1. Prof. Veena Agrawal M.D., MICOG, WHO Fellow USA , Dip in USG Head of Dept of Obst. & Gynaec G. R. Medical College, Gwl, M.P. India Faculty of human Genetics, Jiwaji University Gwl Past President Gwalior Obst & Gynae Society
Dr Sonali Agrawal Senior Resident Dept of Obst. & Gynaec G. R. Medical College, Gwl , M.P
Download the .PPT version of this presentation for off line viewing (512.5 KB) Return to Power Point Presentations Indexsubmit your own material for publication via email with your files attached
2.
Prof & HOD, Obst. & Gynecology ,Medical College & Faculty human Genetics, Jiwaji University Gwalior
Received Dr. Buridge Gold Medal in Physiology & Chancellor's Medal –Best Studt in Science faculty Lucknow University.
Received "Nari Ratan " from Agrawal Mahasabha 2010
Received "Rajaya Swastha Puraskar" from Chief Minister,Madhya Pradesh 2008
Awarded"Sir Shriram Fellowship" - National Academy of Medical Sciences New Delhi 2003
Awarded "Gwalior Gaurav" in 2001
Awarded WHO Fellowship in 1997 to visit USA, worked at Magee Women's Hospital, Pittsburgh and Stanford University California USA
Delivered a guest lecture , Presented papers & chaired session at various National & international Conferences esp: FIGO conferences held at Washington, Santiago South America ,Malaysia & Cape Town South Africa, 13th World Congress Endocrinology'08 at Florence (Italy), 4th Asia Pacific Congress of Maternal Fetal Medicine'08 held at Mcau SAR, China.
Reviewer of Journal of Obst Gynae Japan
Published more than 50 Scientific Papers in national & international journals.
Active member of various scientific, philanthropic and social organizations, and a past president of Gwalior Obst Gynae Society & Lioness club of Gwalior
3. Objectives
Indications in recurrent pregnancy loss (RPL)
Low molecular weight heparin (LMWH) v/s UH
Type of LMWH
Duration of therapy
Trial in Institution
Summary
4.
Habitual or recurrent abortion - 3 or more consecutive SABs, acc to ASRM, 2008 > 2
↑se in procoagulant factors - VII, VIII, X, and fibrinogen, as early as 12 weeks
Fibrinolytic activity is ↓sed - progressively ↑sing PAI-1, PAI-2
Platelet activation & ↑sed production of thromboxane
Anticoagulants
Protein S ↓se by 40-50%, while antithrombin III & protein C remain constant.
↓sed sensitivity to antiaggregation effects of prostacyclin
Vasorelaxation
9. Early Pregnancy
uPA attaches to receptor +nt on 1st trimester Trophoblast cells
Triggers the localized production of plasmin
Catalyzes the destruction of the extracellular matrix
Facilitates implantation
10. Pathophysiology of Haematological / Unexplained RSA
Not fully elucidated
11.
Microthrombi is common in the placental vasculature(Rushton 1988)
Placental thrombosis association with thrombophilic defects (Rai et al 1996: Dizon et al 1997)
Defective decidual endovascular trophoblast invasion (Quenby et al 2004; van den Brule et al., 2005)
Cadherins (E and β ), integrins, & selectins participate embryogenesis, cell growth & differentiation (Frenette & Wagner 1996. Shih et al. 2002)
12.
ECM proteins, laminin & fibronectin, have important effects on trophoblast invasion in implantation (Teller & Beaulieu, 2001; Turck et al 2005)
It is not known why some with thrombophilia express vascular gestational pathologies while others do not – it may relate to local factors affecting coagulation, fibrinolysis and vascular tone at the level of placental vessels (Benjamin Brenner 2005)
13.
Inflammatory cytokine cascades in pathogenesis Bombell & McGuire (2008)
↑sed TF expression ↑es release of reactive O2 species & antiangiogenic molecules from inflammatory cells inducing trophoblast damage & poor pregnancy outcomes Guillermina Girardi 2011
14. How Heparin Works
Potentiates the anti-thrombin effects, Jack Hirsh; 2001
Binds to antiphospholipid antibodies rendering them inactive Di Simone N et al, 1999; Hum Reprod 1997
Immunomodulatory action, by antagonising interferon gamma, a deleterious Th 1 cytokine Fritchley SJ, et al 2000
Modulate trophoblast invasion by effecting ECM proteins & Cadherins Korhonen &Virtanen, 2001 Omer Erden 2006
15.
Modulate trophoblast apoptosis suggesting a direct impact on trophoblast biology Patrick Bose 2005
Inhibits complement activation Girardi Get al 2004
Anti-inflammatory effect Jin-ping Li 2010
16. Efficacy in Hematologic & Unexplained RPL is?
17. In Favor
Successful pregnancies achieved with LMWH in unexplained RSA Miyashita et al., 2003
Improved pregnancy outcome in thrombophilia complicated by miscarriage, RPL & fetal death Alikani 2005; Christiansen et al., 2005.
LMWH safe & effective drug in unexplained RSA when given in 1st trimester & continued throughout pregnancy Badawy AM 2008, Fawzy M 2008
Success rate in excess of 85% Greer IA 2011
18.
