Obstetrics and Gynecology
- Inherited thrombophilia. Prothrombotic disorder. Predisposition to blood clots.
- 1. What every clinician should know
- 2. Diagnosis and differential diagnosis
- 3. Management
- 4. Complications
5. Prognosis and outcome
6. What is the evidence for specific management and treatment recommendations?
Inherited thrombophilia. Prothrombotic disorder. Predisposition to blood clots.
1. What every clinician should know
Thrombophilias are a heterogeneous group of conditions that dispose individuals to thromboembolic events (VTE). Most of these are venous thromboses.
Normal hemostasis involves a delicate balance of procoagulant proteins that promote clot formation in case of bleeding or damaged endothelium and anticoagulant proteins that prevent too much clot from forming, thus impeding blood flow (VTE). Most thrombophilias involve deficiencies or abnormalities in anticoagulant proteins. In some cases, they involve an increase in procoagulant proteins.
Thromboembolism is the number one or number two (most common) cause of maternal death in developed countries. The association between thrombophilias and thromboembolism is very strong. Thrombophilias are associated with an increased risk of adverse obstetric outcomes such as stillbirth, fetal growth impairment and preeclampsia. The association between thrombophilias and obstetric complications is weak and controversial. Most women with thrombophilias have NORMAL pregnancy outcomes.
The most common and important thrombophilias include the factor V Leiden mutation, the prothrombin gene G20210A mutation, antithrombin III (AT III) deficiency, protein C deficiency and protein S deficiency.
Individuals with ancestry from northern Europe and some parts of the Middle East have a higher frequency of heritable thrombophilias.
Individuals with VTE, especially during pregnancy, are at increased risk.
Individuals with a strong family history of VTE (first-degree relatives) are at increased risk.
Individuals with pregnancy complications such as stillbirth are at slightly increased risk for some thrombophilias.
Thrombophilias and adverse pregnancy outcomes
Thrombophilias are a risk factor for fetal death (losses after 10 weeks' gestation) and stillbirth (losses after 20 weeks' gestation). They have NOT been associated with early pregnancy loss or recurrent early pregnancy loss. The factor V Leiden and prothrombin gene mutations are associated with about a three-fold increase in the risk for late fetal losses. This level of risk is similar to demographic factors such as obesity and advanced maternal age. It is noteworthy that thrombophilias have NOT been associated with pregnancy loss in several prospective cohort studies.
Thrombophilias have been associated with an increased risk for preeclampsia in some but not most retrospective studies. In addition, thrombophilias have NOT been associated with preeclampsia in prospective cohort studies.
Thrombophilias have been associated with small-for-gestational-age fetuses in a few retrospective studies. However, there is NO association between small-for-gestational-age fetus and thrombophilias in most retrospective and all prospective studies.
Thrombophilias have been associated with abruption in a handful of small retrospective studies. There is NO association between abruption and thrombophilias in prospective studies.
Thrombophilias and VTE
Thrombophilias increase the risk of VTE associated with pregnancy by about eight-fold. The risk is higher for individuals with more than one thrombophilia. An example is someone who is heterozygous for the factor V Leiden and prothrombin gene mutations. These individuals are referred to as being "compound" heterozygotes.
Most of the thrombophilias are autosomal dominant with variable penetrance. Many individuals are asymptomatic and never suffer a VTE. The risk for thrombosis varies among thrombophilias. ATIII deficiency is the most thrombogenic, followed by protein C deficiency and protein S deficiency. The factor V Leiden and prothrombin G20210A mutations are less thrombogenic still and hyperhomocysteinemia is the least thrombogenic. Although other thrombophilias have been described, their association with VTE is unclear and testing is not currently recommended.
The prevalence of thrombophilias is much higher in women with VTE associated with pregnancy compared to the general population. In women with pregnancy-associated VTE, 20%-40% will have the factor V Leiden, 6%-15% the prothrombin G20210A mutation, 1%-2% protein C and protein S deficiencies, and less than 1% ATIII deficiency. The incidence of the C677T MTHFR mutation is 10%, which is similar to the general population.
Pregnancy and clotting factors
Pregnancy is associated with the following conditions:
Increases in clotting factors (factors II, VII, VIII, X, and XII)
A decrease in the anticoagulant protein S
An increase in plasminogen-activating factor-I (procoagulant)
An increased resistance to activated protein C (resistance to anticoagulant protein)
Prevalence and genetics of specific thrombophilias
As implied by the term, inherited thrombophilias are genetic conditions. The prevalence varies by race/ethnicity and is known for some populations. Pregnancy enhances clotting.
