Cochrane - Revision Ectopico PDF

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
03 salpingostoma sin sutura tubrica versus salpingostoma con sutura tubrica............................................78
03 tasa de permeabilidad tubrica..............................................................................................................79
Copyright John Wiley & Sons Ltd. Usado con permiso de John Wiley & Sons, Ltd.
NDICE DE MATERIAS
04 salpingostoma sola versus en combinacin con un tratamiento mdico......................................................80

03 preservacin tubrica.............................................................................................................................81
05 MTX sistmico versus salpingostoma laparoscpica...................................................................................82
06 MTX local versus salpingostoma laparoscpica...........................................................................................85
07 MTX por va transvaginal mediante gua ecogrfica versus MTX mediante gua laparoscpica...................87
08 MTX por va transvaginal mediante gua ecogrfica versus MTX sistmico de dosis nica intramuscular....88
09 MTX mediante gua laparoscpica versus el mismo rgimen en combinacin con MTX sistmico
intramuscular......................................................................................................................................................89
10 MTX de dosis nica versus MTX de dosis mltiple fija ambos por va intramuscular....................................90
11 MTX 25 mg/m2 versus MTX 50 mg/m2 estndar ambos de dosis nica intramuscular................................90
03 xito del tratamiento con dosis de MTX variable....................................................................................91
12 MTX en lipiodol en suspensin versus MTX en solucin fisiolgica ambos mediante gua laparoscpica....93
ii
NDICE DE MATERIAS
13 MTX versus prostaglandinas ambos mediante gua ecogrfica combinados con la administracin sistmica
del frmaco.........................................................................................................................................................94
14 MTX sistmico solo de dosis nica intramuscular versus en combinacin con mifepristona por va oral.....95
15 MTX sistmico solo de dosis nica intramuscular versus en combinacin con EE2.....................................96
16 glucosa hiperosmolar mediante gua laparoscpica versus otros tratamientos............................................98
17 manejo expectante versus tratamiento mdico............................................................................................100
01 xito del tratamiento primario...............................................................................................................100
02 preservacin tubrica...........................................................................................................................100
iii

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).
Pgina 1
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,
Pgina 2
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)).
Pgina 3
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
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
Tratamiento mdico
metotrexato
glucosa hiperosmolar
prostaglandinas
cloruro de potasio
cloruro de sodio
actinomicina D
etopsido
mifepristona
danazol
anticuerpos anti hCG
Ver los mtodos del Grupo de Trastornos Menstruales y

Subfertilidad utilizados en las revisiones.
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
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)
Pgina 4
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$).ti,ab,hw,tn,mf. (424186)
20 or/6-19 (2549444)
21 nonhuman/ (2672524)
23 or/21-22 (2676117)
24 20 not 23 (1488861)
25 5 and 24 (1353)
26 25 and trial.mp. (457)
27 26 not review$.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)
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
Pgina 5
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
Pgina 6
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
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)).
METOTREXATO VERSUS CIRUGA

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
VAS
DE
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))
Pgina 7
DIFERENTES
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))
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
Pgina 8
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)).
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.
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
3. Salpingostoma sin sutura tubrica versus salpingostoma

con sutura tubrica
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.
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).
Pgina 9
4. Salpingostoma sola versus en combinacin con un

tratamiento mdico
Los efectos secundarios del tratamiento profilctico con

metotrexato, que ocurrieron entre el 5,5% y el 8% de las
mujeres, fueron leves.
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).

fertilidad futura.
No se encontraron diferencias significativas en cuanto a la

preservacin tubrica (OR 0,82; IC del 95%: 0,21 a 3,2).
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).
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.
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.
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).
fertilidad futura.
TRATAMIENTO MDICO
METOTREXATO VERSUS CIRUGA
5. Metotrexato
laparoscpica
sistmico
versus
salpingostoma
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
Pgina 10
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).
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)).
Pgina 11
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
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
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).
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.
fertilidad futura.
DIFERENTE
METOTREXATO
DOSIS/SUSPENSIN
DEL
10. Dosis nica versus dosis mltiple fija ambas por va

intramuscular
Pgina 12
DIFERENTES
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).
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).
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).

fertilidad futura.
METOTREXATO VERSUS/O EN COMBINACIN CON

OTROS TRATAMIENTOS MDICOS
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
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.
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).
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
Slo una mujer de cada grupo de tratamiento present efectos

secundarios.
tubrica ms baja en el grupo de metotrexato (OR 0,17; IC del
95%: 0,0 a 9,1).
intramuscular versus en combinacin con mifepristona por
va oral
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
Pgina 13
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.
tubrica ms baja con metotrexato solo (OR 0,38; IC del 95%:
0,05 a 3,1).
15. Metotrexato sistmico solo en un rgimen intramuscular
de dosis nica versus en combinacin con decoccin
Embarazo Ectpico 2 (EE2)
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).
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
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).
GLUCOSA HIPEROSMOLAR
16. Glucosa hiperosmolar mediante gua laparoscpica

versus otros tratamientos
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.
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
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.
fertilidad futura.

