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Intervenciones para el embarazo ectpico tubrico

Hajenius PJ, Mol F, Mol BWJ, Bossuyt PMM, Ankum WM, van der Veen F
Reproduccin de una revisin Cochrane, traducida y publicada en La Biblioteca Cochrane Plus, 2008, Nmero 2

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NDICE DE MATERIAS RESUMEN...................................................................................................................................................................1 RESUMEN EN TRMINOS SENCILLOS....................................................................................................................2 ANTECEDENTES........................................................................................................................................................2 OBJETIVOS.................................................................................................................................................................4 CRITERIOS PARA LA VALORACIN DE LOS ESTUDIOS DE ESTA REVISIN......................................................4 ESTRATEGIA DE BSQUEDA PARA LA IDENTIFICACIN DE LOS ESTUDIOS....................................................4 MTODOS DE LA REVISIN.....................................................................................................................................5 DESCRIPCIN DE LOS ESTUDIOS..........................................................................................................................6 CALIDAD METODOLGICA.......................................................................................................................................8 RESULTADOS.............................................................................................................................................................9 DISCUSIN...............................................................................................................................................................15 CONCLUSIONES DE LOS AUTORES......................................................................................................................17 AGRADECIMIENTOS................................................................................................................................................17 POTENCIAL CONFLICTO DE INTERS...................................................................................................................17 FUENTES DE FINANCIACIN..................................................................................................................................17 REFERENCIAS.........................................................................................................................................................18 TABLAS......................................................................................................................................................................22 Characteristics of included studies.....................................................................................................................22 Characteristics of excluded studies....................................................................................................................62 Characteristics of ongoing studies......................................................................................................................64 Table 01 Quality of the included studies.............................................................................................................66 CARTULA................................................................................................................................................................69 COMENTARIOS Y CRITICAS....................................................................................................................................70 RESUMEN DEL METANLISIS.................................................................................................................................71 GRFICOS Y OTRAS TABLAS..................................................................................................................................76 01 salpingostoma laparoscpica versus salpingostoma por ciruga abierta.....................................................76 01 xito del tratamiento primario.................................................................................................................76 02 trofoblasto persistente............................................................................................................................76 03 permeabilidad tubrica...........................................................................................................................77 04 embarazo intrauterino posterior..............................................................................................................77 05 embarazo ectpico repetido...................................................................................................................77 02 minilaparotoma versus laparotoma..............................................................................................................78 01 xito del tratamiento primario.................................................................................................................78 03 salpingostoma sin sutura tubrica versus salpingostoma con sutura tubrica............................................78 01 xito del tratamiento primario.................................................................................................................78 02 trofoblasto persistente............................................................................................................................78 03 tasa de permeabilidad tubrica..............................................................................................................79 04 embarazo intrauterino posterior..............................................................................................................79 05 embarazo ectpico repetido...................................................................................................................79
Intervenciones para el embarazo ectpico tubrico

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NDICE DE MATERIAS

04 salpingostoma sola versus en combinacin con un tratamiento mdico......................................................80 01 xito del tratamiento primario.................................................................................................................80 02 trofoblasto persistente............................................................................................................................80 03 preservacin tubrica.............................................................................................................................81 04 permeabilidad tubrica...........................................................................................................................81 05 MTX sistmico versus salpingostoma laparoscpica...................................................................................82 01 xito del tratamiento primario.................................................................................................................82 02 trofoblasto persistente............................................................................................................................82 03 preservacin tubrica.............................................................................................................................83 04 permeabilidad tubrica...........................................................................................................................83 05 embarazo intrauterino posterior..............................................................................................................84 06 embarazo ectpico repetido...................................................................................................................84 06 MTX local versus salpingostoma laparoscpica...........................................................................................85 01 xito del tratamiento primario.................................................................................................................85 02 trofoblasto persistente............................................................................................................................85 03 preservacin tubrica.............................................................................................................................86 04 permeabilidad tubrica...........................................................................................................................86 05 embarazo intrauterino posterior..............................................................................................................86 06 embarazo ectpico repetido...................................................................................................................87 07 MTX por va transvaginal mediante gua ecogrfica versus MTX mediante gua laparoscpica...................87 01 xito del tratamiento primario.................................................................................................................87 02 trofoblasto persistente............................................................................................................................87 08 MTX por va transvaginal mediante gua ecogrfica versus MTX sistmico de dosis nica intramuscular....88 01 xito del tratamiento primario.................................................................................................................88 02 trofoblasto persistente............................................................................................................................88 03 preservacin tubrica.............................................................................................................................88 04 embarazo intrauterino posterior..............................................................................................................89 05 embarazo ectpico repetido...................................................................................................................89 09 MTX mediante gua laparoscpica versus el mismo rgimen en combinacin con MTX sistmico intramuscular......................................................................................................................................................89 01 xito del tratamiento primario.................................................................................................................89 10 MTX de dosis nica versus MTX de dosis mltiple fija ambos por va intramuscular....................................90 01 xito del tratamiento primario.................................................................................................................90 02 trofoblasto persistente............................................................................................................................90 11 MTX 25 mg/m2 versus MTX 50 mg/m2 estndar ambos de dosis nica intramuscular................................90 01 xito del tratamiento primario.................................................................................................................90 02 trofoblasto persistente............................................................................................................................91 03 xito del tratamiento con dosis de MTX variable....................................................................................91 04 preservacin tubrica.............................................................................................................................91 05 permeabilidad tubrica...........................................................................................................................92 06 embarazo intrauterino posterior..............................................................................................................92 07 embarazo ectpico repetido...................................................................................................................92 12 MTX en lipiodol en suspensin versus MTX en solucin fisiolgica ambos mediante gua laparoscpica....93 01 xito del tratamiento primario.................................................................................................................93 02 trofoblasto persistente............................................................................................................................93 ii
Intervenciones para el embarazo ectpico tubrico

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NDICE DE MATERIAS

03 preservacin tubrica.............................................................................................................................93 04 permeabilidad tubrica...........................................................................................................................94 05 embarazo intrauterino posterior..............................................................................................................94 13 MTX versus prostaglandinas ambos mediante gua ecogrfica combinados con la administracin sistmica del frmaco.........................................................................................................................................................94 01 xito del tratamiento primario.................................................................................................................94 02 permeabilidad tubrica...........................................................................................................................95 14 MTX sistmico solo de dosis nica intramuscular versus en combinacin con mifepristona por va oral.....95 01 xito del tratamiento primario.................................................................................................................95 02 trofoblasto persistente............................................................................................................................95 03 preservacin tubrica.............................................................................................................................96 04 permeabilidad tubrica...........................................................................................................................96 15 MTX sistmico solo de dosis nica intramuscular versus en combinacin con EE2.....................................96 01 xito del tratamiento primario.................................................................................................................96 02 embarazo intrauterino posterior..............................................................................................................97 03 embarazo ectpico repetido...................................................................................................................97 16 glucosa hiperosmolar mediante gua laparoscpica versus otros tratamientos............................................98 01 xito del tratamiento primario.................................................................................................................98 02 trofoblasto persistente............................................................................................................................98 03 permeabilidad tubrica...........................................................................................................................99 04 embarazo intrauterino posterior..............................................................................................................99 05 embarazo ectpico repetido...................................................................................................................99 17 manejo expectante versus tratamiento mdico............................................................................................100 01 xito del tratamiento primario...............................................................................................................100 02 preservacin tubrica...........................................................................................................................100

Intervenciones para el embarazo ectpico tubrico

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Intervenciones para el embarazo ectpico tubrico


Hajenius PJ, Mol F, Mol BWJ, Bossuyt PMM, Ankum WM, van der Veen F
Esta revisin debera citarse como: Hajenius PJ, Mol F, Mol BWJ, Bossuyt PMM, Ankum WM, van der Veen F. Intervenciones para el embarazo ectpico tubrico (Revisin Cochrane traducida). En: La Biblioteca Cochrane Plus, 2008 Nmero 2. Oxford: Update Software Ltd. Disponible en: http://www.update-software.com. (Traducida de The Cochrane Library, 2008 Issue 2. Chichester, UK: John Wiley & Sons, Ltd.). Fecha de la modificacin ms reciente: 15 de noviembre de 2006 Fecha de la modificacin significativa ms reciente: 16 de noviembre de 2006

RESUMEN Antecedentes Las opciones de tratamiento para el embarazo ectpico tubrico son; (1) ciruga, p.ej. salpinguectoma o salpingostoma, realizada mediante laparoscopia o ciruga abierta; (2) tratamiento mdico con varios frmacos que se pueden administrar de forma sistmica y/o local mediante diversas vas y (3) manejo expectante. Objetivos Evaluar la efectividad y la seguridad de la ciruga, el tratamiento mdico y el manejo expectante del embarazo ectpico tubrico en cuanto al xito del tratamiento primario, la preservacin tubrica y la fertilidad futura. Estrategia de bsqueda Se realizaron bsquedas en el Registro Especializado de Ensayos Controlados del Grupo Cochrane de Trastornos Menstruales y Subfertilidad (The Cochrane Menstrual Disorders and Subfertility Group's Specialised Register), en el Registro Cochrane de Ensayos Controlados (The Cochrane Controlled Trials Register, CENTRAL) (hasta febrero de 2006), en Current Controlled Trials Register (hasta octubre de 2006) y en MEDLINE (hasta octubre de 2006). Criterios de seleccin Ensayos controlados aleatorios (ECA) que compararon los tratamientos en mujeres con embarazo ectpico tubrico. Recopilacin y anlisis de datos La extraccin de los datos y la evaluacin de la calidad fue realizada de forma independiente por dos revisores. Las diferencias se resolvieron mediante discusin con todos los revisores. Resultados principales Se analizaron 35 estudios sobre el tratamiento del embarazo ectpico tubrico, que describieron 25 comparaciones diferentes. Ciruga La salpingostoma laparoscpica es significativamente menos exitosa que la ciruga abierta en cuanto a la eliminacin del embarazo ectpico tubrico (2 ECAs, n = 165; OR 0,28; IC del 95%: 0,09 a 0,86) debido a la tasa de trofoblasto persistente significativamente ms alta en la ciruga laparoscpica (OR 3,5; IC del 95%: 1,1 a 11). Sin embargo, el enfoque laparoscpico es significativamente menos costoso que la ciruga abierta (p = 0,03). El seguimiento a largo plazo (n = 127) no muestra diferencias en la tasa de embarazo intrauterino (OR 1,2; IC del 95%: 0,59 a 2,5) pero existe una tendencia no significativa a una tasa de embarazo ectpico repetido ms baja (OR 0,47; 95%: 0,15 a 1,5). La salpingostoma sola es significativamente menos exitosa que cuando se combina con una nica inyeccin profilctica de metotrexato (2 ECAs, n = 163; OR 0,25; IC del 95%: 0,08 a 0,76) para prevenir el trofoblasto persistente. Tratamiento mdico El metotrexato sistmico en un rgimen de dosis mltiple fija por va intramuscular presenta una tendencia no significativa a un xito mayor del tratamiento que la salpingostoma laparoscpica (un ECA, n = 100; OR 1,8; IC del 95%: 0,73 a 4,6). El seguimiento a largo plazo no encontr diferencias significativas (n = 74): embarazo intrauterino (OR 0,82; IC del 95%: 0,32 a 2,1) y embarazo ectpico repetido (OR 0,87; IC del 95%: 0,19 a 4,1).
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Una dosis nica intramuscular de metotrexato es significativamente menos exitosa que la salpingostoma laparoscpica (4 ECAs, n = 265; OR 0,38; IC del 95%: 0,20 a 0,71). El xito aumenta con un rgimen de tratamiento con dosis variable, pero no muestra diferencias en comparacin con la salpingostoma laparoscpica (OR 1,1; IC del 95%: 0,52 a 2,3). El seguimiento a largo plazo (n = 98) no muestra diferencias significativas (embarazo intrauterino OR 1,0; IC del 95%: 0,43 a 2,4; embarazo ectpico OR 0,54; IC del 95%: 0,12 a 2,4). La eficacia del metotrexato sistmico solo de dosis nica es significativamente menor que cuando se combina con mifepristona (2 ECA, n = 262; OR 0,59; IC del 95%: 0,35 a 1,0). Lo mismo sucede cuando se agrega la medicina tradicional china (un ECA, n = 78, OR 0,08; IC del 95%: 0,02 a 0,39). En la eliminacin del embarazo ectpico tubrico el tratamiento mdico local administrado de forma transvaginal mediante gua ecogrfica es significativamente mejor que una inyeccin intratubrica "a ciegas" mediante gua laparoscpica (un ECA, n = 36; metotrexato OR 5,8; IC del 95%: 1,3 a 26; un ECA, n = 80, glucosa hiperosmolar OR 0,38; IC del 95%: 0,15 a 0,93). Sin embargo, comparada con la salpingostoma laparoscpica, la inyeccin local de metotrexato administrada de forma transvaginal mediante gua ecogrfica es significativamente menos exitosa (un ECA, n = 78; OR 0,17; IC del 95%: 0,04 a 0,76) pero con un seguimiento a largo plazo positivo (n = 51): una tasa de embarazo intrauterino significativamente ms alta (OR 4,1; IC del 95%: 1,3 a 14) y una tendencia no significativa a una tasa de embarazo ectpico repetido ms baja (OR 0,30; IC del 95%: 0,05 a 1,7). Manejo expectante El manejo expectante es significativamente menos exitoso que el tratamiento con prostaglandina (un ECA, n = 23; OR 0,08; IC del 95%: 0,02 a 0,39). Conclusiones de los autores En el tratamiento quirrgico del embarazo ectpico tubrico la ciruga laparoscpica es un tratamiento coste-efectiva. Una opcin alternativa de tratamiento no quirrgico en pacientes seleccionadas es el tratamiento mdico con metotrexato sistmico. An no ha sido posible evaluar de forma adecuada el manejo expectante.

RESUMEN EN TRMINOS SENCILLOS Aproximadamente 1% de los vulos fecundados se implanta fuera de la cavidad uterina y se convierte en un embarazo extrauterino, conocido como embarazo ectpico. Los embarazos ectpicos pueden ocurrir en cualquier sitio a lo largo del sistema reproductivo, aunque el sitio ms frecuente es la trompa de Falopio. Un embarazo ectpico en la trompa de Falopio, si no se trata, puede provocar rotura tubrica o hemorragia intraabdominal. Las opciones de tratamiento para el embarazo ectpico tubrico son la ciruga, el tratamiento mdico y el manejo expectante. Esta revisin encontr que la ciruga laparoscpica es factible y menos costosa que la ciruga abierta en el tratamiento del embarazo ectpico tubrico. En pacientes seleccionadas se pueden utilizar las opciones de tratamiento no quirrgicas. El tratamiento mdico con metotrexato sistmico es una opcin para las mujeres con embarazo ectpico tubrico sin signos de hemorragia, cuyos niveles en sangre de la hormona del embarazo son relativamente bajos. An no es posible realizar una evaluacin adecuada del manejo expectante del embarazo ectpico tubrico.

ANTECEDENTES El diagnstico de un embarazo ectpico se puede realizar mediante mtodos no invasivos, es decir mediante pruebas sensibles al embarazo (en orina y suero) y mediante una ecografa transvaginal de alta resolucin, que se ha integrado a los algoritmos de diagnstico confiables (Ankum 1993; Mol 1998b). Estos algoritmos, conjuntamente con una mayor conciencia y conocimiento de los factores de riesgo entre profesionales de la atencin sanitaria y pacientes, han hecho posible que se haga un diagnstico temprano y preciso del embarazo ectpico. Los modelos probabilsticos que incluyen una prueba previa de probabilidad de la paciente, determinada por los antecedentes clnicos, as como los hallazgos fsicos, ecogrficos y de laboratorio (niveles sricos de gonadotropina corinica humana [hCG] y de progesterona) mejoraron el tratamiento del embarazo ectpico, particularmente en las mujeres que presentan un embarazo de ubicacin desconocida (Ankum 1995; Mol 1999b; Banerjee 2001; Condous 2004; Condous 2005)). Por lo tanto, el cuadro clnico del embarazo ectpico pas de ser una enfermedad fatal que requiere una ciruga de urgencia a una afeccin ms benigna en pacientes incluso asintomticas en algunas ocasiones. Esto, por otra parte,

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Intervenciones para el embarazo ectpico tubrico

ha dado como resultado cambios importantes en las opciones disponibles para el manejo teraputico. Actualmente es posible realizar intervenciones teraputicas para el embarazo ectpico tubrico antes de que la enfermedad empeore y se pierda la integridad tubrica, lo que permite mejorar el resultado clnico y reducir los costes asociados con una ciruga de urgencia. Adems, los avances en la ciruga laparoscpica permiten un enfoque laparoscpico en la mayora de las pacientes con embarazo ectpico tubrico (Sultana 1992)). La salpingostoma se convirti en una opcin para las pacientes que desean una fertilidad futura. En comparacin con la salpinguectoma, la salpingostoma tiene como objetivo preservar la integridad tubrica para mantener la capacidad reproductiva. Un riesgo muy conocido de la salpingostoma es la extraccin incompleta del tejido trofoblstico, lo que aumenta o estabiliza las concentraciones sricas de hCG despus de la ciruga (trofoblasto persistente), que puede provocar una recurrencia de los sntomas clnicos (Seifer 1990). Para detectar el trofoblasto persistente es obligatoria la monitorizacin posoperatoria de la hCG srica (Hajenius 1995a; Spandorfer 1997)). Las estrategias no quirrgicas, es decir el tratamiento mdico y el manejo expectante, se han convertido en un tema especfico de investigacin, ya que se prescinde de la laparoscopia para el diagnstico del embarazo ectpico tubrico. Es de suma importancia seleccionar el subgrupo de embarazos ectpicos tubricos susceptibles a estas estrategias, sin poner en riesgo a la paciente (Tulandi 1991b; Hochner 1992; Maymon 1996)). La administracin sistmica y local de los frmacos se realiz en pacientes seleccionadas, con un embarazo ectpico tubrico no roto sin hemorragia activa. Los criterios de seleccin utilizados fueron: tamao del embarazo ectpico tubrico, concentraciones sricas mximas de hCG y actividad cardaca fetal. El frmaco utilizado con ms frecuencia en la prctica clnica es el metotrexato. El metotrexato es un antagonista del cido flico que inhibe de novo la sntesis de las purinas y pirimidinas, lo que interfiere con la sntesis de ADN y la proliferacin celular. Secundario a su efecto sobre los tejidos altamente proliferativos, el metotrexato es potencialmente txico cuando se administra en dosis altas. Los efectos secundarios incluyen estomatitis, conjuntivitis, gastroenteritis, deterioro de la funcin heptica, depresin de la mdula sea y fotosensibilidad. Cuando el metotrexato se administra de forma sistmica puede ser mediante un rgimen de dosis mltiple fija por va intramuscular o un rgimen de dosis variable intramuscular. El rgimen de dosis mltiple fija proviene del tratamiento de la enfermedad trofoblstica gestacional descrita por Bagshawe 1989 y Goldstein 1976. Este rgimen se combina con cido folnico (factor citrovorum / leucovorina de rescate) para reducir la toxicidad de la quimioterapia. El rgimen de Bagshawe comprende un total de cuatro inyecciones intramusculares de 50 mg de metotrexato alternadas con inyecciones intramusculares de 6 mg de cido folnico 30 horas despus de

cada inyeccin de metotrexato con un perodo de descanso de seis das. El protocolo teraputico de Goldstein comprende un total de cuatro inyecciones intramusculares de metotrexato 1 mg/kg alternadas con inyecciones intramusculares de cido folnico 0,1 mg/kg 24 horas despus de cada inyeccin de metotrexato. Este rgimen se utiliz por primera vez para tratar a una paciente con un embarazo intersticial (Tanaka 1982). El primer informe de su uso para un embarazo ectpico tubrico fue en una paciente con sndrome de hiperestimulacin ovrica grave, por lo que la ciruga estaba contraindicada (Chotiner 1985). La primera serie de casos de seis pacientes fue descrita por Ory 1986. En 1989, Stovall individualiz la dosis del metotrexato para mejorar el cumplimiento de la paciente, disminuir los efectos secundarios y reducir los costes generales, lo que dio lugar a un rgimen de dosis nica de 50 mg/m2 del rea de superficie corporal, administrada de forma intramuscular sin cido folnico (Stovall 1991; Stovall 1993)). Otros esfuerzos para alcanzar la mxima eficacia y disminuir o eliminar los efectos adversos dieron lugar a diversos protocolos para el tratamiento mdico local administrado dentro del saco gestacional de forma transvaginal mediante gua ecogrfica o laparoscpica. Los frmacos que se han utilizado para el tratamiento local son el metotrexato (Pansky 1989; Fernandez 1993), prostaglandinas (Lindblom 1987; Egarter 1988), y la glucosa hiperosmolar (Lang 1989)). Para evaluar la respuesta al tratamiento despus del tratamiento mdico es obligatoria la monitorizacin minuciosa de la hCG srica para detectar un fracaso inminente del tratamiento y una disminucin inadecuada de las concentraciones sricas de hCG. Las curvas de depuracin de la hCG srica despus del tratamiento con metotrexato sistmico estn disponibles (Hajenius 1997; Saraj 1998; Natale 2004)). En 1955, Lund fue el primero en practicar el manejo expectante en pacientes con probabilidades de presentar un embarazo ectpico sin complicaciones al momento de su ingreso (Lund 1955). La recomendacin del manejo expectante se bas en el conocimiento de que el curso natural de muchos embarazos ectpicos tempranos es un proceso autolimitado, que al final resulta en un aborto o reabsorcin tubrica (Mashiach 1982). Desde el trabajo de estos pioneros, slo se publicaron pocos estudios que describieron el manejo expectante en pacientes seleccionadas con embarazos ectpicos pequeos sin actividad cardaca fetal, un lmite mximo para la concentracin de hCG srica que continu descendiendo y/o una concentracin baja de progesterona srica (Korhonen 1994; Hajenius 1995b; Elson 2004). La monitorizacin minuciosa de la hCG srica es obligatoria para detectar concentraciones sricas de hCG que no disminuyen de forma adecuada. An no se han definido de forma clara cules son los criterios para la intervencin teraputica. Un estudio describi la dinmica de la hCG srica durante la finalizacin espontnea del embarazo ectpico (Korhonen 1994)).

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En resumen, los mdicos ahora disponen de muchas opciones para el tratamiento del embarazo ectpico tubrico: ciruga, p.ej. salpinguectoma o salpingostoma, realizada por laparoscopia o por ciruga abierta tratamiento mdico con una variedad de frmacos que se pueden administrar de forma sistmica y/o local por diversas vas (por va transvaginal mediante gua ecogrfica o laparoscpica) manejo expectante. OBJETIVOS Evaluar la efectividad y la seguridad de la ciruga, el tratamiento mdico y el manejo expectante del embarazo ectpico tubrico en cuanto al xito del tratamiento primario, la preservacin tubrica y la fertilidad futura. CRITERIOS PARA LA VALORACIN DE LOS ESTUDIOS DE ESTA REVISIN Tipos de estudios Slo se consideraron los ensayos controlados aleatorios que compararon un tratamiento con otro para tratar el embarazo ectpico tubrico y en los que la asignacin a cualquiera de los tratamientos se realiz de forma aleatoria. Se excluyeron los ensayos controlados no aleatorios. Tipos de participantes Mujeres con diagnstico de embarazo ectpico tubrico. Tipos de intervencin Ciruga salpinguectoma por ciruga abierta salpingostoma por ciruga abierta salpinguectoma por laparoscopia salpingostoma por laparoscopia Tratamiento mdico metotrexato glucosa hiperosmolar prostaglandinas cloruro de potasio cloruro de sodio actinomicina D etopsido mifepristona danazol anticuerpos anti hCG Manejo expectante ninguna intervencin teraputica, slo la monitorizacin de la hCG srica Tipos de medidas de resultado La definicin utilizada para el xito del tratamiento y el fracaso en y entre los estudios no es uniforme debido a la

heterogeneidad de los tratamientos. Por lo tanto, las medidas de resultado definidas y analizadas en esta revisin son: Medida de resultado primaria xito del tratamiento primario definido como una disminucin sin eventos de la hCG srica hasta niveles indetectables mediante el tratamiento inicial. Por lo tanto, los fracasos del tratamiento se consideraron como reintervenciones (quirrgicas o mdicas) para los sntomas clnicos o el descenso inadecuado de los niveles de hCG, es decir trofoblasto persistente. Medidas de resultado secundarias trofoblasto persistente, definido como un aumento o estabilizacin de las concentraciones sricas de hCG despus de la ciruga o del tratamiento mdico o del manejo expectante y para el que se necesit tratamiento adicional (quirrgico o mdico) preservacin tubrica complicaciones/efectos secundarios calidad de vida relacionada con la salud de las pacientes costes econmicos permeabilidad tubrica, definida como el paso del contraste durante una histerosalpingografa o mediante un segundo examen laparoscpico (second look) a travs de la trompa homolateral y, cuando corresponda, con la inclusin en el denominador de las pacientes que no fueron elegibles para la histerosalpingografa o un segundo examen laparoscpico debido a que ya se les haba practicado una salpinguectoma fertilidad futura, definida como la aparicin de un embarazo espontneo posterior y resultado del embarazo (embarazo intrauterino, embarazo ectpico repetido) en las pacientes que desean un embarazo futuro. ESTRATEGIA DE BSQUEDA PARA LA IDENTIFICACIN DE LOS ESTUDIOS Ver los mtodos del Grupo de Trastornos Menstruales y Subfertilidad utilizados en las revisiones. Esta revisin se realiz en base a la estrategia de bsqueda desarrollada por el Grupo Cochrane de Trastornos Menstruales y Subfertilidad. Se identificaron ensayos relevantes en el Registro Especializado de Ensayos Controlados del Grupo Cochrane de Trastornos Menstruales y Subfertilidad (Cochrane Menstrual Disorders and Subfertility Group) (bsqueda hasta febrero 2006). Tambin se adoptaron las siguientes estrategias mediante la plataforma OVID: MEDLINE (1966 hasta febrero 2006) 1 exp pregnancy, ectopic/ or exp pregnancy, tubal/ (8625) 2 ectopic pregnanc$.mp. (4960) 3 tubal pregnanc$.mp. (1325)

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Intervenciones para el embarazo ectpico tubrico

4 (pregnanc$ adj3 Fallopian$).mp. [mp=title, original title, abstract, name of substance word, subject heading word] (66) 5 (pregnanc$ adj3 tube$).mp. (426) 6 or/1-5 (10124) 7 randomized controlled trial.pt. (211387) 8 controlled clinical trial.pt. (70364) 9 Randomized controlled trials/ (40810) 10 random allocation/ (54389) 11 double-blind method/ (84734) 12 single-blind method/ (9609) 13 or/7-12 (359456) 14 clinical trial.pt. (421236) 15 exp clinical trials/ (173449) 16 (clin$ adj25 trial$).ti,ab,sh. (112179) 17 ((singl$ or doubl$ or tripl$ or trebl$) adj25 (blind$ or mask$)).ti,ab,sh. (83350) 18 placebos/ (24399) 19 placebo$.ti,ab,sh. (104874) 20 random$.ti,ab,sh. (437373) 21 Research design/ (42676) 22 or/14-21 (781830) 23 animal/ not (human/ and animal/) (2928551) 24 13 or 22 (786120) 25 24 not 23 (721337) 26 6 and 25 (417) 27 26 not review.ti. (403) 28 27 not review.ab. (378) 29 28 not retrospect$.mp. [mp=title, original title, abstract, name of substance word, subject heading word] (353) 30 from 29 keep 1-200 (200) 31 from 29 keep 201-353 (153) 32 from 30 keep 1-200 (200) EMBASE 1980 hasta febrero 2006 1 exp ectopic pregnancy/ or exp uterine tube pregnancy/ (6303) 2 ectopic pregnanc$.ab. (3588) 3 tubal pregnanc$.ab. (799) 4 (pregnanc$ adj4 tub$).ab. (2131) 5 or/1-4 (7847) 6 Controlled study/ or randomized controlled trial/ (2112948) 7 double blind procedure/ (58676) 8 single blind procedure/ (5735) 9 crossover procedure/ (17115) 10 drug comparison/ (81248) 11 placebo/ (84044) 12 random$.ti,ab,hw,tn,mf. (324740) 13 latin square.ti,ab,hw,tn,mf. (997) 14 crossover.ti,ab,hw,tn,mf. (30078) 15 cross-over.ti,ab,hw,tn,mf. (10615) 16 placebo$.ti,ab,hw,tn,mf. (130286) 17 ((doubl$ or singl$ or tripl$ or trebl$) adj5 (blind$ or mask$)).ti,ab,hw,tn,mf. (98755) 18 (comparative adj5 trial$).ti,ab,hw,tn,mf. (5252) 19 (clinical adj5 trial$).ti,ab,hw,tn,mf. (424186) 20 or/6-19 (2549444)

