Sections

Overview

Practice Essentials

Pregnancy is a state that conveys 4-5 times the risk of venous thromboembolism (VTE).^{[1, 2, 3]}The prevalence of VTE in pregnancy is 0.8-2.0 per 1000 pregnancies and accounts for 1.1 deaths per 100,000 pregnancies.^{[4, 5, 6, 7, 8, 9, 10]}Approximately 80% of embolic events in pregnancy are venous.^[10]

According to a surveillance study by Creanga et al, 313 women died of thrombotic pulmonary embolism between 2006 and 2010.^[11] These deaths accounted for 9.3% of all pregnancy-related mortality during that period. This is an improvement from the 19.6% mortality from embolism as reported in an earlier study by Chang et al.^[12]

The most important risk factor for pregnancy-related VTE is a patient's prior personal history of VTE.^[13]The second most common risk factor is thrombophilia,^{[14, 15, 16]}which is present in 8-15% of Whites. Although most patients with thrombophilias never develop VTE, at least 20%, and possibly over 50%, of pregnant patients diagnosed with VTE have a thrombophilia.^{[15, 17, 18]}

Since thrombophilias are a common and important risk factor for VTE in pregnancy, the obstetrician must be familiar with appropriate screening for thrombophilia disorders and the management of thrombophilias. The purpose of this review is to assist the clinician in decisions to screen for thrombophilias and to provide thromboprophylaxis.

Evidence is conflicting as to whether thrombophilias convey additional risk of other adverse pregnancy outcomes such as recurrent pregnancy loss (RPL), stillbirths, abruption, or preeclampsia. A brief overview of evidence relating thrombophilias to adverse pregnancy outcomes is provided.

Thrombophilias and complications in pregnancy

The association between inherited thrombophilias and adverse obstetric outcomes such as RPL, preeclampsia, abruption, intrauterine fetal growth restriction (IUGR), and intrauterine fetal demise (IUFD) is controversial. Multiple studies have evaluated the relationship between thrombophilias and pregnancy complications, with conflicting results.^[19]It is unlikely that thrombophilia represents a major risk factor for these adverse pregnancy outcomes, and there are no confirmatory data to define effective treatment in preventing these adverse outcomes.^[20]

Available evidence that suggests an association between inherited thrombophilias and adverse pregnancy outcomes rest on small case-control studies. A review of 79 studies and meta-analyses by Robertson et al in 2005 concluded that heterozygous factor V Leiden and prothrombin mutations may be associated with an approximately twofold risk of miscarriage, IUFD, preeclampsia, and a 4- to 8-fold risk of abruption.^[19]However, most prospective studies have failed to find any correlation between inherited thrombophilias and adverse pregnancy outcomes.^[21]

No randomized placebo-controlled clinical trials have confirmed any benefit in the treatment of thrombophilias (other than antiphospholipid antibody syndrome) in terms of decreasing adverse pregnancy outcomes.^[20] For example, a randomized controlled trial by Quenby et al (ALIFE2) showed that the use of low-dose low molecular weight heparin (LMWH) had no effect on live birth rates among women who had confirmed inherited thrombophilia and two or more pregnancy losses.^[22]

In contrast, an association between antiphospholipid antibody syndrome and adverse pregnancy outcomes has been well-established.^{[16, 19, 23]}Furthermore, evidence supports the use of low-dose aspirin and heparin to decrease the risk of early pregnancy loss in women with lupus anticoagulant and antiphospholipid antibodies.^[24]

Table 1. Pregnancy Complications Associated with Thrombophilia^{[23, 19]} (Open Table in a new window)

