Subscribe to RSS
DOI: 10.1160/TH16-03-0221
Adjusting enoxaparin dosage according to anti-FXa levels and pregnancy outcome in thrombophilic women
A randomised controlled trialPublication History
Received:
19 March 2016
Accepted after major revision:
22 June 2016
Publication Date:
02 December 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/201604/lookinside/thumbnails/10-1160-th16-03-0221-1.jpg)
Summary
Women with thrombophilias and previous placenta-mediated pregnancy complications (PMPC) have an increased risk of both recurrent PMPC and venous thromboembolism (VTE) during subsequent pregnancies. We aimed to examine whether enoxaparin dose adjusted according to anti-factor Xa levels compared to a fixed dose would reduce the risk of PMPC in subsequent pregnancies. In a randomised trial, conducted at a single teaching hospital, pregnant women with thrombophilia and previous PMPC were enrolled in a 1:1 ratio to either a fixed dose of 40 mg daily enoxaparin or adjusted dose according to anti-factor Xa plasma levels. The primary outcome was a composite that included any of the following: pregnancy loss after enrollment, pre-eclampsia, birthweight <10th percentile, placental abruption, or VTE. Overall, 144 women were needed to detect a decrease of 20 % in the incidence of the composite outcome among the adjusted dose group. Between 2009 and 2015, 144 women consented; four in the fixed-dose group were excluded. Overall, 66 and 74 in the fixed- and adjusted-dose groups, respectively, were included. Demographic and obstetric characteristics were comparable. Composite outcome occurred in 12 (18.2 %) and 20 (27.0 %) women in the fixed- and adjusted-dose groups, respectively (p=0.24). Gestational age at delivery, preterm births, and birthweights were similar between the two groups. In conclusion, dose of enoxaparin adjusted according to anti-factor Xa levels compared to fixed dose, does not reduce the risk of PMPC recurrence in thrombophilic women.
ClinicalTrial Registration: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01068795.
-
References
- 1 Berg CJ, Atrash HK, Koonin LM. et al. Pregnancy-related mortality in the United States, 1987–1990. Obstet Gynecol 1996; 88: 161-167.
- 2 Stillbirth Collaborative Research Network Writing Group. Causes of death among stillbirths. J Am Med Assoc 2011; 306: 2459-2468.
- 3 van Rijn BB, Hoeks LB, Bots ML. et al Outcomes of subsequent pregnancy after first pregnancy with early-onset preeclampsia. Am J Obstet Gynecol 2006; 195: 723-728.
- 4 Salim R, Czarnowicki T, Nachum Z. et al. The impact of close surveillance on pregnancy outcome among women with a prior history of antepartum complications attributed to thrombosis: a cohort study. Reprod Biol Endocrinol 2008; 06: 55.
- 5 van Walraven C, Mamdani M, Cohn A. et al Risk of subsequent thromboembolism for patients with pre-eclampsia. Br Med J 2003; 326: 791-792.
- 6 Jacobsen AF, Skjeldestad FE, Sandset PM.. Ante- and postnatal risk factors of venous thrombosis: a hospital-based case-control study. J Thromb Haemost 2008; 06: 905-912.
- 7 Rodger MA, Betancourt MT, Clark P. et al. 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. PLoS Med 2010; 07: e1000292.
- 8 Rey E, Kahn SR, David M. et al. Thrombophilic disorders and fetal loss: a metaanalysis. Lancet 2003; 361: 901-908.
- 9 de Boer K, ten Cate JW, Sturk A. et al Enhanced thrombin generation in normal and hypertensive pregnancy. Am J Obstet Gynecol 1989; 160: 95-100.
- 10 Kupferminc MJ, Eldor A, Steinman N. et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999; 340: 9-13.
- 11 Greer IA, Nelson-Piercy C.. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood 2005; 106: 401-407.
- 12 Bates SM, Greer IA, Middeldorp S. et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e691S-736S.
