Venous Thromboembolism Prophylaxis in Obstetric Patients

Abstract

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.

Keywords

venous thromboembolism deep vein thrombosis pulmonary embolism prophylaxis obstetric

Background

Venous thromboembolism (VTE) is five times more likely to occur in pregnant women compared to the nonpregnant population.¹ VTE accounts for approximately 10% of maternal deaths annually.^1,2 While VTE is associated with significant maternal morbidity and mortality, the overall incidence is low, approximately 1-2 per 1000 pregnancies.³ There are no validated VTE risk-assessment tools for the obstetric population in the U.S., and the available literature surrounding this topic is generally of low quality. Therefore, it is critical to stratify patients by risk early and to identify those who may benefit from VTE prophylaxis. Additionally, individual patient risk factors should undergo thoughtful consideration to weigh bleeding risk, cost, administration burden, and birth implications of anticoagulation in pregnancy. This aids in identification of those most likely to benefit from pharmacologic prophylaxis. This article reviews the hypercoagulable state induced by pregnancy, outlines modifiable and nonmodifiable risk factors for VTE, summarizes the available literature regarding agent selection, dosing, and monitoring, and compares published guideline recommendations from The American College of Obstetricians and Gynecologists (ACOG), The American College of Chest Physicians (ACCP), and the American Society of Hematology (ASH) for VTE prophylaxis in obstetric patients.

Pathophysiology

Hemorrhage can complicate 3%–5% of pregnancies with postpartum hemorrhage remaining a leading cause of maternal mortality, accounting for 11%–12% of maternal deaths in the United States.^4-7 Due to the hemorrhage risk, there is an evolutionary benefit for the coagulation cascade to shift toward a hypercoagulable state during pregnancy. In addition to changes in the coagulation cascade, physiologic changes related to endothelial damage and venous stasis combined with patient-specific risk factors contribute to an increased risk of VTE during the obstetric period.

Hypercoagulability

Modifications in the concentration of coagulation factors that occur during pregnancy contribute to the increased risk of thrombus formation. Throughout the course of pregnancy, concentrations of the procoagulants fibrinogen, Von Willebrand factor (VWF), factor VII, factor VIII, and factor X increase.⁸ The concentrations rise throughout pregnancy and return to normal range by eight weeks postpartum.⁹ Additionally, the concentration of natural anticoagulants decreases during the obstetric period. Protein S levels decrease significantly while resistance to activated protein C increases.⁹ The higher concentration of circulating coagulation factors, and reduction of endogenous anticoagulants, promotes clot formation and activation of the coagulation cascade.

A reduction in fibrinolysis also occurs due to a decrease in tissue plasminogen activator (tPA).⁹ This decrease in tPA is caused by increased plasminogen activator inhibitors 1 and 2 (PAI-1 and PAI-2). Levels of PAI-1 are threefold higher compared to nonpregnant levels.¹⁰ PAI-2 comes from villous cells of the placenta; therefore, concentrations are dependent on placental size.¹¹

These changes shift the balance in the coagulation cascade toward clotting to protect women from hemorrhage during miscarriage and birth. The average volume of blood loss is less than 500 mL for vaginal births and less than 1000 mL for cesarean deliveries.⁴ Blood volume loss could be commonly higher in the event of complications, such as postpartum hemorrhage or placental abruption, if these coagulation changes did not occur.

Endothelial Injury and Dysfunction

Endothelial dysfunction and injury contribute to the risk of thrombosis during pregnancy and the postpartum period. Tissue damage during both vaginal and cesarean delivery triggers the extrinsic coagulation cascade.¹² Besides the inherent tissue damage associated with labor and delivery, increases in the incidence of obesity, sedentary lifestyles, and rising maternal age has contributed to an increase in the rate of hypertension.^8,9 Hypertension causes thickening of the arterial wall leading to endothelial dysfunction. It can also initiate the production of reactive oxygen species and a subsequent decrease in nitric oxide, a vasodilator produced by the endothelium.¹³

Venous Stasis

Pregnancy is associated with both venous distension and insufficiency.¹⁴ There is a complex interplay between hormonal changes, increased plasma blood volume, obstruction from the expanding uterus, and decreased mobility that promotes blood stasis.¹⁴ The expanding uterus causes a 50% reduction in venous flow in the deep leg veins by 25-29 weeks of gestation which lasts until six weeks postpartum.¹⁵ In addition, the left lower extremity is the site of 82% of DVTs in pregnant and postpartum women due to uterine compression of the left common iliac vein by the right common iliac artery.¹⁶

