Enaoxaparin in Recurrent pregnancy loss.

Enoxaparin in PRL adjuvant

1. Enoxaparin in Recurrent Pregnancy Loss

2. Introduction Recurrent Pregnancy Loss (RPL) - d efined as > 3 spontaneous losses of pregnancies before 20 weeks of gestation. Affect 0.8% - 1.4% of fertile couple RPL occur due to known abnormalities in the fetus or the parent Anti- phospholipid antibodies (APS) - most significant cause of RPL with incidence between 20% & 40%. Treatments developed - lifestyle modification, progesterone therapy, HMG, in v itro fertilization and preimplantation genetic diagnosis. Anticoagulants and thromboprophylaxis - explored as the preventive therapies Jiang F. et al. Taiwanese Journal of Obstetrics & Gynecology 60 (2021) 1-8 Mohamed K A A . Middle East Fertility Society Journal (2014) 19, 176–182 Yangming Liu, Nan Shan, Yuan, Bin Tan, Hongbo Qi & Ping Che (2019): The efficacy of enoxaparin for recurrent abortion: a meta-analysis of randomized controlled studies, The Journal of Maternal- Fetal & Neonatal Medicine, DOI: 10.1080/14767058.2019.1608433

3. Aetiology - RPL 50% causes remain unexplained, while other include Abnormal parental chromosome Infections Genetic factors Hormonal abnormalities Environment factors Immunologic abnormalities Heritable or acquired thrombophilia's El Hachem H, Crepaux V, May- Panloup P, Descamps P, Legendre G, Bouet P-E. Recurrent pregnancy loss: current perspectives [J]. Int J Wom Health 2017;ume 9:331e45.

4. Patho-Physiology in RPL Normally, blood in maternal body starts flowing within the intervillous spaces of placenta at around 10 weeks of gestation, which could ensure that the transport of nutrition from blood of the maternal body to the fetal tissue. Abnormal placental function occurrence due to necrosis, infarction and thrombosis. D efective placental function & development might lead to arterial thrombosis that result in pregnancy losses. T hrombophilias with pregnancy cause the RPL, placental damage, and fetal death. Jiang F. et al. The role of low molecular weight heparin on recurrent pregnancy loss: A systematic review and meta- analysisTaiwanese Journal of Obstetrics & Gynecology 60 (2021) 1-8 Franklin RD, Kutteh WH. Antiphospholipid antibodies (APA) and recurrent pregnancy loss: treating a unique APA positive population [J]. Hum Reprod 2002;17(11):2981e5.

5. Antiphospholipid Syndrome (APS) in RPL APS is autoimmune thrombophilia condition marked by presence of blood antibodies that recognize & attack phospholipid-binding proteins, rather than phospholipid. Clinical symptoms - vascular thrombosis & pregnancy complications (recurrent spontaneous miscarriages & maternal thrombosis) Detected in 1–5% of healthy women. Antiphospholipid (APL) antibodies bind to negatively charged phospholipids, protein-binding phospholipids, or both, triggering activation of endothelial cells, monocytes and platelets . Also, activation of classical and alternative complement pathways. APS - responsible for 10–15% recurrent miscarriages , whereas APL antibodies could be identified in 5– 20% of women. Mohamed K A A . Middle East Fertility Society Journal (2014) 19, 176–182

6. Antithrombotic – Key in managing RPL APS increase thrombin generation , leading to thrombotic placental damage. Without treatment , miscarriage rate in subsequent pregnancy is as high as 90%. Evidence persists pregnancy loss in APS could be prevented by antithrombotic treatment Jaffe et al. reported - successful pregnancy outcome is based on development & conservation of a suitable utero-placental circulation Widely accepted - treatment with low dose aspirin & heparin or low molecular weight heparin (LMWH) significantly improve outcome as compared to previous untreated pregnancies Farquharson RG, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment [J]. Obstet Gynecol 2002;100(3):408e13. Jaffe R. First trimester utero-placental circulation: maternal- fetal interaction [J]. J Perinat Med 1998;26(3):168e74. Brenner B. Enoxaparin use in pregnancy: state of the art [J]. Womens Health ( Lond ) 2007;3(1):9e14. Sugi T, Mcintyre JA. Antiphospholipid antibodies (APA) and recurrent pregnancy loss: treating a unique APA positive population [J]. Hum Reprod 2003;18(7):1553e4.

7. LMWH - Off label use in RPL LMWHs such as dalteparin and enoxaparin - clinical and practical drugs used to treat the acute VTE. LHMW - anticoagulant effects, anti-inflammatory and immune-modulatory actions Reported to improve overall pregnancy outcomes for patients experiencing recurrent spontaneous abortion But still, LMWH are often prescribed for RPL as off label use . Reason – less conclusive evidence and few studies did not show significant improvement as compared to control Liu et al. explains enoxaparin might be better in inhibiting circulation of antiphospholipid antibodies , inflammatory pathways and venous thromboembolism in antiphospholipid syndrome Yangming Liu, Nan Shan, Yuan, Bin Tan, Hongbo Qi & Ping Che (2019): The efficacy of enoxaparin for recurrent abortion: a meta-analysis of randomized controlled studies, The Journal of Maternal- Fetal & Neonatal Medicine, DOI: 10.1080/14767058.2019.1608433

8. Guideline - ESHRE Early Pregnancy Guideline Development Group 2018 Recurrent Pregnancy Loss Human Reproduction Open, pp. 1–12, 2018 Conditional approvals already present for Enoxaparin

