Andrew M. Kaunitz, MD

The author has received funding from Barr/Duramed, Bayer, and Warner Chilcott. He is a consultant for Barr/Duramed, Bayer, Warner Chilcott, Kenwood, Noven, and Johnson & Johnson. He holds stock with Sanofi Aventis and Procter & Gamble.

Does estrogen therapy carry more risk than benefit? The answer depends, new data suggest, on the age of the patient, route of administration, and type of progestin.

The past 12 months have yielded important new insights into the risks and benefits of menopausal hormone therapy (HT), including

• landmark reports from the Women’s Health Initiative (WHI) regarding HT and the risk of coronary artery disease
• data from France on the route of HT and risk of thrombosis and on progestin selection and the risk of breast cancer
• data from the Mayo Clinic regarding HT use and subsequent risk of dementia and parkinsonism.

User age determines effects of HT on coronary artery disease

Rossouw JE, Prentice PL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297:1465–1477.

Manson JE, Allison MA, Rossouw JE, et al. Estrogen therapy and coronary-artery calcification. N Engl J Med. 2007;356:2591–2602.

The WHI clinical trials were designed in 1991 and 1992 primarily to determine whether oral menopausal HT protects against coronary artery disease (CAD), as a large body of literature based on observational studies had suggested. Most of those observational studies had involved unopposed oral estrogen.¹

When the estrogen–progestin arm of the WHI was halted in 2002, investigators noted that use of conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) overall was associated with a 29% increase in the risk of CAD (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.02–1.63) and a more than 200% increase in the risk of venous thromboembolism (HR, 2.11; 95% CI, 1.49–2.87), compared with placebo. Subsequent reports explored this connection from different angles ( see the timeline).

In 2007, important—and, for some, startling—findings were published regarding HT and the risk of CAD, most notably:

• When estrogen users from both arms of the WHI trial were combined into one group, those who were less than 10 years since the onset of menopause had a HR for CAD of 0.76 (95% CI, 0.5–1.16), and oral HT was associated with six fewer cases of CAD for every 10,000 woman-years of use. Similar findings were reported for women 50 to 59 years old. Among older WHI participants and those more distant from menopause, HT was associated with an elevated risk of CAD.
• In the same cohort, mean coronary artery calcium scores overall were more favorable among women receiving estrogen than among those randomized to placebo (P=.02). Among women who took the study medication most consistently (at least 80% adherent), an even greater reduction in coronary artery calcification was noted with estrogen use, which was associated with a 61% reduction in the risk of having extensive coronary artery calcification (P=.004). The authors concluded: “… estrogen therapy may have cardioprotective effects in younger (menopausal) women.”

In contrast to earlier WHI reports, which failed to break out risks by user age, these recent publications are consistent with the earlier observational studies of HT and should reassure ObGyns that the patients most likely to experience menopausal symptoms (women in their 50s and early 60s) can use HT without increasing their risk of CAD.

Transdermal estrogen carries a lower risk of VTE than oral administration

Canonico M, Oger E, Plu-Bureau G, et al; Estrogen and Thromboembolism Risk (ESTHER) Study Group. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: The ESTHER study. Circulation. 2007;115:840–845.

As I noted earlier in this article, the initial 2002 WHI report found that oral CEE plus MPA doubled the risk of venous thromboembolism (VTE). Although WHI clinical trials did not study transdermal estrogen, an important observational study comparing VTE risk between oral and transdermal estrogen therapy was conducted in France, where use of transdermal estrogen is more common than in the United States.

In a 2007 report from this large multicenter, case-control study (the Estrogen and Thromboembolism Risk study, or ESTHER), oral menopausal estrogen therapy was associated with a fourfold increase in the risk of VTE (including pulmonary embolism and deep venous thrombosis), compared with nonuse (P<.05), whereas use of transdermal estrogen was not associated with any increase in the risk of VTE.

Type of progestin also played a role

This report also assessed VTE by the type of progestin used by women taking combination estrogen–progestin HT. Micronized progesterone and MPA did not affect the risk of VTE, but norethindrone acetate as well as other progestins not used in the United States did appear to elevate VTE risk.

Transdermal estrogen is as effective as oral therapy

Like oral estrogen therapy, transdermal therapy effectively treats vasomotor symptoms, prevents loss of bone density, and treats genital atrophy.

Because transdermal menopausal estrogen therapy does not increase hepatic production of procoagulant factors, as does oral estrogen, it is biologically plausible that transdermal therapy is safer than oral therapy in terms of the risk of VTE.⁶

Combined with other evidence, the findings of this important French study suggest that ObGyns should consider transdermal therapy when helping menopausal women select a HT regimen.

Micronized progesterone might not raise the risk of breast cancer

Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat. 2008;107:103–111.

In contrast to estrogen-only therapy, long-term use of combination estrogen– progestin HT is associated with a modestly elevated risk of breast cancer.^7-10

In France, micronized progesterone is the progestin most commonly used in HT. In 2008, results from a large French case-control study suggested that—in contrast to combination HT that contains MPA or norethindrone acetate—use of combination HT formulated with micronized progesterone was not associated with an elevated risk of breast cancer.

In women taking menopausal estrogen, the appropriate dosage of micronized progesterone to prevent endometrial hyperplasia is 100 mg nightly or 200 mg for 12 or more nights each month.

Avoid micronized progesterone in patients with peanut allergy

Because micronized progesterone contains peanut oil, patients with a history of peanut allergy should not use it.

Estrogen’s effects on cognition depend on, again, age at use

Rocca WA, Bower JH, Maraganore DM, et al. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology. 2007;69:1074–1083.

Rocca WA, Bower JH, Maraganore DM, et al. Increased risk of parkinsonism in women who underwent oophorectomy before menopause. Neurology. 2008;70:200–209.

One intriguing possibility entertained in recent years is that HT prevents dementia, although data so far have been conflicting. A large, high-quality observational study performed in Utah and published in 2002 provided evidence that HT use by young menopausal women prevents cognitive decline later in life, particularly when HT is used over the long term.¹¹

In contrast, the WHI Memory Study found that HT increases the risk of mild cognitive impairment and dementia.¹² However, that study enrolled an older subgroup of WHI participants (65 to 79 years old at randomization).

Very young estrogen-deprived women stand to benefit from HT

Over the past year, Rocca and colleagues at the Mayo Clinic in Minnesota published two reports assessing the risk of neurologic disease among several thousand Midwestern women who had undergone oophorectomy (unilateral or bilateral) before reaching menopause. A history of oophorectomy, especially in women younger than 38 years, was associated with a significantly increased risk of cognitive impairment and dementia. However, when estrogen therapy was prescribed until at least 50 years of age following bilateral oophorectomy, no increased risk of cognitive impairment was found.

Using similar methods, the same research group at Mayo found that oophorectomy before menopause was associated with a significantly increased risk of parkinsonism (symptoms that did not meet the formal criteria for Parkinson’s disease) as well as an increased risk, which did not attain statistica significance, of Parkinson’s disease itself.

Taken in totality, the evidence suggests that when HT is initiated in young menopausal women, protection against dementia and other neurologic disease may result. These findings parallel the evidence on the risk of CAD during HT use presented at the beginning of this article.

The author has received funding from Barr/Duramed, Bayer, and Warner Chilcott. He is a consultant for Barr/Duramed, Bayer, Warner Chilcott, Kenwood, Noven, and Johnson & Johnson. He holds stock with Sanofi Aventis and Procter & Gamble.

Does estrogen therapy carry more risk than benefit? The answer depends, new data suggest, on the age of the patient, route of administration, and type of progestin.

The past 12 months have yielded important new insights into the risks and benefits of menopausal hormone therapy (HT), including

• landmark reports from the Women’s Health Initiative (WHI) regarding HT and the risk of coronary artery disease
• data from France on the route of HT and risk of thrombosis and on progestin selection and the risk of breast cancer
• data from the Mayo Clinic regarding HT use and subsequent risk of dementia and parkinsonism.

User age determines effects of HT on coronary artery disease

Rossouw JE, Prentice PL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297:1465–1477.

Manson JE, Allison MA, Rossouw JE, et al. Estrogen therapy and coronary-artery calcification. N Engl J Med. 2007;356:2591–2602.

The WHI clinical trials were designed in 1991 and 1992 primarily to determine whether oral menopausal HT protects against coronary artery disease (CAD), as a large body of literature based on observational studies had suggested. Most of those observational studies had involved unopposed oral estrogen.¹

When the estrogen–progestin arm of the WHI was halted in 2002, investigators noted that use of conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) overall was associated with a 29% increase in the risk of CAD (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.02–1.63) and a more than 200% increase in the risk of venous thromboembolism (HR, 2.11; 95% CI, 1.49–2.87), compared with placebo. Subsequent reports explored this connection from different angles ( see the timeline).

In 2007, important—and, for some, startling—findings were published regarding HT and the risk of CAD, most notably:

• When estrogen users from both arms of the WHI trial were combined into one group, those who were less than 10 years since the onset of menopause had a HR for CAD of 0.76 (95% CI, 0.5–1.16), and oral HT was associated with six fewer cases of CAD for every 10,000 woman-years of use. Similar findings were reported for women 50 to 59 years old. Among older WHI participants and those more distant from menopause, HT was associated with an elevated risk of CAD.
• In the same cohort, mean coronary artery calcium scores overall were more favorable among women receiving estrogen than among those randomized to placebo (P=.02). Among women who took the study medication most consistently (at least 80% adherent), an even greater reduction in coronary artery calcification was noted with estrogen use, which was associated with a 61% reduction in the risk of having extensive coronary artery calcification (P=.004). The authors concluded: “… estrogen therapy may have cardioprotective effects in younger (menopausal) women.”

In contrast to earlier WHI reports, which failed to break out risks by user age, these recent publications are consistent with the earlier observational studies of HT and should reassure ObGyns that the patients most likely to experience menopausal symptoms (women in their 50s and early 60s) can use HT without increasing their risk of CAD.

Transdermal estrogen carries a lower risk of VTE than oral administration

Canonico M, Oger E, Plu-Bureau G, et al; Estrogen and Thromboembolism Risk (ESTHER) Study Group. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: The ESTHER study. Circulation. 2007;115:840–845.

As I noted earlier in this article, the initial 2002 WHI report found that oral CEE plus MPA doubled the risk of venous thromboembolism (VTE). Although WHI clinical trials did not study transdermal estrogen, an important observational study comparing VTE risk between oral and transdermal estrogen therapy was conducted in France, where use of transdermal estrogen is more common than in the United States.

In a 2007 report from this large multicenter, case-control study (the Estrogen and Thromboembolism Risk study, or ESTHER), oral menopausal estrogen therapy was associated with a fourfold increase in the risk of VTE (including pulmonary embolism and deep venous thrombosis), compared with nonuse (P<.05), whereas use of transdermal estrogen was not associated with any increase in the risk of VTE.

Type of progestin also played a role

This report also assessed VTE by the type of progestin used by women taking combination estrogen–progestin HT. Micronized progesterone and MPA did not affect the risk of VTE, but norethindrone acetate as well as other progestins not used in the United States did appear to elevate VTE risk.

Transdermal estrogen is as effective as oral therapy

Like oral estrogen therapy, transdermal therapy effectively treats vasomotor symptoms, prevents loss of bone density, and treats genital atrophy.

Because transdermal menopausal estrogen therapy does not increase hepatic production of procoagulant factors, as does oral estrogen, it is biologically plausible that transdermal therapy is safer than oral therapy in terms of the risk of VTE.⁶

Combined with other evidence, the findings of this important French study suggest that ObGyns should consider transdermal therapy when helping menopausal women select a HT regimen.

Micronized progesterone might not raise the risk of breast cancer

Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat. 2008;107:103–111.

In contrast to estrogen-only therapy, long-term use of combination estrogen– progestin HT is associated with a modestly elevated risk of breast cancer.^7-10

In France, micronized progesterone is the progestin most commonly used in HT. In 2008, results from a large French case-control study suggested that—in contrast to combination HT that contains MPA or norethindrone acetate—use of combination HT formulated with micronized progesterone was not associated with an elevated risk of breast cancer.

In women taking menopausal estrogen, the appropriate dosage of micronized progesterone to prevent endometrial hyperplasia is 100 mg nightly or 200 mg for 12 or more nights each month.

Avoid micronized progesterone in patients with peanut allergy

Because micronized progesterone contains peanut oil, patients with a history of peanut allergy should not use it.

Estrogen’s effects on cognition depend on, again, age at use

Rocca WA, Bower JH, Maraganore DM, et al. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology. 2007;69:1074–1083.

Rocca WA, Bower JH, Maraganore DM, et al. Increased risk of parkinsonism in women who underwent oophorectomy before menopause. Neurology. 2008;70:200–209.

One intriguing possibility entertained in recent years is that HT prevents dementia, although data so far have been conflicting. A large, high-quality observational study performed in Utah and published in 2002 provided evidence that HT use by young menopausal women prevents cognitive decline later in life, particularly when HT is used over the long term.¹¹

In contrast, the WHI Memory Study found that HT increases the risk of mild cognitive impairment and dementia.¹² However, that study enrolled an older subgroup of WHI participants (65 to 79 years old at randomization).

Very young estrogen-deprived women stand to benefit from HT

Over the past year, Rocca and colleagues at the Mayo Clinic in Minnesota published two reports assessing the risk of neurologic disease among several thousand Midwestern women who had undergone oophorectomy (unilateral or bilateral) before reaching menopause. A history of oophorectomy, especially in women younger than 38 years, was associated with a significantly increased risk of cognitive impairment and dementia. However, when estrogen therapy was prescribed until at least 50 years of age following bilateral oophorectomy, no increased risk of cognitive impairment was found.

Using similar methods, the same research group at Mayo found that oophorectomy before menopause was associated with a significantly increased risk of parkinsonism (symptoms that did not meet the formal criteria for Parkinson’s disease) as well as an increased risk, which did not attain statistica significance, of Parkinson’s disease itself.

Taken in totality, the evidence suggests that when HT is initiated in young menopausal women, protection against dementia and other neurologic disease may result. These findings parallel the evidence on the risk of CAD during HT use presented at the beginning of this article.

The author has received funding from Barr/Duramed, Bayer, and Warner Chilcott. He is a consultant for Barr/Duramed, Bayer, Warner Chilcott, Kenwood, Noven, and Johnson & Johnson. He holds stock with Sanofi Aventis and Procter & Gamble.

Does estrogen therapy carry more risk than benefit? The answer depends, new data suggest, on the age of the patient, route of administration, and type of progestin.

The past 12 months have yielded important new insights into the risks and benefits of menopausal hormone therapy (HT), including

• landmark reports from the Women’s Health Initiative (WHI) regarding HT and the risk of coronary artery disease
• data from France on the route of HT and risk of thrombosis and on progestin selection and the risk of breast cancer
• data from the Mayo Clinic regarding HT use and subsequent risk of dementia and parkinsonism.

User age determines effects of HT on coronary artery disease

Rossouw JE, Prentice PL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297:1465–1477.

Manson JE, Allison MA, Rossouw JE, et al. Estrogen therapy and coronary-artery calcification. N Engl J Med. 2007;356:2591–2602.

The WHI clinical trials were designed in 1991 and 1992 primarily to determine whether oral menopausal HT protects against coronary artery disease (CAD), as a large body of literature based on observational studies had suggested. Most of those observational studies had involved unopposed oral estrogen.¹

When the estrogen–progestin arm of the WHI was halted in 2002, investigators noted that use of conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) overall was associated with a 29% increase in the risk of CAD (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.02–1.63) and a more than 200% increase in the risk of venous thromboembolism (HR, 2.11; 95% CI, 1.49–2.87), compared with placebo. Subsequent reports explored this connection from different angles ( see the timeline).

In 2007, important—and, for some, startling—findings were published regarding HT and the risk of CAD, most notably:

• When estrogen users from both arms of the WHI trial were combined into one group, those who were less than 10 years since the onset of menopause had a HR for CAD of 0.76 (95% CI, 0.5–1.16), and oral HT was associated with six fewer cases of CAD for every 10,000 woman-years of use. Similar findings were reported for women 50 to 59 years old. Among older WHI participants and those more distant from menopause, HT was associated with an elevated risk of CAD.
• In the same cohort, mean coronary artery calcium scores overall were more favorable among women receiving estrogen than among those randomized to placebo (P=.02). Among women who took the study medication most consistently (at least 80% adherent), an even greater reduction in coronary artery calcification was noted with estrogen use, which was associated with a 61% reduction in the risk of having extensive coronary artery calcification (P=.004). The authors concluded: “… estrogen therapy may have cardioprotective effects in younger (menopausal) women.”

In contrast to earlier WHI reports, which failed to break out risks by user age, these recent publications are consistent with the earlier observational studies of HT and should reassure ObGyns that the patients most likely to experience menopausal symptoms (women in their 50s and early 60s) can use HT without increasing their risk of CAD.

Transdermal estrogen carries a lower risk of VTE than oral administration

Canonico M, Oger E, Plu-Bureau G, et al; Estrogen and Thromboembolism Risk (ESTHER) Study Group. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: The ESTHER study. Circulation. 2007;115:840–845.

As I noted earlier in this article, the initial 2002 WHI report found that oral CEE plus MPA doubled the risk of venous thromboembolism (VTE). Although WHI clinical trials did not study transdermal estrogen, an important observational study comparing VTE risk between oral and transdermal estrogen therapy was conducted in France, where use of transdermal estrogen is more common than in the United States.

In a 2007 report from this large multicenter, case-control study (the Estrogen and Thromboembolism Risk study, or ESTHER), oral menopausal estrogen therapy was associated with a fourfold increase in the risk of VTE (including pulmonary embolism and deep venous thrombosis), compared with nonuse (P<.05), whereas use of transdermal estrogen was not associated with any increase in the risk of VTE.

Type of progestin also played a role

This report also assessed VTE by the type of progestin used by women taking combination estrogen–progestin HT. Micronized progesterone and MPA did not affect the risk of VTE, but norethindrone acetate as well as other progestins not used in the United States did appear to elevate VTE risk.

Transdermal estrogen is as effective as oral therapy

Like oral estrogen therapy, transdermal therapy effectively treats vasomotor symptoms, prevents loss of bone density, and treats genital atrophy.

Because transdermal menopausal estrogen therapy does not increase hepatic production of procoagulant factors, as does oral estrogen, it is biologically plausible that transdermal therapy is safer than oral therapy in terms of the risk of VTE.⁶

Combined with other evidence, the findings of this important French study suggest that ObGyns should consider transdermal therapy when helping menopausal women select a HT regimen.

Micronized progesterone might not raise the risk of breast cancer

Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat. 2008;107:103–111.

In contrast to estrogen-only therapy, long-term use of combination estrogen– progestin HT is associated with a modestly elevated risk of breast cancer.^7-10

In France, micronized progesterone is the progestin most commonly used in HT. In 2008, results from a large French case-control study suggested that—in contrast to combination HT that contains MPA or norethindrone acetate—use of combination HT formulated with micronized progesterone was not associated with an elevated risk of breast cancer.

In women taking menopausal estrogen, the appropriate dosage of micronized progesterone to prevent endometrial hyperplasia is 100 mg nightly or 200 mg for 12 or more nights each month.

Avoid micronized progesterone in patients with peanut allergy

Because micronized progesterone contains peanut oil, patients with a history of peanut allergy should not use it.

Estrogen’s effects on cognition depend on, again, age at use

Rocca WA, Bower JH, Maraganore DM, et al. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology. 2007;69:1074–1083.

Rocca WA, Bower JH, Maraganore DM, et al. Increased risk of parkinsonism in women who underwent oophorectomy before menopause. Neurology. 2008;70:200–209.

One intriguing possibility entertained in recent years is that HT prevents dementia, although data so far have been conflicting. A large, high-quality observational study performed in Utah and published in 2002 provided evidence that HT use by young menopausal women prevents cognitive decline later in life, particularly when HT is used over the long term.¹¹

In contrast, the WHI Memory Study found that HT increases the risk of mild cognitive impairment and dementia.¹² However, that study enrolled an older subgroup of WHI participants (65 to 79 years old at randomization).

Very young estrogen-deprived women stand to benefit from HT

Over the past year, Rocca and colleagues at the Mayo Clinic in Minnesota published two reports assessing the risk of neurologic disease among several thousand Midwestern women who had undergone oophorectomy (unilateral or bilateral) before reaching menopause. A history of oophorectomy, especially in women younger than 38 years, was associated with a significantly increased risk of cognitive impairment and dementia. However, when estrogen therapy was prescribed until at least 50 years of age following bilateral oophorectomy, no increased risk of cognitive impairment was found.

Using similar methods, the same research group at Mayo found that oophorectomy before menopause was associated with a significantly increased risk of parkinsonism (symptoms that did not meet the formal criteria for Parkinson’s disease) as well as an increased risk, which did not attain statistica significance, of Parkinson’s disease itself.

Taken in totality, the evidence suggests that when HT is initiated in young menopausal women, protection against dementia and other neurologic disease may result. These findings parallel the evidence on the risk of CAD during HT use presented at the beginning of this article.

Postpartum tubal sterilization is most often performed using the Pomeroy method, a technique that has remained unchanged since its introduction in 1930. Recently introduced clip technology provides an important alternative for clinicians. The Filshie clip—approved for both postpartum and interval use in 1996—offers efficacy rates similar to the Pomeroy method, with potential advantages for physicians and operating room (OR) personnel.

Tubal sterilization—the number one birth control method in the United States—is the choice of 11 million US women, approximately 28% of the women who use contraception¹ (TABLE 1). Of this total, half of all tubal sterilization procedures are performed postpartum and are more likely to be performed among women aged 20 to 34 than are interval sterilization procedures.²

In this publication, 3 experts describe their clinical experiences with the Filshie clip and review the medical literature on its use in obstetric sterilization. They offer practical pearls for obstetricians who may want to consider using this technology in their practices. Additionally, they review the Filshie clip and other procedures and devices within the context of the evidence in the medical literature concerning efficacy, ease of use, surgeon time required, and the potential for complications.

TABLE 1

Tubal sterilization procedures in the United States, 1994-1996

Adding the Filshie clip to OR options

DR KAUNITZ: Most ob/gyns have been trained to perform obstetric postpartum sterilization using the Pomeroy method—perhaps that’s why it is often viewed as the only option in this setting. However, at my institution, Shands Jacksonville Medical Center, the Filshie clip is routinely used for postpartum tubal sterilization among the approximately 3000 teaching service deliveries we perform each year.

I became familiar with use of the Filshie clip for laparoscopic sterilization in the mid to late 1990s, following its approval for use in the United States. Once I learned that it was approved for use in C-sections and postpartum procedures and that a short applicator was available (FIGURE), I wanted to try it.

FIGURE The Filshie short applicator

Comparing the Filshie clip vs the Pomeroy method

DR KAUNITZ: As part of a resident research project, we performed a small randomized trial that compared perioperative outcomes with obstetric tubal sterilization using the Pomeroy method versus the Filshie clip.³ In this study, we were particularly interested in the procedure because it alleviates the need for the physician to perform incisions near the engorged broad ligament blood vessels present during pregnancy and delivery. The Filshie clip does not require tubal exteriorization, a potential advantage in obese patients and in those who have tubal adhesions.

Reducing operating time

DR KAUNITZ: Our findings revealed that the Filshie clip was faster and was preferred by the surgeons (TABLE 2). Since then, we’ve kept the short applicator in our labor and delivery OR. We use the Filshie clip not only as the dominant laparoscopic procedure but also increasingly for sterilization performed after childbirth (vaginal and cesarean). The Filshie clip is an appealing option that is becoming more important as the C-section rate continues to rise, and an increasing number of sterilizations may be done at the time of the C-section.

TABLE 2

Results of surgeon and operating room technician questionnaires

Making the short applicator available

DR HARKINS: During my residency in 1996, the Filshie clip became popular as a laparoscopic technique. It was at the forefront of my training, although we did learn how to use the Falope ring, etc. I had seen the Filshie clip—with the short applicator—used in obstetric postpartum procedures. But we primarily used the Pomeroy method in that setting.

In 2000, when I was at Fort Hood, Texas, the Filshie clip, with its short applicator, was available in the labor and delivery OR. I believe that its availability in this setting is what encouraged me to use it. During their training, most ob/gyns see the Parkland or Pomeroy methods used for postpartum tubals. It doesn’t occur to them to use the Filshie clip in obstetric cases until they see the short-handle applicator, which is specifically made for obstetric use.

Reversing sterilization

DR SANFILIPPO: It’s important for the device to be readily accessible. For me, the question is “How do we get the short applicator into more surgeons’ hands and get them to think more about performing obstetric-related sterilization with this device?” I’ve always been a fan of the Filshie clip because it’s quick and effective.

As important, it’s a joy to reverse a sterilization that has been performed with this technique. We need to keep in mind that we can’t be certain that the patient—particularly a younger woman—will be happy in the long term with her decision to undergo sterilization. It’s comforting to know that with the Filshie clip, reversal of the sterilization procedure is generally easy to perform and carries a higher success rate compared with procedures that result in greater tubal destruction.