Risk-Assessment

The risk of VTE exists throughout each trimester and is highest in the first six weeks postpartum.¹⁷ One meta-analysis compared the event rate of VTE throughout each trimester and the postpartum period. This review pooled data from 14 studies between 1966-1998. The trimester in which a VTE event occurred was reported in 12 of the 14 studies. The event rate across these studies was 21.9% (95% CI 17.4-27.3) during the first trimester, 33.7% (95% CI 28.1-39.8) during the second trimester, and 47.6% (95% CI 39.2-56.2) during the third trimester. Heterogeneity testing was not significant. An event rate during the antepartum and postpartum period was reported in 9 of the 14 studies. Of these events, 65.5% (95% CI 58.1-72.1) occurred during pregnancy and 34.5% (95% CI 27.9-41.9) occurred during the postpartum period (P = 0.08). This result was also not heterogeneous. There was no significant difference in event rates across these periods, but the length of the antepartum period (280 days) is much longer than the postpartum period (42 days). The estimated distribution of 100 VTE events during the antepartum period is 0.23 per day compared to 0.82 per day in the postpartum period.

Despite the increased risk of VTE in pregnancy, most patients do not require pharmacological prophylaxis due to a low overall incidence of VTE and uncertainty in data about the benefits of chemoprophylaxis in women without additional risk factors.¹⁸ A thorough review of individual risk factors should be conducted to weigh the benefits of VTE prophylaxis against the financial cost, administration burden, and bleed risk. The National Partnership for Maternal Safety (NPMS) was formed in recognition of the need to decrease maternal morbidity and mortality in the U.S.¹⁹ They created three consensus bundles for preventable causes of maternal mortality: hemorrhage, hypertension, and VTE. In the consensus bundle for VTE, completion of a VTE risk-assessment is recommended for all obstetric patients during their first prenatal visit, during all antepartum admissions, immediately postpartum, and upon discharge after delivery.²⁰

There are currently no validated VTE risk-assessment tools in the obstetric population. The NPMS instead suggests using modifications of two other common VTE risk-assessment tools for hospitalized nonpregnant patients: the Caprini and Padua systems.²⁰ These modifications condense the scoring tools to include those conditions most frequently encountered in obstetric patients. The original Caprini score is validated for use in surgical patients and includes an assessment of 20 items.²¹ The modified version in Table 1 represents a version that can be applicable to obstetric patients, but it is not validated for this patient population. A retrospective review evaluating the Caprini score found an incidence of VTE of 0% for a score of 0-1, 0.7% for a score of 2, 1% for a score of 3-4, and 1.9% for a score of 5 or higher.²² Based on the calculated result, the Caprini score will state if VTE prophylaxis is indicated and for what duration.

Table 1.

Caprini Scoring System Modified for Pregnancy.^20,21

Add 1 Point if These Applied now or in the past month	Add 2 Points for Each of the following	Add 3 Points for Each of the following
□ Age 41-60	□ Central venous access	□ Family history of thrombosis
□ Minor surgery (less than 45 minutes)	□ Major surgery (>45 minutes)	□ History of DVT/PE
□ Visible varicose veins	□ Patient confined to bed (>72 hours)	□ Prothrombin 20210A or factor V Leiden
□ Swollen legs (current)		□ Lupus anticoagulant or elevated anticardiolipin antibodies
□ Overweight or obese (BMI >25 kg/m²)		□ Elevated serum homocysteine
□ Currently on bed rest		□ Other congenital or acquired thrombophilia
□ Serious lung disease including pneumonia (<1 month)
□ Pregnancy or postpartum (<1 month)
□ History of unexplained stillborn infant, recurrent spontaneous abortion (≥3), premature birth with toxemia or growth-restricted infant
□ Other risk factors (smoking, diabetes, BMI >40 kg/m², blood transfusions)

The Padua Score is validated in hospitalized patients and includes 11 items to assess.²³ The version modified for obstetric patients is shown in Table 2, but similar to the modified Caprini, it is not validated for this patient population. A score greater than or equal to 4 confers a VTE risk of 11% for patients not receiving prophylaxis or 2.2% risk if they are. NPMS suggests using modifications of these scoring systems for obstetric patients during their first prenatal visit, during all antepartum admissions, immediately postpartum, and upon discharge after delivery.²⁰

Table 2.

Padua Scoring Tool Modified for Pregnancy.^20,23

Baseline Characteristic	Score
□ Previous VTE (excluding superficial vein thrombosis)	3
□ Reduced mobility (bed rest with bathroom privileges for at least 3 days)	3
□ Thrombophilia	3
□ Acute infection and/or rheumatologic disorder	1
□ Overweight or obese (BMI >25 mg/m²)	1
□ Pregnancy	1

Risk Factors

Given the overall low incidence but high morbidity and mortality, individual patient risk factors should be carefully considered to identify those most likely to benefit from pharmacological prophylaxis.³ Potential indications for pharmacological prophylaxis include personal history of VTE, inherited or acquired thrombophilias, cesarean section delivery, and use of assisted reproductive technology.