- 13 Wiener-Megnagi Z, Ben-Shlomo I, Goldberg Y. et al Resistance to activated protein C and the leiden mutation: high prevalence in patients with abruptio placentae. Am J Obstet Gynecol 1998; 179: 1565-1567.
- 14 American College of Obstetricians and Gynecologists Women's Health Care Physicians. ACOG Practice Bulletin No. 138: Inherited thrombophilias in pregnancy. Obstet Gynecol 2013; 122: 706-717.
- 15 Rodger MA, Hague WM, Kingdom J. et al TIPPS Investigators. 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.
- 16 Anderson GD.. Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach. Clin Pharmacokinet 2005; 44: 989-1008.
- 17 Sephton V, Farquharson RG, Topping J. et al. A longitudinal study of maternal dose response to low molecular weight heparin in pregnancy. Obstet Gynecol 2003; 101: 1307-1311.
- 18 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.
- 19 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.
- 20 Regitz-Zagrosek V, Blomstrom Lundqvist C, Borghi C. et al European Society of Gynecology (ESG); Association for European Paediatric Cardiology (AEPC); German Society for Gender Medicine (DGesGM),; ESC Committee for Practice Guidelines. ESC Guidelines on the management of cardiovascular diseases during pregnancy: the Task Force on the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology (ESC). Eur Heart J 2011; 32: 3147-3197.
- 21 Chan WS, Rey E, Kent NE. VTE in Pregnancy Guideline Working Group. et al Society of Obstetricians and Gynecologists of Canada. Venous Thromboembolism and Antithrombotic Therapy in Pregnancy. J Obstet Gynaecol Can 2014; 36: 527-553.
- 22 Brown MA, Lindheimer MD, de Swiet M. et al. The classification and diagnosis of the hypertensive disorders of pregnancy: statement from the International Society for the Study of Hypertension in pregnancy (ISSHP). Hypertens Pregnancy 2001; 20: IX-XIV.
- 23 Dollberg S, Haklai Z, Mimouni FB. et al. Birth weight standards in the live-born population in Israel. Isr Med Assoc J 2005; 07: 311-314.
- 24 Duhl AJ, Paidas MJ, Ural SH. et al Pregnancy and Thrombosis Working Group. Antithrombotic therapy and pregnancy: consensus report and recommendations for prevention and treatment of venous thromboembolism and adverse pregnancy outcomes. Am J Obstet Gynecol 2007; 197: 457.e1-e21.
- 25 Preston FE, Rosendaal FR, Walker ID. et al. Increased fetal loss in women with heritable thrombophilia. Lancet 1996; 348: 913-916.
- 26 Meinardi JR, Middeldorp S, de Kam PJ. et al. Increased risk for fetal loss in carriers of the factor V Leiden mutation. Ann Intern Med 1999; 130: 736-739.
- 27 Pabinger I, Vormittag R.. Thrombophilia and pregnancy outcomes. J Thromb Haemost 2005; 03: 1603-1610.
- 28 Blumenfeld Z, Brenner B.. Thrombophilia-associated pregnancy wastage. Fertil Steril 1999; 72: 765-774.
- 29 Skeith L, Carrier M, Kaaja R. et al. A meta-analysis of low-molecular-weight heparin to prevent pregnancy loss in women with inherited thrombophilia. Blood 2016; 127: 1650-1655.
- 30 van Hoorn ME, Hague WM, van Pampus MG. et al FRUIT investigators. Low-molecular-weight heparin and aspirin in the prevention of recurrent early-onset pre-eclampsia in women with antiphospholipid antibodies: the FRUIT-RCT. Eur J Obstet Gynecol Reprod Biol 2016; 197: 168-173.
- 31 Linnemann B, Scholz U, Rott H. et al. Treatment of pregnancy-associated venous thromboembolism – position paper from the Working Group in Women's Health of the Society of Thrombosis and Haemostasis (GTH). Vasa 2016; 45: 103-118.
- 32 Patel JP, Green B, Patel RK. et al. Population pharmacokinetics of enoxaparin during the antenatal period. Circulation 2013; 128: 1462-1469.