Choosing Filshie vs sutures

DR HARKINS: At our institution, the decision of which technique to use is based on the individual physician’s preference. I estimate that 1 in 4 sterilization procedures are done with the Filshie clip. Often, the staff base their decision on the tubal anatomy they find when performing a C-section.

DR KAUNITZ: Since both the Pomeroy method and the Filshie clip are used in your C-section rooms, what has been your experience with the speed or convenience of the Filshie clip compared with the Pomeroy method?

DR HARKINS: I find the outcomes identical to those that you reported in your article in Contraception (TABLE 2).³

The procedure is performed more quickly with the Filshie clip, and this device is easier to use. At our institution, the scrub technicians are the ones who often ask us to use the Filshie clip because they see that it’s fast and efficient.

DR SANFILIPPO: I’ve had the same experience, but I want to add that the Filshie clip features the least tubal damage—an important point in performing reconstructive surgery. Only 4 mm of tube is affected by clip application.⁴

Reducing risk of bleeding

DR KAUNITZ: We are all familiar with the risk of mesosalpingeal bleeding associated with the Pomeroy method, whether used postpartum via minilaparotomy or at the time of cesarean delivery. The knots or sutures may slip off the cut ends of the tube; this results in persistent postoperative bleeding, perhaps with hemoperitoneum, low hemoglobin, or hypovolemia, which requires relaparotomy.

DR HARKINS: That’s very important—we’ve all had a patient or know a colleague whose patient had to return to the OR because of a hemorrhage in the broad ligament vessel. Obviously, you remember those cases and want to avoid such occurrences. Certainly, using the Filshie clip is a way of eliminating the worry about this complication.

DR KAUNITZ: Although we have no clinical trial data to prove that the Filshie clip results in fewer complications, I feel it is prudent to use a method, such as the Filshie clip, in that it is as effective as others that are available but that it also enables us to minimize unusual negative occurrences.

Training physicians and residents

DR KAUNITZ: In general, gynecologic surgery is moving away from the premise of “see one and then perform one,” but the short learning curve required with the Filshie clip is one of its appeals—it is quite easy to use. If you follow the rules and pay attention to technique, you can become adept at it very quickly.

DR HARKINS: I agree. The Filshie clip translates from the laparoscopic application to the open application very quickly.

DR SANFILIPPO: I would like to advocate for the use of the Filshie clip as part of resident training. Most centers now have a lab for teaching minimally invasive procedures. I’d like to see the Filshie clip incorporated into such training. Teaching this procedure to residents is a good investment for the future.

DR KAUNITZ: I agree—simulation training should feature the short applicator and obstetric-type simulation applications of Filshie clips in the obstetric setting.

DR HARKINS: Unfortunately, teaching the postpartum procedure has never been a priority of training. In thinking about different techniques, I don’t believe we give residents sufficient information about the issues and available techniques of postpartum tubal sterilization. Certainly, translating techniques from laparoscopic to open and having residents learn to use the short applicator is very useful. We should emphasize the obstetric use of the Filshie clip in training so that it becomes second nature for these physicians to consider it among their treatment options.

DR KAUNITZ: I think younger clinicians may not be aware that the Pomeroy method has not changed since the 1930s.

Assessing potential for complications

DR KAUNITZ: What about the possibility of clip migration or extrusion? I’m not aware of any such occurrences, despite our institution’s longstanding experience with Filshie clips; however, the medical literature contains a number of case reports on migration of Filshie clips into or around various visceral structures.⁵ Interestingly, these reports rarely show major morbidity.

In the original data submitted to the Food and Drug Administration (FDA) for premarket approval of the Filshie clip, 5454 cases were reviewed. Of these cases, 8 (0.1%) women reported clip migration, clip expulsion, or foreign body reaction.⁵

DR SANFILIPPO: I have not seen any migrations or complications.

DR HARKINS: I have had situations where a patient has had a prior tubal ligation with Filshie clips, and when she is seen at laparoscopy for an unrelated procedure, I have found Filshie clips free floating or in the lower pelvis. The tubal occlusion was still effective, but the clip was free floating because of necrosis and resorption of a small portion of the fallopian tube.

DR KAUNITZ: You have not run into situations involving migration of Filshie clips into the bladder or bowel, as has been described in rare case reports?

DR HARKINS: No.

Reimbursement issues

DR HARKINS: When I came to Hershey 4 years ago, I wanted to use the Filshie clip. We looked carefully at cost issues. If you compare the costs for the Filshie clip with the costs for the Pomeroy method—and include the pathology charges for handling and reading the tubal specimens—the Filshie clip has advantages: its use does not require pathology costs.

With the Filshie clip, there is the initial purchase of the applicator. The set of clips costs between $70 and $80.⁶ We found that the total pathology costs associated with the Pomeroy method were $185. This included the processing fee for both fallopian tubes and the professional interpretation fees. These costs made the Filshie clip appealing from a financial standpoint and countered the argument that the Pomeroy method is less expensive because it relies on “just cheap sutures.” In actuality, performing a procedure using Filshie clips may be the equivalent or significantly less than the cost of using the Pomeroy method.⁶

People don’t think about the other potential costs as well: if one additional laparotomy a year is required as a result of bleeding from a Pomeroy procedure, that cost also needs to be factored in.

DR KAUNITZ: Are pathology reports important in cases of failure? Is pathology needed even when performing a procedure with a Filshie clip? Or is it sufficient to do the Filshie clip procedure correctly and then document in your operative report that the appropriate anatomy was identified and the appropriate clip application technique was used?

DR HARKINS: Every patient signs a consent form, which contains information about risk of failure. We say that the failure rate is 1 in 300 to 1 in 500, and we emphasize that the procedure is always accompanied by a risk of failure.

DR SANFILIPPO: At laparoscopy, many physicians will document bipolar cautery with a photograph. This may also be applicable for Filshie clip sterilization procedures. I believe that a well-documented operative report is ample protection for postpartum placement.

Other techniques and devices

DR KAUNITZ: Let’s look at the medical literature. Certainly, the pivotal findings on sterilization techniques were reported in the Collaborative Review of Sterilization (CREST) study; however, the Filshie clip was not yet available. The Hulka was used in that trial. From a historical perspective, the Hulka clip was an important new technology, but in CREST, it had the highest 10-year failure rate. The data in TABLE 3 refer to interval procedures but also provide important information about failure rates.

Clearly, the data regarding the Filshie clip are much more favorable than those shown by Hulka in the CREST study.⁷ In addition to the findings from our study, we have good literature from other countries: Graf et al reported 209 obstetric procedures with the Filshie clip, with 0 failures at 24 months.⁸ Yan et al performed 100 Filshie clip procedures postpartum; at 24 months, there were 0 pregnancies.⁹

We should also note that much larger laparoscopic studies underscore the high long-term efficacy obtained with the Filshie clip. The efficacy is comparable to that of the Pomeroy method, as evidenced in the CREST study. Possibly, the long-term results shown with the Filshie clip even surpass those of the Pomeroy method (TABLE 4).

DR HARKINS: The ACOG practice bulletin on sterilization provides 5- and 10-year numbers from CREST and also places them within the context of long-term reversible contraceptive options:

• 5-year cumulative life-table probability of failure of aggregated sterilization was 13/1000 procedures. By comparison, 5-year failure rates for the Copper T 380-A IUD (Paragard) were 14/1000 procedures and 5 to 11/1000 for the levonorgestrel-releasing intrauterine system (Mirena).
• Postpartum partial salpingectomy (Pomeroy or Parkland methods) had the lowest 5- and 10-year cumulative pregnancy rates: 6.3 per 1000 and 7.5 per 1000, respectively.
• Bipolar coagulation 5- and 10-year failure rates were 16.5/1000 and 24.8/1000 procedures, respectively.
• Silicone band or Yoon band (Falope ring) method 5- and 10-year failure rates were 10/1000 and 17.7/1000 procedures, respectively.
• The spring clip (Hulka) 5- and 10-year failure rates were 31.7/1000 and 36.5/1000 procedures, respectively.¹

DR SANFILIPPO: I wonder if we could compare these data to other procedures, such as the Irving technique?

DR KAUNITZ: I worry that older data may be suspect. Certainly, they were not created prospectively, as was the case with CREST, which was a large, prospective, multicenter observational study of 1685 women.

DR KAUNITZ: In terms of obstetric sterilization, are the other techniques, such as Uchida or Irving, relevant?

DR HARKINS: I don’t believe they’re performed on any regular basis.

DR SANFILIPPO: It is useful, from a historical perspective, to be familiar with these techniques. Whereas the Irving technique has a history of postpartum use, the Uchida technique has been more commonly performed as an interval method.

DR HARKINS: Both require more surgery of the fallopian tube than does the Filshie clip or the Pomeroy method. They require more time and involve a larger section of fallopian tube.

DR KAUNITZ: Yes, although they are effective, they may be more difficult to perform and are rarely used.

TABLE 3

Overall 10-year failure rates for interval procedures

TABLE 4

Long-term failure rates for Mark VI hinged Filshie Clip System sterilization (interval procedures)

Summary of the medical literature

In addition to the trials previously discussed by the roundtable participants, various studies and literature searches have reviewed sterilization in general and provide specific additional documentation about the Filshie clip, as follows.

Peterson (2008). This recent overview summarized the literature on sterilization to date, noting that overall sterilization-attributed mortality rates are 1 to 2 procedures per 100,000 performed.¹⁰ For women who undergo a sterilization procedure at the time of C-section delivery, the risk of major morbidity is defined primarily by the risks associated with delivery. Likewise, after vaginal delivery, the risk of major morbidity from sterilization is potentially related to complications of pregnancy or delivery.

It should be noted that the risk of complications has been reported to be significantly higher among women who have diabetes, are obese, have had prior abdominal or pelvic surgery, or receive general anesthesia. Further, data suggest that sterilization has a negligible impact on changes in menstrual patterns. Studies have shown that women who have tubal sterilizations are 4 to 5 times more likely to have subsequent hysterectomies than are women whose partners have had vasectomies. The risk is most significant among women who have gynecologic disorders (menstrual abnormalities, endometriosis, uterine leiomyomata, pelvic inflammatory disease, and ovarian cysts) at the time of sterilization. However, most women with gynecologic disorders at sterilization did not undergo hysterectomy during follow-up. No biological explanation for this increased risk has been identified, and it is unlikely to reflect a biological impact of sterilization. A possible explanation for this association is in the setting of abnormal bleeding, regardless of cause. Women who have been sterilized may be more likely to consider themselves appropriate candidates for hysterectomy than do other women.

Compared with sexually active women using no contraception, women who have been sterilized have a lower overall risk of ectopic pregnancy. However, when pregnancy occurs in a sterilized woman, the risk that the pregnancy is ectopic is high. Following bipolar coagulation, for example, 65% of pregnancies are ectopic. Following use of the Pomeroy or Parkland sterilization methods postpartum, 20% of pregnancies are ectopic, whereas 15% of pregnancies after clip sterilization are ectopic.¹⁰ These observations underscore the importance of ruling out ectopic pregnancy when a woman who has been sterilized is found to be pregnant.

These practice guidelines note that tubal sterilization may be recommended as a safe and effective method for women who want permanent contraception.¹ The procedure is not intended to be reversible and does not protect against sexually transmitted diseases.

Morbidity and mortality rates with tubal ligation are low, although they are higher than those of vasectomy. Efficacy rates are similar. Tubal sterilization is more effective than short-term, user-dependent contraception methods.¹ Failure rates of tubal sterilization are comparable to those of intrauterine contraceptive devices.^10,12

Kovacs (2002). In this retrospective Australian trial, questionnaires assessed the failure rate of the Filshie clip. Of the 30,000 laparoscopic Filshie clip procedures performed, 276 of 277 gynecologists responded (99.6%). A total of 73 failures were reported, providing an estimated failure rate of 2 to 3 per 1000.¹¹ It is worth noting that Kovacs reported no ectopic sterilizations in a review of 30,000 procedures performed with the Filshie clip.¹¹

Penfield (2001). This overview evaluates the literature on the Filshie clip since its initial use in 1981 and reveals a high level of acceptance worldwide because of its effective design and ease of application. It also notes the usefulness of mechanical devices that avoid the risk of accidental electrical burns and reduce the risk of ectopic pregnancy. This review notes that the Filshie clip also features minimal tubal destruction, thereby allowing maximum potential for reversibility. It includes these practical tips for clinicians:

• To prevent dropping the open clip into the abdomen, open the end of the applicator slowly, because the jaw of the applicator opens quicker than the clip can open spontaneously.
• Tubal transection is a rare event that is usually associated with a large fallopian tube that has been clipped too quickly. Close the clip slowly to “milk away” edema. If transection occurs, place a clip on both ends of the transected tube.
• Use of the double-puncture technique for all laparoscopic sterilization procedures is strongly recommended.¹³

Conclusion

The Filshie clip provides an important option for clinicians who perform postpartum sterilization. The medical literature highlights both the safety and efficacy of the device, and also demonstrates that it is easy to use and that procedures performed with this device can be done quickly.

Disclosures

• Dr Harkins is a consultant and surgical instructor for Ethicon Endo-Surgery, Inc.
• Dr Kaunitz is a consultant to Barr Pharmaceuticals, Inc, Bayer HealthCare Pharmaceuticals Inc, Johnson & Johnson, Organon USA Inc, and Warner Chilcott, and has participated in clinical trials supported by Barr Pharmaceuticals, Inc, Bayer HealthCare Pharmaceuticals Inc, Organon USA Inc, and Warner Chilcott.
• Dr Sanfilippo receives grant/research support from Barr Pharmaceuticals, Inc, and is on the speaker’s bureau for Merck & Co., Inc., and Bayer HealthCare Pharmaceuticals Inc.

Postpartum tubal sterilization is most often performed using the Pomeroy method, a technique that has remained unchanged since its introduction in 1930. Recently introduced clip technology provides an important alternative for clinicians. The Filshie clip—approved for both postpartum and interval use in 1996—offers efficacy rates similar to the Pomeroy method, with potential advantages for physicians and operating room (OR) personnel.

Tubal sterilization—the number one birth control method in the United States—is the choice of 11 million US women, approximately 28% of the women who use contraception¹ (TABLE 1). Of this total, half of all tubal sterilization procedures are performed postpartum and are more likely to be performed among women aged 20 to 34 than are interval sterilization procedures.²

In this publication, 3 experts describe their clinical experiences with the Filshie clip and review the medical literature on its use in obstetric sterilization. They offer practical pearls for obstetricians who may want to consider using this technology in their practices. Additionally, they review the Filshie clip and other procedures and devices within the context of the evidence in the medical literature concerning efficacy, ease of use, surgeon time required, and the potential for complications.

TABLE 1

Tubal sterilization procedures in the United States, 1994-1996

Adding the Filshie clip to OR options

DR KAUNITZ: Most ob/gyns have been trained to perform obstetric postpartum sterilization using the Pomeroy method—perhaps that’s why it is often viewed as the only option in this setting. However, at my institution, Shands Jacksonville Medical Center, the Filshie clip is routinely used for postpartum tubal sterilization among the approximately 3000 teaching service deliveries we perform each year.

I became familiar with use of the Filshie clip for laparoscopic sterilization in the mid to late 1990s, following its approval for use in the United States. Once I learned that it was approved for use in C-sections and postpartum procedures and that a short applicator was available (FIGURE), I wanted to try it.

FIGURE The Filshie short applicator

Comparing the Filshie clip vs the Pomeroy method

DR KAUNITZ: As part of a resident research project, we performed a small randomized trial that compared perioperative outcomes with obstetric tubal sterilization using the Pomeroy method versus the Filshie clip.³ In this study, we were particularly interested in the procedure because it alleviates the need for the physician to perform incisions near the engorged broad ligament blood vessels present during pregnancy and delivery. The Filshie clip does not require tubal exteriorization, a potential advantage in obese patients and in those who have tubal adhesions.

Reducing operating time

DR KAUNITZ: Our findings revealed that the Filshie clip was faster and was preferred by the surgeons (TABLE 2). Since then, we’ve kept the short applicator in our labor and delivery OR. We use the Filshie clip not only as the dominant laparoscopic procedure but also increasingly for sterilization performed after childbirth (vaginal and cesarean). The Filshie clip is an appealing option that is becoming more important as the C-section rate continues to rise, and an increasing number of sterilizations may be done at the time of the C-section.

TABLE 2

Results of surgeon and operating room technician questionnaires

Making the short applicator available

DR HARKINS: During my residency in 1996, the Filshie clip became popular as a laparoscopic technique. It was at the forefront of my training, although we did learn how to use the Falope ring, etc. I had seen the Filshie clip—with the short applicator—used in obstetric postpartum procedures. But we primarily used the Pomeroy method in that setting.

In 2000, when I was at Fort Hood, Texas, the Filshie clip, with its short applicator, was available in the labor and delivery OR. I believe that its availability in this setting is what encouraged me to use it. During their training, most ob/gyns see the Parkland or Pomeroy methods used for postpartum tubals. It doesn’t occur to them to use the Filshie clip in obstetric cases until they see the short-handle applicator, which is specifically made for obstetric use.

Reversing sterilization

DR SANFILIPPO: It’s important for the device to be readily accessible. For me, the question is “How do we get the short applicator into more surgeons’ hands and get them to think more about performing obstetric-related sterilization with this device?” I’ve always been a fan of the Filshie clip because it’s quick and effective.

As important, it’s a joy to reverse a sterilization that has been performed with this technique. We need to keep in mind that we can’t be certain that the patient—particularly a younger woman—will be happy in the long term with her decision to undergo sterilization. It’s comforting to know that with the Filshie clip, reversal of the sterilization procedure is generally easy to perform and carries a higher success rate compared with procedures that result in greater tubal destruction.

Choosing Filshie vs sutures

DR HARKINS: At our institution, the decision of which technique to use is based on the individual physician’s preference. I estimate that 1 in 4 sterilization procedures are done with the Filshie clip. Often, the staff base their decision on the tubal anatomy they find when performing a C-section.

DR KAUNITZ: Since both the Pomeroy method and the Filshie clip are used in your C-section rooms, what has been your experience with the speed or convenience of the Filshie clip compared with the Pomeroy method?

DR HARKINS: I find the outcomes identical to those that you reported in your article in Contraception (TABLE 2).³

The procedure is performed more quickly with the Filshie clip, and this device is easier to use. At our institution, the scrub technicians are the ones who often ask us to use the Filshie clip because they see that it’s fast and efficient.

DR SANFILIPPO: I’ve had the same experience, but I want to add that the Filshie clip features the least tubal damage—an important point in performing reconstructive surgery. Only 4 mm of tube is affected by clip application.⁴

Reducing risk of bleeding

DR KAUNITZ: We are all familiar with the risk of mesosalpingeal bleeding associated with the Pomeroy method, whether used postpartum via minilaparotomy or at the time of cesarean delivery. The knots or sutures may slip off the cut ends of the tube; this results in persistent postoperative bleeding, perhaps with hemoperitoneum, low hemoglobin, or hypovolemia, which requires relaparotomy.

DR HARKINS: That’s very important—we’ve all had a patient or know a colleague whose patient had to return to the OR because of a hemorrhage in the broad ligament vessel. Obviously, you remember those cases and want to avoid such occurrences. Certainly, using the Filshie clip is a way of eliminating the worry about this complication.

DR KAUNITZ: Although we have no clinical trial data to prove that the Filshie clip results in fewer complications, I feel it is prudent to use a method, such as the Filshie clip, in that it is as effective as others that are available but that it also enables us to minimize unusual negative occurrences.

Training physicians and residents

DR KAUNITZ: In general, gynecologic surgery is moving away from the premise of “see one and then perform one,” but the short learning curve required with the Filshie clip is one of its appeals—it is quite easy to use. If you follow the rules and pay attention to technique, you can become adept at it very quickly.

DR HARKINS: I agree. The Filshie clip translates from the laparoscopic application to the open application very quickly.

DR SANFILIPPO: I would like to advocate for the use of the Filshie clip as part of resident training. Most centers now have a lab for teaching minimally invasive procedures. I’d like to see the Filshie clip incorporated into such training. Teaching this procedure to residents is a good investment for the future.

DR KAUNITZ: I agree—simulation training should feature the short applicator and obstetric-type simulation applications of Filshie clips in the obstetric setting.

DR HARKINS: Unfortunately, teaching the postpartum procedure has never been a priority of training. In thinking about different techniques, I don’t believe we give residents sufficient information about the issues and available techniques of postpartum tubal sterilization. Certainly, translating techniques from laparoscopic to open and having residents learn to use the short applicator is very useful. We should emphasize the obstetric use of the Filshie clip in training so that it becomes second nature for these physicians to consider it among their treatment options.

DR KAUNITZ: I think younger clinicians may not be aware that the Pomeroy method has not changed since the 1930s.

Assessing potential for complications

DR KAUNITZ: What about the possibility of clip migration or extrusion? I’m not aware of any such occurrences, despite our institution’s longstanding experience with Filshie clips; however, the medical literature contains a number of case reports on migration of Filshie clips into or around various visceral structures.⁵ Interestingly, these reports rarely show major morbidity.

In the original data submitted to the Food and Drug Administration (FDA) for premarket approval of the Filshie clip, 5454 cases were reviewed. Of these cases, 8 (0.1%) women reported clip migration, clip expulsion, or foreign body reaction.⁵

DR SANFILIPPO: I have not seen any migrations or complications.

DR HARKINS: I have had situations where a patient has had a prior tubal ligation with Filshie clips, and when she is seen at laparoscopy for an unrelated procedure, I have found Filshie clips free floating or in the lower pelvis. The tubal occlusion was still effective, but the clip was free floating because of necrosis and resorption of a small portion of the fallopian tube.

DR KAUNITZ: You have not run into situations involving migration of Filshie clips into the bladder or bowel, as has been described in rare case reports?

DR HARKINS: No.

Reimbursement issues

DR HARKINS: When I came to Hershey 4 years ago, I wanted to use the Filshie clip. We looked carefully at cost issues. If you compare the costs for the Filshie clip with the costs for the Pomeroy method—and include the pathology charges for handling and reading the tubal specimens—the Filshie clip has advantages: its use does not require pathology costs.

With the Filshie clip, there is the initial purchase of the applicator. The set of clips costs between $70 and $80.⁶ We found that the total pathology costs associated with the Pomeroy method were $185. This included the processing fee for both fallopian tubes and the professional interpretation fees. These costs made the Filshie clip appealing from a financial standpoint and countered the argument that the Pomeroy method is less expensive because it relies on “just cheap sutures.” In actuality, performing a procedure using Filshie clips may be the equivalent or significantly less than the cost of using the Pomeroy method.⁶

People don’t think about the other potential costs as well: if one additional laparotomy a year is required as a result of bleeding from a Pomeroy procedure, that cost also needs to be factored in.

DR KAUNITZ: Are pathology reports important in cases of failure? Is pathology needed even when performing a procedure with a Filshie clip? Or is it sufficient to do the Filshie clip procedure correctly and then document in your operative report that the appropriate anatomy was identified and the appropriate clip application technique was used?

DR HARKINS: Every patient signs a consent form, which contains information about risk of failure. We say that the failure rate is 1 in 300 to 1 in 500, and we emphasize that the procedure is always accompanied by a risk of failure.

DR SANFILIPPO: At laparoscopy, many physicians will document bipolar cautery with a photograph. This may also be applicable for Filshie clip sterilization procedures. I believe that a well-documented operative report is ample protection for postpartum placement.

Other techniques and devices

DR KAUNITZ: Let’s look at the medical literature. Certainly, the pivotal findings on sterilization techniques were reported in the Collaborative Review of Sterilization (CREST) study; however, the Filshie clip was not yet available. The Hulka was used in that trial. From a historical perspective, the Hulka clip was an important new technology, but in CREST, it had the highest 10-year failure rate. The data in TABLE 3 refer to interval procedures but also provide important information about failure rates.

Clearly, the data regarding the Filshie clip are much more favorable than those shown by Hulka in the CREST study.⁷ In addition to the findings from our study, we have good literature from other countries: Graf et al reported 209 obstetric procedures with the Filshie clip, with 0 failures at 24 months.⁸ Yan et al performed 100 Filshie clip procedures postpartum; at 24 months, there were 0 pregnancies.⁹

We should also note that much larger laparoscopic studies underscore the high long-term efficacy obtained with the Filshie clip. The efficacy is comparable to that of the Pomeroy method, as evidenced in the CREST study. Possibly, the long-term results shown with the Filshie clip even surpass those of the Pomeroy method (TABLE 4).

DR HARKINS: The ACOG practice bulletin on sterilization provides 5- and 10-year numbers from CREST and also places them within the context of long-term reversible contraceptive options:

• 5-year cumulative life-table probability of failure of aggregated sterilization was 13/1000 procedures. By comparison, 5-year failure rates for the Copper T 380-A IUD (Paragard) were 14/1000 procedures and 5 to 11/1000 for the levonorgestrel-releasing intrauterine system (Mirena).
• Postpartum partial salpingectomy (Pomeroy or Parkland methods) had the lowest 5- and 10-year cumulative pregnancy rates: 6.3 per 1000 and 7.5 per 1000, respectively.
• Bipolar coagulation 5- and 10-year failure rates were 16.5/1000 and 24.8/1000 procedures, respectively.
• Silicone band or Yoon band (Falope ring) method 5- and 10-year failure rates were 10/1000 and 17.7/1000 procedures, respectively.
• The spring clip (Hulka) 5- and 10-year failure rates were 31.7/1000 and 36.5/1000 procedures, respectively.¹

DR SANFILIPPO: I wonder if we could compare these data to other procedures, such as the Irving technique?