The highest predictor for developing a VTE during pregnancy is personal history of VTE.²⁴ A retrospective cohort study by Pabinger et al. included 109 women who had at least one pregnancy after an episode of VTE.²⁵ The incidence of VTE during pregnancy was compared to VTE incidence during a nonpregnant period. Recurrence rates per 100 patient-years were 10.9% during pregnancy and 3.7% outside of pregnancy. For patients with a history of VTE, guidelines from ACOG, ACCP, and ASH have recommendations regarding pharmacologic prophylaxis depending on if the VTE was provoked as noted in Table 3. Prophylaxis is recommended in both antepartum and postpartum periods if the previous thrombus was unprovoked and in the postpartum period only if the thrombus was provoked.^24,26,27

Table 3.

UFH and Enoxaparin Dosing Recommendations Based on Indication and Guideline^24,26,27,37 * = Intermediate Dose; ** = Adjusted Dose.

	ASH	ACOG	ACCP
History of single unprovoked VTE
Antepartum	Prophylaxis, int dose, or adj dose* LMWH	Clinical vigilance, prophylaxis, or int dose* LMWH	Recommends antepartum anticoagulant prophylaxis
Postpartum	Prophylaxis, int dose, or adj dose* LMWH	Postpartum prophylaxis	No recommendation
History of single provoked VTE unrelated to pregnancy
Antepartum	Surveillance without anticoagulation	Clinical vigilance	Suggests against anticoagulant prophylaxis
Postpartum	Surveillance without anticoagulation; Prophylaxis if the patient has additional risk factors	Anticoagulant prophylaxis	Anticoagulant prophylaxis
Homozygosity for factor V Leiden or prothrombin gene mutation
Antepartum	Homozygous for factor V Leiden: Antithrombotic prophylaxis; Homozygous for prothrombin gene mutation without a family history of VTE: Suggest against prophylaxis; Unable to reach recommendation for family history of VTE	Prophylactic LMWH or UFH	Clinical vigilance if no family history of VTE; Prophylactic or int dose* LMWH if family history of VTE
Postpartum	Suggest prophylaxis	Anticoagulation	Prophylaxis with prophylactic or int dose* LMWH for 6 weeks
Heterozygosity for factor V Leiden or prothrombin gene mutation
Antepartum	Suggests against using antepartum antithrombotic prophylaxis to prevent a first VTE regardless of family history of VTE	Either clinical surveillance or prophylactic LMWH or UFH	Suggest antepartum clinical surveillance
Postpartum	Without family history of VTE: Suggests against antithrombotic prophylaxis ;With a family history of VTE: Suggest against antithrombotic prophylaxis	Either clinical surveillance or anticoagulation if there are additional risk factors	Clinical surveillance if there is no family history of VTE Prophylactic or int dose* LMWH for six weeks if there is a family history of VTE
Protein C deficiency
Antepartum	Suggest against antithrombotic prophylaxis	Either clinical surveillance or prophylactic LMWH or UFH	Clinical surveillance
Postpartum	Without a family history of VTE: Suggest against antithrombotic prophylaxis; With a family history of VTE suggest postpartum prophylaxis	Either clinical surveillance or anticoagulation with additional risk factors	Clinical surveillance if no family history of VTE; Prophylactic or int dose* LMWH if there is a family history of VTE
Protein S deficiency
Antepartum	Suggest against prophylaxis	Either clinical surveillance or prophylactic LMWH or UFH	Clinical surveillance
Postpartum	Without a family history of VTE: Suggest against prophylaxis; With a family history of VTE: Suggest postpartum prophylaxis	Either clinical surveillance or anticoagulation if there are additional risk factors	Clinical surveillance if no family history of VTE; Prophylaxis with prophylactic or int dose* LMWH for six weeks if a family history of VTE
Compound Heterozygosity
Antepartum	Antithrombotic prophylaxis	Prophylactic LMWH or UFH	Clinical surveillance
Postpartum	Antithrombotic prophylaxis	Anticoagulation	Clinical surveillance if no family history of VTE; Prophylactic or int dose* LMWH for six weeks if family history of VTE
Antithrombin deficiency
Antepartum	Without a family history of VTE suggest against prophylaxis	Prophylactic LMWH or UFH	Clinical surveillance
Antepartum	With a family history of VTE: Recommend prophylaxis	Prophylactic LMWH or UFH	Clinical surveillance
Postpartum	Without a family history of VTE: Suggest against prophylaxis	Anticoagulation	Clinical surveillance if no family history
Postpartum	With a family history of VTE: Recommend prophylaxis	Anticoagulation	Prophylactic or int dose* LMWH for six weeks if a family history
Antiphospholipid syndrome
Antepartum	No recommendation	Clinical surveillance of prophylactic LMWH/UFH	Clinical surveillance of prophylactic LMWH/UFH
Postpartum	No recommendation	Clinical surveillance of prophylactic LMWH/UFH	Clinical surveillance of prophylactic LMWH/UFH