The factor V Leiden mutation causes an abnormality in the factor V protein. Normally, activated factor V is inactivated by the protein C: protein S complex. The abnormal factor V Leiden protein is harder to inactivate and thus clot continues to form.
The condition is autosomal dominant. Heterozygous individuals are affected. Rare individuals are homozygous.
The factor V Leiden mutation is present in about 5% of European Caucasians, 8%-9% of Scandinavians, 1%-3% of African Americans. It is rare in black Africans and in Asians.
The prothrombin G20210A gene mutation is a mutation in the prothrombin (factor II) promoter that leads to an increase in prothrombin of 150%-200%. The condition is autosomal dominant. Heterozygous individuals are affected. Rare individuals are homozygous. The prothrombin gene is present in about 2%-3 % of European Caucasians.
Protein C deficiency involves a decrease in the amount and/or activity of protein C. Protein C deficiency is autosomal dominant and has been associated with over 160 mutations. Heterozygous individuals are affected. Protein C deficiency is present in 0.2%-0.5% of European Caucasians.
Protein S deficiency involves a decrease in the amount, activity or cofactor activity of protein S. Protein S deficiency is autosomal dominant. Heterozygous individuals are affected. Protein S deficiency is present in 0.8% of Caucasians.
Antithrombin III deficiency involves a decrease in the amount or activity of ATIII. ATIII deficiency is autosomal dominant. Heterozygous individuals are affected. ATIII deficiency is rare and occurs in about 0.07% of Caucasians.
Hyperhomocysteinemia is associated with myocardial infarction. The association with VTE is weak.
There are several mutations associated with hyperhomocysteinemia. Homocysteine levels are affected by many factors and many individuals with these mutations have normal levels of homocysteine. The most common is the C677T methylenetetrahydrofolate reductase (MTHFR) mutation. Only homozygotes are affected. 10 - 11% of European Caucasians are homozygous for the C677T MTHFR mutation. The second most common is the A1298C MTHFR mutation. Only homozygotes are affected. 4 - 6% of European Caucasians are homozygous for the A1298C MTHFR mutation.
Rare individuals have the cystathionine-beta-synthase mutation (1 in 200,000). Heterozygotes with this mutation are affected.
2. Diagnosis and differential diagnosis
Diagnosis of most thrombophilias is relatively straightforward and is accomplished with blood tests. Differential diagnosis is not a major issue when evaluating a patient for heritable thrombophilias. Tests for thrombophilias can be affected by anticoagulant therapy and pregnancy.
Who should be tested for thrombophilias?
The patient population that should be tested for thrombophilias is controversial.
Patients with VTE should be tested for thrombophilias
Some authorities advise testing patients with a first-degree relative with high-risk thrombophilia (eg, ATIII deficiency).
Some authorities advise testing patients with a first-degree relative with VTE prior to 50 years of age who did not have a clear inciting event (such as hip surgery).
Most authorities do NOT recommend testing for heritable thrombophilias in patients with adverse obstetric outcomes such as stillbirth, preeclampsia, SGA fetus or abruption.
Specific tests for thrombophilias
Factor V Leiden is a genetic test that can be assessed with a blood sample. It is reliable even if the patient is taking anticoagulant therapy or if she is pregnant. The test will be reported as negative, heterozygous (affected), or homozygous (affected). This can also be assessed by a functional assay that evaluates factor V resistance to activated protein C. The latter assay is not valid in women taking anticoagulant therapy. Although this assay will identify a slightly different group of women than the factor V Leiden assay, in most cases it is easiest to simply order the factor V Leiden assay.
The prothrombin gene G20210A mutation is a genetic test that can be assessed with a blood sample. It is reliable even if the patient is taking anticoagulant therapy or if she is pregnant. The test will be reported as negative, heterozygous (affected), or homozygous (affected).
The test for ATII deficiency is a clotting test. It is not reliable if the patient is taking anticoagulant therapy. In such cases, testing should be delayed until the patient is no longer taking anticoagulant therapy. The test is reliable in pregnancy.