Thrombophilia	First-Trimester Loss	Late Fetal Loss	Preeclampsia	Abruption	Fetal Growth Restriction
Factor V Leiden, homozygous	2.71 (1.32-5.58)*	1.98 (0.4-9.69)	1.87 (0.44-7.88)	8.43 (0.41-171.20)	4.64 (0.19-115.68)
Factor V Leiden, heterozygous	1.68 (1.09-2.58)*	2.06 (1.1-3.86)*	2.19 (1.46-3.27)*	4.70 (1.13-19.59)*	2.68 (0.59-12.13)
Prothrombin, heterozygous	2.49 (1.24-5.00)*	2.66 (1.28-5.53)*	2.54 (1.52-4.23)*	7.71 (3.01-19.76)*	2.92 (0.62-13.70)
MTHFR C677T, homozygous	1.40 (0.77-2.55)	1.31 (0.89-1.91)	1.37 (1.07-1.76)*	1.47 (0.40-5.35)	1.24 (0.84-1.82)
Antithrombin deficiency	0.88 (0.17-4.48)	7.63 (0.3-196.36)	3.89 (0.16-97.19)	1.08 (0.06-18.12)	N/A
Protein C deficiency	2.29 (0.20-26.43)	3.05 (0.24-38.51)	5.15 (0.26-102.22)	5.93 (0.23-151.58)	N/A
Protein S deficiency	3.55 (0.35-35.72)	20.09 (3.7-109.15)*	2.83 (0.76-10.57)	2.11 (0.47-9.34)	N/A
Anticardiolipin antibodies	3.40 (1.33-8.68)*	3.30 (1.62-6.70)*	2.73 (1.65-4.51)*	1.42 (0.42-4.77)	6.91 (2.70-17.68)*
Lupus anticoagulant	2.97 (1.03-8.56)*	2.38 (0.81-6.70)	1.45 (0.76-2.75)	N/A	N/A
Acquired APCR	4.04 (1.67-9.76)*	0.90 (0.21-3.86)	1.80 (0.70-4.61)	1.25 (0.36-4.37)	N/A
Hyperhomocystinemia	6.25 (1.37-28.42)	0.98 (0.17-5.55)	3.49 (1.21-10.11)*	2.40 (0.36-15.89)	N/A
*Statistically significant Abbreviation: MTHFR, methylene tetrahydrofolate reductase deficiency

Pathophysiology

Pregnancy is a state characterized by the Virchow triad, which includes hypercoagulability, venous stasis, and endothelial injury, in turn promoting thrombosis. It is a state of hypercoagulability due to alterations of coagulation proteins. Factors I, II, VII, VIII, IX, and X increase in pregnancy. Resistance to the anticoagulant protein C is increased, and the protein S level, a cofactor to protein C, decreases.^[25]. PAI-1 (plasminogen activator Inhibitor type 1) levels increase five-fold, which reduces fibrinolytic activity.^[26]Thrombophilic disorders can exacerbate the effects of these changes in coagulation proteins, can increase the procoagulant effect (eg, increased factor II associated with prothrombin mutation G20210A), or can decrease the effect of anticoagulants (eg, deficiency of protein C or factor V Leiden mutation), thus increasing the patient’s risk for VTE.

In pregnancy, venous stasis also increases as the lower-extremity veins dilate, followed by venous compression by the gravid uterus and enlarging iliac arteries. Situations of decreased mobility (eg, surgery, cesarean delivery, bedrest, prolonged travel, or air travel) may exacerbate stasis. Endothelial injury may occur antepartum or at the time of delivery.^[18]The combination of these factors culminate to increase risk of VTE in the pregnant and postpartum patient.

Etiology

The most important risk factor for a women experiencing pregnancy-related VTE is prior personal history of VTE.^{[13, 3]}The second most common risk factor is thrombophilia,^{[14, 15, 16]}which is present in 8-15% of Whites. Although most patients with thrombophilias never develop VTE, at least 20%, and possibly over 50%, of pregnant patients diagnosed with VTE have a thrombophilia.^{[15, 17, 18]}

Inherited thrombophilias are a group of genetic predispositions to VTE. Different thrombophilias are associated with different risks for VTE. They can be classified as low or high risk based on the relative increased risk of VTE associated with the specific thrombophilia. Antiphospholipid antibody syndrome is considered an acquired thrombophilia and is diagnosed based on clinical history and laboratory testing.

