Venous thromboembolism (VTE), including both pulmonary embolism (PE) and deep vein thrombosis (DVT), is the leading cause of maternal death in developed countries. Pregnancy is associated with an increased risk of VTE due to physiologic changes during the obstetric period that promote a hypercoagulable state. Appropriate use of prophylactic anticoagulants can decrease the event rate of thrombus formation in at-risk patients. In the United States, there is not a validated risk-assessment tool for VTE in obstetric patients or a clear consensus on initiation and optimal dosing strategy for the prophylactic use of anticoagulants. This article reviews the mechanism of coagulation disturbance that leads to an increased risk of VTE in obstetric patients, as well as the available literature surrounding pharmacologic prophylaxis.
WiegersHMGMiddeldorpS. Contemporary best practice in the management of pulmonary embolism during pregnancy. Ther Adv Respir Dis. 2020;14:1753466620914222. doi:10.1177/1753466620914222.
4.
Committee on Practice Bulletins-Obstetrics. Practice bulletin No. 183: postpartum hemorrhage. Obstet Gynecol. 2017;130(4):e168-e186. doi:10.1097/AOG.0000000000002351.
5.
McLintockC. Prevention and treatment of postpartum hemorrhage: focus on hematological aspects of management. Hematology. 2020;2020(1):542-546. doi:10.1182/hematology.2020000139.
6.
NathanLM. An overview of obstetric hemorrhage. Semin Perinatol. 2019;43(1):2-4. doi:10.1053/j.semperi.2018.11.001.
7.
Trends in Postpartum Hemorrhage in High Resource Countries: A Review and Recommendations from the International Postpartum Hemorrhage Collaborative Group - PubMed. Ann Arbor: University of Michigan. https://pubmed-ncbi-nlm-nih-gov.proxy.lib.umich.edu/19943928/
8.
KujovichJL. Hormones and pregnancy: thromboembolic risks for women. Br J Haematol. 2004;126(4):443-454. doi:10.1111/j.1365-2141.2004.05041.x.
9.
BremmeKA. Haemostatic changes in pregnancy. Best Pract Res Clin Haematol. 2003;16(2):153-168. doi:10.1016/S1521-6926(03)00021-5.
10.
WrightJGCooperPAstedtB, et al.Fibrinolysis during normal human pregnancy: complex inter-relationships between plasma levels of tissue plasminogen activator and inhibitors and the euglobulin clot lysis time. Br J Haematol. 1988;69(2):253-258. doi:10.1111/j.1365-2141.1988.tb07630.x.
11.
LecanderIAstedtB. Isolation of a new specific plasminogen activator inhibitor from pregnancy plasma. Br J Haematol. 1986;62(2):221-228. doi:10.1111/j.1365-2141.1986.tb02925.x.
12.
PaltaSSaroaRPaltaA. Overview of the coagulation system. Indian J Anaesth. 2014;58(5):515-523. doi:10.4103/0019-5049.144643.
13.
TaddeiSVirdisAGhiadoniLSudanoISalvettiA. Endothelial dysfunction in hypertension. J Cardiovasc Pharmacol. 2001;38:S11.
14.
Ropacka-LesiakMJarosławKBręborowiczG. Pregnancy-dependent blood flow velocity changes in lower extremities veins in venous insufficiency. Ginekol Pol. 2015;86(9):659-665.
15.
MacklonNSGreerIABowmanAW. An ultrasound study of gestational and postural changes in the deep venous system of the leg in pregnancy. Br J Obstet Gynaecol. 1997;104(2):191-197. doi:10.1111/j.1471-0528.1997.tb11043.x.
16.
JamesAHTapsonVFGoldhaberSZ. Thrombosis during pregnancy and the postpartum period. Am J Obstet Gynecol. 2005;193(1):216-219. doi:10.1016/j.ajog.2004.11.037.
17.
RayJGChanWS. Deep vein thrombosis during pregnancy and the puerperium: a meta-analysis of the period of risk and the leg of presentation. Obstet Gynecol Surv. 1999;54(4):265-271. doi:10.1097/00006254-199904000-00023.
18.
MiddletonPShepherdEGomersallJC. Venous thromboembolism prophylaxis for women at risk during pregnancy and the early postnatal period. Cochrane Database Syst Rev. 2021;3(3):CD001689. doi:10.1002/14651858.CD001689.pub4.
19.