DR KAUNITZ: I worry that older data may be suspect. Certainly, they were not created prospectively, as was the case with CREST, which was a large, prospective, multicenter observational study of 1685 women.

DR KAUNITZ: In terms of obstetric sterilization, are the other techniques, such as Uchida or Irving, relevant?

DR HARKINS: I don’t believe they’re performed on any regular basis.

DR SANFILIPPO: It is useful, from a historical perspective, to be familiar with these techniques. Whereas the Irving technique has a history of postpartum use, the Uchida technique has been more commonly performed as an interval method.

DR HARKINS: Both require more surgery of the fallopian tube than does the Filshie clip or the Pomeroy method. They require more time and involve a larger section of fallopian tube.

DR KAUNITZ: Yes, although they are effective, they may be more difficult to perform and are rarely used.

TABLE 3

Overall 10-year failure rates for interval procedures

TABLE 4

Long-term failure rates for Mark VI hinged Filshie Clip System sterilization (interval procedures)

Summary of the medical literature

In addition to the trials previously discussed by the roundtable participants, various studies and literature searches have reviewed sterilization in general and provide specific additional documentation about the Filshie clip, as follows.

Peterson (2008). This recent overview summarized the literature on sterilization to date, noting that overall sterilization-attributed mortality rates are 1 to 2 procedures per 100,000 performed.¹⁰ For women who undergo a sterilization procedure at the time of C-section delivery, the risk of major morbidity is defined primarily by the risks associated with delivery. Likewise, after vaginal delivery, the risk of major morbidity from sterilization is potentially related to complications of pregnancy or delivery.

It should be noted that the risk of complications has been reported to be significantly higher among women who have diabetes, are obese, have had prior abdominal or pelvic surgery, or receive general anesthesia. Further, data suggest that sterilization has a negligible impact on changes in menstrual patterns. Studies have shown that women who have tubal sterilizations are 4 to 5 times more likely to have subsequent hysterectomies than are women whose partners have had vasectomies. The risk is most significant among women who have gynecologic disorders (menstrual abnormalities, endometriosis, uterine leiomyomata, pelvic inflammatory disease, and ovarian cysts) at the time of sterilization. However, most women with gynecologic disorders at sterilization did not undergo hysterectomy during follow-up. No biological explanation for this increased risk has been identified, and it is unlikely to reflect a biological impact of sterilization. A possible explanation for this association is in the setting of abnormal bleeding, regardless of cause. Women who have been sterilized may be more likely to consider themselves appropriate candidates for hysterectomy than do other women.

Compared with sexually active women using no contraception, women who have been sterilized have a lower overall risk of ectopic pregnancy. However, when pregnancy occurs in a sterilized woman, the risk that the pregnancy is ectopic is high. Following bipolar coagulation, for example, 65% of pregnancies are ectopic. Following use of the Pomeroy or Parkland sterilization methods postpartum, 20% of pregnancies are ectopic, whereas 15% of pregnancies after clip sterilization are ectopic.¹⁰ These observations underscore the importance of ruling out ectopic pregnancy when a woman who has been sterilized is found to be pregnant.

These practice guidelines note that tubal sterilization may be recommended as a safe and effective method for women who want permanent contraception.¹ The procedure is not intended to be reversible and does not protect against sexually transmitted diseases.

Morbidity and mortality rates with tubal ligation are low, although they are higher than those of vasectomy. Efficacy rates are similar. Tubal sterilization is more effective than short-term, user-dependent contraception methods.¹ Failure rates of tubal sterilization are comparable to those of intrauterine contraceptive devices.^10,12

Kovacs (2002). In this retrospective Australian trial, questionnaires assessed the failure rate of the Filshie clip. Of the 30,000 laparoscopic Filshie clip procedures performed, 276 of 277 gynecologists responded (99.6%). A total of 73 failures were reported, providing an estimated failure rate of 2 to 3 per 1000.¹¹ It is worth noting that Kovacs reported no ectopic sterilizations in a review of 30,000 procedures performed with the Filshie clip.¹¹

Penfield (2001). This overview evaluates the literature on the Filshie clip since its initial use in 1981 and reveals a high level of acceptance worldwide because of its effective design and ease of application. It also notes the usefulness of mechanical devices that avoid the risk of accidental electrical burns and reduce the risk of ectopic pregnancy. This review notes that the Filshie clip also features minimal tubal destruction, thereby allowing maximum potential for reversibility. It includes these practical tips for clinicians:

• To prevent dropping the open clip into the abdomen, open the end of the applicator slowly, because the jaw of the applicator opens quicker than the clip can open spontaneously.
• Tubal transection is a rare event that is usually associated with a large fallopian tube that has been clipped too quickly. Close the clip slowly to “milk away” edema. If transection occurs, place a clip on both ends of the transected tube.
• Use of the double-puncture technique for all laparoscopic sterilization procedures is strongly recommended.¹³

Conclusion

The Filshie clip provides an important option for clinicians who perform postpartum sterilization. The medical literature highlights both the safety and efficacy of the device, and also demonstrates that it is easy to use and that procedures performed with this device can be done quickly.

Disclosures

• Dr Harkins is a consultant and surgical instructor for Ethicon Endo-Surgery, Inc.
• Dr Kaunitz is a consultant to Barr Pharmaceuticals, Inc, Bayer HealthCare Pharmaceuticals Inc, Johnson & Johnson, Organon USA Inc, and Warner Chilcott, and has participated in clinical trials supported by Barr Pharmaceuticals, Inc, Bayer HealthCare Pharmaceuticals Inc, Organon USA Inc, and Warner Chilcott.
• Dr Sanfilippo receives grant/research support from Barr Pharmaceuticals, Inc, and is on the speaker’s bureau for Merck & Co., Inc., and Bayer HealthCare Pharmaceuticals Inc.

Postpartum tubal sterilization is most often performed using the Pomeroy method, a technique that has remained unchanged since its introduction in 1930. Recently introduced clip technology provides an important alternative for clinicians. The Filshie clip—approved for both postpartum and interval use in 1996—offers efficacy rates similar to the Pomeroy method, with potential advantages for physicians and operating room (OR) personnel.

Tubal sterilization—the number one birth control method in the United States—is the choice of 11 million US women, approximately 28% of the women who use contraception¹ (TABLE 1). Of this total, half of all tubal sterilization procedures are performed postpartum and are more likely to be performed among women aged 20 to 34 than are interval sterilization procedures.²

In this publication, 3 experts describe their clinical experiences with the Filshie clip and review the medical literature on its use in obstetric sterilization. They offer practical pearls for obstetricians who may want to consider using this technology in their practices. Additionally, they review the Filshie clip and other procedures and devices within the context of the evidence in the medical literature concerning efficacy, ease of use, surgeon time required, and the potential for complications.

TABLE 1

Tubal sterilization procedures in the United States, 1994-1996

Adding the Filshie clip to OR options

DR KAUNITZ: Most ob/gyns have been trained to perform obstetric postpartum sterilization using the Pomeroy method—perhaps that’s why it is often viewed as the only option in this setting. However, at my institution, Shands Jacksonville Medical Center, the Filshie clip is routinely used for postpartum tubal sterilization among the approximately 3000 teaching service deliveries we perform each year.

I became familiar with use of the Filshie clip for laparoscopic sterilization in the mid to late 1990s, following its approval for use in the United States. Once I learned that it was approved for use in C-sections and postpartum procedures and that a short applicator was available (FIGURE), I wanted to try it.

FIGURE The Filshie short applicator

Comparing the Filshie clip vs the Pomeroy method

DR KAUNITZ: As part of a resident research project, we performed a small randomized trial that compared perioperative outcomes with obstetric tubal sterilization using the Pomeroy method versus the Filshie clip.³ In this study, we were particularly interested in the procedure because it alleviates the need for the physician to perform incisions near the engorged broad ligament blood vessels present during pregnancy and delivery. The Filshie clip does not require tubal exteriorization, a potential advantage in obese patients and in those who have tubal adhesions.

Reducing operating time

DR KAUNITZ: Our findings revealed that the Filshie clip was faster and was preferred by the surgeons (TABLE 2). Since then, we’ve kept the short applicator in our labor and delivery OR. We use the Filshie clip not only as the dominant laparoscopic procedure but also increasingly for sterilization performed after childbirth (vaginal and cesarean). The Filshie clip is an appealing option that is becoming more important as the C-section rate continues to rise, and an increasing number of sterilizations may be done at the time of the C-section.

TABLE 2

Results of surgeon and operating room technician questionnaires

Making the short applicator available

DR HARKINS: During my residency in 1996, the Filshie clip became popular as a laparoscopic technique. It was at the forefront of my training, although we did learn how to use the Falope ring, etc. I had seen the Filshie clip—with the short applicator—used in obstetric postpartum procedures. But we primarily used the Pomeroy method in that setting.

In 2000, when I was at Fort Hood, Texas, the Filshie clip, with its short applicator, was available in the labor and delivery OR. I believe that its availability in this setting is what encouraged me to use it. During their training, most ob/gyns see the Parkland or Pomeroy methods used for postpartum tubals. It doesn’t occur to them to use the Filshie clip in obstetric cases until they see the short-handle applicator, which is specifically made for obstetric use.

Reversing sterilization

DR SANFILIPPO: It’s important for the device to be readily accessible. For me, the question is “How do we get the short applicator into more surgeons’ hands and get them to think more about performing obstetric-related sterilization with this device?” I’ve always been a fan of the Filshie clip because it’s quick and effective.

As important, it’s a joy to reverse a sterilization that has been performed with this technique. We need to keep in mind that we can’t be certain that the patient—particularly a younger woman—will be happy in the long term with her decision to undergo sterilization. It’s comforting to know that with the Filshie clip, reversal of the sterilization procedure is generally easy to perform and carries a higher success rate compared with procedures that result in greater tubal destruction.

Choosing Filshie vs sutures

DR HARKINS: At our institution, the decision of which technique to use is based on the individual physician’s preference. I estimate that 1 in 4 sterilization procedures are done with the Filshie clip. Often, the staff base their decision on the tubal anatomy they find when performing a C-section.

DR KAUNITZ: Since both the Pomeroy method and the Filshie clip are used in your C-section rooms, what has been your experience with the speed or convenience of the Filshie clip compared with the Pomeroy method?

DR HARKINS: I find the outcomes identical to those that you reported in your article in Contraception (TABLE 2).³

The procedure is performed more quickly with the Filshie clip, and this device is easier to use. At our institution, the scrub technicians are the ones who often ask us to use the Filshie clip because they see that it’s fast and efficient.

DR SANFILIPPO: I’ve had the same experience, but I want to add that the Filshie clip features the least tubal damage—an important point in performing reconstructive surgery. Only 4 mm of tube is affected by clip application.⁴

Reducing risk of bleeding

DR KAUNITZ: We are all familiar with the risk of mesosalpingeal bleeding associated with the Pomeroy method, whether used postpartum via minilaparotomy or at the time of cesarean delivery. The knots or sutures may slip off the cut ends of the tube; this results in persistent postoperative bleeding, perhaps with hemoperitoneum, low hemoglobin, or hypovolemia, which requires relaparotomy.

DR HARKINS: That’s very important—we’ve all had a patient or know a colleague whose patient had to return to the OR because of a hemorrhage in the broad ligament vessel. Obviously, you remember those cases and want to avoid such occurrences. Certainly, using the Filshie clip is a way of eliminating the worry about this complication.

DR KAUNITZ: Although we have no clinical trial data to prove that the Filshie clip results in fewer complications, I feel it is prudent to use a method, such as the Filshie clip, in that it is as effective as others that are available but that it also enables us to minimize unusual negative occurrences.

Training physicians and residents

DR KAUNITZ: In general, gynecologic surgery is moving away from the premise of “see one and then perform one,” but the short learning curve required with the Filshie clip is one of its appeals—it is quite easy to use. If you follow the rules and pay attention to technique, you can become adept at it very quickly.

DR HARKINS: I agree. The Filshie clip translates from the laparoscopic application to the open application very quickly.

DR SANFILIPPO: I would like to advocate for the use of the Filshie clip as part of resident training. Most centers now have a lab for teaching minimally invasive procedures. I’d like to see the Filshie clip incorporated into such training. Teaching this procedure to residents is a good investment for the future.

DR KAUNITZ: I agree—simulation training should feature the short applicator and obstetric-type simulation applications of Filshie clips in the obstetric setting.

DR HARKINS: Unfortunately, teaching the postpartum procedure has never been a priority of training. In thinking about different techniques, I don’t believe we give residents sufficient information about the issues and available techniques of postpartum tubal sterilization. Certainly, translating techniques from laparoscopic to open and having residents learn to use the short applicator is very useful. We should emphasize the obstetric use of the Filshie clip in training so that it becomes second nature for these physicians to consider it among their treatment options.

DR KAUNITZ: I think younger clinicians may not be aware that the Pomeroy method has not changed since the 1930s.

Assessing potential for complications

DR KAUNITZ: What about the possibility of clip migration or extrusion? I’m not aware of any such occurrences, despite our institution’s longstanding experience with Filshie clips; however, the medical literature contains a number of case reports on migration of Filshie clips into or around various visceral structures.⁵ Interestingly, these reports rarely show major morbidity.

In the original data submitted to the Food and Drug Administration (FDA) for premarket approval of the Filshie clip, 5454 cases were reviewed. Of these cases, 8 (0.1%) women reported clip migration, clip expulsion, or foreign body reaction.⁵

DR SANFILIPPO: I have not seen any migrations or complications.

DR HARKINS: I have had situations where a patient has had a prior tubal ligation with Filshie clips, and when she is seen at laparoscopy for an unrelated procedure, I have found Filshie clips free floating or in the lower pelvis. The tubal occlusion was still effective, but the clip was free floating because of necrosis and resorption of a small portion of the fallopian tube.

DR KAUNITZ: You have not run into situations involving migration of Filshie clips into the bladder or bowel, as has been described in rare case reports?

DR HARKINS: No.

Reimbursement issues

DR HARKINS: When I came to Hershey 4 years ago, I wanted to use the Filshie clip. We looked carefully at cost issues. If you compare the costs for the Filshie clip with the costs for the Pomeroy method—and include the pathology charges for handling and reading the tubal specimens—the Filshie clip has advantages: its use does not require pathology costs.

With the Filshie clip, there is the initial purchase of the applicator. The set of clips costs between $70 and $80.⁶ We found that the total pathology costs associated with the Pomeroy method were $185. This included the processing fee for both fallopian tubes and the professional interpretation fees. These costs made the Filshie clip appealing from a financial standpoint and countered the argument that the Pomeroy method is less expensive because it relies on “just cheap sutures.” In actuality, performing a procedure using Filshie clips may be the equivalent or significantly less than the cost of using the Pomeroy method.⁶

People don’t think about the other potential costs as well: if one additional laparotomy a year is required as a result of bleeding from a Pomeroy procedure, that cost also needs to be factored in.

DR KAUNITZ: Are pathology reports important in cases of failure? Is pathology needed even when performing a procedure with a Filshie clip? Or is it sufficient to do the Filshie clip procedure correctly and then document in your operative report that the appropriate anatomy was identified and the appropriate clip application technique was used?

DR HARKINS: Every patient signs a consent form, which contains information about risk of failure. We say that the failure rate is 1 in 300 to 1 in 500, and we emphasize that the procedure is always accompanied by a risk of failure.

DR SANFILIPPO: At laparoscopy, many physicians will document bipolar cautery with a photograph. This may also be applicable for Filshie clip sterilization procedures. I believe that a well-documented operative report is ample protection for postpartum placement.

Other techniques and devices

DR KAUNITZ: Let’s look at the medical literature. Certainly, the pivotal findings on sterilization techniques were reported in the Collaborative Review of Sterilization (CREST) study; however, the Filshie clip was not yet available. The Hulka was used in that trial. From a historical perspective, the Hulka clip was an important new technology, but in CREST, it had the highest 10-year failure rate. The data in TABLE 3 refer to interval procedures but also provide important information about failure rates.

Clearly, the data regarding the Filshie clip are much more favorable than those shown by Hulka in the CREST study.⁷ In addition to the findings from our study, we have good literature from other countries: Graf et al reported 209 obstetric procedures with the Filshie clip, with 0 failures at 24 months.⁸ Yan et al performed 100 Filshie clip procedures postpartum; at 24 months, there were 0 pregnancies.⁹

We should also note that much larger laparoscopic studies underscore the high long-term efficacy obtained with the Filshie clip. The efficacy is comparable to that of the Pomeroy method, as evidenced in the CREST study. Possibly, the long-term results shown with the Filshie clip even surpass those of the Pomeroy method (TABLE 4).

DR HARKINS: The ACOG practice bulletin on sterilization provides 5- and 10-year numbers from CREST and also places them within the context of long-term reversible contraceptive options:

• 5-year cumulative life-table probability of failure of aggregated sterilization was 13/1000 procedures. By comparison, 5-year failure rates for the Copper T 380-A IUD (Paragard) were 14/1000 procedures and 5 to 11/1000 for the levonorgestrel-releasing intrauterine system (Mirena).
• Postpartum partial salpingectomy (Pomeroy or Parkland methods) had the lowest 5- and 10-year cumulative pregnancy rates: 6.3 per 1000 and 7.5 per 1000, respectively.
• Bipolar coagulation 5- and 10-year failure rates were 16.5/1000 and 24.8/1000 procedures, respectively.
• Silicone band or Yoon band (Falope ring) method 5- and 10-year failure rates were 10/1000 and 17.7/1000 procedures, respectively.
• The spring clip (Hulka) 5- and 10-year failure rates were 31.7/1000 and 36.5/1000 procedures, respectively.¹

DR SANFILIPPO: I wonder if we could compare these data to other procedures, such as the Irving technique?

DR KAUNITZ: I worry that older data may be suspect. Certainly, they were not created prospectively, as was the case with CREST, which was a large, prospective, multicenter observational study of 1685 women.

DR KAUNITZ: In terms of obstetric sterilization, are the other techniques, such as Uchida or Irving, relevant?

DR HARKINS: I don’t believe they’re performed on any regular basis.

DR SANFILIPPO: It is useful, from a historical perspective, to be familiar with these techniques. Whereas the Irving technique has a history of postpartum use, the Uchida technique has been more commonly performed as an interval method.

DR HARKINS: Both require more surgery of the fallopian tube than does the Filshie clip or the Pomeroy method. They require more time and involve a larger section of fallopian tube.

DR KAUNITZ: Yes, although they are effective, they may be more difficult to perform and are rarely used.

TABLE 3

Overall 10-year failure rates for interval procedures

TABLE 4

Long-term failure rates for Mark VI hinged Filshie Clip System sterilization (interval procedures)

Summary of the medical literature

In addition to the trials previously discussed by the roundtable participants, various studies and literature searches have reviewed sterilization in general and provide specific additional documentation about the Filshie clip, as follows.

Peterson (2008). This recent overview summarized the literature on sterilization to date, noting that overall sterilization-attributed mortality rates are 1 to 2 procedures per 100,000 performed.¹⁰ For women who undergo a sterilization procedure at the time of C-section delivery, the risk of major morbidity is defined primarily by the risks associated with delivery. Likewise, after vaginal delivery, the risk of major morbidity from sterilization is potentially related to complications of pregnancy or delivery.

It should be noted that the risk of complications has been reported to be significantly higher among women who have diabetes, are obese, have had prior abdominal or pelvic surgery, or receive general anesthesia. Further, data suggest that sterilization has a negligible impact on changes in menstrual patterns. Studies have shown that women who have tubal sterilizations are 4 to 5 times more likely to have subsequent hysterectomies than are women whose partners have had vasectomies. The risk is most significant among women who have gynecologic disorders (menstrual abnormalities, endometriosis, uterine leiomyomata, pelvic inflammatory disease, and ovarian cysts) at the time of sterilization. However, most women with gynecologic disorders at sterilization did not undergo hysterectomy during follow-up. No biological explanation for this increased risk has been identified, and it is unlikely to reflect a biological impact of sterilization. A possible explanation for this association is in the setting of abnormal bleeding, regardless of cause. Women who have been sterilized may be more likely to consider themselves appropriate candidates for hysterectomy than do other women.

Compared with sexually active women using no contraception, women who have been sterilized have a lower overall risk of ectopic pregnancy. However, when pregnancy occurs in a sterilized woman, the risk that the pregnancy is ectopic is high. Following bipolar coagulation, for example, 65% of pregnancies are ectopic. Following use of the Pomeroy or Parkland sterilization methods postpartum, 20% of pregnancies are ectopic, whereas 15% of pregnancies after clip sterilization are ectopic.¹⁰ These observations underscore the importance of ruling out ectopic pregnancy when a woman who has been sterilized is found to be pregnant.

These practice guidelines note that tubal sterilization may be recommended as a safe and effective method for women who want permanent contraception.¹ The procedure is not intended to be reversible and does not protect against sexually transmitted diseases.

Morbidity and mortality rates with tubal ligation are low, although they are higher than those of vasectomy. Efficacy rates are similar. Tubal sterilization is more effective than short-term, user-dependent contraception methods.¹ Failure rates of tubal sterilization are comparable to those of intrauterine contraceptive devices.^10,12

Kovacs (2002). In this retrospective Australian trial, questionnaires assessed the failure rate of the Filshie clip. Of the 30,000 laparoscopic Filshie clip procedures performed, 276 of 277 gynecologists responded (99.6%). A total of 73 failures were reported, providing an estimated failure rate of 2 to 3 per 1000.¹¹ It is worth noting that Kovacs reported no ectopic sterilizations in a review of 30,000 procedures performed with the Filshie clip.¹¹

Penfield (2001). This overview evaluates the literature on the Filshie clip since its initial use in 1981 and reveals a high level of acceptance worldwide because of its effective design and ease of application. It also notes the usefulness of mechanical devices that avoid the risk of accidental electrical burns and reduce the risk of ectopic pregnancy. This review notes that the Filshie clip also features minimal tubal destruction, thereby allowing maximum potential for reversibility. It includes these practical tips for clinicians:

• To prevent dropping the open clip into the abdomen, open the end of the applicator slowly, because the jaw of the applicator opens quicker than the clip can open spontaneously.
• Tubal transection is a rare event that is usually associated with a large fallopian tube that has been clipped too quickly. Close the clip slowly to “milk away” edema. If transection occurs, place a clip on both ends of the transected tube.
• Use of the double-puncture technique for all laparoscopic sterilization procedures is strongly recommended.¹³

Conclusion

The Filshie clip provides an important option for clinicians who perform postpartum sterilization. The medical literature highlights both the safety and efficacy of the device, and also demonstrates that it is easy to use and that procedures performed with this device can be done quickly.

Disclosures

• Dr Harkins is a consultant and surgical instructor for Ethicon Endo-Surgery, Inc.
• Dr Kaunitz is a consultant to Barr Pharmaceuticals, Inc, Bayer HealthCare Pharmaceuticals Inc, Johnson & Johnson, Organon USA Inc, and Warner Chilcott, and has participated in clinical trials supported by Barr Pharmaceuticals, Inc, Bayer HealthCare Pharmaceuticals Inc, Organon USA Inc, and Warner Chilcott.
• Dr Sanfilippo receives grant/research support from Barr Pharmaceuticals, Inc, and is on the speaker’s bureau for Merck & Co., Inc., and Bayer HealthCare Pharmaceuticals Inc.

EXPERT COMMENTARY

In Summer 2002, the WHI randomized trial of CEE plus MPA was stopped after the WHI Writing Group concluded that data showed more risks than benefits from therapy. The risks included venous thromboembolism and stroke, cardiovascular disease, coronary heart disease, and invasive breast cancer, while benefits were reduced risk of fracture and colorectal cancer. In this latest update, WHI investigators report on outcomes 3 years after discontinuation of the study medication.

Risk–benefit ratio improved

In contrast to findings at the time that hormone therapy was discontinued in the WHI, no increased risk of thrombosis, coronary heart disease, or stroke was observed during the subsequent 3 years in women who had taken CEE plus MPA. Furthermore, neither a statistically significant increase in the risk of invasive breast cancer nor a lower risk of fracture or colorectal malignancy was observed after discontinuation.

The global risk index for the entire 8 years of follow-up (hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.03–1.21), which was elevated at the time the trial was stopped, was noted to be 1.11 (95% CI, 0.99–1.27) during the 3 years after discontinuation. All-cause death rate was higher after discontinuation than during overall follow-up, although this difference was not statistically significant (HR, 1.15; 95% CI, 0.95–1.39 and HR, 1.04; 95% CI, 0.91–1.18, respectively).