Low-risk inherited thrombophilias include the following:

Heterozygous factor V Leiden
Heterozygous prothrombin G20210A mutation
Protein S deficiency
Protein C deficiency

These thrombophilias are classified as low risk based on retrospective studies suggesting that they convey less than 1% risk of VTE in a pregnant patient without a personal history of VTE. Prior personal history of VTE, however, greatly augments the risk of VTE. In the presence of a thrombophilia, a patient with a personal history of VTE has much greater risk of developing VTE than in the absence of such a history.

High-risk inherited thrombophilias include the following:

Homozygous factor V Leiden
Homozygous prothrombin G20210A mutation
Compound heterozygous factor V Leiden with prothrombin mutation
Antithrombin deficiency

Based on available evidence from retrospective studies, these thrombophilias convey a greater than 1% risk of VTE in pregnant patients, even those without a personal history of VTE. As with low-risk thrombophilias, a personal history of VTE is the most important risk factor and further increases the VTE risk.

Low-risk thrombophilias

Heterozygous factor V Leiden

Factor V, a procoagulant, is normally inactivated by protein C, but factor V Leiden mutations convey resistance of factor V to degradation by activated protein C. This mutation is present in approximately 5% of European populations and 3% of African Americans.^[27]It is very rare in Asian and African persons.

The overall risk of VTE in women with factor V Leiden mutation and no personal or family history of VTE is low (approximately 0.3%). However, in patients with a personal or family history of VTE, the risk of VTE during pregnancy is approximately 10%. These studies defined family history as a first-degree relative with VTE before age 50 years.^{[27, 28, 29, 30, 31]}Homozygous carriers of factor V Leiden mutation with no personal history of VTE have a risk of VTE in pregnancy of approximately 1.5%, but those with a personal history of VTE or an affected first-degree relative have a much higher risk (approximately 17%).^{[28, 3]}

Factor V Leiden mutation is common and is implicated in a large number of pregnancy-related VTE cases. However, retrospective studies indicate that up to 40% of women with VTE in pregnancy are heterozygous carriers of a factor V Leiden mutation.^{[27, 28, 29, 30, 31]}

Heterozygous prothrombin G20210A mutations

Prothrombin mutation G20210A results in elevated levels of prothrombin (factor II), increasing the risk of VTE. Two to three percent of people of European descent are heterozygous carriers of this mutation, and it is very uncommon among populations of non-European descent.^[32]

Case-control studies show that prothrombin mutation increases the VTE risk 3-15 times the background risk in pregnancy.^{[30, 33]}Prothrombin mutation is found in 17% of pregnancy-associated VTE cases.

Heterozygous prothrombin mutation carriers with no personal or family history have a low risk (< 0.5%) of VTE in pregnancy.^[30]In contrast, women with a personal or family history of VTE have greater than 10% risk in pregnancy.^[30]Women with factor V Leiden and prothrombin mutation are also at greater risk of VTE, approximately 4%-5%.

Protein S deficiency

Protein S is a vitamin K–dependent anticoagulant protein that is activated by protein C to ultimately decrease the conversion of prothrombin to thrombin. More than 130 mutations that decrease either transcription of or activity of protein S have been reported. The carrier rate in the general population is reported to be 0.03%-0.13%.^{[27, 34, 35]}In patients with no prior history of VTE, the risk of pregnancy-associated VTE is 0.1%; however, 6%-7% of women with a history of VTE and protein S deficiency have a VTE during pregnancy.^[36]Homozygous protein S deficiency results in neonatal purpura fulminans and is typically diagnosed shortly after birth.

