-analysis. We performed subgroup analysis for each of the four primary outcomes, dividing the studies into whether they performed enterostomy or PA. These analyses were only performed if the total number of studies was five or more. The subgroup analysis only included studies, which reported complete data regarding the number of survivors undergoing treatment and the number of sequelae resulting from that particular treatment.

We assessed between-study heterogeneity by calculating the I2 statistic.11 We fitted univariate linear mixed effects metare-gression models (DerSimonian and Laird) for the recurrence of NEC, stricture, stricture following enterostomy, IF and adhesion ileus in order to examine whether the following explanatory factors applied: study period (1995 and before, 1996–2004, since 2005); resection before enterostomy (yes, no); and type of surgical treatment (enterostomy, PA or PD).7 We calculated the transformed (double arcsine transformation) regression coefficient and performed the QE test for residual heteroge-neity to determine if the heterogeneity could be explained by the possible explanatory factor and the QM test of moderators to show if there is a difference in the prevalence of the exam-ined outcomes between the categories of the explanatory factor. Statistical significance was assumed at p<0.05. We performed statistical analysis using the software program R V.3.2 with the metapackage V.4.2 (especially the commands ‘metaprop’ and ‘metareg’). We evaluated the study quality and risk of bias by using a GRADEpro analysis (GRADEpro GDT: GRADEpro Guideline Development Tool (Software). McMaster University, 2015 (developed by Evidence Prime). Available from gradepro. org).

rEsulTsstudy selectionOur initial screen identified 9601 articles (see online supplemen-tary appendix C). We excluded 3249 duplicates and 6078 studies on the basis of titles and abstracts. A total of 219 articles were excluded based on a full-text analysis. Three articles were added via reference list scanning, resulting in 58 eligible articles.

study characteristics and quality assessmentWe excluded several studies from our meta-analysis due to overlapping study populations.2 12–16 Some studies17–25 showed partially overlapping study populations with Autmizguine et al,26 however described different GI outcomes. Thyoka et al published two studies with a largely overlapping study popu-lation, but reported different outcomes.27 28 The studies of Hall et al/Thyoka et al28 29 and Autmizguine et al/O’Connor and Sawin18 26 showed only a small partial overlap and provided mostly unique information. Therefore, we included all four studies (see online supplementary appendix D).



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Table 1 lists the study characteristics, reported sequelae and interventions performed. The eligible articles described a total of 4260 patients undergoing surgical intervention for NEC, of whom 2996 (70%) survived the acute phase.2 12 13 15–69 Most patient cohorts were small (surgical NEC median 44 patients per study, range 7–706, see table 2). Only six studies were prospec-tive,19 21 25 42 57 60 of which only four studies involved multiple centres.19 21 25 57 The quality of studies included in the analysis for the main outcomes as based on GRADEpro analysis was very poor (see online supplementary appendix P).

synthesis of resultsFigure 1 shows an overview of the described GI sequelae after NEC surgery identified by our review.

Table 3 illustrates an overview of the sequelae, which occurred in surgical NEC survivors examined in the studies chosen for meta-analysis. We found considerable heterogeneity for the weighted mean prevalence of all sequelae (I2 range: 38%–90%) and a lack of application of standardised nomenclatures of the different outcomes.

recurrence of nECRecurrence of NEC was reported in n=10 studies.2 12 27 29 31–34 36 60 Its overall prevalence ranged from 0% to 23% (weighted mean prevalence 8%; 95% CI 3% to 15%, I2=68%) (see online supplementary appendix E).

Recurrence of NEC was more common following enterostomy (range 5%–40%) than after PA (range 0%–26%; weighted mean 6%; 95% CI 0% to 18%, see online supplementary appendix F).

Intestinal failureIF was reported in 33 studies.2 12 16 18–24 28 31–34 38 39 44 47–50 53 54 56–64 The weighted mean prevalence was 13% (95% CI 7% to 19%, I2=90%). IF was more common following enterostomy (11%; 95% CI 3% to 23%) than after PA (range 0%–8%) (see table 3 and online supplementary appendices G and H).

stricturesOf 34 studies which explicitly reported stric-tures,2 12 13 15 16 18 26 28–38 41–55 69 seven studies were not included in the meta-analysis. Strictures occurred in 24% (95% CI 17% to 31%). Strictures were more common following intestinal resec-tion and enterostomy than after PA, and occurred more often after enterostomy without bowel resection than after enteros-tomy with bowel resection (see figure 2 and online supplemen-tary appendices I–K).