The test for protein C deficiency is a clotting test. It is not reliable if the patient is taking anticoagulant therapy. In such cases, testing should be delayed until the patient is no longer taking anticoagulant therapy. The test is not reliable in pregnancy or if the patient is taking estrogen-containing oral contraceptives. In such cases, testing should be delayed until 6 weeks postpartum.
The test for protein S deficiency is a clotting test. It is not reliable if the patient is taking anticoagulant therapy. In such cases, testing should be delayed until the patient is no longer taking anticoagulant therapy. The test is not reliable in pregnancy or if the patient is taking estrogen-containing oral contraceptives. In fact, it is particularly unreliable in pregnancy. In such cases, testing should be ideally delayed until 6 weeks postpartum. Although it is somewhat controversial, there is some evidence that levels of FREE protein S antigen at less than0% in the second trimester and less than 24% in the third trimester indicate protein S deficiency during pregnancy. Thus, if testing must be done during pregnancy, these values can be used as a threshold for the condition.
Testing for hyperhomocysteinemia can be complicated. It is accomplished with a blood test. It is best to obtain homocysteine levels when the patient is fasting for 12 hours. A level of greater than 10 mg/dL is considered elevated. The tests for mutations associated with hyperhomocysteinemia are genetic tests and can be obtained anytime with a blood test. Most authorities do NOT recommend testing for hyperhomocysteinemia or mutations associated with hyperhomocysteinemia in cases of VTE.
If it is difficult to interpret the laboratory values for thrombophilias, especially the functional assays. Itmay be useful to arrange consultation with a hematologist.
The key issue regarding antepartum management of thrombophilias is the prevention of VTE. It is controversial as to which patients should receive antepartum thromboprophylaxis or anticoagulant therapy, for which there are several options. Treatment of patients with anticoagulant therapy intended to improve obstetric outcome is considered experimental. Additional antenatal fetal surveillance should be performed for the usual obstetric indications.
The goal of intrapartum management is to avoid both VTE and bleeding. Often there is a desire to have safe neuraxial analgesia. There is always the potential need for surgery. There are several options for intrapartum anticoagulant therapy.
There are several options for postpartum anticoagulant therapy
Timing and route of delivery
Iatrogenic preterm birth is not indicated due to a diagnosis of thrombophilia (or VTE). It is reasonable to offer an induction of labor or to schedule a cesarean after 39 weeks gestation in order to optimally manage anticoagulant therapy. Cesarean delivery in women with thrombophilia should be reserved for the usual obstetric indications.
Antenatal fetal testing
There is no proven efficacy to additional antenatal fetal testing such as NSTs for the sole indication of thrombophilia or thrombophilia with VTE. In patients with prior adverse obstetric outcomes (with or without thrombophilias), testing should be accomplished based on obstetric history (eg, prior stillbirth).
Antepartum anticoagulant therapy for obstetric indications
There are no evidence-based recommendations for the use of antepartum anticoagulant therapy in an attempt to improve obstetric outcome in patients with prior adverse obstetric outcomes such as pregnancy loss, preeclampsia, small for gestational age fetus, and abruption. Some thrombophilias are mild risk factors for these adverse obstetric events. Accordingly, it is possible that anticoagulant therapy could decrease the risk of adverse obstetric events in patients with thrombophilias. However, this has not been proven in appropriate clinical trials. Although several retrospective studies and one RCT suggested that LMWH was beneficial in patients with thrombophilias and adverse obstetric outcomes, others have shown no benefit. Thus, treatment should be considered experimental.
Postpartum anticoagulant therapy
Postpartum anticoagulant therapy is usually initiated 6-12 hours after a cesarean delivery or 6 hours after a catheter is removed from the epidural space. Thromboprophylactic or full anticoagulant dosing can now be the same as in non-pregnant individuals. In patients who do not require life-long anticoagulation, thromboprophylaxis should be continued for 6 weeks postpartum. This can be accomplished with unfractionated heparin, LMWH or warfarin. All are considered safe in women who are breast feeding.
In patients who require life-long anticoagulation or full anticoagulation for longer than six weeks postpartum, warfarin can be initiated after delivery, typically at an initial dose of 5 mg per day (unless a pre-pregnancy dose is known). The goal is an INR of 2.0 - 3.0. LMWH or unfractionated heparin should be initiated and continued until the INR is therapeutic for two days.
