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Cervical cancer is the most common cancer caused by the human papillomavirus (HPV),¹ but the scope of HPV-related disease is considerably broader. As many as 90% of anal cancers, as well as 40% of vulvar and penile cancers, are attributable to HPV infection.² Furthermore, high-risk HPV types contribute significantly to cases of vulvar and vaginal disease³ and low-risk types of HPV are thought to cause up to 1 million cases of genital warts each year.⁴ Vaccination has been shown to be highly effective in preventing HPV infection⁵ and its sequelae.⁶

Some of these findings were presented in detail on November 10, 2008, by 3 experts at a symposium supported by an independent educational grant from Merck & Co., Inc., at the American Society for Reproductive Medicine 64th Annual Meeting in San Francisco. These clinicians also presented promising results showing cross-protection against several HPV types; provided tips to improve detection of vaginal lesions; and discussed the implications of gender-neutral vaccination. Following are short synopses of each physician’s presentation.

Epidemiology and natural history of HPV in benign and malignant disease: Primary prevention of CIN3 and AIS with HPV vaccination

J. THOMAS COX, MD

Most sexually active women will acquire HPV in their lifetime.⁷ Although the infection clears in most cases, it does persist in some women. Long-term persistence of HPV infection—particularly with high-risk types—has been established as a necessary cause of precancerous lesions.⁸ In fact, the high-risk HPV types 16 and 18 are responsible for 70% of squamous cell carcinoma cases and 86% of cases of adenocarcinoma.⁹

Persistent HPV infection and cervical intraepithelial neoplasia 3 (CIN 3) allow random mutations to accumulate that can eventually lead to cancer. When mutations occur in normal cells, the cell upregulates the expression of proteins that repair the mutation or precipitate apoptosis. High-risk types of the HPV virus produce proteins that inhibit this process, allowing cells to live despite mutations. In the worst case, these cells continue to grow and mutate, forming a malignancy over many years that invades the basement membrane.

Prophylactic administration of the HPV vaccine effectively prevents the development of CIN 1, 2, 3, and adenocarcinoma in situ (AIS). In patients who tested negative for the vaccine HPV types during the administration of the 3-dose vaccine, protection against high-grade cervical lesions (CIN 2 and 3) and AIS was between 97% and 100% at 3 years.^6,10 Vaccination was also effective in eliminating the development of genital warts and CIN 1, which are caused by low-risk HPV types 6 and 11.⁶

Additionally, vaccination appears to offer cross-protection, ie, partial protection against infection with HPV types related to 16 or 18, such as the high-risk types 45, 31, 33, and 52.¹¹

Update on HPV: Genital warts, VIN, VAIN, and vulvar/vaginal cancer

HOPE K. HAEFNER, MD

Vulvo-vaginal disease and genital warts can be sequelae of HPV infection. Genital warts represent a large burden: Treatment costs account for nearly one-third of annual medical expenses for sexually transmitted infections.¹² And vulvar intraepithelial neoplasia (VIN) is a growing burden. Although the incidence of VIN remains low, rates of diagnosis of VIN 2 and 3 are increasing.¹³ This is particularly troubling, given that 10% of untreated VIN 3 progresses to cancer.¹⁴ Further, VIN may not be diagnosed until it has progressed, because only subjective diagnostic criteria exist for low-grade VIN.¹⁵

Visual inspection is used to identify genital warts and vulvar or vaginal lesions. Vulvar or vaginal lesions are more difficult to detect with colposcopy than are cervical lesions, due to the wider target area and tangential angle of viewing. Applying a solution of 5% acetic acid and leaving it for 3 to 5 minutes will facilitate evaluation; small vaginal lesions are best detected with Lugol’s solution.

A bimanual examination that includes palpation of the vagina should be conducted in order to rule out invasive cancer.