21 nonhuman/ (2672524) 22 animal/ not (human/ and animal/) (12800) 23 or/21-22 (2676117) 24 20 not 23 (1488861) 25 5 and 24 (1353) 26 25 and trial.mp. (457) 27 26 not review$.ti,ab. (386) 28 27 not retrospect$.tw. (369) 29 from 28 keep 1-200 (200) 30 from 28 keep 201-369 (169) 31 from 29 keep 1-200 (200) CINAHL - Cumulative Index to Nursing , Allied Health Literature <1982 hasta abril. semana 2, 2006> 1 ectopic pregnancy.mp. or exp Pregnancy, Ectopic/ (464) 2 tubal pregnanc$.ti,ab. (17) 3 (pregnanc$ adj3 tube$).ti,ab. (34) 4 (pregnanc$ adj3 Fallopian).ti,ab. (1) 5 or/1-4 (498) 6 Controlled study/ or randomized controlled trial/ (27455) 7 (drug$ adj5 compar$).ti,ab,hw,tn,mf. (1948) 8 placebo/ (3068) 9 random$.ti,ab,hw,tn,mf. (48102) 10 latin square.ti,ab,hw,tn,mf. (78) 11 crossover.ti,ab,hw,tn,mf. (3322) 12 cross-over.ti,ab,hw,tn,mf. (12095) 13 placebo$.ti,ab,hw,tn,mf. (8488) 14 ((doubl$ or singl$ or tripl$ or trebl$) adj5 (blind$ or mask$)).ti,ab,hw,tn,mf. (10562) 15 (comparative adj5 trial$).ti,ab,hw,tn,mf. (2078) 16 (clinical adj5 trial$).ti,ab,hw,tn,mf. (32500) 17 or/6-16 (80740) 18 animal/ not (human/ and animal/) (608) 19 17 not 18 (80704) 20 5 and 19 (18) 21 from 20 keep 1-18 (18) Adems de las bsquedas descritas anteriormente los bibliotecarios clnicos del Department of Obstetrics and Gynaecology, Academic Medical Centre, University of Amsterdam realizaron bsquedas bibliogrficas mensuales en MEDLINE con la estrategia de bsqueda "ectopic pregnancy" y/o "tubal ectopic pregnancy" (desde enero de 1995 hasta julio de 2006). Adems se realiz un esfuerzo para identificar e incluir ensayos no publicados, por ejemplo, mediante bsquedas en Current Controlled Trials Register en internet (www.controlledtrials.com, julio de 2006) y bsquedas en los libros de resmenes de las convenciones anuales de ESHRE y ASRM. MTODOS DE LA REVISIN Dos revisores inspeccionaron todas las citas identificadas mediante las estrategias de bsqueda. Para identificar los estudios elegibles se obtuvieron los resmenes de todas las

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citas. Se obtuvieron los informes completos de todos los estudios elegibles. PH y BM evaluaron de forma independiente si los estudios cumplan los criterios de inclusin para esta revisin. Desde 2004, los autores que realizaron esta evaluacin fueron PH y FM. Los estudios que fueron excluidos se presentan en la seccin de estudios excluidos con las razones de su exclusin. PH y BM evaluaron de forma independiente la calidad de todos los estudios elegibles para esta revisin y la extraccin de los datos hasta 2004, y a partir de esta fecha lo hicieron PH y FM. Las diferencias de opinin se registraron y resolvieron mediante consenso con todos los revisores. Los ensayos incluidos se analizaron en cuanto a los siguientes criterios de calidad y detalles metodolgicos. Esta informacin, cuando estuvo disponible, se present en la tabla de "Estudios incluidos". Cuando fue posible, se solicit informacin a los autores sobre los datos que faltaban. Las diferencias de opinin se registraron y resolvieron mediante consenso con todos los revisores. Caractersticas del ensayo 1. mtodo de asignacin al azar 2. calidad del ocultamiento de la asignacin 3. grado de cegamiento 4. clculo del poder estadstico realizado con anticipacin 5. financiacin 6. aprobacin del comit tico mdico 7. ensayo nico o multicntrico 8. anlisis del tipo intencin de tratar (intention-to-treat analysis) 9. nmero de mujeres asignadas al azar, detalles sobre los abandonos o prdidas durante el seguimiento 10. duracin, momento de realizacin y localizacin del estudio Tipos de Participantes: 1. diagnstico de embarazo ectpico (mediante un hallazgo transvaginal por ecografa de un saco gestacional ectpico con un tero vaco, mediante un principio de zona discriminatoria de hCG srica con un tero vaco, y/o por laparoscopia o laparotoma) 2. concentracin srica de hCG (lmite superior) 3. tamao del embarazo tubrico 4. presencia de actividad cardaca fetal 5. presencia de hemoperitoneo Intervenciones 1. tipo de ciruga 2. frmaco utilizado para el tratamiento mdico 3. dosis y va de administracin del tratamiento mdico 4. manejo expectante Medida de resultado primaria xito del tratamiento mediante el tratamiento inicial Medidas de resultado secundarias 1. trofoblasto persistente 2. preservacin tubrica 3. complicaciones/efectos secundarios 4. calidad de vida relacionada con la salud de las pacientes

5. costes 6. permeabilidad tubrica 7. fertilidad futura (embarazo intrauterino posterior y embarazo ectpico repetido) Los anlisis estadsticos se realizaron segn las guas estadsticas para los revisores del Grupo Cochrane de Trastornos Menstruales y Subfertilidad. Se generaron tablas de dos por dos para cada estudio para las medidas de resultado dicotmicas. Los efectos en cada estudio se expresaron como odds-ratios (OR) con intervalos de confianza del 95%. Cuando se dispuso de datos suficientes, se calcul una estadstica general para cada medida de resultado mediante el mtodo de Peto (modelo de efectos fijos). La heterogeneidad entre los resultados de los diferentes estudios se analiz mediante la inspeccin de la dispersin de los puntos de datos en los grficos y la superposicin de sus intervalos de confianza, y mediante la verificacin de la estadstica I2. Un valor superior a 50% se consider como heterogeneidad significativa. En caso de heterogeneidad estadstica se investig la heterogeneidad clnica de los ensayos originales. Se estableci contacto con los autores principales en un intento de obtener los datos faltantes en el artculo original para realizar los anlisis de las medidas de resultado definidas. DESCRIPCIN DE LOS ESTUDIOS A partir de las citas identificadas mediante la estrategia de bsqueda, se identificaron 69 informes elegibles. Se excluyeron ocho estudios debido a que los tratamientos no se asignaron al azar (ver tabla "Caractersticas de los estudios excluidos": Lund 1955; Koninckx 1991; Murphy 1992; Laatikainen 1993; O'Shea 1994; Porpora 1996; Colacurci 1998; Kaya 2002). Cuatro estudios se publicaron en chino. Estos estudios estn en espera de evaluacin por los revisores, pues todava se tienen que traducir. (Peng 1997; Su 2002; Wei 2003; Hu 2003). Cinco estudios estn en curso (Hajenius 1 y Hajenius 2, Amsterdam, Pases Bajos; Jurkovic, Londres, Reino Unido; Fernandez 1 y Fernandez 2, Francia, Current Controlled Trials Register). Siete estudios publicaron sus resultados en ms de un informe (publicacin doble). estudio primario Lundorff 1991ay publicacin doble de Lundorff 1993a; Lundorff 1993b; Lindblom 1997; Lundorff 1997 estudio primario Fernandez 1990 y publicacin doble Fernandez 1991 estudio primario Fernandez 1995y publicacin doble de Fernandez 1996 estudio primario Rozenberg 2003y publicacin doble de Garbin 2004

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Seis estudios informaron sus datos de seguimiento y/u otras medidas de resultado secundarias en otro informe estudio primario Lundorff 1991a y datos de seguimiento en Lundorff 1991b; Lundorff 1992; Gray 1995 estudio primario Vermesh 1989 y datos de seguimiento en Vermesh 1992 estudio primario Hajenius 1997 y datos de seguimiento en Nieuwkerk 1998a, Mol 1999a, Dias Pereira 1999 estudio primario Sowter 2001a y datos de seguimiento en Sowter 2001b estudio primario Gjelland 1995 y datos de seguimiento en Hordnes 1997 estudio primario Yalcinkaya 1996 y datos de seguimiento en Yalcinkaya 2000 Por lo tanto, en esta revisin se analizaron 35 estudios sobre el tratamiento del embarazo ectpico tubrico que describieron 25 comparaciones diferentes agrupadas en: 1. ciruga 2. tratamiento mdico metotrexato versus ciruga diferente va de administracin del metotrexato diferente dosis/suspensin del metotrexato metotrexato versus/o en combinacin con tratamientos mdicos glucosa hiperosmolar 3. manejo expectante

Los detalles adicionales sobre los estudios incluidos se proporcionan en la tabla "Caractersticas de los estudios incluidos" y en la tabla adicional "Calidad de los estudios". CIRUGA 1. Salpingostoma laparoscpica versus salpingostoma por ciruga abierta (Vermesh 1989; Vermesh 1992; Lundorff 1991a; Lundorff 1991b; Lundorff 1992; Gray 1995)) 2. Minilaparotoma versus laparotoma (Sharma 2003)) 3. Salpingostoma sin sutura tubrica versus salpingostoma con sutura tubrica (Tulandi 1991a; Fujishita 2004)) 4. Salpingostoma sola versus salpingostoma combinada con tratamiento mdico a. con una dosis nica intramuscular de metotrexato (Graczykowski 1997; Elmoghazy 2000)) b. con una inyeccin de vasopresina dentro del mesosalpinge (Ugur 1996)) c. con una inyeccin de oxitocina dentro del mesosalpinge (Fedele 1998)) TRATAMIENTO MDICO

otros 5. Metotrexato sistmico versus salpingostoma laparoscpica a. en un rgimen de dosis mltiple fija por va intramuscular (Hajenius 1997; Nieuwkerk 1998a; Dias Pereira 1999; Mol 1999a)) b. en un rgimen de dosis variable por va intramuscular (Fernandez 1998; Saraj 1998; Sowter 2001a; Sowter 2001b; El-Sherbiny 2003)) 6. Metotrexato local versus salpingostoma laparoscpica a. por va transvaginal mediante gua ecogrfica (Fernandez 1995; Fernandez 1998)) b. mediante gua laparoscpica (Mottla 1992; Zilber 1996)) METOTREXATO POR ADMINISTRACIN DIFERENTES VAS DE

METOTREXATO VERSUS CIRUGA

Un estudio se tradujo del chino al ingls (Wang 1998). Un estudio present dos comparaciones diferentes que se analizaron por separado (Fernandez 1998)). Se estableci contacto con seis autores para obtener los datos que faltaban en el artculo original y realizar los anlisis de las medidas de resultado definidas (Dr Fujishita, Japan, Dr Fernandez, France, Dr Rozenberg, France, Dr Hines, USA , Dr Yalcinkaya, USA and Dr. El Sherbiny, Egypt) los cuales respondieron. Los estudios se realizaron en 19 pases diferentes: Austria (Lang 1990; Egarter 1991), Canada (Tulandi 1991a), China (Wang 1998), Egipto (Elmoghazy 2000; El-Sherbiny 2003), Finlandia (Korhonen 1996), Francia (Fernandez 1991; Fernandez 1994; Fernandez 1995; Fernandez 1998; Rozenberg 2003), Grecia (Tzafettas 1994), India (Sharma 2003), Irn (Alleyassin 2006), Israel (Shulman 1992; Sadan 2001), Italia (Fedele 1998), Japn (Fujishita 1995b; Fujishita 2004), Pases Bajos (Hajenius 1997; Dias Pereira 1999; Nieuwkerk 1998a; Mol 1999a), Nueva Zelanda (Sowter 2001a; Sowter 2001b), Noruega (Gjelland 1995; Hordnes 1997), Suecia (Lundorff 1991a; Lundorff 1991b; Lundorff 1992; Gray 1995; Landstrom 1998), Turqua (Ugur 1996), Reino Unido (Gazvani 1998), Estados Unidos de Amrica (Vermesh 1989; Vermesh 1992; Mottla 1992; Cohen 1996; Graczykowski 1997; Saraj 1998; Yalcinkaya 1996; Yalcinkaya 2000; Klauser 2005)).

7. por va transvaginal mediante gua ecogrfica versus mediante gua laparoscpica (Tzafettas 1994)) 8. por va transvaginal mediante gua ecogrfica versus dosis nica intramuscular (Fernandez 1994; Fernandez 1998; Cohen 1996)) 9. mediante gua laparoscpica versus el mismo rgimen en combinacin con metotrexato sistmico intramuscular (Shulman 1992)) DIFERENTE DOSIS/SUSPENSIN DE METOTREXATO 10. Dosis nica versus dosis mltiple fija ambas por va intramuscular (Klauser 2005; Alleyassin 2006)) 11. metotrexato 25 mg/m2 versus metotrexato estndar 50 mg/m2 ambos en un rgimen de dosis nica intramuscular (Yalcinkaya 1996; Yalcinkaya 2000))

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12. en lipiodol en suspensin versus en solucin fisiolgica ambos mediante gua laparoscpica (Fujishita 1995b)) METOTREXATO VERSUS/O EN COMBINACIN CON OTROS TRATAMIENTOS MDICOS 13. Metotrexato versus prostaglandinas ambos de forma transvaginal mediante gua ecogrfica en combinacin con la administracin sistmica del frmaco (Fernandez 1991)) 14. Metotrexato sistmico solo en un rgimen de dosis nica intramuscular versus en combinacin con mifepristona por va oral (Gazvani 1998; Rozenberg 2003)) 15. Metotrexato sistmico solo en un rgimen de dosis nica intramuscular versus en combinacin con decoccin Embarazo Ectpico 2 (EE2) (hierbas chinas) (Wang 1998)) GLUCOSA HIPEROSMOLAR 16. Glucosa hiperosmolar intratubrica mediante gua laparoscpica versus otros tratamientos a. versus metotrexato local mediante gua laparoscpica (Sadan 2001)) b. versus glucosa hiperosmolar por va transvaginal mediante gua ecogrfica (Gjelland 1995; Hordnes 1997)) c. versus prostaglandinas locales y sistmicas (Lang 1990)) d. junto con prostaglandinas locales versus metotrexato en un rgimen oral (Landstrom 1998)) MANEJO EXPECTANTE 17. manejo expectante versus tratamiento mdico a. versus metotrexato sistmico en un rgimen oral de dosis baja (Korhonen 1996)) b. versus prostaglandinas locales y sistmicas (Egarter 1991)) CALIDAD METODOLGICA En general la calidad metodolgica de los 35 estudios incluidos se consider subptima, debido en gran parte a la falta de informacin detallada sobre la asignacin y la asignacin al azar en ms de la mitad de los estudios. Los detalles adicionales sobre la calidad de los ensayos estn disponibles en las tablas "Caractersticas de los estudios incluidos" y "Calidad de los estudios incluidos". Mtodo de asignacin aleatoria Los 35 estudios indicaron que la asignacin fue al azar. Diecinueve ensayos describieron el mtodo de asignacin (Alleyassin 2006; Cohen 1996; El-Sherbiny 2003; Fedele 1998; Fernandez 1991; Fernandez 1994; Fernandez 1995; Fernandez 1998; Fujishita 2004; Gazvani 1998; Graczykowski 1997; Hajenius 1997; Korhonen 1996; Lang 1990; Mottla 1992; Rozenberg 2003; Sharma 2003; Sowter 2001a; Vermesh 1989)). Ocultamiento de la asignacin Once estudios describieron el ocultamiento de la asignacin (Alleyassin 2006; Cohen 1996; Fedele 1998; Fernandez 1994; Gazvani 1998; Hajenius 1997; Korhonen 1996; Rozenberg 2003; Sowter 2001a; Vermesh 1989; Yalcinkaya 2000)).

Cegamiento El cegamiento al tratamiento no fue aplicable en la mayora de las comparaciones. Dos estudios emplearon doble cegamiento (Yalcinkaya 1996; actualizacin Yalcinkaya 2000; Sadan 2001), mientras que dos estudios fueron doble ciego controlados con placebo (Korhonen 1996; Rozenberg 2003)). El cdigo se abri despus del final del tratamiento de la ltima paciente. Clculo del poder estadstico Nueve estudios informaron un clculo del poder estadstico realizado previamente (Alleyassin 2006; Egarter 1991; Fujishita 2004; Gazvani 1998; Hajenius 1997; Korhonen 1996; Rozenberg 2003; Sowter 2001a; Yalcinkaya 2000)) Tamao de la muestra Todos los estudios tuvieron tamaos de la muestra pequeos. Slo seis estudios incluyeron 100 mujeres o ms (Alleyassin 2006n=108, Hajenius 1997 n=100, Graczykowski 1997n=129, Fernandez 1998 n=100, Rozenberg 2003n=212, Yalcinkaya 2000n=100). Se pudo realizar un metanlisis en ocho comparaciones que incluyeron de 60 a 265 mujeres (comparaciones 1, 3, 4, 5b, 6b, 8, 10 y 14). Abandonos Cuatro estudios mencionaron el nmero de exclusiones despus de la asignacin al azar (Lundorff 1991a; Mottla 1992; Hajenius 1997; Saraj 1998)). Se excluy una paciente (1%) despus de la asignacin al azar en el estudio de Saraj 1998 (sin embarazo ectpico) y cuatro (29%) en el estudio de Lundorff 1991a (sin embarazo tubrico y dificultades tcnicas). La alta tasa de exclusiones en el estudio de Mottla 1992 (43% [9/21]) y en el estudio de Hajenius 1997 (29% [40/140]) fue el resultado de las exclusiones secundarias durante la laparoscopia (es decir, rotura tubrica, hemorragia activa, ningn embarazo ectpico tubrico, tamao del embarazo ectpico, falta de visibilidad de la pelvis), debido a que las mujeres se asignaron antes de la laparoscopia confirmatoria. Hajenius 1997 seal que la asignacin al azar en el momento de la laparoscopia pudo evitar estas exclusiones secundarias, pero que los comits de tica consideraron que un diseo en el que las mujeres no conocieran el resultado de la asignacin al azar antes de la ciruga no era tico. Para prevenir un posible sesgo de seleccin, un cirujano que no conoca el resultado de la asignacin al azar evalu los criterios de exclusin secundarios. En un estudio de seguimiento de este ensayo, que inform sobre la calidad de vida relacionada con la salud, 11 de las 100 mujeres (11%) no hablaban el idioma holands o ingls lo suficientemente bien como para completar los cuestionarios (Nieuwkerk 1998a)). Interrupcin prematura del ensayo Cuatro estudios se interrumpieron antes de tiempo. El estudio de Mottla 1992 que compar metotrexato mediante gua laparoscpica versus salpingostoma laparoscpica se interrumpi antes de lo previsto debido a los resultados decepcionantes en el grupo de tratamiento mdico; no se

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menciona una regla de interrupcin preplanificada. El estudio de Sadan 2001 que compar metotrexato versus glucosa hiperosmolar ambos mediante gua laparoscpica se interrumpi despus de un anlisis intermedio de los datos de 20 pacientes debido a una tasa ms alta de fracaso en el grupo de glucosa hiperosmolar. El estudio de Egarter 1991 que compar prostaglandinas con manejo expectante se interrumpi de forma temprana despus del primer anlisis intermedio debido a que el xito del tratamiento primario fue menor en el grupo de manejo expectante. El estudio de Rozenberg 2003 se interrumpi despus del segundo anlisis intermedio debido a que se cumplieron los criterios de la regla de interrupcin. Esta regla de interrupcin se bas en la prueba triangular descrita por Whitehead 1992. Publicacin Todos los estudios, excepto cuatro, se publicaron como artculos completos. Esos cuatro estudios se publicaron slo como resmenes de congresos (Yalcinkaya 1996; Elmoghazy 2000; Yalcinkaya 2000; Klauser 2005)). Prdidas durante el seguimiento Diez estudios mencionaron las prdidas durante el seguimiento para la fertilidad futura, que vari entre 0,9% (Rozenberg 2003), 1% (Lundorff 1992), 2.4% (Yalcinkaya 1996), 10% (Dias Pereira 1999), 11% (Graczykowski 1997), 14% (Sowter 2001a) y el 18% (Fernandez 1998), 25% (Vermesh 1992), 44% (Yalcinkaya 2000) y el 47% (Tulandi 1991a)). En un estudio de seguimiento del ensayo de Hajenius 1997 que inform la calidad de vida relacionada con la salud, el 5,6% de las participantes no entreg alguno de los cuestionarios (Nieuwkerk 1998a)). RESULTADOS CIRUGA 1. Salpingostoma laparoscpica versus salpingostoma por ciruga abierta Los resultados combinados de dos estudios, que incluyeron 165 mujeres hemodinmicamente estables con un embarazo ectpico tubrico pequeo no roto (Vermesh 1989; Lundorff 1991a), mostraron que la salpingostoma laparoscpica fue significativamente menos exitosa que la ciruga abierta en cuanto a la eliminacin del embarazo ectpico tubrico (OR 0,28; IC del 95%: 0,09 a 0,86). Lo anterior se debi principalmente a la tasa de trofoblasto persistente significativamente ms alta de la ciruga laparoscpica (OR 3,5; IC del 95%: 1,1 a 11). La ciruga laparoscpica fue significativamente menos costosa que la ciruga abierta (Gray 1995)). La media de los costes fue 28 058 versus 32 699 coronas suecas, p = 0,03 (? 3 127 versus 3 644). Estos ahorros en los costes fueron el resultado de un tiempo de ciruga significativamente ms corto (73 minutos versus 88 minutos; p < 0,001), una menor prdida de sangre perioperatoria (79 ml versus 195 ml; p < 0,01), una duracin

ms corta de la estancia hospitalaria (uno y dos das versus tres y cinco das; p < 0,01) y una convalecencia ms corta (11 das versus 24 das; p < 0,001). Hubo una tendencia no significativa a una tasa de permeabilidad tubrica ms baja despus de la ciruga laparoscpica (OR 0,58; IC del 95%: 0,23 a 1,4), que se evalu en 110 mujeres despus de un seguimiento de una a 29 semanas (Vermesh 1989; Lundorff 1991b)). El seguimiento a largo plazo se evalu en 127 mujeres que deseaban fertilidad futura (Lundorff 1992; Vermesh 1992)). No se encontraron diferencias en el nmero de embarazos intrauterinos posteriores (OR 1,2; IC del 95%: 0,59 a 2,5) y hubo una tendencia no significativa a una tasa de embarazo ectpico repetido ms baja (OR 0,47; IC del 95%: 0,15 a 1,5). 2. Minilaparotoma versus laparotoma En un estudio que incluy 60 mujeres con un embarazo ectpico (Sharma 2003), se trat con xito a todas las mujeres. En las mujeres asignadas a una minilaparotoma sin la utilizacin de compresas o retractores no fue necesario realizar la conversin a laparotoma convencional. En el grupo de laparotoma convencional la incisin fue vertical en 22 de las 30 pacientes. Las complicaciones postoperatorias fueron significativamente menores en el grupo de minilaparotoma que en el grupo de laparotoma convencional (leo paraltico 10% versus 27%, p = 0,045; infeccin de la herida 3% versus 17%, p = 0,045). Los parmetros de los costes fueron significativamente menores en el grupo de minilaparotoma que en el grupo de laparotoma convencional (media del tiempo de ciruga: 38 min. versus 54 min.; p = 0,033 y alta 3,4 das versus 6,9 das; p = 0,015). No hubo datos disponibles sobre permeabilidad tubrica y fertilidad futura. 3. Salpingostoma sin sutura tubrica versus salpingostoma con sutura tubrica Los resultados combinados de dos estudios, que incluyeron 109 mujeres con un embarazo ectpico ampular no roto (Tulandi 1991a; Fujishita 2004), mostraron que hubo una tendencia no significativa a un menor xito del tratamiento despus de la salpingostoma sin sutura tubrica que cuando se sutur la trompa (OR 0,16; IC del 95%: 0,02 a 1,23). Lo anterior ocurri debido a que a 4 mujeres con trofoblasto persistente del grupo sin sutura se les dej la trompa abierta para que cicatrizara por segunda intencin. A estas mujeres se les trat adems, de forma exitosa, con metotrexato. Hubo una tendencia no significativa a una tasa de permeabilidad tubrica ms baja despus de la salpingostoma sin sutura tubrica (OR 0,38; IC del 95%: 0,06 a 2,4). La fertilidad futura se evalu en 88 mujeres. No se encontraron diferencias en el nmero de embarazos intrauterinos posteriores (OR 1,1; IC del 95%: 0,44 a 2,6) ni en el nmero de embarazos ectpicos repetidos (OR 1,2; IC del 95%: 0,38 a 3,8).

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4. Salpingostoma sola versus en combinacin con un tratamiento mdico a. con una dosis nica intramuscular de metotrexato Los resultados de dos estudios que incluyeron 163 mujeres con un embarazo ectpico tubrico (Graczykowski 1997, Elmoghazy 2000), mostraron que la salpingostoma sola fue significativamente menos exitosa (OR 0,25; IC del 95%: 0,08 a 0,76), debido a la mayor incidencia de trofoblasto persistente (OR 4,1; IC del 95%: 1,3 a 13) que cuando se suministr una dosis nica profilctica de metotrexato sistmico (1 mg/kg intramuscular) dentro de las 24 horas posteriores a la ciruga. Los efectos secundarios del tratamiento profilctico con metotrexato, que ocurrieron entre el 5,5% y el 8% de las mujeres, fueron leves. No hubo datos disponibles sobre permeabilidad tubrica y fertilidad futura. b. con una inyeccin de vasopresina dentro del mesosalpinge Un estudio que incluy 40 mujeres hemodinmicamente estables con un embarazo ectpico pequeo no roto (Ugur 1996), mostr que cuando se realiz salpingostoma sin inyeccin de vasopresina dentro del mesosalpinge hubo una tendencia no significativa a un menor xito del tratamiento debido a un nmero mayor de conversiones a ciruga abierta por hemorragia no controlable, que cuando la vasopresina se inyect de forma profilctica dentro del mesosalpinge (OR 0,35; IC del 95%: 0,09 a 1,5). La permeabilidad tubrica se evalu en 31 mujeres a las que se les practic una histerosalpingografa. Hubo una tendencia no significativa a una tasa de permeabilidad tubrica ms baja despus de la salpingostoma sin una inyeccin de vasopresina dentro del mesosalpinge (OR 0,42; IC del 95%: 0,10 a 1,9). No hubo datos disponibles sobre fertilidad futura. c. con una inyeccin de oxitocina dentro del mesosalpinge Un estudio multicntrico que incluy 25 mujeres hemodinmicamente estables con un embarazo ectpico pequeo no roto (Fedele 1998), inform que una inyeccin dentro del mesosalpinge de 20 UI de oxitocina diluidas en 20 ml de solucin fisiolgica tres minutos antes de la incisin tubrica redujo de forma significativa la prdida de sangre intra y postoperatoria, con una extraccin ms fcil del embarazo ectpico tubrico (p < 0,05) y sin efectos secundarios. Sin embargo, estos efectos positivos de la inyeccin de oxitocina dentro del mesosalpinge no se reflejaron en el xito del tratamiento primario (OR 0,15; IC del 95%: 0,00 a 7,3). No hubo datos disponibles sobre permeabilidad tubrica y fertilidad futura. TRATAMIENTO MDICO METOTREXATO VERSUS CIRUGA 5. Metotrexato laparoscpica sistmico versus salpingostoma

a. en un rgimen de dosis mltiple fija por va intramuscular En un estudio multicntrico, 100 mujeres hemodinmicamente estables con un embarazo ectpico tubrico no roto, confirmado mediante laparoscopia, sin actividad cardaca fetal ni signos de hemorragia activa, se asignaron a metotrexato sistmico (1 mg/kg peso corporal por va intramuscular los das 0, 2, 4, 6, alternado con cido folnico 0,1 mg/kg peso corporal por va oral los da 1, 3, 5, 7) y a salpingostoma laparoscpica (Hajenius 1997)). No hubo lmites en la concentracin srica de hCG o en el tamao del embarazo ectpico tubrico. La media de la concentracin srica de hCG en las mujeres tratadas con metotrexato fue 1950 UI/l (110 a 19 500). Hubo una tendencia no significativa a un xito mayor del tratamiento con el tratamiento con metotrexato sistmico (OR 1,8; IC del 95%: 0,73 a 4,6). No se encontraron diferencias significativas en cuanto a la preservacin tubrica (OR 0,82; IC del 95%: 0,21 a 3,2). El 61% de las pacientes tratadas con metotrexato sistmico present complicaciones y/o efectos secundarios, comparado con slo el 12% del grupo de salpingostoma. En el grupo de salpingostoma prcticamente todas las complicaciones comprendieron los efectos secundarios del metotrexato sistmico en las mujeres tratadas por trofoblasto persistente. La calidad de vida relacionada con la salud se afect ms despus del metotrexato sistmico que despus de la salpingostoma laparoscpica (Nieuwkerk 1998a)). Las mujeres que recibieron tratamiento mdico mostraron ms limitaciones en el funcionamiento fsico, de roles y social, presentaron percepciones de salud peores, menos energa, ms dolor, ms sntomas fsicos, una calidad de vida general peor y estaban ms deprimidas que las mujeres tratadas con ciruga (p < 0,05). El tratamiento con metotrexato sistmico fue significativamente ms costoso que la salpingostoma laparoscpica (Mol 1999a)). La media de los costes totales por paciente fue de $ 5 721 para el metotrexato sistmico y de $ 4 066 para la salpingostoma laparoscpica con una diferencia de medias de $ 1 655 (IC del 95%: 906 a 2 414). En el grupo de metotrexato se incluyeron los costes de la laparoscopia confirmatoria, aunque en la prctica real no ocurrira en el caso de las mujeres con un embarazo ectpico que reciben metotrexato. Sin embargo, las reintervenciones que slo fueron necesarias en las mujeres con concentraciones sricas iniciales de hCG > 1 500 UI/l, generaron costes adicionales considerables en el grupo de metotrexato debido a la estancia hospitalaria prolongada (4,5 versus 2,5 das). Adems, los costes debidos a la prdida de productividad fueron mayores en el grupo de metotrexato sistmico (38 versus 28 das de trabajo perdidos). El anlisis de subgrupos indic que la diferencia en los costes totales entre el metotrexato sistmico ($ 4 399) y la salpingostoma laparoscpica ($ 4 185) fue inferior slo en las mujeres con una concentracin srica inicial de hCG < 1 500 UI/l, aunque esta diferencia no fue significativa ($ 214; IC del 95%: -283 a 676). En un anlisis de escenarios se calcul que