Intrapartum anticoagulant therapy
In patients at relatively low risk for thrombosis it is reasonable to stop anticoagulant therapy during labor and delivery. This would include patients with thrombophilias and remote thromboses. They should wear pneumatic compression devices during labor and delivery. It is reasonable to offer an induction of labor in appropriate candidates between 39-40 weeks' gestation so as to be able to control anticoagulant therapy.
Thromboprophylactic doses of LMWH and unfractionated heparin can be stopped 12 hours prior to the need for neuraxial analgesia or anesthesia. Alternatively, the patient should be advised to stop taking anticoagulant therapy upon spontaneous rupture of membranes or the onset of labor. Anesthesiologists will permit neuraxial analgesia in the setting of a normal PTT in patients taking unfractionated heparin. In those taking LMWH, anti-Xa results usually take too long to be useful in labor. Neuraxial analgesia/anesthesia is considered safe if it has been 12 hours since the last thromboprophylactic dose of LMWH or 24 hours since the last full anticoagulant dose of LMWH. In cases wherein urgent cesarean delivery is needed, anticoagulation can be reversed with protamine sulfate.
In patients at extremely high risk for VTE, such as women with pulmonary embolus a few days prior to delivery, it is reasonable to continue full dose anticoagulation during labor and delivery. This is accomplished with a continuous intravenous infusion of unfractionated heparin. This can be turned off in theevent of bleeding or the need for surgery. Neuraxial anesthesia is contraindicated. Protamine sulfate can be used to reverse anticoagulant effects. This circumstance is rare.
In patients at high risk for VTE, such as those with multiple prior VTE and a major thrombophilia, another approach is to continue a low dose of thromboprophylaxis with unfractionated heparin (5000 units subcutaneously [SC] twice daily) during labor. Although neuraxial analgesia is contraindicated, vaginal delivery can usually be safely accomplished with no increase in the risk for bleeding.
Patients with ATIII deficiency may benefit from treatment with ATIII concentrate during labor or prior to cesarean delivery. Dosing and monitoring of levels should be discussed with a hematologist or pharmacist.
Anticoagulation during pregnancy can be accomplished with either low molecular weight heparin (LMWH) or unfractionated heparin. In general, LMWH is preferable to unfractionated heparin owing to more consistent bioavailability, less risk of heparin-induced thrombocytopenia, less risk of osteopenia and less need to assess levels of anticoagulation in women taking full anticoagulant therapy. Unfractionated heparin is preferable to LMWH in women who may spontaneously labor (typically after 36 weeks' gestation) since it is less likely to interfere with safe neuraxial analgesia. Also, it may be less expensive than LMWH. LMWH is strongly preferred in women needing full anticoagulant therapy through 36 weeks gestation.
There is little meaningful difference in LMWH and unfractionated heparin in women receiving thromboprophylactic doses. In such cases, it is reasonable to use unfractionated heparin if cost/access to LMWH is an issue.
Thromboprophylaxis with unfractionated heparin in non-pregnant women is accomplished with 5000 units SC every 12 hours. Most authorities advise a slight increase in the dose during pregnancy. Due to an increase in pro-coagulant proteins, a meaningful percentage of women will not achieve appropriate levels of anticoagulation with the usual "non-pregnant" dose. A simple way to accomplish this is to use 7500 units SC twice daily (every 12 hours). Alternatively, one could use 5000-7500 units SC twice daily in the first trimester, 7500-10,000 units SC twice daily in the second trimester and 10,000 units SC twice daily in the third trimester.
Thromboprophylaxis with LMWH in non-pregnant women is accomplished with enoxaparin 40mg SC daily, dalteparin 5000 units SC daily, or tinzaparin 4500 units SC daily. Some authorities advise a slight increase in the dose during pregnancy. For example, enoxaparin 30mg SC twice daily.
Complete anticoagulation with unfractionated heparin is accomplished with twice daily (every 12 hours) or thrice daily (every 8 hours) dosing to achieve a PTT of 1.5 - 2.0 X control 6 hours after injection. Some data support more reliable tissue levels with thrice-daily dosing.
Complete anticoagulation with LMWH is accomplished with weight-based dosing. Examples include enoxaparin 1mg/kg twice daily, dalteparin 200 units/kg daily, dalteparin 100 units/kg twice daily and tinzaparin 175 units/kg daily. Some authorities advise assessment of anticoagulant levels because of the altered pharmacokinetics of pregnancy. The goal in patients taking enoxaparin is an anti-Xa level of 0.6 - 1.0 units/mL 6 hours after dosing.