Protein S deficiency is diagnosed using assays to detect levels of free, total, and activity of protein S. All 3 of these values are inversely related to gestational age, complicating diagnosis in pregnancy. A diagnosis of protein S deficiency is more reliable when evaluated in a nonpregnant woman. Activity of free levels of less than 55% correlate with the diagnosis in nonpregnant individuals. Suggested cutoff values for diagnosis in pregnancy are less than 30% in the second trimester and less than 24% in the third trimester.^[37]

Protein C deficiency

Protein C is a vitamin K–dependent anticoagulant protein that degrades factor V and factor VIII. Over 160 mutations that cause protein C deficiency have been reported. It is inherited in autosomal-dominant fashion, although the risk of VTE for different mutations may vary widely.^[27]Homozygous protein C deficiency, like homozygous protein S deficiency, causes neonatal purpura fulminans and is typically diagnosed shortly after birth.

Protein C mutations are found in 0.2%-0.3 % of the population and convey a 6- to 12-fold increased risk for a first episode of VTE in pregnancy.^{[27, 38]}In patients with no history of VTE, the overall risk of pregnancy-related VTE is low (0.1%-0.8%). Patients with a personal or family history of VTE have a 2%-7% risk of VTE during pregnancy.^{[27, 38, 39, 40]}

High-risk thrombophilias

Homozygous factor V Leiden

Homozygous factor V Leiden mutation is rare (0.06% of the general population). The VTE risks among pregnant women who are homozygous carriers of factor V Leiden in pregnancy are 1.5% in women without a history of VTE and approximately 17% in women with a history of prior VTE.^{[27, 28, 29, 30, 31]}

Homozygous prothrombin G20210A mutations

As with homozygous factor V Leiden mutation, homozygous prothrombin mutation is rare (< 1% of the general population). Pregnant women without a history of VTE have an approximate 2.8% risk of pregnancy-related VTE, and women with a history of VTE have at least a 17% risk of VTE in pregnancy.^{[27, 29, 30, 31]}

Compound factor V Leiden mutation/heterozygous prothrombin

This combination of thrombophilic gene mutations is found in 0.01% of the population. It is more thrombogenic than either homozygous factor V Leiden or homozygous prothrombin mutations. Among pregnant women, 4.7% of those with no history of VTE develop VTE in pregnancy. The risk of VTE in pregnancy is at least 20% in women with a history of VTE.^{[29, 30, 41]}

Antithrombin deficiency

Antithrombin is an anticoagulating protein that inactivates thrombin and factors IX, X, XI, and XII.^[42]Over 250 mutations that can reduce its level or activity have been described.^{[27, 38]}

Antithrombin deficiency is a rare thrombophilia (1 per 2500 of the general population). Deficiency of antithrombin is a highly thrombogenic thrombophilia and conveys a risk of 3%-7% for development of VTE in pregnant women with no prior history of VTE and a 40% risk of VTE in pregnant women with a prior history of VTE.^{[27, 36, 38]}Homozygous antithrombin deficiency is lethal before or shortly after birth.

Acquired thrombophilia: Antiphospholipid antibody syndrome

Antiphospholipid antibody syndrome is a disorder characterized by clinical and laboratory findings. The clinical criteria that should prompt an evaluation for APLAS includes any one of the following events^[43]:

One or more unexplained fetal losses of a morphologically normal fetus after 10 weeks
At least one preterm birth prior to 34 weeks indicated for preeclampsia/eclampsia and/or features of placental insufficiency
At least 3 consecutive unexplained miscarriages prior to 10 weeks and absent maternal anatomic or hormonal abnormalities and without paternal or maternal chromosomal abnormalities
A history of vascular (arterial or venous) thrombosis

Laboratory criteria includes any one of the following (these laboratory findings must be abnormal twice, at least 12 weeks apart, to meet diagnostic criteria)^[43]:

Anticardiolipin immunoglobulin G (IgG) or immunoglobulin M (IgM) antibodies greater than 99th percentile
Antibeta2-glycoprotein I IgG or IgM antibodies greater than 99th percentile
The presence of lupus anticoagulant