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el metotrexato sistmico fue menos costoso comparado con la salpingostoma laparoscpica slo cuando se administr como parte de una estrategia de tratamiento totalmente no invasiva y en las mujeres con una concentracin srica inicial de hCG < 1 500 UI/l (coste total $ 2 991). En tal escenario, sin una laparoscopia confirmatoria, los costes totales fueron iguales a los de la salpingostoma laparoscpica en las mujeres con una concentracin srica inicial de hCG que vari de 1 500 a 3 000 UI/l ($ 3 885), aunque en las mujeres con una concentracin srica inicial de hCG > 3 000 el metotrexato sistmico fue ms costoso ($ 4 975) (Mol 1999a)). La tasa de permeabilidad tubrica evaluada en 81 mujeres no difiri (OR 0,84; IC del 95%: 0,35 a 2,0). La medida de resultado fertilidad se evalu en 74 mujeres que intentaron concebir 18 meses despus del cumplimiento del tratamiento. No se encontraron diferencias significativas en cuanto al embarazo intrauterino espontneo (OR 0,82; IC del 95%: 0,32 a 2,1) o los embarazos ectpicos repetidos (OR 0,87; IC del 95%: 0,19 a 4,1) (Dias Pereira 1999)). b. en un rgimen de dosis variable por va intramuscular Los resultados combinados de cuatro estudios que incluyeron 265 mujeres hemodinmicamente estables con un embarazo ectpico tubrico pequeo no roto (Fernandez 1998; Saraj 1998; Sowter 2001a; Sowter 2001b, El-Sherbiny 2003) mostraron que para la eliminacin del embarazo ectpico tubrico una dosis nica de metotrexato sistmico por va intramuscular (50 mg/m2 o 1 mg/kg peso corporal) fue significativamente menos exitosa que la salpingostoma laparoscpica (OR 0,38; IC del 95%: 0,20 a 0,71). Este hallazgo fue principalmente el resultado de un descenso inadecuado de las concentraciones sricas de hCG, por lo que se necesitaron inyecciones adicionales de metotrexato (OR 3,3; IC del 95%: 1,7 a 6,7). Al agrupar los datos hubo una heterogeneidad significativa (I2 de 52%). Veintisiete de las 120 mujeres tratadas con una dosis nica de metotrexato presentaron un descenso inadecuado de las concentraciones sricas de hCG. De estas 27 mujeres a cuatro se les practic una ciruga, mientras que 23 recibieron inyecciones adicionales de metotrexato de forma exitosa, excepto en tres casos. De las 20 mujeres tratadas con xito con metotrexato adicional, 17 mujeres recibieron dos dosis, 2 mujeres tres dosis y una mujer cuatro dosis. El xito del tratamiento aument con un rgimen de metotrexato de dosis variable, pero no mostr diferencias con la salpingostoma laparoscpica (OR 1,1; IC del 95%: 0,52 a 2,3). No se informaron eventos adversos en el grupo de laparoscopia, aunque 4 mujeres del grupo de metotrexato presentaron efectos secundarios (dos presentaron lceras bucales leves, dos mujeres presentaron sequedad ocular y una mujer experiment sequedad vaginal) No se informaron eventos adversos en el grupo de laparoscopia, aunque 4 mujeres del grupo de metotrexato presentaron efectos secundarios (dos presentaron lceras bucales

leves, dos mujeres presentaron sequedad ocular y una mujer, sequedad vaginal) Sowter 2001a(Sowter 2001a ). Los criterios de seleccin utilizados en los estudios fueron un lmite superior de hCG srica (< 5 000 UI/l, Sowter 2001a, < 10 000 UI/l El-Sherbiny 2003), ausencia de frecuencia cardaca fetal positiva (Saraj 1998; Sowter 2001a, El-Sherbiny 2003), tamao pequeo del embarazo ectpico tubrico (< 3,5 cm Saraj 1998; Sowter 2001a, < 4 cm, El-Sherbiny 2003) y una puntuacin preteraputica < 13 (Fernandez 1998). La media de las concentraciones sricas de hCG en las mujeres tratadas con metotrexato fue 3120 UI/l (Fernandez 1998) 3 162 UI/l (Saraj 1998), 927 UI/l (Sowter 2001a) y 2 274 UI/l (El-Sherbiny 2003)). Las mujeres tratadas con metotrexato presentaron un funcionamiento fsico significativamente mejor que el de las mujeres tratadas con ciruga laparoscpica (se observaron diferencias significativas en el funcionamiento fsico SF 36 que favorecieron el metotrexato en el da 4 de seguimiento pero no en las otras dimensiones del SF 36 o en las puntuaciones de ansiedad y depresin, p < 0,01). No se hallaron diferencias en el funcionamiento psicolgico (Sowter 2001a)). El metotrexato de dosis nica signific un ahorro del 52% de los costes directos, comparado con la ciruga laparoscpica: la media de los costes directos por paciente fue $ NZ 1 470 (? 787) y $ NZ 3 083 (? 1 650), respectivamente. Esta diferencia significativa de $ NZ 1 613 (IC del 95%: 1 166 a 2 061) (? 863; IC del 95%: 624 a 1 103) se debi a los ahorros originados por la disminucin en la utilizacin del quirfano y la estancia hospitalaria. Adems, el metotrexato de dosis nica signific un ahorro del 40% de los costes indirectos: la media de los costes indirectos por paciente fue $ NZ 1 141 (? 610) y $ NZ 1 899 (? 1 016), respectivamente, con una diferencia de medias de $ NZ 758 (IC del 95%: 277 a 1 240) (? 406; IC del 95%: 148 a 664). El anlisis de subgrupos indic que la diferencia en los costes indirectos se perdi en las mujeres con una concentracin srica inicial de hCG > 1 500 UI/l, debido al seguimiento prolongado y a una tasa de reintervenciones quirrgicas ms alta (Sowter 2001b)). En un anlisis de escenarios se calcul que los ahorros en los costes del metotrexato de dosis nica permanecieron bajo una gama amplia de presuposiciones alternativas acerca de los costes de la unidad. La permeabilidad tubrica se pudo evaluar en 115 mujeres (Saraj 1998; Sowter 2001a, El-Sherbiny 2003) y no mostr diferencias significativas entre los dos grupos de tratamiento (OR 1,5; IC del 95%: 0,69 a 3,1). La fertilidad futura se evalu en 98 mujeres. No se encontraron diferencias significativas en cuanto al nmero de embarazos intrauterinos posteriores (OR 1,0; IC del 95%: 0,43 a 2,4), aunque hubo una tendencia no significativa a una tasa de embarazo ectpico repetido ms baja (OR 0,54; IC del 95%: 0,12 a 2,4) (Fernandez 1998; Saraj 1998, El-Sherbiny 2003)).

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6. Metotrexato local versus salpingostoma laparoscpica a. por va transvaginal mediante gua ecogrfica Un estudio actualizado en 1998, que incluy 78 mujeres con un embarazo ectpico con una puntuacin preteraputica < 13 (Fernandez 1998), mostr que para la eliminacin del embarazo ectpico tubrico el metotrexato 1 mg/kg peso corporal por va transvaginal mediante gua ecogrfica present un xito significativamente menor que la salpingostoma laparoscpica (OR 0,17; IC del 95%: 0,04 a 0,76). Este hallazgo fue principalmente el resultado de la tasa de trofoblasto persistente ms alta (OR 4,9; IC del 95%: 0,99 a 24), para la cual se necesitaron inyecciones adicionales de metotrexato sistmico. Las intervenciones adicionales fueron exitosas para todas las pacientes, lo que se refleja en una tasa de preservacin tubrica de 100%. La media de las concentraciones sricas de hCG en las mujeres tratadas con metotrexato local fue de 3 805 UI/l. En el informe original donde se asignaron 40 mujeres (Fernandez 1995), la permeabilidad tubrica homolateral se evalu en 35 mujeres y no se encontraron diferencias (OR 0,94; IC del 95%: 0,12 a 7,3). La fertilidad futura se evalu en 51 mujeres. El nmero de embarazos intrauterinos posteriores fue significativamente mayor (OR 4,1; IC del 95%: 1,3 a 14) despus del tratamiento con metotrexato local y hubo una tendencia no significativa a una tasa de embarazo ectpico repetido ms baja (OR 0,30; IC del 95%: 0,05 a 1,7). b. mediante gua laparoscpica Los resultados combinados de dos estudios, que incluyeron 60 mujeres hemodinmicamente estables con un embarazo ectpico tubrico pequeo no roto sin signos de hemorragia activa (Mottla 1992; Zilber 1996), mostraron una tendencia no significativa a un menor xito del tratamiento con 25 mg de metotrexato mediante gua laparoscpica, comparado con salpingostoma laparoscpica (OR 0,26; IC del 95%: 0,06 a 1,1). La media de las concentraciones sricas de hCG en las mujeres tratadas con metotrexato local fue 1 214 UI/l (Zilber 1996). En el ensayo de Mottla 1992, los autores interpretaron errneamente el ascenso inicial de la hCG srica despus del tratamiento mdico local como un fracaso del tratamiento, debido a que aparentemente estaban poco familiarizados con los patrones de depuracin de la hCG srica despus del metotrexato. Estas mujeres se trataron de forma quirrgica debido a trofoblasto persistente (OR 3,9; IC del 95%: 0,93 a 16). Estas cirugas adicionales no repercutieron de forma significativa sobre la preservacin tubrica (OR 0,16; IC del 95%: 0,01a 2,5). Un estudio (Zilber 1996) inform la fertilidad futura en 34 mujeres. No se encontraron diferencias significativas en cuanto a los embarazos intrauterinos posteriores (OR 0,87; IC del 95%: 0,15 a 5,0), aunque hubo una tendencia no significativa a una tasa de embarazo ectpico repetido ms baja (OR 0,15; IC del 95%: 0,00 a 7,7).

METOTREXATO POR ADMINISTRACIN

DIFERENTES

VAS

DE

7. Por va transvaginal mediante gua ecogrfica versus mediante gua laparoscpica Los resultados de un estudio, que incluy 36 mujeres hemodinmicamente estables con un embarazo ectpico pequeo no roto (Tzafettas 1994), indicaron que el xito del tratamiento con 100 mg de metotrexato administrado por va transvaginal mediante gua ecogrfica fue significativamente mejor que una inyeccin intratubrica "ciega" de 100 mg de metotrexato mediante gua laparoscpica (OR 5,8; IC del 95%: 1,3 a 26). No hubo datos disponibles sobre permeabilidad tubrica y fertilidad futura. 8. Por va transvaginal mediante gua ecogrfica versus dosis nica intramuscular Los resultados combinados de tres estudios, que incluyeron 95 mujeres con un embarazo ectpico pequeo no roto (Fernandez 1994; Fernandez 1998; Cohen 1996), mostraron una tendencia no significativa a un xito mayor del tratamiento primario despus del metotrexato local (OR 2,14; IC del 95%: 0,82 a 5,6). En el grupo de metotrexato local se aspir el contenido tubrico y se administr metotrexato 1 mg/kg. Slo una mujer present efectos secundarios leves y se trat con metotrexato de dosis nica (50 mg/m2). El resultado fertilidad se evalu en 51 mujeres. No se encontraron diferencias significativas en cuanto al nmero de embarazos intrauterinos posteriores (OR 1,5; IC del 95%: 0,43 a 5,3) ni de embarazos ectpicos repetidos (OR 4,1; IC del 95%: 0,05 a 307). Al agrupar los datos para los embarazos intrauterinos hubo una heterogeneidad significativa (I2 de 72%). 9. Mediante gua laparoscpica versus el mismo rgimen en combinacin con metotrexato sistmico intramuscular En un estudio que slo incluy 15 mujeres hemodinmicamente estables con un embarazo ectpico tubrico pequeo no roto (Shulman 1992), hubo una tendencia no significativa a un xito menor del tratamiento primario despus del metotrexato local solo (12,5 mg) que cuando este rgimen se combin con metotrexato sistmico (0,5 mg/kg por va oral durante cinco das alternos con cido folnico) (OR 0,12; IC del 95%: 0,0 a 6,0). No se observaron complicaciones ni efectos secundarios en ambos grupos de tratamiento. No hubo datos disponibles sobre permeabilidad tubrica y fertilidad futura. DIFERENTE METOTREXATO DOSIS/SUSPENSIN DEL

10. Dosis nica versus dosis mltiple fija ambas por va intramuscular

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Los resultados de dos estudios que incluyeron 159 mujeres con un diagnstico clnico de embarazo ectpico (Klauser 2005 y Alleyassin 2006), no mostraron diferencias significativas en cuanto al xito del tratamiento primario entre los dos grupos de tratamiento (OR 0,89; IC del 95%: 0,32 a 2,5). La media de las concentraciones sricas de hCG vari de 2 230 UI/l a 2 973 UI/l en el grupo de dosis nica (50 mg/m2) y de 2 180 UI/l a 2 244 UI/l en el grupo de dosis mltiple (1 mg/kg). En el estudio de Alleyassin 20066 de 54 mujeres con una disminucin inadecuada de la concentracin srica de hCG despus del metotrexato de dosis nica se trataron con xito con una segunda dosis. Por otro lado, el estudio de Klauser 2005 inform efectos secundarios leves en el 28% del grupo de dosis nica versus el 10% del grupo de dosis mltiple (p = 0,2). En el estudio de Alleyassin 2006 se informaron complicaciones en el 28% del grupo de dosis nica versus el 37% del grupo de dosis mltiple (p = 0,3). No hubo datos disponibles sobre permeabilidad tubrica y fertilidad futura. 11. 25 de mg/m2 versus lo estndar 50 mg/m2 ambos en un rgimen intramuscular de dosis nica Un estudio doble ciego actualizado en 2000, (Yalcinkaya 1996; Yalcinkaya 2000), que incluy 100 mujeres hemodinmicamente estables con un embarazo ectpico tubrico no roto mostr una tendencia no significativa a un menor xito del tratamiento despus de una dosis baja de metotrexato en comparacin con la administracin estndar de 50 mg/m2 (OR 0,68; IC del 95%: 0,30 a 1,5). Se necesit una segunda inyeccin de metotrexato para tratar el descenso inadecuado de las concentraciones sricas de hCG en el 31% (15/48) del grupo de dosis baja y en el 25% (13/52) del grupo de tratamiento estndar. El xito del tratamiento con este rgimen de dosis variable no difiri entre los dos grupos (OR 0,77; IC del 95%: 0,24 a 2,5). La media de las concentraciones sricas de hCG fue 2 405 UI/l (+/ - 3 204) y 2 841 (+/ - 4 132) UI/l, respectivamente y hubo actividad cardaca fetal en 2 (4,2%) y 7 (13,4%) mujeres, respectivamente. Los efectos secundarios no difirieron entre los dos grupos. La permeabilidad tubrica, evaluada en 37 mujeres, no difiri entre los dos grupos de tratamiento (OR 0,90; IC del 95%: 0,25 a 3,2). La fertilidad futura se evalu en 56 mujeres. No se encontraron diferencias significativas en cuanto al nmero de embarazos intrauterinos posteriores (OR 1,1; IC del 95%: 0,37 a 3,2). Hubo una tendencia no significativa a una tasa de embarazo ectpico repetido ms baja en el grupo de dosis baja (OR 0,56; IC del 95%: 0,10 a 3,0). 12. Metotrexato en lipiodol en suspensin versus metotrexato en solucin fisiolgica ambos mediante gua laparoscpica

A partir de los resultados de los estudios in vitro y experimentos con animales, se encontr que el metotrexato disuelto en lipiodol en suspensin con fosfatidilcolina agregada como un estabilizador de dispersin gener concentraciones tisulares altas, lo que prolonga el efecto del frmaco (Fujishita 1995a). Los resultados de un estudio pequeo que incluy 26 mujeres con un embarazo ectpico pequeo no roto sin actividad cardaca fetal (Fujishita 1995b), mostr que entre 20 mg y 50 mg de metotrexato disuelto en lipidiol fue significativamente ms exitoso para la eliminacin del embarazo ectpico tubrico que 20 mg a 50 mg de metotrexato en solucin fisiolgica (OR 6,0; IC del 95%: 1,3 a 27) debido a que la tasa de trofoblasto persistente fue ms baja en el grupo de lipidiol (OR 0,22; IC del 95%: 0,05 a 1,1). Hubo una tendencia no significativa a una tasa de permeabilidad tubrica ms alta (OR 2,1; IC del 95%: 0,29 a 15) y una tasa de embarazo intrauterino posterior ms baja en el grupo de lipidiol (OR 0,43; IC del 95%: 0,07 a 2,6). METOTREXATO VERSUS/O EN COMBINACIN CON OTROS TRATAMIENTOS MDICOS 13. Metotrexato versus prostaglandinas ambos de forma transvaginal mediante gua ecogrfica en combinacin con la administracin sistmica del frmaco En un estudio, que incluy 21 mujeres hemodinmicamente estables con un embarazo ectpico tubrico (Fernandez 1991), no se encontraron diferencias significativas en cuanto al xito del tratamiento primario entre el tratamiento con metotrexato (1 mg/kg local y sistmico) y el tratamiento con prostaglandina (OR 1,0; IC del 95%: 0,17a 6,0). Los autores no mencionaron el nmero de intervenciones quirrgicas adicionales realizadas por grupo. Slo una mujer de cada grupo de tratamiento present efectos secundarios. Hubo una tendencia no significativa a una tasa de permeabilidad tubrica ms baja en el grupo de metotrexato (OR 0,17; IC del 95%: 0,0 a 9,1). No hubo datos disponibles sobre fertilidad futura. 14. Metotrexato sistmico solo en un rgimen de dosis nica intramuscular versus en combinacin con mifepristona por va oral Los resultados combinados de dos estudios, que incluyeron 262 mujeres hemodinmicamente estables con un embarazo ectpico no roto sin signos de hemorragia activa (Gazvani 1998, Rozenberg 2003), indicaron que el metotrexato solo de dosis nica (50 mg/m2) fue significativamente menos exitoso en la eliminacin del embarazo ectpico tubrico que cuando se agregaron 600 mg de mifepristona (antiprogesterona) (OR 0,59; IC del 95%: 0,35 a 1,0). El trofoblasto persistente ocurri con ms frecuencia con el metotrexato solo (OR 1,4; IC del 95%: 0,69 a 2,7). En el estudio de Gazvani 1998, aunque todos los embarazos tubricos se confirmaron por laparoscopia, la media de las concentraciones sricas de hCG fue baja en ambos grupos

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de tratamiento, es decir 346 UI/l (rango 52 a 12 700) y 497 UI/l (rango 30 a 4 200), respectivamente. En el estudio de Rozenberg 2003, que utiliz un algoritmo diagnstico no laparoscpico, la media de las concentraciones sricas de hCG fue 1 679 UI/l (rango 652 a 3 658) y 1620 UI/l (rango 805 a 3 190), respectivamente. En el estudio de Gazvani 1998 slo dos mujeres de cada grupo de tratamiento presentaron efectos secundarios, aunque en el estudio de Rozenberg 2003se observaron ms efectos secundarios (gastritis 30 versus 34, estomatitis 6 versus 8, alopecia reversible 3 versus 3 mujeres). No se encontraron diferencias en cuanto a la preservacin tubrica (OR 0,73; IC del 95%: 0,37 a 1,4). La permeabilidad tubrica slo se pudo evaluar para 24 mujeres. Hubo una tendencia no significativa a una tasa de permeabilidad tubrica ms baja con metotrexato solo (OR 0,38; IC del 95%: 0,05 a 3,1). No hubo datos disponibles sobre fertilidad futura. 15. Metotrexato sistmico solo en un rgimen intramuscular de dosis nica versus en combinacin con decoccin Embarazo Ectpico 2 (EE2) En un estudio que incluy 78 mujeres con un embarazo ectpico tubrico (Wang 1998) el metotrexato solo de dosis nica (50 a 70 mg/m2) fue significativamente menos exitoso en la eliminacin del embarazo ectpico tubrico que cuando se agreg la decoccin (una hierba china) Embarazo Ectpico 2 (EE2) (OR 0,08; IC del 95%: 0,02 a 0,39). El nmero de embarazos intrauterinos posteriores fue significativamente menor (OR 0,19; IC del 95%: 0,07 a 0,51), aunque hubo una tendencia no significativa a una tasa de embarazo ectpico repetido ms alta (OR 4,2; IC del 95%: 0,74 a 23). GLUCOSA HIPEROSMOLAR 16. Glucosa hiperosmolar mediante gua laparoscpica versus otros tratamientos a. versus metotrexato mediante gua laparoscpica En un estudio doble ciego (Sadan 2001) hubo una tendencia no significativa que indic que la glucosa hiperosmolar fue menos exitosa que 25 mg de metotrexato (OR 0,30; IC del 95%: 0,05 a 2,0) en la eliminacin de embarazo ectpico tubrico en mujeres hemodinmicamente estables con un embarazo ectpico tubrico no roto < 4 cm confirmado por laparoscopia. Esta tendencia fue el resultado de la tasa de intervencin por trofoblasto persistente ms alta en el grupo de glucosa hiperosmolar (OR 2,7; IC del 95%: 0,24 a 29) y tasas de intervenciones quirrgicas por rotura tubrica ms altas. El estudio se interrumpi despus del anlisis intermedio de los datos de 20 mujeres. No hubo datos disponibles sobre permeabilidad tubrica y fertilidad futura.

b. versus glucosa hiperosmolar por va transvaginal mediante gua ecogrfica Los resultados de un estudio que incluy 80 mujeres con un embarazo ectpico pequeo no roto y una concentracin srica de hCG < 3 000 UI/l (Gjelland 1995), mostr que la glucosa hiperosmolar administrada mediante gua laparoscpica fue significativamente menos exitosa que cuando se administr por va transvaginal mediante gua ecogrfica (OR 0,38; IC del 95%: 0,15 a 0,93). Este hallazgo se debi a dificultades tcnicas que necesitaron conversin a laparotoma incluso sin administrar el tratamiento mdico y a las reintervenciones quirrgicas por trofoblasto persistente en el grupo de laparoscopia (OR 2,0; IC del 95%: 0,74 a 5,2). En un estudio de seguimiento el autor no mencion la permeabilidad tubrica por grupo de tratamiento (Hordnes 1997)). La fertilidad futura se evalu en 36 mujeres. Hubo una tendencia no significativa a una tasa de embarazo intrauterino posterior ms alta (OR 3,3; IC del 95%: 0,88 a 12) y a una tasa de embarazo ectpico repetido ms alta (OR 1,7; IC del 95%: 0,29 a 10) en el grupo de tratamiento administrado mediante gua laparoscpica. c. versus prostaglandinas locales y sistmicas En un estudio que incluy 31 mujeres con un embarazo ectpico tubrico no roto y una concentracin de hCG en orina < 5 000 UI/l (Lang 1990), hubo una tendencia no significativa a un xito mayor del tratamiento primario despus de la glucosa hiperosmolar (OR 8,5; IC del 95%: 0,51a 142). Los efectos secundarios slo se observaron en el grupo de prostaglandina y ocurrieron en el 60% de las pacientes. No se encontraron diferencias entre los dos grupos de tratamiento en cuanto a la tasa de permeabilidad tubrica evaluada en 14 mujeres (OR 0,73; IC del 95%: 0,04 a 13). No hubo datos disponibles sobre fertilidad futura. d. junto con prostaglandinas locales versus metotrexato sistmico en un rgimen oral En un estudio multicntrico que incluy 31 mujeres hemodinmicamente estables con un embarazo ectpico tubrico no roto confirmado por laparoscopia y una concentracin srica de hCG < 3 000 UI/l (Landstrom 1998), hubo una tendencia no significativa a un xito menor del tratamiento primario del tratamiento con inyeccin local (OR 0,60; IC del 95%: 0,06 a 6,3) en comparacin con un tratamiento oral no invasivo con metotrexato. Sin embargo, la media de las concentraciones sricas de hCG fue baja, es decir, 932 UI/l (rango 54 a 4 446) y 810 UI/l (rango 104 a 3 085), respectivamente. No hubo datos disponibles sobre permeabilidad tubrica y fertilidad futura. MANEJO EXPECTANTE 17. Manejo expectante versus tratamiento mdico

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a. versus metotrexato sistmico en un rgimen oral de dosis baja En un estudio doble ciego controlado con placebo que incluy 60 mujeres hemodinmicamente estables con un embarazo ectpico tubrico pequeo sin actividad cardaca fetal y una concentracin srica de hCG < 5 000 UI/l (Korhonen 1996), no se encontraron diferencias significativas en cuanto al xito del tratamiento primario (OR 1,0; IC del 95%: 0,31a 3,3) entre el manejo expectante y 2,5 mg/kg de metotrexato por va oral durante cinco das. Sin embargo, la media de las concentraciones sricas de hCG fue baja, es decir 211 UI/l (rango 20 a 1 343) en el grupo de manejo expectante y 395 UI/l (rango 61 a 4 279) en el grupo de metotrexato. En este ensayo controlado con placebo el 23% de las pacientes en ambos grupos de tratamiento necesitaron una ciruga. Los autores no mencionaron qu pacientes fracasaron, por qu fracasaron y cmo fueron tratadas posteriormente. No hubo datos disponibles sobre permeabilidad tubrica y fertilidad futura. b. versus prostaglandinas locales y sistmicas Los resultados de un estudio pequeo controlado con placebo que incluy 23 mujeres con un embarazo ectpico no roto y una concentracin srica de hCG < 2 500 UI/l (Egarter 1991), mostraron que el manejo expectante fue significativamente menos exitoso que el tratamiento con prostaglandina (OR 0,08; IC del 95%: 0,02 a 0,39). No se inform ningn efecto secundario. No hubo datos disponibles sobre permeabilidad tubrica y fertilidad futura. DISCUSIN En esta revisin sobre el tratamiento del embarazo ectpico tubrico se analizaron 35 estudios con 25 comparaciones diferentes. Estas comparaciones se agruparon en tres categoras; (1) ciruga, (2) tratamiento mdico y (3) manejo expectante. Muchas comparaciones tuvieron nicamente un solo estudio, a pequea escala. El escaso nmero de participantes, en especial en la evaluacin del resultado fertilidad, dificultaron la obtencin de comparaciones confiables de las diversas medidas de resultado. La calidad metodolgica de los 35 estudios incluidos fue deficiente. En el 53% se especific el procedimiento de asignacin al azar, aunque slo en el 32% se ocult la asignacin. En cerca de la mitad de los estudios los autores se centraron en el resultado a corto plazo (la eliminacin del embarazo ectpico tubrico). En la evaluacin de los tratamientos para el embarazo ectpico tubrico, la efectividad a corto plazo sola no es la medida de resultado adecuada debido a que el embarazo ectpico tubrico finalmente se eliminar en todas las mujeres, ya sea mediante un tratamiento primario solo o combinado con intervenciones adicionales. Por lo tanto, es importante centrarse

en las estrategias de tratamiento en su totalidad incluidos los efectos secundarios, los inconvenientes del tratamiento, los costes y por ltimo, pero no menos importante, la medida de resultado fertilidad futura. CIRUGA La salpingostoma laparoscpica es factible en las mujeres con un embarazo ectpico tubrico y sus costes son menores cuando se compara con la ciruga abierta. Este beneficio se debe equilibrar contra una tasa de trofoblasto persistente significativamente ms alta en comparacin con la ciruga abierta. El seguimiento a largo plazo no mostr diferencias significativas en cuanto a fertilidad futura. En el caso de que an se necesite una laparotoma, la misma se puede realizar mediante una tcnica de minilaparotoma. El uso profilctico de una inyeccin nica de metotrexato reduce de forma significativa la tasa de trofoblasto persistente. Sin embargo, el nmero de mujeres necesario a tratar con metotrexato para evitar una mujer con trofoblasto persistente es 10, lo que hace que la utilidad de esta estrategia sea muy cuestionable. La monitorizacin de las concentraciones sricas de hCG parece una mejor opcin. El uso adicional de vasopresina y oxitocina inyectadas en la trompa antes de la ciruga no tiene repercusin sobre el xito del tratamiento. En conclusin, en el tratamiento quirrgico del embarazo ectpico tubrico la ciruga laparoscpica es un tratamiento coste-efectivo. TRATAMIENTO MDICO Los frmacos utilizados en el tratamiento mdico del embarazo ectpico tubrico fueron principalmente metotrexato y, ocasionalmente, glucosa hiperosmolar y prostaglandinas. En vista de los efectos secundarios del metotrexato como un agente quimioteraputico, este frmaco se compar con las prostaglandinas y con la glucosa hiperosmolar. Comparado con las prostaglandinas solas o combinadas con la glucosa hiperosmolar, no se encontraron diferencias significativas en cuanto al xito del tratamiento o los efectos secundarios. Un ensayo que compar metotrexato versus glucosa hiperosmolar sola se interrumpi antes de lo previsto debido a la alta tasa de fracaso en el grupo de glucosa hiperosmolar. El metotrexato se puede administrar de forma local en la trompa, as como de forma sistmica. La administracin transvaginal de metotrexato mediante gua ecogrfica requiere la visualizacin el saco gestacional ectpico, as como habilidades especficas y experiencia por parte del mdico. Esta forma de administracin es menos invasiva y ms efectiva que la inyeccin intratubrica "ciega" mediante gua laparoscpica, pero ambas modalidades de administracin son menos efectivas que la salpingostoma laparoscpica en la eliminacin del embarazo ectpico tubrico. Adems, con el metotrexato local mediante gua laparoscpica existen los riesgos de la anestesia y la insercin de los trcares, lo que convierte a la ciruga laparoscpica en el tratamiento de eleccin obvio.