Indications for antepartum anticoagulant therapy
Patients with acute VTE should undergo complete anticoagulation with LMWH or unfractionated heparin for 3 to 6 months after the acute event. This is true regardless of thrombophilia status. Most authorities tend to advise 6 months of complete anticoagulation after an acute event that occurs during pregnancy. If the 6 months is over before the end of the pregnancy, in most cases the anticoagulation should be reduced to a thromboprophylactic dose. The patient requires full anticoagulation for multiple thromboses or thrombophilia status as below.
Patients with two or more prior VTE should undergo complete anticoagulation throughout the antepartum period, regardless of thrombophilia status. Alternatively, it is acceptable to treat these women with thromboprophylaxis if they are not undergoing life-long anticoagulant therapy (but this is rare).
Patients with a single prior thrombosis and a "major" or high-risk thrombophilia should undergo complete anticoagulation throughout the antepartum period. Examples of a major thrombophilia include ATIII deficiency, homozygotes for the factor V Leiden mutation, homozygotes for the prothrombin G20210A mutation, and compound heterozygotes for the factor V Leiden and prothrombin G20210A mutations. The same is true for women with antiphospholipid syndrome, an acquired thrombophilia covered in a separate chapter.
Patients with a "minor" or low-risk thrombophilia such as heterozygotes for the factor V Leiden mutation and the prothrombin G20210A mutation, protein C deficiency and protein S deficiency and a single prior thrombosis should undergo thromboprophylaxis during the antepartum period.
It is controversial as to the best antepartum treatment for patients with thrombophilia and no personal history of VTE. Most authorities advise antepartum thromboprophylaxis for women with a major thrombophilia and no prior VTE. It is considered acceptable to either use no thromboprophylaxis or thromboprophylaxis in patients with minor thrombophilia and no prior VTE. Patients with a strong family history of VTE are at higher risk for VTE than women with no family history of VTE.
Bleeding is extremely rare in patients taking thromboprophylactic doses of heparins. It is a risk in patients taking full anticoagulant doses. Risks can be minimized by being sure that dosing is appropriate and that the patient avoids activities with the potential for traumatic injury. Protamine sulfate can be used to reverse the anticoagulant effects of heparins in emergency settings.
Most patients will have small amounts of bruising at the site of heparin injections. In some cases, the patient has a localized allergic skin reaction with inflammation and discomfort. In such cases, it is reasonable to change between unfractionated heparin and LMWH in hopes that it is better tolerated. Rarely, it is necessary to use one of the alternative anticoagulant therapies described in the section on HIT.
This is probably reversible once the unfractionated heparin or LMWH is stopped. This is worse with unfractionated heparin than with LMWH. There appears to be a dose response—the higher the dose of heparin, the worse the osteopenia.
It is NOT necessary to obtain routine DEXA scans in women taking heparins. Although of unproven efficacy, there may be benefit to having women on heparin take supplemental calcium and vitamin D and engage in axial skeleton weight-bearing exercise.
Heparin-induced thrombocytopenia (HIT)
HIT is a serious complication of therapy with unfractionated heparin or LMWH. It is rare (< 1%) during pregnancy but CAN occur. It can lead to life-threatening paradoxical thrombosis.
All patients taking any dose of unfractionated heparin should be screened for HIT, as should all patients taking full anticoagulant doses of LMWH. Screening should be accomplished with serial platelet counts every 1-3 days from day 4-14 of therapy. If the platelet count decreases, HIT can be confirmed with assessment of antibodies against heparin-platelet factor 4 complex and a 14C serotonin-release assay.
Both unfractionated and LMWH have cross-reactivity. Thus, if HIT develops on one agent, it is UNSAFE to switch to the other. Alternative anticoagulants in patients with HIT include fondaparinux, danaparoid, lepirudin, bivalirudin, and Argatroban.
The major complication of thrombophilias during pregnancy and the postpartum period is VTE.
The risk of VTE during pregnancy without thromboprophylaxis is estimated to be between 1:200 and 1:400 in women heterozygous for the factor V Leiden mutation and no personal or family history of thrombosis. The risk is estimated to be as high as 10% in factor V Leiden heterozygotes with a personal history of VTE. The risk is 1%-2% for homozygotes with no personal or family history of VTE. The risk is estimated as 17% in homozygotes with a personal history of VTE.
