Thrombosis is a leading cause of maternal morbidity and mortality throughout the world. Pregnancy can be considered a "pro-thrombotic" state. During pregnancy, major changes occur in the coagulation system. Because of these coagulation changes, women with predisposing risk factors for venous thromboembolism (VTE) need to plan their pregnancies with special consideration.

The risk of complications with particular contraceptive methods is increased in women with risk factors for VTE. Therefore, the effect of the contraceptive method on the underlying disease, as well as the risks of pregnancy, must be assessed along with the patient’s acceptance and ability to comply with the method.

Pathogenesis of Thrombosis

The major predisposing factors to VTE are the activation of blood coagulation and venous stasis. Venous thrombi originate at specific sites of reduced blood flow in the venous valves. An eddy current creates a stagnation of venous flow which results in platelet-fibrin thrombus. This platelet-fibrin thrombus serves as the nidus for thrombus propagation.

Although venous thrombi may often appear to develop "spontaneously", many VTEs are associated with thrombophilia. Thrombophilia is defined as a predisposition to thrombosis. Abnormalities that are associated with clinical thrombophilia include heritable defects and acquired defects. (Table 1)

Table 1 Abnormalities associated with venous thrombosis

Other conditions may be considered "provoking" risk factors. Table 2 lists factors known to be responsible for causing venous thrombosis. In most instances more than one predisposing factor is present.

Table 2 Risk factors associated with venous thromboembolism

The idea has been proposed that mortality could be used to assess the risk vs. benefits of different contraceptive methods while, at the same time, taking into account the risks of pregnancy to the mother and the fetus.

Women with previous VTE or thrombophilic defects have been known to have an increased risk of not only pregnancy related thromboembolism, but also vascular complications, including preeclampsia and fetal loss.

There are several essential considerations for family planning for the patient with predisposing risk factors for VTE.

• Assess the risk of pregnancy (to mother and fetus)

• Maintain good control of the underlying medical condition before, during and after pregnancy

• Choose contraceptive method that has maximum efficacy, and is also readily reversible for planning pregnancies

• Avoid contraceptive methods that exacerbate the underlying medical condition

• Avoid methods which interact with medications taken for the medical condition

The risk of VTE is increased approximately fivefold during pregnancy; thrombosis occurs at a rate of 1 in 1000 to 2000 pregnancies. Because there is an increased prothrombic potential found in normal pregnancies, women with predisposing risk factors for VTE are at a further increased risk of VTE during pregnancy.

Levels of most procoagulant factors (Von Willebrand factor, factors V, VII, VIII, IX, XII and fibrinogen) are all elevated. The anticoagulants, AT and protein C remain at normal levels while the protein S level is decreased by 40 percent. Acquired activated protein C-resistance is present and fibrinolysis is inhibited with decreased plasminogen activator inhibitor.

Although there are anatomic, hormonal and genetic causes for miscarriage, defects in the coagulation proteins or platelets account for about 30-50% of all miscarriages due to placental vascular insufficiency or non-viability of the fetus caused by thrombosis.

In an recent study Factor V Leiden was found in 43.5% of women with pregnancy related thrombosis. In an attempt to reduce the incidence of pregnancy associated VTE, some researchers have advocated screening of all women for the Factor V Leiden mutation during early pregnancy. At present, it is not recommended that all pregnant women be routinely screened for thombophilic abnormalities. It is suggested that selected women (with personal or confirmed family history of VTE) be screened for heritable defects to allow for pregnancy management planning.

A wide variety of medical conditions may have their onset or be exacerbated during pregnancy or after pregnancy. Therefore, it is essential that a woman with underlying medical conditions, which predisposes them to VTE, maintain good control of her medical condition before, during and after pregnancy. For example, a woman with systemic lupus erythematosus (SLE) faces a substantial risk of spontaneous abortion and stillbirth. Lupus flare-ups and whether the patient has the lupus antiphospholipid antibodies increase thrombosis risk. Consideration of the degree activity of the patient’s medical condition is critical in family planning.

The incidence of women with medical problems increases with age. Since, women are increasingly postponing their first childbirth until after the age 30, a growing number of women with medical problems need a form of contraception that is highly effective, readily reversible for planning pregnancies, and without side effects that may exacerbate the coexisting medical condition.

• Intrauterine devices (IUDs) are moderately effective.
• Barrier methods have relatively poor contraceptive efficacy, particularly when used without meticulous care.
• Periodic Abstinence (Rhythm Methods) have a major disadvantage of a relatively high pregnancy rate.
• Sterilization is 100% effective and usually permanent. It may play a role in women with medical conditions dictating limitation of family size.

• Intrauterine devices (IUDs) may increase risk of developing pelvic inflammatory disease
• Barrier methods have fairly minor and infrequent adverse effects
• Periodic Abstinence does not have any adverse effects.
• Vasectomy is associated with minimal morbidity, whereas tubal ligation is a more complex procedure.

The combined pill is a highly effective contraceptive when used strictly according to instructions, but considerable motivation is required to regularly take a daily pill for long periods of time. Oral contraceptives are readily reversible.

Controversies still exist about the relative safety of various oral contraceptive formulations. Increased risk of thrombosis is primarily associated with the estrogen content of oral contraceptives. Doses of ethinyloestradiol (EE) have decreased from more than 100m g to 20 m g.

