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FecundaciFecundaciónón&&
HBPMHBPM
¿Una nueva herramienta… ?
Dr. Vladimir Rosa SalazarUnidad de Corta Estancia/Trombosis.Servicio de Medicina Interna.Hospital Universitario Virgen de la Arrixaca, Murcia.
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Vladimir Rosa Salazar.Unidad de Corta Estancia.Medicina Interna.Referencia para la ETEV.Consultores de todos lo Servicios.Seguimiento ambulatorio de todos los pacientes. Colaboración con otras especialidadesRotación de residentes.
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Trombosis Trombosis venosa venosa profunda (TVP).profunda (TVP).
Embolia Embolia pulmonar (EP).pulmonar (EP).
Enfermedad Tromboembólica
Venosa
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Tromboprofilaxis & Gestación
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fibrina fibrina
dimero D dimero D
factores II, VII, VIII, X factores II, VII, VIII, X
proteína S proteína S
resistencia proteína C activada resistencia proteína C activada
Haematologica/Edición española 2009;94 (extra 1).
Estado de trombofilia adquiridoEstado de trombofilia adquirido
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Tromboprofilaxis durante la gestación
Tromboprofilaxis
A.A.S.
Compresi ón
HBPM
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Tromboprofilaxis durante la gestación
Prevención ETEVPrevención ETEV
Tratamiento ETEVTratamiento ETEV
Prevención complicaciones vasculares gestacionales
Prevención complicaciones vasculares gestacionales
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Complicaciones obstétricas
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PreeclampsiaPreeclampsia
Restricción del crecimiento intrauterino
Restricción del crecimiento intrauterino
Desprendimiento prematuro de placenta
Desprendimiento prematuro de placenta
Óbito fetal intrauteroÓbito fetal intrautero
Esterilidad sin causa aparente
Esterilidad sin causa aparente
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AbortosPreEclam
RCIUDPNIESCA
Trombofilia hereditaria
Sd. antifosfolípido
Reproducción 2011;26:127-136
Ausencia de Trombofilia
Trombofilia adquirida
Complicaciones vasculares gestacionalesComplicaciones vasculares gestacionales
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Mayor incidencia de pérdida gestacional en pacientes con trombofilia
Elevada prevalencia de trombofilias en las pérdidas recurrentes
Demostración de trombosis de los vasos deciduales en estos casos
SAFTrombosis
vasosdeciduales
Pérdidasgestacionales
recurrentes
Trombofilia
Haematologica/Edición española 2009;94 (extra 1).
Mecanismo trombogénico de la pérdida gestacional
Mecanismo trombogénico de la pérdida gestacional
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www.themegallery.com
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Criterio Criterio clínico clínico
SAFSAF
Criterio Criterio analíticoanalítico
Reproducción 2011;26:127-136
Trombofilia adquiridaTrombofilia adquirida
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Reproducción 2011;26:127-136
CriteriosCriterios clínicos de SAFCriteriosCriterios clínicos de SAF
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HBPM: dosis anticoagulantes.
HBPM: dosis profilácticas.
Valorar:HBPM +/- AAS.
Pérdidas fetales previas
Trombosisarterial o venosaprevia
SAFsin
eventos
Haematologica/Edición española 2009;94 (extra 1).
Tratamiento SAF en gestanteTratamiento SAF en gestante
A.A.S + HBPM
A.A.S + HBPM HBPMHBPM Vigilancia
AcVigilancia
Ac
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Hornstein MD et al. Fertil Steril 2000;73:330-3.
OBJECTIVE: To evaluate whether the presence of antiphospholipid antibodies among women
undergoing IVF affects the likelihood of IVF success.DESIGN:
A meta-analysis of seven eligible studies on antiphospholipid antibodies and IVF outcome.
MAIN OUTCOME MEASURE(S): Odds ratios (ORs) and 95% confidence intervals (CIs) of an association between the
presence of antiphospholipid antibodies and both clinical pregnancy and live birth from IVF.
RESULT(S): There was no significant association between antiphospholipid abnormalities and
either clinical pregnancy (OR 0.99; 95% CI 0.64-1.53) or live birth (OR 1.07; 95% CI 0.66-1.75) in IVF patients.
Antiphospholipid antibodies and in vitro fertilization sucess: a meta-analysis
Antiphospholipid antibodies and in vitro fertilization sucess: a meta-analysis
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ESTERILIDAD ESTERILIDAD SIN CAUSA SIN CAUSA APARENTEAPARENTE
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No hay clara evidencia de la asociación ESCA, fallo de implantación y trombofilia.Diferentes estudios con resultados contradictorios.Según RCOG y la ASMR (2011): No está justificado aún el cribado ni de trombofilia ni
SAF. No está justificado el tratamiento.
No es irracional pedir el estudio de trombofilia. Aclarar antes con el paciente las implicaciones del
resultado.
Reproducción 2011;26:127-136
Esterilidad de causa aparenteEsterilidad de causa aparente
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RCOG 2011:No indicación de AAS ni heparina en abortos
recurrentes.Unica indicación en el SAF.