HPV types 6 and 11 cause 90% of genital warts.¹⁶ High-risk HPV types 16 and 18 are responsible for many cases of vaginal and vulvar disease³:

• 76% of VIN 2/3
• 64% of vaginal intraepithelial neoplasia (VAIN) 2/3
• 42% of vulvar cancer

A meta-analysis of 3 randomized controlled trials evaluated the development of vulvar or vaginal lesions with prophylactic administration of the HPV vaccine.¹⁷ Among women who were HPV negative before and during administration of the HPV vaccine, the vaccine was 100% effective in preventing VIN 2/3 and VAIN 2/3 related to either HPV 16 or 18. The incidence of VIN 2/3 and VAIN 2/3 decreased by 71% among women who had previously been exposed to HPV.

Penile, anal, and oropharyngeal cancer: The potential for primary prevention with HPV vaccination

JOEL PALEFSKY, MD

To date, no HPV vaccine has been approved for use in men. However, some evidence suggests that their vaccination could reduce the burden of HPV-related disease in men and transmission of HPV to women.

HPV infection causes cancer in approximately 10,000 US men annually.¹⁸ Head and neck cancers account for the majority of these cases, followed by anal and penile cancers. Other HPV-related diseases seen in men include genital warts and recurrent respiratory papillomatosis.

HPV-associated anal cancer is increasing in prevalence, particularly among high-risk individuals, such as men who have sex with men (MSM) and HIV-positive men and women.¹⁹ The rate of anal cancer among MSM is 35 to 70 cases per 100,000 men, depending on HIV status.¹⁸ This is comparable to the rate of cervical cancer prior to the advent of cervical cytology screening, and well above the current cervical cancer rate of 8 to 10 cases per 100,000 women.

Among all MSM, 66% are infected with HPV and 42% have anal intraepithelial neoplasia, a cancer precursor.¹⁹ Two key pieces of evidence suggest that vaccination of men would be effective. First, the heavily keratinized, hair-bearing skin of external male genitalia is identical to that of the vulva. Based on this, it has been suggested that the beneficial effects of the vaccine in preventing genital warts in females may also be seen in males. Secondly, in studies, 9- to 15-year-old boys who received the quadrivalent vaccine had higher anti-HPV titers than even the young-adult women. Because the vaccine is known to be protective at the lower titers seen in the women, investigators suspect that it will also work in the boys.

Cervical cancer is the most common cancer caused by the human papillomavirus (HPV),¹ but the scope of HPV-related disease is considerably broader. As many as 90% of anal cancers, as well as 40% of vulvar and penile cancers, are attributable to HPV infection.² Furthermore, high-risk HPV types contribute significantly to cases of vulvar and vaginal disease³ and low-risk types of HPV are thought to cause up to 1 million cases of genital warts each year.⁴ Vaccination has been shown to be highly effective in preventing HPV infection⁵ and its sequelae.⁶

Some of these findings were presented in detail on November 10, 2008, by 3 experts at a symposium supported by an independent educational grant from Merck & Co., Inc., at the American Society for Reproductive Medicine 64th Annual Meeting in San Francisco. These clinicians also presented promising results showing cross-protection against several HPV types; provided tips to improve detection of vaginal lesions; and discussed the implications of gender-neutral vaccination. Following are short synopses of each physician’s presentation.

Epidemiology and natural history of HPV in benign and malignant disease: Primary prevention of CIN3 and AIS with HPV vaccination

J. THOMAS COX, MD

Most sexually active women will acquire HPV in their lifetime.⁷ Although the infection clears in most cases, it does persist in some women. Long-term persistence of HPV infection—particularly with high-risk types—has been established as a necessary cause of precancerous lesions.⁸ In fact, the high-risk HPV types 16 and 18 are responsible for 70% of squamous cell carcinoma cases and 86% of cases of adenocarcinoma.⁹

Persistent HPV infection and cervical intraepithelial neoplasia 3 (CIN 3) allow random mutations to accumulate that can eventually lead to cancer. When mutations occur in normal cells, the cell upregulates the expression of proteins that repair the mutation or precipitate apoptosis. High-risk types of the HPV virus produce proteins that inhibit this process, allowing cells to live despite mutations. In the worst case, these cells continue to grow and mutate, forming a malignancy over many years that invades the basement membrane.

