Do Anti-Factor Xa Levels have any Impact on Pregnancy Outcome in Women with Previous Adverse Outcomes?

Abstract

Objective Low-molecular-weight heparin (LMWH) is used during pregnancy in women diagnosed with thrombophilia for prevention of thromboembolic events and prevention of recurrent pregnancy loss. Prophylactic dosing does not always achieve target anti-FXa levels of 0.2–0.6 IU/ml. We aimed to determine if anti-FXa levels, measured in the first trimester, have an influence on pregnancy outcome.

Material and Methods Eighty-one first-trimester women with a history of adverse pregnancy outcomes under LMWH therapy during pregnancy were enrolled in this study. Anti-FXa levels were measured in the first trimester, and fetal and maternal outcomes were recorded.

Results The mean age of women was 28±4 (19–40) and mean anti-FXa level 0.44±0.93 IU/ml. No bleeding or clotting complications were associated with LMWH administration. Anti-FXa levels did not have a relationship with gestational age at birth, fetal weight, type of delivery, cesarean indications, postpartum bleeding, APGAR scores, or admission to the neonatal intensive care unit (p>0.005). Anti-FXa levels were not correlated with live birth rates.

Conclusion Anti-FXa levels did not have an influence on pregnancy and fetal outcomes. The effect of LMWH on pregnancy outcomes may not be due to anticoagulant activity but other mechanisms.

Keywords

Anti-FXa level - low molecular weight heparin - recurrent pregnancy loss - pregnancy