9. RCOG Guidelines RCOG mentions Enoxaparin has better in miscarriage patients. Heparin has insufficient evidence.

10. MoHFW guidelines mention LMWH best for rx of recurrent spontaneous hemorrhage especially in patients with APS and improves live birth rate

11. American College of Chest Physicians (ACCP) Guidelines on Antithrombotic and Thrombolytic Therapy, 9th edition (2012) Recommends use of LMWH in venous thromboembolism, thrombophilia, and antithrombotic prophylaxis and treatment in pregnant and lactating women outlined in the following sections: Women Receiving Anticoagulation Who Become Pregnant Or Are Considering Pregnancy Breastfeeding Assisted Reproduction Caesarean Section - Thromboprophylaxis Acute Venous Thromboembolism Treatment During Pregnancy Prevention Of Recurrent Venous Thromboembolism During Pregnancy Prevention Of Venous Thromboembolism During Pregnancy In Women With Thrombophilia Thrombophilia In Women With Pregnancy Complications Prevention Of Preeclampsia In Women Without Thrombophilia Mechanical Prosthetic Valves In Pregnant Women

12. SUMMARY OF GUIDELINES FOR USING ANTICOAGULANT IN RPL

13. Clinical Studies with Enoxaparin

14. Enoxaparin & Aspirin therapy for RPL due to APS Outcome data from patients who had miscarriage Outcome data from patients who had live births Obstetric and maternal complications of patients who delivered a live born. Highly significant difference Significantly greater number of live births Lower rates of preterm births Enoxaparin 40 mg subcutaneous once a day was administered, when cardiac activity was seen on ultrasound Middle East Fertility Society Journal (2014) 19, 176–182

15. Higher live births with the use of LMWH group when compared with control groups (RR ¼ 1.19; 95%CI, 1.03 to 1.38; P ¼ 0.02) Primary outcome - L ive births Jiang F. et al. The role of low molecular weight heparin on recurrent pregnancy loss: A systematic review and meta- analysisTaiwanese Journal of Obstetrics & Gynecology 60 (2021) 1-8 Out of these 8 studies, 5 studies evaluated the use of enoxaparin

16. Patients treated with LMWH had significant lower miscarriage rates than those from normal controls (RR ¼ 0.62; 95%CI, 0.43 to 0.91; P ¼ 0.01 Jiang F. et al. The role of low molecular weight heparin on recurrent pregnancy loss: A systematic review and meta- analysisTaiwanese Journal of Obstetrics & Gynecology 60 (2021) 1-8 Primary outcome - M iscarriage rates

17. Objective – to compare effects of low dose aspirin (LDA) alone & with combination of LMWH & LDA in women with recurrent miscarriage. Total - 150 women enrolled (75 per treatment group). Combination group significantly lower number of miscarriages (22 [29%] vs. 43 [47%], P < 0.001) significantly higher number of live births compared LDA alone (53 [71%] vs. 32 [42%], P < 0.001). LMWH was well tolerated and no maternal or fetal complications Elmahashi et al. BMC Research Notes 2014, 7:23 Combination of LDA and LMWH is better than LDA alone for the maintenance of pregnancy in patients with recurrent first trimester miscarriages.

18. European Journal of Obstetrics & Gynecology and Reproductive Biology 234 (2019) 53–57 Results - compared to control intervention, enoxaparin treatment has no substantial impact on live births, miscarriage rate. Reason – Pasquier study used enoxaparin 40 mg daily SC, initiated from inclusion visit (before 5 weeks’ gestation) & continued by self-injection until 35 weeks’ gestation & other RCT reports 4000 IU/day enoxaparin beginning at 6 weeks of gestation till the end of their pregnancy. Need More Evidence Sufficient duration of enoxaparin treatment is important for its efficacy.

19. Adv Ther (2020) 37:27–40 Pregnancy loss risk reduced by 42 % in enoxaparin monotherapy compared to control groups Pregnancy loss risk was significantly reduced by 58 % with enoxaparin plus aspirin compared to aspirin alone (p\0.0001) Safety - Incidence of thromboembolic events were rare. Risk of bleeding was lower with enoxaparin compared to aspirin.

20. Demographic data of the study group (n = 35) Outcome of 35 pregnancies in women with antiphospholipid syndrome & recurrent miscarriage treated with low-dose enoxaparin and aspirin. 28 pregnancies (80%) resulted in live birth Low-dose (20 mg) enoxaparin & low-dose (75 mg) aspirin treatment produce a high live birth rate in women with APS and recurrent miscarriage. RBMOnline - Vol 19. No 2. 2009 216-220 Reproductive BioMedicine Online; www.rbmonline.com/Article/3642 on web 24 June 2009

21. Case Reports – Successful Pregnancy outcomes Conclusion - Enoxaparin used in RPL without APL positivity helped in getting a live term delivery Int J Fam Commun Med. 2017;1(3):65‒66

22. LMWH Safety in Pregnancy LMWHs don’t pass through the blood-placental barrier , providing the safety of using it for pregnant patients. N o significant differences found in maternal severe side effects (thrombocytopenia, bleeding episodes and pre-eclampsia) between LMWH groups and control groups in studies conducted. Few include I ncrease in skin reactions at the injection site. Bazzan M, Donvito V. Low-molecular-weight heparin during pregnancy [J]. Thromb Res 2001;101(1):V175e86. Jiang F. et al. The role of low molecular weight heparin on recurrent pregnancy loss: A systematic review and meta- analysisTaiwanese Journal of Obstetrics & Gynecology 60 (2021) 1-8