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Comparado con las vas de administracin locales, el metotrexato sistmico es prctico, ms fcil de administrar y menos dependiente de las habilidades mdicas. Combinado con herramientas de diagnstico no invasivas, el metotrexato sistmico ofrece la posibilidad de un tratamiento ambulatorio no invasivo. Por lo tanto, la comparacin entre el metotrexato sistmico y la salpingostoma laparoscpica es de suma importancia. El metotrexato sistmico en un rgimen de dosis mltiple fija intramuscular versus salpingostoma laparoscpica no mostr diferencias significativas a corto y largo plazo en las medidas de resultado mdicas. La calidad de vida relacionada con la salud se vio afectada con mayor severidad despus del metotrexato sistmico. Sin embargo, en un estudio de casos y controles, las mujeres indicaron que estaban dispuestas a tolerar los mayores inconvenientes del tratamiento con metotrexato sistmico para obtener el beneficio de un tratamiento totalmente no invasivo del embarazo ectpico tubrico (Nieuwkerk 1998b). En tal escenario de tratamiento, se calcul que el metotrexato sistmico sera menos costoso slo en las mujeres con una concentracin srica inicial de hCG < 1 500 UI/l, aunque los costes seran similares a los de la salpingostoma laparoscpica en las mujeres con una concentracin srica inicial de hCG de entre 1 500 y 3 000 UI/l, y ms costoso an en las mujeres con una concentracin srica inicial de hCG > 3 000 UI/l (Mol 1999a)). El metotrexato de dosis nica intramuscular es significativamente menos efectivo que la salpingostoma laparoscpica. Con frecuencia se necesitan inyecciones adicionales para tratar el descenso inadecuado de las concentraciones sricas de hCG , lo que da lugar a un rgimen de dosis variable. El xito del tratamiento con este rgimen de dosis variable no es significativamente diferente al de la salpingostoma laparoscpica en la eliminacin del embarazo ectpico tubrico. El anlisis de subgrupos nuevamente mostr que los ahorros econmicos de este rgimen de metotrexato se pierden en las mujeres con una concentracin srica inicial de hCG > 1 500 UI/l. No se encontraron diferencias al comparar el metotrexato sistmico en dosis diferentes: un rgimen de dosis nica versus el rgimen de dosis mltiple fija y una dosis ms baja (25 mg/m2) versus la dosis estndar de 50 mg/m2. La eficacia del metotrexato de dosis nica mejora al agregar la mifepristona, aunque se excluye un efecto de un tratamiento prolongado. Lo mismo sucede cuando se agrega la medicina tradicional china. El hallazgo experimental que mostr que el metotrexato disuelto en lipiodol en suspensin es ms efectivo que el metotrexato en solucin fisiolgica no se implement en la prctica mdica debido a las altas concentraciones tisulares y a la prolongacin del efecto del frmaco. En conclusin, en el tratamiento mdico del embarazo ectpico tubrico el metotrexato sistmico se puede administrar en un rgimen de dosis mltiple fija o en un rgimen de dosis variable

en las mujeres con concentraciones sricas iniciales de hCG bajas. El rgimen de dosis mltiple fija comprende 1 mg/kg peso corporal de metotrexato por va intramuscular los da 0, 2, 4, 6 alternado con cido folnico 0,1 mg/kg por va oral los das 1, 3, 5, 7 seguido de seis das sin medicacin. El da 14 se suministra un segundo ciclo si la concentracin srica de hCG en ese da est un 40% por encima del valor inicial del da 0. Un rgimen de dosis variable comprende una nica inyeccin de 1 mg/kg peso corporal o 50 mg/m2 rea de superficie corporal de metotrexato por va intramuscular con una inyeccin adicional de metotrexato si la concentracin srica de hCG entre los das cuatro a siete no logra descender < 15% del valor inicial del da uno. Si durante cualquier semana sucesiva del seguimiento la hCG srica nuevamente no logra descender al menos un 15%, se administra otra inyeccin de metotrexato. Si despus de la administracin de tres inyecciones la hCG srica no desciende como lo indican los criterios anteriores, se recomienda el tratamiento quirrgico. Los autores de esta revisin opinan que se deben tener en cuenta los siguientes criterios cuando se considera el tratamiento mdico con metotrexato (sistmico) para el embarazo ectpico tubrico (ASRM 2006): Evaluacin antes del tratamiento: concentracin srica de hCG, recuento sanguneo completo, pruebas de funcionamiento heptico y renal, tipo y cribado. Reglas vitales: cumplimiento adecuado por la paciente, no consumir alcohol, aspirina o frmacos antiinflamatorios no esteroides o suplementos de cidos folnico, abstinencia sexual, evitar la exposicin a los rayos solares, ingesta de lquido de al menos 1,5 l diarios, colutorios diarios con solucin fisiolgica al 0,9% y en el caso de estomatitis colutorios con clorhexidina al 0,12%. Seguimiento: antgeno D intramuscular si el factor Rhesus es negativo, alivio del dolor con paracetamol, monitorizacin de la hCG srica hasta que el nivel sea indetectable, ecografa transvaginal, recuentos sanguneos completos, pruebas de funcionamiento heptico y renal, retraso del embarazo durante al menos tres meses despus del tratamiento debido a la teratogenicidad del metotrexato. MANEJO EXPECTANTE El nico estudio que compar metotrexato sistmico y manejo expectante no es informativo desde un punto de vista mdico. La va de administracin oral y la dosis baja de metotrexato utilizada en este estudio (2,5 mg/da durante cinco das) son poco frecuentes y propensas al fracaso. Este estudio prcticamente representa una comparacin entre dos tratamientos placebo debido a que mostr tasas similares de xito de 77% en ambos grupos de tratamiento. Otro estudio, que se interrumpi antes de lo previsto, mostr que el tratamiento con prostaglandina en pacientes seleccionadas (concentracin srica de hCG < 2 500 UI/l) es significativamente mejor que el manejo expectante y no presenta efectos secundarios.

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En conclusin, no se puede realizar an una evaluacin adecuada del manejo expectante del embarazo ectpico tubrico. CONCLUSIONES DE LOS AUTORES Implicaciones para la prctica La ciruga laparoscpica es un tratamiento coste-efectivo en mujeres con embarazo ectpico tubrico. El metotrexato sistmico es una opcin alternativa de tratamiento no quirrgico si el diagnstico del embarazo ectpico tubrico se establece de forma no invasiva, por lo que ofrece una opcin de tratamiento ambulatorio completamente no invasivo. El metotrexato sistmico slo se puede recomendar para las mujeres hemodinmicamente estables con un embarazo ectpico tubrico no roto y sin signos de hemorragia activa que presentan concentraciones sricas iniciales de hCG bajas. Implicaciones para la investigacin CIRUGA An no se puede asegurar cul de las dos cirugas, la salpingostoma o la salpinguectoma, se debe realizar. Las desventajas inherentes a la salpingostoma, es decir el riesgo de trofoblasto persistente y embarazo ectpico tubrico repetido que generan costes adicionales, slo se justifican si este enfoque da lugar a una tasa de embarazo intrauterino espontneo ms alta, y as se evitan los inconvenientes del tratamiento y los costes del tratamiento por infertilidad posterior despus de la salpinguectoma. Una revisin de estudios de cohorte que compararon el resultado fertilidad despus de la salpingostoma y salpinguectoma para el embarazo ectpico tubrico, no mostr efectos beneficiosos de la ciruga conservadora sobre la tasa de embarazo intrauterino, mientras que el riesgo de embarazo ectpico repetido aument, aunque no de forma significativa (Clausen 1996; Mol 1996). Un estudio comparativo retrospectivo que inform un anlisis de tablas de mortalidad revel un efecto beneficioso de la salpingostoma en comparacin con la salpinguectoma para el embarazo ectpico tubrico en cuanto al resultado fertilidad en mujeres con patologa tubrica contralateral (Mol 1998a). Se desconoce si la salpingostoma es beneficiosa para las mujeres sin patologa tubrica. Hasta la fecha existen dos ensayos en curso que comparan la salpingostoma versus salpinguectoma en estas mujeres y la repercusin sobre la fertilidad futura (Hajenius 1; Fernandez 2). TRATAMIENTO MDICO/MANEJO EXPECTANTE

Las investigaciones futuras se deben centrar en los programas de dosis del metotrexato sistmico, los efectos secundarios, la calidad de vida de las pacientes y los costes. Un estudio que est a punto de comenzar comparar metotrexato en un rgimen de dosis nica intramuscular versus manejo expectante en mujeres con un embarazo persistente de ubicacin desconocida con concentraciones sricas de hCG estables < 2 000 UI/l (Hajenius 2). Hasta el momento a este subgrupo particular de mujeres, que representa cerca del 10% de las mujeres con un presunto embarazo ectpico (Kirk 2006) se le ha ofrecido tratamiento mdico con metotrexato (Hajenius 1995b; Condous 2004)). Recientemente comenz un ensayo bien diseado que evaluar el manejo expectante en el tratamiento del embarazo ectpico tubrico. En un contexto doble ciego se compar una dosis nica de metotrexato intramuscular con placebo, en mujeres seleccionadas con un embarazo ectpico y una concentracin srica de hCG < 1 500 UI/l (Jurkovic)). AGRADECIMIENTOS Los revisores agradecen a la Sra. Xu Hairong por la traduccin del estudio de Wang 1998del chino al idioma ingls. POTENCIAL CONFLICTO DE INTERS Los revisores fueron los investigadores del ensayo controlado aleatorio que compar el metotrexato sistmico en un rgimen de dosis mltiple versus salpingostoma laparoscpica (Hajenius 1997), financiado mediante una subvencin del Health Insurance Funds Counsil, Amstelveen, Pases Bajos (OG 93/007) desde 1993 hasta 1996. El Profesor F van der Veen es un miembro de la Sociedad holandesa contra el Curanderismo. Lamenta incluir estudios con medicinas alternativas complementarias. FUENTES DE FINANCIACIN Recursos externos Clinical Fellow grant (no:907-00-154) from ZonMw, The Netherlands, Organisation for Health Research and Development, The Hague NETHERLANDS Recursos internos No se facilitaron las fuentes de financiacin

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REFERENCIAS
Referencias de los estudios incluidos en esta revisin Alleyassin 2006 {published data only} Alleyassin A, Khademi A, Aghahosseini M, Safdarian L, Badenoosh B, Akbari Hamed E. Comparison of success rates in the medical management of ectopic pregnancy with single-dose and multiple-dose administration of methotrexate: a prospective, randomized clinical trial. Fertility and Sterility 2006;85(6):1661-6. Cohen 1996 {published data only} Cohen DR, Falcone T, Khalife S, Hemmings R. Methotrexate: Local versus intramuscular. Fertility & Sterility 1996;65:206-7. Dias Pereira 1999 {published data only} Dias Pereira G, Hajenius PJ, Mol BWJ, Ankum WM, Hemrika DJ, Bossuyt PMM, et al. Fertility outcome after systemic methotrexate and laparoscopic salpingostomy for tubal pregnancy. Lancet 1999;353:724-5. Egarter 1991 {published data only} Egarter C, Kiss H, Husslein P. Prostaglandin versus expectant management in early tubal pregnancy. Prostaglandins Leukotrienes & Essential Fatty Acids 1991;42:177-9. El-Sherbiny 2003 {published data only} El-Sherbiny MT, El-Gharieb IH, Mera IM. Methotrexate verus laparoscopic surgery for the management of unruptured tubal pregnancy. Middle east Fertility Society Journal 2003;8(3):256-62. Elmoghazy 2000 {published data only} Elmoghazy DAM, Nour-El-Dine NM. Prevention of persistent ectopic pregnancy with single dose methotrexate after surgical conservation of the tube. Abstracts of the XVI FIGO World Congress of Obstetrics & Gynecology. Washington DC, USA: 2000:57. Fedele 1998 {published data only} Fedele L, Bianchi S, Tozzi L, Zanconato G, Silvestre V. Intramesosalpingeal injection of oxytocin in conservative laparoscopic treatment for tubal pregnancy: preliminary results. Human Reproduction 1998;13:3042-4. Fernandez 1991 {published data only} Fernandez H, Baton C. Treatment of ectopic pregnancy by transvaginal aspiration: Prospective randomized clinical trial of Methotrexate versus Sulprostone by sonographic injection followed by systemic injection. Contraception, Fertilite, Sexualite 1990;18(4):261-5. *Fernandez H, Baton C, Lelaidier C, Frydman R. Conservative management of ectopic pregnancy: prospective randomized clinical trial of methotrexate versus prostaglandin sulprostone by combined transvaginal and systemic administration. Fertility & Sterility 1991;55:746-50. Fernandez 1994 {published data only} Fernandez H, Bourget P, Ville Y, Lelaidier C, Frydman R. Treatment of unruptured tubal pregnancy with methotrexate: pharmacokinetic analysis of local versus intramuscular administration. Fertility & Sterility 1994;62:943-7. Fernandez 1995 {published data only} *Fernandez H, Pauthier S, Doumerc S, Lelaidier C, Olivennes F, Ville Y, et al. Ultrasound guided injection of methotrexate versus laparoscopic salpingotomy in ectopic pregnancy. Fertility & Sterility 1995;63:25-9. Fernandez H, Pauthier S, Sitbon D, Vincent Y, Doumerc S. Role of conservative therapy and medical treatment in ectopic pregnancy: literature review and clinical trial comparing medical treatment and conservative laparoscopic treatment. Contraception Fertilite Sexualite 1996;24:297-302. Fernandez 1998 {published data only} Fernandez H, Yves Vincent S, Pauthier S, Audibert F, Frydman R. Randomized trial of conservative laparoscopic treatment and methotrexate administration in ectopic pregnancy and subsequent fertility. Human Reproduction 1998;13:3239-43.

Fujishita 1995b {published data only} Fujishita A, Ishimaru T, Masuzaki H, Samejima T, Matsuwaki T, Ortega Chavez R, et al. Local injection of methotrexate dissolved in saline versus methotrexate suspensions for the conservative treatment of ectopic pregnancy. Human Reproduction 1995;10:3280-3. Fujishita 2004 {published data only} Fujishita A, Masuzaki H, Newaz Khan K, Kitajima M, Hiraki K, Ishimaru T. Laparoscopic salpingotomy for tubal pregnancy: comparison of linear salpingotomy with and without suturing. Human Reproduction 2004;19(5):1195-1200. Gazvani 1998 {published data only} Gazvani MR, Baruah DN, Alfirevic Z, Emery SJ. Mifepristone in combination with methotrexate for the medical mangement of tubal pregnancy: a randomized controlled trial. Human Reproduction 1998;13:1987-90. Gjelland 1995 {published data only} Gjelland K, Hordnes K, Tjugum J, Augensen K, Bergsj P. Treatment of ectopic pregnancy by local injection of hypertonic glucose: a randomized trial comparing administration guided by transvaginal ultrasound or laparoscopy. Acta Obstetricia et Gynecologica Scandinavica 1995;74:629-34. Graczykowski 1997 {published data only} Graczykowski JW, Mishell DR. Methotrexate prophylaxis for persistent ectopic pregnancy after conservative treatment by salpingostomy. Obstetrics & Gynecology 1997;89:118-22. Gray 1995 {published data only} Gray DT, Thorburn J, Lundorff P, Strandell A, Lindblom B. A cost-effectiveness study of a randomised trial of laparoscopy versus laparotomy for ectopic pregnancy. Lancet 1995;345:1139-43. Hajenius 1997 {published data only} *Hajenius PJ, Engelsbel S, Mol BWJ, Van der Veen F, Ankum WM, Bossuyt PMM, et al. Randomised trial of systemic methotrexate versus laparoscopic salpingostomy in tubal pregnancy. Lancet 1997;350:774-9. Hordnes 1997 {published data only} Hordnes K. Reproductive outcome after treatment of ectopic pregnancy with local injection of hypertonic glucose. Acta Obstetricia et Gynecologica Scandinavica 1997;76:703-5. Klauser 2005 {unpublished data only} Klauser CK, May WL, Johnson VK, Cowan BD, Hines RS. Methotrexate for ectopic pregnancy: a randomized single dose compared with multiple dose. Obstetrics and Gynaecology. 2005; Vol. 105:64S. Korhonen 1996 {published data only} Korhonen J, Stenman U, Ylostalo P. Low-dose oral methotrexate with expectant management of ectopic pregnancy. Obstetrics & Gynecology 1996;88:775-8. Landstrom 1998 {published data only} Landstrom G, Bryman I, Ekstrom P, Engman M, Gunnarsson J, Hjersing M, et al. Ectopic pregnancy: local medical treatment versus oral methotrexate therapy - a multicentre pilot study. Human Reproduction 1998;13:38. Lang 1990 {published data only} Lang PF, Weiss PA, Mayer HO, Haas JG, Honigl W. Conservative treatment of ectopic pregnancy with local injection of hyperosmolar glucose solution or prostaglandin F2a: a prospective randomised study. Lancet 1990;336:78-81. Lundorff 1991a {published data only} Lundorff P. Laparoscopic surgery in ectopic pregnancy. Acta Obstetrica et Gynecologica Scandinavica 1997;164:81-4. Lundorff P. Treatment of ectopics and subsequent adhesion formation. Progress in Clinical Biological Research 1993;381:139-47.

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*Lundorff P, Thorburn J, Hahlin M, Kallfelt B, Lindblom B. Laparoscopic surgery in ectopic pregnancy. A randomized trial versus laparotomy. Acta Obstetricia et Gynecologica Scandinavica 1991;70:343-8. Lundorff 1991b {published data only} Lindblom B, Lundorff P, Thorburn J. Second-look laparoscopy after ectopic pregnancy. Proceedings of the 6th annual Congress of the European Scociety for Gynaecological Endoscopy. Birmingham, UK: December 1997; Vol. Supplement 2:1. Lundorff P. Treatment of ectopics and subsequent adhesion formation. Progress in Clinical Biological Research 1993;381:139-47. *Lundorff P, Hahlin M, Kallfelt B, Thorburn J, Lindblom B. Adhesion formation after laparoscopic surgery in tubal pregnancy: a randomized trial versus laparotomy. Fertility & Sterility 1991;55:911-5. Lundorff 1992 {published data only} Lundorff P. Treatment of ectopics and subsequent adhesion formation. Progress in Clinical Biological Research 1993;381:139-47. Lundorff P, Thorburn J, Lindblom B. Fertility after conservative surgical treatment of ectopic pregnancy, evaluated in a ranomized trial. Ugeskr-Laeger 1993;155(41):3282-6. *Lundorff P, Thorburn J, Lindblom B. Fertility outcome after conservative surgical treatment of ectopic pregnancy evaluated in a randomized trial. Fertility & Sterility 1992;57:998-1002. Mol 1999a {published data only} Mol BWJ, Hajenius PJ, Engelsbel S, Ankum WM, Hemrika DJ, Van der Veen F, et al. The treatment of tubal pregnancy in The Netherlands: an economic evaluation of systemic methotrexate and laparoscopic salpingostomy. American Journal of Obstetrics & Gynecology 1999;181:945-51. Mottla 1992 {published data only} Mottla GL, Rulin MC, Guzick DS. Lack of resolution of ectopic pregnancy by intratubal injection of methotrexate. Fertility & Sterility 1992;57:685-7. Nieuwkerk 1998a {published data only} Nieuwkerk PT, Hajenius PJ, Ankum WM, Van der Veen F, Wijker W, Bossuyt PMM. Systemic methotrexate therapy versus laparoscopic salpingostomy in patients with tubal pregnancy. Part I. Impact on patients' health related quality of life. Fertility & Sterility 1998;70:511-7. Rozenberg 2003 {published data only} Garbin O, de Tayrac R, de Poncheville L, Coiffic J, Lucot JP, Le Goueff F, et al. Medical treatment of ectopic pregnancy; a randomized clinical trial comparing methotrexate-mifepristone and methotrexate-placebo. J Gynecol Obstet Biol Reprod 2004;33(5):391-400. *Rozenberg P, Chevret S, Camus E, de Tyrac R, Garbin O, Poncheville L, et al. Medical treatment of ectopic pregnancies: a randomized clinical trial comapring methotrexate-mifepristone and methotrexate-placebo. Human Reproduction 2003;18(9):1802-8. Sadan 2001 {published data only} Sadan O, Ginath S, Debby A, Rotmensch S, Golan A, Zakut H, et al. Methotrexate versus hyperosmolar glucose in the treatment of extrauterine pregnancy. Archives of Gynecology Obstetrics 2001;265:82-4. Saraj 1998 {published data only} Saraj AJ, Wilcox JG, Najmabadi S, Stein SM, Johnson MB, Paulson RJ. Resolution of hormonal markers of ectopic gestation: a randomized trial comparing single dose intramuscular methotrexate with salpingostomy. Obstetrics & Gynecology 1998;92:989-94. Sharma 2003 {published data only} Sharma JB, Gupta S, Malhotra M, Arora R. A randomized controlled comparison of minilaparotomy and laparotomy in ectopic pregnancy cases. Indian Journal of Medical Sciences 2003;57(11):493-500.

Shulman 1992 {published data only} Shulman A, Maymon R, Zmira N, Lotan M, Holtzinger M, Bahary C. Conservative treatment of ectopic pregnancy and its effect on corpus luteum activity. Gynecologic Obstetric Investigation 1992;33:161-4. Sowter 2001a {published data only} Sowter MC, Farquhar CM, Petrie KJ, Gudex G. A randomised trial comparing single dose systemic methotrexate and laparoscopic surgery for the treatment of unruptured ectopic pregnancy. British Journal of Obstetrics & Gynaecology 2001;108(2):192-203. Sowter 2001b {published data only} Sowter MC, Farquhar CM, Gudex G. An economic evaluation of single dose systemic methotrexate and laparoscopic surgery for the treatment of unruptured ectopic pregnancy. British Journal of Obstetrics & Gynaecology 2001;108(2):204-12. Tulandi 1991a {published data only} Tulandi T, Guralnick M. Treatment of tubal ectopic pregnancy by salpingotomy with or without tubal suturing and salpingectomy. Fertility & Sterility 1991;55:53-5. Tzafettas 1994 {published data only} Tzafettas J, Anapliotis S, Zournatzi V, Boucklis A, Oxouzoglou N, Bondis J. Transvaginal intra amniotic injection of methotrexate in early ectopic pregnancy. Advantages over the laparoscopic approach. Early Human Development 1994;39:101-7. Ugur 1996 {published data only} Ugur M, Yesilyurt H, Soysal S, Gokmen O. Prophylactic vasopressin during laparoscopic salpingotomy for ectopic pregnancy. Journal of the American Association Gynecologic Laparoscopists 1996;3:365-8. Vermesh 1989 {published data only} Vermesh M, Silva PD, Rosen GF, Stein AL, Fossum GT, Sauer MV. Management of unruptured ectopic gestation by linear salpingostomy: a prospective, randomized clinical trial of laparoscopy versus laparotomy. Obstetrics & Gynecology 1989;73:400-4. Vermesh 1992 {published data only} Vermesh M, Presser SC. Reproductive outcome after linear salpingostomy for ectopic gestation: a prospective 3 year follow up. Fertility & Sterility 1992;57:682-4. Wang 1998 {published data only} Wang J, Yang Q, Yu Z. Clinical study of tubal pregnancy treated with integrated traditional Chinese and Western medicine. Zhongguuo Zhong Xi Yi Jie Z Zhi (Chinese Journal of Integrated Traditional and Western Medicine) 1998;18:531-3. Yalcinkaya 1996 {published data only} Yalcinkaya TM, Brown SE, Thomas DW, Heywood ER, Resley TC, DePond RT. A comparison of 25 mg/m2 and 50 mg/m2 dose of methotrexate for the treatment of ectopic pregnancy. Abstract of the Scientific Oral and Poster Sessions of the American Society for Reproductive Medicine. Boston, USA: November 1996:O-027. Yalcinkaya 2000 {published data only} Yalcinkaya TM, Brown SE, Mertz HL, Thomas DW. A comparison of 25 mg/m2 vs 50 mg/m2 dose of methotrexate (MTX) for the treatment of ectopic pregnancy (EP). J Soc Gynecol Invest. 2000; Vol. 7, issue 1:179A. Zilber 1996 {published data only} Zilber U, Pansky M, Bukovsky I, Golan A. Laparoscopic salpingostomy versus laparoscopic local methotrexate injection in the management of unruptured ectopic gestation. American Journal of Obstetrics & Gynecology 1996;175:600-2.

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Referencias de los estudios excluidos de esta revisin Colacurci 1998 Colacurci N, De Franciscis P, Zarcone R, Fortunato N, Passaro M, Mollo A, et al. Time length of negativization of hCG serum values after either surgical or medical treatment of ectopic pregnancy. Panminerva Medica 1998;40(3):223-5. Kaya 2002 Kaya H, Babar Y, Ozmen S, Ozkaya O, Karci M, Aydin AR, et al. Intra tubal methotrexate for prevention of persistent ectopic pregnancy after salpingostomy. J Am Assoc Gynecol Laparosc 2002;9(4):464-7. Koninckx 1991 Koninckx PR, Witters K, Brosens J, Stemers N, Oosterlynck D, Meuleman C. Conservative laparoscopic treatment of ectopic pregnancies using the CO2 laser. British Journal of Obstetrics & Gynaecology 1991;98:1254-9. Laatikainen 1993 Laatikainen T, Tuomivaara L, Kaar K. Comparison of a local injection of hyperosmolar glucose solution with salpingostomy for the conservative treatment of tubal pregnancy. Fertility & Sterility 1993;60:80-4. Lund 1955 Lund J. Early ectopic pregnancy -comments on conservative treatment. Journal of Obstetrics & Gynecology of the British Empire 1955;62:70-6. Murphy 1992 Murphy AA, Nager CW, Wujek JJ, Kettel LM, Torp VA, Chin HG. Operative laparoscopy versus laparotomy for the management of ectopic pregnancy: a prospective trial. Fertility & Sterility 1992;57:1180-5. O'Shea 1994 O Shea RT, Thompson GR, Harding A. Intra amniotic methotrexate versus CO2 laser laparoscopic salpingotomy in the management of tubal ectopic pregnancy a prospective randomized trial. Fertility & Sterility 1994;62:876-8. Porpora 1996 Porpora MG, Oliva MM, De Cristofaro A, Montanino G, Cosmi EV. Comparison of local methotrexate and linear salpingostomy in the conservative laparoscopic treatment of ectopic pregnancy. Journal of the American Association of Gynecologic Laparoscopists 1996;3:271-6. Referencias de los estudios en espera de evaluacin Hu 2003 Peng 1997 Su 2002 Wei 2003 Referencias de los estudios en marcha Fernandez 1 Unknown. Randomized controlled trial between medical treatment by methotrexate versus conservative surgical treatment to evaluate subsequent fertility. Ongoing study 08-2004. Fernandez 2 Unknown. Randomised controlled trial between conservative versus radical surgical treatment to evaluate subsequent fertility. Ongoing study 08-2004. Hajenius 1 Unknown. A randomised controlled trial of salpingostomy versus salpingectomy for tubal pregnancy; impact on future fertility. Ongoing study 01-09-2004. Hajenius 2 Unknown. Randomised controlled trial of systemic MTX in an intramuscular single shot regimen versus expectant management. Ongoing study 01-02-2006.

Jurkovic Unknown. Randomised double blind placebo controlled trial of single dose methotrexate versus expectant management in women with tubal ectopic pregnancy. Ongoing study 01-09-2005. Referencias adicionales Ankum 1993 Ankum WM, Van der Veen F, Hamerlynck JVThH, Lammes FB. Laparoscopy; A dispensable tool in the diagnosis of ectopic pregnancy?. Human Reproduction 1993;8:1301-6. Ankum 1995 Ankum WM, van der Veen F, Hamerlynck HV, Lammes FB. Suspected ectopic pregnancy. What to do when human chorionic gonadotropin levels are below the discriminatory zone. Suspected ectopic pregnancy. What to do when human chorionic gonadotropin levels are below the discriminatory zone. Suspected ectopic pregnancy. What to do when human chorionic gonadotropin levels are below the discriminatory zone. suspected ectopic pregnancy. What to do when the serum human chorionic gonadotrophin levles. Journal of Reproductive Medicine 1995;40:525-8. ASRM 2006 The Practice Committee of the American Society for Reproductive Medicine. Medical treatment of ectopic pregnancy. Fertility and Sterility 2006;86(Supplement 5):96-102. Bagshawe 1989 Bagshawe KD, Kent J, Newlands ES, Begent RH, Rustin GJ. The role of low dose methotrexate and folinic acid in gestational trophoblastic tumors. British Journal of Obstetrics and Gynaecology 1989;96:795-802. Banerjee 2001 Banerjee S, Aslam N, Woelfer B, Lawrence A, Elson J, Jurkovic D. Expectant management of early pregnancies of unknown location: a prospective evaluation of methods to predict spontaneous resolution of pregnancy. British Journal of Obstetrics and Gynaecology 2001;108:158-63. Chotiner 1985 Chotiner HC. Nonsurgical management of ectopic pregnancy associated with severe hyperstimulation syndrome. Obstetrics and Gynecology 1985;66:740-3. Clausen 1996 Clausen I. Conservative versus radical surgery for tubal pregnancy. Acta Obstetrica Gynecologica Scandinavia 1996;75:8-12. Condous 2004 Condous G, Okaro E, Khalid A, Timmerman D Lu C, Zhou Y, van Huffel S, Bourne T. The use of a new logistic regression model for prediciting the outcome of pregnancies of unknown location. Human Reproduction 2004;19:1900-10. Condous 2005 Condous G, Kirk E, Lu C, Van Huffel S, Gevaert O, De Moor B, De Smet F, Timmerman D, Bourne T. Diagnostic accuracy of varying discriminatory zones for the prediction of ectopic pregnancy in women with a pregnancy of unknown location. Ultrasound in Obstetrics and Gynecology 2005;26:770-775. Egarter 1988 Egarter Ch, Husslein P. Treatment of tubal pregnancy by prostaglandins. Lancet 1988;14:1104-5. Elson 2004 Elson J, Tailor A, Banerjee S, Salim R, Hillaby K, Jurkovic D. Expectant mangement of tubal ectopic pregnancy: prediction of succesful outcome using decision tree analysis. Ultrasound in Obstetrics and Gynaecology 2004;23:552-6. Fernandez 1993 Fernandez H, Baton C, Beniflan JL, Frydman R, Lelaidier C. Methotrexate treatment of ectopic pregnancy: 100 cases treated by primary transvaginal injection under sonographic control. Fertility & Sterility 1993;59:773-7.