Prophylactic administration of the HPV vaccine effectively prevents the development of CIN 1, 2, 3, and adenocarcinoma in situ (AIS). In patients who tested negative for the vaccine HPV types during the administration of the 3-dose vaccine, protection against high-grade cervical lesions (CIN 2 and 3) and AIS was between 97% and 100% at 3 years.^6,10 Vaccination was also effective in eliminating the development of genital warts and CIN 1, which are caused by low-risk HPV types 6 and 11.⁶

Additionally, vaccination appears to offer cross-protection, ie, partial protection against infection with HPV types related to 16 or 18, such as the high-risk types 45, 31, 33, and 52.¹¹

Update on HPV: Genital warts, VIN, VAIN, and vulvar/vaginal cancer

HOPE K. HAEFNER, MD

Vulvo-vaginal disease and genital warts can be sequelae of HPV infection. Genital warts represent a large burden: Treatment costs account for nearly one-third of annual medical expenses for sexually transmitted infections.¹² And vulvar intraepithelial neoplasia (VIN) is a growing burden. Although the incidence of VIN remains low, rates of diagnosis of VIN 2 and 3 are increasing.¹³ This is particularly troubling, given that 10% of untreated VIN 3 progresses to cancer.¹⁴ Further, VIN may not be diagnosed until it has progressed, because only subjective diagnostic criteria exist for low-grade VIN.¹⁵

Visual inspection is used to identify genital warts and vulvar or vaginal lesions. Vulvar or vaginal lesions are more difficult to detect with colposcopy than are cervical lesions, due to the wider target area and tangential angle of viewing. Applying a solution of 5% acetic acid and leaving it for 3 to 5 minutes will facilitate evaluation; small vaginal lesions are best detected with Lugol’s solution.

A bimanual examination that includes palpation of the vagina should be conducted in order to rule out invasive cancer.

HPV types 6 and 11 cause 90% of genital warts.¹⁶ High-risk HPV types 16 and 18 are responsible for many cases of vaginal and vulvar disease³:

• 76% of VIN 2/3
• 64% of vaginal intraepithelial neoplasia (VAIN) 2/3
• 42% of vulvar cancer

A meta-analysis of 3 randomized controlled trials evaluated the development of vulvar or vaginal lesions with prophylactic administration of the HPV vaccine.¹⁷ Among women who were HPV negative before and during administration of the HPV vaccine, the vaccine was 100% effective in preventing VIN 2/3 and VAIN 2/3 related to either HPV 16 or 18. The incidence of VIN 2/3 and VAIN 2/3 decreased by 71% among women who had previously been exposed to HPV.

Penile, anal, and oropharyngeal cancer: The potential for primary prevention with HPV vaccination

JOEL PALEFSKY, MD

To date, no HPV vaccine has been approved for use in men. However, some evidence suggests that their vaccination could reduce the burden of HPV-related disease in men and transmission of HPV to women.

HPV infection causes cancer in approximately 10,000 US men annually.¹⁸ Head and neck cancers account for the majority of these cases, followed by anal and penile cancers. Other HPV-related diseases seen in men include genital warts and recurrent respiratory papillomatosis.

HPV-associated anal cancer is increasing in prevalence, particularly among high-risk individuals, such as men who have sex with men (MSM) and HIV-positive men and women.¹⁹ The rate of anal cancer among MSM is 35 to 70 cases per 100,000 men, depending on HIV status.¹⁸ This is comparable to the rate of cervical cancer prior to the advent of cervical cytology screening, and well above the current cervical cancer rate of 8 to 10 cases per 100,000 women.

Among all MSM, 66% are infected with HPV and 42% have anal intraepithelial neoplasia, a cancer precursor.¹⁹ Two key pieces of evidence suggest that vaccination of men would be effective. First, the heavily keratinized, hair-bearing skin of external male genitalia is identical to that of the vulva. Based on this, it has been suggested that the beneficial effects of the vaccine in preventing genital warts in females may also be seen in males. Secondly, in studies, 9- to 15-year-old boys who received the quadrivalent vaccine had higher anti-HPV titers than even the young-adult women. Because the vaccine is known to be protective at the lower titers seen in the women, investigators suspect that it will also work in the boys.