Most thrombus formation in antiphospholipid antibody syndrome is venous (65-70%); however, it is important to consider this diagnosis in women with arterial thrombi or VTE in unusual sites (eg, retinal, subclavian, digital and brachial arteries).^[44]Four to six percent of strokes in otherwise healthy patients younger than 50 years are attributable to antiphospholipid antibody syndrome.^{[45, 46]}Lupus anticoagulant and antiphospholipid antibodies are frequently found in patients with systemic lupus erythematosus.

In a nonpregnant patient with antiphospholipid antibodies with no history of VTE, the risk of developing thromboembolism is less than 1% per year.^[47]Prospective studies demonstrate a 5-12% risk of pregnancy-related thromboembolism in patients with antiphospholipid antibody syndrome.^{[48, 49]}

The pathophysiology of thrombophilia in antiphospholipid antibody syndrome is unclear. Hypotheses include that the phospholipid antibodies may bind and interfere with normal coagulation proteins.^[50]For further information, please refer to Antiphospholipid Syndrome and Pregnancy.

Thrombophilias of uncertain significance

Methylene tetrahydrofolate reductase mutations

MTHFR mutations are a common cause for elevated levels of homocysteine, which was previously identified as a risk factor for VTE; however, recent data suggest that it is a weak risk factor.^[51]Homozygosity for the C677T polymorphism is present in 8%-16% of European populations, while homozygosity for the A1298C polymorphism is present in 4%-6% of European populations.^{[52, 53]}These mutations have not been shown to increase VTE risk.^[54]

A large meta-analysis failed to show any association between MTHFR mutations and hyperhomocysteinemia and VTE in pregnancy.^[19]Currently, ACOG recommends against screening for MTHFR mutations or measuring fasting homocysteine for evaluation of thrombophilia in pregnancy.^[20]

Other potential thrombophilias

Other candidate thrombophilias include Apo-E protein polymorphisms,^[55]protein Z deficiency,^{[37, 56]}and alterations in the PAI-1 gene. There are inadequate data regarding the association of these potential thrombophilias and the risk of VTE in pregnancy. At this time, ACOG recommends against evaluation for these potential thrombophilias.^[20]

Epidemiology

Pregnancy is a state that conveys 4-5 times the risk of venous thromboembolism (VTE).^{[1, 2]}The prevalence of VTE in pregnancy is 0.8-2.0 per 1000 pregnancies and accounts for 1.1 deaths per 100,000 pregnancies.^{[4, 5, 6, 7, 8, 9, 10]}Approximately 80% of embolic events in pregnancy are venous.^[10]

As stated above, 8-15% of Whites are carriers of a thrombophilia gene. Only a small portion of these individuals go on to be diagnosed with VTE in pregnancy; however, 20-50% of patients diagnosed with VTE have a thrombophilia.^{[15, 17, 18]}

Workup

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Table 1. Pregnancy Complications Associated with Thrombophilia ^{[23, 19]}