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Fujishita 1995a Fujishita A, Ishimaru T, Masuzaki H, Samejima T, Matsuwaki T, Ortega Chavez R, et al. A new approach to methotrexate and lipiodol suspensions for ectopic pregnancy. Preliminary in vitro and animal experiments. International Journal of Obstetrics & Gynecology 1995;21:529-35. Goldstein 1976 Goldstein DP, Goldstein PR, Bottomly P, Osathanondh R, Marean AR. Methotrexate with citrovorum factor rescue for nonmetastatic gestational trophoblastic neoplasms. Obstetrics and Gynecology 1976;46:321-3. Hajenius 1995a Hajenius PJ, Mol BWJ, Ankum WM, Veen van der F, Bossuyt PMM, Lammes FB. Clearance curves of serum human chorionic gonadotrophin for the diagnosis of persistent trophoblast. Human Reproduction 1995;10:683-7. Hajenius 1995b Hajenius PJ, Mol BWJ, Ankum WM, van der Veen F, Bossuyt PMM, Lammes FB. Suspected ectopic pregnancy: Expectant management in patients with negative sonographic findings and low serum hCG concentrations. Early Pregnancy: Biology and Medicine 1995;1:258-62. Hochner 1992 Hochner-Celniker D, Ron M, Goshen R, Zacut D, Amir G, Yagel S. Rupture of ectopic pregnancy following disappearance of serum beta subunit of hCG. Obstetrics & Gynecology 1992;79:826-7. Kirk 2006 Kirk E, Condous G, Bourne T. The non-surgical management of ectopic pregnancy. Utrasound in Obstetrics and Gynecology 2006;27:91-100. Korhonen 1994 Korhonen J, Stenman UH, Ylstalo P. Serum human chorionic gonadotropin dynamics during spontaneous resolution of ectopic pregnancy. Fertility & Sterility 1994;61:632-6. Lang 1989 Lang P, Weiss PAM, Mayer HO. Local application of hyperosmolar glucose solution in tubal pregnancy. Lancet 1989;2:922-3. Lindblom 1987 Lindblom B, Hahlin M, Kllfelt B, Hamberger L. Local Prostaglandin F2a injection for termination of ectopic pregnancy. Lancet 1987;4:776-7. Mashiach 1982 Mashiach S, Carp HJA, Serr DM. Non operative management of ectopic pregnancy: a preliminary report. Journal of Reproductive Medicine 1982;27:127. Maymon 1996 Maymon R, Shulman A. Maymon R, Shulman A [Controversies and problems in the current management of tubal pregnancy]. Human Reproduction Update 1996;2:541-51. Mol 1996 Mol BWJ, Hajenius PJ, Ankum WM, Van der Veen F, Bossuyt PMM. Conservative versus radical surgery for tubal pregnancy - letter to the editor. Acta Obstetricia et Gynecologica Scandinavica 1996;75:866-7. Mol 1998a Mol BWJ, Matthijsse HM, Tinga DJ, Huynh VT, Hajenius PJ, Ankum WM, et al. Fertility after conservative and radical surgery for tubal pregnancy. Human Reproduction 1998;13:1804-9. Mol 1998b Mol BWJ, Hajenius PJ, Engelsbel S, Ankum WM, Van der Veen F, Hemrika DJ, et al. Serum human chorionic gonadotropin measurement in the diagnosis of ectopic pregnancy when transvaginal sonography is inconclusive. Fertility & Sterility 1998;70:972-981.

Mol 1999b Mol BW, van der Veen F, Bossuyt PM. Implementation of probabilistic decision rules improves the predictive values of algorithms in the diagnostic management of ectopic pregnancy. Human Reproduction 1999;14:2855-62. Natale 2004 Natale A, Candiani M, Barbieri M, Calia C, Odorizzi MP, Busacca M. Pre and post treatment patterns of human chorionic gonadotropin for early detection of persistence after a single dose of methotrexate for ectopic pregnancy. European Journal of Obstetrics and Gynecology and Reproductive Biology 2004;117:87-92. Nieuwkerk 1998b Nieuwkerk PT, Hajenius PJ, Van der Veen F, Ankum WM, Wijker W, Bossuyt PMM. Systemic methotrexate therapy versus laparoscopic salpingostomy in tubal pregnancy. Part II Patient preferences for systemic methotrexate. Fertility & Sterility 1998;7:518-22. Ory 1986 Ory SJ, Alelei L, Villanueva AL, Sand PK, Tamura RK. Conservative treatment of ectopic pregnancy with methotrexate. American Journal of Obstetrics & Gynecology 1986;154:1299-306. Pansky 1989 Pansky M, Bukovsky I, Golan A, Langer R, Schneider D, Arieli S, et al. Local methotrexate injection: A nonsurgical treatment of ectopic pregnancy. Obstetrics & Gynecology 1989;161:393-6. Seifer 1990 Seifer DB, Gutman JN, Doyle MB, Jones EE, Diamond MP, DeCherney AH. Persistent ectopic pregnancy following laparoscopic linear salpingostomy. Obstetrics & Gynecology 1990;76:1121-5. Spandorfer 1997 Spandorfer SD, Sawin SW, Benjamin I, Barnhart KT. Postoperative day 1 serum human chorionic gonadotropin level as a predictor of persistent ectopic pregnancy after conservative surgical management. Fertility & Sterility 1997;68:430-4. Stovall 1991 Stovall TG, Ling FW, Gray LA. Single-dose methotrexate for treatment of ectopic pregnancy. Obstetrics & Gynecology 1991;77:754-7. Stovall 1993 Stovall TG, Ling FW. Single-dose methotrexate: An expanded clinical trial. American Journal of Obstetrics & Gynecology 1993;168:1759-65. Sultana 1992 Sultana CJ, Easley K, Collins RL. Outcome of laparoscopic versus traditional surgery for ectopic pregnancies. Fertility & Sterility 1992;57:285-9. Tanaka 1982 Tanaka T, Haydshi H, Kutsuzawa T, Fujimoto S, Ichinoe K. Treatment of interstitial ectopic pregnancy with methotrexate: report of a successful case. Fertility and Sterility 1982;37:851-2. Tulandi 1991b Tulandi T, Hemmings R, Khalifa F. Rupture of ectopic pregnancy in women with low and declining serum -human chorionic gonadotropin concentrations. Fertility & Sterility 1991;56:786-7. Whitehead 1992 Whitehead J. The design and analysis of sequential clinical trials. Ellis Horwood. Chichester: Ellis Horwood, 1992. * El asterisco seala los documentos ms importantes para este estudio

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TABLAS Characteristics of included studies Study Methods Alleyassin 2006 Randomization using sealed envelopes, with block randomization using a computer generated random table Single center A sample size of 49 women in each group was calculated to find a 21% difference in success rate of single dose and multiple dose treatment (alpha < 0.05 and beta = 0.2) No source of funding stated Ethical commitee approval Published as full paper Hemodynamically stable women with a tubal mass < 3.5 cm in diameter on transvaginal sonography with absence of fetal heart beat and serum hCG < 15,000 IU/l and fear of patient future infertility Number of women randomized: 108 The trial was carried out at Dr. Shariati Hospital Tehran, Iran between September 23, 2003 to March 21, 2005 Single dose systemic MTX 50 mg/m2 IM versus multiple dose systemic MTX 1.0 mg/kg IM on days 0,2,4,6 alternated folinic acid 0.1 mg/kg oral on days 1,3,5,7 Treatment success method of diagnosis: complete elimination of the ectopic pregnancy (serum hCG < 15 IU/L) Persistent trophoblast method of diagnosis: in the single dose group if the serum hCG concentration on day 7 did not decrease by 15% after one week of treatment or serum hCG not < 15 IU/l after 6 weeks of treatment. In the multiple dose group if the serum hCG concentration did not decrease by 15% in 48 hours or serum hCG not < 15 IU/l after 6 weeks of treatment. Persistent trophoblast was treated with single dose systemic MTX. Need for surgery hCG clearance time method of diagnosis: the mean number of days to reach serum hCG concentrations < 15 IU/l Complications method of diagnosis: MTX related side effects were recorded Ectopic pregnancy was diagnosed if serum hCG > 1,800 IU/l and no viable intra uterine pregnancy was evident and if the serum hCG concentration was < 1,800 IU/l but plateauing or < 50% increase over 48 hours A - Adequate Cohen 1996 Randomization using computer generated random number tables Single center No power calculation No source of funding stated Ethical commitee approval not stated Published as full paper

Participants

Interventions Outcomes

Notes

Allocation concealment Study Methods

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Characteristics of included studies Participants Clinically stable women with an ectopic pregnancy (< 3.5 cm) with rising serum hCG concentrations Number of women randomized: 20 The trial was carried out at the McGill University, Cleveland, Ohio, USA Timing and duration of the trial not stated MTX 1 mg/kg transvaginally under sonographic guidance versus systemic MTX single dose 50 mg/m2 IM Treatment success method of diagnosis: an uneventful decline of serum hCG to undetectable levels (< 12 IU/l) Treatment failure method of diagnosis: a subsequent necessary surgical intervention for abdominal pain Persistent trophoblast method of diagnosis: a second methotrexate injection by the same route as the initial one for a serum hCG decline < 15% or a rise between days 4 and 7, or a plateau between the weekly levels hCG resolution time method of diagnosis: mean number of days for serum hCG to become < 12 IU/L Ectopic mass resolution time method of diagnosis: mean number of days for the ectopic mass to become undetectable on transvaginal sonography Side effects method of diagnosis: not clearly stated, ie. follow-up of blood counts and liver enzymes Serum MTX levels method of diagnosis: not stated Pregnancy outcome method of diagnosis: occurrence of pregnancy, follow-up not stated

Interventions Outcomes

Notes Allocation concealment Study Methods A - Adequate Dias Pereira 1999 Randomization by a computer program with block randomization, with stratification for pre-existing tubal pathology and initial serum hCG concentration. Randomization was done before a confirmative laparoscopy. Multi center Tubal patency rate after laparoscopic salpingostomy was assumed to be 80%. A sample size of 100 patients would allow to detect a difference in tubal patency rate, in favour of systemic methotrexate, of 18%, with a two-sided chi square test at p = 0.05 and with a power of 80% Funding by the Health Insurance Funds Council, Amstelveen, The Netherlands Ethical commitee approval Intention to treat analysis Published as letter to the editor

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Characteristics of included studies Participants Hemodynamically stable women with a laparoscopically confirmed unruptured tubal pregnancy without fetal cardiac activity and no signs of active bleeding, no contraindications to receiving systemic MTX, (leucopenia, thrombocytopenia, or high concentrations of liver enzymes or serum creatinine) or contraindications to laparoscopic surgery, (documented extensive pelvic adhesions, large fibroid uterus, and severe ovarian hyperstimulation syndrome) Number of women randomized: 74 Number of women originally randomized 140 Secondary exclusions for nontubal pregnancy, tubal rupture, and/or active bleeding: 40 Lost to follow-up: 10 No desire for future pregnancy: 16 The trial took place in six Dutch hospitals: the Academic Medical Center of the University of Amsterdam, the Onze Lieve Vrouwe Gasthuis and the University Hospital Free University in Amsterdam and the University Hospitals of Groningen, Nijmegen and Utrecht, The Netherlands between January 1, 1994 and September 1, 1996 Systemic MTX 1.0 mg/kg IM on days 0,2,4,6 alternated folinic acid 0.1 mg/kg oral on days 1,3,5,7 versus laparoscopic salpingostomy Fertility outcome method of diagnosis: cumulative frequency and pregnancy outcome of first subsequent pregnancy by means of telephonic contacts or questionnaires

Interventions Outcomes

Notes Allocation concealment Study Methods A - Adequate Egarter 1991 Randomization during laparoscopy, method not stated Single center Interim analysis was planned in order to stop the study as soon as a statistical trend for any of the groups could be demonstrated. It was estimated that a sample of about 20 patients per group would be required Funding by the Medizininisch Wissenschaftlicher Fonds der Brgermeisters der Bundeshauptstadt Wien and by the Japan Society for the Promotion of Science Ethical commitee approval Published as full paper Women with a laparoscopically confirmed unruptured tubal pregnancy without active bleeding and a serum hCG concentration < 2,500 IU/l Number of women randomized: 23 The trial was carried out at the I Univ Frauenklinik, Vienna, Austria Timing and duration of the trial not stated 10 mg PGF2alpha in 1.5-2 ml into the the tubal pregnancy + 25 mg conjugated estrogens injected into the ipsilateral ovary under laparoscopic guidance + 500 mg synthetic PGE2 derivate IM twice daily during the first 3 postoperative days versus 1.5-2 ml isotonic NaCl solution injected into the tubal pregnancy under laparoscopic guidance versus no medical therapy at all

Participants

Interventions

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Characteristics of included studies Outcomes Treatment success method of diagnosis: an uneventful decline of serum hCG to undetectable levels Treatment failure method of diagnosis: a subsequent surgical intervention with removal of the tubal pregnancy for postoperatively rising serum hCG concentrations and/or increase in clinical/abdominal symptoms Hospitalization time method of diagnosis: number of days in the hospital Side effects method of diagnosis: not stated If possible, all women were released from the hospital on the second postoperative day B - Unclear El-Sherbiny 2003 Method of randomization by computer Multi center No power calculation No source of funding stated No ethical commitee approval Published as full paper hemodynamically stable patients with confirmed diagnosis of unruptured tubal pregnancy < 4 cm without fetal cardiac activity and a serum hCG < 10,000 IU/l and no contraindications for laparoscopic surgery or MTX (elevated serum liver enzymes, creatinine > 1.3 mg/dl, WBCs < 3,000/mm3 and platelets < 50,000/mm3) and desire for future pregnancy Number of women initially randomized: 55 The trial was carried out at two governmental hospitals (Damietta General Hospital and El Mataria Teaching Hospital in Cairo) and two private hospitals (El-Sherbiny Hospital in Damietta and Mera Center in El Mansoura) in Egypt between February 1996 trough July 2001 Single dose systemic MTX (50 mg/m2) versus laparoscopic surgery Treatment success method of diagnosis: an uneventful decline of serum hCG to undetectable levels ( < 5 IU/l) Tubal patency method of diagnosis: by hysterosalpingogram 3-6 months post treatment Persistent trophoblast method of diagnosis: < 50% fall of initial level in serum hCG by day 7 or 90% by day 12, or started to plateau or rise thereafter Fertility outcome method of diagnosis: intra uterine pregnancy and repeat ectopic pregnancy within one year post treatment follow up

Notes Allocation concealment Study Methods

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Characteristics of included studies Notes The authors were contacted by e-mail for further information on the trial. In all centers a non-laparoscopic diagnostic algorithm was followed to diagnose tubal ectopic pregnancy Salpingostomy was performed unless there was an indication for salpingectomy (n=8), ie. uncontrollable post salpingostomy bleeding (n=2), tubal rupture (n=1), severe peritubal adhesions (n=2), or recurrent ectopic pregnancy in the same tube on patients request (n=3). Persistent trophoblast was treated with 50mg/m2 MTX orally Pregnancy was allowed after 3 months Women who did not conceive were offered an hysterosalpingogram post ectopic treatment B - Unclear Elmoghazy 2000 Method of randomization not stated Single center No power calculation Source of funding not stated Ethical commitee approval not stated Published as abstract All women with early diagnosed tubal pregnancy who underwent surgical conservation of the tube Number of women randomized: 47 The trial was carried out El-Minia University in Egypt Timing and duration of the trial not stated Conservative surgery of the tube and a single dose of MTX postoperatively (1 mg/kg IM) within 24 hours versus conservative surgery alone Treatment success method of diagnosis: an uneventful decline of serum hCG to undetectable levels ( < 15 IU/l) Persistent trophoblast method of diagnosis: a rise or plateau of serum hCG concentration postoperatively or an inadequate decline (< 20% between two consecutive measurements taken seven days apart) Side effects method of diagnosis: recording of any complication related to MTX and measurement of complete blood picture, liver and kidney functions before and one week after MTX dose

Allocation concealment Study Methods

Participants

Interventions Outcomes

Notes Allocation concealment Study Methods B - Unclear Fedele 1998 Randomization by telephone using a computer generated list before salpingotomy Multi center No power calculation Source of funding not stated Ethical commitee approval Published as full paper

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Characteristics of included studies Participants Women with a laparoscopically confirmed unruptured tubal pregnancy < 5 cm without adhesions involving the salpinx Number of women randomized: 25 The trial took place at the University of Verona, the University of Milano, and Ospedale di Gallarate, Gallerate, Italy, between October 1995 and June, 1997 Laparoscopic salpingotomy with intramesosalpingeal injection of 20 IU oxytocin diluted in 20 ml saline versus laparoscopic salpingotomy with intramesosalpingeal injection of 20 ml saline alone Treatment success method of diagnosis: conversion to salpingectomy Bleeding during salpingotomy method of diagnosis: by means of an assessment form using scores 1 to 3 1. minimal, 2. moderate, 3. abundant Removal of the pregnancy method of diagnosis: by means of an assessment form using scores 1 to 3 1. easy, 2. moderately difficult, 3. difficult Bleeding at the site of the pregnancy method of diagnosis: by means of an assessment form using scores 1 to 3 1. minimal, 2. moderate, 3. abundant The decision to perform salpingotomy was made by the surgeon on the basis of an overall clinical assessment (age, obstetric history, desire for children and general conditions) and intraoperative findings (nonruptured tube, size < 5 cm, absence of adhesions ivolving the salpinx, and conditions of the contralateral tube) The surgeons were not blinded for the intervention A - Adequate Fernandez 1991 Randomization using a random number table Single center No power calculation No source of funding stated Ethical commitee approval Published as full paper Women with a transvaginal sonographical finding of a gestational sac in the fallopian tube with an empty uterus, and no evidence of fluid in the pouch of Douglas, and without abdominal pain Number of women randomized: 21 The trial was carried out at the Hpital Antoine Bclre, Clamart, France between April 1, 1989 and December 31, 1989 MTX 1mg/kg transvaginally under sonographic guidance on day 1 combined with systemic MTX 1mg/kg IM on days 3,5,7 alternated with folinic acid 0.1 mg/kg IM on days 2,4,6,8 versus Sulprostone 500 mg transvaginally under sonographic guidance on day 1, combined with 500 mg IM on days 2,3

Interventions

Outcomes

Notes

Allocation concealment Study Methods

Participants

Interventions

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Characteristics of included studies Outcomes Treatment success method of diagnosis: an uneventful decline of serum hCG to undetectable levels (< 10 IU/l) Treatment success analyzed from initial hCG level method of diagnosis: initial serum hCG level < 1000 IU/l versus 1000-5000 IU/l versus > 5000 IU/l Treatment failure method of diagnosis: operative reintervention (laparoscopy) for the occurrence of abdominal pain or rising serum hCG concentrations hCG resolution time method of diagnosis: mean number of days for serum hCG to become < 10 IU/l Hospitalization time method of diagnosis: number of days in the hospital Side effects method of diagnosis: complete blood count, liver and kidney function test monitored twice weekly Tubal patency method of diagnosis: by hysterosalpingogram 2 months after the first menstruation Pregnancy outcome method of diagnosis: recording desire for pregnancy and occurrence and outcome of pregnancy, follow-up > 6 months Before injecting medical therapy the tubal content was aspirated and 2.5 cm3 volume of both drugs was administered into the ectopic sac Women were discharged from the hospital when serum hCG levels dropped below 30% of preoperative level, excluding the women treated on an outpatient basis B - Unclear Fernandez 1994 Randomization by blinded computer generated random number tables Single center No power calculation No source of funding stated Ethical commitee approval Published as full paper Women with an unruptured ectopic pregnancy clearly visualized by transvaginal sonography and a predictive therapeutic score < 14 Number of women randomized: 48 The trial was carried out at the Hpital Antoine Bclre, Clamart, France between July and October 1991 MTX 1 mg/kg injected transvaginally under sonographic guidance combined with systemic MTX 1 mg/kg IM after 48 hours versus MTX 1 mg/kg transvaginally under sonographic guidance versus MTX 0.5 mg/kg transvaginally under sonographic guidance versus systemic single dose MTX 1 mg/kg IM

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Characteristics of included studies Outcomes Treatment success method of diagnosis: an uneventful decline of serum hCG to undetectable levels (< 10 IU/l) by primary treatment Treatment failure method of diagnosis: an operative reintervention for the occurrence of unusual abdominal pain or an inadequate decrease of serum hCG (40% above the hCG values observed on the normal regression curve 10 days after initial MTX administration) Persistent trophoblast method of diagnosis: additional systemic MTX injections IM for serum hCG concentrations 20% above the hCG values observed on the normal regression curve 10 days after initial MTX administration hCG resolution time method of diagnosis: number of days for serum hCG to become < 10 IU/l Side effects method of diagnosis: occurrence of stomatitis, complete blood count and renal and liver function tests at days 2 and 15 after MTX administration MTX plasma levels (fluorescent polarization immuno assay) and pharmacokinetic parameters ie.terminal phase rate constant, terminal half life, area under the curve, mean residence time, time to maximal concentration, maximal concentration and minimal concentration after 48 hours method of diagnosis: venous blood samples at 0.25, 0.5, 1, 2, 6, 12, 24, 36, 48 hours after MTX administration Pretherapeutic predictive score are six criteria graded on the scale from 1 to 3; gestational age, serum hCG level, serum progesterone level, existence of abdominal pain, ultrasound evaluation of hemoperitoneum volume, and heamatosalpinx diameter Before injecting medical therapy the tubal content was aspirated A - Adequate Fernandez 1995 Randomization using a random number table Single center No power calculation No source of funding stated Ethical commitee approval Published as full paper All women with ectopic pregnancy visualized by transvaginal sonography with a pretherapeutic score < 13, and no suspicion of rupture or liver or kidney diseases and/or abnormal laboratory parameters with elevated liver enzymes or neutropenia that contraindicated MTX treatment Number of women randomized: 40 The trial was carried out at the Hpital Antoine Bclre, Clamart, France between September 1, 1992 and October 1, 1993 MTX 1 mg/kg transvaginally under sonographic guidance versus laparoscopic salpingostomy

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Characteristics of included studies Outcomes Treatment success method of diagnosis: an uneventful decline of serum hCG to undetectable levels (< 10 IU/l) by primary treatment Treatment failure method of diagnosis: additional injection of systemic MTX IM or surgical reintervention for persistence of high serum hCG concentrations, or the occurrence of abdominal pain hCG resolution time method of diagnosis: mean number of days for serum hCG to become < 10 IU/l Hospitalization time method of diagnosis: number of postoperative days in the hospital Side effects method of diagnosis: liver function test and red and white cell counts on day 10 Tubal patency method of diagnosis: by hysterosalpingogram 2 months after the first menstrual period Pregnancy outcome method of diagnosis: recording desire for pregnancy and occurrence and outcome of pregnancy by personal or telephonic contact, follow-up > 6 months Part of the results are updated in the study of Fernandez 1998 Pretherapeutic predictive score are six criteria graded on the scale from 1 to 3; gestational age, serum hCG level, serum progesterone level, existence of abdominal pain, ultrasound evaluation of hemoperitoneum volume, and heamatosalpinx diameter Before injecting medical therapy the tubal content was aspirated In the MTX group women were monitored on an outpatient basis, unless they lived too far of the hospital. In the laparoscopy group women were hospitalized for 2 days as is usual in France B - Unclear Fernandez 1998 Randomization using a random number table Single center No power calculation No source of funding stated Ethical commitee approval Published as full paper All women with ectopic pregnancy visualized by transvaginal or transabdominal sonography with a pretherapeutic score < 13, and no suspicion of rupture or liver or kidney diseases and/or abnormal laboratory parameters with elevated liver enzymes or neutropenia that contraindicated MTX treatment Number of women randomized: 100 Lost to follow up: 18 No desire for pregnancy: 26 The trial was carried out at the Hpital Antoine Bclre, Clamart, France between September 1, 1992 and October 1, 1995 MTX 1 mg/kg transvaginally under sonographic guidance versus laparoscopic salpingostomy and systemic single dose MTX 1 mg/kg IM (in women whose ectopic pregnancy could not be safely or easily punctured) versus laparoscopic salpingostomy

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Characteristics of included studies Outcomes Treatment success method of diagnosis: an uneventful decline of serum hCG to undetectable levels (< 10 IU/l) by primary treatment Tubal preservation method of diagnosis: tubal preservation after primary treatment plus any additional conservative therapeutic interventions Treatment failure method of diagnosis: additional injection of systemic MTX IM or surgical reintervention for persistence of high serum hCG concentrations, or the occurrence of abdominal pain or both hCG resolution time method of diagnosis: mean number of days for serum hCG to become < 10 IU/l Hospitalization time method of diagnosis: number of postoperative days in the hospital Pregnancy outcome method of diagnosis: recording desire for pregnancy and occurrence and outcome of pregnancy by personal or telephonic contact, follow-up > 1 year Results have been reported earlier for 40 women (20 treated by local MTX under sonographic guidance and 20 by laparoscopic salpingostomy) in the study of Fernandez 1995 Pretherapeutic predictive score are six criteria graded on the scale from 1 to 3; gestational age, serum hCG level, serum progesterone level, existence of abdominal pain, ultrasound evaluation of hemoperitoneum volume, and heamatosalpinx diameter In the MTX group women were monitored on an outpatient basis, unless they lived too far of the hospital or the procedure was preformed after 16.00 hours. In the laparoscopy group women were hospitalized for 2 days as is recommended in France and reimbursed by the French national health insurance system. B - Unclear Fujishita 1995b Method of randomization not stated Single center No power calculation No source of funding stated Ethical commitee approval not stated Published as full paper All women with desire for future pregnancy with an unruptured ectopic pregnancy (< 5 cm), estimated blood loss into the peritoneal cavity < 500 ml, no active bleeding, and no fetal cardiac activity Number of women randomized: 26 The trial was carried out at the Nagasaki University School of Medicine, Nagasaki, Japan between May 1991 to July 1993 MTX 20-50 mg dissolved in 2 ml physiological saline versus MTX 20-50 mg dissolved in 2 ml lipiodol with phoshatidylcholine both under laparoscopic guidance

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Characteristics of included studies Outcomes Treatment success method of diagnosis: an uneventful decline of urine and serum hCG to undetectable levels (< 2 IU/l) Treatment failure method of diagnosis: rupture Persistent trophoblast method of diagnosis: additional systemic MTX 20 mg IM for 4 days for a rise or less than smoothly decline in serum hCG hCG resolution time method of diagnosis: mean number of days for urine hCG and serum hCG to become < 2 IU/l Complications method of diagnosis: not stated Tubal patency method of diagnosis:by hysterosalpingogram 3 months after initial treatment Pregnancy outcome method of diagnosis: recording desire for pregnancy and occurrence and outcome of pregnancy, follow-up 6-31 months MTX dose in first four women 20 mg, remaining women 50 mg In one woman MTX suspension was administered transvaginally under sonographic guidance B - Unclear Fujishita 2004 Method of randomization by computer generated randomization list Single center 50 patients were needed to reduce the adhesion rate from 50% after salpingotomy with suturing to 25% in the non suturing group No source of funding stated Ethical commitee approval Published as full paper Hemodynamically stable women with a tubal pregnancy without signs of active bleeding and no severe adhesions in the tubal wall in whom successfull salpingotomy was performed Number of women randomized: 75 Number of patients for second look laparoscopy: 38 Lost to follow up: 9 Desire for pregnancy: 22 The trial was carried out at Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan between May 1996 to December 2002 Salpingotomy without tubal suturing versus salpingotomy with tubal suturing