Three years after the trial was discontinued, risk of any diagnosis of cancer was modestly higher than during active trial in women who had taken hormones (HR, 1.24; 95% CI, 1.04–1.48). An increased incidence of cancer in these women appeared to reflect a higher risk of a diagnosis of cancer other than ones prespecified as outcomes (especially lung).

EXPERT COMMENTARY

In Summer 2002, the WHI randomized trial of CEE plus MPA was stopped after the WHI Writing Group concluded that data showed more risks than benefits from therapy. The risks included venous thromboembolism and stroke, cardiovascular disease, coronary heart disease, and invasive breast cancer, while benefits were reduced risk of fracture and colorectal cancer. In this latest update, WHI investigators report on outcomes 3 years after discontinuation of the study medication.

Risk–benefit ratio improved

In contrast to findings at the time that hormone therapy was discontinued in the WHI, no increased risk of thrombosis, coronary heart disease, or stroke was observed during the subsequent 3 years in women who had taken CEE plus MPA. Furthermore, neither a statistically significant increase in the risk of invasive breast cancer nor a lower risk of fracture or colorectal malignancy was observed after discontinuation.

The global risk index for the entire 8 years of follow-up (hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.03–1.21), which was elevated at the time the trial was stopped, was noted to be 1.11 (95% CI, 0.99–1.27) during the 3 years after discontinuation. All-cause death rate was higher after discontinuation than during overall follow-up, although this difference was not statistically significant (HR, 1.15; 95% CI, 0.95–1.39 and HR, 1.04; 95% CI, 0.91–1.18, respectively).

Three years after the trial was discontinued, risk of any diagnosis of cancer was modestly higher than during active trial in women who had taken hormones (HR, 1.24; 95% CI, 1.04–1.48). An increased incidence of cancer in these women appeared to reflect a higher risk of a diagnosis of cancer other than ones prespecified as outcomes (especially lung).

EXPERT COMMENTARY

In Summer 2002, the WHI randomized trial of CEE plus MPA was stopped after the WHI Writing Group concluded that data showed more risks than benefits from therapy. The risks included venous thromboembolism and stroke, cardiovascular disease, coronary heart disease, and invasive breast cancer, while benefits were reduced risk of fracture and colorectal cancer. In this latest update, WHI investigators report on outcomes 3 years after discontinuation of the study medication.

Risk–benefit ratio improved

In contrast to findings at the time that hormone therapy was discontinued in the WHI, no increased risk of thrombosis, coronary heart disease, or stroke was observed during the subsequent 3 years in women who had taken CEE plus MPA. Furthermore, neither a statistically significant increase in the risk of invasive breast cancer nor a lower risk of fracture or colorectal malignancy was observed after discontinuation.

The global risk index for the entire 8 years of follow-up (hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.03–1.21), which was elevated at the time the trial was stopped, was noted to be 1.11 (95% CI, 0.99–1.27) during the 3 years after discontinuation. All-cause death rate was higher after discontinuation than during overall follow-up, although this difference was not statistically significant (HR, 1.15; 95% CI, 0.95–1.39 and HR, 1.04; 95% CI, 0.91–1.18, respectively).

Three years after the trial was discontinued, risk of any diagnosis of cancer was modestly higher than during active trial in women who had taken hormones (HR, 1.24; 95% CI, 1.04–1.48). An increased incidence of cancer in these women appeared to reflect a higher risk of a diagnosis of cancer other than ones prespecified as outcomes (especially lung).

Neither the total number of mammography exams interpreted over the preceding year nor the percentage of mammograms that were diagnostic affected the radiologists’ performance.

EXPERT COMMENTARY

Previous studies have suggested high variability among radiologists who interpret diagnostic mammograms. In this study, funded by the National Cancer Institute, mammograms were considered positive when they were interpreted as suspicious or highly suggestive of cancer (BI-RADS 4 or 5), or when biopsy or surgical consultation was recommended. All others were considered negative. Breast cancer was confirmed if the woman was diagnosed with invasive or in situ breast cancer within 1 year of the diagnostic mammogram. Sensitivity was defined as the percentage of positive examinations among women diagnosed with breast cancer, and the false-positive rate as the percentage of positive examinations among women without a breast cancer diagnosis.

Diagnostic mammograms are more likely to be positive

The prevalence of breast cancer is 10 times higher in women undergoing diagnostic mammography than it is in women undergoing screening mammography. That makes the high variability in diagnostic interpretation reported in this study especially troubling.

High sensitivity expedites the diagnosis of breast cancer, but also tends to increase the rate of false positives, which lead to invasive procedures and considerable anxiety among women who do not have breast cancer. Therefore, it is preferable to achieve high sensitivity without excessive numbers of false positives.

In this study, radiologists practicing at an academic center were more accurate at breast cancer diagnosis than their nonacademic peers, but this improvement was of borderline statistical significance—and few of the radiologists studied practiced in an academic setting. Moreover, women who get diagnostic mammograms at academic centers may differ from other women. In the US, most mammograms are read by general radiologists.

Alas, no concrete suggestions

This study highlights considerable variability among radiologists interpreting diagnostic mammograms, but does not specify how these mammograms can be interpreted more consistently. ObGyns should keep up-to-date on training and quality-control measures that may influence how radiologists interpret mammograms and other breast imaging.

Neither the total number of mammography exams interpreted over the preceding year nor the percentage of mammograms that were diagnostic affected the radiologists’ performance.

EXPERT COMMENTARY

Previous studies have suggested high variability among radiologists who interpret diagnostic mammograms. In this study, funded by the National Cancer Institute, mammograms were considered positive when they were interpreted as suspicious or highly suggestive of cancer (BI-RADS 4 or 5), or when biopsy or surgical consultation was recommended. All others were considered negative. Breast cancer was confirmed if the woman was diagnosed with invasive or in situ breast cancer within 1 year of the diagnostic mammogram. Sensitivity was defined as the percentage of positive examinations among women diagnosed with breast cancer, and the false-positive rate as the percentage of positive examinations among women without a breast cancer diagnosis.

Diagnostic mammograms are more likely to be positive

The prevalence of breast cancer is 10 times higher in women undergoing diagnostic mammography than it is in women undergoing screening mammography. That makes the high variability in diagnostic interpretation reported in this study especially troubling.

High sensitivity expedites the diagnosis of breast cancer, but also tends to increase the rate of false positives, which lead to invasive procedures and considerable anxiety among women who do not have breast cancer. Therefore, it is preferable to achieve high sensitivity without excessive numbers of false positives.

In this study, radiologists practicing at an academic center were more accurate at breast cancer diagnosis than their nonacademic peers, but this improvement was of borderline statistical significance—and few of the radiologists studied practiced in an academic setting. Moreover, women who get diagnostic mammograms at academic centers may differ from other women. In the US, most mammograms are read by general radiologists.

Alas, no concrete suggestions

This study highlights considerable variability among radiologists interpreting diagnostic mammograms, but does not specify how these mammograms can be interpreted more consistently. ObGyns should keep up-to-date on training and quality-control measures that may influence how radiologists interpret mammograms and other breast imaging.

Neither the total number of mammography exams interpreted over the preceding year nor the percentage of mammograms that were diagnostic affected the radiologists’ performance.

EXPERT COMMENTARY

Previous studies have suggested high variability among radiologists who interpret diagnostic mammograms. In this study, funded by the National Cancer Institute, mammograms were considered positive when they were interpreted as suspicious or highly suggestive of cancer (BI-RADS 4 or 5), or when biopsy or surgical consultation was recommended. All others were considered negative. Breast cancer was confirmed if the woman was diagnosed with invasive or in situ breast cancer within 1 year of the diagnostic mammogram. Sensitivity was defined as the percentage of positive examinations among women diagnosed with breast cancer, and the false-positive rate as the percentage of positive examinations among women without a breast cancer diagnosis.

Diagnostic mammograms are more likely to be positive

The prevalence of breast cancer is 10 times higher in women undergoing diagnostic mammography than it is in women undergoing screening mammography. That makes the high variability in diagnostic interpretation reported in this study especially troubling.

High sensitivity expedites the diagnosis of breast cancer, but also tends to increase the rate of false positives, which lead to invasive procedures and considerable anxiety among women who do not have breast cancer. Therefore, it is preferable to achieve high sensitivity without excessive numbers of false positives.

In this study, radiologists practicing at an academic center were more accurate at breast cancer diagnosis than their nonacademic peers, but this improvement was of borderline statistical significance—and few of the radiologists studied practiced in an academic setting. Moreover, women who get diagnostic mammograms at academic centers may differ from other women. In the US, most mammograms are read by general radiologists.

Alas, no concrete suggestions

This study highlights considerable variability among radiologists interpreting diagnostic mammograms, but does not specify how these mammograms can be interpreted more consistently. ObGyns should keep up-to-date on training and quality-control measures that may influence how radiologists interpret mammograms and other breast imaging.

Combining Pap and HPV testing raised sensitivity to 100% and incrementally increased the percentage of women referred for colposcopy (7.9%), compared with Pap (2.9%) or HPV testing (6.1%) alone.

EXPERT COMMENTARY

This study from Canada involving more than 10,000 nonpregnant women is likely the first randomized, controlled trial of HPV testing “as a stand-alone screening test for cervical cancer precursors in a North American population with access to quality care,” the authors observe. All participants were screened using both Pap and HPV testing, with roughly half of them undergoing the Pap test first and the other half undergoing HPV testing first. Those whose cytologic results were classified as atypical squamous cells or higher underwent colposcopy, as did all women testing positive for oncogenic HPV strains. Colposcopy was also performed in a random sample of women who had negative screening tests.

Although this trial was partially funded by an unrestricted grant from Merck Frosst Canada, the company “had no role in the design of the study, data accrual, data interpretation, or manuscript preparation,” the authors note.

Many clinicians already use both tests

Many clinicians in the United States have integrated HPV testing into cervical cancer screening on a “reflex” basis. That is, any woman whose Pap test result is classified as atypical squamous cells has her cytologic sample tested for oncogenic HPV strains. If it is HPV-positive, the woman is triaged to colposcopy.

Switch to routine HPV testing is likely a matter of time

The high sensitivity of HPV testing makes its use as primary screening particularly appealing for women who are infrequently screened.

Although sensitivity reached 100% when HPV testing was added to conventional Pap testing, it remains unclear whether both tests should be used routinely in cervical cancer screening. As Mayrand and colleagues point out in this trial, routine use of both tests “only marginally improved sensitivity as compared with HPV testing alone, while doubling the number of tests and increasing referrals.”

These important findings may propel clinicians who manage cervical cancer screening programs to make the shift from cytology-based evaluation toward routine HPV testing as the primary screen.

Combining Pap and HPV testing raised sensitivity to 100% and incrementally increased the percentage of women referred for colposcopy (7.9%), compared with Pap (2.9%) or HPV testing (6.1%) alone.

EXPERT COMMENTARY

This study from Canada involving more than 10,000 nonpregnant women is likely the first randomized, controlled trial of HPV testing “as a stand-alone screening test for cervical cancer precursors in a North American population with access to quality care,” the authors observe. All participants were screened using both Pap and HPV testing, with roughly half of them undergoing the Pap test first and the other half undergoing HPV testing first. Those whose cytologic results were classified as atypical squamous cells or higher underwent colposcopy, as did all women testing positive for oncogenic HPV strains. Colposcopy was also performed in a random sample of women who had negative screening tests.

Although this trial was partially funded by an unrestricted grant from Merck Frosst Canada, the company “had no role in the design of the study, data accrual, data interpretation, or manuscript preparation,” the authors note.

Many clinicians already use both tests

Many clinicians in the United States have integrated HPV testing into cervical cancer screening on a “reflex” basis. That is, any woman whose Pap test result is classified as atypical squamous cells has her cytologic sample tested for oncogenic HPV strains. If it is HPV-positive, the woman is triaged to colposcopy.

Switch to routine HPV testing is likely a matter of time

The high sensitivity of HPV testing makes its use as primary screening particularly appealing for women who are infrequently screened.

Although sensitivity reached 100% when HPV testing was added to conventional Pap testing, it remains unclear whether both tests should be used routinely in cervical cancer screening. As Mayrand and colleagues point out in this trial, routine use of both tests “only marginally improved sensitivity as compared with HPV testing alone, while doubling the number of tests and increasing referrals.”

These important findings may propel clinicians who manage cervical cancer screening programs to make the shift from cytology-based evaluation toward routine HPV testing as the primary screen.

Combining Pap and HPV testing raised sensitivity to 100% and incrementally increased the percentage of women referred for colposcopy (7.9%), compared with Pap (2.9%) or HPV testing (6.1%) alone.

EXPERT COMMENTARY

This study from Canada involving more than 10,000 nonpregnant women is likely the first randomized, controlled trial of HPV testing “as a stand-alone screening test for cervical cancer precursors in a North American population with access to quality care,” the authors observe. All participants were screened using both Pap and HPV testing, with roughly half of them undergoing the Pap test first and the other half undergoing HPV testing first. Those whose cytologic results were classified as atypical squamous cells or higher underwent colposcopy, as did all women testing positive for oncogenic HPV strains. Colposcopy was also performed in a random sample of women who had negative screening tests.

Although this trial was partially funded by an unrestricted grant from Merck Frosst Canada, the company “had no role in the design of the study, data accrual, data interpretation, or manuscript preparation,” the authors note.

Many clinicians already use both tests

Many clinicians in the United States have integrated HPV testing into cervical cancer screening on a “reflex” basis. That is, any woman whose Pap test result is classified as atypical squamous cells has her cytologic sample tested for oncogenic HPV strains. If it is HPV-positive, the woman is triaged to colposcopy.

Switch to routine HPV testing is likely a matter of time

The high sensitivity of HPV testing makes its use as primary screening particularly appealing for women who are infrequently screened.

Although sensitivity reached 100% when HPV testing was added to conventional Pap testing, it remains unclear whether both tests should be used routinely in cervical cancer screening. As Mayrand and colleagues point out in this trial, routine use of both tests “only marginally improved sensitivity as compared with HPV testing alone, while doubling the number of tests and increasing referrals.”

These important findings may propel clinicians who manage cervical cancer screening programs to make the shift from cytology-based evaluation toward routine HPV testing as the primary screen.

Expert Commentary

Because depression is fairly common among women of reproductive age and is often treated with SSRIs, the issue of teratogenicity is important. Earlier investigations suggested that use of these drugs—particularly paroxetine—during early pregnancy increases the risk of heart defects. These two ongoing case-control studies help clarify the relationship between prenatal use of SSRIs and birth defects, although the issue still has not been addressed definitively.

Both studies involved large populations

The first study was conducted by investigators from the Centers for Disease Control and Prevention and the University of British Columbia. It involved 9,622 infants with major birth defects and 4,092 control infants, all of whom were born between 1997 and 2002. Case infants were identified using birth-defect surveillance systems in eight US states, and control infants were randomly selected from the same regions. A woman was considered exposed to an SSRI if she used any of the medications from 1 month before to 3 months after conception.

Investigators found no significant association between maternal SSRI use in early pregnancy and most categories of birth defects, including congenital heart defects. However, they found a significant association between maternal SSRI use and anencephaly (odds ratio [OR], 2.4; 95% confidence interval [CI], 1.1–5.1), craniosynostosis (OR, 2.5; 95% CI, 1.5–4.0), and omphalocele (OR, 2.8; 95% CI, 1.3–5.7). Use of paroxetine correlated with higher pooled ORs for these three birth defects, as well as a significantly increased risk of right ventricular outflow tract obstruction.

The study by Louik and associates was funded by the National Institutes of Health and GlaxoSmithKline, the manufacturer of Paxil. It involved 9,849 infants with major birth defects and 5,860 control infants, all of whom were born in the United States or Canada between 1993 and 2005. All infants in the case and control groups were identified through their participation in the Slone Epidemiology Center Birth Defects Study, a continuing analysis of medication use in pregnancy. Because Louik and colleagues focused on first-trimester use of SSRIs, exposure was defined as use of any SSRI from 28 days before the last menstrual period through the fourth lunar month (112 days after the last menstrual period.

Use of SSRIs overall was not associated with heart defects, craniosynostosis, or omphalocele, but a significant association was found between paroxetine use and right ventricular outflow tract obstruction (based on 6 exposed subjects) and between septal defects and sertraline use (based on 13 exposed subjects).

TABLE

SSRIs in pregnancy: How they stack up

Weigh slight risk of defects against risks associated with discontinuation

These studies confirm that SSRIs are not major teratogens. Nevertheless, any woman planning to conceive and who is worried about using an SSRI during pregnancy should weigh these findings against the risks associated with discontinuing an SSRI during pregnancy.

Heightened surveillance may be justified

Consider second-trimester targeted ultrasonography to rule out fetal anomalies in women who take an SSRI in early pregnancy. And consider psychiatric monitoring for women who discontinue an SSRI before conception or in early pregnancy.

Expert Commentary

Because depression is fairly common among women of reproductive age and is often treated with SSRIs, the issue of teratogenicity is important. Earlier investigations suggested that use of these drugs—particularly paroxetine—during early pregnancy increases the risk of heart defects. These two ongoing case-control studies help clarify the relationship between prenatal use of SSRIs and birth defects, although the issue still has not been addressed definitively.

Both studies involved large populations

The first study was conducted by investigators from the Centers for Disease Control and Prevention and the University of British Columbia. It involved 9,622 infants with major birth defects and 4,092 control infants, all of whom were born between 1997 and 2002. Case infants were identified using birth-defect surveillance systems in eight US states, and control infants were randomly selected from the same regions. A woman was considered exposed to an SSRI if she used any of the medications from 1 month before to 3 months after conception.

Investigators found no significant association between maternal SSRI use in early pregnancy and most categories of birth defects, including congenital heart defects. However, they found a significant association between maternal SSRI use and anencephaly (odds ratio [OR], 2.4; 95% confidence interval [CI], 1.1–5.1), craniosynostosis (OR, 2.5; 95% CI, 1.5–4.0), and omphalocele (OR, 2.8; 95% CI, 1.3–5.7). Use of paroxetine correlated with higher pooled ORs for these three birth defects, as well as a significantly increased risk of right ventricular outflow tract obstruction.

The study by Louik and associates was funded by the National Institutes of Health and GlaxoSmithKline, the manufacturer of Paxil. It involved 9,849 infants with major birth defects and 5,860 control infants, all of whom were born in the United States or Canada between 1993 and 2005. All infants in the case and control groups were identified through their participation in the Slone Epidemiology Center Birth Defects Study, a continuing analysis of medication use in pregnancy. Because Louik and colleagues focused on first-trimester use of SSRIs, exposure was defined as use of any SSRI from 28 days before the last menstrual period through the fourth lunar month (112 days after the last menstrual period.

Use of SSRIs overall was not associated with heart defects, craniosynostosis, or omphalocele, but a significant association was found between paroxetine use and right ventricular outflow tract obstruction (based on 6 exposed subjects) and between septal defects and sertraline use (based on 13 exposed subjects).

TABLE

SSRIs in pregnancy: How they stack up

Weigh slight risk of defects against risks associated with discontinuation

These studies confirm that SSRIs are not major teratogens. Nevertheless, any woman planning to conceive and who is worried about using an SSRI during pregnancy should weigh these findings against the risks associated with discontinuing an SSRI during pregnancy.

Heightened surveillance may be justified

Consider second-trimester targeted ultrasonography to rule out fetal anomalies in women who take an SSRI in early pregnancy. And consider psychiatric monitoring for women who discontinue an SSRI before conception or in early pregnancy.

Expert Commentary

Because depression is fairly common among women of reproductive age and is often treated with SSRIs, the issue of teratogenicity is important. Earlier investigations suggested that use of these drugs—particularly paroxetine—during early pregnancy increases the risk of heart defects. These two ongoing case-control studies help clarify the relationship between prenatal use of SSRIs and birth defects, although the issue still has not been addressed definitively.

Both studies involved large populations

The first study was conducted by investigators from the Centers for Disease Control and Prevention and the University of British Columbia. It involved 9,622 infants with major birth defects and 4,092 control infants, all of whom were born between 1997 and 2002. Case infants were identified using birth-defect surveillance systems in eight US states, and control infants were randomly selected from the same regions. A woman was considered exposed to an SSRI if she used any of the medications from 1 month before to 3 months after conception.

Investigators found no significant association between maternal SSRI use in early pregnancy and most categories of birth defects, including congenital heart defects. However, they found a significant association between maternal SSRI use and anencephaly (odds ratio [OR], 2.4; 95% confidence interval [CI], 1.1–5.1), craniosynostosis (OR, 2.5; 95% CI, 1.5–4.0), and omphalocele (OR, 2.8; 95% CI, 1.3–5.7). Use of paroxetine correlated with higher pooled ORs for these three birth defects, as well as a significantly increased risk of right ventricular outflow tract obstruction.

The study by Louik and associates was funded by the National Institutes of Health and GlaxoSmithKline, the manufacturer of Paxil. It involved 9,849 infants with major birth defects and 5,860 control infants, all of whom were born in the United States or Canada between 1993 and 2005. All infants in the case and control groups were identified through their participation in the Slone Epidemiology Center Birth Defects Study, a continuing analysis of medication use in pregnancy. Because Louik and colleagues focused on first-trimester use of SSRIs, exposure was defined as use of any SSRI from 28 days before the last menstrual period through the fourth lunar month (112 days after the last menstrual period.

Use of SSRIs overall was not associated with heart defects, craniosynostosis, or omphalocele, but a significant association was found between paroxetine use and right ventricular outflow tract obstruction (based on 6 exposed subjects) and between septal defects and sertraline use (based on 13 exposed subjects).

TABLE

SSRIs in pregnancy: How they stack up

Weigh slight risk of defects against risks associated with discontinuation

These studies confirm that SSRIs are not major teratogens. Nevertheless, any woman planning to conceive and who is worried about using an SSRI during pregnancy should weigh these findings against the risks associated with discontinuing an SSRI during pregnancy.

Heightened surveillance may be justified

Consider second-trimester targeted ultrasonography to rule out fetal anomalies in women who take an SSRI in early pregnancy. And consider psychiatric monitoring for women who discontinue an SSRI before conception or in early pregnancy.

Expert Commentary

Although rare, ovarian cancer usually is diagnosed late; for this reason, it is the most lethal gynecologic cancer in the US. In the Million Women Study, a massive cohort study carried out in the United Kingdom, roughly 950,000 postmenopausal women were surveyed between 1996 and 2001 and approximately 3 years later. Participants had no history of bilateral oophorectomy or ovarian cancer upon entry into the trial. Of these women, 50% had never used HRT, 30% were current users, and 20% had used it in the past. Over the course of the trial, 2,273 ovarian cancers were diagnosed, and 1,593 women died from the disease.

Elevated risk after 5 years of use

Compared with never users, women who had currently used HRT for longer than 5 years had a higher risk of 1) being given a diagnosis of (relative risk [RR], 1.20; 95% confidence interval [CI], 1.09–1.32) and 2) dying from (RR, 1.23; 95% CI, 1.09–1.38) ovarian cancer. However, current users with less than 5 years of use had no significantly elevated risk.

Other studies have suggested an association between HRT and ovarian cancer, but most have lacked power to determine the incidence of this rare malignancy. Although both estrogen-only and combination HRT were associated with ovarian cancer in current users in this trial, the findings are otherwise similar to those in regard to HRT and incident breast cancer.¹ In the WHI, there was no elevated risk of breast cancer when a woman used combination HRT for less than 5 years.²

Some will choose to counsel women about possible elevated risk

Because the Million Women Study is an observational study, with HRT exposure reported by participants, selection bias is possible (ie, respondents with ovarian cancer may be more likely to report HRT use). With this caveat, some clinicians may choose to counsel women that more than 5 years of unopposed estrogen or combination HRT may increase the risk of ovarian cancer, just as combination HRT raises the risk of breast cancer. A shorter duration of HRT does not appear to increase the risk of ovarian cancer and will probably serve the needs of many symptomatic, newly menopausal women.

Expert Commentary

Although rare, ovarian cancer usually is diagnosed late; for this reason, it is the most lethal gynecologic cancer in the US. In the Million Women Study, a massive cohort study carried out in the United Kingdom, roughly 950,000 postmenopausal women were surveyed between 1996 and 2001 and approximately 3 years later. Participants had no history of bilateral oophorectomy or ovarian cancer upon entry into the trial. Of these women, 50% had never used HRT, 30% were current users, and 20% had used it in the past. Over the course of the trial, 2,273 ovarian cancers were diagnosed, and 1,593 women died from the disease.

Elevated risk after 5 years of use

Compared with never users, women who had currently used HRT for longer than 5 years had a higher risk of 1) being given a diagnosis of (relative risk [RR], 1.20; 95% confidence interval [CI], 1.09–1.32) and 2) dying from (RR, 1.23; 95% CI, 1.09–1.38) ovarian cancer. However, current users with less than 5 years of use had no significantly elevated risk.