Thrombophilia	First-Trimester Loss	Late Fetal Loss	Preeclampsia	Abruption	Fetal Growth Restriction
Factor V Leiden, homozygous	2.71 (1.32-5.58)*	1.98 (0.4-9.69)	1.87 (0.44-7.88)	8.43 (0.41-171.20)	4.64 (0.19-115.68)
Factor V Leiden, heterozygous	1.68 (1.09-2.58)*	2.06 (1.1-3.86)*	2.19 (1.46-3.27)*	4.70 (1.13-19.59)*	2.68 (0.59-12.13)
Prothrombin, heterozygous	2.49 (1.24-5.00)*	2.66 (1.28-5.53)*	2.54 (1.52-4.23)*	7.71 (3.01-19.76)*	2.92 (0.62-13.70)
MTHFR C677T, homozygous	1.40 (0.77-2.55)	1.31 (0.89-1.91)	1.37 (1.07-1.76)*	1.47 (0.40-5.35)	1.24 (0.84-1.82)
Antithrombin deficiency	0.88 (0.17-4.48)	7.63 (0.3-196.36)	3.89 (0.16-97.19)	1.08 (0.06-18.12)	N/A
Protein C deficiency	2.29 (0.20-26.43)	3.05 (0.24-38.51)	5.15 (0.26-102.22)	5.93 (0.23-151.58)	N/A
Protein S deficiency	3.55 (0.35-35.72)	20.09 (3.7-109.15)*	2.83 (0.76-10.57)	2.11 (0.47-9.34)	N/A
Anticardiolipin antibodies	3.40 (1.33-8.68)*	3.30 (1.62-6.70)*	2.73 (1.65-4.51)*	1.42 (0.42-4.77)	6.91 (2.70-17.68)*
Lupus anticoagulant	2.97 (1.03-8.56)*	2.38 (0.81-6.70)	1.45 (0.76-2.75)	N/A	N/A
Acquired APCR	4.04 (1.67-9.76)*	0.90 (0.21-3.86)	1.80 (0.70-4.61)	1.25 (0.36-4.37)	N/A
Hyperhomocystinemia	6.25 (1.37-28.42)	0.98 (0.17-5.55)	3.49 (1.21-10.11)*	2.40 (0.36-15.89)	N/A
*Statistically significant Abbreviation: MTHFR, methylene tetrahydrofolate reductase deficiency

Table 2. Management of Pregnancy in a Patient With a History of VTE

Clinical Scenario	Antepartum Management	Postpartum Management
Low-risk thrombophilia without prior VTE	Surveillance without anticoagulation or prophylactic LMWH or UFH	Surveillance without anticoagulation OR postpartum anticoagulation in the presence of additional risk factors (eg, obesity, prolonged immobility, first-degree relative with VTE before age 50 years)
Low-risk thrombophilia with a single episode of VTE in a patient not receiving long-term anticoagulation therapy	Prophylactic or intermediate LMWH/UFH or surveillance without anticoagulation therapy	Anticoagulation therapy or intermediate-dose LMWH/UFH
High-risk thrombophilia (antithrombin deficiency, homozygous factor V Leiden, homozygous prothrombin mutation G20210A, double heterozygous factor V Leiden and prothrombin mutation G20210A) without prior VTE	Prophylactic LMWH or UFH	Anticoagulation therapy
High-risk thrombophilia with previous single episode of VTE in a patient not receiving long-term anticoagulation therapy	Prophylactic-, intermediate-dose, or adjusted-dose LMWH or UFH	Anticoagulation therapy or intermediate- or adjusted-dose LMWH/UFH for 6 weeks
No thrombophilia with single prior episode of VTE with a transient risk factor no longer present and VTE not associated with pregnancy- or estrogen-related risk factor	Surveillance without anticoagulation	Anticoagulation therapy
No thrombophilia with single prior episode of VTE associated with transient risk factor associated with pregnancy or estrogen related	Prophylactic-dose LMWH/UFH	Anticoagulation therapy
No thrombophilia with single prior episode VTE without associated risk factor in a patient not receiving long-term anticoagulation therapy	Prophylactic-dose LMWH/UFH	Anticoagulation therapy
Thrombophilia or no thrombophilia with 2 or more VTE episodes in a patient not receiving long-term anticoagulation therapy	Prophylactic or therapeutic dose of either LMWH or UFH	Anticoagulation therapy or therapeutic dose LMWH/UFH for 6 weeks
Thrombophilia or no thrombophilia with 2 or more VTE episodes in a patient receiving long-term anticoagulation therapy	Therapeutic dose of either LMWH or UFH	Resumption of long-term anticoagulation therapy
Abbreviations: LMWH, low molecular weight heparin; UFH, unfractionated heparin