ACCP Chest 2012:No indicación de determinación de TH en CVG (2C).Indicación de estudio de SAF en abortos de repetición (1B).No indicación de HBPM para prevención 2ª de PE (2C).Indicación de AAS en mujeres de alto riesgo de PE (1B).
Holbrook A et al. Chest 2012;141:152S-184S.RCOG.SAC Opinion Paper 26, junio 2011.
RecomendacionesRecomendaciones
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International Society on Thrombosis and Haemostasis:
No recomienda el tratamiento antitrombótico para los abortos de repetición en general.
Existen grupos específicos: las que tiene trombofilia hereditaria, 3 o + abortos o pérdidas en el 2ª trimestre que se podían beneficiar y donde se necesitan ensayos clínicos.
Considerar los beneficios de la HBPM en la implantación de las mujeres con FIV.
Greer IA et al. J Thromb Haemost 2011;1:302-5.
.
RecomendacionesRecomendaciones
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Reproducción asistida
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FecundaciónFecundaciónIn VitroIn Vitro
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Caso ClínicoCaso Clínico
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Mujer 37 años.3 inseminaciones fallidas.1ª FIV fallida.Actualmente 2ª FIV.¿Iniciamos HBPM?.¿Qué dosis?.¿Iniciamos AAS?.¿AAS + HBPM?.
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¿ Qué harían en condiciones normales ?
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HBPMHBPM
Efectos anticoagulantesEfectos anticoagulantes
Efectos pleiotrópicosEfectos pleiotrópicos
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Efectos pleiotrópicos HBPMEfectos pleiotrópicos HBPM
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Tromboprofilaxis & FIV
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Riesgo eventos Riesgo eventos tromboembólicostromboembólicos
Riesgo 10 veces superior Riesgo 10 veces superior
Estimulacion ovárica controlada
Estimulacion ovárica controlada
Riesgo 100 veces superiorRiesgo 100 veces superior
Sd. Hiperestimulación ovárica
Sd. Hiperestimulación ovárica
Rova K et al. Fertil Steril 2011;97:95-100.
Incidencia: 0.1% Incidencia: 0.1%
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Hiperestrogenismo Hiperestrogenismo
Alteraciones de la coagulación
Alteraciones de la coagulación
HemoconcentraciónHemoconcentración
Sd. Hiperestimulación Sd. Hiperestimulación ováricaovárica
Rova K et al. Fertil Steril 2011;97:95-100.
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www.themegallery.com
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Estudio Jordano 2005.
83 mujeres + trombofilia y
fallo de 3 o + FIV:42: Enoxaparina 40 mg/d.
41: Placebo.
HBPM el día del transfer hasta nacimiento o muerte fetal.
Human Fertility 2008;11:246-253.
Low molecular weight heparin in the treatment of recurrent IVF-ET failure and thrombophilia: A prospective randomized
placebo-controlled trial
Low molecular weight heparin in the treatment of recurrent IVF-ET failure and thrombophilia: A prospective randomized
placebo-controlled trial
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Resultados: tasa de implantación :
20.9% vs 6.1%. P<0.001.
tasa de embarazo:
31% vs 9.6%. P>0.05.
tasa de nacimientos vivos:
23.8% vs 2.8%. P<0.05.
– tasa de abortos: P<0.05.
No diferencias en las complicaciones.
Human Fertility 2008;11:246-253.
Low molecular weight heparin in the treatment of recurrent IVF-ET failure and thrombophilia: A prospective randomized
placebo-controlled trial
Low molecular weight heparin in the treatment of recurrent IVF-ET failure and thrombophilia: A prospective randomized
placebo-controlled trial
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Estudio turco 2006-2008.
Estudio prospectivo randomizado abierto .
150 mujeres. <38 años.
Sin trombofilia.
Al menos 2 FIV fallidas.
Enoxaparina 1 mg/Kg/d el día del transfer:No gestación: 12 días.
Gestación: 12 semanas.
B. Urman et al. Hum Reprod 2009;7:1640-47.
Luteal phase empirical low molecular weight heparin administration in patients with failed ICSI embryo transfer
cucle: a randomized open-labeled pilot trial
Luteal phase empirical low molecular weight heparin administration in patients with failed ICSI embryo transfer
cucle: a randomized open-labeled pilot trial
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B. Urman et al. Hum Reprod 2009;7:1640-47.
Luteal phase empirical low molecular weight heparin administration in patients with failed ICSI embryo transfer
cucle: a randomized open-labeled pilot trial
Luteal phase empirical low molecular weight heparin administration in patients with failed ICSI embryo transfer
cucle: a randomized open-labeled pilot trial
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Estudio italiano 2003-2005.
172 mujeres sin trombofilia.
Primera FIV.86 dalteparina 2500 UI/d.
86: placebo.
HBPM el día del transfer hasta nacimiento o muerte fetal.
Resultados: no estadisticamente significativo de tasa de implantación, gestación y nacimientos vivos.
Reproductive BioMedicine Online 2011;22:615-20.Thrombosis Research 2009;123:S8-S15.