Other studies have suggested an association between HRT and ovarian cancer, but most have lacked power to determine the incidence of this rare malignancy. Although both estrogen-only and combination HRT were associated with ovarian cancer in current users in this trial, the findings are otherwise similar to those in regard to HRT and incident breast cancer.¹ In the WHI, there was no elevated risk of breast cancer when a woman used combination HRT for less than 5 years.²

Some will choose to counsel women about possible elevated risk

Because the Million Women Study is an observational study, with HRT exposure reported by participants, selection bias is possible (ie, respondents with ovarian cancer may be more likely to report HRT use). With this caveat, some clinicians may choose to counsel women that more than 5 years of unopposed estrogen or combination HRT may increase the risk of ovarian cancer, just as combination HRT raises the risk of breast cancer. A shorter duration of HRT does not appear to increase the risk of ovarian cancer and will probably serve the needs of many symptomatic, newly menopausal women.

Expert Commentary

Although rare, ovarian cancer usually is diagnosed late; for this reason, it is the most lethal gynecologic cancer in the US. In the Million Women Study, a massive cohort study carried out in the United Kingdom, roughly 950,000 postmenopausal women were surveyed between 1996 and 2001 and approximately 3 years later. Participants had no history of bilateral oophorectomy or ovarian cancer upon entry into the trial. Of these women, 50% had never used HRT, 30% were current users, and 20% had used it in the past. Over the course of the trial, 2,273 ovarian cancers were diagnosed, and 1,593 women died from the disease.

Elevated risk after 5 years of use

Compared with never users, women who had currently used HRT for longer than 5 years had a higher risk of 1) being given a diagnosis of (relative risk [RR], 1.20; 95% confidence interval [CI], 1.09–1.32) and 2) dying from (RR, 1.23; 95% CI, 1.09–1.38) ovarian cancer. However, current users with less than 5 years of use had no significantly elevated risk.

Other studies have suggested an association between HRT and ovarian cancer, but most have lacked power to determine the incidence of this rare malignancy. Although both estrogen-only and combination HRT were associated with ovarian cancer in current users in this trial, the findings are otherwise similar to those in regard to HRT and incident breast cancer.¹ In the WHI, there was no elevated risk of breast cancer when a woman used combination HRT for less than 5 years.²

Some will choose to counsel women about possible elevated risk

Because the Million Women Study is an observational study, with HRT exposure reported by participants, selection bias is possible (ie, respondents with ovarian cancer may be more likely to report HRT use). With this caveat, some clinicians may choose to counsel women that more than 5 years of unopposed estrogen or combination HRT may increase the risk of ovarian cancer, just as combination HRT raises the risk of breast cancer. A shorter duration of HRT does not appear to increase the risk of ovarian cancer and will probably serve the needs of many symptomatic, newly menopausal women.

<huc>A.</huc>Yes. In this study from France, the association between estrogen–progestin regimens and breast cancer varied significantly, depending on the progestin. The relative risk of invasive breast cancer was 1.08 for progesterone (95% confidence interval 0.89–1.31), 1.16 for dydrogesterone (0.94–1.43), and 1.69 for other progestins (1.50–1.91).

Expert Commentary

Fear of breast cancer discourages many women from using menopausal hormone therapy (HT), and fuels anxiety among patients and physicians alike. A large body of evidence from clinical trials and observational studies indicates that the use of estrogen-only therapy for less than 5 years has minimal, if any, impact on the risk of breast cancer.^1-5 In contrast, use of combination estrogen–progestin hormone therapy for more than 5 years is associated with an elevated risk of breast cancer,^3,6,7 and this risk is greater than the risk associated with the use of estrogen alone. This modestly increased risk is comparable to the elevated risk of breast cancer associated with lifestyle choices such as daily alcohol use, postmenopausal obesity, and lack of regular exercise.⁸

Few have focused on effects of specific progestins

Because the addition of a progestin to estrogen therapy in women with a uterus appears to play a key role in increasing the risk of breast cancer, and because a variety of progestins are available (including levonorgestrel, medroxyprogesterone acetate [MPA], norethindrone acetate, and progesterone), it makes sense to ask whether some progestins increase the risk of breast cancer more than others.

Although MPA is the most widely used progestin in menopausal practice in this country—and was the progestin used in the Women’s Health Initiative (WHI) trial of combination HT—other progestins are more common in Europe. The evidence has not definitively demonstrated that the choice of progestin affects the degree of breast cancer risk in women using HT.³

Large French population had high rate of HT use

HT is commonly used by menopausal women in France, and progesterone is the most widely prescribed progestin for endometrial protection, as Fournier and colleagues note. They conducted this large, prospective cohort study to assess HT use and breast cancer risk in almost 100,000 French teachers and wives of teachers, with intriguing results. Among the women followed in this study, 70% had used HT. The mean age at initiation was 52.4 years, and the mean duration of use and followup was 7 and 8.1 years, respectively.

Findings in regard to estrogen differ from those of other studies

Overall, the risk of being diagnosed with invasive breast cancer was significantly elevated with the use of estrogen alone, at a relative risk of 1.29 (95% confidence interval 1.02–1.65). This small elevation contrasts the findings of the WHI and Nurses’ Health studies, which identified no increased risk of breast cancer with estrogen alone.^4,5

Transdermal estrogen is widely used in menopausal women in France; route of estrogen administration did not affect breast cancer risk in this study.

Progesterone was associated with no elevated risk

The use of combination HT with MPA or norethindrone acetate was associated with higher relative risks than estrogen alone: 1.48 (1.02–2.16) and 2.11 (1.56–2.86), respectively. In contrast, combination HT with progesterone was not associated with an elevated risk of breast cancer, with a relative risk of 1.08 (0.89–1.31).

Fournier and colleagues point out that theirs is the first epidemiologic study to assess the risk of breast cancer associated with HT containing progesterone. They also cite recent data in postmenopausal primates indicating that combination HT with micronized progesterone causes lower rates of proliferation in lobular and ductal breast epithelium, compared with MPA-based hormone therapy.⁹

Clinical recommendations: For now, simply ensure adequate progestin

The findings of a single study generally should not dictate clinical practice. It remains the standard of care to ensure sufficient progestin (whether levonorgestrel, MPA, norethindrone acetate, or micronized progesterone) to prevent endometrial hyperplasia when prescribing HT for menopausal women with a uterus.

The findings of this study raise the possibility that progesterone may be safer than other progestins with respect to breast neoplasia. Additional epidemiologic data assessing the safety of progesterone in comparison with other progestins are welcome, but studies would need to be conducted in regions like France, where progesterone is widely used.

In the meantime, ObGyns who wish to prescribe micronized progesterone as part of combination HT should rule out peanut allergy and advise patients to take the micronized tablets at bedtime because of their tendency to cause sleepiness. The appropriate dosage of micronized progesterone to prevent endometrial proliferation in menopausal women using estrogen is 100 mg nightly or 200 mg cyclically for 12 or more days each month.¹⁰

<huc>A.</huc>Yes. In this study from France, the association between estrogen–progestin regimens and breast cancer varied significantly, depending on the progestin. The relative risk of invasive breast cancer was 1.08 for progesterone (95% confidence interval 0.89–1.31), 1.16 for dydrogesterone (0.94–1.43), and 1.69 for other progestins (1.50–1.91).

Expert Commentary

Fear of breast cancer discourages many women from using menopausal hormone therapy (HT), and fuels anxiety among patients and physicians alike. A large body of evidence from clinical trials and observational studies indicates that the use of estrogen-only therapy for less than 5 years has minimal, if any, impact on the risk of breast cancer.^1-5 In contrast, use of combination estrogen–progestin hormone therapy for more than 5 years is associated with an elevated risk of breast cancer,^3,6,7 and this risk is greater than the risk associated with the use of estrogen alone. This modestly increased risk is comparable to the elevated risk of breast cancer associated with lifestyle choices such as daily alcohol use, postmenopausal obesity, and lack of regular exercise.⁸

Few have focused on effects of specific progestins

Because the addition of a progestin to estrogen therapy in women with a uterus appears to play a key role in increasing the risk of breast cancer, and because a variety of progestins are available (including levonorgestrel, medroxyprogesterone acetate [MPA], norethindrone acetate, and progesterone), it makes sense to ask whether some progestins increase the risk of breast cancer more than others.

Although MPA is the most widely used progestin in menopausal practice in this country—and was the progestin used in the Women’s Health Initiative (WHI) trial of combination HT—other progestins are more common in Europe. The evidence has not definitively demonstrated that the choice of progestin affects the degree of breast cancer risk in women using HT.³

Large French population had high rate of HT use

HT is commonly used by menopausal women in France, and progesterone is the most widely prescribed progestin for endometrial protection, as Fournier and colleagues note. They conducted this large, prospective cohort study to assess HT use and breast cancer risk in almost 100,000 French teachers and wives of teachers, with intriguing results. Among the women followed in this study, 70% had used HT. The mean age at initiation was 52.4 years, and the mean duration of use and followup was 7 and 8.1 years, respectively.

Findings in regard to estrogen differ from those of other studies

Overall, the risk of being diagnosed with invasive breast cancer was significantly elevated with the use of estrogen alone, at a relative risk of 1.29 (95% confidence interval 1.02–1.65). This small elevation contrasts the findings of the WHI and Nurses’ Health studies, which identified no increased risk of breast cancer with estrogen alone.^4,5

Transdermal estrogen is widely used in menopausal women in France; route of estrogen administration did not affect breast cancer risk in this study.

Progesterone was associated with no elevated risk

The use of combination HT with MPA or norethindrone acetate was associated with higher relative risks than estrogen alone: 1.48 (1.02–2.16) and 2.11 (1.56–2.86), respectively. In contrast, combination HT with progesterone was not associated with an elevated risk of breast cancer, with a relative risk of 1.08 (0.89–1.31).

Fournier and colleagues point out that theirs is the first epidemiologic study to assess the risk of breast cancer associated with HT containing progesterone. They also cite recent data in postmenopausal primates indicating that combination HT with micronized progesterone causes lower rates of proliferation in lobular and ductal breast epithelium, compared with MPA-based hormone therapy.⁹

Clinical recommendations: For now, simply ensure adequate progestin

The findings of a single study generally should not dictate clinical practice. It remains the standard of care to ensure sufficient progestin (whether levonorgestrel, MPA, norethindrone acetate, or micronized progesterone) to prevent endometrial hyperplasia when prescribing HT for menopausal women with a uterus.

The findings of this study raise the possibility that progesterone may be safer than other progestins with respect to breast neoplasia. Additional epidemiologic data assessing the safety of progesterone in comparison with other progestins are welcome, but studies would need to be conducted in regions like France, where progesterone is widely used.

In the meantime, ObGyns who wish to prescribe micronized progesterone as part of combination HT should rule out peanut allergy and advise patients to take the micronized tablets at bedtime because of their tendency to cause sleepiness. The appropriate dosage of micronized progesterone to prevent endometrial proliferation in menopausal women using estrogen is 100 mg nightly or 200 mg cyclically for 12 or more days each month.¹⁰

<huc>A.</huc>Yes. In this study from France, the association between estrogen–progestin regimens and breast cancer varied significantly, depending on the progestin. The relative risk of invasive breast cancer was 1.08 for progesterone (95% confidence interval 0.89–1.31), 1.16 for dydrogesterone (0.94–1.43), and 1.69 for other progestins (1.50–1.91).

Expert Commentary

Fear of breast cancer discourages many women from using menopausal hormone therapy (HT), and fuels anxiety among patients and physicians alike. A large body of evidence from clinical trials and observational studies indicates that the use of estrogen-only therapy for less than 5 years has minimal, if any, impact on the risk of breast cancer.^1-5 In contrast, use of combination estrogen–progestin hormone therapy for more than 5 years is associated with an elevated risk of breast cancer,^3,6,7 and this risk is greater than the risk associated with the use of estrogen alone. This modestly increased risk is comparable to the elevated risk of breast cancer associated with lifestyle choices such as daily alcohol use, postmenopausal obesity, and lack of regular exercise.⁸

Few have focused on effects of specific progestins

Because the addition of a progestin to estrogen therapy in women with a uterus appears to play a key role in increasing the risk of breast cancer, and because a variety of progestins are available (including levonorgestrel, medroxyprogesterone acetate [MPA], norethindrone acetate, and progesterone), it makes sense to ask whether some progestins increase the risk of breast cancer more than others.

Although MPA is the most widely used progestin in menopausal practice in this country—and was the progestin used in the Women’s Health Initiative (WHI) trial of combination HT—other progestins are more common in Europe. The evidence has not definitively demonstrated that the choice of progestin affects the degree of breast cancer risk in women using HT.³

Large French population had high rate of HT use

HT is commonly used by menopausal women in France, and progesterone is the most widely prescribed progestin for endometrial protection, as Fournier and colleagues note. They conducted this large, prospective cohort study to assess HT use and breast cancer risk in almost 100,000 French teachers and wives of teachers, with intriguing results. Among the women followed in this study, 70% had used HT. The mean age at initiation was 52.4 years, and the mean duration of use and followup was 7 and 8.1 years, respectively.

Findings in regard to estrogen differ from those of other studies

Overall, the risk of being diagnosed with invasive breast cancer was significantly elevated with the use of estrogen alone, at a relative risk of 1.29 (95% confidence interval 1.02–1.65). This small elevation contrasts the findings of the WHI and Nurses’ Health studies, which identified no increased risk of breast cancer with estrogen alone.^4,5

Transdermal estrogen is widely used in menopausal women in France; route of estrogen administration did not affect breast cancer risk in this study.

Progesterone was associated with no elevated risk

The use of combination HT with MPA or norethindrone acetate was associated with higher relative risks than estrogen alone: 1.48 (1.02–2.16) and 2.11 (1.56–2.86), respectively. In contrast, combination HT with progesterone was not associated with an elevated risk of breast cancer, with a relative risk of 1.08 (0.89–1.31).

Fournier and colleagues point out that theirs is the first epidemiologic study to assess the risk of breast cancer associated with HT containing progesterone. They also cite recent data in postmenopausal primates indicating that combination HT with micronized progesterone causes lower rates of proliferation in lobular and ductal breast epithelium, compared with MPA-based hormone therapy.⁹

Clinical recommendations: For now, simply ensure adequate progestin

The findings of a single study generally should not dictate clinical practice. It remains the standard of care to ensure sufficient progestin (whether levonorgestrel, MPA, norethindrone acetate, or micronized progesterone) to prevent endometrial hyperplasia when prescribing HT for menopausal women with a uterus.

The findings of this study raise the possibility that progesterone may be safer than other progestins with respect to breast neoplasia. Additional epidemiologic data assessing the safety of progesterone in comparison with other progestins are welcome, but studies would need to be conducted in regions like France, where progesterone is widely used.

In the meantime, ObGyns who wish to prescribe micronized progesterone as part of combination HT should rule out peanut allergy and advise patients to take the micronized tablets at bedtime because of their tendency to cause sleepiness. The appropriate dosage of micronized progesterone to prevent endometrial proliferation in menopausal women using estrogen is 100 mg nightly or 200 mg cyclically for 12 or more days each month.¹⁰

I am delighted that Dr. Michael McClung, an internationally recognized expert in skeletal health, has agreed to review current evidence on the prevention of osteoporotic fractures in menopausal women in the latter part of this article.

New WHI analysis confirms safety of short-term combination HT

Anderson GL, Chlebowski RT, Rossouw JE, et al. Prior hormone therapy and breast cancer risk in the Women’s Health Initiative randomized trial of estrogen and progestin. Maturitas. 2006;55:103–115.

At the annual San Antonio Breast Cancer Symposium in December, investigators presented data showing that the incidence of breast cancer in US women decreased by 7% from 2002 to 2003, a striking decline that was most prominent among women aged 50 to 69 years. The presenters speculated that the plummeting rates of HT use following publication of the initial Women’s Health Initiative (WHI) findings in the summer of 2002 (in regard to the estrogen–progestin arm²) might be responsible for this decline.³

The major media attention that followed this presentation makes one thing clear: Concerns about developing breast cancer with HT use continue to fuel anxiety among women. Although secular trend data on the national breast cancer incidence can help generate hypotheses, they cannot explain the trends. What can shed light on the association between estrogen–progestin HT and breast cancer are important new data recently released by WHI investigators.

Women new to HT had no increased risk of breast cancer

In the 2006 subgroup analysis of WHI participants in the estrogen–progestin arm, investigators focused on HT use before enrollment in the trial. Recall that in this part of the WHI, 16,608 women with an intact uterus were randomized to conjugated equine estrogen plus medroxyprogesterone acetate or placebo. Use of the study medication was stopped after a mean follow-up of 5.6 years (mean exposure to HT: 4.4 years). Overall, the risk of invasive breast cancer was slightly higher with combination HT than placebo (hazard ratio [HR] 1.24; 95% confidence interval [CI] 1.01–1.54).²

In the 2006 report from the 2002 WHI study of estrogen–progestin HT versus placebo, investigators compared the risk of being diagnosed with breast cancer in 12,297 women who had not used HT prior to study enrollment with the risk in 4,311 participants who had previously used HT. Of the previous users, 42% reported less than 2 years of use prior to WHI enrollment, and 36% reported more than 4 years of HT prior to WHI enrollment.

The findings: Among WHI participants who had never before used HT, the use of estrogen–progestin HT in the study was not associated with an elevated risk of being diagnosed with breast cancer (HR 1.02; 95% CI 0.77–1.36). However, among previous HT users, the additional use of HT in the WHI study was associated with a risk nearly double that of placebo users (HR 1.96, 95% CI 1.17–3.27).

The reassuring results of this WHI subgroup analysis received little media attention in the United States, probably because the report appeared in a journal that has low readership in this country. WHI and other findings allow us to reassure women who have undergone hysterectomy that use of unopposed estrogen has little, if any, impact on breast cancer risk in menopausal women.^4,5 This new WHI subgroup analysis, along with a recent review of European and North American data,⁶ allows ObGyns to counsel women with an intact uterus that up to 5 years of combination estrogen–progestin hormone therapy also has little, if any, impact on breast cancer risk.

Not much to recommend among nonhormonal therapies

Newton KM, Reed SD, LaCroix AZ, Grothaus LC, Ehrlich K, Guiltinan J. Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy or placebo. Ann Intern Med. 2006;145:869–879.

Grady D. Clinical practice. Management of menopausal symptoms. N Engl J Med. 2006;355:2338–2347.

Grady D, Cohen B, Tice J, et al. Ineffectiveness of sertraline for treatment of menopausal hot flushes: a randomized controlled trial. Obstet Gynecol. 2007;109:823–830.

Loprinzi CL, Kugler JW, Barton DL, et al. Phase III trial of gabapentin alone or in conjunction with an antidepressant in the management of hot flashes in women who have inadequate control with an antidepressant alone: NCCTG N03C5. J Clin Oncol. 2007;25:308–312.

Since publication of the initial WHI findings in 2002,² interest in nonhormonal management of vasomotor symptoms has increased among menopausal women and their clinicians. The botanical black cohosh and “nutraceutical” soy or isoflavone supplements represent the nonprescription remedies most widely used for relief of hot flashes. Unfortunately, accumulating evidence does not support the efficacy of these popular remedies.

In a recent NIH-funded, randomized, double-blind, placebo-controlled clinical trial, Newton and colleagues compared the following interventions:

• black cohosh, 160 mg daily
  
• daily multibotanical supplement that included 200 mg of black cohosh and 9 other ingredients
  
• the multibotanical supplement plus counseling regarding dietary soy
  
• conjugated equine estrogen, 0.625 mg daily (with or without 2.5 mg of medroxyprogesterone acetate)
  
• placebo
  

The findings: At 3, 6, and 12 months, women allocated to estrogen (with or without progestin) had statistically significant relief of symptoms. In contrast, women allocated to botanical and/or herbal supplements experienced minimal relief, comparable to the effects of placebo.

The findings of this important study, as well as those of Grady, are discouraging: Black cohosh, botanicals, and encouraging increased soy intake are ineffective in the treatment of vasomotor symptoms.

Evidence on antidepressants is inconclusive

Selective serotonin reuptake inhibitors (SSRIs) and the antidepressant venlafaxine have been assessed for their effects on menopausal vasomotor symptoms, particularly in breast cancer survivors. In a recent review and also a randomized trial, Grady reports that the SSRIs citalopram and sertraline do not appear to be effective, and the findings in regard to the SSRI fluoxetine and venlafaxine have been inconsistent. Compared with placebo, the SSRI paroxetine has eased vasomotor symptoms to a modest degree in breast cancer survivors, but had little effect in women who have not had the disease.

Breast cancer survivors often take tamoxifen or aromatase inhibitors, medications that can induce or aggravate hot flashes. Breast cancer survivors also have a higher prevalence of mood disorders. These factors suggest that the experience and treatment of menopausal symptoms differ between breast cancer survivors and the general population.

Overall, Grady notes, for women with bothersome vasomotor symptoms who have no history of breast cancer, clinical trials of antidepressants have not been encouraging.

Gabapentin is more effective than antidepressants, but with a price

Clinical trials of gabapentin suggest that this anticonvulsant is moderately effective in the nonhormonal treatment of vasomotor symptoms, and the phase III trial by Loprinzi and colleagues finds it to be more effective therapy for vasomotor symptoms than antidepressants.

The drawback? This drug must be taken 2 or 3 times daily, and side effects (including fatigue) limit its attractiveness.

When deciding whom to treat, consider risk as well as BMD

Sanders KM, Nicholson GC, Watts JJ, et al. Half the burden of fragility fractures in the community occur in women without osteoporosis. When is fracture prevention cost-effective? Bone. 2006;38:694–700.

The diagnosis of osteoporosis in postmenopausal women is now based on a threshold bone mineral density (BMD) T-score of –2.5. However, BMD is only one of several important risk factors for fracture, and most patients who experience a fracture related to osteoporosis do not have BMD values in the range consistent with osteoporosis, as Sanders and colleagues observe. Therefore, clinicians are faced with this question: Which patients who do not have osteoporosis should be treated to prevent fracture?

The World Health Organization (WHO) task force on fracture risk assessment, under the leadership of Professor John Kanis, has developed an algorithm to estimate fracture probability in individual patients.⁷ This algorithm is based on a sophisticated analysis of almost all of the large epidemiological studies performed worldwide that have assessed relationships between clinical risk factors and fracture risk. By including the 3 major risk factors (age, BMD, and fracture history), as well as weaker risk factors (family history of hip fracture, current smoking, excess alcohol intake, and history of chronic glucocorticoid use), the absolute risk of developing a fracture of the spine, wrist, hip, or shoulder over the next 10 years will be estimated. This information will be the basis for revised guidelines by the National Osteoporosis Foundation (NOF) and other organizations. The new guidelines will include recommendations for treating patients at or above a certain threshold of fracture risk rather than a certain BMD threshold. The new treatment threshold will be based on a combination of cost- and clinical effectiveness.

The WHO algorithm and revised NOF guidelines are expected later this year.

New paradigm will shift focus to older women

This revised approach will shift the focus of therapy from young postmenopausal women at low fracture risk toward older women who do not have osteoporosis but do have an increased risk of fracture by virtue of their age and other factors.⁸ This will direct therapy more appropriately to patients who stand to gain the most and in whom therapy has been proven to reduce fracture risk.

Despite concerns, bisphosphonates appear to be safe for the long term

Bisphosphonates are the most extensively studied and widely used treatment for osteoporosis. Alendronate, the first bisphosphonate approved for the treatment of osteoporosis in the United States, has been available for more than 11 years. In general, all 3 of the currently approved bisphosphonates are well tolerated, and studies following patients for 7 to 10 years have not demonstrated significant adverse events or evidence of skeletal harm with long-term use.^9-11 However, because the drugs accumulate in the skeleton, there is a theoretical concern that long-term use will lead to over-suppression of bone turnover.

Small series of patients receiving bisphosphonates have described unusual fractures, evidence of low formation, and poor fracture healing, suggesting skeletal harm in at least some patients.¹² Bone biopsies performed in patients who received alendronate for 10 years or risedronate for 5 years showed evidence of bone remodeling in all the biopsy samples.^11,13 There was no progressive inhibition of bone metabolism in those biopsies compared with biopsies taken from patients who had received shorter-term treatment.

These findings are consistent with bone-turnover marker data suggesting no progressive suppression of bone turnover with continued use.^10,11,13 Biochemical indices of bone resorption are reduced to the lower half of the normal premenopausal range within about 3 months of beginning therapy, and values remain at that new level as long as patients receive the drug.

Risk of osteonecrosis of the jaw is low in general population

Woo SB, Hellstein JW, Kalmar JR. Narrative review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med. 2006;144:753–761.

Bilezikian JP. Osteonecrosis of the jaw—do bisphosphonates pose a risk? N Engl J Med. 2006;355:2278–2281.

An association between bisphosphonate therapy and nonhealing lesions of the jaw (so-called osteonecrosis of the jaw) has been observed, but primarily affects patients with cancer-related bone diseases who receive high doses of intravenous therapy in addition to chemotherapy. Patients receiving oral doses of bisphosphonates for osteoporosis in Paget’s disease have also had these lesions, as Woo and colleagues point out.

