Gerson Weiss, MD

A.No. In this retrospective family cohort study from the Netherlands, women who had protein S, protein C, or antithrombin deficiency had a greater baseline risk of venous thromboembolism (VTE), and the risk increased when they used combination oral contraceptives.

Expert Commentary

This report confirms the greater risk of VTE in women with protein S, protein C, or antithrombin deficiency, compared with unaffected women. When they used oral contraceptives (OCs), women with 1 or more of these deficiencies had 10 times the risk of VTE that unaffected women had. And when they had additional thrombophilic deficiencies—such as a second deficiency of protein S or C or antithrombin; factor V Leiden; or prothrombin G20210A—their risk of VTE was further amplified.

Because women with thrombophilic deficiency have a higher baseline risk of VTE, they developed VTE while taking OCs—or during pregnancy, another high-risk setting—at a younger age than their non–OC-using or nonpregnant counterparts, but the overall incidence of VTE during their reproductive years did not increase.

Family cohort framework facilitated study of rare mutations

A retrospective family cohort study is a good design to control for events in similar populations with relatively rare mutational occurrences. This study was adequately powered for its major observations, but lost power and significance when it focused on women with multiple thrombophilic deficiencies. Nevertheless, it confirmed the greater risk of VTE with OC use in thrombophilic women, and clarified the absolute risk of VTE over a woman’s reproductive life, which remains fairly stable because women with thrombophilic deficiencies are at such high risk to begin with.

The study also demonstrated that women with a thrombophilic deficiency have a high risk of multiple deficiencies.

Findings may not be applicable to women with other deficiencies

When a woman has a deficiency other than protein S, protein C, or antithrombin, these findings may not be valid. For example, factor V Leiden mutation is strongly associated with VTE in OC users. It is unclear whether the observation of a stable absolute risk of VTE in OC users would have held up if factor V Leiden was one of the major deficiencies studied.

Bottom line: Pay attention to the family history

This study highlights the importance of a good family history. Women who have family members known to have a thrombophilic deficiency should avoid OCs or be tested for all deficiencies and given oral contraceptives only if they prove to be free of deficiencies. These tests are very expensive and are not cost-effective in a general population screen.

A.No. In this retrospective family cohort study from the Netherlands, women who had protein S, protein C, or antithrombin deficiency had a greater baseline risk of venous thromboembolism (VTE), and the risk increased when they used combination oral contraceptives.

Expert Commentary

This report confirms the greater risk of VTE in women with protein S, protein C, or antithrombin deficiency, compared with unaffected women. When they used oral contraceptives (OCs), women with 1 or more of these deficiencies had 10 times the risk of VTE that unaffected women had. And when they had additional thrombophilic deficiencies—such as a second deficiency of protein S or C or antithrombin; factor V Leiden; or prothrombin G20210A—their risk of VTE was further amplified.

Because women with thrombophilic deficiency have a higher baseline risk of VTE, they developed VTE while taking OCs—or during pregnancy, another high-risk setting—at a younger age than their non–OC-using or nonpregnant counterparts, but the overall incidence of VTE during their reproductive years did not increase.

Family cohort framework facilitated study of rare mutations

A retrospective family cohort study is a good design to control for events in similar populations with relatively rare mutational occurrences. This study was adequately powered for its major observations, but lost power and significance when it focused on women with multiple thrombophilic deficiencies. Nevertheless, it confirmed the greater risk of VTE with OC use in thrombophilic women, and clarified the absolute risk of VTE over a woman’s reproductive life, which remains fairly stable because women with thrombophilic deficiencies are at such high risk to begin with.

The study also demonstrated that women with a thrombophilic deficiency have a high risk of multiple deficiencies.

Findings may not be applicable to women with other deficiencies

When a woman has a deficiency other than protein S, protein C, or antithrombin, these findings may not be valid. For example, factor V Leiden mutation is strongly associated with VTE in OC users. It is unclear whether the observation of a stable absolute risk of VTE in OC users would have held up if factor V Leiden was one of the major deficiencies studied.