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Characteristics of included studies Outcomes Treatment success method of diagnosis: an uneventful decline of serum hCG to undetectable levels Persistent trophoblast method of diagnosis: uneventful decline of serum hCG for which addtional MTX (20 mg im for 4 days) was installed Operation time: method of diagnosis; mean operation time in minutes Tubal patency method of diagnosis: number of patent ipsilateral tubes at second look laparoscopy by chromopertubation Peritubal adhesion rate method of diagnosis: degree of ipsilateral adhesions conform the American Fertility Society classification 1998 at second look laparoscopy Tubal fistula Method of diagnosis: at second look laparoscopy Reproductive performance method of diagnosis: (cumulative) intrauterine (viable fetus) and ectopic pregnancy rate after 6-65 months The authors were contacted to provide more data on persistent trophoblast and how this was treated and on the number of women with spontaneous pregnancies. Surgery was performed by laparoscopy Tubal suturing was performed by closing the incision in one layer by one or two interrupted sutures using absorbable stiches Second look laparoscopy was performed 3 months after the initial operation The authors included pregnancies that were the result of IVF-ET B - Unclear Gazvani 1998 Randomization by consecutively numbered envelopes. A computer generated randomization sequence was used. Randomization was done after a confirmative laparoscopy. Single center Sample size was not based on prespecified power calculations as this study was a feasibility study. The aim was to recuit all eligible women in a 24 month period No source of funding stated Ethical commitee approval not stated Intention to treat analysis Published as full paper Hemodynamically stable women with a laparoscopically confirmed unruptured tubal pregnancy without active bleeding from the fimbrial end, < 4 cm on transvaginal sonography, no contraindications to receiving systemic MTX (hepatic or renal dysfuction, haemorrhagic disordes or women on anticoagulant therapy, long term corticosteroid users, smokers > 35 years) Number of women randomized: 50 The trial took place at the Early Pregnancy Unit at Singleton Hospital, Swansea, United Kingdom between April 1994 and April 1996 Single dose systemic MTX (50 mg/m2 IM) alone versus the same regimen in combination with mifepristone 600 mg orally

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Characteristics of included studies Outcomes Treatment success method of diagnosis: complete elimination of the ectopic pregnancy (serum hCG < 12 IU/L) by primary treatment Persistent trophoblast method of diagnosis: if the serum hCG concentration on day 7 did not decrease by 15% as compared to the value on day 4. Persistent trophoblast was treated with single dose systemic MTX (50 mg/m2 im). Tubal preservation method of diagnosis: tubal preservation after primary treatment plus any additional conservative therapeutic interventions hCG clearance time method of diagnosis: the median number of days to reach serum hCG concentrations < 12 IU/l Side effects and complications method of diagnosis: follow-up of complete blood counts, liver and renal function tests Tubal patency method of diagnosis: by hysterosalpingography performed after complete resolution of the ectopic pregnancy and following a first normal period Overall tubal patency method of diagnosis: tubal patency including those patients who underwent salpingectomy Peritoneal lavage was carried out at confirmative laparoscopy A - Adequate Gjelland 1995 Method of randomization not stated Single center No power calculation No source of funding stated Ethical commitee approval Published as full paper Women with an ectopic pregnancy (< 4 cm) on transvaginal ultrasound and serum hCG concentration < 3,000 IU/l, and little or no intraabdominal bleeding Number of women randomized: 80 The trial was carried out at Haukeland University Hospital, Bergen, Norway between September 1991 and January 1994 Hyperosmolar glucose 50% 10-20 ml transvaginally under sonographic guidance versus hyperosmolar glucose 50% 10-20 ml under laparoscopic guidance

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Characteristics of included studies Outcomes Treatment success method of diagnosis: an uneventful decline of serum hCG to undetectable levels ( < 5 IU/l) Treatment failure method of diagnosis: transvaginal sonography group: second injection for persistent trophoblast and/or surgical reintervention after second glucose injection laparoscopy group: conversion to laparotomy for technical difficulties related to substandard laparoscopic equipment and poor training, and for intraabdominal adhesions or surgical reintervention for an increase in serum hCG Persistent trophoblast method of diagnosis: transvaginal sonography group: second injection for an increase of serum hCG hCG resolution time method of diagnosis: mean number of days for serum hCG to become < 5 IU/l in the successfully treated group Hospital stay method of diagnosis: number of days in the hospital, analyzed for both successfully and unsuccessfully treated women Tubal patency method of diagnosis: by hysterosalpingogram at least 4 months after treatment

Notes Allocation concealment Study Methods B - Unclear Graczykowski 1997 Method of randomization by drawing cards Single center No power calculation Funding in part by National Institutes of Health grant to GCRC M01 RR-43, Betheseda, Maryland, USA Ethical commitee approval Published as full paper All women who underwent (laparoscopic) salpingostomy for tubal ectopic pregnancy without signs of severe anemia (WBC < 4000/ml, hematocrit < 26%), signs of active liver disease (bilirubin > 1.2 mg/dl, SGOT/SGPT > 70 IU/dl) or signs of kidney disease (serum creatinine > 1.4 mg/dl), leukemia, bone marrow abnormalities, or allergy to MTX Number of women randomized: 129 Lost to follow-up: 13 The trial was carried out at Los Angeles County and University of Southern California Medical Center, USA between July 1993 and March 1995 Salpingostomy and a single dose of MTX postoperatively (1 mg/kg IM) within 24 hours versus salpingostomy alone

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Characteristics of included studies Outcomes Treatment success method of diagnosis: an uneventful decline of serum hCG to undetectable levels ( < 15 IU/l) Persistent trophoblast method of diagnosis: increase of serum hCG concentration postoperatively or an inadequate decline (< 20% between two consecutive measurements taken three days apart) hCG resolution time method of diagnosis: mean number of days for serum hCG to become undetectable (< 15 mIU/ml) Side effects method of diagnosis: questionaire about any symptoms and possible side effects related to the medication and measurement of complete blood count, bilirubin, and SGOT/SGPT

Notes Allocation concealment Study Methods C - Inadequate Gray 1995 Randomization during laparoscopy by sealed envelopes, stratification into 6 subgroups based on age and an existing risk scoring scheme Single center No power calculation Funding by Swedish Medical Research Council and by the Gteborg Medical Society Gteborg, Sweden Ethical commitee approval Published as full paper Hemodynamically stable women with a laparoscopically confirmed tubal pregnancy (< 4 cm) and serum hCG concentrations < 10,000 IU/l (if known at the time of randomization). Women with a tubal pregnancy < 1 cm and serum hCG concentration < 1,000 IU/l were excluded as were women in whom the tubal pregnancy was not anatomically accessible for laparoscopic removal Number of women randomized: 109 The trial was carried out at Sahlgrenska University Hospital, Gteburg, Sweden between May 1, 1987 and June 30, 1989 Laparoscopy versus laparotomy Treatment success method of diagnosis: elimination of trophoblastic activity documented by a fall in serum hCG to nonpregnant levels (< 20 IU/l) beyond postoperative day 7 Treatment failure method of diagnosis: medical or surgical interventions for elimination of residual trophoblastic activity. Operative complications that required surgical intervention or inpatient observation were analyzed separately Total costs of care method of diagnosis: multiplying the unit cost by each type of care by the number of units used Cost effectiveness method of diagnosis: effectiveness of the surgical strategies including additional interventions of follow-up, relative to the costs incurred Sensitivity and treshold analyses method of diagnosis: changing key baseline assumptions about clinical outcomes and patterns of care

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Characteristics of included studies Notes Surgery was planned between 08.00 and 17.00 h Monday to Friday when at least two of five laparoscopic surgeons were on duty Risk scoring scheme: previous ectopic pregnancy, IUCD in situ, history of infertility, previous abdominal surgery, age < 27, 27-31, > 31 years Unless salpingectomy was otherwise indicated, all laparoscopy and laparotomy procedures were planned as tube sparing linear salpingotomies Health care resources: hospital bed use from day of surgery onwards, investigation of incidental findings made during ectopic pregnancy surgery, hospital, physician, and laboratory costs for follow-up and repeat hospital stay Types of care: duration of surgeons operation, duration of diagnostic laparoscopy and randomization, duration of therapeutic portion procedure, duration of total theatre time, duration of postoperative stay in recovery room,women requiring transfusions, postoperative lenght of stay, women requiring second medical/surgical intervention for persistent trophoblast, women readmitted for postoperative abdominal pain, number of postoperative outpatient gynecology visits/patient, number of follow-up ultrasounds, duration of follow-up Costs were based on total costs instead of fixed (overhead) versus variable (volume dependant) costs estimated with data between November 1992 and March 1993 from Huddinge University Hospital/ Karolinska Institute Stockholm, Sweden B - Unclear Hajenius 1997 Randomization by a computer program with block randomization, with stratification for pre-existing tubal pathology and initial serum hCG concentration. Randomization was done before a confirmative laparoscopy Multi center Tubal patency rate after laparoscopic salpingostomy was assumed to be 80%. A sample size of 100 women would allow to detect a difference in tubal patency rate, in favour of systemic methotrexate, of 18%, with a two-sided chi square test at p = 0.05 and with a power of 80% Funding by the Health Insurance Funds Council, Amstelveen, The Netherlands Ethical commitee approval Intention to treat analysis Published as full paper Hemodynamically stable women with a laparoscopically confirmed unruptured tubal pregnancy without fetal cardiac activity and no signs of active bleeding, no contraindications to receiving systemic MTX, (leucopenia, thrombocytopenia, or high concentrations of liver enzymes or serum creatinine) or contraindications to laparoscopic surgery, (documented extensive pelvic adhesions, large fibroid uterus, and severe ovarian hyperstimulation syndrome) Number of women randomized: 100 Number of women originally randomized 140 Secondary exclusions for nontubal pregnancy, tubal rupture, and/or active bleeding: 40 The trial took place in six Dutch hospitals: the Academic Medical Center of the University of Amsterdam, the Onze Lieve Vrouwe Gasthuis and the University Hospital Free University in Amsterdam and the University Hospitals of Groningen, Nijmegen and Utrecht, The Netherlands between January 1, 1994 and September 1, 1996 Systemic MTX 1.0 mg/kg IM on days 0,2,4,6 alternated folinic acid 0.1 mg/kg oral on days 1,3,5,7 versus laparoscopic salpingostomy

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Characteristics of included studies Outcomes Treatment success method of diagnosis: complete elimination of the tubal pregnancy (serum hCG < 2 IU/L) and preservation of the tube by primary treatment Persistent trophoblast method of diagnosis: in patients treated with systemic MTX, by a serum hCG concentration above 40% of the initial value on day 14. In patients treated by salpingostomy, by rising or plateauing serum hCG concentrations. In both treatment groups persistent trophoblast was treated with systemic MTX. Tubal preservation method of diagnosis: tubal preservation after primary treatment plus any additional conservative therapeutic interventions hCG clearance time method of diagnosis: the median number of days to reach undetectable serum hCG levels Side effects and complications method of diagnosis: follow-up of complete blood counts, liver and renal function tests to detect MTX toxicity and anaesthesia effects Tubal patency method of diagnosis: by hysterosalpingography performed three months after completion of treatment Overall tubal patency method of diagnosis: tubal patency including those patients who underwent salpingectomy Pre-existing tubal pathology was defined as previous ectopic pregnancy, previous tubal surgery, previous pelvic inflammatory disease, or proven tubal pathology by hysterosalpingography or laparoscopy In women with persistent bleeding from the tube after removal of the trophoblastic tissue by laparoscopic salpingostomy, bleeding points were identified and controlled with bipolar coagulation, with an effort not to damage the tubal mucosa. If still unsuccessful a salpingectomy was performed either by laparoscopy or by laparotomy A - Adequate Hordnes 1997 Method of randomization not stated Single center No power calculation No source of funding stated Ethical commitee approval Published as full paper Women with an ectopic pregnancy (< 4 cm) on transvaginal sonography and a serum hCG concentration < 3,000 IU/l and little or no intraabdominal bleeding Number of women randomized: 80 The trial was carried out at Haukeland University Hospital, Bergen, Norway between September 1991 and January 1994 Hyperosmolar glucose 50% 10-20 ml transvaginally under sonographic guidance versus hyperosmolar glucose 50% 10-20 ml under laparoscopic guidance Fertility outcome method of diagnosis: pregnancy rates and pregnancy outcome in successfully treated women trying to conceive, contacted by a questionnaire 23-51 months after treatment

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Characteristics of included studies Notes Allocation concealment Study Methods B - Unclear Klauser 2005 Method of randomization not stated Single center No power calculation No source of funding stated Ethical commitee approval Published as abstract Women with a clinical diagnosis of an unruptured ectopic pregnancy (upper limit serum hCG concentration 10,000 IU/l) Number of women randomized: 51 The trial was carried out at University of Mississippi Medical Center, Jackson, MS, USA Single dose MTX (50 mg/m2) versus multiple dose MTX (1 mg/kg on day 1,3,5) Treatment success method of diagnosis: an uneventful decline of serum hCG to undetectable levels (< 5 IU/l) Need for surgery Side effects serum hCG resolution time method of diagnosis: number of days for serum hCG to become < 5 IU/l Not mentioned if leucovorin was given on alternating days (day 2,4,6) B - Unclear Korhonen 1996 Randomization was done in the hospital pharmacy using a table of random numbers. The code was opened after the end of treatment of the last patient Double blind, placebo controlled study, single center A trial of 58 women had an 80% chance of detecting a statistically significant difference of 30% between rates of recovery without laparoscopy No source of funding stated Ethical commitee approval Published as full paper Women with an ectopic pregnancy ( < 4 cm) and a serum hCG concentration < 5,000 IU/l with no or mild abdominal pain. Patients with a rise in serum hCG > 50% in 2 days were excluded Number of women randomized: 60 The trial was carried out at Helsinki University Central Hospital, Finland during a 3 year period Systemic MTX 2.5 mg/day orally during 5 days versus expectant management

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Characteristics of included studies Outcomes Treatment success method of diagnosis: an uneventful decline of serum hCG to undetectable levels (< 5 IU/l) Treatment failure method of diagnosis: a laparoscopic intervention for rising or plateauing serum hCG concentrations and/or for severe clinical symptoms, ie. increasing abdominal pain or signs of intraabdominal haemorrhage on transvaginal sonography hCG resolution time method of diagnosis: number of days for serum hCG to become < 5 IU/l

Notes Allocation concealment Study Methods A - Adequate Landstrom 1998 Method of randomization not stated Multi center No power calculation No source of funding stated Ethical commitee approval not stated Published as abstract Hemodynamically stable women with a tubal pregnancy at diagnostic laparoscopy and a serum hCG concentration < 3,000 IU/l Number of women randomized: 31 The trial took place in the following Swedish hospitals: Sahlgrenska University, Gotenborg, Ostersund Hospital, Sodertalje Hospital, Karlskrona Hospital, University Hospital Malmo and Akademiska University Hospital Uppsala, Sweden. Timing and duration of the trial not stated Systemic MTX in a oral regimen versus prostaglandins F2a and hyperosmolar glucose under laparoscopic guidance Treatment success method of diagnosis: complete elimination of the tubal pregnancy and preservation of the tube by primary treatment Postoperative abdominal pain and vaginal bleeding method of diagnosis:abdominal pain and vaginal bleeding after treatment as indicated by the women in a questionnaire

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Notes Allocation concealment Study Methods B - Unclear Lang 1990 Randomization by computer Single center No power calculation No source of funding stated Ethical commitee approval Published as full paper Hemodynamically stable women with a laparoscopically confirmed unruptured tubal pregnancy without active bleeding, and a urinary hCG concentration < 5,000 IU/l Number of women randomized: 31 The trial was carried out at the University of Graz, Austria, during a 9 month period

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Characteristics of included studies Interventions Prostaglandin F2a 7.5-10 mg in 1.5-2.0 ml solvent injected in the gestational sac and 25 mg conjugated oestrogen injected in the corpus luteum of the ipsilateral ovary under laparoscopic guidance combined with systemic Prostaglandin-E2 derivate 500 mg IM on the first 2 postoperative days versus hyperosmolar glucose 10-20 ml 50% under laparoscopic guidance Treatment success method of diagnosis: an uneventful decline of serum hCG to undetectable levels (< 5 IU/l) Treatment failure method of diagnosis: surgical intervention for increasing or plateauing hCG levels and clinical signs of imminent tubal rupture hCG resolution time method of diagnosis: number of days for urinary hCG and serum hCG to become undetectable (< 5 IU/l) Hospitalisation time method of diagnosis: number of days in the hospital Side effects method of diagnosis: postoperative complaints by women Tubal patency method of diagnosis: by hysterosalpingogram after an interval of at least 3 menstrual cycles Pregnancy outcome method of diagnosis: occurrence and outcome of pregnancy, desire of pregnancy and follow-up not stated Before medical therapy was installed, any free blood in the abdomen was suctioned off Women were discharged from the hospital when the urinary hCG level fell on 2 consecutive days B - Unclear Lundorff 1991a Randomization during laparoscopy by sealed envelopes, with stratification into 6 subgroups based on age and an existing risk scoring scheme Single center No power calculation Funding by Swedish Medical Research Council and by the Gteborg Medical Society Gteborg, Sweden Ethical commitee approval Published as full paper Hemodynamically stable women with a laparoscopically confirmed ampullary tubal pregnancy (< 4 cm) and a serum hCG concentration < 10,000 IU/l. Patients in whom the tubal pregnancy was not anatomically accessible for laparoscopic removal were excluded Number of women randomized 105 Number of women orginally randomized 109, 4 secondary exclusions in the laproscopy group for nontubal pregnancy and technical difficulties The trial was carried out at Sahlgrenska University Hospital, Gteburg, Sweden between May 1, 1987 and June 30, 1989 Laparoscopy versus laparotomy

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Characteristics of included studies Outcomes Treatment failure method of diagnosis: second operative intervention for persistent trophoblast and/or bleeding, or second line therapy with methotrexate for persistent trophoblast or abdominal pains or discomfort Operating time method of diagnosis: time from the start of uterine cannulation for diagnostic laparoscopy to application of bandage after surgery hCG resolution time method of diagnosis: number of days for serum hCG until nonpregnant levels (< 20 IU/l) Hospital stay method of diagnosis: number of days in the hospital Total duration sick leave method of diagnosis: not stated, in days Surgery was planned between 08.00 and 17.00 h Monday to Friday when at least two of five laparoscopic surgeons were on duty Risk scoring scheme: previous ectopic pregnancy, intra uterine device in situ, history of infertility, previous abdominal surgery, age < 27, 27-31, > 31 years All surgical procedures were planned as tube sparing linear salpingotomies regardless of the operative approach Note: In the study of Gray 1996, describing the economic analysis, numbers for primary treatment success were revised B - Unclear Lundorff 1991b Randomization during laparoscopy by sealed envelopes, stratification into 6 subgroups based on age and an existing risk scoring scheme Single center No power calculation Funding by Swedish Medical Research Council and by the Gteborg Medical Society Gteborg, Sweden Ethical commitee approval Published as full paper Hemodynamically stable women with a laparoscopically confirmed ampullary tubal pregnancy (< 4 cm) and a serum hCG concentration < 10,000 IU/l. Patients in whom the tubal pregnancy was not anatomically accessible for laparoscopic removal were excluded Number of women randomized: 73 Number of women originally randomized 109, 4 secondary exclusions, 18 no desire for pregnancy, 9 conceived before second look laparoscopy, 5 pregnancies by in vitro fertilization The trial was carried out at Sahlgrenska University Hospital, Gteburg, Sweden between May 1, 1987 and June 30, 1989 Laparoscopy versus laparotomy

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Characteristics of included studies Outcomes Pelvic adhesion formation method of diagnosis: adhesion and tubal score at second look laparoscopy in women with desire for future fertility after 1-29 weeks compared with the score at surgery of the tubal pregnancy by a risk scoring scheme. * Adhesion score (ipsi and contra lateral); impaired, unchanged and improved status * Tubal status (contra lateral); impaired, unchanged and improved status * Tubal patency (ipsi and contralateral); open or closed for dye solution at second look laparoscopy Surgery was planned between 08.00 and 17.00 h Monday to Friday when at least two of five laparoscopic surgeons were on duty Risk scoring scheme: previous ectopic pregnancy, intra uterine device in situ, history of infertility, previous abdominal surgery, age < 27, 27-31, > 31 years All surgical procedures were planned as tube sparing linear salpingotomies regardless of the operative approach Score systemsurface involved: (1/4, 2/4, 3/4, 4/4)location: ovary, proximal tube, distal tubeadhesions: filmy, vascular, densescoring: grade 1 absence, grade 2 mild, grade 3 moderate, grade 4 severe Scores were registered on a preprinted form and lysis of adhesions was noted Improvements of adhesions were regarded as unchanged status because improvement was considered a result of lysis of adhesions at primary surgery B - Unclear Lundorff 1992 Randomization by sealed envelopes, stratification into 6 subgroups based on age and an existing risk scoring scheme Single center No power calculation Funding by Swedish Medical Research Council and by the Gteborg Medical Society Gteborg, Sweden Ethical commitee approval Published as full paper Hemodynamically stable women with a laparoscopically confirmed ampullary tubal pregnancy (< 4 cm) and a serum hCG concentration < 10,000 IU/l. Patients in whom the tubal pregnancy was not anatomically accessible for laparoscopic removal were excluded Number of women randomized: 87 Number of women originally randomized: 109, secondary exclusions 4, lost to follow up 1, no desire for pregnancy 17 The trial was carried out at Sahlgrenska University Hospital, Gteburg, Sweden between May 1, 1987 and June 30, 1989 with follow-up 1 year after surgery, or end of study period in August 1990 Laparoscopy versus laparotomy Fertility outcome method of diagnosis: cumulative frequency and pregnancy outcome of first subsequent pregnancy by means of questionnaires

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Characteristics of included studies Notes Surgery was planned between 08.00 and 17.00 h Monday to Friday when at least two of five laparoscopic surgeons were on duty Risk scoring scheme: previous ectopic pregnancy, intra uterine device in situ, history of infertility, previous abdominal surgery, age < 27, 27-31, > 31 years All surgical procedures were planned as tube sparing linear salpingotomies regardless of the operative approach A subanalysis was done to assess fertility outcome in patients with or without adhesions adn in patients with or without bilateral patency, contralateral patency, and ipsilateral patency B - Unclear Mol 1999a Randomization by a computer program with block randomization, with stratification for pre-existing tubal pathology and initial serum hCG concentration. Randomization was done before a confirmative laparoscopy Multi center Tubal patency rate after laparoscopic salpingostomy was assumed to be 80%. A sample size of 100 women would allow to detect a difference in tubal patency rate, in favour of systemic methotrexate, of 18%, with a two-sided chi square test at p = 0.05 and with a power of 80% Funding by the Health Insurance Funds Council, Amstelveen, The Netherlands Ethical commitee approval Intention to treat analysis Published as full paper Hemodynamically stable women with a laparoscopically confirmed unruptured tubal pregnancy without fetal cardiac activity and no signs of active bleeding, no contraindications to receiving systemic MTX, (leucopenia, thrombocytopenia, or high concentrations of liver enzymes or serum creatinine) or contraindications to laparoscopic surgery, (documented extensive pelvic adhesions, large fibroid uterus, and severe ovarian hyperstimulation syndrome) Number of women randomized: 100 Number of women originally randomized 140 Secondary exclusions for nontubal pregnancy, tubal rupture, and/or active bleeding:40 The trial took place in six Dutch hospitals: the Academic Medical Center of the University of Amsterdam, the Onze Lieve Vrouwe Gasthuis and the University Hospital Free University in Amsterdam and the University Hospitals of Groningen, Nijmegen and Utrecht, The Netherlands between January 1, 1994 and September 1, 1996 Systemic MTX 1.0 mg/kg IM on days 0,2,4,6 alternated folinic acid 0.1 mg/kg oral on days 1,3,5,7 versus laparoscopic salpingostomy

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Characteristics of included studies Outcomes Direct (medical) costs method of diagnosis: by multiplying used resources and resource unit prices. Used medical resources were duration of confirmative laparoscopy, duration of laparoscopic salpingostomy, conversions to salpingectomy, conversions to open surgery, initial injections with methotrexate, hospital stay from the moment of randomization in days, additional surgical and medical treatments, blood transfusions, consultations by other subspecialties, transvaginal sonograms, serum hCG measurements, and visits to the outpatient clinic. Resource unit prices reflected; unit costs for staff, materials, equipment, housing, depreciation, and overheads, the latter both at department level and at hospital level Indirect or time costs method of diagnosis: by multiplying used resources and resource unit prices. Used resources were professional and non-professional domiciliary care, transportation costs, and productivity loss. The price of productivity loss was calculated with the friction method, based on age and sex stratified data of the Dutch population Mean costs method of diagnosis: sum of direct medical costs and indirect or time costs Standardized unit costs were calculated for the Academic Medical Center and subsequently applied to resource use observed in women treated in other centers over time Trial specific resource utilization and associated costs were excluded from the analysis Information concerning indirect (time) costs was collected by means of questionnaire. Of 30 women who did not complete the questionnaire, data was extrapolated The friction method presumes that in a situation of existing unemployment in society, workers are replaced 10 weeks after the onset of their disease by a previously unemployed worker. As a consequence, costs due to production loss are limited to a period of 10 weeks Correction for differential timing of economic costs was not appropriate Sensitivity analysis was performed to explore the effect of plausible changes in key variables on the results of the cost analysis. Key variables considered were; reintervention rate (surgical or medical), duration of initial hospital stay, number of transvaginal sonograms, number of serum hCG measurements, and duration of production loss Subgroup analysis was performed to evaluate if the costs of both treatments depended on patient characteristics at baseline. Patient characteristics considered in the subgroup analysis were presence of abdominal pain and the initial serum hCG concentration Scenario analysis was performed to estimate the costs of systemic methotrexate in a scenario without a confirmative laparoscopy and of systemic methotrexate in a single shot scenario A - Adequate Mottla 1992 Randomization before laparoscopy by using a random table Single center No power calculation No source of funding stated Ethical commitee approval Published as full paper

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Characteristics of included studies Participants Hemodynamically stable women with a laparoscopically confirmed unruptured ectopic pregnancy (< 3 cm) and < 100 ml blood within the peritoneal cavity Number of women randomized: 12 Number of women orginally randomized: 21, 9 secondary exclusions for nontubal pregnancy, nonvisibility of the pelvis, size of ectopic pregnancy > 3 cm The trial was carried out at Magee Womens hospital, USA between March 8, 1990 and November 13, 1990 MTX 12.5 mg - 25 mg under laparoscopic control versus laparoscopic salpingostomy Treatment success method of diagnosis:an uneventful decline of serum hCG to undectable levels (< 10 IU/l) Treatment failure method of diagnosis: surgical intervention for rising or plateauing serum hCG concentrations Persistent trophoblast method of diagnosis: additional systemic MTX for persistent trophoblast, not defined Tubal patency method of diagnosis: by hysterosalpingogram, interval not stated Pregnancy outcome method of diagnosis: number of intrauterine pregnancies and repeat ectopic pregnancies MTX 12.5 mg in 2 cc saline was changed after the first 3 patients to 25 mg in 7 cc saline In the MTX group 5 ml of normal saline containing 5 U of vasopressin was injected in the mesosalpinx and fallopian tube surrounding the hematosalpinx The study was discontinued because of poor results in the MTX injection group B - Unclear Nieuwkerk 1998a Randomization by a computer program with block randomization, with stratification for pre-existing tubal pathology and initial serum hCG concentration. Randomization was done before a confirmative laparoscopy Multi center Tubal patency rate after laparoscopic salpingostomy was assumed to be 80%. A sample size of 100 women would allow to detect a difference in tubal patency rate, in favour of systemic methotrexate, of 18%, with a two-sided chi square test at p = 0.05 and with a power of 80% Funding by the Health Insurance Funds Council, Amstelveen, The Netherlands Ethical commitee approval Intention to treat analysis Published as full paper