There is much that we do not know about this clinical problem, including its pathogenesis, whether the risk increases with longer-term use, and whether stopping therapy reduces the risk of developing lesions or improves the outcome of lesions already present. We do know that the incidence of exposed bone in the jaw in patients receiving bisphosphonate therapy for osteoporosis is low, estimated to range from 1 in 1,000 to 1 in 100,000 patients, according to Bilezikian.

Risk is very small, compared with potential benefits

It is important to put this risk in perspective. Based on data from the alendronate Fracture Intervention Trials (FIT), we have estimates of hip and spine fracture risk in certain types of patients. For example, for women age 68 with a femoral neck T-score of –2.5 or lower and no vertebral fractures, the likelihood of a clinical fracture over a mean treatment interval of 4.2 years was 19.6%.¹⁴ In women age 71 with a femoral neck T-score of –2.5 and 1 or more vertebral fractures, spine and hip fractures occurred in 15% and 2.2% of subjects, respectively, over 2.9 years.¹⁵ In these populations, alendronate reduced the risk of both hip and spine fracture by about 50%. For women without a vertebral fracture, the absolute reduction in the risk of clinical fracture over 4.2 years was 6.5% (number needed to treat [NNT]=15). In patients with a vertebral fracture, the absolute reduction in the incidence of further spine and hip fracture was 8.6% over 2.9 years (NNT=12).

This information argues strongly that the concern about osteonecrosis of the jaw does not justify withholding bisphosphonate therapy from patients with osteoporosis. The risk of such lesions in otherwise healthy patients with osteoporosis is very low (much lower than the risk of fracture), and most lesions heal spontaneously when treatment is stopped.

Clinical recommendations

For patients using or considering bisphosphonate therapy for osteoporosis, the following measures may be helpful:

• Have regular dental checkups and routine preventive dental care.
  
• If invasive dental procedures are planned, such as tooth extraction or implants, complete the dental work and allow the bone to heal before beginning bisphosphonate therapy.
  
• If a patient on bisphosphonate therapy plans invasive dental work, stop treatment for 3 months before the procedure and do not restart it until the jaw lesion is healed. Although there is no firm evidence that this strategy is helpful, it is certain that discontinuing bisphosphonate for a few months does not harm the skeleton.
  
• If a patient on bisphosphonate develops exposed bone, stop the drug and consult a dentist or oral surgeon experienced in the care of these lesions.
  

Some can take a holiday from bisphosphonate therapy

Black DM, Schwartz AV, Ensrud KE, et al, for the FLEX Research Group. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-Term Extension (FLEX): a randomized trial. JAMA. 2006;296:2927–2938.

There is evidence that bone metabolism continues to be affected for some time when alendronate is stopped after 2 to 5 years of treatment, as Black and colleagues found in the Fracture Intervention Trial Long-Term Extension (FLEX) and others have demonstrated.¹⁰ This raises the possibility that patients can take a “drug holiday” after several years of treatment. (This study was also reported in the March issue of OBG Management in “Examining the Evidence,” with a commentary by Steven R. Goldstein, MD.)

The FLEX trial attempted to determine whether it is better to continue or stop alendronate after several years’ exposure. One thousand ninety-nine women who had taken alendronate for 3 to 6 years in the FIT trials were randomly assigned to 5 or 10 mg of alendronate daily or placebo. All subjects received 500 mg of calcium and small vitamin D supplements and were followed for an additional 5 years.

The 2 alendronate groups were pooled for the analyses. Patients who switched to placebo for 5 years had declines in BMD at the total hip (2.4%) and spine (3.7%), compared with those who continued alendronate. However, values at the end of 5 years without therapy remained at or above pretreatment levels. Indices of bone turnover increased modestly when therapy was discontinued, but again the rates of bone turnover remained substantially lower than pretreatment values.

Fractures were collected as an exploratory endpoint. Compared with women who stopped treatment, women who continued alendronate reduced their risk of developing a clinical vertebral fracture by 55% (from 5.3% in the placebo group to 2.4% in the alendronate group). No difference was observed in the incidence of nonvertebral fractures between the 2 groups.

Who should take a holiday, and who can stay put?

Unfortunately, this study does not clearly answer the question. Patients at high risk for spine fracture, including those with a previous fracture, appeared to fare better if they continued treatment. Patients at lower risk did equally well whether they stopped or continued alendronate. This suggests that it would be appropriate to stop treatment in women who are not at high risk, including women who do not have osteoporosis by BMD criteria and have not experienced a fragility fracture since menopause.

The reason for stopping therapy in patients at low risk is because there was no added benefit observed with continued treatment, not because of concerns about risk.

When should the holiday end?

If treatment is stopped, the clinical question of whether and when to restart treatment becomes a challenge. The changes in bone density after treatment is stopped are too small to discern in individual patients. In theory, monitoring one or more bone-turnover markers is a more sensitive way to determine when the effects of bisphosphonates on skeletal remodeling are dissipating, but this approach is backed by very little clinical experience.

Another unresolved issue is whether the response after stopping treatment is the same in patients taking risedronate, ibandronate, or lower doses of alendronate.

I am delighted that Dr. Michael McClung, an internationally recognized expert in skeletal health, has agreed to review current evidence on the prevention of osteoporotic fractures in menopausal women in the latter part of this article.

New WHI analysis confirms safety of short-term combination HT

Anderson GL, Chlebowski RT, Rossouw JE, et al. Prior hormone therapy and breast cancer risk in the Women’s Health Initiative randomized trial of estrogen and progestin. Maturitas. 2006;55:103–115.

At the annual San Antonio Breast Cancer Symposium in December, investigators presented data showing that the incidence of breast cancer in US women decreased by 7% from 2002 to 2003, a striking decline that was most prominent among women aged 50 to 69 years. The presenters speculated that the plummeting rates of HT use following publication of the initial Women’s Health Initiative (WHI) findings in the summer of 2002 (in regard to the estrogen–progestin arm²) might be responsible for this decline.³

The major media attention that followed this presentation makes one thing clear: Concerns about developing breast cancer with HT use continue to fuel anxiety among women. Although secular trend data on the national breast cancer incidence can help generate hypotheses, they cannot explain the trends. What can shed light on the association between estrogen–progestin HT and breast cancer are important new data recently released by WHI investigators.

Women new to HT had no increased risk of breast cancer

In the 2006 subgroup analysis of WHI participants in the estrogen–progestin arm, investigators focused on HT use before enrollment in the trial. Recall that in this part of the WHI, 16,608 women with an intact uterus were randomized to conjugated equine estrogen plus medroxyprogesterone acetate or placebo. Use of the study medication was stopped after a mean follow-up of 5.6 years (mean exposure to HT: 4.4 years). Overall, the risk of invasive breast cancer was slightly higher with combination HT than placebo (hazard ratio [HR] 1.24; 95% confidence interval [CI] 1.01–1.54).²

In the 2006 report from the 2002 WHI study of estrogen–progestin HT versus placebo, investigators compared the risk of being diagnosed with breast cancer in 12,297 women who had not used HT prior to study enrollment with the risk in 4,311 participants who had previously used HT. Of the previous users, 42% reported less than 2 years of use prior to WHI enrollment, and 36% reported more than 4 years of HT prior to WHI enrollment.

The findings: Among WHI participants who had never before used HT, the use of estrogen–progestin HT in the study was not associated with an elevated risk of being diagnosed with breast cancer (HR 1.02; 95% CI 0.77–1.36). However, among previous HT users, the additional use of HT in the WHI study was associated with a risk nearly double that of placebo users (HR 1.96, 95% CI 1.17–3.27).

The reassuring results of this WHI subgroup analysis received little media attention in the United States, probably because the report appeared in a journal that has low readership in this country. WHI and other findings allow us to reassure women who have undergone hysterectomy that use of unopposed estrogen has little, if any, impact on breast cancer risk in menopausal women.^4,5 This new WHI subgroup analysis, along with a recent review of European and North American data,⁶ allows ObGyns to counsel women with an intact uterus that up to 5 years of combination estrogen–progestin hormone therapy also has little, if any, impact on breast cancer risk.

Not much to recommend among nonhormonal therapies

Newton KM, Reed SD, LaCroix AZ, Grothaus LC, Ehrlich K, Guiltinan J. Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy or placebo. Ann Intern Med. 2006;145:869–879.

Grady D. Clinical practice. Management of menopausal symptoms. N Engl J Med. 2006;355:2338–2347.

Grady D, Cohen B, Tice J, et al. Ineffectiveness of sertraline for treatment of menopausal hot flushes: a randomized controlled trial. Obstet Gynecol. 2007;109:823–830.

Loprinzi CL, Kugler JW, Barton DL, et al. Phase III trial of gabapentin alone or in conjunction with an antidepressant in the management of hot flashes in women who have inadequate control with an antidepressant alone: NCCTG N03C5. J Clin Oncol. 2007;25:308–312.

Since publication of the initial WHI findings in 2002,² interest in nonhormonal management of vasomotor symptoms has increased among menopausal women and their clinicians. The botanical black cohosh and “nutraceutical” soy or isoflavone supplements represent the nonprescription remedies most widely used for relief of hot flashes. Unfortunately, accumulating evidence does not support the efficacy of these popular remedies.

In a recent NIH-funded, randomized, double-blind, placebo-controlled clinical trial, Newton and colleagues compared the following interventions:

• black cohosh, 160 mg daily
  
• daily multibotanical supplement that included 200 mg of black cohosh and 9 other ingredients
  
• the multibotanical supplement plus counseling regarding dietary soy
  
• conjugated equine estrogen, 0.625 mg daily (with or without 2.5 mg of medroxyprogesterone acetate)
  
• placebo
  

The findings: At 3, 6, and 12 months, women allocated to estrogen (with or without progestin) had statistically significant relief of symptoms. In contrast, women allocated to botanical and/or herbal supplements experienced minimal relief, comparable to the effects of placebo.

The findings of this important study, as well as those of Grady, are discouraging: Black cohosh, botanicals, and encouraging increased soy intake are ineffective in the treatment of vasomotor symptoms.

Evidence on antidepressants is inconclusive

Selective serotonin reuptake inhibitors (SSRIs) and the antidepressant venlafaxine have been assessed for their effects on menopausal vasomotor symptoms, particularly in breast cancer survivors. In a recent review and also a randomized trial, Grady reports that the SSRIs citalopram and sertraline do not appear to be effective, and the findings in regard to the SSRI fluoxetine and venlafaxine have been inconsistent. Compared with placebo, the SSRI paroxetine has eased vasomotor symptoms to a modest degree in breast cancer survivors, but had little effect in women who have not had the disease.

Breast cancer survivors often take tamoxifen or aromatase inhibitors, medications that can induce or aggravate hot flashes. Breast cancer survivors also have a higher prevalence of mood disorders. These factors suggest that the experience and treatment of menopausal symptoms differ between breast cancer survivors and the general population.

Overall, Grady notes, for women with bothersome vasomotor symptoms who have no history of breast cancer, clinical trials of antidepressants have not been encouraging.

Gabapentin is more effective than antidepressants, but with a price

Clinical trials of gabapentin suggest that this anticonvulsant is moderately effective in the nonhormonal treatment of vasomotor symptoms, and the phase III trial by Loprinzi and colleagues finds it to be more effective therapy for vasomotor symptoms than antidepressants.

The drawback? This drug must be taken 2 or 3 times daily, and side effects (including fatigue) limit its attractiveness.

When deciding whom to treat, consider risk as well as BMD

Sanders KM, Nicholson GC, Watts JJ, et al. Half the burden of fragility fractures in the community occur in women without osteoporosis. When is fracture prevention cost-effective? Bone. 2006;38:694–700.

The diagnosis of osteoporosis in postmenopausal women is now based on a threshold bone mineral density (BMD) T-score of –2.5. However, BMD is only one of several important risk factors for fracture, and most patients who experience a fracture related to osteoporosis do not have BMD values in the range consistent with osteoporosis, as Sanders and colleagues observe. Therefore, clinicians are faced with this question: Which patients who do not have osteoporosis should be treated to prevent fracture?

The World Health Organization (WHO) task force on fracture risk assessment, under the leadership of Professor John Kanis, has developed an algorithm to estimate fracture probability in individual patients.⁷ This algorithm is based on a sophisticated analysis of almost all of the large epidemiological studies performed worldwide that have assessed relationships between clinical risk factors and fracture risk. By including the 3 major risk factors (age, BMD, and fracture history), as well as weaker risk factors (family history of hip fracture, current smoking, excess alcohol intake, and history of chronic glucocorticoid use), the absolute risk of developing a fracture of the spine, wrist, hip, or shoulder over the next 10 years will be estimated. This information will be the basis for revised guidelines by the National Osteoporosis Foundation (NOF) and other organizations. The new guidelines will include recommendations for treating patients at or above a certain threshold of fracture risk rather than a certain BMD threshold. The new treatment threshold will be based on a combination of cost- and clinical effectiveness.

The WHO algorithm and revised NOF guidelines are expected later this year.

New paradigm will shift focus to older women

This revised approach will shift the focus of therapy from young postmenopausal women at low fracture risk toward older women who do not have osteoporosis but do have an increased risk of fracture by virtue of their age and other factors.⁸ This will direct therapy more appropriately to patients who stand to gain the most and in whom therapy has been proven to reduce fracture risk.

Despite concerns, bisphosphonates appear to be safe for the long term

Bisphosphonates are the most extensively studied and widely used treatment for osteoporosis. Alendronate, the first bisphosphonate approved for the treatment of osteoporosis in the United States, has been available for more than 11 years. In general, all 3 of the currently approved bisphosphonates are well tolerated, and studies following patients for 7 to 10 years have not demonstrated significant adverse events or evidence of skeletal harm with long-term use.^9-11 However, because the drugs accumulate in the skeleton, there is a theoretical concern that long-term use will lead to over-suppression of bone turnover.

Small series of patients receiving bisphosphonates have described unusual fractures, evidence of low formation, and poor fracture healing, suggesting skeletal harm in at least some patients.¹² Bone biopsies performed in patients who received alendronate for 10 years or risedronate for 5 years showed evidence of bone remodeling in all the biopsy samples.^11,13 There was no progressive inhibition of bone metabolism in those biopsies compared with biopsies taken from patients who had received shorter-term treatment.

These findings are consistent with bone-turnover marker data suggesting no progressive suppression of bone turnover with continued use.^10,11,13 Biochemical indices of bone resorption are reduced to the lower half of the normal premenopausal range within about 3 months of beginning therapy, and values remain at that new level as long as patients receive the drug.

Risk of osteonecrosis of the jaw is low in general population

Woo SB, Hellstein JW, Kalmar JR. Narrative review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med. 2006;144:753–761.

Bilezikian JP. Osteonecrosis of the jaw—do bisphosphonates pose a risk? N Engl J Med. 2006;355:2278–2281.

An association between bisphosphonate therapy and nonhealing lesions of the jaw (so-called osteonecrosis of the jaw) has been observed, but primarily affects patients with cancer-related bone diseases who receive high doses of intravenous therapy in addition to chemotherapy. Patients receiving oral doses of bisphosphonates for osteoporosis in Paget’s disease have also had these lesions, as Woo and colleagues point out.

There is much that we do not know about this clinical problem, including its pathogenesis, whether the risk increases with longer-term use, and whether stopping therapy reduces the risk of developing lesions or improves the outcome of lesions already present. We do know that the incidence of exposed bone in the jaw in patients receiving bisphosphonate therapy for osteoporosis is low, estimated to range from 1 in 1,000 to 1 in 100,000 patients, according to Bilezikian.

Risk is very small, compared with potential benefits

It is important to put this risk in perspective. Based on data from the alendronate Fracture Intervention Trials (FIT), we have estimates of hip and spine fracture risk in certain types of patients. For example, for women age 68 with a femoral neck T-score of –2.5 or lower and no vertebral fractures, the likelihood of a clinical fracture over a mean treatment interval of 4.2 years was 19.6%.¹⁴ In women age 71 with a femoral neck T-score of –2.5 and 1 or more vertebral fractures, spine and hip fractures occurred in 15% and 2.2% of subjects, respectively, over 2.9 years.¹⁵ In these populations, alendronate reduced the risk of both hip and spine fracture by about 50%. For women without a vertebral fracture, the absolute reduction in the risk of clinical fracture over 4.2 years was 6.5% (number needed to treat [NNT]=15). In patients with a vertebral fracture, the absolute reduction in the incidence of further spine and hip fracture was 8.6% over 2.9 years (NNT=12).

This information argues strongly that the concern about osteonecrosis of the jaw does not justify withholding bisphosphonate therapy from patients with osteoporosis. The risk of such lesions in otherwise healthy patients with osteoporosis is very low (much lower than the risk of fracture), and most lesions heal spontaneously when treatment is stopped.

Clinical recommendations

For patients using or considering bisphosphonate therapy for osteoporosis, the following measures may be helpful:

• Have regular dental checkups and routine preventive dental care.
  
• If invasive dental procedures are planned, such as tooth extraction or implants, complete the dental work and allow the bone to heal before beginning bisphosphonate therapy.
  
• If a patient on bisphosphonate therapy plans invasive dental work, stop treatment for 3 months before the procedure and do not restart it until the jaw lesion is healed. Although there is no firm evidence that this strategy is helpful, it is certain that discontinuing bisphosphonate for a few months does not harm the skeleton.
  
• If a patient on bisphosphonate develops exposed bone, stop the drug and consult a dentist or oral surgeon experienced in the care of these lesions.
  

Some can take a holiday from bisphosphonate therapy

Black DM, Schwartz AV, Ensrud KE, et al, for the FLEX Research Group. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-Term Extension (FLEX): a randomized trial. JAMA. 2006;296:2927–2938.

There is evidence that bone metabolism continues to be affected for some time when alendronate is stopped after 2 to 5 years of treatment, as Black and colleagues found in the Fracture Intervention Trial Long-Term Extension (FLEX) and others have demonstrated.¹⁰ This raises the possibility that patients can take a “drug holiday” after several years of treatment. (This study was also reported in the March issue of OBG Management in “Examining the Evidence,” with a commentary by Steven R. Goldstein, MD.)

The FLEX trial attempted to determine whether it is better to continue or stop alendronate after several years’ exposure. One thousand ninety-nine women who had taken alendronate for 3 to 6 years in the FIT trials were randomly assigned to 5 or 10 mg of alendronate daily or placebo. All subjects received 500 mg of calcium and small vitamin D supplements and were followed for an additional 5 years.

The 2 alendronate groups were pooled for the analyses. Patients who switched to placebo for 5 years had declines in BMD at the total hip (2.4%) and spine (3.7%), compared with those who continued alendronate. However, values at the end of 5 years without therapy remained at or above pretreatment levels. Indices of bone turnover increased modestly when therapy was discontinued, but again the rates of bone turnover remained substantially lower than pretreatment values.

Fractures were collected as an exploratory endpoint. Compared with women who stopped treatment, women who continued alendronate reduced their risk of developing a clinical vertebral fracture by 55% (from 5.3% in the placebo group to 2.4% in the alendronate group). No difference was observed in the incidence of nonvertebral fractures between the 2 groups.

Who should take a holiday, and who can stay put?

Unfortunately, this study does not clearly answer the question. Patients at high risk for spine fracture, including those with a previous fracture, appeared to fare better if they continued treatment. Patients at lower risk did equally well whether they stopped or continued alendronate. This suggests that it would be appropriate to stop treatment in women who are not at high risk, including women who do not have osteoporosis by BMD criteria and have not experienced a fragility fracture since menopause.

The reason for stopping therapy in patients at low risk is because there was no added benefit observed with continued treatment, not because of concerns about risk.

When should the holiday end?

If treatment is stopped, the clinical question of whether and when to restart treatment becomes a challenge. The changes in bone density after treatment is stopped are too small to discern in individual patients. In theory, monitoring one or more bone-turnover markers is a more sensitive way to determine when the effects of bisphosphonates on skeletal remodeling are dissipating, but this approach is backed by very little clinical experience.

Another unresolved issue is whether the response after stopping treatment is the same in patients taking risedronate, ibandronate, or lower doses of alendronate.

I am delighted that Dr. Michael McClung, an internationally recognized expert in skeletal health, has agreed to review current evidence on the prevention of osteoporotic fractures in menopausal women in the latter part of this article.

New WHI analysis confirms safety of short-term combination HT

Anderson GL, Chlebowski RT, Rossouw JE, et al. Prior hormone therapy and breast cancer risk in the Women’s Health Initiative randomized trial of estrogen and progestin. Maturitas. 2006;55:103–115.

At the annual San Antonio Breast Cancer Symposium in December, investigators presented data showing that the incidence of breast cancer in US women decreased by 7% from 2002 to 2003, a striking decline that was most prominent among women aged 50 to 69 years. The presenters speculated that the plummeting rates of HT use following publication of the initial Women’s Health Initiative (WHI) findings in the summer of 2002 (in regard to the estrogen–progestin arm²) might be responsible for this decline.³

The major media attention that followed this presentation makes one thing clear: Concerns about developing breast cancer with HT use continue to fuel anxiety among women. Although secular trend data on the national breast cancer incidence can help generate hypotheses, they cannot explain the trends. What can shed light on the association between estrogen–progestin HT and breast cancer are important new data recently released by WHI investigators.

Women new to HT had no increased risk of breast cancer

In the 2006 subgroup analysis of WHI participants in the estrogen–progestin arm, investigators focused on HT use before enrollment in the trial. Recall that in this part of the WHI, 16,608 women with an intact uterus were randomized to conjugated equine estrogen plus medroxyprogesterone acetate or placebo. Use of the study medication was stopped after a mean follow-up of 5.6 years (mean exposure to HT: 4.4 years). Overall, the risk of invasive breast cancer was slightly higher with combination HT than placebo (hazard ratio [HR] 1.24; 95% confidence interval [CI] 1.01–1.54).²

In the 2006 report from the 2002 WHI study of estrogen–progestin HT versus placebo, investigators compared the risk of being diagnosed with breast cancer in 12,297 women who had not used HT prior to study enrollment with the risk in 4,311 participants who had previously used HT. Of the previous users, 42% reported less than 2 years of use prior to WHI enrollment, and 36% reported more than 4 years of HT prior to WHI enrollment.

The findings: Among WHI participants who had never before used HT, the use of estrogen–progestin HT in the study was not associated with an elevated risk of being diagnosed with breast cancer (HR 1.02; 95% CI 0.77–1.36). However, among previous HT users, the additional use of HT in the WHI study was associated with a risk nearly double that of placebo users (HR 1.96, 95% CI 1.17–3.27).

The reassuring results of this WHI subgroup analysis received little media attention in the United States, probably because the report appeared in a journal that has low readership in this country. WHI and other findings allow us to reassure women who have undergone hysterectomy that use of unopposed estrogen has little, if any, impact on breast cancer risk in menopausal women.^4,5 This new WHI subgroup analysis, along with a recent review of European and North American data,⁶ allows ObGyns to counsel women with an intact uterus that up to 5 years of combination estrogen–progestin hormone therapy also has little, if any, impact on breast cancer risk.

Not much to recommend among nonhormonal therapies

Newton KM, Reed SD, LaCroix AZ, Grothaus LC, Ehrlich K, Guiltinan J. Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy or placebo. Ann Intern Med. 2006;145:869–879.

Grady D. Clinical practice. Management of menopausal symptoms. N Engl J Med. 2006;355:2338–2347.

Grady D, Cohen B, Tice J, et al. Ineffectiveness of sertraline for treatment of menopausal hot flushes: a randomized controlled trial. Obstet Gynecol. 2007;109:823–830.

Loprinzi CL, Kugler JW, Barton DL, et al. Phase III trial of gabapentin alone or in conjunction with an antidepressant in the management of hot flashes in women who have inadequate control with an antidepressant alone: NCCTG N03C5. J Clin Oncol. 2007;25:308–312.

Since publication of the initial WHI findings in 2002,² interest in nonhormonal management of vasomotor symptoms has increased among menopausal women and their clinicians. The botanical black cohosh and “nutraceutical” soy or isoflavone supplements represent the nonprescription remedies most widely used for relief of hot flashes. Unfortunately, accumulating evidence does not support the efficacy of these popular remedies.

In a recent NIH-funded, randomized, double-blind, placebo-controlled clinical trial, Newton and colleagues compared the following interventions:

• black cohosh, 160 mg daily
  
• daily multibotanical supplement that included 200 mg of black cohosh and 9 other ingredients
  
• the multibotanical supplement plus counseling regarding dietary soy
  
• conjugated equine estrogen, 0.625 mg daily (with or without 2.5 mg of medroxyprogesterone acetate)
  
• placebo
  

The findings: At 3, 6, and 12 months, women allocated to estrogen (with or without progestin) had statistically significant relief of symptoms. In contrast, women allocated to botanical and/or herbal supplements experienced minimal relief, comparable to the effects of placebo.

The findings of this important study, as well as those of Grady, are discouraging: Black cohosh, botanicals, and encouraging increased soy intake are ineffective in the treatment of vasomotor symptoms.