fertilidad futura.
MANEJO EXPECTANTE
17. Manejo expectante versus tratamiento mdico
Pgina 14
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.
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.
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.
Pgina 15
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.
Pgina 16
En conclusin, no se puede realizar an una evaluacin

adecuada del manejo expectante del embarazo ectpico tubrico.
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)).
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
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).
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
TRATAMIENTO MDICO/MANEJO EXPECTANTE
Recursos internos
No se facilitaron las fuentes de financiacin
Pgina 17
REFERENCIAS
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Fujishita A, Ishimaru T, Masuzaki H, Samejima T, Matsuwaki T, Ortega
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*Fernandez H, Pauthier S, Doumerc S, Lelaidier C, Olivennes F, Ville Y,
et al. Ultrasound guided injection of methotrexate versus laparoscopic
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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 H, Yves Vincent S, Pauthier S, Audibert F, Frydman R.
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*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.
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Pgina 18
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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, 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, 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.
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.
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.
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.
Pgina 19
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.
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
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.
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.
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.
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.
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.
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.
Referencias de los estudios en espera de evaluacin

Hu 2003
Peng 1997
Su 2002
Wei 2003
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.
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.
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.
Pgina 20
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.
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
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.
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.
Kirk 2006
Kirk E, Condous G, Bourne T. The non-surgical management of ectopic
pregnancy. Utrasound in Obstetrics and Gynecology 2006;27:91-100.
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.
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.
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
Pgina 21
TABLAS
Characteristics of included studies
Study
Alleyassin 2006
Methods
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
Participants
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
Interventions
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
Outcomes
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
Notes
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
Allocation concealment
A - Adequate
Study
Cohen 1996
Methods
Randomization using computer generated random number tables

Single center
No power calculation
Ethical commitee approval not stated
Pgina 22

Participants
Clinically stable women with an ectopic pregnancy (< 3.5 cm) with rising serum hCG
concentrations
The trial was carried out at the McGill University, Cleveland, Ohio, USA
Timing and duration of the trial not stated
Interventions
MTX 1 mg/kg transvaginally under sonographic guidance versus systemic MTX single
dose 50 mg/m2 IM
Outcomes
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
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
Notes
A - Adequate
Study
Dias Pereira 1999
Methods
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
Intention to treat analysis
Published as letter to the editor
Pgina 23

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 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
Interventions
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
Outcomes
Fertility outcome
method of diagnosis: cumulative frequency and pregnancy outcome of first subsequent
pregnancy by means of telephonic contacts or questionnaires
Notes
A - Adequate
Study
Egarter 1991
Methods
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
Participants
Women with a laparoscopically confirmed unruptured tubal pregnancy without active

bleeding and a serum hCG concentration < 2,500 IU/l
The trial was carried out at the I Univ Frauenklinik, Vienna, Austria
Interventions
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
Pgina 24

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
Notes
If possible, all women were released from the hospital on the second postoperative
day
B - Unclear
Study
El-Sherbiny 2003
Methods
Method of randomization by computer

Multi center
No ethical commitee approval
Participants
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
Interventions
Single dose systemic MTX (50 mg/m2) versus laparoscopic surgery
Outcomes
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
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
Pgina 25

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
Study
Elmoghazy 2000
Methods
Method of randomization not stated

Single center
Source of funding not stated
Published as abstract
Participants
All women with early diagnosed tubal pregnancy who underwent surgical conservation
of the tube
The trial was carried out El-Minia University in Egypt
Interventions
Conservative surgery of the tube and a single dose of MTX postoperatively (1 mg/kg
IM) within 24 hours versus conservative surgery alone
Outcomes
Treatment success
method of diagnosis: an uneventful decline of serum hCG to undetectable levels ( <
15 IU/l)
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
Notes
B - Unclear
Study
Fedele 1998
Methods
Randomization by telephone using a computer generated list before salpingotomy

Multi center
Source of funding not stated
Pgina 26

Participants
Women with a laparoscopically confirmed unruptured tubal pregnancy < 5 cm without

adhesions involving the salpinx
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
Interventions
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
Outcomes
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
1. easy, 2. moderately difficult, 3. difficult
Bleeding at the site of the pregnancy
1. minimal, 2. moderate, 3. abundant
Notes
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
Study
Fernandez 1991
Methods
Randomization using a random number table

Single center
Participants
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
The trial was carried out at the Hpital Antoine Bclre, Clamart, France between April
1, 1989 and December 31, 1989
Interventions
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
Pgina 27

Outcomes
Treatment success
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
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
Notes
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
Study
Fernandez 1994
Methods
Randomization by blinded computer generated random number tables

Single center
Participants
Women with an unruptured ectopic pregnancy clearly visualized by transvaginal

sonography and a predictive therapeutic score < 14
The trial was carried out at the Hpital Antoine Bclre, Clamart, France between July
and October 1991
Interventions
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
Pgina 28

Outcomes
Treatment success
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)
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
Notes
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
Study
Fernandez 1995
Methods

Single center
Participants
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
The trial was carried out at the Hpital Antoine Bclre, Clamart, France between
September 1, 1992 and October 1, 1993
Interventions
MTX 1 mg/kg transvaginally under sonographic guidance versus laparoscopic

salpingostomy
Pgina 29

Outcomes
Treatment success
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: 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
pregnancy by personal or telephonic contact, follow-up > 6 months
Notes
Part of the results are updated in the study of Fernandez 1998

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
Study
Fernandez 1998
Methods

Single center
Participants
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
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
Interventions
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
Pgina 30

Outcomes
Treatment success
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: number of postoperative days in the hospital
Pregnancy outcome
pregnancy by personal or telephonic contact, follow-up > 1 year
Notes
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
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
Study
Fujishita 1995b
Methods

Single center
Participants
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
The trial was carried out at the Nagasaki University School of Medicine, Nagasaki,
Japan between May 1991 to July 1993
Interventions
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
Pgina 31

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
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
Tubal patency
method of diagnosis:by hysterosalpingogram 3 months after initial treatment
Pregnancy outcome
pregnancy, follow-up 6-31 months
Notes
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
Study
Fujishita 2004
Methods
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
Participants
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 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
Interventions
Salpingotomy without tubal suturing versus salpingotomy with tubal suturing
Pgina 32

