Obstetric Risks and Other Problems Associated with Thrombophilia
by Beth A. Pletcher, MD, September 1999

Over the past 25 years maternal mortality from hemorrhage, complications of eclampsia and bacterial sepsis have steadily declined while mortality due to pulmonary embolism (PE) has not changed much at all. Factors predisposing to deep vein thromboses (DVTs) in pregnancy include: venous stasis, hypercoagulability and possibly vascular damage incurred at the time of delivery. Inherited predisposition to hypercoagulability (thrombophilia) increases a woman's risk for thrombosis, especially during pregnancy. Identifying women at increased risk for thrombosis may allow clinicians the chance to intervene before or during pregnancy, thereby reducing morbidity and mortality.

Risk Factors

Below are a number of features seen more often in women with inherited predisposition to thrombosis.

• DVTs at a young age

• Family history of maternal or paternal relatives with DVTs or "phlebitis"

• Pulmonary embolism

• Placental abruption

• IUGR

• Severe preeclampsia

Thrombophilic Factors

Below are some of the inherited and acquired factors that contribute to thrombophilia in both men and women.

A. Inherited Factors

• The Factor V Leiden (FVL) mutation, present in 3-8% of the general population, leads to less than normal anticoagulant response to activated protein C resulting in an increased risk for venous thrombosis. Individuals with one copy of the FVL gene mutation (heterozygotes) have a slightly increased risk for thrombosis whereas homozygotes have a significantly greater risk. Heterozygotes also have a slightly increased risk for fetal loss after the first trimester with a 2 fold increase in FVL heterozygosity found in women with three or more pregnancy losses compared to controls. In one study, FVL was found in 20% of women with preeclampsia, placental abruption or stillbirth compared to 6% of controls. It is also found in as many as 50% of women with estrogen-related thrombosis.

• The prothrombin II (PTII) mutation, present in 1-2% of the general population, is associated with a 3 fold increase in thrombotic events in pregnant women, approaching a risk during pregnancy of 10%. It is also associated with an increased risk for placental abruption and IUGR but not preeclampsia.

• A homozygous methylenetetrahydrofolate reductase (MTHFR) mutation, present in 1-4% of the general population, is associated with a 3 fold increase in obstetrical complications including preeclampsia and placental abruption.

B. Acquired or Inherited Factors

• Protein S deficiency (PSD)#, present in up to 2% of the general population, is found in approximately 6% of women with obstetrical complications and includes a relatively high risk for stillbirth. Although there are inherited causes of PSD, more often other factors result in PSD such as nephrotic syndrome, liver dysfunction, intercurrent illness, inflammation, pregnancy and use of estrogens. Ironically, thrombosis itself may induce PSD. Along with protein C deficiency and antithrombin III deficiency, PSD is associated with a significant risk for thrombotic events during pregnancy.

• Protein C deficiency (PCD)#, present in about 1.5% of the general population, is associated with a lower risk for obstetrical complications than PSD. However, PCD combined with a FVL mutation is a relatively common cause of DVTs and show a higher risk for thrombosis compared to FVL alone.

• Antithrombin III deficiency (ATIII)#, present in less than 0.5% of the general population, as with PSD and PCD, may rarely result from mutational events and instead occurs more commonly in individuals with confounding medical conditions or in association with use of one of a number of medications. Because of its relative rarity, actual risks for thrombotic events are difficult to estimate, but without question this entity contributes to thrombotic risks during pregnancy.

# Actual mutations in any of these genes, although less common than acquired deficiencies, greatly increase an individual's lifetime risk for thrombosis with an estimated 50% risk for a thrombotic event by age 40 and an 85% risk by age 50.