Adhesion ileusAdhesion ileus was reported in 20 studies.2 15 16 18 28 31 32 36–38 44 47 48 50 58 60 61 65 67 69 The weighted mean prevalence was 6% (95% CI 4% to 9%). Its occurrence was similar after enterostomy and PA (see online supplementary appendices L and M).

stoma complicationsStoma complications were reported in 20 studies and the reported prevalence of complications ranged from 4% to 71% of all stomas performed and between 5% and 71% in survivors after enterostomy.15 16 18 22 29 33–37 44 47 49 58 61

Reported problems were stoma prolapse (% of stomas performed: range 4%–17% and % of stoma survivors: range 5%–33%), stoma stenosis (3%–15% and 5%–8%, respec-tively), skin problems (5%–23% and not reported, respectively),

necrosis (3%–10% and 5%, respectively), retraction (5% and 7%, respectively) and parastomal hernia (3%–17% and 5%–25%, respectively).

hepatobiliary sequelaeHepatobiliary complications were reported in 12 studies.2 23–25 34 37 39 40 59 65 66 68 Biliary stasis was reported to occur in 5% (1/21)37 and in 33% (51/153),59 biliary stones in 1% (1/90)39 and in 23% (4/17),40 abnormal liver histology in 100% (24/24)68 and liver disease in 5% (8/153)66 of patients with surgical NEC irrespective of receiving parenteral nutrition (PN) or not.

Among patients receiving PN, the following hepatobiliary complications were described: biliary stasis in 14% (21/147),24 15% (4/26),2 34% (10/29)65 and 35% (13/37)66; liver disease in 15% (4/26),2 35% (13/37),6658% (37/64)23 and 71% (89/127).25

Anastomotic sequelaeAnastomotic complications were reported in nine studies (range 0%–7% overall and 0%–12% in survi-vors).18 29 32 36 38 43 44 49 60 Problems were mostly anastomotic leakage (0%–8% overall)18 32 36 38 43 44 49 60 and stricture (0%–8% overall).18 32 36 38 43 44

Other digestive problemsDiarrhoea and frequent loose stools were reported in five studies (range 5%–24% overall).34 39 40 48 62 Chardot et al found diges-tive problems in 32% of study participants.39 Constipation was described with a frequency of 6%.38 40 A long-term follow-up study (median 36 months) found that the most common GI problems were constipation, encopresis, gastro-oesophageal reflux disease and subacute bowel obstruction.38

heterogeneity of resultsMetaregression showed that the heterogeneity observed could only partly be explained by the examined explanatory factors (see online supplementary appendix N). The type of surgical treatment explained some of the heterogeneity for stricture, as there was a trend of a lower stricture prevalence in patients who underwent PA (p=0.073) and a significant higher preva-lence for patients who underwent enterostomy without resection (p=0.002).

DIsCussIOnIn our systematic review and meta-analysis, which included 4260 patients after NEC surgery in 58 studies, we found a wide range of intestinal sequelae with single complications, occur-ring in up to a quarter of patients. Intestinal strictures were the most commonly observed complication (25%). These strictures occurred more often following stoma creation (30%) than after PA (8%), and more often if enterostomy was not combined with intestinal resection (72%) than if associated with resection (30%).

strengths and weaknesses of the studyThis is the first systematic review assessing somatic sequelae after NEC. The main strength of this review was the liberal and broad search strategy. It enabled a large number of studies to be iden-tified, aiming to include all studies that mentioned any type of complication following surgery for acute NEC.