Outcomes
Treatment success
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
Notes
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
Study
Gazvani 1998
Methods
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
Participants

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)
The trial took place at the Early Pregnancy Unit at Singleton Hospital, Swansea, United
Kingdom between April 1994 and April 1996
Interventions
Single dose systemic MTX (50 mg/m2 IM) alone versus the same regimen in
combination with mifepristone 600 mg orally
Pgina 33

Outcomes
Treatment success
IU/L) by primary treatment
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
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
Notes
Peritoneal lavage was carried out at confirmative laparoscopy
A - Adequate
Study
Gjelland 1995
Methods

Single center
Participants
Women with an ectopic pregnancy (< 4 cm) on transvaginal ultrasound and serum hCG
concentration < 3,000 IU/l, and little or no intraabdominal bleeding
The trial was carried out at Haukeland University Hospital, Bergen, Norway between
September 1991 and January 1994
Interventions
Hyperosmolar glucose 50% 10-20 ml transvaginally under sonographic guidance versus

hyperosmolar glucose 50% 10-20 ml under laparoscopic guidance
Pgina 34

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
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
B - Unclear
Study
Graczykowski 1997
Methods
Method of randomization by drawing cards

Single center
Funding in part by National Institutes of Health grant to GCRC M01 RR-43, Betheseda,
Maryland, USA
Participants
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
The trial was carried out at Los Angeles County and University of Southern California
Medical Center, USA between July 1993 and March 1995
Interventions
Salpingostomy and a single dose of MTX postoperatively (1 mg/kg IM) within 24 hours
versus salpingostomy alone
Pgina 35

Outcomes
Treatment success
method of diagnosis: an uneventful decline of serum hCG to undetectable levels ( <
15 IU/l)
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
C - Inadequate
Study
Gray 1995
Methods
Randomization during laparoscopy by sealed envelopes, stratification into 6 subgroups

based on age and an existing risk scoring scheme
Single center
Funding by Swedish Medical Research Council and by the Gteborg Medical Society
Gteborg, Sweden
Participants
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
The trial was carried out at Sahlgrenska University Hospital, Gteburg, Sweden between
May 1, 1987 and June 30, 1989
Interventions
Laparoscopy versus laparotomy
Outcomes
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
Pgina 36

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
Study
Hajenius 1997
Methods

done before a confirmative laparoscopy
Multi center
size of 100 women would allow to detect a difference in tubal patency rate, in favour
a power of 80%
Participants

40
Interventions
Pgina 37

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
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
hCG clearance time
method of diagnosis: the median number of days to reach undetectable serum hCG
levels
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
salpingectomy
Notes
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
Study
Hordnes 1997
Methods

Single center
Participants
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
The trial was carried out at Haukeland University Hospital, Bergen, Norway between
September 1991 and January 1994
Interventions
Hyperosmolar glucose 50% 10-20 ml transvaginally under sonographic guidance versus

hyperosmolar glucose 50% 10-20 ml under laparoscopic guidance
Outcomes
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
Pgina 38

Notes
B - Unclear
Study
Klauser 2005
Methods

Single center
Participants
Women with a clinical diagnosis of an unruptured ectopic pregnancy

(upper limit serum hCG concentration 10,000 IU/l)
The trial was carried out at University of Mississippi Medical Center, Jackson, MS, USA
Interventions
Single dose MTX (50 mg/m2) versus multiple dose MTX (1 mg/kg on day 1,3,5)
Outcomes
Treatment success
IU/l)
Need for surgery
Side effects
serum hCG resolution time
Notes
Not mentioned if leucovorin was given on alternating days (day 2,4,6)
B - Unclear
Study
Korhonen 1996
Methods
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
Participants
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
The trial was carried out at Helsinki University Central Hospital, Finland during a 3 year
period
Interventions
Systemic MTX 2.5 mg/day orally during 5 days versus expectant management
Pgina 39

Outcomes
Treatment success
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
Notes
A - Adequate
Study
Landstrom 1998
Methods

Multi center
Participants
Hemodynamically stable women with a tubal pregnancy at diagnostic laparoscopy and

a serum hCG concentration < 3,000 IU/l
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
Interventions
Systemic MTX in a oral regimen versus prostaglandins F2a and hyperosmolar glucose
under laparoscopic guidance
Outcomes
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
Notes
B - Unclear
Study
Lang 1990
Methods
Randomization by computer
Single center
Participants

pregnancy without active bleeding, and a urinary hCG concentration < 5,000 IU/l
The trial was carried out at the University of Graz, Austria, during a 9 month period
Pgina 40

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
Outcomes
Treatment success
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
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
Notes
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
Study
Lundorff 1991a
Methods
Randomization during laparoscopy by sealed envelopes, with stratification into 6

subgroups based on age and an existing risk scoring scheme
Single center
Gteborg, Sweden
Participants
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
May 1, 1987 and June 30, 1989
Interventions
Pgina 41

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
Total duration sick leave
method of diagnosis: not stated, in days
Notes
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
Study
Lundorff 1991b
Methods
Randomization during laparoscopy by sealed envelopes, stratification into 6 subgroups

based on age and an existing risk scoring scheme
Single center
Gteborg, Sweden
Participants

excluded
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
May 1, 1987 and June 30, 1989
Interventions
Pgina 42