Besides a personal history of VTE, the next most important individual risk factor is presence of a thrombophilia.²⁴ Of women who develop a VTE during pregnancy, 40% are heterozygous for factor V Leiden.²⁸ Homozygosity for factor V Leiden in women without a personal or family history of VTE confers a 1%–2% risk for VTE while women with a personal or family history have a 17% risk for VTE (Table 4).²⁹

Table 4.

Risk of Developing a VTE Associated With a Given Thrombophilia.^{25,28-32,75,76}

	Without Personal or Family History of Thrombosis	With Personal or Family History of Thrombosis
Personal History of VTE	N/A	10.9%
Homozygosity for factor V Leiden	1%–2%	17%
Homozygosity for Prothrombin G20210A	2%–3%	Not reported
Compound Heterozygosity	4%–5%	Not reported
Protein C deficiency	0.7%	2%–8%
Protein S deficiency	Not reported	5%–7%

Prothrombin G20210A is present in 17% of women who develop VTE during pregnancy.³⁰ Women who are homozygous for prothrombin gene mutation without a personal or family history of VTE have a 2%-3% risk for VTE. Women can also be heterozygous for both factor V Leiden and prothrombin gene mutation. This compound heterozygosity has a synergistic effect leading to a 4%–5% risk of VTE in the absence of personal or family history of VTE (Table 4).

Two other types of thrombophilias include protein C deficiency and protein S deficiency. Women without a personal or family history of VTE in the setting of protein C deficiency have a risk of ∼0.7% of developing a VTE during pregnancy.²⁶ Women with a positive personal or family history have an estimated risk of 2%-8%.³¹ Women with a positive personal or family history of VTE in the setting of protein S deficiency have a risk of 5%-7% for developing VTE during pregnancy (Table 4).³²

Examples of acquired thrombophilias include antiphospholipid syndrome (APS) and human immunodeficiency virus (HIV).³³ The most common acquired thrombophilia in pregnancy is APS which is characterized by circulating antibodies such as anticardiolipin antibodies (aCL) or lupus anticoagulant (LA).³⁴ Women with APS have a 5%-12% risk of VTE during pregnancy.^35,36 Due to an overall lack of data, ACOG and ACCP state that clinical surveillance, prophylactic unfractionated heparin (UFH), or prophylactic low-molecular-weight heparin (LMWH) may be warranted both antepartum and postpartum (Table 3).^26,37

Cesarean section is considered an independent risk factor for development of VTE.³⁸ The overall incidence of VTE ranges from 1-18 events per 1000 cesarean deliveries.^39-49 A meta-analysis completed by Blondon et al. in 2010 found an estimated incidence of approximately three VTEs per 1000 cesarean deliveries which is approximately a fourfold increased risk compared to vaginal delivery.³⁸ Assessment of risk, type of VTE prophylaxis, and duration recommendations differ among the guidelines.^24,26,27 ACCP utilizes a risk-assessment tool extrapolated from the general surgery population to identify obstetric patients likely to benefit from VTE prophylaxis following cesarean delivery.^26,50 From this data, prophylaxis is suggested for women with an absolute risk greater than or equal to 3%, which is based on the presence of one major risk factor or two minor risk factors listed in Table 5.²⁶ Regarding duration, ACCP again looks to data from general surgery patients and suggests pharmacologic prophylaxis until discharge unless ongoing risk factors are present.^50-54

Table 5.

Risk Factors for VTE Yielding Risk of Postpartum VTE >3%.^26,50

Major Risk Factor

Immobility

Postpartum hemorrhage (≥1000 mL with surgery)

Previous VTE

Preeclampsia with fetal growth restriction

Thrombophilia

Antithrombin deficiency

Factor V Leiden

Prothrombin G20210A

Medical conditions

Systemic lupus erythematosus

Heart disease

Sickle cell disease

Blood transfusion

Postpartum infection

Minor risk Factor

BMI >30 kg/m²

Multiple pregnancy

Postpartum hemorrhage > 1L

Smoking >10 cigarettes/day

Fetal growth restriction

Thrombophilia

Protein C deficiency

Protein S deficiency

Preeclampsia

ACCP also recommends the use of mechanical prophylaxis in place of, or in addition to, pharmacologic prophylaxis.²⁶ When used in place of pharmacologic prophylaxis, mechanical prophylaxis had less major bleeding (RR, 0.51; 95% CI, 0.40-0.64) but a higher risk of VTE (RR, 1.8; 95% CI, 1.2-2.8).⁵⁰

