Varese 20 Settembre 2012
Terapia antitrombotica nelle
pazienti sottoposte a PMA
Francesco Dentali
Dipartimento di Medicina Clinica, Università
dell'Insubria, Ospedale di Circolo, Varese
Terapia antitrombotica
Potenziale utilizzo
• Prevenzione del TEV (OHSS)
• Aumento dei nati-vivi
Terapia antitrombotica
Potenziale utilizzo
• Prevenzione del TEV (OHSS)
• Aumento dei nati-vivi
Tasso di “natalità”
• Dopo un ciclo di
IVF solo il 34%
delle donne hanno
una gravidanza e
solo il 28% avrà un
bambino
Terapia antitrombotica
• Acido Acetil Salicilico (antiaggreganti
piastrinici?)
• EBPM (ENF?)
• Associazione Terapeutica
Infertility Causes
• Suboptimal uterine perfusion
• Subsequent reduced endometrial
receptivity
Potential effect of Low-dose ASA
• Enhancement of uterine and ovarian blood flow
and tissue perfusion by decreasing platelet
aggregation and inhibiting vasoconstriction
• Increasement of endometrial receptivity and
blastocyst implantation.
Risultati
Singoli Studi (I)
Rubinstein et al; Fertil and Steril 1999
Risultati
Singoli Studi (II)
Pakkila et al; Human Reprod 2005
End points indiretti
Khairy et al; Fertil Steril 2007
• Up to November
2011
• 17 studies
• 6610 patients
End Points
• Live Birth
• Pregnancy Rate
• Miscarriage
Dentali et al; JTH 2012 in press
Sensitivity Analyses
• Jadad’s scale
• Lost to follow up (<5%)
• Accepted definition of clinical pregnancy
• Peer Reviewed Journal
Dentali et al; JTH 2012 in press
Subgroup Analyses
• Cause of infertility
• Type of induction protocol (short vs. long)
• Type of assisted reproduction techniques
(IVF, ICSI);
• Time of aspirin introduction and duration of
aspirin therapy
• History of ET failure
Dentali et al; JTH 2012 in press
Risultati
Live-Birth
Dentali et al; JTH 2012 in press
Risultati
Pregnancy Rate
Dentali et al; JTH 2012 in press
Risultati
Miscarriage
Dentali et al; JTH 2012 in press
Risultati
Sensitivity Analyses
Dentali et al; JTH 2012 in press
Risultati
Subgroup Analyses
• Only IVF
- Live birth
OR
1.20 (0.96–1.51)
- Pregnancy
OR
1.35 (1.11–1.65)
- Miscarriage OR
1.15 (0.74–1.80)
• Aspirin administered at least 1 day before ET
- Live birth
OR
0.91 (0.70–1.19)
- Pregnancy
OR
1.21 (1.01–1.44)
- Miscarriage OR 1.12 (0.65–1.92)
• At least one preceding ET failure
- Live birth
OR 1.02 (0.56–1.88)
- Pregnancy
OR 1.47 (0.91–2.37)
- Miscarriage OR 0.72 (0.19–2.74)
Dentali et al; JTH 2012 in press
Risultati
Subgroup Analyses
• Long induction protocol
- Live birth
OR
1.09 (0.90–1.32)
- Pregnancy
OR
1.20 (0.98–1.47)
- Miscarriage OR
1.13 (0.79–1.62)
• Aspirin consumption during the entire period of pregnancy
- Live birth
OR
0.90 (0.65–1.26)
- Pregnancy
OR 0.89 (0.65–1.22)
- Miscarriage OR 1.01 (0.48–2.11)
Dentali et al; JTH 2012 in press
Potential effect of Heparin
• Alteration of the hemostatic response to ovarian
stimulation
• Modulation of trophoblast differentiation and
invasion
• Reduction of the risk of thrombosis
• Up to July 2011
• 3 studies
• 405 patients
End Points
• Live Birth
• Pregnancy Rate
Dentali et al; JTH 2011
Included Studies
Heparin, dose
Noci
(2011)
Inclusion Criteria
Dalteparin 2500 U Pts undergoing IVF
or
ICSI
Urmann Enoxaparin
History of > 2
(2009)
1 mg kg)1 day–1 previously failed
fresh ET cycles
Qublan Enoxaparin 40 mg History of 3 previous
(2008)
IVF failures
Risultati
Live-Birth
Dentali et al; JTH 2012 in press
Risultati
Pregnancy Rates
Dentali et al; JTH 2011
Studi non randomizzati
CPR 34.6% vs 33.9%
LBR 30.7% vs 29.1%
Berker et al; Fertil Steril 2011
Studi non randomizzati
105 CP in 569 cycles (18.8%).
• PR 17.19% (88/512) vs 29.52% (17/57) (p = 0.006).
• In women > 36 yrs PR 15.53% vs 35.71% (p = 0.007)
• No difference was found in younger women.
• No statistical difference between the presence of inherited
thrombophilia and PR in treated and untreated cycles.
Lodigiani et al; Womens Health 2011
Heparin and Aspirin
Antiphospholipid antibodies
IR 25.7% vs 19.4%
Kutteh et al; Human Reprod 1997
Benefici in sottogruppi?
• Maternal Age
• Ovarian Reserve/Infertility cause
• Thrombophilic abnormalities
• Other….
Thrombophilia and ART
Studi caso controllo
FVL OR 3.08 (95% CI 1.77-5.36)
Di Nisio; Blood 2011
Thrombophilia and ART
Studi caso controllo/ anticorpi antifosfolipidi
OR 3.33 (95% CI 1.77-6.36)
Di Nisio; Blood 2011
Thrombophilia and ART
Studi per coorte
• Nessuna associazione significativa tra
ART failure e FVL
• Nessuna associazione significativa tra
ART failure e anticorpi antifosfolipidi
Di Nisio; Blood 2011
Altri Interventi…
Cicarette Smoking and Clinical Pregnancy Rate in AR
Waylen et al; Human Reprod Update 2009
Conclusioni
• Basse dosi di ASA non sono efficaci nel
migliorare l’outcome delle PMA
• L’EBPM potrebbe invece avere un
piccolo ruolo
• La loro efficacia in particolari
sottogruppi non è chiara
Conclusioni
• Ulteriori studi sono necessari per
valutare il ruolo dell’EBPM e della
terapia di associazione
• Il ruolo della terapia antitrombotica
nelle pazienti con alterazioni
trombofiliche (APS e altro) rimane da
definire