The generalisability of our results is limited by the large hetero-geneity of the complication prevalence, study periods, study designs, study locations, study population sizes and outcome



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mpl

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ions

Pn-a

ssoc

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d co

mpl

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ions

Ade-

Ajay

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l219

96U

KR/

U26

19E,

PA

++

++

+−

−

+N

R

Agua

yo e

t al1 7

2009

USA

R/U

7363

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−

−

−

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−

−

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NR

Andr

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−

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N

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2010

Sout

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rica

R/U

119

82PD

, E, P

A, O

−

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−

−

Med

ian

36 m

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nge

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39 m

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Autm

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2012

UK

R/U

3737

NR

−

−

−

−

−

−

−

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edia

n 24

mon

ths,

rang

e 5–

62 m

onth

s

Burn

and

et a

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KR/

U11

681

E, P

A, O

−

−

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−

−

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N

R

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2002

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daR/

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−

−

+−

−

−

−

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N

R

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dot e

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2003

Fran

ceR/

M90

74PD

, E, P

A, O

−

+−

−

−

−

+

−

Med

ian

24 m

onth

s, ra

nge

1–24

7 m

onth

s

Chou

dhry

and

Gra

nt 67

2006

UK

R/U

3131

O−

−

−

+

−

−

−

−

Med

ian

39 m

onth

s, ra

nge

2 m

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s to

6 ye

ars

Chris

tens

en e

t al56

2002

Denm

ark

R/U

4444

NR

−

+−

−

−

−

−

−

N

R

Davi

es e

t al40

1999

UK

R/U

1717

O−

−

−

−

−

−

+

−

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ian

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year

s, ra

nge

5.5–

13.7

year

s

Dem

estr

e et

al57

2002

Spai

nP/

M44

33PD

−

+−

−

−

−

−

−

N

R

Duro

et a

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10U

SAP/

M12

912

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, O−

+

−

−

−

−

−

−

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e th

an 9

0 da

ys

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et a

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712

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−

−

−

−

−

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+

NR

Eich

er e

t al58

2012

Ger

man

yR/

U9

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−

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−

−

N

R

Elfv

in e

t al59

2015

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daR/

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−

−

−

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N

R

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A+

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−

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−

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nge

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mon

ths

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rd e

t al42

1991

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ium

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1110

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−

−

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−

−

−

−

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ean

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year

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nge

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year

s, SD

1.1

year

Fasc

hing

et a

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94Au

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R/U

1913

E, O

−

−

++

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−

−

N

R

Faso

li et

al31

1999

UK

R/U

8358

E, P

A+

++

−

+−

−

−

M

ean

42 m

onth

s, ra

nge

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6920

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N

R

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ance

R/U

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−

−

−

N

R

Gfro

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any

R/U

5747

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A, O

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+

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−

1

year

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ore

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1994

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−

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n 38

mon

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rang

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–72

mon

ths

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R/U

3728

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−

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++

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day

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stud

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147

103

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atto

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−

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2011

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edia

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Thyo

ka e

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2012

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R

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2014

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R/U

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2005

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eyR/

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−

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−

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e 3–

28 m

onth

s

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a co

mpl

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incl

ude

stom

a st

rictu

re, s

tom

a pr

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se, s

tom

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cros

is, s

tom

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trac

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la, p

aras

tom

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erni

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riatio

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asto

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ompl

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incl

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anas

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ictu

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Live

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plic

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clud

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olel

ithia

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bilia

ry s

tasi

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spis

sate

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yndr

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isea

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ssoc

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mpl

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incl

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pare

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al n

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asso

ciat

ed li

ver d

isea

se (P

NAL

D), t

otal

par

ente

ral n

utrit

ion

(TPN

) cho

lest

asis,

TPN

sep

sis.

Surg

ical

NEC

sur

vivo

rs in

clud

e in

fant

s tr

eate

d su

rgic

ally

for a

cute

NEC

who

sur

vive

d ≥

14 d

ays

post

surg

ery.