Assisted reproductive technology (ART) includes treatment and procedures where oocytes or embryos are handled (i.e., in vitro fertilization-embryo transfer, gamete intrafallopian transfer, zygote intrafallopian transfer, and frozen embryo transfer).⁵⁵ ART has been associated with a low increased risk of VTE (0.1%).⁵⁶ A higher incidence of VTE has been observed in patients who experience ovarian hyperstimulation syndrome (OHSS), a complication of ART therapy. OHSS is characterized by third space fluid accumulation, respiratory dysfunction, and renal impairment often requiring intensive care hospitalization.⁵⁷ When OHSS develops, the absolute risk of VTE increases to 4%.⁵⁶ There is limited data regarding the use of VTE prophylaxis in both the ART and OHSS populations. ACCP estimated the effect of LMWH prophylaxis in women undergoing ART by extrapolating data from patients who underwent hip arthroplasty.^26,58 In the presence of severe OHSS, prophylaxis with enoxaparin may result in a reduction of 26 VTEs per 1000 women treated (NNT is 39), without increased risk of significant bleeding. In the absence of OHSS, the NNT is 781. For women undergoing assisted reproduction who develop severe OHSS, ACCP recommends VTE prophylaxis for 3 months following resolution of OHSS.²⁶

VTE Prevention With Medication

Agents used in the general adult population for VTE prophylaxis include UFH, LMWH, direct thrombin inhibitors (DTI), factor Xa inhibitors, and vitamin K antagonists (VKA). Of these agents, DTIs and factor Xa inhibitors, such as dabigatran, apixaban, and rivaroxaban, should not be used antepartum due to their potential ability to cross the placenta and their unknown impact on reproduction.²⁷ VKAs, such as warfarin, are also generally not recommended in pregnancy because they cross the placenta and can lead to warfarin embryopathy.²⁶ An exception is use of a VKA in a pregnant patient with a mechanical mitral valve. A systematic review found that the risk of thromboembolic complications was highest when UFH was used throughout pregnancy in women with a mechanical mitral valve.⁵⁹ In order to balance the risk of congenital anomalies and risk of VTE, UFH or LMWH is recommended in the first trimester followed by warfarin therapy in the second and third trimester for this indication. Overall, national guidelines recommend use of UFH or LMWH as preferred anticoagulants during the obstetric period.^24,26,27

The benefits of UFH during pregnancy include its inability to cross the placenta, safety in renal failure, measurable effect with activated partial thromboplastin time (aPTT) and anti-factor Xa (anti-Xa), and availability of a reversal agent.⁶⁰ Disadvantages of UFH include its unpredictable pharmacokinetic profile, bruising at the injection site, frequency of injection, risk of heparin-induced thrombocytopenia (HIT), and the risk of major bleeding.

Compared to UFH, the benefits of LMWH include the inability to cross the placenta, dosing frequency, predictability of effect, lower incidence of HIT, and bleeding risk relative to UFH.⁶¹ Disadvantages of LMWH include renal dose adjustment when creatinine clearance falls below 30 mL/min, injection site pain, cost, and longer half-life where consideration must be given to patients who receive neuraxial analgesia during labor.

A study by Casele et al. was performed that compared the incidence of VTE events with UFH and LMWH.⁶² This study observed two VTEs in patients on LMWH (3%, n = 60) and four VTEs in patients on UFH (7%, n = 57). This corresponded to a risk ratio of 0.47 (95% CI 0.09-2.49) demonstrating noninferiority between the two agents further solidifying practitioners’ preference for LMWHs during pregnancy and postpartum. By consensus, LMWH is the preferred agent for VTE prophylaxis in obstetric patients.^24,26,27

The physiologic changes associated with pregnancy have led to questions regarding optimal LMWH dosing. Beginning at 6-8 weeks of gestation, maternal blood volume begins to increase, and by 32 weeks of gestation, maternal blood volume will increase by 40%-50%.⁶³ Renal plasma flow also increases by 40%-65%, and glomerular filtration rate increases by 50%-85% compared to non-pregnant women due to renal vasodilation during pregnancy. Since a direct measure of LMWH levels does not exist, anti-Xa levels are measured as a surrogate marker of drug concentration. Anti-Xa level monitoring is not recommended in the general population given the predictable pharmacokinetic profile of LMWH. However, there may be utility in monitoring anti-Xa levels in certain populations such as patients with renal insufficiency or at the extremes of body weight. A study conducted by Lebaudy et al. evaluated the potential impact of the obstetric physiologic changes on the pharmacokinetics of enoxaparin.⁶⁴ They found that drug clearance increased throughout the initial trimesters of pregnancy and then stabilized around 20 weeks of gestation. In addition, the volume of distribution increased slowly throughout the first and second trimesters and then increased rapidly after 30 weeks of gestation. Based on a computed pharmacokinetics model, they found that with a prophylactic regimen of enoxaparin 40 mg subcutaneously once daily, the peak anti-Xa level decreased with pregnancy progression. In the first trimester, the mean anti-Xa level was 0.47 IU/ml compared to 0.32 IU/mL in the third trimester (P = 0.002). The goal peak enoxaparin anti-Xa level for VTE prophylaxis in pregnancy has not been determined; however, studies evaluating enoxaparin use in trauma or obese patients for VTE prophylaxis suggest a goal peak anti-Xa level of 0.2-0.4 IU/mL.^65,66