Publication History

Received: 06 August 2019

Accepted after revision: 21 February 2020

Article published online:
01 April 2020

• References

• 1 Simeone R, Giacomello R, Bruno G. et al. Thrombogenesis in thrombophilic pregnancy: evaluation of low-molecular-weight heparin prophylaxis. Acta haematologica 2017; 137: 201-206. DOI: 10.1159/000467385.
• 2 Keskinkılıç B, Uygur D, Özcan A. et al. Pulmonary Embolism associated with hyperemesis gravidarum two case reports. Gynecol Obstet Reprod Med 2017; 23: 169-170 DOI: 10.21613/gorm.2016.490.
• 3 Boban A, Paulus S, Lambert C. et al. The value and impact of anti-Xa activity monitoring for prophylactic dose adjustment of low-molecular-weight heparin during pregnancy: a retrospective study. Blood Coag. Fibrinolysis 2017; 28: 199-204 DOI: 10.1097/MBC.0000000000000573.
• 4 Clark NP, Delate T, Cleary SJ. et al. Analysis of unfractionated heparin dose requirements to target therapeutic anti-Xa intensity during pregnancy. Thrombosis research 2010; 125: 402-405 DOI: 10.1016/j.thromres.2009.07.014.
• 5 Petrie S, Barras M, Lust K. et al. Evaluation of therapeutic enoxaparin in a pregnant population at a tertiary hospital. Intern Med J 2016; 46: 826-833. DOI: 10.1111/imj.13117.
• 6 Fox NS, Laughon SK, Bender SD. et al. Anti-factor Xa plasma levels in pregnant women receiving low molecular weight heparin thromboprophylaxis. Obstet Gynecol 2008; 112: 884-889 DOI: 10.1097/AOG.0b013e31818638dc.
• 7 McDonnell BP, Glennon K, McTiernan A. et al. Adjustment of therapeutic LMWH to achieve specific target anti-FXa activity does not affect outcomes in pregnant patients with venous thromboembolism. J Thromb Thrombolysis 2017; 43: 105-111 DOI: 10.1007/s11239-016-1409-5.
• 8 Berresheim M, Wilkie J, Nerenberg KA. et al. A case series of LMWH use in pregnancy: should trough anti-Xa levels guide dosing?. Thromb Res 2014; 134: 1234-1240 DOI: 10.1016/j.thromres.2014.09.033.
• 9 Gyamfi C, Cohen R, Desancho MT. et al. Prophylactic dosing adjustment in pregnancy based upon measurements of anti-factor Xa levels. J Matern Fetal Neonatal Med 2005; 18: 329-331 DOI: 10.1080/14767050500275796.
• 10 Rodger MA, Gris JC, de Vries JIP. et al. Low-molecular-weight heparin and recurrent placenta-mediated pregnancy complications: a meta-analysis of individual patient data from randomised controlled trials. Lancet 2016; 388: 2629-2641 DOI: 10.1016/S0140-6736(16)31139-4.
• 11 Dodd JM, McLeod A, Windrim RC, Kingdom J. Antithrombotic therapy for improving maternal or infant health outcomes in women considered at risk of placental dysfunction. Cochrane Database Syst Rev 2013; (7): CD006780. Published 2013 Jul 24. DOI: 10.1002/14651858.CD006780.pub3.
• 12 Hekimoğlu R, Pergin A, Uğur Y. et al. Impaired implantation and hereditary thrombophila; expression of LIF (leukemia inhibitory factor) on extravillous trophoblasts. Gynecol Obstet Reprod Med 2012; 18: 123-126
• 13 Heifetz SA. Thrombosis of the umbilical cord: analysis of 52 cases and literature review. Pediatr Pathol 1988; 8: 37-54
• 14 de Jong PG, Kaandorp S, Di Nisio M. et al. Aspirin and/or heparin for women with unexplained recurrent miscarriage with or without inherited thrombophilia. Cochrane Database Syst Rev. 2014 DOI: 10.1002/14651858.CD004734.pub4
• 15 Mazarico E, Peguero A, Camprubi M. et al. Study protocol for a randomised controlled trial: treatment of early intrauterine growth restriction with low molecular weight heparin (TRACIP). BMJ Open 2018; 8: e020501. DOI: 10.1136/bmjopen-2017-020501.
• 16 Türkçüoğlu I, Engin Üstün Y, Üstün Y. Recurrent placental abruption with methylenetetrahydrofolate reductase C667t heterozygosity: a case report. Gynecol Obstet Reprod Med 2007; 13: 176-178
• 17 Thomsen A, Greer I. Thromboembolic disease in pregnancy and the puerperium: acute management (Green-top Guideline No. 37b). Royal College of Obstetricians and Gynaecologists. 2015 1.
• 18 ACOG Practice Bulletin No 196: Thromboembolism in Pregnancy. Obstet Gynecol 2018; 132: e1-e17 DOI: 10.1097/AOG.0000000000002706.
• 19 Friedrich E, Hameed AB. Fluctuations in anti-factor Xa levels with therapeutic enoxaparin anticoagulation in pregnancy. J Perinatol 2010; 30: 253-257 doi:10.1038/jp.2009.164
• 20 Imbalzano E, Creazzo M, Trapani G. et al. Ineffective treatment of low-molecular-weight heparin in obese subject with traumatic fractures of the leg. Int J Angiol 2016; 25: e16-e18 DOI: 10.1055/s-0034-1396899.
• 21 Malinoski D, Jafari F, Ewing T. et al. Standard prophylactic enoxaparin dosing leads to inadequate anti-Xa levels and increased deep venous thrombosis rates in critically ill trauma and surgical patients. J Trauma 2010; 68: 874-880. DOI: 10.1097/TA.0b013e3181d32271.
• 22 Uysal N, Dikensoy E, Balat Ö. Outcome of obstetric patients admitted to a medical intensive care unit in Southeastern Turkey. Gynecol Obstet Reprod Med 2009; 15: 22-24
• 23 Rodger MA, Hague WM, Kingdom J. et al. Antepartum dalteparin versus no antepartum dalteparin for the prevention of pregnancy complications in pregnant women with thrombophilia (TIPPS): a multinational open-label randomised trial. Lancet 2014; 384: 1673-1683 DOI: 10.1016/S0140-6736(14)60793-5.
• 24 Hansen AT, Sandager P, Ramsing M. et al. Tinzaparin for the treatment of foetal growth retardation: an open-labelled randomized clinical trial. Thromb Res 2018; 170: 38-44. DOI: 10.1016/j.thromres.2018.08.006.
• 25 Salim R, Nachum Z, Gavish I. et al. Adjusting enoxaparin dosage according to anti-FXa levels and pregnancy outcome in thrombophilic women. A randomised controlled trial. Thromb Haemost 2016; 116: 687-695 DOI: 10.1160/TH16-03-0221.
• 26 Ivanov P, Komsa-Penkova R, Ivanov I. et al. [High risk of recurrent spontaneous abortion during second trimester in women carriers of polymorphism A2 in platelet glycoprotein IIb/IIIa]. Akush Ginekol (Sofiia) 2008; 47: 3-9
• 27 Vlachadis N, Tsamadias V, Vrachnis N. et al. Genetic heterogeneity of platelet glycoproteins Ia and IIIa and the risk of spontaneous miscarriages. J Matern Fetal Neonatal Med 2017; 30: 1309-1313. DOI: 10.1080/14767058.2016.1212330.
• 28 von Tempelhoff GF, Schelkunov O, Demirhan A. et al. Thrombelastometric results and platelet function during pregnancy in women receiving low molecular weight heparin with a history of recurrent/late abortion – a retrospective analysis. Clin Hemorheol Microcirc 2015; 61: 99-110 DOI: 10.3233/CH-151949.