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
Notes
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
Study
Lundorff 1992
Methods
Randomization by sealed envelopes, stratification into 6 subgroups based on age and

an existing risk scoring scheme
Single center
Gteborg, Sweden
Participants

excluded
Number of women originally randomized: 109, secondary exclusions 4, lost to follow
up 1, no desire for pregnancy 17
May 1, 1987 and June 30, 1989 with follow-up 1 year after surgery, or end of study
period in August 1990
Interventions
Outcomes
Fertility outcome
method of diagnosis: cumulative frequency and pregnancy outcome of first subsequent
pregnancy by means of questionnaires
Pgina 43

Notes
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
Study
Mol 1999a
Methods

Multi center
a power of 80%
Participants

Secondary exclusions for nontubal pregnancy, tubal rupture, and/or active bleeding:40
Interventions
Pgina 44

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
Notes
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
Study
Mottla 1992
Methods
Randomization before laparoscopy by using a random table

Single center
Pgina 45

Participants
Hemodynamically stable women with a laparoscopically confirmed unruptured ectopic

pregnancy (< 3 cm) and < 100 ml blood within the peritoneal cavity
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
Interventions
MTX 12.5 mg - 25 mg under laparoscopic control versus laparoscopic salpingostomy
Outcomes
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
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
Notes
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
Study
Nieuwkerk 1998a
Methods

Multi center
a power of 80%
Pgina 46

Participants

ovarian hyperstimulation syndrome) and with sufficient Dutch or English skills to
complete questionnaires
40
Insufficient Dutch or English skills: 11
Interventions
Outcomes
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
Notes
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
Pgina 47

Study
Rozenberg 2003
Methods
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
Participants
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)
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.
Interventions
Single dose systemic MTX (50 mg/m2 IM) alone versus the same regimen in
combination with mifepristone 600 mg orally
Pgina 48

Outcomes
Treatment success
method of diagnosis: uneventful decline of serum hCG to undetectable levels (serum
hCG < 10 mIU/ml) by primary treatment
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: 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
Notes
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
Study
Sadan 2001
Methods
Double blind
Single center
Participants
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
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
Interventions
MTX 25 mg in 3 ml fluid versus 3 ml hyperosmolar glucose 50% both into the gestational
sac under laparoscopic guidance
Pgina 49

Outcomes
Treatment success
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
Notes
The study was discontinued after an interim analysis after 20 patients due to the higher
failure rate in the hyperosmolar glucose group
B - Unclear
Study
Saraj 1998
Methods
Randomization procedure by sealed envelopes

Multi center
Participants
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
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
Interventions
Single dose systemic MTX (1 mg/kg IM) versus laparoscopic salpingostomy
Outcomes
Treatment success
IU/L) and preservation of the tube by primary treatment
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
hCG clearance time
< 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
of treatment
Pgina 50

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
Study
Sharma 2003
Methods
Randomization procedure by computer generated numbers

Single center
Participants
Patients with suspected ectopic pregnancy and no significant medical disease like
diabetes, hypertension or previous laparotomy
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
Interventions
Minilaparotomy versus laparotomy
Outcomes
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
Notes
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
Pgina 51

Study
Shulman 1992
Methods

Single center
Participants

pregnancy (< 4 cm) without active bleeding
The trial was carried out at Sapir Medical Centre, Kfar Saba Israel during an 18 month
period
Interventions
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)
Outcomes
Treatment success
method of diagnosis: uneventful decline of serum hCG to undetectable levels
Treatment failure
method of diagnosis: tubal rupture
hCG resolution time
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
Notes
At laparoscopy any free blood was suctioned away
B - Unclear
Study
Sowter 2001a
Methods
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
Pgina 52

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)
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
Interventions
Multiple dose systemic MTX (50 mg/m2) versus laparoscopic surgery (single dose data
available)
Outcomes
Treatment success
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
hCG clearance time
< 5 IU/l
Tubal patency
of follow-up
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
Pgina 53

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
Study
Sowter 2001b
Methods
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
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 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)
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
Interventions
Single dose systemic MTX (50 mg/m2) versus laparoscopic surgery
Outcomes
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
Pgina 54

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
Study
Tulandi 1991a
Methods

Single center
Participants
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 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
Interventions
Salpingostomy without tubal suturing versus salpingostomy with tubal suturing
Outcomes
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
Notes
Surgery was performed by laparotomy

Desire of pregnancy is not stated
Intra uterine pregnancy is not divided into viable pregnancies or abortions
B - Unclear
Study
Tzafettas 1994
Methods

Multicenter
Pgina 55

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
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
Interventions
MTX 100 mg in 4 ml saline transvaginally under sonographic guidance versus MTX

100 mg in 4 ml saline under laparoscopic guidance
Outcomes
Treatment success
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
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
Notes
B - Unclear
Study
Ugur 1996
Methods
Method of randomization not stated, with stratification for size of the ectopic pregnancy
Single center
Participants
Hemodynamically stable women with a laparoscopically confirmed unruptured ectopicl

pregnancy (< 5 cm)
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
Interventions
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
Pgina 56

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
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
Notes
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
Study
Vermesh 1989
Methods
Randomization at the time of laparoscopy by sequential selection of unmarked opaque

envelopes containing a coded card
Single center
Funding by National Institute of Health
Participants
Hemodynamically stable women with a laparoscopically confirmed unruptured isthmic

or ampullary tubal pregnancy (< 5 cm) without pelvic adhesions precluding complete
visualisation of the pelvis
The trial was carried out at Women's Hospital, University of Southern California, Los
Angeles USA between October 1986 and February 1988
Interventions
Salpingostomy by laparoscopy versus salpingostomy by laparotomy
Pgina 57