Following this population kinetics study, four randomized control trials evaluated the utility of anti-Xa based dose adjustments for VTE prophylaxis during pregnancy (Table 6).^67-70 The largest of these studies was conducted by Salim et al. and included 66 patients in a fixed-dose enoxaparin group and 74 patients in an adjusted-dose enoxaparin group.⁶⁷ The fixed-dose group received enoxaparin 40 mg subcutaneously once daily, and the adjusted-dose group received enoxaparin 40 mg subcutaneously once daily which was then dose-adjusted based on anti-Xa levels. The primary outcome was a composite of pregnancy loss, preeclampsia, birth of a small-for-gestational-age infant, placental abruption, or VTE. Secondary endpoints included gestational age at delivery, preterm births, delivery mode, and maternal complications related to enoxaparin. The primary composite outcome occurred in 12 of the fixed-dose patients and 20 of the adjusted-dose patients. Of these events, none were VTE. Additionally, all other aspects of the composite outcome failed to achieve statistical significance. The only secondary outcome found to be statistically significant was postpartum hemorrhage which occurred in five patients in the fixed-dose group and zero patients in the adjusted-dose group (P = 0.02).

Table 6.

Utility of anti-Xa Based Dose Adjustments.^67–70

Author	Indication	Population	Intervention	Anti-Xa Data	Results
Salim et al⁶⁶	Thrombophilia	Anti-Xa adjusted LMWH (n = 74) or fixed dose LMWH (n = 66)	Enoxaparin	23 doses adjusted in anti-Xa adjusted group	Thrombosis: No events
			Enoxaparin		Bleeding: No events considered a side effect from LMWH Fixed dose group: PPH, n = 5
			Adjusted: 40 mg daily, adjusted to anti-Xa Fixed: 40 mg daily (Aspirin given to women with APS in both groups)
Abou-Nassar et al⁶⁷	Thrombophilia	Prophylactic LMWH (n = 85) or no intervention (n = 46)	Dalteparin	No dose adjustments	Thrombosis: Not reported
Abou-Nassar et al⁶⁷	Thrombophilia	Prophylactic LMWH (n = 85) or no intervention (n = 46)	Fixed dose of 5000 U/day until 20 weeks gestation, then 5000 U twice daily until 37 weeks gestation	No dose adjustments	Bleeding: Not reported
Ensom et al⁶⁸	APS	LMWH (n = 13) or UFH (n = 18)	Dalteparin	No dose adjustments	Thrombosis: No events
Ensom et al⁶⁸	APS	LMWH (n = 13) or UFH (n = 18)	Fixed: Prepregnancy and first trimester = 2500 U/day; second trimester = 5000 U/day; third trimester 7500 U/day	No dose adjustments	Bleeding: Not reported
Pettilӓ et al⁶⁹	Indication for thromboprophylaxis	Prophylactic LMWH (n = 50) or UFH (n = 55)	Dalteparin	35/50 doses adjusted	Thrombosis: No events
Pettilӓ et al⁶⁹	Indication for thromboprophylaxis	Prophylactic LMWH (n = 50) or UFH (n = 55)	Initial dose based on weight, anti-Xa adjusted	35/50 doses adjusted	Bleeding: Risk of any bleeding: 0.18 (95% CI: 0.07-0.29). Bleeding complication without need for transfusion (n = 9/50)

Based on the findings summarized in Table 6, dose adjustment of LMWH based on anti-Xa levels is not recommended.^67-70 Current guidelines from ACOG, ASH, and ACCP align on the guidance against utilization of anti-Xa monitoring for dose adjustment of LMWH for prophylaxis; however, they do not align on the specific doses (Tables 7-8).^24,26,27 The California Quality Improvement Toolkit utilized these guidelines to provide a consensus of recommendations (Table 9).⁷¹

Table 7.

Heparin Dosing Strategies^24,26,27 subQ = subcutaneous.