Evaluation

Since many women with inherited or acquired thrombotic factors never experience obstetrical complications and at least half of patients with such complications do not have any recognized laboratory abnormalities, it is important to consider who might benefit from screening and when testing should be done. For the inherited factors, timing of testing is not critical since they employ molecular technologies. However, for the other factors, it might be wise to wait until at least one month following an acute thrombotic event or obstetrical problem before doing assays for PSD, PCD or ATIII. Below is a list of circumstances where thrombophilia testing might be considered.

• A patient with a personal or family history of DVT or PE

• A patient with a prior pregnancy with severe preeclampsia, multiple late pregnancy losses of unknown etiology, prior placental abruption or prior pregnancy with unexplained IUGR

• A patient with a personal or family history of early onset MI (<45 years)

Because risks for thrombosis are increased somewhat in young women taking oral contraceptives and some women may actually carry more than one of these inherited thrombophilia factors, the question comes up as to the possible benefits of screening women prior to starting low dose oral contraceptives. There is no data at the present time to suggest a significant decrease in the morbidity or mortality in young women on birth control pills who have been screened for these thrombophilia factors. Furthermore, if women who test positive are denied access to these medications, there actually may be a higher rate of unwanted pregnancies and the concomitant risks that are inherent to pregnancy itself. That being said, it appears that these risk/benefit studies need to be done to answer these questions with certainty. Furthermore, before starting oral contraceptives, patients with a strong family history of DVT or PE need to be identified so that selective screening may be offered. Women who are found to carry two factors (such as FVL and PTII or FVL and PCD) should be strongly cautioned about use of these medications and may require careful evaluation and/or treatment before and during pregnancy. Over time we anticipate that these questions will be answered so that women may comfortably take oral contraceptive without unnecessary worry about potential thrombotic complications.

Testing Options

One way to examine the laboratory studies is to divide the tests into the molecular and non-molecular assays. Molecular testing can be done for the most common mutations associated with a heritable increased risk for thrombosis including: FVL heterozygotes, FVL homozygotes, PTII heterozygotes and MTHFR homozygotes. Assays for PSD, PCD, ATIII and anticardiolipin antibodies may also be done depending upon the clinical scenario with the caveat about not testing for deficiencies too close to a thrombotic event that could result in a false positive test. Regardless of the availability of testing, it is clearly up to individual providers to decide which if any of these tests is indicated for a given patient. Since many thrombotic events are not related to any of the predisposing factors, and aging, trauma and prolonged bed rest alone may contribute more to thrombotic events than all of these factors combined, it is important to recognize when the history is significant enough to warrant screening. Surely over the next few years many more studies will be done to elucidate the actual risks and relative contributions of each of these factors in the genesis of thromboses and their relationship to untoward pregnancy outcome.

REFERENCES

1. Bonnar, J. (1999). Can more be done in obstetric and gynecologic practice to reduce morbidity and mortality associated with venous thromboembolism? American Journal of Obstetrics and Gynecology, 180(4): 784-791.

2. Bucciarelli, P., et al. (1999). Risk of venous thromboembolism and clinical manifestations in carriers of antithrombin, protein C, protein S deficiency, or activated protein C resistance: A multicenter collaborative family study. Arteriosclerosis, Thrombosis and Vascular Biology, 19: 1026-1033.

3. Kupferminc, M. J., et al. (1999). Increased frequency of genetic thrombophilia in women with complications of pregnancy. New England Journal of Medicine, 340(1): 9-13.

4. Meinardi, J. R., et al. (1999). Increased risk for fetal loss in carriers of factor V Leiden mutation. Annals of Internal Medicine, 130(9): 736-739.

5. Redondo, M., et al. (1999). Coagulation factors II, V, VII, and X, prothrombin gene 20210G to A transition, and factor V Leiden in coronary artery disease: High factor V clotting activity is an independent risk factor for myocardial infarction. Arteriosclerosis, Thrombosis and Vascular Biology, 19: 1020-1025.

6. Sibai, B. M. (1999). Thrombophilias and adverse outcomes of pregnancy- What should a clinician do? New England Journal of Medicine, 340 (1): 50-51.