Outcomes
Morbidity
method of diagnosis: intraoperative estimated bloodloss, intraoperative complications,
short term complications, persistent trophoblast, long term complications
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
Return to full activity
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
Notes
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
Study
Vermesh 1992
Methods
Randomization by sequential selection of unmarked opaque envelopes containing a

coded card
Single center
Participants
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 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
Interventions
Salpingostomy by laparoscopy versus salpingostomy by laparotomy
Outcomes
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
A - Adequate
Pgina 58

Study
Wang 1998
Methods

Randomization in a 1:2 scheme
Single center
Participants
Women with a swollen fallopian tube at gynecological examination, ectopic pregnancy

seen with ultrasound and serum hCG > 3.1 microg/L
The trial was carried out at Health of Mothers and Children Hospital in Shanxi province,
China during a three months period
Interventions
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
Outcomes
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
Ectopic pregnancy disappearance time
method of diagnosis: mean number of days for the ectopic mass to become undetectable
Notes
B - Unclear
Study
Yalcinkaya 1996
Methods

Double blind study, single center
Participants
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
The trial was carried out at West Verginia University Health Sciences Center, Charleston
Division, Charleston, West Verginia, USA between January 1994 and March 1996
Interventions
Single dose systemic MTX 25 mg/m2 IM versus single dose systemic MTX 50 mg/m2
IM
Pgina 59

Outcomes
Treatment success
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
< 5 IU/l
Side effects
method of diagnosis: MTX related side effects were recorded and complete blood count
and AST levels
Notes
Ectopic pregnancy was diagnosed by history and examination
B - Unclear
Study
Yalcinkaya 2000
Methods
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.
Participants
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 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
Interventions
Single dose systemic MTX 25 mg/m2 IM versus single dose systemic MTX 50 mg/m2
IM
Pgina 60

Outcomes
Treatment success
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
< 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
Notes
MTX injection could only be repeated once
A - Adequate
Study
Zilber 1996
Methods

Single center
Participants
Women with a laparoscopically confirmed unruptured tubal pregnancy tubal pregnancy

(< 3 cm) without active bleeding and full visualization of the pelvis
The trial was carried out at Assaf Harofeh Medical Center, Israel between January
1991 and December 1992
Interventions
MTX 25 mg in 3 ml physiologic solution under laparoscopic guidance versus

laparoscopic salpingostomy
Pgina 61

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
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
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
Notes
Follow-up up to 18 months: 34 with desire for future fertility
B - Unclear
Characteristics of excluded studies

Study
Reason for exclusion
Colacurci 1998
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.
Kaya 2002
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.
Koninckx 1991
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.
Pgina 62

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.
Lund 1955
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.
Murphy 1992
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.
Pgina 63

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.
Porpora 1996
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.
Characteristics of ongoing studies

Study
Fernandez 1
Trial name or title
Randomized controlled trial between medical treatment by methotrexate versus conservative

surgical treatment to evaluate subsequent fertility
Participants
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
Interventions
Single dose methotrexate versus laparoscopic conservative surgery with a single dose
methotrexate postoperatively
Outcomes
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
Starting date
08-2004
Contact information
Fernandez H, Antoine Beclere Hospital Clamart, France

Multicenter study in France
Study
Fernandez 2
Trial name or title
Randomised controlled trial between conservative versus radical surgical treatment to evaluate
subsequent fertility
Participants
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
Interventions
Conservative versus radical surgery both laparoscopically
Outcomes
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
Starting date
08-2004
Pgina 64

Contact information
Fernandez H, Antoine Beclere Hospital Clamart, France

Multicenter study study in France
Study
Hajenius 1
Trial name or title
A randomised controlled trial of salpingostomy versus salpingectomy for tubal pregnancy;

impact on future fertility
Participants
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
Interventions
salpingostomy versus salpingectomy (by laparoscopy or by laparotomy)
Outcomes
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.
Starting date
01-09-2004
Contact information
Hajenius PJ. Academic Medical Center, University of Amsterdam, The Netherlands

International multicenter trial in the Netherlands, Sweden, Norway, Denmark, United Kingdom
Study
Hajenius 2
Trial name or title
Randomised controlled trial of systemic MTX in an intramuscular single shot regimen versus
expectant management
Participants
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
Interventions
systemic MTX (1 mg/kg) in an intramuscular single shot regimen versus expectant

management
Outcomes
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
Starting date
01-02-2006
Contact information
Hajenius PJ. Academic Medical Center, University of Amsterdam, The Netherlands

Multicenter study in the Netherlands
Study
Jurkovic
Trial name or title
Randomised double blind placebo controlled trial of single dose methotrexate versus expectant
management in women with tubal ectopic pregnancy
Pgina 65

Participants
Inclusion criteria:
Hemodynamic stability
No hemoperitoneum
Non-viable pregnancy
hCG < 1,500 IU/l
Normal renal, liver function and normal blood parameters
Interventions
systemic MTX 50 mg/m2 im versus saline as placebo
Outcomes
The primary outcome measure is the number of surgical procedures.