Effect of dalteparin sodium administration on IVF outcome in non-thrombophilic young women: a pilot study
Effect of dalteparin sodium administration on IVF outcome in non-thrombophilic young women: a pilot study
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Berker et al. Fertil Steril 2011;95:2499-502.
Estudio Turco.
Estudio observacional retrospectivo.
Mujeres con al menos 2 fallos de implantación ICSI-ET sin trombofilia.
Enoxaparina 40 mg (104 mujeres) vs nada (193 mujeres).
No hubo diferencias significativas.
The role of low-molecular-weight heparin in recurrent implantation failure; a prospective, quasi-randomized,
controlled study
The role of low-molecular-weight heparin in recurrent implantation failure; a prospective, quasi-randomized,
controlled study
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Estudio observacional retrospectivo Italiano 2004-2009.
2 fallos de FIV.
265 mujeres. 569 ciclos.
HBPM el día del transfer hasta nacimiento o muerte fetal.
Resultados: tasa de implantación y embarazo (20.9% vs 6.1% y 31% vs 9.6%). P<0.001, p<0.05.
tasa de nacimientos vivos: 23.8% vs 2.8%. P<0.05.
tasa de abortos. P<0.05.
No hubo diferencias en las complicaciones.C. Lodigiani et al.
Women´s Health 2011;7:425-431.
Low molecular weight heparin in women with repeated implantation failure
Low molecular weight heparin in women with repeated implantation failure
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¿En que se basa la supuesta asociación ?
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Tamaño muestra.Diferentes poblaciones.Diferentes patologías.Diferentes HBPM.Diferentes trombofilias.Diferentes valoración de resultados.
Estudios Caso-control.Resultados dispares e inconsistentes.
Estudios Caso-control.Resultados dispares e inconsistentes.
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MetaanálisisMetaanálisis
Revisiones sistemáticasRevisiones
sistemáticas
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Metaanalisis inglés.
10 estudios.
No mayor tasa de embarazos.
No mayor tasa de nacimientos.
Estudios pequeños.
Estudios heterogéneos.
Pocas mujeres incluidas.
Seshadri S et al.Reproductive BioMedicine Online 2012;25:572-84.
Effect of heparin on the outcome of IVF treatment: a systematic review and meta-analysis
Effect of heparin on the outcome of IVF treatment: a systematic review and meta-analysis
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Chest 2012;141:152S-84S.
ACCP 2012ACCP 2012 En las mujeres
sometidas a técnicas de reproducción asistida,
recomendamos no utilizar profilaxis antitrombótica sistemática.
Grado 1B.
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ACCP 2012ACCP 2012
En las mujeres sometidas a técnicas de reproducción asistida que desarrollan síndrome de hiperestimulación ovárica grave, sugerimos HBPM a dosis profilácticas hasta pasados 3 meses de la resolución de dicho síndrome.
Grado 2C.Chest 2012;141:152S-84S.
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ConclusionesConclusiones
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www.themegallery.com
La HBPM puede ser útil: efectos La HBPM puede ser útil: efectos pleiotrópicos.pleiotrópicos.No existe evidencia clara en el No existe evidencia clara en el uso sistemático de HBPM en FIV.uso sistemático de HBPM en FIV.No existe evidencia clara en el No existe evidencia clara en el uso de HBPM en FIV en mujeres uso de HBPM en FIV en mujeres con trombofilia.con trombofilia.HBPM son seguras.HBPM son seguras.
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Muchas gracias
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Muchas gracias
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TrombofiliaTrombofilia && Complicaciones Vasculares Complicaciones Vasculares GestacionalesGestacionales
TrombofiliaTrombofilia && Complicaciones Vasculares Complicaciones Vasculares GestacionalesGestacionales
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Genetic Thrombophilias and Intrauterine Growth Restriction: A Meta-analysis
The association between inherited thrombophil ias and IUGR can only be discerned in case-control studies and seems to be largely because of publication bias.
Obstetr Gynecol 2009;113:1206-1216
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Inherited thrombophilia and preeclampsia within a multicenter cohort: the Montreal Preeclampsia Study
Am J Obstet Gynecol 2009;200:151.
We did not f ind evidence to support an association between inherited thrombophil ia and increased risk of preeclampsia. Placental underperfusion is associated with preeclampsia, but this does not appear to be consequent to thrombophil ia.
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Odds of placenta mediated pregnancy complications in FVL (homozygous or heterozygous)posit ive women.
Rodger et al 2010. PLosMedicine 2010;7:1-11.
The Association of Factor V Leiden and Prothrombin Gene Mutation and Placenta-Mediated Pregnancy Complications: A Systematic Review and Meta-analysis of
Prospective Cohort Studies
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Odds of PMPCin PGM (homozygous or heterozygous) posit ive women.
Rodger et al 2010. PLosMedicine 2010;7:1-11.
The Association of Factor V Leiden and Prothrombin Gene Mutation and Placenta-Mediated Pregnancy Complications: A Systematic Review and Meta-analysis of
Prospective Cohort Studies