E, e

nter

osto

my;

IF, i

ntes

tinal

failu

re; M

, mul

ticen

tre;

n, t

otal

num

ber;

NEC

, nec

rotis

ing

ente

roco

litis

; NR,

not

repo

rted

; O, o

ther

s, in

clud

ing

lapa

roto

my

not o

ther

wis

e sp

ecifi

ed, o

pen

and

clos

e la

paro

tom

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lip a

nd d

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ctio

n no

t oth

erw

ise

spec

ified

, deb

ridem

ent a

nd c

losu

re o

f per

fora

tion;

P, p

rosp

ectiv

e; P

A, p

rimar

y an

asto

mos

is;

PD, p

erito

neal

dra

inag

e; P

N, p

aren

tera

l nut

ritio

n; R

, ret

rosp

ectiv

e; R

eNEC

, rec

urre

nce

of N

EC; S

BS, s

hort

bow

el s

yndr

ome;

U, u

nice

ntre

.

Tabl

e 1

Cont

inue

d



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definitions of the studies we included. All these factors therefore result in a low certainty of results.

There are areas of potential bias in this systematic review, including publication bias, language bias, outcome reporting bias, misclassification bias and selection bias.

Since only published studies were included, a publication bias in this review is very likely.

Another potential bias could result from the fact that no studies published before 1990 were included. Within the included period of time, metaregression did not show an influence of the study year on the heterogeneity of results.

Owing to the fact that only studies in English were included, there is a potential language bias. However, an investigation by

Jüni et al proposed that the exclusion of studies not published in English might only exert a minor effect on pooled results.70

There is potential for outcome reporting bias in this system-atic review, as we were not able to include data if the studies did not separately document the number of sequelae that occurred in their surgically and medically treated patients. Our meta-analysis did not include studies where the number of surgical NEC survivors was lower than 10 resulting in possible outcome reporting bias.

The fact that many authors did not provide definitions or used inconsistent nomenclatures for their outcomes may have led to a misclassification bias.

Finally, because the type of surgical treatment performed in each study was at the discretion of the treating physician, there may have been selection bias.

strengths and weaknesses in relation to other studiesOur finding of less strictures after PA as compared with enteros-tomy is an argument against the concept that direct anastomosis should be avoided during an inflammatory process like NEC. However, one cannot argue that PA is basically the safer tech-nique because intraoperative decisions were at the discretion of the attending surgeons.

The finding that strictures occurred less often in enterostomy patients who had undergone resection prior to stoma forma-tion as compared with those who had not undergone intestinal resection might be due to ongoing inflammation and scarring of affected intestine not being removed. However, reports on the stricture rate after enterostomy without resection vary between stenosis rates of 90%45 49 and 9%.28 In the study of Thyoka et al the proportion of patients who died before outcome assessment might have flawed results.28

A major concern of this study is the large heterogeneity of the reported prevalence.

There was almost no correlation between the heterogeneity observed and the possible reasons for the heterogeneity accounted for in our metaregression analysis. Disease severity and the intes-tinal extent of disease may have majorly influenced the reported outcome variables. Accordingly, Fasoli et al described an elevated stricture rate in association with pan NEC.31 Heterogeneity of disease prevalence might have been influenced by inconsistent disease definitions. Concerning IF, SBS and prolonged PN, the differences between terms were often not sufficiently clear. A large number of publications defined SBS as the ‘dependence on PN for more than 90 days’ without indicating small bowel length. The Canadian Association of Paediatric Surgeons defines IF as the need for PN for more than 42 days after surgery or having a residual small bowel length that is <25%.59

Implications for clinical practice, unanswered questions and future researchOur results reveal for the first time, that intestinal sequelae of surgical NEC are frequent and heterogeneous, and therefore deserve more attention. Preterm infants are generally followed for neurodevelopmental assessment. The standardisation of surgical procedures, indications and nomenclatures, the estab-lishment of disease registries with a long-term follow-up as well as well-conducted prospective treatment studies are necessary in order to better characterise or reduce the long-term GI sequelae of NEC.