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Characteristics of included studies Participants Hemodynamically stable women with a laparoscopically confirmed unruptured tubal pregnancy without fetal cardiac activity and no signs of active bleeding, no contraindications to receiving systemic MTX, (leucopenia, thrombocytopenia, or high concentrations of liver enzymes or serum creatinine) or contraindications to laparoscopic surgery, (documented extensive pelvic adhesions, large fibroid uterus, and severe ovarian hyperstimulation syndrome) and with sufficient Dutch or English skills to complete questionnaires Number of women randomized: 79 Number of women originally randomized 140 Secondary exclusions for nontubal pregnancy, tubal rupture, and/or active bleeding: 40 Insufficient Dutch or English skills: 11 Lost to follow-up: 5 The trial took place in six Dutch hospitals: the Academic Medical Center of the University of Amsterdam, the Onze Lieve Vrouwe Gasthuis and the University Hospital Free University in Amsterdam and the University Hospitals of Groningen, Nijmegen and Utrecht, The Netherlands between January 1, 1994 and September 1, 1996 Systemic MTX 1.0 mg/kg IM on days 0,2,4,6 alternated folinic acid 0.1 mg/kg oral on days 1,3,5,7 versus laparoscopic salpingostomy Health related quality of life method of diagnosis: health related quality of life over time (time effect), differences in health related quality of life between both treatment groups (treatment effect), and interaction between changes in health related quality of life over time and treatment group (time by treatment effect) was assessed by several standard self-administered psychometric measures with established reliability and validity The Medical Outcomes Study Short-form (MOS) comprises six sub-scales: physical functioning, role functioning and social functioning, mental health, health perceptions, and pain. A sub-scale measuring energy level was added to the original questionnaire The Rotterdam Symptom Checklist (RSCL) comprises four sub-scales: physical symptoms, psychological distress, activity level, and a single item measuring overall quality of life The State-Trait Anxiety Inventory (STAI) comprises pecific measures of anxiety and depression The Self-rating Depression Scale (SDS) measures the subjective experience of depression as characterized by affective, cognitive, behavioural and psychological symptoms The first set of questionnaires was completed after randomization but before confirmative laparoscopy. Patients received three sets of questionnaires when they were discharged from the hospital.These questionnaires were completed at home, two days, two weeks, and four weeks after confirmative laparoscopy. Women received the fifth set of questionnaires sixteen weeks after confirmative laparoscopy. Before and four weeks after confirmative laparoscopy only the MOS was administered. At other time points all questionnaires were administered. Trait anxiety was measured only once, two days after confirmative laparoscopy Reference values from the general population if available from manuals or the literature A subanalysis was performed taking into account the initial serum hCG concentration and the presence of abdominal pain at the start of treatment as covariates. A second subanalysis was performed, taking into account the presence of side effects of methotrexate after two weeks and the need for additional interventions after primary treatment as covariates, on data assessed at two weeks and four weeks after the start of treatment. A - Adequate
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Characteristics of included studies Study Methods Rozenberg 2003 Randomization based on a computer generated list and balanced in blocks of variable size, stratified by center, was carried out by sealed opaque enveloppes, stored in the pharmacy of each hospital. The enveloppe was openend immediately before the allocated treatment was administered. Double blind, placebo controlled study, multi center Success rate of methotrexate was assumed to be 80%. It was calculated that a sample size of 316 women had to be enrolled to demonstrate a benefit of > 15% in the methotrexate-miepristone group (ie success rate 95%) controlling for a type I error of 5% and a power of 90% (two-sided test) Funding by Assistance Publique- Hopiteaux de Paris, Delegation regionale a la Recherche Clinique Ethical commitee approval Intention to treat analysis Published as full paper Hemodynamically stable women > 18 years with no signs of active bleeding or haemoperitoneum in whom an ectopic pregnancy was diagnosed by using a non-laparoscopic algorithm combining transvaginal sonography (an unuptured mass, an ectopic pregnancy with fetal cardiac activity), quantitative serum hCG (serum hCG > 1,500 mIU/ml and no intra uterine sac seen by ultrasonography or serum hCG < 1,500 mIU/ml and a persistent abnormal increase [ < 50% increase over 48 hr], and/or curettage showing no trophoblastic villi. Women must live within 1 hr drive from the hospital, should not be living alone, and have no contraindications for MTX or mifepristone (serum amino transferase concentrations > 2 fold the normal level, serum creatinine concentration > 1.5 mg/dl or leucopenia < 2,000/ml, trombocytopenia < 100,000/ml, suprarenal gland dysfunction, active pulmonary disease, peptic ulcer disease, overt or biological evidence of immunodefiency, known sensitivity) Number of women randomized: 212 Lost to follow-up: 2 The trial took place between October 1999 and April 2001 in France in the following 18 centers: Dreux Hospital, Bichat-Claude Bernard Hospital Paris, La Conception Hospital Marseille, Clemenceau Hospital Caen, La Tronche Hospital Grenoble, Franco Britanic Hospital Levallois, Orsay Hospital, Boucicaut Hospital, Notre Dame de Bon-Secours Hospital Metz, Antoine Beclere Hospital Clamart, Poissy Saint Germain Hospital Poissy Cedex, CMCO Schiltigheim, CHRU Tours, Hotel Dieux Hospital Rennes, Jeanne de Flandre Hospital Lille, Evreux Hospital, Dreux Hospital, Paul gelle Hospital Roubaix, Annecy Hospital. Single dose systemic MTX (50 mg/m2 IM) alone versus the same regimen in combination with mifepristone 600 mg orally

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Characteristics of included studies Outcomes Treatment success method of diagnosis: uneventful decline of serum hCG to undetectable levels (serum hCG < 10 mIU/ml) by primary treatment Persistent trophoblast method of diagnosis: if the serum hCG concentration on day 7 did not decrease by 15% as compared to the value on day 4 or fetal cardiac activity was still present on day 7 after the first or the subsequent dose of MTX. Persistent trophoblast was treated with single dose systemic MTX (50 mg/m2 im) Tubal preservation method of diagnosis: tubal preservation after primary treatment plus any additional conservative therapeutic interventions Side effects and complications method of diagnosis: follow-up of complete blood counts, liver and renal function tests, gastritis, stomatitis, abdominal pain, reversible alopecia hCG resolution time method of diagnosis: number of days for serum hCG to become undetectable Hospitalization time method of diagnosis: number of days in the hospital A stopping rule was installed based on the triangular test (Whitehead 1992). This test consists of drawing stopping boundaries on the plot of the difference in efficacy against its precision, which complied with type I error and power requirements. If the computed points lay outside the boundaries, the trial was stopped. Inspections were done after inclusion of 60 women in each group. Two patients with persistent trophoblast refused a second injection of methotrexate and were treated surgically Two patients in the methotrexate alone group were lost to follow up One patient in the methotrexate-mifepristone group required emergency surgery for tubal rupture one day after serum hCG < 12 mIU/ml A - Adequate Sadan 2001 Double blind Method of randomization not stated Single center No source of funding stated No power calculation Ethical commitee approval not stated Published as full paper Hemodynamically stable women with sonografically confirmed diagnosis of an extra uterine pregnancy with rising or plateauing serum hCG levels who wished to preserve their fertility potential. At confirmative laparoscopy an intact tubal sac < 4 cm and no evidence of intra abdominal bleeding Number of women randomized: 20 The trial was carried out at Edith Wolson Medical Center, Holon, and Sackler Faculty of Medicine, Tel Aviv Israel.Timing and duration of the trial not stated MTX 25 mg in 3 ml fluid versus 3 ml hyperosmolar glucose 50% both into the gestational sac under laparoscopic guidance

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Characteristics of included studies Outcomes Treatment success method of diagnosis: an uneventful decline of serum hCG to undetectable levels hCG resolution time method of diagnosis: mean daily decrease in serum hCG in % of the initial serum hCG Persistent trophoblast method of diagnosis: rising serum hCG levels for which an adjuvant intramuscular injection of MTX was given Hospitalization time method of diagnosis: number of days in the hospital The study was discontinued after an interim analysis after 20 patients due to the higher failure rate in the hyperosmolar glucose group B - Unclear Saraj 1998 Randomization procedure by sealed envelopes Multi center No power calculation No source of funding stated Ethical commitee approval Published as full paper Hemodynamically stable women in good maternal health weighing < 90 kg and desiring future pregnancy with an unruptured ectopic pregnancy < 3.5 cm on transvaginal sonography without fetal cardiac activity and no contraindications to receiving systemic MTX (hematocrit < 30%, white blood cell count < 2,000/mm3, platelet count < 100,000/mm3, elevated liver enzymes, medical disease (especially hepatic, renal or cardicac disease) and alcohol abuse Number of women initially randomized: 75 secondary exclusion for no ectopic pregnancy: 1 The trial was carried out at Women's and Children's Hospital of the Los Angeles County and University of Southern California Medical Center, USA, between June 1995 and April 1997 Single dose systemic MTX (1 mg/kg IM) versus laparoscopic salpingostomy Treatment success method of diagnosis: complete elimination of the ectopic pregnancy (serum hCG < 15 IU/L) and preservation of the tube by primary treatment Persistent trophoblast method of diagnosis: in patients treated with systemic single dose MTX if the serum hCG concentration on day 7 did not decrease by 15% as compared to the value on day 4. In patients treated by salpingostomy, by postoperative rising or plateauing serum hCG concentrations. In both treatment groups persistent trophoblast was treated with single dose systemic MTX (1 mg/kg IM). Tubal preservation method of diagnosis: tubal preservation after primary treatment plus any additional conservative therapeutic interventions hCG clearance time method of diagnosis: the median number of days to reach serum hCG concentrations < 15 IU/l Progesterone clearance time method of diagnosis: the median number of days to reach serum progesterone concentrations < 1.5 ng/ml Tubal patency method of diagnosis: by hysterosalpingography performed three months after completion of treatment
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Characteristics of included studies Overall tubal patency method of diagnosis: tubal patency including those patients who underwent salpingectomy Fertility outcome method of diagnosis: pregnancy outcome of first subsequent pregnancy nine months after treatment Notes The diagnosis ectopic pregnancy was based on history, physical examination, transvaginal sonography and quantitative serum hCG concentrations using a diagnostic algorithm including uterine curettage In the MTX group women were treated on an outpatient basisl. In the laparoscopy group women were hospitalized for 6-8 hours postoperatively. B - Unclear Sharma 2003 Randomization procedure by computer generated numbers Single center No power calculation No source of funding stated Ethical commitee approval Published as full paper Patients with suspected ectopic pregnancy and no significant medical disease like diabetes, hypertension or previous laparotomy Number of women randomized: 60 The trial was carried out at Maulana Azad Medical College and associated Lok Nayak Hospital, New Delhi-110002, India between January 1998 to March 2001 Minilaparotomy versus laparotomy Mean operative time method of diagnosis: in minutes Per and postoperative complications: method of diagnosis: mean blood loss in ml, number of patients with bloodtransusions, fever, paralytic ileus, urinary tract infections and wound infection Mobility method of diagnosis: mean day of mobility, starting normal diet, discharge from hospital The minilaparotomy technique is an incision of the skin by 4-6 cm long suprapubic transverse incision and opening of the abdomen by Cohen's technique (tearing rectus sheath laterally and peritoneum with fingers). The fundus of the uterus was exteriorized along with the affected tube using 2 fingers. No packs or retractors were used. Antibiotics were 3 doses of 1.2 g Coamoyclav at 8 hourly intervals. The choice of type and lenght of the incision in the (standard) laparotomy group (more than 6 cm incision) was left to the operating surgeon. Antibiotics were ciprofloxaxin and metrodinazole for 7 days Laparoscopy was performed to confirm the diagnosis ectopic pregnancy in 19 out of 30 in the minilaparotomy group (63%) and 15 out of 30 (50%) in the laparotomy group Salpingosotmy or salpingectomy was performed depending on the age, parity and condition of the affected and opposite tube B - Unclear

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Characteristics of included studies Study Methods Shulman 1992 Method of randomization not stated Single center No power calculation No source of funding stated Ethical commitee approval not stated Published as full paper Hemodynamically stable women with a laparoscopically confirmed unruptured tubal pregnancy (< 4 cm) without active bleeding Number of women randomized: 15 The trial was carried out at Sapir Medical Centre, Kfar Saba Israel during an 18 month period MTX 12.5 mg in 7 ml under laparoscopic guidance versus MTX 12.5 mg in 7 ml physiologic solution under laparoscopic guidance combined with systemic MTX 0.5 mg/kg orally (days 0,2,4,6,8) alternated with folinic acid 0.1 mg/kg (days 1,3,5,7,9) Treatment success method of diagnosis: uneventful decline of serum hCG to undetectable levels Treatment failure method of diagnosis: tubal rupture hCG resolution time method of diagnosis: number of days for serum hCG to become undetectable Corpus luteum activity method of diagnosis: serum hCG 17E2 and progesterone clearance rate Intraoperative complications and side effects method of diagnosis: postoperative complaints, blood cell count, liver enzymes and kidney function At laparoscopy any free blood was suctioned away B - Unclear Sowter 2001a Unblocked randomization procedure by a computer programme and allocation details were contained in sequentially numbered opaque envelopes sealed by a third party Open pragmatic multi center randomized controlled trial Power calculations were made for detecting differences in treatment success rate using a two sided (2 test at a 5% level of significance and with a study power of 80%. It was assumed in these calculations that in women with a serum hCG level under 5000 IU/l a persistent trophoblast rate of 5% or less following laparoscopic surgery could be expected. To detect a difference in treatment success rate of 20%, 49 women in each group would be needed No source of funding stated Ethical commitee approval Intention to treat analysis Published as full paper

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Characteristics of included studies Participants Hemodynamically stable women with an unruptured tubal pregnancy < 3.5 cm and minimal haemoperitoneum on transvaginal sonography (<300mL) without fetal cardiac activity and a rsing serum hCG < 5,000 IU/l and no contraindications to MTX (leukopaenia, thrombocytopaenia, elevated serum liver enzymes or creatinine) or contraindications to laparoscopic surgery, (documented extensive pelvic adhesions, large fibroid uterus, and severe ovarian hyperstimulation syndrome) Number of women initially randomized: 62 lost to follow-up: 7 The trial was carried out at three hospitals in Auckland, New Sealand, (National Women's Hospital, North Shore Hospital, Middlemore Hospital) between 28 July 1997 and 27 September 1998 Multiple dose systemic MTX (50 mg/m2) versus laparoscopic surgery (single dose data available) Treatment success method of diagnosis: complete elimination of the ectopic pregnancy (serum hCG < 5 IU/L) and preservation of the tube by primary treatment Persistent trophoblast method of diagnosis: in patients treated with systemic single dose MTX if the serum hCG concentration between day 4 and day 7 did not decrease by 15% as compared to the value on day 0, or was plateauing or rising after day 7. In patients treated by salpingostomy, if the serum hCG concentration on day 7 did not decrease by 50% as compared to the value on day 0, or was plateauing or rising after day 7. In both treatment groups persistent trophoblast was treated with single dose systemic MTX Tubal preservation method of diagnosis: tubal preservation after primary treatment plus any additional conservative therapeutic interventions hCG clearance time method of diagnosis: the median number of days to reach serum hCG concentrations < 5 IU/l Tubal patency method of diagnosis: by hysterosalpingography performed three months after completion of follow-up Overall tubal patency method of diagnosis: tubal patency including those patients who underwent salpingectomy Health related quality of life method of diagnosis: differences in health related quality of life between both treatment groups was assessed by several psychological and side effects questionnaires at the time of tial entry, day 4,10 and 28 The Short-form 36 (SF-36) comprises eight sub-scales: physical functioning, physical role limitation, bodily pain, social role limitation, general mental health, role limitation due to emotional problems, vitality, and general health perception. The state scale of the State-trait anxiety Inventory21: A 20-item state scale measuring current anxiety. The Center for Epidemiologic Studies Depression (CES-D) scale22: A 20-item depression scale designed to identify depression in the general population. The physical symptom component of the Rotterdam symptom checklist23: A four component (physical symptoms, psychological distress, activity level, and quality of life) questionnaire originally used to assess the health related quality of life of patients receiving cancer treatment. The questionnaire was modified by the addition of possible side effects relevant to the treatment of ectopic pregnancy (shoulder-tip pain, pelvic pain, vaginal bleeding) and by asking women to also record the number of days on which side effects were experienced and any additional symptoms they considered to be possible side-effects
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Characteristics of included studies Notes A non laparoscopic diagnostic algorithm was used to diagnose the presence of an ectopic pregnancy The authors stated that salpingotomy was always performed in preference of salpingectomy. In this review the results of the medical outcome measures were recalculated as if the comparison were single dose systemic MTX (50 mg/m2) versus laparoscopic salpingotomy A - Adequate Sowter 2001b Unblocked randomization procedure by a computer programme and allocation details were contained in sequentially numbered opaque envelopes sealed by a third party Open pragmatic multi center randomized controlled trial Power calculations were made for detecting differences in treatment success rate using a two sided (2 test at a 5% level of significance and with a study power of 80%. It was assumed in these calculations that in women with a serum hCG level under 5000 IU/l a persistent trophoblast rate of 5% or less following laparoscopic surgery could be expected. To detect a difference in treatment success rate of 20%, 49 women in each group would be needed No source of funding stated Ethical commitee approval Intention to treat analysis Published as full paper Hemodynamically stable women with an unruptured tubal pregnancy < 3.5 cm and minimal haemoperitoneum on transvaginal sonography (300mL) without fetal cardiac activity and a rising serum hCG < 5,000 IU/l and no contraindications to MTX (leukopaenia, thrombocytopaenia, elevated serum liver enzymes or creatinine) or contraindications to laparoscopic surgery, (documented extensive pelvic adhesions, large fibroid uterus, and severe ovarian hyperstimulation syndrome) Number of women initially randomized: 62 The trial was carried out at three hospitals in Auckland, New Sealand, (National Women's Hospital, North Shore Hospital, Middlemore Hospital) between 28 July 1997 and 27 September 1998 Single dose systemic MTX (50 mg/m2) versus laparoscopic surgery Direct costs method of diagnosis: by multiplying used resources and resource unit prices, ie. costs of investigations, initial and follow-up visits to the gynecology assessment unit, drugs used, operative and anaesthetics, in patients hotel, and any costs associated with additonal treatments, hospital readmission and complications Indirect costs method of diagnosis: the reduction of paid and unpaid production due to patient's treatment and costs of transport and other (non) medical expenses

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Characteristics of included studies Notes Standardized unit costs were calculated for the National Women's Hospital and subsequently applied to resource use observed in women treated in other two centers Trial specific resource utilization and associated costs were excluded from the analysis Information concerning indirect costs was collected by means of questionnaire. Of 4 women who did not complete the questionnaire, data was extrapolated Sensitivity analysis was performed on direct costs for each cost component assuming that unit costs were 50%, 150% and 200% of base case unit costs Subgroup analysis was performed to explore the effect of serum hCG on the results of the cost analysis Scenario analysis was performed to determine the overall costs savings per patient if all eligle women were treated with MTX A - Adequate Tulandi 1991a Method of randomization not stated Single center No power calculation No source of funding stated Ethical commitee approval Published as full paper Women with an unruptured ampullary ectopic pregnancy at laparotomy with the contralateral tube in situ and no history of a recurrent ectopic pregnancy Number of women randomized: 34 number of women for second look laparoscopy: 18 The trial was carried out at Royal Victoria Hospital Mc Gill University Montral, Quebec, Canada Time and duration of the trial not stated Salpingostomy without tubal suturing versus salpingostomy with tubal suturing Treatment success method of diagnosis: an uneventful postoperative course Periadnexal adhesions method of diagnosis: degree of adhesions conform the American Fertility Society classification at second look laparoscopy/laparotomy for recurrent ectopic pregnancy, follow-up not stated Tubal fistula Method of diagnosis: at second look laparoscopy Reproductive performance method of diagnosis: cumulative intrauterine and ectopic pregnancy probability at 12 and 24 months, desire of pregnancy not stated Surgery was performed by laparotomy Desire of pregnancy is not stated Intra uterine pregnancy is not divided into viable pregnancies or abortions B - Unclear Tzafettas 1994 Method of randomization not stated Multicenter No power calculation No source of funding stated Ethical commitee approval not stated Published as full paper
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Characteristics of included studies Participants Hemodynamically stable women with an unruptured ectopic pregnancy (< 4cm) confirmed by ultrasound (identification of the gestational sac) or when not visible by laparoscopy, serum hCG not declining in two consecutive measurements at least 24 hrs apart, and < 100 ml of blood in the pelvis Number of women randomized: 36 The trial was carried out at University Department of Obstetrics and Gynecology in the Hippokrateio Hospital and the Blue Cross Infertility Centre Thessaloniki, Greece between November 1992 and November 1993 MTX 100 mg in 4 ml saline transvaginally under sonographic guidance versus MTX 100 mg in 4 ml saline under laparoscopic guidance Treatment success method of diagnosis: an uneventful decline of serum hCG to undetectable levels (< 20 IU/l) Treatment failure method of diagnosis: laparotomy for detection of nearly 100 ml blood in the pouch of Douglas at transvaginal sonography or persistent lower abdominal pain Persistent trophoblast method of diagnosis: additional 50 mg MTX in 2 ml saline was installed into the affected fallopian tube by transuterine tubal catheterisation for no decline in serum hCG within 10 days hCG resolution time method of diagnosis: number of weeks for serum hCG to become < 20 IU/l Serum MTX levels method of diagnosis: venous blood sample twice weekly determination by fluorescence polarization immunoassay Side effects method of diagnosis: not stated Before injecting medical therapy the tubal content was aspirated B - Unclear Ugur 1996 Method of randomization not stated, with stratification for size of the ectopic pregnancy Single center No power calculation No source of funding stated Ethical commitee approval not stated Published as full paper Hemodynamically stable women with a laparoscopically confirmed unruptured ectopicl pregnancy (< 5 cm) Number of women randomized: 40 The trial took place in the Reproductive Endocrinology and Endoscopic Surgery Clinic of Tahir Burak Women's Hospital, Ankara, Turkey between January 1993 and December 1994 Laparoscopic salpingotomy with prophylactic vasopressin injection 5-10 ml (5IU diluted in 20 ml saline) into the proximal and distal mesosalpinx versus laparoscopic salpingotomy alone

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Characteristics of included studies Outcomes Electrocoagulation for hemostasis method of diagnosis: number of women requiring electrocoagulation for hemostasis Treatment failure method of diagnosis: number of women requiring a conversion to laparotomy for failed hemostasis at laparoscopy Persistent trophoblast method of diagnosis: not defined Operation time method of diagnosis: operation time in minutes hCG clearance time method of diagnosis: rate and magnitude to reach undetectable serum hCG levels (< 10 IU/l) Complications method of diagnosis: potential complications of vasopressin ( hypertension, bradycardia, delayed bleeding) % change of hemoglobin postoperatively Tubal patency method of diagnosis: by hysterosalpingogram 3 months after the operation in women successfully treated by primary treatment In women with persistent bleeding from the tube after removal of the trophoblastic tissue, bleeding points were identified and controlled with bipolar coagulation, with an effort not to damage the tubal mucosa. If bleeders were not precisely localized, pressure was applied to stop the bleeding. If still unsuccessful, hemostasis was attepted in the mesosalpingeal arcade when possible. To avoid a salpingectomy and any further damage to the tube by extensive electrocoagulation, hemostasis was attempted at lenght by laparotomy B - Unclear Vermesh 1989 Randomization at the time of laparoscopy by sequential selection of unmarked opaque envelopes containing a coded card Single center No power calculation Funding by National Institute of Health Ethical commitee approval Published as full paper Hemodynamically stable women with a laparoscopically confirmed unruptured isthmic or ampullary tubal pregnancy (< 5 cm) without pelvic adhesions precluding complete visualisation of the pelvis Number of women randomized: 60 The trial was carried out at Women's Hospital, University of Southern California, Los Angeles USA between October 1986 and February 1988 Salpingostomy by laparoscopy versus salpingostomy by laparotomy

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Characteristics of included studies Outcomes Morbidity method of diagnosis: intraoperative estimated bloodloss, intraoperative complications, short term complications, persistent trophoblast, long term complications Persistent trophoblast method of diagnosis: second operation for persistently rising serum hCG titers hCG resolution time method of diagnosis: number of days for serum hCG to become undetectable (< 1.5 IU/l) Hospital stay method of diagnosis: not stated, in days Return to full activity method of diagnosis: not stated, in days Costs method of diagnosis: not stated, related with hospital stay Tubal patency method of diagnosis: by hysterosalpingographam 12 weeks after treatment Fertility outcome method of diagnosis: pregnancy rates and pregnancy outcome in patients trying to conceive, contacted by telephone follow-up 6 months During operation other pelvic fertility factors were assessed, and the maximal amount of surgery directed toward the contralateral tube was lysis of adhesions A - Adequate Vermesh 1992 Randomization by sequential selection of unmarked opaque envelopes containing a coded card Single center No power calculation No source of funding stated Ethical commitee approval Published as full paper Hemodynamically stable women with a laparoscopically confirmed unruptured isthmic or ampullary tubal pregnancy (< 5 cm) without pelvic adhesions precluding complete visualisation of the pelvis Number of women randomized: 40 Number of women originally randomized 60, 15 lost to follow up, 5 no desire future pregnancy The trial was carried out at Women's Hospital, University of Southern California, Los Angeles USA between October 1986 and February 1988 Salpingostomy by laparoscopy versus salpingostomy by laparotomy Reproductive outcome after 1 and 3 years method of diagnosis: pregnancy outcome and life table analysis by means of periodic office visits, telephone calls, and letters, medical records, or records maintained by the Public Health Department

Notes Allocation concealment Study Methods

Participants

Interventions Outcomes

Notes Allocation concealment A - Adequate

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Characteristics of included studies Study Methods Wang 1998 Method of randomization not stated Randomization in a 1:2 scheme Single center No power calculation No source of funding stated Ethical commitee approval not stated Published as full paper Women with a swollen fallopian tube at gynecological examination, ectopic pregnancy seen with ultrasound and serum hCG > 3.1 microg/L Number of women randomized: 78 The trial was carried out at Health of Mothers and Children Hospital in Shanxi province, China during a three months period Single dose systemic MTX 50-70 mg/m2 IM versus the same regimen in combination Ectopic Pregnancy 2 (EP2) decoction, ie a chinese herb one dose a day, one dose per two days in the last two months Treatment success method of diagnosis: an uneventful decline of serum hCG to undectable levels Fertility outcome method of diagnosis: pregnancy outcome serum hCG clearance time method of diagnosis: number of days for serum hCG to become undetectable Ectopic pregnancy disappearance time method of diagnosis: mean number of days for the ectopic mass to become undetectable

Participants

Interventions

Outcomes

Notes Allocation concealment Study Methods B - Unclear Yalcinkaya 1996 Method of randomization not stated Double blind study, single center No power calculation No source of funding stated Ethical commitee approval not stated Published as abstract Hemodynamically stable women with an ectopic pregnancy < 3.5 cm on transvaginal sonography with rising or plateauing serum hCG concentrations without liver or kidney disease Number of women initially randomized: 41 Lost to follow-up: 1 The trial was carried out at West Verginia University Health Sciences Center, Charleston Division, Charleston, West Verginia, USA between January 1994 and March 1996 Single dose systemic MTX 25 mg/m2 IM versus single dose systemic MTX 50 mg/m2 IM

Participants

Interventions

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Characteristics of included studies Outcomes Treatment success method of diagnosis: complete elimination of the ectopic pregnancy (serum hCG < 5 IU/L) and preservation of the tube by primary treatment Persistent trophoblast method of diagnosis: if the serum hCG concentration on day 7 did not decrease by 15% as compared to the value on day 4. Persistent trophoblast was treated with single dose systemic MTX. Treatment failure method of diagnosis:tubal rupture or significant haemoperitoneum presenting with severe abdominal pain and falling haemoglobin hCG clearance time method of diagnosis: the median number of days to reach serum hCG concentrations < 5 IU/l Side effects method of diagnosis: MTX related side effects were recorded and complete blood count and AST levels Ectopic pregnancy was diagnosed by history and examination B - Unclear Yalcinkaya 2000 Randomization by sealed envelopes at the central pharmacy Double blind block randomized study, single center The need for a second MTX injection with MTX 50 mg was 28%. It was calculated in this bioequivalency study that 47 women were needed to detect an increase to 56% with a power of 0.80. No source of funding stated Ethical commitee approval not stated Published as abstract Hemodynamically stable women with an ectopic pregnancy < 3.5 cm on transvaginal sonography with rising or plateauing serum hCG concentrations without liver or kidney disease and desire for future pregnancy Number of women randomized: 100 Number of patients available for fertility follow-up: 56 The trial was carried out at West Verginia University Health Sciences Center, Charleston Division, Charleston, West Verginia, USA between January 1994 through September 1998 Single dose systemic MTX 25 mg/m2 IM versus single dose systemic MTX 50 mg/m2 IM

Notes Allocation concealment Study Methods

Participants

Interventions

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Characteristics of included studies Outcomes Treatment success method of diagnosis: complete elimination of the ectopic pregnancy (serum hCG < 5 IU/L) and preservation of the tube by primary treatment Persistent trophoblast method of diagnosis: if the serum hCG concentration on day 7 did not decrease > 15% as compared to the value on day 4. Persistent trophoblast was treated with single dose systemic MTX. Treatment failure method of diagnosis: tubal rupture or significant haemoperitoneum presenting with severe abdominal pain and falling haemoglobin hCG clearance time method of diagnosis: the median number of days to reach serum hCG concentrations < 5 IU/l Side effects method of diagnosis: MTX related side effects were recorded and complete blood count and AST levels Tubal patency method of diagnosis: by hysterosalpingography MTX injection could only be repeated once A - Adequate Zilber 1996 Method of randomization not stated Single center No power calculation No source of funding stated Ethical commitee approval not stated Published as full paper Women with a laparoscopically confirmed unruptured tubal pregnancy tubal pregnancy (< 3 cm) without active bleeding and full visualization of the pelvis Number of women randomized: 48 The trial was carried out at Assaf Harofeh Medical Center, Israel between January 1991 and December 1992 MTX 25 mg in 3 ml physiologic solution under laparoscopic guidance versus laparoscopic salpingostomy

Notes Allocation concealment Study Methods

Participants

Interventions

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Characteristics of included studies Outcomes Treatment success method of diagnosis: an uneventful decline of serum hCG (< 10 IU/l) Treatment failure method of diagnosis: additional single systemic injection of MTX or surgical intervention for persistent trophoblast Persistent trophoblast method of diagnosis: persistenly rising serum hCG concentrations hCG resolution time method of diagnosis: number of days for serum hCG to become < 10 IU/L Intra-operative blood loss method of diagnosis: amount of blood loss in milliliters Operation time method of diagnosis: duration of operation in minutes Hospitalization time method of diagnosis: number of days in the hospital Complications method of diagnosis: wound infection, fever, blood transfusions Pregnancy outcome method of diagnosis: number of intrauterine pregnancies in patients with further attempts at conceiving was assessed by telephone calls and letters Follow-up up to 18 months: 34 with desire for future fertility B - Unclear

Notes Allocation concealment

Characteristics of excluded studies Study Colacurci 1998 Reason for exclusion This multicenter study compared single dose systemic MTX (50 mg IM) versus laparoscopic salpingostomy in 33 hemodynamically stable women with an unruptured ectopic pregnancy < 4 cm on transvaginal sonography with serum hCG concentrations < 10,000 IU/l and no hepatic or renal dysfunction or abnormal blood count. The trial was carried out at Second University of Naples and Federico II University, Naples, Italy, between January 1994 to March 1995. The method of randomization was by hospital number, reason for exclusion. This study compared laparoscopic salpingotomy and a single dose of intratubal MTX peroperatively (1 mg/kg) versus salpingotomy alone in 65 hemodynamically stable women with a tubal pregnancy (< 4 cm) without evidence of tubal rupture and no signs of hepatic or kidney disfunction who underwent salpingotomy. The trial was carried out in University of Suleyman Demiral Isparta 32040 in Turkey. Timing and duration of the trial not stated. Method of randomization was by hospital number in a 1:2 scheme, reason for exclusion. This study compared laparoscopic salpingostomy by CO2 laser versus microsurgical salpingotomy by laparotomy in hemodynamically stable women with an ectopic pregnancy. The trial was carried out at University Hospital Gasthuisberg, Leuven, Belgium between 1988 and 1 December 1989 and was funded by NFWO (Belgian National Foundations for Research). This study is not seen as a randomised controlled trial nor a controlled clinical trial whereas treatment was dependent on the surgeon in charge. Only two surgeons were capable of doing laser-endoscopy whereas the other consultants only performed microsurgery.