	ACCP	ACOG	ASH
Prophylactic UFH	UFH 5000 units subQ Q12H	First Trimester: UFH 5000-7500 units subQ Q12H	No recommendations provided
		Second Trimester: UFH 7500-10,000 units subQ Q12H
		Third Trimester: UFH 10,000 units subQ Q12H
Intermediate-dose UFH	UFH subQ Q12H adjusted for goal anti-Xa 0.1-0.3 U/mL	---
Adjusted-dose UFH	UFH subQ Q12H adjusted for therapeutic aPTT	UFH 10,000 units (or more) subQ Q12H adjusted to aPTT (1.5-2.5 × control)

Table 8.

Enoxaparin Dosing Strategies^24,26,27 subQ = subcutaneous.

	ACCP (H)	ACOG	ASH
Prophylactic LMWH	Enoxaparin 40 mg subQ Q24	Enoxaparin 40 mg subQ Q24H	Enoxaparin 40 mg subQ Q24H
Intermediate-dose LMWH	Enoxaparin 40 mg subQ Q12	Enoxaparin 40 mg subQ Q12H	---
Adjusted-dose LMWH	Enoxaparin 1 mg/kg Q12	Enoxaparin 1 mg/kg Q12H target anti-Xa 0.6-1 U/mL	Enoxaparin 1 mg/kg Q12H

Table 9.

The California Quality Improvement Toolkit Provides Dosing Recommendations Based on Available Data.⁷¹

Clinical History	Risk Level	Management
- Low risk thrombophilia (isolated)	Low	No treatment
- Low risk thrombophilia with family history of VTE
- Prior provoked VTE
- Prior idiopathic VTE	Medium	Prophylactic dose (UFH or LMWH)
- Prior VTE with pregnancy or oral contraceptive
- Prior VTE with low-risk thrombophilia
- Family history of VTE with high-risk thrombophilia
- Current VTE or other conditions requiring therapeutic dose of anticoagulation	High	Therapeutic dose (UFH or LMWH)
- Multiple prior VTE episodes
- Prior VTE with high-risk thrombophilia
- Prior VTE with APS

A retrospective cohort study completed in the Netherlands by Roeters van Lennep et al. evaluated LMWH dosing based on risk stratification.⁷² The study extrapolated women into either intermediate-risk or high-risk groups. Women were stratified into the intermediate-dose group (n = 34) if they had a single episode of provoked VTE, low-risk thrombophilia and a first-degree family history of VTE, or VTE in first-degree family member without a thrombophilia. Women were stratified into the high-risk group (n = 57) if they had a high-risk thrombophilia, single episode of unprovoked VTE, single episode of VTE and thrombophilia, or greater than or equal to two episodes of VTE not on long-term anticoagulation. The intermediate-risk group received nadroparin 2850 IU subcutaneously once daily for 6 weeks postpartum. The high-risk group received nadroparin 2850 IU subcutaneously once daily during pregnancy and for 6 weeks postpartum. The primary outcome was pregnancy related symptomatic VTE, and the secondary outcome was postpartum hemorrhage defined as greater than 500 mL of blood loss. There was a total of seven VTEs in 126 pregnancies (5.6%, 95% CI [4.3-16.6]), all of which occurred in the high-risk group. Two of the seven VTE events occurred during the antepartum period, and five of the seven VTE events occurred during the postpartum period.⁷² Postpartum hemorrhage occurred in 30.3% of patients in the intermediate-risk group and 16.4% of patients in the high-risk group (P = 0.12) demonstrating no statistically significant difference. Based on these results, researchers concluded that higher doses of LMWH may be needed in women at high-risk of VTE. However, two of the five VTEs that occurred in the postpartum period were after the 6-week postpartum study period and should not have been included in the analysis. The recommendation to increase the enoxaparin dose would increase the risk of hemorrhage. Additionally, providers would need to recognize the patient is receiving enoxaparin and hold the medication 12-24 hours prior to delivery for women who desire neuraxial analgesia.

The results of the Roeters van Lennep et al. study prompted a similar investigation to be conducted in New Zealand by Cox et al.⁷³ This retrospective cohort study analyzed patients from 1999-2014 who were at risk of pregnancy associated VTE. Patients were stratified based on the origin of their clot history. Women with a history of provoked VTE (n = 49) received enoxaparin 40 mg subcutaneously once daily for 6 weeks postpartum. Women with a history of idiopathic or hormone provoked VTE (n = 74) received enoxaparin 40 mg subcutaneously once daily during pregnancy and for 6 weeks postpartum. The primary outcome was breakthrough VTE, and the secondary outcome was postpartum hemorrhage defined as blood loss greater than 500 mL. There were two (1.2%) VTE events and both occurred antepartum in the idiopathic VTE group. Postpartum hemorrhage occurred in 27 of 73 (37%) patients in the provoked VTE group and 32 of 88 (36.4%) in the unprovoked VTE group (P = 0.93).⁷³ Based on the low overall event rate, researchers concluded that the failure rate of enoxaparin 40 mg subcutaneously once daily is acceptably low, and higher doses are unnecessary.