Bottom line: Pay attention to the family history

This study highlights the importance of a good family history. Women who have family members known to have a thrombophilic deficiency should avoid OCs or be tested for all deficiencies and given oral contraceptives only if they prove to be free of deficiencies. These tests are very expensive and are not cost-effective in a general population screen.

A.No. In this retrospective family cohort study from the Netherlands, women who had protein S, protein C, or antithrombin deficiency had a greater baseline risk of venous thromboembolism (VTE), and the risk increased when they used combination oral contraceptives.

Expert Commentary

This report confirms the greater risk of VTE in women with protein S, protein C, or antithrombin deficiency, compared with unaffected women. When they used oral contraceptives (OCs), women with 1 or more of these deficiencies had 10 times the risk of VTE that unaffected women had. And when they had additional thrombophilic deficiencies—such as a second deficiency of protein S or C or antithrombin; factor V Leiden; or prothrombin G20210A—their risk of VTE was further amplified.

Because women with thrombophilic deficiency have a higher baseline risk of VTE, they developed VTE while taking OCs—or during pregnancy, another high-risk setting—at a younger age than their non–OC-using or nonpregnant counterparts, but the overall incidence of VTE during their reproductive years did not increase.

Family cohort framework facilitated study of rare mutations

A retrospective family cohort study is a good design to control for events in similar populations with relatively rare mutational occurrences. This study was adequately powered for its major observations, but lost power and significance when it focused on women with multiple thrombophilic deficiencies. Nevertheless, it confirmed the greater risk of VTE with OC use in thrombophilic women, and clarified the absolute risk of VTE over a woman’s reproductive life, which remains fairly stable because women with thrombophilic deficiencies are at such high risk to begin with.

The study also demonstrated that women with a thrombophilic deficiency have a high risk of multiple deficiencies.

Findings may not be applicable to women with other deficiencies

When a woman has a deficiency other than protein S, protein C, or antithrombin, these findings may not be valid. For example, factor V Leiden mutation is strongly associated with VTE in OC users. It is unclear whether the observation of a stable absolute risk of VTE in OC users would have held up if factor V Leiden was one of the major deficiencies studied.

Bottom line: Pay attention to the family history

This study highlights the importance of a good family history. Women who have family members known to have a thrombophilic deficiency should avoid OCs or be tested for all deficiencies and given oral contraceptives only if they prove to be free of deficiencies. These tests are very expensive and are not cost-effective in a general population screen.

A Not at all. On the contrary, it increases the risk among continent women and worsens symptoms in incontinent ones, according to a study of Women’s Health Initiative (WHI) participants.

Expert commentary

Based on weak evidence, some experts have recommended hormone replacement therapy (HRT) as initial treatment of urinary incontinence in hypoestrogenic menopausal women. In fact, HRT has been used for this indication for several decades, mainly because there are estrogen receptors on urinary tract tissues.

This substudy of the WHI involving 27,347 women contradicts the longstanding practice of prescribing HRT for urinary incontinence: Both conjugated equine estrogen (CEE) and CEE with medroxyprogesterone acetate (MPA) stimulated new symptoms or aggravated existing ones.

How these data stack up

These findings are consistent with those of the Heart and Estrogen/Progestin Replacement Study (HERS),¹ but contradict small observational studies. In addition, a large cross-sectional investigation of osteoporotic fractures had found estrogen use in post-menopausal women to be associated with almost double the risk of daily urinary incontinence—though these findings did little to change clinical practice.²

Major advantages of the WHI study are its large size and great statistical power. Since medications were not prescribed for therapy and since this was a blinded study, the placebo effect was also neutralized. Participants were followed over 3 years.

Unfortunately, the study provides no information for women below the age of 50.

What about other HRT formulations?