LMWHs effective in patients without thrombophilias, mechanisms still unclear Silvia D'Ippolito et al 2011
Two trials compared enoxaparin 20 mg day−1 vs. no tx or placebo in unexplained RSA and reported higher rates of success with LMWH. I. A. GREER 2011
19. Against
LMWH/ASA did not confer incremental benefit compared to ASA alone Carl A et al HepASA Trial 2009
Regardless of tx regimen, no of prior losses, or aPL positivity, 80% of RPL cohort had a successful pregnancy outcome Carl A et al HepASA Trial 2009
Anticoagulants is not recommended in unexplained two miscarriages without inherited thrombophilia Cochrane Database Syst Rev 2009
Not advocated for unexplained RSA Robert W. Rebar, 2010
20.
LMWH - No place in RSA Middeldorp S 2011
Randomized multicentre trial - No significant difference in live birth rate with enoxaparin tx v/s aspirin or a combination of both v/s aspirin RSA with or without thrombophilia Visser J 2011
Not support the use of LMWH RSA without APLS SPIN 2011
21. Advantage of LMWH v/s UFH
Both bind to plasma proteins, endothelium, & macrophages thus affecting bioavailability, LMWH 85% v/s UFH's 10% Rowan JA, 2006
Less osteoporosis, haemorrhage, thrombocytopenia
Longer half-life, Sc once or twice a day,
Equally effective
Does not require lab tests, APTT
Average mol wt: UFH 20000 Da & LMWH 3000 Da
22.
Less effect on thrombin compared to UFH, but maintains same effect on Factor Xa.
Easy route of self-administration
Do not cross the placenta and has no teratogenic or fetotoxic risks or fetal bleeding
lack of secretion in breast milk
Anticoagulant effects of UFH are reversible with protamine sulphate, effect on LMWH is limited
23. Are LMWH Doses Important?
In the Live-Enox study, compared two dose of enoxaparin 40 and 80 mg with no differences in outcomes Brenner el al 2005
Dosing of anticoagulants in pregnant women is determined by the severity of the thromboembolic disease. Rowan JA, 2006
24. Duration of Heparin Therapy
Should not extend unnecessarily - osteopenia
Monitor by platelet count, PTT &/or anti-Xa activity wkly for the first 3 wks & every 4±6 weeks thereafter
Long-term use of LMWH in pregnancy well tolerated, with very low adverse effects Santoro, Rita 2009
25. Type of LMWH to be used
ACCP:"Because LMWHs are prepared by different methods of depolymerisation, they differ to some extent in pharmacokinetic properties and anticoagulant profiles, and are not clinically interchangeable" Geerts W, et al. Chest. 2004;
LMWHs have varied Biologics with Differing Structures, Activities, and Clinical Effects Jawed Fareed 2008,
26. Type of LMWHs
Bemiparin
Enoxaparin
Dalteparin
Nadroparin
Tinzaparin
27.
Bemiparin
Dalteparin
Enoxaparin
Nadroparin
Tinzaparin
28. Bemiparin
2nd generation LMWH
More advanced pharmacological profile
Unknown whether crosses placental barrier
Safe & resulted in improved gestational outcome, Santamara A. 2007
No teratogenic effects in Animal studies, potential risk for humans is unknown 2010
Safe, ↑ live birth rate & no maternal & fetal complications in prevention of APS RSA Alalaf S, 2011.
29. ACCP 2004 Recommendations
30. LMWH in RPL of Unknown Etiology
Objectives: To assess the efficacy of LMWH in RPA without identifiable causes.
Design: Prospective study
Setting: Dept of Obst & Gynecology, G.R. Medical College, & Agrawal Hospital & Research centre Gwalior, M.P., India from June2008 to Oct 2010
31. Materials and Methods
Selection criteria-
Pts with >2 Preg loss
aged 20 to 35 yrs
Total 123 patients
Pts acc to no. of Previous losses
2 loss– 30
3 loss– 27
4 – 6 loss – 72
7 loss – 3
10 loss - 1
Exclusion criteria: abnormal parental karyotype, +ce of ut pathology on TVS, -ce of APLS, -ce of endocrine disorders .
32.
Bemaparin 2500sc /day & 75 mg of aspirin/day soon after preg test +ve
Continued till 4months in pt with 2-3 abortions, in all other cases until 36 wks' gestation
Along with intense pregnancy surveillance
Stopped 12 hrs before delivery.
33.
Primary outcome measure was live birth rate
Secondary outcomes included
Miscarriage rate,
Prevalence of obstetric complications
Preeclampsia,
IUGR
PPH
34. Results
103 pt had live birth i.e. 83%, more success in 4 and above losses
Most of the miscarriages during the study occurred in the 1st trimester (93%) and 28% even before 7 weeks gestation
PET is not more only in 5% cases
IUGR – 10%
Mild PPH – only in cases in which LMWH continued till 36 weeks' gestation
35. Conclusion
Study provides good evidence that antithrombotic therapy should be advocated for unexplained recurrent miscarriage.
Limitations of study:
No controlled comparative placebo cases
Not all causes of thrombophilia was excluded
36. Key Message
Adequately powered & properly controlled trials are needed to assess the efficacy of LMWHs in RPL ± thrombophilia - currently underway
Antithrombotic intervention should not be recommended for unexplained RSA in general.
There may be specific groups such as those with an thrombophilia, or with ≥ 3 losses, or 2nd trimester losses