Cervical cancer is the most common cancer caused by the human papillomavirus (HPV),¹ but the scope of HPV-related disease is considerably broader. As many as 90% of anal cancers, as well as 40% of vulvar and penile cancers, are attributable to HPV infection.² Furthermore, high-risk HPV types contribute significantly to cases of vulvar and vaginal disease³ and low-risk types of HPV are thought to cause up to 1 million cases of genital warts each year.⁴ Vaccination has been shown to be highly effective in preventing HPV infection⁵ and its sequelae.⁶

Some of these findings were presented in detail on November 10, 2008, by 3 experts at a symposium supported by an independent educational grant from Merck & Co., Inc., at the American Society for Reproductive Medicine 64th Annual Meeting in San Francisco. These clinicians also presented promising results showing cross-protection against several HPV types; provided tips to improve detection of vaginal lesions; and discussed the implications of gender-neutral vaccination. Following are short synopses of each physician’s presentation.

Epidemiology and natural history of HPV in benign and malignant disease: Primary prevention of CIN3 and AIS with HPV vaccination

J. THOMAS COX, MD

Most sexually active women will acquire HPV in their lifetime.⁷ Although the infection clears in most cases, it does persist in some women. Long-term persistence of HPV infection—particularly with high-risk types—has been established as a necessary cause of precancerous lesions.⁸ In fact, the high-risk HPV types 16 and 18 are responsible for 70% of squamous cell carcinoma cases and 86% of cases of adenocarcinoma.⁹

Persistent HPV infection and cervical intraepithelial neoplasia 3 (CIN 3) allow random mutations to accumulate that can eventually lead to cancer. When mutations occur in normal cells, the cell upregulates the expression of proteins that repair the mutation or precipitate apoptosis. High-risk types of the HPV virus produce proteins that inhibit this process, allowing cells to live despite mutations. In the worst case, these cells continue to grow and mutate, forming a malignancy over many years that invades the basement membrane.

Prophylactic administration of the HPV vaccine effectively prevents the development of CIN 1, 2, 3, and adenocarcinoma in situ (AIS). In patients who tested negative for the vaccine HPV types during the administration of the 3-dose vaccine, protection against high-grade cervical lesions (CIN 2 and 3) and AIS was between 97% and 100% at 3 years.^6,10 Vaccination was also effective in eliminating the development of genital warts and CIN 1, which are caused by low-risk HPV types 6 and 11.⁶

Additionally, vaccination appears to offer cross-protection, ie, partial protection against infection with HPV types related to 16 or 18, such as the high-risk types 45, 31, 33, and 52.¹¹

Update on HPV: Genital warts, VIN, VAIN, and vulvar/vaginal cancer

HOPE K. HAEFNER, MD

Vulvo-vaginal disease and genital warts can be sequelae of HPV infection. Genital warts represent a large burden: Treatment costs account for nearly one-third of annual medical expenses for sexually transmitted infections.¹² And vulvar intraepithelial neoplasia (VIN) is a growing burden. Although the incidence of VIN remains low, rates of diagnosis of VIN 2 and 3 are increasing.¹³ This is particularly troubling, given that 10% of untreated VIN 3 progresses to cancer.¹⁴ Further, VIN may not be diagnosed until it has progressed, because only subjective diagnostic criteria exist for low-grade VIN.¹⁵

Visual inspection is used to identify genital warts and vulvar or vaginal lesions. Vulvar or vaginal lesions are more difficult to detect with colposcopy than are cervical lesions, due to the wider target area and tangential angle of viewing. Applying a solution of 5% acetic acid and leaving it for 3 to 5 minutes will facilitate evaluation; small vaginal lesions are best detected with Lugol’s solution.

A bimanual examination that includes palpation of the vagina should be conducted in order to rule out invasive cancer.

HPV types 6 and 11 cause 90% of genital warts.¹⁶ High-risk HPV types 16 and 18 are responsible for many cases of vaginal and vulvar disease³:

• 76% of VIN 2/3
• 64% of vaginal intraepithelial neoplasia (VAIN) 2/3
• 42% of vulvar cancer

A meta-analysis of 3 randomized controlled trials evaluated the development of vulvar or vaginal lesions with prophylactic administration of the HPV vaccine.¹⁷ Among women who were HPV negative before and during administration of the HPV vaccine, the vaccine was 100% effective in preventing VIN 2/3 and VAIN 2/3 related to either HPV 16 or 18. The incidence of VIN 2/3 and VAIN 2/3 decreased by 71% among women who had previously been exposed to HPV.