The most recent study that examined enoxaparin prophylactic dosing was the Highlow study.⁷⁴ This investigator-initiated, multicenter, international, randomized, open-label, superiority study evaluated the efficacy and safety of intermediate-dose vs low-dose LMWH in pregnant women with a history of VTE. Patients from 70 hospitals in nine countries were included for a total of 1100 women. The study included pregnant women greater than or equal to 18 years old, gestational age less than or equal to 14 weeks, and with a history of confirmed VTE. Women were excluded if the previous VTE was related to a major risk factor (i.e., surgery), if they had an indication for therapeutic anticoagulation, or a contraindication to LMWH. Subjects were randomly assigned to fixed low-dose LMWH (n = 555) or weight-adjusted intermediate-dose LMWH (n = 555). Doses were stratified based on weight (Table 10) and continued through 6 weeks postpartum. The weight for the fixed low-dose group was based on the weight at randomization and was not changed for the duration of the study.⁷⁴ The weight for the intermediate dose group was monitored at every visit, and the dose was changed as needed.

Table 10.

Dosing Regimen for the Highlow Trial.⁷⁴ Patients Were Randomized Before 14 weeks Gestation and Continued Therapy Until 6 weeks Postpartum.

Trial Group	Weight (kg)	Enoxaparin Dose
Low-dose LMWH	<100 kg	40 mg
Low-dose LMWH	≥100 kg	60 mg
Intermediate-dose LMWH	<50 kg	60 mg
	50 to <70 kg	80 mg
	70 to <100 kg	100 mg
	≥100 kg	120 mg

The efficacy outcome was recurrent VTE, and the safety outcomes included bleeding, blood transfusion, and mortality.⁷⁴ Recurrent VTE occurred in 16 of 555 (3%) subjects in the low-dose group and 11 of 555 (2%) subjects in the intermediate-dose group (RR 0.69 [95% CI 0.32-1.47]). For secondary outcomes, bleeding occurred in 23 of 520 (4%) subjects in the safety population (RR 1.16 [95% CI 0.65-2.09]). Intermediate-dose LMWH was not associated with decreased rates of VTE recurrence; therefore, the authors concluded that fixed low-dose LMWH is appropriate to prevent recurrent VTE during pregnancy and the postpartum period. Some limitations of the study included patient-reported adherence and deviations from the dosing protocol. Deviations from the dosing protocol likely occurred due to the open-label design and variation of individual provider’s practice.

Guidelines

Three societies, ACOG, ACCP, and ASH, have developed national guidelines for managing obstetric patients at risk for VTE.^24,26,27 The most recent of these guidelines was published in 2018 and does not reflect the most current literature available. As a result of the low quality and limited volume of available evidence, variation exists among national guidelines. Dosing recommendations for UFH and LMWH are shown in Tables 7 and 8. ACOG utilizes increasing doses of heparin throughout the pregnancy due to physiologic changes in blood volume and clearance while ACCP recommends the same dose throughout.^24,26 The predictable profile of enoxaparin has created a consensus for dosing recommendations.

Dosage selection depends on the indication, interpretation of the associated risk of VTE, and the accompanying literature. Table 3 contains common indications for thromboprophylaxis and recommendations from national guidelines. In patients with a history of a single unprovoked VTE, there is a wide range of recommended doses. In the antepartum period, ACCP is the only guideline that provides the option of surveillance while ACOG and ASH recommend some degree of prophylaxis.^24,26,27 All three recommend prophylaxis in the postpartum period. In patients with a history of a provoked VTE unrelated to pregnancy, there seems to be consensus among guidelines against prophylaxis in the antepartum period. However, in the 6 weeks postpartum, ACOG recommends surveillance while ACCP and ASH recommend prophylaxis. When considering thrombophilias, ACOG, ACCP, and ASH make varying recommendations with the available literature for the antepartum and postpartum period.

Conclusion

Pregnancy induces a hypercoagulable state that can lead to thrombosis in the presence of additional risk factors. When pharmacologic prophylaxis is indicated, LMWH is the preferred agent. However, there is a lack of high-quality data to guide initiation of thromboembolism prophylaxis which has led to variation among recommendations from national guidelines. Individual patient risk factors should undergo thoughtful consideration to weigh bleeding risk, cost, administration burden, and birth implications of anticoagulation in pregnancy. Additional prospective trials are needed to further elucidate optimal risk-assessment, dosing strategies, and duration of VTE prophylactic therapy in the obstetric population.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Emma L Klaserner

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