The risk of VTE during pregnancy without thromboprophylaxis is estimated to be less than 1:200 in women heterozygous for the prothrombin gene G20210A mutation and no personal or family history of VTE. The risk is greater than 10% if they have a personal history of VTE. The risk of homozygotes with no personal or family history of VTE is 2%-3%. The risk for homozygotes with prior VTE is increased.
The risk of VTE during pregnancy without thromboprophylaxis in compound heterozygotes (heterozygous for both the factor V Leiden and prothrombin gene G20210A mutations) in women with no personal or family history of VTE is 4%-5%.
The risk of VTE in women with protein C deficiency during pregnancy without thromboprophylaxis and a prior thrombosis or family history of thrombosis is 2%-7%. There is almost always a family history of thrombosis in families with protein C deficiency.
The risk of VTE during pregnancy without thromboprophylaxis and a prior thrombosis or family history of VTE in women with protein S deficiency is 6%-7%. There is almost always a family history of VTE in families with protein S deficiency.
The risk of VTE in women with ATIII deficiency during pregnancy without thromboprophylaxis and a prior thrombosis or family history of thrombosis is not known precisely but is estimated to be increased by 15-fold. There is almost always a family history of thrombosis in families with ATIII deficiency.
5. Prognosis and outcome
The patient should be advised that pregnancy outcomes are excellent in most women with thrombophilias. Indeed, prospective studies indicate outcomes similar to women without thrombophilias. Some thrombophilias may be a slight risk factor for some adverse pregnancy outcomes, similar to things like obesity, race and age. However, there is no evidence that obstetric or medical interventions improve outcomes.
Women with prior adverse pregnancy outcomes and thrombophilias have an increase in the recurrence risk for adverse pregnancy outcomes that is based on their past obstetric history rather than their thrombophilia status. Thus, women with prior stillbirth have an increased risk of subsequent stillbirth that is unrelated to their laboratory testing for thrombophilias or history of VTE. Individuals with thrombophilias are at life-long increased risk for VTE. They should avoid situations that increase the risk for VTE if possible. An example would be estrogen-containing oral contraceptives. (Screening all women for thrombophilias prior to initiating treatment with oral contraceptives is not recommended).
If such situations cannot be avoided (eg, hip surgery or desired pregnancy), they should receive thromboprophylaxis. Some women with thrombophilias require life-long anticoagulation. It is advised that all women with thrombophilias seek consultation with a hematologist to discuss their optimal non-pregnant anticoagulant management, especially given the large amount of ongoing research intended to clarify these issues.
6. What is the evidence for specific management and treatment recommendations?
"ACOG Practice Bulletin #124". Obstet Gynecol. vol. 118. 2011. pp. 730-40.(Excellent and up-to-date overview that is geared towards the practicing clinician)
Franco, RF, Reitsma, PH. "Genetic risk factors of venous thromboembolism". Hum Genet. vol. 109. 2001. pp. 369-84.(Good overview of thrombophilias)
Robertson, L, Wu, O, Langhorne, P, Twaddle, S, Clark, P, Lowe, GD. "Thrombophilia in pregnancy: a systematic review. Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study". Br J Haematol. vol. 132. 2006. pp. 171-96.(Summary of screening and treatment in pregnancy)
Dizon-Townson, D, Miller, C, Sibai, B, Spong, CY, Thom, E, Wendel, G. "The relationship of the factor V Leiden mutation and pregnancy outcomes for mother and fetus. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network". Obstet Gynecol. vol. 106. 2005. pp. 517-24.(Prospective study of factor V Leiden and pregnancy outcomes)
Silver, RM, Zhao, Y, Spong, CY, Sibai, B, Wendel, G, Wenstrom, K. "Prothrombin gene G20210A mutation and obstetric complications. Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network". Obstet Gynecol. vol. 115. 2010. pp. 14-20.(Prospective study of prothrombin gene G20210A and pregnancy outcomes)
Rodger, MA, Paidas, M, McLintock, C, Middeldorp, S, Kahn, S, Martinelli, I. "Inherited thrombophilia and pregnancy complications revisited". Obstet Gynecol. vol. 112. 2008. pp. 320-4.(Excellent discussion of the relationship between thrombophilias and adverse obstetric outcomes)
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