D’AltonMEMainEKMenardMKLevyBS. The national partnership for maternal safety. Obstet Gynecol. 2014;123(5):973. doi:10.1097/AOG.0000000000000219.
20.
D’AltonMEFriedmanAMSmileyRM, et al.National partnership for maternal safety: consensus bundle on venous thromboembolism. Obstet Gynecol. 2016;128(4):688-698. doi:10.1097/AOG.0000000000001579.
21.
CapriniJAArcelusJIHastyJHTamhaneACFabregaF. Clinical assessment of venous thromboembolic risk in surgical patients. Semin Thromb Hemost. 1991;17(Suppl 3):304-312.
22.
BahlVHuHMHenkePKWakefieldTWCampbellDACapriniJA. A validation study of a retrospective venous thromboembolism risk scoring method. Ann Surg. 2010;251(2):344-350. doi:10.1097/SLA.0b013e3181b7fca6.
23.
BarbarSNoventaFRossettoV, et al.A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score. J Thromb Haemost JTH. 2010;8(11):2450-2457. doi:10.1111/j.1538-7836.2010.04044.x.
24.
American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics. ACOG practice bulletin No. 196: thromboembolism in pregnancy. Obstet Gynecol. 2018;132(1):e1-e17. doi:10.1097/AOG.0000000000002706.
25.
PabingerIGrafenhoferHKyrlePA, et al.Temporary increase in the risk for recurrence during pregnancy in women with a history of venous thromboembolism. Blood. 2002;100(3):1060-1062. doi:10.1182/blood-2002-01-0149.
26.
BatesSMGreerIAMiddeldorpSVeenstraDLPrabulosAMVandvikPO. VTE, thrombophilia, antithrombotic therapy, and pregnancy. Chest. 2012;141(2):e691S-e736S. doi:10.1378/chest.11-2300.
27.
BatesSMRajasekharAMiddeldorpS, et al.American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy. Blood Adv. 2018;2(22):3317-3359. doi:10.1182/bloodadvances.2018024802.
28.
American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins–Obstetrics. ACOG practice bulletin No. 197: inherited thrombophilias in pregnancy. Obstet Gynecol. 2018;132(1):e18-e34. doi:10.1097/AOG.0000000000002703.
29.
ZotzRBGerhardtAScharfRE. Inherited thrombophilia and gestational venous thromboembolism. Best Pract Res Clin Haematol. 2003;16(2):243-259. doi:10.1016/s1521-6926(03)00022-7.
30.
GerhardtAScharfREBeckmannMW, et al.Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med. 2000;342(6):374-380. doi:10.1056/NEJM200002103420602.
31.
ConardJHorellouMHVan DredenPLecompteTSamamaM. Thrombosis and pregnancy in congenital deficiencies in AT III, protein C or protein S: study of 78 women. Thromb Haemostasis. 1990;63(2):319-320.
32.
CrolesFNNasserinejadKDuvekotJJKruipMJMeijerKLeebeekFW. Pregnancy, thrombophilia, and the risk of a first venous thrombosis: systematic review and bayesian meta-analysis. BMJ. 2017;359:j4452. doi:10.1136/bmj.j4452.
KhareMNelson-PiercyC. Acquired thrombophilias and pregnancy. Best Pract Res Clin Obstet Gynaecol. 2003;17(3):491-507. doi:10.1016/s1521-6934(03)00013-0.
35.
BranchDWSilverRMBlackwellJLReadingJCScottJR. Outcome of treated pregnancies in women with antiphospholipid syndrome: an update of the Utah experience. Obstet Gynecol. 1992;80(4):614-620.
36.
LimaFKhamashtaMABuchananNMKerslakeSHuntBJHughesGR. A study of sixty pregnancies in patients with the antiphospholipid syndrome. Clin Exp Rheumatol. 1996;14(2):131-136.
37.
Committee on Practice Bulletins—ObstetricsAmerican College of Obstetricians and Gynecologists. Practice bulletin No. 132: antiphospholipid syndrome. Obstet Gynecol. 2012;120(6):1514-1521. doi:10.1097/01.AOG.0000423816.39542.0f.
38.
BlondonMCasiniAHoppeKKBoehlenFRighiniMSmithNL. Risks of venous thromboembolism after cesarean sections: a meta-analysis. Chest. 2016;150(3):572-596. doi:10.1016/j.chest.2016.05.021.
39.