Evidence on antidepressants is inconclusive

Selective serotonin reuptake inhibitors (SSRIs) and the antidepressant venlafaxine have been assessed for their effects on menopausal vasomotor symptoms, particularly in breast cancer survivors. In a recent review and also a randomized trial, Grady reports that the SSRIs citalopram and sertraline do not appear to be effective, and the findings in regard to the SSRI fluoxetine and venlafaxine have been inconsistent. Compared with placebo, the SSRI paroxetine has eased vasomotor symptoms to a modest degree in breast cancer survivors, but had little effect in women who have not had the disease.

Breast cancer survivors often take tamoxifen or aromatase inhibitors, medications that can induce or aggravate hot flashes. Breast cancer survivors also have a higher prevalence of mood disorders. These factors suggest that the experience and treatment of menopausal symptoms differ between breast cancer survivors and the general population.

Overall, Grady notes, for women with bothersome vasomotor symptoms who have no history of breast cancer, clinical trials of antidepressants have not been encouraging.

Gabapentin is more effective than antidepressants, but with a price

Clinical trials of gabapentin suggest that this anticonvulsant is moderately effective in the nonhormonal treatment of vasomotor symptoms, and the phase III trial by Loprinzi and colleagues finds it to be more effective therapy for vasomotor symptoms than antidepressants.

The drawback? This drug must be taken 2 or 3 times daily, and side effects (including fatigue) limit its attractiveness.

When deciding whom to treat, consider risk as well as BMD

Sanders KM, Nicholson GC, Watts JJ, et al. Half the burden of fragility fractures in the community occur in women without osteoporosis. When is fracture prevention cost-effective? Bone. 2006;38:694–700.

The diagnosis of osteoporosis in postmenopausal women is now based on a threshold bone mineral density (BMD) T-score of –2.5. However, BMD is only one of several important risk factors for fracture, and most patients who experience a fracture related to osteoporosis do not have BMD values in the range consistent with osteoporosis, as Sanders and colleagues observe. Therefore, clinicians are faced with this question: Which patients who do not have osteoporosis should be treated to prevent fracture?

The World Health Organization (WHO) task force on fracture risk assessment, under the leadership of Professor John Kanis, has developed an algorithm to estimate fracture probability in individual patients.⁷ This algorithm is based on a sophisticated analysis of almost all of the large epidemiological studies performed worldwide that have assessed relationships between clinical risk factors and fracture risk. By including the 3 major risk factors (age, BMD, and fracture history), as well as weaker risk factors (family history of hip fracture, current smoking, excess alcohol intake, and history of chronic glucocorticoid use), the absolute risk of developing a fracture of the spine, wrist, hip, or shoulder over the next 10 years will be estimated. This information will be the basis for revised guidelines by the National Osteoporosis Foundation (NOF) and other organizations. The new guidelines will include recommendations for treating patients at or above a certain threshold of fracture risk rather than a certain BMD threshold. The new treatment threshold will be based on a combination of cost- and clinical effectiveness.

The WHO algorithm and revised NOF guidelines are expected later this year.

New paradigm will shift focus to older women

This revised approach will shift the focus of therapy from young postmenopausal women at low fracture risk toward older women who do not have osteoporosis but do have an increased risk of fracture by virtue of their age and other factors.⁸ This will direct therapy more appropriately to patients who stand to gain the most and in whom therapy has been proven to reduce fracture risk.

Despite concerns, bisphosphonates appear to be safe for the long term

Bisphosphonates are the most extensively studied and widely used treatment for osteoporosis. Alendronate, the first bisphosphonate approved for the treatment of osteoporosis in the United States, has been available for more than 11 years. In general, all 3 of the currently approved bisphosphonates are well tolerated, and studies following patients for 7 to 10 years have not demonstrated significant adverse events or evidence of skeletal harm with long-term use.^9-11 However, because the drugs accumulate in the skeleton, there is a theoretical concern that long-term use will lead to over-suppression of bone turnover.

Small series of patients receiving bisphosphonates have described unusual fractures, evidence of low formation, and poor fracture healing, suggesting skeletal harm in at least some patients.¹² Bone biopsies performed in patients who received alendronate for 10 years or risedronate for 5 years showed evidence of bone remodeling in all the biopsy samples.^11,13 There was no progressive inhibition of bone metabolism in those biopsies compared with biopsies taken from patients who had received shorter-term treatment.

These findings are consistent with bone-turnover marker data suggesting no progressive suppression of bone turnover with continued use.^10,11,13 Biochemical indices of bone resorption are reduced to the lower half of the normal premenopausal range within about 3 months of beginning therapy, and values remain at that new level as long as patients receive the drug.

Risk of osteonecrosis of the jaw is low in general population

Woo SB, Hellstein JW, Kalmar JR. Narrative review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med. 2006;144:753–761.

Bilezikian JP. Osteonecrosis of the jaw—do bisphosphonates pose a risk? N Engl J Med. 2006;355:2278–2281.

An association between bisphosphonate therapy and nonhealing lesions of the jaw (so-called osteonecrosis of the jaw) has been observed, but primarily affects patients with cancer-related bone diseases who receive high doses of intravenous therapy in addition to chemotherapy. Patients receiving oral doses of bisphosphonates for osteoporosis in Paget’s disease have also had these lesions, as Woo and colleagues point out.

There is much that we do not know about this clinical problem, including its pathogenesis, whether the risk increases with longer-term use, and whether stopping therapy reduces the risk of developing lesions or improves the outcome of lesions already present. We do know that the incidence of exposed bone in the jaw in patients receiving bisphosphonate therapy for osteoporosis is low, estimated to range from 1 in 1,000 to 1 in 100,000 patients, according to Bilezikian.

Risk is very small, compared with potential benefits

It is important to put this risk in perspective. Based on data from the alendronate Fracture Intervention Trials (FIT), we have estimates of hip and spine fracture risk in certain types of patients. For example, for women age 68 with a femoral neck T-score of –2.5 or lower and no vertebral fractures, the likelihood of a clinical fracture over a mean treatment interval of 4.2 years was 19.6%.¹⁴ In women age 71 with a femoral neck T-score of –2.5 and 1 or more vertebral fractures, spine and hip fractures occurred in 15% and 2.2% of subjects, respectively, over 2.9 years.¹⁵ In these populations, alendronate reduced the risk of both hip and spine fracture by about 50%. For women without a vertebral fracture, the absolute reduction in the risk of clinical fracture over 4.2 years was 6.5% (number needed to treat [NNT]=15). In patients with a vertebral fracture, the absolute reduction in the incidence of further spine and hip fracture was 8.6% over 2.9 years (NNT=12).

This information argues strongly that the concern about osteonecrosis of the jaw does not justify withholding bisphosphonate therapy from patients with osteoporosis. The risk of such lesions in otherwise healthy patients with osteoporosis is very low (much lower than the risk of fracture), and most lesions heal spontaneously when treatment is stopped.

Clinical recommendations

For patients using or considering bisphosphonate therapy for osteoporosis, the following measures may be helpful:

• Have regular dental checkups and routine preventive dental care.
  
• If invasive dental procedures are planned, such as tooth extraction or implants, complete the dental work and allow the bone to heal before beginning bisphosphonate therapy.
  
• If a patient on bisphosphonate therapy plans invasive dental work, stop treatment for 3 months before the procedure and do not restart it until the jaw lesion is healed. Although there is no firm evidence that this strategy is helpful, it is certain that discontinuing bisphosphonate for a few months does not harm the skeleton.
  
• If a patient on bisphosphonate develops exposed bone, stop the drug and consult a dentist or oral surgeon experienced in the care of these lesions.
  

Some can take a holiday from bisphosphonate therapy

Black DM, Schwartz AV, Ensrud KE, et al, for the FLEX Research Group. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-Term Extension (FLEX): a randomized trial. JAMA. 2006;296:2927–2938.

There is evidence that bone metabolism continues to be affected for some time when alendronate is stopped after 2 to 5 years of treatment, as Black and colleagues found in the Fracture Intervention Trial Long-Term Extension (FLEX) and others have demonstrated.¹⁰ This raises the possibility that patients can take a “drug holiday” after several years of treatment. (This study was also reported in the March issue of OBG Management in “Examining the Evidence,” with a commentary by Steven R. Goldstein, MD.)

The FLEX trial attempted to determine whether it is better to continue or stop alendronate after several years’ exposure. One thousand ninety-nine women who had taken alendronate for 3 to 6 years in the FIT trials were randomly assigned to 5 or 10 mg of alendronate daily or placebo. All subjects received 500 mg of calcium and small vitamin D supplements and were followed for an additional 5 years.

The 2 alendronate groups were pooled for the analyses. Patients who switched to placebo for 5 years had declines in BMD at the total hip (2.4%) and spine (3.7%), compared with those who continued alendronate. However, values at the end of 5 years without therapy remained at or above pretreatment levels. Indices of bone turnover increased modestly when therapy was discontinued, but again the rates of bone turnover remained substantially lower than pretreatment values.

Fractures were collected as an exploratory endpoint. Compared with women who stopped treatment, women who continued alendronate reduced their risk of developing a clinical vertebral fracture by 55% (from 5.3% in the placebo group to 2.4% in the alendronate group). No difference was observed in the incidence of nonvertebral fractures between the 2 groups.

Who should take a holiday, and who can stay put?

Unfortunately, this study does not clearly answer the question. Patients at high risk for spine fracture, including those with a previous fracture, appeared to fare better if they continued treatment. Patients at lower risk did equally well whether they stopped or continued alendronate. This suggests that it would be appropriate to stop treatment in women who are not at high risk, including women who do not have osteoporosis by BMD criteria and have not experienced a fragility fracture since menopause.

The reason for stopping therapy in patients at low risk is because there was no added benefit observed with continued treatment, not because of concerns about risk.

When should the holiday end?

If treatment is stopped, the clinical question of whether and when to restart treatment becomes a challenge. The changes in bone density after treatment is stopped are too small to discern in individual patients. In theory, monitoring one or more bone-turnover markers is a more sensitive way to determine when the effects of bisphosphonates on skeletal remodeling are dissipating, but this approach is backed by very little clinical experience.

Another unresolved issue is whether the response after stopping treatment is the same in patients taking risedronate, ibandronate, or lower doses of alendronate.

Decisive new data on risks and benefits of hormonal contraception will change how we manage many patients. These findings prompted the American College of Obstetricians and Gynecologists (ACOG) to update its practice bulletin (released in June) on hormonal contraception in women with coexisting medical conditions.¹ Among the most notable areas of change:

1. Family history of breast cancer or BRCA1 or 2 mutations. Combination oral contraceptives (OCs) do not appear to increase the risk of breast cancer in these women, and do help prevent ovarian cancer.
2. Concomitant medications. More women are using enzyme-inducing anticonvulsants for conditions other than seizure disorders; some affect steroid levels.
3. Obesity. Progestin-only and intrauterine methods may be better for obese women older than 35 years, who face an elevated baseline risk of venous thromboembolism.
4. Lupus. Combination OCs are safe in women with stable, mild disease who are seronegative for antiphospholipid antibodies.
5. Depot medroxyprogesterone acetate (DMPA). Although bone density declines in women using DMPA, it recovers within 3 years after the drug is discontinued.
6. Patch and ring. Until method-specific data come in, assume that the patch and ring have the same contraindications as combination OCs.

For the fine points on these and other findings, we talked with Dr. Andrew M. Kaunitz, who assisted ACOG with preparation of the new bulletin.¹

1. Breast cancer risk

OCs do not add to existing high risk

OBG Management: Women who have a family history of breast cancer have a higher-than-average risk of developing the cancer themselves, and it is widely assumed that estrogen further heightens that risk. Should these women avoid combination OCs?

KAUNITZ: No. Although these women have been reluctant to use hormonal contraceptives (as have many caregivers), we now have several lines of reassuring evidence.

Among the studies demonstrating safety of hormonal methods in this population is the 2002 Women’s CARE study, conducted by the Centers for Disease Control and Prevention and sponsored by the National Institute of Child Health and Human Development, which found no elevated risk of breast cancer in women currently or formerly using OCs, compared with women who had never used them.

This study compared 4,575 women who had breast cancer with 4,682 controls. The relative risk of breast cancer was 1.0 (95% confidence interval 0.8–1.3) among current OC users and 0.9 (0.8–1.0) among women who had previously used OCs. The relative risk did not increase consistently with higher doses or longer use.² Nor did use of OCs add risk in women with a family history of breast cancer.²

OBG Management: An editorial accompanying that study said: “The importance of this finding for public health is enormous, because more than 75% of the women in the study had used oral contraceptives.”³

KAUNITZ: Yes, but this does not mean that women with a positive family history have no increased risk of breast cancer—they do. Rather, the use of hormonal contraceptives does not augment that risk further.

OBG Management: What about women with other high-risk factors, such as germline mutations? Do OCs increase their risk of breast cancer?

KAUNITZ: No. In the largest study to date of breast cancer risk associated with prior or current OC use in women 35 to 64 years of age with BRCA1 and 2 mutations, low-dose OC formulations did not increase it.⁴ In fact, OC use was associated with a significantly reduced risk of breast cancer in BRCA1 mutation carriers (odds ratio 0.22; 95% confidence interval 0.10–0.49).⁴

Pill reduces risk of ovarian cancer in BRCA carriers

KAUNITZ: It is also important to remember the higher risk of ovarian cancer in women with BRCA mutations. We now know that use of the Pill reduces ovarian cancer risk in BRCA-positive women, just as it does in the general population. In a study involving 451 women with BRCA1 or 2 mutations, who self-reported their lifetime history of OC use (or nonuse), the odds ratio for ovarian cancer associated with OC use for a minimum of 1 year was 0.85 (95% confidence interval 0.53–1.36) and declined by 5% (1%–9%) with each additional year of use (P for trend=.01). Use for 6 years or more carried an odds ratio of 0.62 (0.35–1.09).⁵

The bottom line: Women with a family history of breast cancer in general or BRCA1 or BRCA2 mutations more specifically, who have not completed childbearing or who want to avoid prophylactic mastectomy/oophorectomy, can use the Pill to prevent ovarian cancer without increasing their risk of breast cancer.^5,6

2. Concomitant medications

Some drugs decrease steroid levels

Anticonvulsants

OBG Management: Many, perhaps most, women with medical conditions are already taking some kind of medication. What do ObGyns need to know about interactions between hormonal contraceptives and other medications, such as anticonvulsants and antibiotics?

KAUNITZ: We regularly encounter patients who are using anticonvulsants, both older and newer formulations.

Off-label use of anticonvulsants for indications other than seizure disorders (eg, bipolar disease) is increasing.

Levetiracetam and zonisamide. The revised practice bulletin includes pharmacokinetic data on 2 new anticonvulsants—levetiracetam⁷ and zonisamide.⁸ Fortunately, neither appears to reduce contraceptive steroid levels in women who are also taking combination OCs.

Which dosage, which method? Some widely used anticonvulsants do decrease steroid levels (TABLE 1); although some clinicians prescribe OCs containing 50 μg of ethinyl estradiol to offset the reduction, there is no evidence that this strategy is effective. The ObGyn may consider prescribing pills containing 30 to 35 μg of estradiol rather than lower doses, although again, we lack data to support this recommendation.

Another important point: Because serum steroid levels of women using progestin-only OCs and implants are lower than for combination OCs, low-dose progestin-only methods (progestin-only minipills and progestin implants) do not represent by themselves optimal contraceptives for women taking drugs (eg, anticonvulsants) that increase liver enzymes.^9,10

This recommendation does not include the levonorgestrel-releasing intrauterine system. Contraceptive effects remain high with its use, even when anticonvulsants or other liver enzyme-inducing drugs are taken.¹¹

DMPA, a high-dose progestin contraceptive, has not been formally studied in this regard; the efficacy of this injectable contraceptive does not appear to be reduced by concomitant use of enzyme inducers.³⁰ Interestingly enough, DMPA has anticonvulsant effects itself and therefore may represent a particularly attractive contraceptive for women taking anticonvulsants.¹²

TABLE 1

Some anticonvulsants reduce steroid levels in women taking OCs, and some do not

Antibiotics

KAUNITZ: As for antibiotics, we have often been taught that many drugs lower the efficacy of combination OCs, but in fact it is not clear that they do.

Rifampin. The only antibiotic for which we have pharmacokinetic evidence of substantially lower steroid levels is rifampin¹³ (although anecdotal reports of OC failure in women taking other antibiotics have been noted). Therefore, any woman who is taking rifampin should be advised that OCs (combination or progestin-only), transdermal or vaginal contraceptives, and hormonal implants are inadequate birth control (TABLE 2).

TABLE 2

Rifampin decreases steroid levels in women taking combination OCs; other anti-infectives do not

Antiretrovirals

KAUNITZ: Several small trials suggest that contraceptive steroid levels in OC users may be affected by antiretroviral medications (TABLE 3), but we lack clinical outcome studies.

TABLE 3

Antiretrovirals may affect steroid levels in women taking OCs

St. John’s wort

KAUNITZ: Another medication I want to mention is St. John’s wort, an over-the-counter hepatic enzyme inducer that many women take for depression. One clinical trial found elevated progestin and estrogen metabolism in women taking combination OCs and St. John’s wort concomitantly, as well as increased likelihood of breakthrough bleeding and ovulation.

St. John’s wort (300 mg thrice daily) was associated with a 13% to 15% reduction in the dose exposure of combination OCs containing 20 μg of ethinyl estradiol.¹⁴ So it is important to ask about St. John’s wort when counseling a woman about contraception.

St. John’s wort raised progestin and estrogen metabolism and increased breakthrough bleeding and ovulation in women taking OCs

3. Obesity

In obese women over 35, avoid combination OCs

OBG Management: ObGyns are seeing increasing numbers of overweight and obese women. Has selection of hormonal contraception for these women changed?

KAUNITZ: Yes. We now have a recognized obesity epidemic on our hands—and obesity, age over 35 years, and use of combination OCs all represent independent risk factors for thrombosis—prompting the question: Are there safer alternatives to combination OCs for obese women older than 35?

Tenfold risk for thromboembolism. Among the evidence addressing this question, a 2003 Dutch study found that women with a body mass index (BMI) greater than 25 who used combination OCs had 10 times the risk of venous thromboembolism of lean controls who did not use the Pill.¹⁵

Thus, progestin-only and intrauterine contraceptive methods may be more appropriate for older obese women. This language about obesity and combination contraceptives was not in the earlier version of the practice bulletin.

No need to rule out the patch

OBG Management: Aren’t some hormonal contraceptives less effective in obese women?

KAUNITZ: In a 2002 analysis of pooled data, women in the highest weight category (≥90 kg) who were using the contraceptive patch had a higher pregnancy rate than lower-weight women.¹⁶ However, this finding does not rule out use of the patch in overweight women who prefer it to less effective methods. Rather, it should be kept in mind when counseling these patients about their options.

Although the new ACOG bulletin cites data from Holt et al¹⁷ suggesting a higher failure rate in obese women using combination OCs, other OC clinical trials have not confirmed this association.^18,19 In a study by Anderson and colleagues,¹⁸ which found no pregnancies among the heaviest women, the mean weight was 155.9 lb, but ranged from 91.0 to 360.0 lb, and the mean BMI was 26.0, but ranged from 15.2 to an extreme of 56.5!

What about DMPA? We also lack evidence of higher pregnancy rates among overweight women using DMPA (150-mg intramuscular or 104-mg subcutaneous formulations).^20,21

4. Lupus

OCs are an option in some women with lupus

OBG Management: As The New England Journal of Medicine observed last year, there has been an “implicit moratorium” on prescribing combination hormonal contraceptives in women with systemic lupus erythematosus (SLE) because clinicians have feared that exogenous estrogens might exacerbate disease.²² This moratorium derives from data suggesting that estrogens worsen SLE, while androgens appear to protect against the condition.

The new practice bulletin now indicates that oral contraceptives are an option for this population. What is behind the change?

KAUNITZ: We now have data from 2 randomized clinical trials^23,24 indicating that women can safely use combination OCs if they:

• have stable, mild disease
• are seronegative for antiphospholipid antibodies
• have no history of thrombosis

Disease remained stable. In the first trial,²⁴ 162 women with mild, stable SLE were randomized to combination OCs, progestin-only pills, or the copper IUD. Their disease level was established at baseline and over 12 months, using the Systemic Lupus Erythematosus Disease Activity Index. Disease remained stable in all 3 groups.

Estrogen did not increase severity of SLE. In the second trial,²³ 183 women with inactive or stable active SLE were randomized to combination OCs or placebo. The primary endpoint for this trial was severe lupus flare: 7 of 91 women (7.7%) in the OC group experienced a flare, compared with 7 of 92 women (7.6%) taking placebo. Thus, estrogen does not appear to increase the severity of SLE.

OBG Management: Isn’t another concern about patients with SLE the substantial risk of thrombosis?

KAUNITZ: Yes. In the first study,²⁴ 2 thromboses occurred in women taking OCs, and 2 occurred in women using the progestin-only pill. All the women with thromboses were seropositive for antiphospholipid antibodies. Hence, we need to exclude the presence of these antibodies in women with SLE prior to prescribing combination estrogen-progestin contraception. In women with lupus and a history of thrombosis, as with all women with a history of thrombosis, we should avoid combination hormonal contraception.

In the second study,²³ which compared women on combination OCs to a placebo group, the OC group experienced 1 case of deep venous thrombosis (DVT) and 1 clotted graft. The placebo group experienced 1 case of DVT, 1 ocular thrombosis, 1 superficial thrombophlebitis, and 1 death (after the trial ended).

5. DMPA and bone density

DMPA does not appear to have long-term impact

OBG Management: There has been some furor over DMPA’s effect on bone mineral density (BMD). What are the latest findings in this area?

KAUNITZ: Studies assessing BMD in former DMPA users, including postmenopausal women, show that prior use of DMPA does not appear to have any long-term impact on BMD.^25,26 In addition, more recent longitudinal data indicate that after DMPA is discontinued BMD fully recovers, which appears to take about 3 years in adults and as little as 1 year in teens.^27,28

One population-based prospective cohort study followed 457 nongravid women aged 18 to 39 years. These women had bone density measured every 6 months for 3 years using dual-energy x-ray absorptiometry. Although bone density decreased among DMPA users at the spine and total hip compared with nonusers, there was no difference in bone density 30 months after discontinuation of birth control injections.²⁷

In a study of 170 adolescent women 14 to 18 years of age, 80 were DMPA users and 90 were nonusers. Bone density was measured every 6 months for 24 or 36 months, and declined significantly at the hip and spine in DMPA users. Sixty-one women discontinued DMPA during the course of the study. After discontinuation, bone density increased at all anatomical sites, recovering completely over the course of 1 year.²⁸

Although the US Food and Drug Administration issued a black box warning in the fall of 2004 that use of DMPA should be reconsidered after 2 years, particularly in teens, the studies I just mentioned suggest there should be no routine restrictions on the use of DMPA in terms of skeletal health, and that DMPA use by itself is not an indication for bone density measurement.

6. Patch and ring

Assume contraindications are the same as for OCs

OBG Management: What about newer forms of combination contraceptives such as the patch and ring?

KAUNITZ: The new practice bulletin contains information on the patch, the ring, and the levonorgestrel-releasing IUD, which were not available when the earlier bulletin was prepared. In that version we talked about combination pills only.

Even so, we continue to have much more data on the Pill than the ring or patch. For that reason, until more data become available, the patch and the ring should be assumed to have the same contraindications as combination OCs. We have very little data—if any—on the use of newer combination contraceptives in high-risk women or those with medical problems.

Decisive new data on risks and benefits of hormonal contraception will change how we manage many patients. These findings prompted the American College of Obstetricians and Gynecologists (ACOG) to update its practice bulletin (released in June) on hormonal contraception in women with coexisting medical conditions.¹ Among the most notable areas of change:

1. Family history of breast cancer or BRCA1 or 2 mutations. Combination oral contraceptives (OCs) do not appear to increase the risk of breast cancer in these women, and do help prevent ovarian cancer.
2. Concomitant medications. More women are using enzyme-inducing anticonvulsants for conditions other than seizure disorders; some affect steroid levels.
3. Obesity. Progestin-only and intrauterine methods may be better for obese women older than 35 years, who face an elevated baseline risk of venous thromboembolism.
4. Lupus. Combination OCs are safe in women with stable, mild disease who are seronegative for antiphospholipid antibodies.
5. Depot medroxyprogesterone acetate (DMPA). Although bone density declines in women using DMPA, it recovers within 3 years after the drug is discontinued.
6. Patch and ring. Until method-specific data come in, assume that the patch and ring have the same contraindications as combination OCs.

For the fine points on these and other findings, we talked with Dr. Andrew M. Kaunitz, who assisted ACOG with preparation of the new bulletin.¹

1. Breast cancer risk

OCs do not add to existing high risk

OBG Management: Women who have a family history of breast cancer have a higher-than-average risk of developing the cancer themselves, and it is widely assumed that estrogen further heightens that risk. Should these women avoid combination OCs?

KAUNITZ: No. Although these women have been reluctant to use hormonal contraceptives (as have many caregivers), we now have several lines of reassuring evidence.

Among the studies demonstrating safety of hormonal methods in this population is the 2002 Women’s CARE study, conducted by the Centers for Disease Control and Prevention and sponsored by the National Institute of Child Health and Human Development, which found no elevated risk of breast cancer in women currently or formerly using OCs, compared with women who had never used them.