Kaya 2002

Koninckx 1991

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Characteristics of excluded studies Laatikainen 1993 This study compared hyperosmolar glucose (50%) in 10-20 ml under laparoscopic guidance versus laparoscopic salpingostomy in 40 women with a laparoscopically confirmed unruptured tubal pregnancy (< 4 cm) without fetal cardiac activity, and a serum hCG concentration < 5000 IU/l and no history of a recurrent ectopic pregnancy. The trial was carried out at Oulo University Central Hospital, Oulu, Finland between October 1990 to February 1992. Randomization by even or odd day of birth, reason for exclusion. This study has been frequently quoted as being the first randomised controlled trial in the treatment of ectopic pregnancy. However, if carefully read, this study really is a retrospective comparative study comparing expectant management versus open surgery in women with ectopic pregnancy. Lund described in 1955 the short and long term outcome of two standard treatment regimens in 204 women, who had been treated for ectopic pregnancy between 1930 and 1946 at the Gentofte County hospital in Copenhagen, Denmark. In two departments of this hospital standard treatment for "subacute women with a typical course of ectopic pregnancy and a positive pregnancy test, who had no demonstrable hemoperitoneum on admission and were not acutely ill" was confinment to bed until the pregnancy test became negative and pain ceased (n=119), whereas in one other department all such women were consistently subjected to operation (n=85). Expectant management was successful in 57% (68/119) of women. In 20% (27/119) an operation was done for signs of a large intra abdominal haemorrhage, ie. "catastrophe" , whereas in 23% (24/119) of women an operation was done after 4 weeks stay in the hospitalwith no signs of the disease becoming quiescent. Fertility outcome in patients with desire for future pregnancy was similar in the expectant management group (n=101) and in the surgery group (n=73). The intra uterine pregnancy rate was 46% and 44%, respectively whereas the repeat ectopic pregnancy rate was 15% in both treatment groups. Reasons for exclusion: 1. This study is not a randomized controlled trial. 2. The diagnosis ectopic pregnancy does not meet the inclusion criteria as defined for this review, ie. by the transvaginal sonographical finding of an ectopic gestational sac with an empty uterus, by a serum hCG discriminatory zone principle with an empty uterus, and/or by laparoscopy or by open surgery. This study compared laparoscopy versus laparotomy in 63 hemodynamically stable women with a laparoscopically confirmed ectopic pregnancy. Number of women orginally randomized 73. Secondary exclusions in the laparoscopy group: nontubal pregnancy (1), unavailability of equipment (3), unavailability of trained physicians (3), dense adhesions (1), uncontrollable bleeding from the mesosalpinx (1), excessive size of the ectopic pregnancy (1). The trial was carried out at University of California, San Diego Medical Center, california, USA between April 1988 and December 1989. Method of randomization was on alternating months, reason for exclusion.

Lund 1955

Murphy 1992

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Characteristics of excluded studies O'Shea 1994 This study compared MTX 20 mg in 0.8 ml normal saline under laparoscopic guidance versus laparoscopic salpingostomy by CO2 laser in 53 hemodynamically stable women with a laparoscopically confirmed unruptured ectopic pregnancy (< 4 cm). The trial was carried out at Flinders University and Flinders Medical Centre, Adelaine Australia. Method of randomization was before laparoscopy on the basis of hospital numbers, reason for exclusion. This study compared MTX 20 - 50 mg in 4 ml saline solution under laparoscopic guidance and oral calcium folinate 16.2 mg/day (day 1-7) versus laparoscopic salpingostomy in 14 hemodynamically stable women a laparoscopically confirmed unruptured tubal ampullary pregnancy (< 5 cm) without fetal cardiac activity. The trial was carried out at La Sapienza, University of Rome, Rome Italy between July 1991 to May 1994. The method of randomization was that the first seven consecutive women meeting the inclusion criteria were treated medically, whereas the following seven women by laparoscopic salpingostomy. This was the reason for exclusion.

Porpora 1996

Characteristics of ongoing studies Study Trial name or title Participants Fernandez 1 Randomized controlled trial between medical treatment by methotrexate versus conservative surgical treatment to evaluate subsequent fertility Patients > 18 years diagnosed with a non active ectopic pregnancy defined by score or algorithm and with desire of future pregnancy Exclusion criteria: pregnant after failed contraception or after IVF-ET Single dose methotrexate versus laparoscopic conservative surgery with a single dose methotrexate postoperatively Primary outcome is subsequent fertility with 2 years follow up. Secondary outcomes are complications of treatment; time to hospitalisation; serum hCG clearance curve; success rate 08-2004 Fernandez H, Antoine Beclere Hospital Clamart, France Multicenter study in France Study Trial name or title Participants Fernandez 2 Randomised controlled trial between conservative versus radical surgical treatment to evaluate subsequent fertility Patients > 18 years diagnosed with ectopic pregnancy by ultrasound and with desire of future pregnancy Exclusion criteria: pregnant after failed contraception or after IVF-ET Conservative versus radical surgery both laparoscopically Primary outcome is subsequent fertility with 2 years follow up every 6 months. Secondary outcomes are complications of treatment; time to hospitalisation; serum hCG clearance curve; success rate 08-2004

Interventions Outcomes

Starting date Contact information

Interventions Outcomes

Starting date

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Characteristics of ongoing studies Contact information Fernandez H, Antoine Beclere Hospital Clamart, France Multicenter study study in France Study Trial name or title Participants Hajenius 1 A randomised controlled trial of salpingostomy versus salpingectomy for tubal pregnancy; impact on future fertility All hemodynamically stable women > 18 years with a presumptive diagnosis of tubal pregnancy, who are scheduled for surgical treatment Exclusion criteria: no desire for future pregnancy, pregnant after IVF-ET, tubal rupture whenever this tubal rupture interferes with the possibility to perform a salpingostomy, contralateral tubal pathology salpingostomy versus salpingectomy (by laparoscopy or by laparotomy) Primary outcome measure is the occurrence of a spontaneous vital intra uterine pregnancy. Other outcome measures are repeat ectopic pregnancy, costs (including duration of surgery, additional costs of persistent trophoblast or repeat ectopic pregnancy, or other peri/per/post operative complications and start of fertility treatment, ie. IVF-ET), patients' preferences. 01-09-2004 Hajenius PJ. Academic Medical Center, University of Amsterdam, The Netherlands International multicenter trial in the Netherlands, Sweden, Norway, Denmark, United Kingdom Study Trial name or title Participants Hajenius 2 Randomised controlled trial of systemic MTX in an intramuscular single shot regimen versus expectant management Inclusion criteria: Hemodynamically stable women > 18 years with suspected ectopic pregnancy in whom serum hCG concentration is < 2,000 IU/L but plateauing at three measurements with 2-days intervals. Exclusion criteria: viable ectopic pregnancy, abnormalities in liver or renal function or in full blood count systemic MTX (1 mg/kg) in an intramuscular single shot regimen versus expectant management Primary outcome is an uneventful decline of serum hCG to an undetectable level by primary treatment. Secondary outcomes are number of (re)interventions (additional MTX or surgical procedures), treatment complications, future fertility, health related quality of life, financial costs, and patients' preferences 01-02-2006 Hajenius PJ. Academic Medical Center, University of Amsterdam, The Netherlands Multicenter study in the Netherlands Study Trial name or title Jurkovic Randomised double blind placebo controlled trial of single dose methotrexate versus expectant management in women with tubal ectopic pregnancy

Interventions Outcomes

Starting date Contact information

Interventions Outcomes

Starting date Contact information

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Characteristics of ongoing studies Participants Inclusion criteria: Hemodynamic stability No hemoperitoneum Non-viable pregnancy hCG < 1,500 IU/l Normal renal, liver function and normal blood parameters systemic MTX 50 mg/m2 im versus saline as placebo The primary outcome measure is the number of surgical procedures. The secondary outcome measure is the intra uterine pregnancy rate within 3 years. 01-09-2005 Jurkovic D. Early Pregnancy Unit, Kings Hospital, London, United Kingdom Single center study

Interventions Outcomes Starting date Contact information

TAB LAS ADICIONALES Table 01 Quality of the included studies Study ID Alleyassin 2006 Randomisation Allocation method concealed computer adequate with generated sealed random envelopes number tables computer adequate generated random number tables computer program unclear by computer unclear computer generated list random number table adequate unclear unclear unclear adequate by telephone unclear Blinding no no of patients drop outs 108 0 lost to follow up 0

Cohen 1996

NA

20

Dias Pereira 1999 Egarter 1991 El-Sherbiny 2003 Elmoghazy 2000 Fedele 1998 Fernandez 1991 Fernandez 1994

NA NA NA no no NA NA

140 23 55 47 25 21 48

40 0 0 0 0 0 0

10 0 0 0 0 0 0

blinded adequate computer generated random number tables random number table unclear

Fernandez 1995

NA

40

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Table 01 Quality of the included studies Fernandez 1998 random number table unclear unclear unclear NA no no 100 26 75 0 0 0 18 0 9

Fujishita 1995b unclear Fujishita 2004 computer generated randomization list computer generated randomization sequence unclear drawing cards unclear

Gazvani 1998

adequate with consecutively numbered enveloppes unclear inadequate unclear although sealed envelopes adequate unclear unclear

no

50

Gjelland 1995 Graczykowski 1997 Gray 1995

NA no NA

80 129 105

0 0

0 13

Hajenius 1997 computer program Hordnes 1997 Klauser 2005 unclear unclear

NA NA no yes

140 80 51 60

40 0 0 0

0 0 0 0

Korhonen 1996 table of random adequate via numbers hospital pharmacy Landstrom 1998 Lang 1990 unclear by computer unclear unclear unclear although sealed envelopes unclear although sealed envelopes unclear although sealed envelopes adequate unclear

NA NA NA

31 31 109

0 0 4

0 0 0

Lundorff 1991a unclear

Lundorff 1991b unclear

NA

109

36

Lundorff 1992

unclear

NA

109

21

Mol 1999a Mottla 1992

computer program random table

NA NA

140 21

40 9

0 0

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Table 01 Quality of the included studies Nieuwkerk 1998a Rozenberg 2003 computer program computer generated list adequate NA 140 212 51 0 5 2

adequate with yes sealed opaque envelopes stored in the pharmacy unclear unclear although sealed envelopes unclear yes NA

Sadan 2001 Saraj 1998

unclear unclear

20 75

0 1

0 0

Sharma 2003

computer generated numbers

NA

60

Shulman 1992 unclear Sowter 2001a computer program

unclear adequate with sequentially numbered opaque evelopes sealed by a third party adequate with sequentially numbered opaque evelopes sealed by a third party unclear unclear unclear adequate with sequential selection of umarked opaque envelope adequate with sequential selection of umarked opaque envelope unclear

no NA

15 62

0 0

0 7

Sowter 2001b

computer program

NA

62

Tulandi 1991a

unclear

no NA no NA

34 36 40 60

0 0 0 0

16 0 0 0

Tzafettas 1994 unclear Ugur 1996 unclear

Vermesh 1989 coded card

Vermesh 1992 coded card

NA

60

15

Wang 1998

unclear

no

78

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Table 01 Quality of the included studies Yalcinkaya 1996 Yalcinkaya 2000 unclear unclear unclear adequate with sealed envelopes at the central pharmacy unclear yes yes 41 100 0 0 1 44

Zilber 1996

unclear

NA

48

CARTULA Titulo Autor(es) Contribucin de los autores Intervenciones para el embarazo ectpico tubrico Hajenius PJ, Mol F, Mol BWJ, Bossuyt PMM, Ankum WM, van der Veen F Petra Hajenius: dirigi la redaccin del protocolo y de la revisin, realiz las bsquedas iniciales de los ensayos en las bases de datos, particip en la seleccin de los ensayos para su inclusin, realiz de forma independiente la extraccin de los datos y la evaluacin de la calidad de los ensayos incluidos, se encarg del anlisis estadstico, de la interpretacin de los datos y de la actualizacin de la revisin. Femke Mol: realiz la bsqueda de los ensayos en las bases de datos desde 2004, particip en la seleccin de los ensayos nuevos para su inclusin en la revisin actualizada, realiz la extraccin de los datos de forma independiente y realiz observaciones sobre el borrador de la revisin actualizada. Ben Willem Mol: realiz de forma independiente la extraccin de los datos y la evaluacin de la calidad de los ensayos incluidos, se encarg del anlisis estadstico y de la interpretacin de los datos y realiz observaciones sobre los borradores del protocolo y la revisin. Patrick Bossuyt: realiz observaciones sobre los borradores del protocolo y la revisin, y aport a la revisin sus conocimientos y experiencia sobre epidemiologa y estadstica. Pim Ankum: formul observaciones sobre los borradores del protocolo y la revisin y aport su experiencia clnica a la revisin. Fulco van der Veen: inici y conceptualiz la revisin, realiz las bsquedas de los resmenes de las reuniones de ESHRE y ASRM, realiz observaciones sobre los borradores del protocolo y la revisin y aport su experiencia clnica a la revisin. La informacin no est disponible

Nmero de protocolo publicado inicialmente Nmero de revisin publicada inicialmente Fecha de la modificacin ms reciente" "Fecha de la modificacin SIGNIFICATIVA ms reciente

1999/1

15 noviembre 2006

16 noviembre 2006

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Cambios ms recientes

Desde la publicacin de la revisin Cochrane en el ao 2000 (nmero 2) se identificaron 26 estudios nuevos. De estos estudios se excluyeron dos porque eran ensayos controlados no aleatorios (Colacurci 1998, Kaya 2002). Cinco estudios fueron una publicacin doble, cuatro estn en espera de evaluacin debido a dificultades de traduccin, cinco estn en curso o por empezar, y diez se incluyeron en esta revisin (Wang 1998, Elmoghazy 2000, Yalcinkaya 2000, Sadan 2001, Rozenberg 2003, Sharma 2003, El-Sherbiny 2003, Fujishita 2004, Klauser 2005, Alleyassin 2006).Se incorpor un revisor nuevo y se describe la contribucin de cada revisor.Se realizaron cambios textuales en toda la revisin por sugerencias de los evaluadores externos y como resultado de la inclusin de los estudios nuevos y la exclusin de los ensayos controlados no aleatorios. Los efectos del tratamiento se expresan como odds-ratios de Peto.Los estudios, y en consecuencia la distribucin de la revisin, se dividieron en tres grupos principales:1. ciruga2. tratamiento mdico3. manejo expectanteSe agreg una tabla adicional con un resumen de la calidad metodolgica de los estudios incluidos. 01 octubre 2006

Fecha de bsqueda de nuevos estudios no localizados Fecha de localizacin de nuevos estudios an no incluidos/excluidos Fecha de localizacin de nuevos estudios incluidos/excluidos Fecha de modificacin de la seccin conclusiones de los autores Direccin de contacto

El autor no facilit la informacin

01 agosto 2006

18 octubre 2006

Dr Petra Hajenius Gynecologist Obstetrics and Gynecology (H4-205) Academic Medical Center, University of Amsterdam Meibergdreef 9 Amsterdam 1105 AZ NETHERLANDS Tlefono: 31-20-5663654 E-mail: p.hajenius@amc.nl Facsimile: 31-20-6963489 CD000324 Cochrane Menstrual Disorders and Subfertility Group HM-MENSTR

Nmero de la Cochrane Library Grupo editorial Cdigo del grupo editorial

COMENTARIOS Y CRITICAS Interventions for tubal ectopic pregnancy


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Resumen: ABSTRACT Excessively long. Text could be converted to numbers. Re-write to conform to new structure. TYPES OF STUDIES Inclusion of unpublished studies not as per protocol. TYPES OF INTERVENTION Unclear format of this section. METHODOLOGICAL QUALITIES OF INCLUDED STUDIES Omit mention of Koninckx 1991. Highlight rate of exclusions after randomisation in medical treatment. SURGICAL TREATMENT move case-control study to Discussion section Under comparison 7, the result for tubal preservation is quoted as "RR 1.0, 95%CI 1.0, 1.0". This confidence interval must be wrong. DISCUSSION AND IMPLICATIONS FOR RESEARCH Conflicting messages on laparoscopic surgery. CONCLUSIONS-IMPLICATIONS FOR PRACTICE Balance of emphasis on surgery vs MTX. IMPLICATIONS FOR RESEARCH Long discussion obscures the clear messages about future research. EXCLUDED STUDIES Reconsider grounds for excluding info on Lund 1955, or at least commenting on the study. Gentofte spelling. CONFLICT OF INTEREST: None. Contestacin del autor: The review has been updated. Colaboradores: Phil Alderson, April 1999

RESUMEN DEL METANLISIS 01 salpingostoma laparoscpica versus salpingostoma por ciruga abierta Resultado 01 xito del tratamiento primario 02 trofoblasto persistente 03 permeabilidad tubrica 04 embarazo intrauterino posterior 05 embarazo ectpico repetido N de estudios 2 2 2 2 2 N de participantes 165 165 110 127 127 Mtodo estadstico Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Tamao del efecto 0.28 [0.09, 0.86] 3.47 [1.06, 11.28] 0.58 [0.23, 1.42] 1.21 [0.59, 2.45] 0.47 [0.15, 1.47]

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02 minilaparotoma versus laparotoma Resultado 01 xito del tratamiento primario N de estudios 1 N de participantes 60 Mtodo estadstico Odds-Ratio de Peto IC del 95% Tamao del efecto No estimable

03 salpingostoma sin sutura tubrica versus salpingostoma con sutura tubrica Resultado 01 xito del tratamiento primario 02 trofoblasto persistente 03 tasa de permeabilidad tubrica 04 embarazo intrauterino posterior 05 embarazo ectpico repetido N de estudios 2 2 1 2 2 N de participantes 109 109 66 88 88 Mtodo estadstico Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Tamao del efecto 0.16 [0.02, 1.23] 6.16 [0.81, 46.56] 0.38 [0.06, 2.35] 1.07 [0.44, 2.57] 1.20 [0.38, 3.81]

04 salpingostoma sola versus en combinacin con un tratamiento mdico Resultado 01 xito del tratamiento primario 02 trofoblasto persistente 03 preservacin tubrica 04 permeabilidad tubrica N de estudios N de participantes Mtodo estadstico Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% 05 MTX sistmico versus salpingostoma laparoscpica Resultado 01 xito del tratamiento primario 02 trofoblasto persistente 03 preservacin tubrica 04 permeabilidad tubrica 05 embarazo intrauterino posterior N de estudios N de participantes Mtodo estadstico Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Tamao del efecto Subtotales nicamente Subtotales nicamente Subtotales nicamente Subtotales nicamente Subtotales nicamente Tamao del efecto Subtotales nicamente Subtotales nicamente Subtotales nicamente Subtotales nicamente

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05 MTX sistmico versus salpingostoma laparoscpica 06 embarazo ectpico repetido Odds-Ratio de Peto IC del 95% Subtotales nicamente

06 MTX local versus salpingostoma laparoscpica Resultado 01 xito del tratamiento primario 02 trofoblasto persistente 03 preservacin tubrica 04 permeabilidad tubrica 05 embarazo intrauterino posterior 06 embarazo ectpico repetido N de estudios N de participantes Mtodo estadstico Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Tamao del efecto Subtotales nicamente Subtotales nicamente Subtotales nicamente Subtotales nicamente Subtotales nicamente Subtotales nicamente

07 MTX por va transvaginal mediante gua ecogrfica versus MTX mediante gua laparoscpica Resultado 01 xito del tratamiento primario 02 trofoblasto persistente N de estudios 1 1 N de participantes 36 36 Mtodo estadstico Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Tamao del efecto 5.75 [1.29, 25.71] 0.27 [0.05, 1.38]

08 MTX por va transvaginal mediante gua ecogrfica versus MTX sistmico de dosis nica intramuscular Resultado 01 xito del tratamiento primario 02 trofoblasto persistente 03 preservacin tubrica 04 embarazo intrauterino posterior 05 embarazo ectpico repetido N de estudios 3 3 1 2 1 N de participantes 95 95 24 51 31 Mtodo estadstico Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Tamao del efecto 2.14 [0.82, 5.56] 0.40 [0.13, 1.18] 2.08 [0.19, 22.17] 1.52 [0.43, 5.31] 4.09 [0.05, 307.06]

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Intervenciones para el embarazo ectpico tubrico

09 MTX mediante gua laparoscpica versus el mismo rgimen en combinacin con MTX sistmico intramuscular Resultado 01 xito del tratamiento primario N de estudios 1 N de participantes 15 Mtodo estadstico Odds-Ratio de Peto IC del 95% Tamao del efecto 0.12 [0.00, 5.96]

10 MTX de dosis nica versus MTX de dosis mltiple fija ambos por va intramuscular Resultado 01 xito del tratamiento primario 02 trofoblasto persistente N de estudios 2 1 N de participantes 159 108 Mtodo estadstico Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Tamao del efecto 0.89 [0.32, 2.50] 2.92 [0.70, 12.23]

11 MTX 25 mg/m2 versus MTX 50 mg/m2 estndar ambos de dosis nica intramuscular Resultado 01 xito del tratamiento primario 02 trofoblasto persistente 03 xito del tratamiento con dosis de MTX variable 04 preservacin tubrica 05 permeabilidad tubrica 06 embarazo intrauterino posterior 07 embarazo ectpico repetido N de estudios 1 1 1 1 1 1 1 N de participantes 100 100 100 100 37 56 56 Mtodo estadstico Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Tamao del efecto 0.68 [0.30, 1.54] 1.36 [0.57, 3.24] 0.77 [0.24, 2.45] 0.45 [0.09, 2.35] 0.90 [0.25, 3.22] 1.08 [0.37, 3.16] 0.56 [0.10, 3.01]

12 MTX en lipiodol en suspensin versus MTX en solucin fisiolgica ambos mediante gua laparoscpica Resultado 01 xito del tratamiento primario 02 trofoblasto persistente 03 preservacin tubrica 04 permeabilidad tubrica 05 embarazo intrauterino posterior N de estudios 1 1 1 1 1 N de participantes 26 26 26 22 18 Mtodo estadstico Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Tamao del efecto 5.96 [1.31, 27.05] 0.22 [0.05, 1.06] 9.55 [0.56, 163.09] 2.06 [0.29, 14.60] 0.43 [0.07, 2.60]

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13 MTX versus prostaglandinas ambos mediante gua ecogrfica combinados con la administracin sistmica del frmaco Resultado 01 xito del tratamiento primario 02 permeabilidad tubrica N de estudios 1 1 N de participantes 21 14 Mtodo estadstico Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Tamao del efecto 1.00 [0.17, 5.98] 0.17 [0.00, 9.12]

14 MTX sistmico solo de dosis nica intramuscular versus en combinacin con mifepristona por va oral Resultado 01 xito del tratamiento primario 02 trofoblasto persistente 03 preservacin tubrica 04 permeabilidad tubrica N de estudios 2 2 2 1 N de participantes 262 262 262 24 Mtodo estadstico Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Tamao del efecto 0.59 [0.35, 0.99] 1.37 [0.69, 2.71] 0.73 [0.37, 1.42] 0.38 [0.05, 3.14]

15 MTX sistmico solo de dosis nica intramuscular versus en combinacin con EE2 Resultado 01 xito del tratamiento primario 02 embarazo intrauterino posterior 03 embarazo ectpico repetido N de estudios 1 1 1 N de participantes 78 78 78 Mtodo estadstico Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Tamao del efecto 0.08 [0.02, 0.39] 0.19 [0.07, 0.51] 4.18 [0.74, 23.45]

16 glucosa hiperosmolar mediante gua laparoscpica versus otros tratamientos Resultado 01 xito del tratamiento primario 02 trofoblasto persistente 03 permeabilidad tubrica 04 embarazo intrauterino posterior 05 embarazo ectpico repetido N de estudios N de participantes Mtodo estadstico Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Tamao del efecto Subtotales nicamente Subtotales nicamente Subtotales nicamente Subtotales nicamente Subtotales nicamente

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17 manejo expectante versus tratamiento mdico Resultado 01 xito del tratamiento primario 02 preservacin tubrica N de estudios N de participantes Mtodo estadstico Odds-Ratio de Peto IC del 95% Odds-Ratio de Peto IC del 95% Tamao del efecto Subtotales nicamente Subtotales nicamente

GRFICOS Y OTRAS TABLAS Fig. 01 salpingostoma laparoscpica versus salpingostoma por ciruga abierta
01.01 xito del tratamiento primario

01.02 trofoblasto persistente

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01.03 permeabilidad tubrica

01.04 embarazo intrauterino posterior

01.05 embarazo ectpico repetido

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Fig. 02 minilaparotoma versus laparotoma


02.01 xito del tratamiento primario

Fig. 03 salpingostoma sin sutura tubrica versus salpingostoma con sutura tubrica
03.01 xito del tratamiento primario

03.02 trofoblasto persistente

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03.03 tasa de permeabilidad tubrica

03.04 embarazo intrauterino posterior

03.05 embarazo ectpico repetido

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Fig. 04 salpingostoma sola versus en combinacin con un tratamiento mdico


04.01 xito del tratamiento primario

04.02 trofoblasto persistente

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04.03 preservacin tubrica

04.04 permeabilidad tubrica

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Fig. 05 MTX sistmico versus salpingostoma laparoscpica


05.01 xito del tratamiento primario

05.02 trofoblasto persistente

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05.03 preservacin tubrica

05.04 permeabilidad tubrica

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05.05 embarazo intrauterino posterior

05.06 embarazo ectpico repetido

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Fig. 06 MTX local versus salpingostoma laparoscpica


06.01 xito del tratamiento primario

06.02 trofoblasto persistente

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06.03 preservacin tubrica

06.04 permeabilidad tubrica

06.05 embarazo intrauterino posterior

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06.06 embarazo ectpico repetido

Fig. 07 MTX por va transvaginal mediante gua ecogrfica versus MTX mediante gua laparoscpica
07.01 xito del tratamiento primario

07.02 trofoblasto persistente

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Fig. 08 MTX por va transvaginal mediante gua ecogrfica versus MTX sistmico de dosis nica intramuscular
08.01 xito del tratamiento primario

08.02 trofoblasto persistente

08.03 preservacin tubrica

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08.04 embarazo intrauterino posterior

08.05 embarazo ectpico repetido

Fig. 09 MTX mediante gua laparoscpica versus el mismo rgimen en combinacin con MTX sistmico intramuscular
09.01 xito del tratamiento primario

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Fig. 10 MTX de dosis nica versus MTX de dosis mltiple fija ambos por va intramuscular
10.01 xito del tratamiento primario

10.02 trofoblasto persistente

Fig. 11 MTX 25 mg/m2 versus MTX 50 mg/m2 estndar ambos de dosis nica intramuscular
11.01 xito del tratamiento primario

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11.02 trofoblasto persistente

11.03 xito del tratamiento con dosis de MTX variable

11.04 preservacin tubrica

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11.05 permeabilidad tubrica

11.06 embarazo intrauterino posterior

11.07 embarazo ectpico repetido

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Fig. 12 MTX en lipiodol en suspensin versus MTX en solucin fisiolgica ambos mediante gua laparoscpica
12.01 xito del tratamiento primario

12.02 trofoblasto persistente

12.03 preservacin tubrica

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12.04 permeabilidad tubrica

12.05 embarazo intrauterino posterior

Fig. 13 MTX versus prostaglandinas ambos mediante gua ecogrfica combinados con la administracin sistmica del frmaco
13.01 xito del tratamiento primario

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13.02 permeabilidad tubrica

Fig. 14 MTX sistmico solo de dosis nica intramuscular versus en combinacin con mifepristona por va oral
14.01 xito del tratamiento primario

14.02 trofoblasto persistente

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14.03 preservacin tubrica

14.04 permeabilidad tubrica

Fig. 15 MTX sistmico solo de dosis nica intramuscular versus en combinacin con EE2
15.01 xito del tratamiento primario

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15.02 embarazo intrauterino posterior

15.03 embarazo ectpico repetido

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Fig. 16 glucosa hiperosmolar mediante gua laparoscpica versus otros tratamientos


16.01 xito del tratamiento primario

16.02 trofoblasto persistente

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16.03 permeabilidad tubrica

16.04 embarazo intrauterino posterior

16.05 embarazo ectpico repetido

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Fig. 17 manejo expectante versus tratamiento mdico


17.01 xito del tratamiento primario

17.02 preservacin tubrica

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