JacobsenAFSkjeldestadFESandsetPM. Ante- and postnatal risk factors of venous thrombosis: a hospital-based case-control study. J Thromb Haemost JTH. 2008;6(6):905-912. doi:10.1111/j.1538-7836.2008.02961.x.
40.
GhermanRBGoodwinTMLeungBByrneJDHethumumiRMontoroM. Incidence, clinical characteristics, and timing of objectively diagnosed venous thromboembolism during pregnancy. Obstet Gynecol. 1999;94(5 Pt 1):730-734. doi:10.1016/s0029-7844(99)00426-3.
41.
MacklonNSGreerIA. Venous thromboembolic disease in obstetrics and gynaecology: the Scottish experience. Scot Med J. 1996;41(3):83-86. doi:10.1177/003693309604100305.
42.
BlondonMPerrierANendazM, et al.Thromboprophylaxis with low-molecular-weight heparin after cesarean delivery. Thromb Haemostasis. 2010;103(1):129-137. doi:10.1160/TH09-06-0349.
43.
BergqvistABergqvistDHallböökT. Acute deep vein thrombosis (DVT) after cesarean section. Acta Obstet Gynecol Scand. 1979;58(5):473-476. doi:10.3109/00016347909154070.
44.
ChanLYSLamKYMMetreweliCLauTK. Duplex ultrasound screening for deep vein thrombosis in Chinese after cesarean section. Acta Obstet Gynecol Scand. 2005;84(4):368-370. doi:10.1111/j.0001-6349.2005.00591.x.
45.
JacobsenAFDrolsumAKlowNEDahlGFQvigstadESandsetPM. Deep vein thrombosis after elective cesarean section. Thromb Res. 2004;113(5):283-288. doi:10.1016/j.thromres.2004.03.008.
46.
KalroBNDavidsonRAOwenP. Low incidence of asymptomatic deep venous thrombosis following caesarean section: a colour Doppler study. Health Bull. 1999;57(6):418-421.
47.
LindqvistPDahlbäckBMarŝálK. Thrombotic risk during pregnancy: a population study. Obstet Gynecol. 1999;94(4):595-599. doi:10.1016/s0029-7844(99)00308-7.
48.
SiaWWPowrieROCooperAB, et al.The incidence of deep vein thrombosis in women undergoing cesarean delivery. Thromb Res. 2009;123(3):550-555. doi:10.1016/j.thromres.2008.06.004.
49.
SimpsonELLawrensonRANightingaleALFarmerRD. Venous thromboembolism in pregnancy and the puerperium: incidence and additional risk factors from a London perinatal database. BJOG An Int J Obstet Gynaecol. 2001;108(1):56-60. doi:10.1111/j.1471-0528.2001.00004.x.
50.
GouldMKGarciaDAWrenSM, et al.Prevention of VTE in nonorthopedic surgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):e227S-e277S. doi:10.1378/chest.11-2297.
51.
WhiteRHZhouHRomanoPS. Incidence of symptomatic venous thromboembolism after different elective or urgent surgical procedures. Thromb Haemostasis. 2003;90(3):446-455. doi:10.1160/TH03-03-0152.
52.
BergqvistDAgnelliGCohenAT, et al.Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N Engl J Med. 2002;346(13):975-980. doi:10.1056/NEJMoa012385.
53.
BergqvistD. Prolonged prophylaxis in postoperative medicine - PubMed. 1997. 23(2):149-154. doi:10.1055/s-2007-996083
54.
Prolonged prophylaxis with dalteparin to prevent late thromboembolic complications in patients undergoing major abdominal surgery: a multicenter randomized open-label study. J Thromb Haemost. 2006;4(11):2384–2390. https://pubmed.ncbi.nlm.nih.gov/16881934/
MáraMKoryntováDRezábekK, et al.[Thromboembolic complications in patients undergoing in vitro fertilization: retrospective clinical study]. Ceska Gynekol. 2004;69(4):312-316.
57.
AbramovYElchalalUSchenkerJG. Obstetric outcome of in vitro fertilized pregnancies complicated by severe ovarian hyperstimulation syndrome: a multicenter study. Fertil Steril. 1998;70(6):1070-1076. doi:10.1016/S0015-0282(98)00350-1.
58.
HullRDPineoGFSteinPD, et al.Extended out-of-hospital low-molecular-weight heparin prophylaxis against deep venous thrombosis in patients after elective hip arthroplasty: a systematic review. Ann Intern Med. 2001;135(10):858-869. doi:10.7326/0003-4819-135-10-200111200-00006.