The secondary outcome measure is the intra uterine pregnancy rate within 3 years.
Starting date
01-09-2005
Contact information
Jurkovic D. Early Pregnancy Unit, Kings Hospital, London, United Kingdom

Single center study
TAB LAS ADICIONALES

Table 01 Quality of the included studies
Study ID
Randomisation Allocation
method
concealed
Blinding
no of patients drop outs
lost to follow
up
Alleyassin
2006
computer
adequate with
generated
sealed
random
envelopes
number tables
no
108
Cohen 1996
computer
adequate
generated
random
number tables
NA
20
Dias Pereira
1999
computer
program
adequate
NA
140
40
10
Egarter 1991
unclear
unclear
NA
23
El-Sherbiny
2003
by computer
unclear
NA
55
Elmoghazy
2000
unclear
unclear
no
47
Fedele 1998
computer
generated list
adequate by
telephone
no
25
Fernandez
1991
random
number table
unclear
NA
21
Fernandez
1994
blinded
adequate
computer
generated
random
number tables
NA
48
Fernandez
1995
random
number table
NA
40
unclear
Pgina 66

Fernandez
1998
random
number table
unclear
NA
100
18
Fujishita 1995b unclear
unclear
no
26
Fujishita 2004
computer
generated
randomization
list
unclear
no
75
Gazvani 1998
computer
generated
randomization
sequence
adequate with
consecutively
numbered
enveloppes
no
50
Gjelland 1995
unclear
unclear
NA
80
Graczykowski
1997
drawing cards
inadequate
no
129
13
Gray 1995
unclear
unclear
although
sealed
envelopes
NA
105
Hajenius 1997 computer

program
adequate
NA
140
40
Hordnes 1997
unclear
unclear
NA
80
Klauser 2005
unclear
unclear
no
51
Korhonen 1996 table of random adequate via

numbers
hospital
pharmacy
yes
60
Landstrom
1998
unclear
unclear
NA
31
Lang 1990
by computer
unclear
NA
31
Lundorff 1991a unclear
unclear
although
sealed
envelopes
NA
109
Lundorff 1991b unclear
unclear
although
sealed
envelopes
NA
109
36
Lundorff 1992
unclear
unclear
although
sealed
envelopes
NA
109
21
Mol 1999a
computer
program
adequate
NA
140
40
Mottla 1992
random table
unclear
NA
21
Pgina 67

Nieuwkerk
1998a
computer
program
adequate
NA
140
51
Rozenberg
2003
computer
generated list
adequate with yes

sealed opaque
envelopes
stored in the
pharmacy
212
Sadan 2001
unclear
unclear
yes
20
Saraj 1998
unclear
unclear
although
sealed
envelopes
NA
75
Sharma 2003
computer
generated
numbers
unclear
NA
60
Shulman 1992 unclear
unclear
no
15
Sowter 2001a
computer
program
adequate with
sequentially
numbered
opaque
evelopes
sealed by a
third party
NA
62
Sowter 2001b
computer
program
adequate with
sequentially
numbered
opaque
evelopes
sealed by a
third party
NA
62
Tulandi 1991a
unclear
unclear
no
34
16
Tzafettas 1994 unclear
unclear
NA
36
Ugur 1996
unclear
no
40
Vermesh 1989 coded card
adequate with
sequential
selection of
umarked
opaque
envelope
NA
60
Vermesh 1992 coded card
adequate with
sequential
selection of
umarked
opaque
envelope
NA
60
15
Wang 1998
unclear
no
78
unclear
unclear
Pgina 68

Yalcinkaya
1996
unclear
unclear
yes
41
Yalcinkaya
2000
unclear
adequate with
sealed
envelopes at
the central
pharmacy
yes
100
44
Zilber 1996
unclear
unclear
NA
48
CARTULA
Titulo
Autor(es)
Contribucin de los autores
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.
Nmero de protocolo publicado

inicialmente
La informacin no est disponible
Nmero de revisin publicada

inicialmente
1999/1
Fecha de la modificacin ms
reciente"
15 noviembre 2006
"Fecha de la modificacin
SIGNIFICATIVA ms reciente
16 noviembre 2006
Pgina 69
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.
Fecha de bsqueda de nuevos

estudios no localizados
01 octubre 2006
Fecha de localizacin de nuevos

estudios an no
incluidos/excluidos
El autor no facilit la informacin
Fecha de localizacin de nuevos

estudios incluidos/excluidos
01 agosto 2006
Fecha de modificacin de la
seccin conclusiones de los
autores
18 octubre 2006
Direccin de contacto
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
Nmero de la Cochrane Library
CD000324
Grupo editorial
Cochrane Menstrual Disorders and Subfertility Group
Cdigo del grupo editorial
HM-MENSTR
COMENTARIOS Y CRITICAS
Interventions for tubal ectopic pregnancy
Pgina 70
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
N de
estudios
N de
participantes
Mtodo estadstico
Tamao del efecto
01 xito del tratamiento primario
165
Odds-Ratio de Peto IC del

95%
0.28 [0.09, 0.86]
02 trofoblasto persistente
165

95%
3.47 [1.06, 11.28]
03 permeabilidad tubrica
110

95%
0.58 [0.23, 1.42]
04 embarazo intrauterino posterior
127

95%
1.21 [0.59, 2.45]
05 embarazo ectpico repetido
127

95%
0.47 [0.15, 1.47]
Pgina 71
02 minilaparotoma versus laparotoma

Resultado
N de
estudios
N de
participantes
60
Mtodo estadstico
Tamao del efecto

95%
No estimable
03 salpingostoma sin sutura tubrica versus salpingostoma con sutura tubrica

Resultado
N de
estudios
N de
participantes
Mtodo estadstico
Tamao del efecto
109

95%
0.16 [0.02, 1.23]
109

95%
6.16 [0.81, 46.56]
03 tasa de permeabilidad tubrica
66

95%
0.38 [0.06, 2.35]
88

95%
1.07 [0.44, 2.57]
88

95%
1.20 [0.38, 3.81]
04 salpingostoma sola versus en combinacin con un tratamiento mdico