This study compared 4,575 women who had breast cancer with 4,682 controls. The relative risk of breast cancer was 1.0 (95% confidence interval 0.8–1.3) among current OC users and 0.9 (0.8–1.0) among women who had previously used OCs. The relative risk did not increase consistently with higher doses or longer use.² Nor did use of OCs add risk in women with a family history of breast cancer.²

OBG Management: An editorial accompanying that study said: “The importance of this finding for public health is enormous, because more than 75% of the women in the study had used oral contraceptives.”³

KAUNITZ: Yes, but this does not mean that women with a positive family history have no increased risk of breast cancer—they do. Rather, the use of hormonal contraceptives does not augment that risk further.

OBG Management: What about women with other high-risk factors, such as germline mutations? Do OCs increase their risk of breast cancer?

KAUNITZ: No. In the largest study to date of breast cancer risk associated with prior or current OC use in women 35 to 64 years of age with BRCA1 and 2 mutations, low-dose OC formulations did not increase it.⁴ In fact, OC use was associated with a significantly reduced risk of breast cancer in BRCA1 mutation carriers (odds ratio 0.22; 95% confidence interval 0.10–0.49).⁴

Pill reduces risk of ovarian cancer in BRCA carriers

KAUNITZ: It is also important to remember the higher risk of ovarian cancer in women with BRCA mutations. We now know that use of the Pill reduces ovarian cancer risk in BRCA-positive women, just as it does in the general population. In a study involving 451 women with BRCA1 or 2 mutations, who self-reported their lifetime history of OC use (or nonuse), the odds ratio for ovarian cancer associated with OC use for a minimum of 1 year was 0.85 (95% confidence interval 0.53–1.36) and declined by 5% (1%–9%) with each additional year of use (P for trend=.01). Use for 6 years or more carried an odds ratio of 0.62 (0.35–1.09).⁵

The bottom line: Women with a family history of breast cancer in general or BRCA1 or BRCA2 mutations more specifically, who have not completed childbearing or who want to avoid prophylactic mastectomy/oophorectomy, can use the Pill to prevent ovarian cancer without increasing their risk of breast cancer.^5,6

2. Concomitant medications

Some drugs decrease steroid levels

Anticonvulsants

OBG Management: Many, perhaps most, women with medical conditions are already taking some kind of medication. What do ObGyns need to know about interactions between hormonal contraceptives and other medications, such as anticonvulsants and antibiotics?

KAUNITZ: We regularly encounter patients who are using anticonvulsants, both older and newer formulations.

Off-label use of anticonvulsants for indications other than seizure disorders (eg, bipolar disease) is increasing.

Levetiracetam and zonisamide. The revised practice bulletin includes pharmacokinetic data on 2 new anticonvulsants—levetiracetam⁷ and zonisamide.⁸ Fortunately, neither appears to reduce contraceptive steroid levels in women who are also taking combination OCs.

Which dosage, which method? Some widely used anticonvulsants do decrease steroid levels (TABLE 1); although some clinicians prescribe OCs containing 50 μg of ethinyl estradiol to offset the reduction, there is no evidence that this strategy is effective. The ObGyn may consider prescribing pills containing 30 to 35 μg of estradiol rather than lower doses, although again, we lack data to support this recommendation.

Another important point: Because serum steroid levels of women using progestin-only OCs and implants are lower than for combination OCs, low-dose progestin-only methods (progestin-only minipills and progestin implants) do not represent by themselves optimal contraceptives for women taking drugs (eg, anticonvulsants) that increase liver enzymes.^9,10

This recommendation does not include the levonorgestrel-releasing intrauterine system. Contraceptive effects remain high with its use, even when anticonvulsants or other liver enzyme-inducing drugs are taken.¹¹

DMPA, a high-dose progestin contraceptive, has not been formally studied in this regard; the efficacy of this injectable contraceptive does not appear to be reduced by concomitant use of enzyme inducers.³⁰ Interestingly enough, DMPA has anticonvulsant effects itself and therefore may represent a particularly attractive contraceptive for women taking anticonvulsants.¹²

TABLE 1

Some anticonvulsants reduce steroid levels in women taking OCs, and some do not

Antibiotics

KAUNITZ: As for antibiotics, we have often been taught that many drugs lower the efficacy of combination OCs, but in fact it is not clear that they do.

Rifampin. The only antibiotic for which we have pharmacokinetic evidence of substantially lower steroid levels is rifampin¹³ (although anecdotal reports of OC failure in women taking other antibiotics have been noted). Therefore, any woman who is taking rifampin should be advised that OCs (combination or progestin-only), transdermal or vaginal contraceptives, and hormonal implants are inadequate birth control (TABLE 2).

TABLE 2

Rifampin decreases steroid levels in women taking combination OCs; other anti-infectives do not

Antiretrovirals

KAUNITZ: Several small trials suggest that contraceptive steroid levels in OC users may be affected by antiretroviral medications (TABLE 3), but we lack clinical outcome studies.

TABLE 3

Antiretrovirals may affect steroid levels in women taking OCs

St. John’s wort

KAUNITZ: Another medication I want to mention is St. John’s wort, an over-the-counter hepatic enzyme inducer that many women take for depression. One clinical trial found elevated progestin and estrogen metabolism in women taking combination OCs and St. John’s wort concomitantly, as well as increased likelihood of breakthrough bleeding and ovulation.

St. John’s wort (300 mg thrice daily) was associated with a 13% to 15% reduction in the dose exposure of combination OCs containing 20 μg of ethinyl estradiol.¹⁴ So it is important to ask about St. John’s wort when counseling a woman about contraception.

St. John’s wort raised progestin and estrogen metabolism and increased breakthrough bleeding and ovulation in women taking OCs

3. Obesity

In obese women over 35, avoid combination OCs

OBG Management: ObGyns are seeing increasing numbers of overweight and obese women. Has selection of hormonal contraception for these women changed?

KAUNITZ: Yes. We now have a recognized obesity epidemic on our hands—and obesity, age over 35 years, and use of combination OCs all represent independent risk factors for thrombosis—prompting the question: Are there safer alternatives to combination OCs for obese women older than 35?

Tenfold risk for thromboembolism. Among the evidence addressing this question, a 2003 Dutch study found that women with a body mass index (BMI) greater than 25 who used combination OCs had 10 times the risk of venous thromboembolism of lean controls who did not use the Pill.¹⁵

Thus, progestin-only and intrauterine contraceptive methods may be more appropriate for older obese women. This language about obesity and combination contraceptives was not in the earlier version of the practice bulletin.

No need to rule out the patch

OBG Management: Aren’t some hormonal contraceptives less effective in obese women?

KAUNITZ: In a 2002 analysis of pooled data, women in the highest weight category (≥90 kg) who were using the contraceptive patch had a higher pregnancy rate than lower-weight women.¹⁶ However, this finding does not rule out use of the patch in overweight women who prefer it to less effective methods. Rather, it should be kept in mind when counseling these patients about their options.

Although the new ACOG bulletin cites data from Holt et al¹⁷ suggesting a higher failure rate in obese women using combination OCs, other OC clinical trials have not confirmed this association.^18,19 In a study by Anderson and colleagues,¹⁸ which found no pregnancies among the heaviest women, the mean weight was 155.9 lb, but ranged from 91.0 to 360.0 lb, and the mean BMI was 26.0, but ranged from 15.2 to an extreme of 56.5!

What about DMPA? We also lack evidence of higher pregnancy rates among overweight women using DMPA (150-mg intramuscular or 104-mg subcutaneous formulations).^20,21

4. Lupus

OCs are an option in some women with lupus

OBG Management: As The New England Journal of Medicine observed last year, there has been an “implicit moratorium” on prescribing combination hormonal contraceptives in women with systemic lupus erythematosus (SLE) because clinicians have feared that exogenous estrogens might exacerbate disease.²² This moratorium derives from data suggesting that estrogens worsen SLE, while androgens appear to protect against the condition.

The new practice bulletin now indicates that oral contraceptives are an option for this population. What is behind the change?

KAUNITZ: We now have data from 2 randomized clinical trials^23,24 indicating that women can safely use combination OCs if they:

• have stable, mild disease
• are seronegative for antiphospholipid antibodies
• have no history of thrombosis

Disease remained stable. In the first trial,²⁴ 162 women with mild, stable SLE were randomized to combination OCs, progestin-only pills, or the copper IUD. Their disease level was established at baseline and over 12 months, using the Systemic Lupus Erythematosus Disease Activity Index. Disease remained stable in all 3 groups.

Estrogen did not increase severity of SLE. In the second trial,²³ 183 women with inactive or stable active SLE were randomized to combination OCs or placebo. The primary endpoint for this trial was severe lupus flare: 7 of 91 women (7.7%) in the OC group experienced a flare, compared with 7 of 92 women (7.6%) taking placebo. Thus, estrogen does not appear to increase the severity of SLE.

OBG Management: Isn’t another concern about patients with SLE the substantial risk of thrombosis?

KAUNITZ: Yes. In the first study,²⁴ 2 thromboses occurred in women taking OCs, and 2 occurred in women using the progestin-only pill. All the women with thromboses were seropositive for antiphospholipid antibodies. Hence, we need to exclude the presence of these antibodies in women with SLE prior to prescribing combination estrogen-progestin contraception. In women with lupus and a history of thrombosis, as with all women with a history of thrombosis, we should avoid combination hormonal contraception.

In the second study,²³ which compared women on combination OCs to a placebo group, the OC group experienced 1 case of deep venous thrombosis (DVT) and 1 clotted graft. The placebo group experienced 1 case of DVT, 1 ocular thrombosis, 1 superficial thrombophlebitis, and 1 death (after the trial ended).

5. DMPA and bone density

DMPA does not appear to have long-term impact

OBG Management: There has been some furor over DMPA’s effect on bone mineral density (BMD). What are the latest findings in this area?

KAUNITZ: Studies assessing BMD in former DMPA users, including postmenopausal women, show that prior use of DMPA does not appear to have any long-term impact on BMD.^25,26 In addition, more recent longitudinal data indicate that after DMPA is discontinued BMD fully recovers, which appears to take about 3 years in adults and as little as 1 year in teens.^27,28

One population-based prospective cohort study followed 457 nongravid women aged 18 to 39 years. These women had bone density measured every 6 months for 3 years using dual-energy x-ray absorptiometry. Although bone density decreased among DMPA users at the spine and total hip compared with nonusers, there was no difference in bone density 30 months after discontinuation of birth control injections.²⁷

In a study of 170 adolescent women 14 to 18 years of age, 80 were DMPA users and 90 were nonusers. Bone density was measured every 6 months for 24 or 36 months, and declined significantly at the hip and spine in DMPA users. Sixty-one women discontinued DMPA during the course of the study. After discontinuation, bone density increased at all anatomical sites, recovering completely over the course of 1 year.²⁸

Although the US Food and Drug Administration issued a black box warning in the fall of 2004 that use of DMPA should be reconsidered after 2 years, particularly in teens, the studies I just mentioned suggest there should be no routine restrictions on the use of DMPA in terms of skeletal health, and that DMPA use by itself is not an indication for bone density measurement.

6. Patch and ring

Assume contraindications are the same as for OCs

OBG Management: What about newer forms of combination contraceptives such as the patch and ring?

KAUNITZ: The new practice bulletin contains information on the patch, the ring, and the levonorgestrel-releasing IUD, which were not available when the earlier bulletin was prepared. In that version we talked about combination pills only.

Even so, we continue to have much more data on the Pill than the ring or patch. For that reason, until more data become available, the patch and the ring should be assumed to have the same contraindications as combination OCs. We have very little data—if any—on the use of newer combination contraceptives in high-risk women or those with medical problems.

Decisive new data on risks and benefits of hormonal contraception will change how we manage many patients. These findings prompted the American College of Obstetricians and Gynecologists (ACOG) to update its practice bulletin (released in June) on hormonal contraception in women with coexisting medical conditions.¹ Among the most notable areas of change:

1. Family history of breast cancer or BRCA1 or 2 mutations. Combination oral contraceptives (OCs) do not appear to increase the risk of breast cancer in these women, and do help prevent ovarian cancer.
2. Concomitant medications. More women are using enzyme-inducing anticonvulsants for conditions other than seizure disorders; some affect steroid levels.
3. Obesity. Progestin-only and intrauterine methods may be better for obese women older than 35 years, who face an elevated baseline risk of venous thromboembolism.
4. Lupus. Combination OCs are safe in women with stable, mild disease who are seronegative for antiphospholipid antibodies.
5. Depot medroxyprogesterone acetate (DMPA). Although bone density declines in women using DMPA, it recovers within 3 years after the drug is discontinued.
6. Patch and ring. Until method-specific data come in, assume that the patch and ring have the same contraindications as combination OCs.

For the fine points on these and other findings, we talked with Dr. Andrew M. Kaunitz, who assisted ACOG with preparation of the new bulletin.¹

1. Breast cancer risk

OCs do not add to existing high risk

OBG Management: Women who have a family history of breast cancer have a higher-than-average risk of developing the cancer themselves, and it is widely assumed that estrogen further heightens that risk. Should these women avoid combination OCs?

KAUNITZ: No. Although these women have been reluctant to use hormonal contraceptives (as have many caregivers), we now have several lines of reassuring evidence.

Among the studies demonstrating safety of hormonal methods in this population is the 2002 Women’s CARE study, conducted by the Centers for Disease Control and Prevention and sponsored by the National Institute of Child Health and Human Development, which found no elevated risk of breast cancer in women currently or formerly using OCs, compared with women who had never used them.

This study compared 4,575 women who had breast cancer with 4,682 controls. The relative risk of breast cancer was 1.0 (95% confidence interval 0.8–1.3) among current OC users and 0.9 (0.8–1.0) among women who had previously used OCs. The relative risk did not increase consistently with higher doses or longer use.² Nor did use of OCs add risk in women with a family history of breast cancer.²

OBG Management: An editorial accompanying that study said: “The importance of this finding for public health is enormous, because more than 75% of the women in the study had used oral contraceptives.”³

KAUNITZ: Yes, but this does not mean that women with a positive family history have no increased risk of breast cancer—they do. Rather, the use of hormonal contraceptives does not augment that risk further.

OBG Management: What about women with other high-risk factors, such as germline mutations? Do OCs increase their risk of breast cancer?

KAUNITZ: No. In the largest study to date of breast cancer risk associated with prior or current OC use in women 35 to 64 years of age with BRCA1 and 2 mutations, low-dose OC formulations did not increase it.⁴ In fact, OC use was associated with a significantly reduced risk of breast cancer in BRCA1 mutation carriers (odds ratio 0.22; 95% confidence interval 0.10–0.49).⁴

Pill reduces risk of ovarian cancer in BRCA carriers

KAUNITZ: It is also important to remember the higher risk of ovarian cancer in women with BRCA mutations. We now know that use of the Pill reduces ovarian cancer risk in BRCA-positive women, just as it does in the general population. In a study involving 451 women with BRCA1 or 2 mutations, who self-reported their lifetime history of OC use (or nonuse), the odds ratio for ovarian cancer associated with OC use for a minimum of 1 year was 0.85 (95% confidence interval 0.53–1.36) and declined by 5% (1%–9%) with each additional year of use (P for trend=.01). Use for 6 years or more carried an odds ratio of 0.62 (0.35–1.09).⁵

The bottom line: Women with a family history of breast cancer in general or BRCA1 or BRCA2 mutations more specifically, who have not completed childbearing or who want to avoid prophylactic mastectomy/oophorectomy, can use the Pill to prevent ovarian cancer without increasing their risk of breast cancer.^5,6

2. Concomitant medications

Some drugs decrease steroid levels

Anticonvulsants

OBG Management: Many, perhaps most, women with medical conditions are already taking some kind of medication. What do ObGyns need to know about interactions between hormonal contraceptives and other medications, such as anticonvulsants and antibiotics?

KAUNITZ: We regularly encounter patients who are using anticonvulsants, both older and newer formulations.

Off-label use of anticonvulsants for indications other than seizure disorders (eg, bipolar disease) is increasing.

Levetiracetam and zonisamide. The revised practice bulletin includes pharmacokinetic data on 2 new anticonvulsants—levetiracetam⁷ and zonisamide.⁸ Fortunately, neither appears to reduce contraceptive steroid levels in women who are also taking combination OCs.

Which dosage, which method? Some widely used anticonvulsants do decrease steroid levels (TABLE 1); although some clinicians prescribe OCs containing 50 μg of ethinyl estradiol to offset the reduction, there is no evidence that this strategy is effective. The ObGyn may consider prescribing pills containing 30 to 35 μg of estradiol rather than lower doses, although again, we lack data to support this recommendation.

Another important point: Because serum steroid levels of women using progestin-only OCs and implants are lower than for combination OCs, low-dose progestin-only methods (progestin-only minipills and progestin implants) do not represent by themselves optimal contraceptives for women taking drugs (eg, anticonvulsants) that increase liver enzymes.^9,10

This recommendation does not include the levonorgestrel-releasing intrauterine system. Contraceptive effects remain high with its use, even when anticonvulsants or other liver enzyme-inducing drugs are taken.¹¹

DMPA, a high-dose progestin contraceptive, has not been formally studied in this regard; the efficacy of this injectable contraceptive does not appear to be reduced by concomitant use of enzyme inducers.³⁰ Interestingly enough, DMPA has anticonvulsant effects itself and therefore may represent a particularly attractive contraceptive for women taking anticonvulsants.¹²

TABLE 1

Some anticonvulsants reduce steroid levels in women taking OCs, and some do not

Antibiotics

KAUNITZ: As for antibiotics, we have often been taught that many drugs lower the efficacy of combination OCs, but in fact it is not clear that they do.

Rifampin. The only antibiotic for which we have pharmacokinetic evidence of substantially lower steroid levels is rifampin¹³ (although anecdotal reports of OC failure in women taking other antibiotics have been noted). Therefore, any woman who is taking rifampin should be advised that OCs (combination or progestin-only), transdermal or vaginal contraceptives, and hormonal implants are inadequate birth control (TABLE 2).

TABLE 2

Rifampin decreases steroid levels in women taking combination OCs; other anti-infectives do not

Antiretrovirals

KAUNITZ: Several small trials suggest that contraceptive steroid levels in OC users may be affected by antiretroviral medications (TABLE 3), but we lack clinical outcome studies.

TABLE 3

Antiretrovirals may affect steroid levels in women taking OCs

St. John’s wort

KAUNITZ: Another medication I want to mention is St. John’s wort, an over-the-counter hepatic enzyme inducer that many women take for depression. One clinical trial found elevated progestin and estrogen metabolism in women taking combination OCs and St. John’s wort concomitantly, as well as increased likelihood of breakthrough bleeding and ovulation.

St. John’s wort (300 mg thrice daily) was associated with a 13% to 15% reduction in the dose exposure of combination OCs containing 20 μg of ethinyl estradiol.¹⁴ So it is important to ask about St. John’s wort when counseling a woman about contraception.

St. John’s wort raised progestin and estrogen metabolism and increased breakthrough bleeding and ovulation in women taking OCs

3. Obesity

In obese women over 35, avoid combination OCs

OBG Management: ObGyns are seeing increasing numbers of overweight and obese women. Has selection of hormonal contraception for these women changed?

KAUNITZ: Yes. We now have a recognized obesity epidemic on our hands—and obesity, age over 35 years, and use of combination OCs all represent independent risk factors for thrombosis—prompting the question: Are there safer alternatives to combination OCs for obese women older than 35?

Tenfold risk for thromboembolism. Among the evidence addressing this question, a 2003 Dutch study found that women with a body mass index (BMI) greater than 25 who used combination OCs had 10 times the risk of venous thromboembolism of lean controls who did not use the Pill.¹⁵

Thus, progestin-only and intrauterine contraceptive methods may be more appropriate for older obese women. This language about obesity and combination contraceptives was not in the earlier version of the practice bulletin.

No need to rule out the patch

OBG Management: Aren’t some hormonal contraceptives less effective in obese women?

KAUNITZ: In a 2002 analysis of pooled data, women in the highest weight category (≥90 kg) who were using the contraceptive patch had a higher pregnancy rate than lower-weight women.¹⁶ However, this finding does not rule out use of the patch in overweight women who prefer it to less effective methods. Rather, it should be kept in mind when counseling these patients about their options.

Although the new ACOG bulletin cites data from Holt et al¹⁷ suggesting a higher failure rate in obese women using combination OCs, other OC clinical trials have not confirmed this association.^18,19 In a study by Anderson and colleagues,¹⁸ which found no pregnancies among the heaviest women, the mean weight was 155.9 lb, but ranged from 91.0 to 360.0 lb, and the mean BMI was 26.0, but ranged from 15.2 to an extreme of 56.5!

What about DMPA? We also lack evidence of higher pregnancy rates among overweight women using DMPA (150-mg intramuscular or 104-mg subcutaneous formulations).^20,21

4. Lupus

OCs are an option in some women with lupus

OBG Management: As The New England Journal of Medicine observed last year, there has been an “implicit moratorium” on prescribing combination hormonal contraceptives in women with systemic lupus erythematosus (SLE) because clinicians have feared that exogenous estrogens might exacerbate disease.²² This moratorium derives from data suggesting that estrogens worsen SLE, while androgens appear to protect against the condition.

The new practice bulletin now indicates that oral contraceptives are an option for this population. What is behind the change?

KAUNITZ: We now have data from 2 randomized clinical trials^23,24 indicating that women can safely use combination OCs if they:

• have stable, mild disease
• are seronegative for antiphospholipid antibodies
• have no history of thrombosis

Disease remained stable. In the first trial,²⁴ 162 women with mild, stable SLE were randomized to combination OCs, progestin-only pills, or the copper IUD. Their disease level was established at baseline and over 12 months, using the Systemic Lupus Erythematosus Disease Activity Index. Disease remained stable in all 3 groups.

Estrogen did not increase severity of SLE. In the second trial,²³ 183 women with inactive or stable active SLE were randomized to combination OCs or placebo. The primary endpoint for this trial was severe lupus flare: 7 of 91 women (7.7%) in the OC group experienced a flare, compared with 7 of 92 women (7.6%) taking placebo. Thus, estrogen does not appear to increase the severity of SLE.

OBG Management: Isn’t another concern about patients with SLE the substantial risk of thrombosis?

KAUNITZ: Yes. In the first study,²⁴ 2 thromboses occurred in women taking OCs, and 2 occurred in women using the progestin-only pill. All the women with thromboses were seropositive for antiphospholipid antibodies. Hence, we need to exclude the presence of these antibodies in women with SLE prior to prescribing combination estrogen-progestin contraception. In women with lupus and a history of thrombosis, as with all women with a history of thrombosis, we should avoid combination hormonal contraception.

In the second study,²³ which compared women on combination OCs to a placebo group, the OC group experienced 1 case of deep venous thrombosis (DVT) and 1 clotted graft. The placebo group experienced 1 case of DVT, 1 ocular thrombosis, 1 superficial thrombophlebitis, and 1 death (after the trial ended).

5. DMPA and bone density

DMPA does not appear to have long-term impact

OBG Management: There has been some furor over DMPA’s effect on bone mineral density (BMD). What are the latest findings in this area?

KAUNITZ: Studies assessing BMD in former DMPA users, including postmenopausal women, show that prior use of DMPA does not appear to have any long-term impact on BMD.^25,26 In addition, more recent longitudinal data indicate that after DMPA is discontinued BMD fully recovers, which appears to take about 3 years in adults and as little as 1 year in teens.^27,28

One population-based prospective cohort study followed 457 nongravid women aged 18 to 39 years. These women had bone density measured every 6 months for 3 years using dual-energy x-ray absorptiometry. Although bone density decreased among DMPA users at the spine and total hip compared with nonusers, there was no difference in bone density 30 months after discontinuation of birth control injections.²⁷

In a study of 170 adolescent women 14 to 18 years of age, 80 were DMPA users and 90 were nonusers. Bone density was measured every 6 months for 24 or 36 months, and declined significantly at the hip and spine in DMPA users. Sixty-one women discontinued DMPA during the course of the study. After discontinuation, bone density increased at all anatomical sites, recovering completely over the course of 1 year.²⁸

Although the US Food and Drug Administration issued a black box warning in the fall of 2004 that use of DMPA should be reconsidered after 2 years, particularly in teens, the studies I just mentioned suggest there should be no routine restrictions on the use of DMPA in terms of skeletal health, and that DMPA use by itself is not an indication for bone density measurement.

6. Patch and ring

Assume contraindications are the same as for OCs

OBG Management: What about newer forms of combination contraceptives such as the patch and ring?

KAUNITZ: The new practice bulletin contains information on the patch, the ring, and the levonorgestrel-releasing IUD, which were not available when the earlier bulletin was prepared. In that version we talked about combination pills only.

Even so, we continue to have much more data on the Pill than the ring or patch. For that reason, until more data become available, the patch and the ring should be assumed to have the same contraindications as combination OCs. We have very little data—if any—on the use of newer combination contraceptives in high-risk women or those with medical problems.