COnClusIOnsWe conclude that GI sequelae in neonates surviving surgery for NEC are frequent; however, in studies the prevalence differs

Table 2 Characteristics of included studies

Total number of studies n=58 (100%)

Publication year

1990–1999 21 (36)

2000–2009 13 (22)

≥2010 24 (41)

Study location

Europe 33 (57)

USA and/or Canada 18 (31)

Other 7 (12)

Study design

Retrospective 52 (90)

Prospective 6 (10)

Trial type

Unicentre 46 (79)

Multicentre 12 (21)

Surgical NEC, n

<50 31 (53)

51–100 14 (24)

>100 13 (22)

Median 44

Range 7–706

Age at diagnosis

Only preterm (<37 weeks/VLBW/ELBW) 7 (12)

Only term-born 1 (2)

All age groups 50 (86)

Type of surgical treatment*

Peritoneal drainage 16 (16)

Enterostomy 40 (39)

Primary anastomosis 23 (23)

Other 23 (23)

Assessed complications

Recurrent NEC 10 (8)

SBS 20 (17)

Stricture 34 (29)

Adhesion ileus 16 (13)

Stomal complications 18 (15)

Anastomotic complications 8 (7)

Hepatobiliary complications 5 (4)

PN-associated complications 8 (6)

All data are listed as n (%).*Many studies performed more than one type of surgical treatment or assessed several complications and are thus listed more than once.ELBW, extreme low birth weight; n, total number; NEC, necrotising enterocolitis; PN, parenteral nutrition; SBS, short bowel syndrome; VLBW, very low birth weight.



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Figure 1 Overview of the described gastrointestinal (GI) complications following the surgical treatment of necrotising enterocolitis (NEC). The references are detailed in the online supplementary appendix O.

Table 3 Weighted mean prevalence of stricture, recurrence of NEC, SBS and adhesion ileus

Assessed complicationsstudiesn

survivorsn

Eventsn

range(%)

Weighted mean prevalence(%) 95% CI

heterogeneity (I2)(%) Forest plot

Stricture* 27 1660 339 0–90 24 17 to 31 85 Online supplementary appendix I

Stricture after E† 14 612 195 0–51 30 23 to 37 71 Online supplementary appendix J

Stricture after PA† 8 209 36 0–44 8 0 to 23 85 Online supplementary appendix K

Recurrence of NEC 7 366 37 0–23 8 3 to 15 68 Online supplementary appendix E

Recurrence of NEC after E† 3 53 7 5–40 – – – –

Recurrence of NEC after PA† 5 138 12 0–26 6 0 to 18 71 Online supplementary appendix F

IF 23 1362 241 0–52 13 7 to 19 90 Online supplementary appendix G

IF after E† 7 211 29 0–40 11 3 to 22 74 Online supplementary appendix H

IF after PA† 3 107 6 0–8 – – – –

Adhesion ileus 14 727 51 0–26 6 4 to 9 38 Online supplementary appendix K

Adhesion ileus after E† 7 227 15 0–18 5 2 to 9 8 Online supplementary appendix M

Adhesion ileus after PA† 4 126 7 0–11 – – –

*Only in studies which reported more than 10 patients per surgical method.†Only includes the studies which reported these data for their surgical NEC survivors.E, enterostomy; IF, intestinal failure; n, total number; NEC, necrotising enterocolitis; PA, primary anastomosis; SBS, short bowel syndrome.



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considerably. Due to serious limitations of the studies included in this systematic review, conclusions may only be drawn with caution. Despite the growing awareness of the consequences of NEC, there are still insufficient data available on the long-term implications of the disease.

Acknowledgements We thank Christian von Grafenstein for his editorial support.

Contributors EMH and SCM conceptualised and designed the study, drafted the initial manuscript, performed and interpreted the statistical analysis, were part of the writing committee, and critically reviewed and revised the manuscript. SB, MG and MK partially performed and interpreted the statistical analysis, were part of the writing committee and critically reviewed the manuscript. UK conceptualised and designed the study, drafted the initial manuscript, together with EMH and SCM, interpreted the data, was part of the writing committee, and critically reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests None declared.

Patient consent Not required.

Provenance and peer review Not commissioned; externally peer reviewed.

Data sharing statement No additional data available.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

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Figure 2 Strictures after surgical intervention for necrotising enterocolitis: forest plot showing the heterogeneity and weighted mean prevalence in the included publications. A, anastomosis (primary); E, enterostomy; E+R, enterostomy after intestinal resection; E−R, enterostomy without intestinal resection; PD, peritoneal drainage.



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secuelas gastrointestinales después de cirugía por ... · que después de la anastomosis primaria...

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