Coagulation changes similar to those seen in VTE risk factors are observed during the use of oral contraceptive agents containing estrogen. Table 3

Table 3 Risk factors for VTE compared with modifications of hemostasis during oral contraceptives

Relatively new findings that oral contraceptives containing the third generation progestogens (desogestrel or gestodene) carry a higher risk of VTE compared to second generation OCs has generated much controversy. Cohen and Edwards published a journal article Conclusions: the relative safety of modern oral contraceptives in Human Reproduction Update 1999. This article critically assesses the original four studies published in 1995-1996. The question is raised whether such adverse pharmacological effects are biologically plausible and that the studies have failed to confirm any causation between third generation progestogens and increased risk of VTE. It is concluded that all recent papers indicate the equivalence of safety of second and third generation OCs, as the effects of various confounders and biases (age, family history of VTE, BMI, varicose veins, previous births, HTN during pregnancy and duration of OC use) have been identified and analyzed.

The "mini-pills" are less effective than the combined pill and require very high motivation for meticulous attention to pill taking and are also susceptible to various drug interactions.

The silastic implant systems (NorplantÒ ) are designed to provide constant contraception over 5 years, therefore not readily reversible for family planning.

The injectable progestogen only form (Depo-ProveraÒ , depot medroxyprogesterone acetate) is highly effective and return to fertility time is an average of 18 months.

Through correspondence with a Pharmacia & Upjohn drug information specialist it was reported that in a study sponsored by Pharmacia & UpJohn, 3857 women received DMPA 150mg every 3 month for a median duration of 12 months. There was a slight increase over time in coagulation time and no effect in platelet count or prothrombin time. Eleven women developed thrombophlebitis or thromboembolism during the study. Regardless of the few reports of thromboembolic events with the use of DMPA for contraception, the use of DMPA in patients with such a history is considered a contraindication.

Studies have shown that that there is little or no increased risk of stroke, VTE, or acute myocardial infarction (AMI) associated with the use of these products. The results of the World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception showed that the odds ratio for cardiovascular disease associated with the use of oral and injectable progestogen only contraceptives and combined injectable contraceptives, respectively were 1.14 (95% CI:0.79-1.63), 1.02 (0.68-1.54) and 0.95 (0.49-1.86)

However, there is a small non-significant increase in the odds ration for VTE in association with the use of oral and injectable progestogen-only contraceptives.

DMPA contraception offers women with predisposing risk factors for VTE safe, effective convenient and reversible fertility regulation. The patient cases presented illustrate a small proportion of challenging candidates for whom the use of DMPA may represent a prudent choice. We must keep in mind that all factors of family planning affect the choice for contraceptive methods.

With individual consideration and recommendations based on relevant behavioral and medical considerations, clinicians can maximize their patient’s success in family planning.

Because DMPA offers women with predisposing factors a highly effective contraceptive method with no apparent increased risk of thrombosis, it represents an appropriate contraceptive choice. Clinicians should be aware that prescribing DMPA for women with predisposing risk factors reflects an off-label use not approved by the FDA.

PLEASE ALSO SEE ORAL CONTRACEPTIVES AND WARFARIN

Disorders of Hemostasis and Thrombosis, Text Book

Thrombophilias: diagnosis and treatment of thrombophilia relating to contraception and pregnancy. Seminars in Hematology 36(3 Suppl 4):2-9, 1999 July

Risk Factor of Venous Thromboembolism in pregnancy. Current Opinion in Pulmonary Medicine. 5(4):227-32, 1999 July

Thrombophilia in Pregnancy. Journal of Clinical Pathology. 53(8):573-80, 2000 August

Skegg DC, Safety and efficacy of fertility-regulating methods: a decade of research. Bulletin of the World Health Organization 1999; 77(9):713-21

Cohen J; Edwards RG, Conclusions: The relative safety of modern oral contraceptives. Human Reproductive Update 1999 Nov-Dec; 5(6):756-71

Benagiano G, Primiero FM, Safety of modern oral contraception: the options for women: Lessons to be learned. Human Reproduction Update 1999, Vol. 5:633-38

Fraser IS, Contraceptive choice for women with risk factors. Drug Safety. 8(4):271-9 1993 April

Conard J, Biological coagulation finding in third generation oral contraceptives. Human Reproductive Update 5 (6):672-80 1999 Nov-Dec

Depo-Provera Contraception Injection, Patient Package Insert, Pharmacia and Upjohn

Cardiovascular Disease and Use of Oral and Injectable Progestogen-Only Contraceptives and Combined Injectable Contraceptive. Contraception 1998;57:315-324

Frederiksen MC, Depot Medroxyprogesterone Acetate Contraception in Women with Medical Problems. The Journal of Reproductive Medicine. Vol 41, No. 5(Suppl) 1996 May

Kaunitz AM, Long-acting injectable contraception with depot medroxyprogesterone. Am J Obstet Gynecol Vol 170, No. 5, Part 2 1994 May

Kaunitz AM, Injectable Depot Medroxyprogesterone Acetate Contraception: An Update for U.S. Clinicians. International Journal of Fertility and Women’s Medicine Vol 43:No.2: 1998 Mar-Apr

© 2001 Deborah K. Coon Used by permission

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Last updated February 18, 2007