Only 1 dose of CEE with and without a single dose of MPA was utilized, although the authors cite an observational study³ of different formulations of estrogen-progestin and estrogen alone that “suggested an increased risk” of urinary incontinence with HRT. The authors also note that theirs is the first randomized trial to demonstrate that estrogen alone increases urinary incontinence.

The bottom line

Without any convincing evidence to the contrary, clinicians should avoid prescribing estrogen—with or without a progestin—to prevent or treat urinary incontinence in menopausal women.

A Not at all. On the contrary, it increases the risk among continent women and worsens symptoms in incontinent ones, according to a study of Women’s Health Initiative (WHI) participants.

Expert commentary

Based on weak evidence, some experts have recommended hormone replacement therapy (HRT) as initial treatment of urinary incontinence in hypoestrogenic menopausal women. In fact, HRT has been used for this indication for several decades, mainly because there are estrogen receptors on urinary tract tissues.

This substudy of the WHI involving 27,347 women contradicts the longstanding practice of prescribing HRT for urinary incontinence: Both conjugated equine estrogen (CEE) and CEE with medroxyprogesterone acetate (MPA) stimulated new symptoms or aggravated existing ones.

How these data stack up

These findings are consistent with those of the Heart and Estrogen/Progestin Replacement Study (HERS),¹ but contradict small observational studies. In addition, a large cross-sectional investigation of osteoporotic fractures had found estrogen use in post-menopausal women to be associated with almost double the risk of daily urinary incontinence—though these findings did little to change clinical practice.²

Major advantages of the WHI study are its large size and great statistical power. Since medications were not prescribed for therapy and since this was a blinded study, the placebo effect was also neutralized. Participants were followed over 3 years.

Unfortunately, the study provides no information for women below the age of 50.

What about other HRT formulations?

Only 1 dose of CEE with and without a single dose of MPA was utilized, although the authors cite an observational study³ of different formulations of estrogen-progestin and estrogen alone that “suggested an increased risk” of urinary incontinence with HRT. The authors also note that theirs is the first randomized trial to demonstrate that estrogen alone increases urinary incontinence.

The bottom line

Without any convincing evidence to the contrary, clinicians should avoid prescribing estrogen—with or without a progestin—to prevent or treat urinary incontinence in menopausal women.

A Not at all. On the contrary, it increases the risk among continent women and worsens symptoms in incontinent ones, according to a study of Women’s Health Initiative (WHI) participants.

Expert commentary

Based on weak evidence, some experts have recommended hormone replacement therapy (HRT) as initial treatment of urinary incontinence in hypoestrogenic menopausal women. In fact, HRT has been used for this indication for several decades, mainly because there are estrogen receptors on urinary tract tissues.

This substudy of the WHI involving 27,347 women contradicts the longstanding practice of prescribing HRT for urinary incontinence: Both conjugated equine estrogen (CEE) and CEE with medroxyprogesterone acetate (MPA) stimulated new symptoms or aggravated existing ones.

How these data stack up

These findings are consistent with those of the Heart and Estrogen/Progestin Replacement Study (HERS),¹ but contradict small observational studies. In addition, a large cross-sectional investigation of osteoporotic fractures had found estrogen use in post-menopausal women to be associated with almost double the risk of daily urinary incontinence—though these findings did little to change clinical practice.²

Major advantages of the WHI study are its large size and great statistical power. Since medications were not prescribed for therapy and since this was a blinded study, the placebo effect was also neutralized. Participants were followed over 3 years.

Unfortunately, the study provides no information for women below the age of 50.

What about other HRT formulations?

Only 1 dose of CEE with and without a single dose of MPA was utilized, although the authors cite an observational study³ of different formulations of estrogen-progestin and estrogen alone that “suggested an increased risk” of urinary incontinence with HRT. The authors also note that theirs is the first randomized trial to demonstrate that estrogen alone increases urinary incontinence.

The bottom line

Without any convincing evidence to the contrary, clinicians should avoid prescribing estrogen—with or without a progestin—to prevent or treat urinary incontinence in menopausal women.