Resultado
N de
estudios
N de
participantes
Mtodo estadstico
Tamao del efecto

95%
Subtotales
nicamente

95%
Subtotales
nicamente
03 preservacin tubrica

95%
Subtotales
nicamente

95%
Subtotales
nicamente
05 MTX sistmico versus salpingostoma laparoscpica

Resultado
N de
estudios
N de
participantes
Mtodo estadstico
Tamao del efecto

95%
Subtotales
nicamente

95%
Subtotales
nicamente

95%
Subtotales
nicamente

95%
Subtotales
nicamente

95%
Subtotales
nicamente
Pgina 72
05 MTX sistmico versus salpingostoma laparoscpica


95%
Subtotales
nicamente
06 MTX local versus salpingostoma laparoscpica

Resultado
N de
estudios
N de
participantes
Mtodo estadstico
Tamao del efecto

95%
Subtotales
nicamente

95%
Subtotales
nicamente

95%
Subtotales
nicamente

95%
Subtotales
nicamente

95%
Subtotales
nicamente

95%
Subtotales
nicamente
07 MTX por va transvaginal mediante gua ecogrfica versus MTX mediante gua laparoscpica
Resultado
N de
estudios
N de
participantes
Mtodo estadstico
Tamao del efecto
36

95%
5.75 [1.29, 25.71]
36

95%
0.27 [0.05, 1.38]
08 MTX por va transvaginal mediante gua ecogrfica versus MTX sistmico de dosis nica intramuscular
Resultado
N de
estudios
N de
participantes
Mtodo estadstico
Tamao del efecto
95

95%
2.14 [0.82, 5.56]
95

95%
0.40 [0.13, 1.18]
24

95%
2.08 [0.19, 22.17]
51

95%
1.52 [0.43, 5.31]
31

95%
4.09 [0.05, 307.06]
Pgina 73
09 MTX mediante gua laparoscpica versus el mismo rgimen en combinacin con MTX sistmico
intramuscular
Resultado
N de
estudios
N de
participantes
15
Mtodo estadstico
Tamao del efecto

95%
0.12 [0.00, 5.96]
10 MTX de dosis nica versus MTX de dosis mltiple fija ambos por va intramuscular
Resultado
N de
estudios
N de
participantes
Mtodo estadstico
Tamao del efecto
159

95%
0.89 [0.32, 2.50]
108

95%
2.92 [0.70, 12.23]
11 MTX 25 mg/m2 versus MTX 50 mg/m2 estndar ambos de dosis nica intramuscular
Resultado
N de
estudios
N de
participantes
Mtodo estadstico
Tamao del efecto
100

95%
0.68 [0.30, 1.54]
100

95%
1.36 [0.57, 3.24]
03 xito del tratamiento con dosis

de MTX variable
100

95%
0.77 [0.24, 2.45]
100

95%
0.45 [0.09, 2.35]
37

95%
0.90 [0.25, 3.22]
56

95%
1.08 [0.37, 3.16]
56

95%
0.56 [0.10, 3.01]
12 MTX en lipiodol en suspensin versus MTX en solucin fisiolgica ambos mediante gua laparoscpica
Resultado
N de
estudios
N de
participantes
Mtodo estadstico
Tamao del efecto
26

95%
5.96 [1.31, 27.05]
26

95%
0.22 [0.05, 1.06]
26

95%
9.55 [0.56, 163.09]
22

95%
2.06 [0.29, 14.60]
18

95%
0.43 [0.07, 2.60]
Pgina 74
13 MTX versus prostaglandinas ambos mediante gua ecogrfica combinados con la administracin sistmica
del frmaco
Resultado
N de
estudios
N de
participantes
Mtodo estadstico
Tamao del efecto
21

95%
1.00 [0.17, 5.98]
14

95%
0.17 [0.00, 9.12]
14 MTX sistmico solo de dosis nica intramuscular versus en combinacin con mifepristona por va oral
Resultado
N de
estudios
N de
participantes
Mtodo estadstico
Tamao del efecto
262

95%
0.59 [0.35, 0.99]
262

95%
1.37 [0.69, 2.71]
262

95%
0.73 [0.37, 1.42]
24

95%
0.38 [0.05, 3.14]
15 MTX sistmico solo de dosis nica intramuscular versus en combinacin con EE2
Resultado
N de
estudios
N de
participantes
Mtodo estadstico
Tamao del efecto
78

95%
0.08 [0.02, 0.39]
78

95%
0.19 [0.07, 0.51]
78

95%
4.18 [0.74, 23.45]
16 glucosa hiperosmolar mediante gua laparoscpica versus otros tratamientos

Resultado
N de
estudios
N de
participantes
Mtodo estadstico
Tamao del efecto

95%
Subtotales
nicamente

95%
Subtotales
nicamente

95%
Subtotales
nicamente

95%
Subtotales
nicamente

95%
Subtotales
nicamente
Pgina 75
17 manejo expectante versus tratamiento mdico

Resultado
N de
estudios
N de
participantes
Mtodo estadstico
Tamao del efecto

95%
Subtotales
nicamente

95%
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
Pgina 76
01.03 permeabilidad tubrica
01.04 embarazo intrauterino posterior
01.05 embarazo ectpico repetido
Pgina 77
Fig. 02 minilaparotoma versus laparotoma

Fig. 03 salpingostoma sin sutura tubrica versus salpingostoma con sutura tubrica
Pgina 78
03.03 tasa de permeabilidad tubrica
Pgina 79
Fig. 04 salpingostoma sola versus en combinacin con un tratamiento mdico