59.
ChanWSAnandSGinsbergJS. Anticoagulation of pregnant women with mechanical heart valves: a systematic review of the literature. Arch Intern Med. 2000;160(2):191-196. doi:10.1001/archinte.160.2.191.
60.
JamesAHAbelDEBrancazioLR. Anticoagulants in pregnancy. Obstet Gynecol Surv. 11:61-63.
61.
HirshJWarkentinTEShaughnessySG, et al.Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest. 2001;119(1 Suppl):64S-94S. doi:10.1378/chest.119.1_suppl.64s.
62.
CaseleHL. The use of unfractionated heparin and low molecular weight heparins in pregnancy. Clin Obstet Gynecol. 2006;49(4):895-905. doi:10.1097/01.grf.0000211958.45874.63.
63.
Soma-PillayPCatherineNPTolppanenHMebazaaATolppanenHMebazaaA. Physiological changes in pregnancy. Cardiovasc J Afr. 2016;27(2):89-94. doi:10.5830/CVJA-2016-021.
64.
LebaudyCHulotJAmouraZ, et al.Changes in enoxaparin pharmacokinetics during pregnancy and implications for antithrombotic therapeutic strategy. Clin Pharmacol Ther. 2008;84(3):370-377. doi:10.1038/clpt.2008.73.
65.
KarcutskieCADharmarajaAPatelJ, et al.Association of anti–factor xa–guided dosing of enoxaparin with venous thromboembolism after trauma. JAMA Surg. 2018;153(2):144-149. doi:10.1001/jamasurg.2017.3787.
66.
TahainehLEdailySMGharaibehSF. Anti-factor Xa levels in obese patients receiving enoxaparin for treatment and prophylaxis indications. Clin Pharmacol Adv Appl. 2018;10:63-70. doi:10.2147/CPAA.S161599.
67.
SalimRNachumZGavishIRomanoSBravermanMGarmiG. Adjusting enoxaparin dosage according to anti-FXa levels and pregnancy outcome in thrombophilic women. A randomised controlled trial. Thromb Haemostasis. 2016;116(4):687-695. doi:10.1160/TH16-03-0221.
68.
Abou-NassarKKovacsMJKahnSR, et al.The effect of dalteparin on coagulation activation during pregnancy in women with thrombophilia. A randomized trial. Thromb Haemostasis. 2007;98(1):163-171.
69.
EnsomMHHStephensonMD. Pharmacokinetics of low molecular weight heparin and unfractionated heparin in pregnancy. J Soc Gynecol Invest. 2004;11(6):377-383. doi:10.1016/j.jsgi.2004.02.007.
70.
PettiläVKaajaRLeinonenPEkbladUKatajaMIkkalaE. Thromboprophylaxis with low molecular weight heparin (dalteparin) in pregnancy. Thromb Res. 1999;96(4):275-282. doi:10.1016/s0049-3848(99)00110-3.
71.
PetersonNHameedABFriedmanA. Improving health care response to maternal venous thromboembolism. In: (California Maternal Quality Care Collaborative Toolkit to Transform Maternity Care) Developed under Contract #11-10006 with the California Department of Public Health; Maternal, Child and Adolescent Health Division. California: Published by the California Maternal Quality Care Collaborative; 2018.
72.
Roeters van LennepJEMeijerEKlumperFJCMMiddeldorpJMBloemenkampKWMMiddeldorpS. Prophylaxis with low-dose low-molecular-weight heparin during pregnancy and postpartum: is it effective?J Thromb Haemost JTH. 2011;9(3):473-480. doi:10.1111/j.1538-7836.2011.04186.x.
73.
CoxSEslickRMcLintockC. Effectiveness and safety of thromboprophylaxis with enoxaparin for prevention of pregnancy-associated venous thromboembolism. J Thromb Haemost JTH. 2019;17(7):1160-1170. doi:10.1111/jth.14452.
74.
BistervelsIMBuchmüllerAWiegersHMG, et al.Intermediate-dose versus low-dose low-molecular-weight heparin in pregnant and post-partum women with a history of venous thromboembolism (Highlow study): an open-label, multicentre, randomised, controlled trial. Lancet Lond Engl. 2022;400(10365):1777-1787. doi:10.1016/S0140-6736(22)02128-6.