Pgina 80
04.03 preservacin tubrica
Pgina 81
Fig. 05 MTX sistmico versus salpingostoma laparoscpica

Pgina 82
Pgina 83
Pgina 84
Fig. 06 MTX local versus salpingostoma laparoscpica

Pgina 85
Pgina 86
Fig. 07 MTX por va transvaginal mediante gua ecogrfica versus MTX mediante gua laparoscpica
Pgina 87
Fig. 08 MTX por va transvaginal mediante gua ecogrfica versus MTX sistmico de dosis nica intramuscular
Pgina 88
Fig. 09 MTX mediante gua laparoscpica versus el mismo rgimen en combinacin con MTX sistmico
intramuscular
Pgina 89
Fig. 10 MTX de dosis nica versus MTX de dosis mltiple fija ambos por va intramuscular
Fig. 11 MTX 25 mg/m2 versus MTX 50 mg/m2 estndar ambos de dosis nica intramuscular
Pgina 90
11.03 xito del tratamiento con dosis de MTX variable
Pgina 91
Pgina 92
Fig. 12 MTX en lipiodol en suspensin versus MTX en solucin fisiolgica ambos mediante gua laparoscpica
Pgina 93
Fig. 13 MTX versus prostaglandinas ambos mediante gua ecogrfica combinados con la administracin
sistmica del frmaco
Pgina 94
Fig. 14 MTX sistmico solo de dosis nica intramuscular versus en combinacin con mifepristona por va
oral
Pgina 95
Fig. 15 MTX sistmico solo de dosis nica intramuscular versus en combinacin con EE2
Pgina 96
Pgina 97
Fig. 16 glucosa hiperosmolar mediante gua laparoscpica versus otros tratamientos

Pgina 98
Pgina 99
Fig. 17 manejo expectante versus tratamiento mdico

Pgina 100

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Intervenciones para el embarazo ectpico tubrico

Si desea suscribirse a "La Biblioteca Cochrane Plus", contacte con:

04 salpingostoma sola versus en combinacin con un tratamiento mdico......................................................80

Intervenciones para el embarazo ectpico tubrico

Intervenciones para el embarazo ectpico tubrico

Intervenciones para el embarazo ectpico tubrico

Intervenciones para el embarazo ectpico tubrico

RESUMEN EN TRMINOS SENCILLOS

una prueba previa de probabilidad de la paciente, determinada

Intervenciones para el embarazo ectpico tubrico

ha dado como resultado cambios importantes en las opciones

cada inyeccin de metotrexato con un perodo de descanso de

Intervenciones para el embarazo ectpico tubrico

En resumen, los mdicos ahora disponen de muchas opciones

heterogeneidad de los tratamientos. Por lo tanto, las medidas

Ver los mtodos del Grupo de Trastornos Menstruales y

Esta revisin se realiz en base a la estrategia de bsqueda

Intervenciones para el embarazo ectpico tubrico

4 (pregnanc$ adj3 Fallopian$).mp. [mp=title, original title,

Intervenciones para el embarazo ectpico tubrico

citas. Se obtuvieron los informes completos de todos los

Intervenciones para el embarazo ectpico tubrico

Seis estudios informaron sus datos de seguimiento y/u otras

Los detalles adicionales sobre los estudios incluidos se

Un estudio se tradujo del chino al ingls (Wang 1998). Un

METOTREXATO VERSUS CIRUGA

7. por va transvaginal mediante gua ecogrfica versus mediante

Intervenciones para el embarazo ectpico tubrico

12. en lipiodol en suspensin versus en solucin fisiolgica

Intervenciones para el embarazo ectpico tubrico

menciona una regla de interrupcin preplanificada. El estudio

ms corta de la estancia hospitalaria (uno y dos das versus tres

3. Salpingostoma sin sutura tubrica versus salpingostoma

Intervenciones para el embarazo ectpico tubrico

4. Salpingostoma sola versus en combinacin con un

Los efectos secundarios del tratamiento profilctico con

a. en un rgimen de dosis mltiple fija por va intramuscular

No hubo datos disponibles sobre permeabilidad tubrica y

No se encontraron diferencias significativas en cuanto a la

b. con una inyeccin de vasopresina dentro del mesosalpinge

El 61% de las pacientes tratadas con metotrexato sistmico

a. con una dosis nica intramuscular de metotrexato

La permeabilidad tubrica se evalu en 31 mujeres a las que se

La calidad de vida relacionada con la salud se afect ms

Intervenciones para el embarazo ectpico tubrico

el metotrexato sistmico fue menos costoso comparado con la

leves, dos mujeres presentaron sequedad ocular y una mujer,

Intervenciones para el embarazo ectpico tubrico

6. Metotrexato local versus salpingostoma laparoscpica

7. Por va transvaginal mediante gua ecogrfica versus

10. Dosis nica versus dosis mltiple fija ambas por va

Intervenciones para el embarazo ectpico tubrico

Los resultados de dos estudios que incluyeron 159 mujeres con

A partir de los resultados de los estudios in vitro y experimentos

No hubo datos disponibles sobre permeabilidad tubrica y

METOTREXATO VERSUS/O EN COMBINACIN CON

11. 25 de mg/m2 versus lo estndar 50 mg/m2 ambos en un

13. Metotrexato versus prostaglandinas ambos de forma

comparacin con la administracin estndar de 50 mg/m2 (OR

Slo una mujer de cada grupo de tratamiento present efectos

Intervenciones para el embarazo ectpico tubrico

de tratamiento, es decir 346 UI/l (rango 52 a 12 700) y 497 UI/l

b. versus glucosa hiperosmolar por va transvaginal mediante