Penile, anal, and oropharyngeal cancer: The potential for primary prevention with HPV vaccination

JOEL PALEFSKY, MD

To date, no HPV vaccine has been approved for use in men. However, some evidence suggests that their vaccination could reduce the burden of HPV-related disease in men and transmission of HPV to women.

HPV infection causes cancer in approximately 10,000 US men annually.¹⁸ Head and neck cancers account for the majority of these cases, followed by anal and penile cancers. Other HPV-related diseases seen in men include genital warts and recurrent respiratory papillomatosis.

HPV-associated anal cancer is increasing in prevalence, particularly among high-risk individuals, such as men who have sex with men (MSM) and HIV-positive men and women.¹⁹ The rate of anal cancer among MSM is 35 to 70 cases per 100,000 men, depending on HIV status.¹⁸ This is comparable to the rate of cervical cancer prior to the advent of cervical cytology screening, and well above the current cervical cancer rate of 8 to 10 cases per 100,000 women.

Among all MSM, 66% are infected with HPV and 42% have anal intraepithelial neoplasia, a cancer precursor.¹⁹ Two key pieces of evidence suggest that vaccination of men would be effective. First, the heavily keratinized, hair-bearing skin of external male genitalia is identical to that of the vulva. Based on this, it has been suggested that the beneficial effects of the vaccine in preventing genital warts in females may also be seen in males. Secondly, in studies, 9- to 15-year-old boys who received the quadrivalent vaccine had higher anti-HPV titers than even the young-adult women. Because the vaccine is known to be protective at the lower titers seen in the women, investigators suspect that it will also work in the boys.

DR SULAK: The estrogen and progestin doses in oral contraceptives (OCs) have steadily decreased since the 1960s; however, until recently, we’ve kept the same 21/7-day regimen. Due to the high doses in the first-generation OCs, the hormones lingered into the week off. With the low-dose pills and a 7-day hormone-free interval (HFI), we have seen problems such as ovulation, estrogen withdrawal symptoms, and unscheduled bleeding (ie, breakthrough bleeding or spotting).

DR LIU: The physiology of ovarian follicle development explains why many of these problems occur. In the normal menstrual cycle, follicle-stimulating hormone (FSH) levels increase dramatically during the first 2 days of menses, driving the development of as many as 10 early (primordial) follicles. As estrogen and inhibin B levels increase and suppress FSH, only the follicle with the greatest ability to generate FSH receptors within itself survives this low-FSH environment to become the “egg of the month.”

During the HFI of an OC regimen, FSH begins to rebound just as it does in a normal menstrual cycle. With very-low-dose estrogen/progestin OCs, this rebound occurs rapidly and follicles begin to develop. If the follicle develops to a critical stage—which might be as small as 14 mm—escape ovulation may occur, despite the resumption of active OC pills and dampening of FSH.¹ In fact, up to 30% of women may ovulate on OCs when the HFI is increased.¹

DR SULAK: It is amazing how rapidly the pituitary wakes up and starts producing FSH—and how responsive the ovary is! Studies have shown that the dramatic rise in FSH occurs around the fourth day of a 7-day HFI, followed rapidly by the rise in 17-beta estradiol from the ovarian follicles.^2,3 We reported a 500% increase in estradiol, from 10 pg to almost 60 pg—and that was using a 30 mcg pill.²

I am amazed that more people taking OCs do not conceive. The reason failure rates are not higher is due in large part to the “backup mechanisms” of the pill, such as cervical mucous thickening and thinning of the endometrial lining.

Development of extended-regimen OCs

DR LIU: Starting in 1998 with the approval of Mircette, we’ve begun to see a number of modifications to the 21/7 regimen.

DR SULAK: Mircette is a regimen of 21 days of 20 mcg ethinyl estradiol (EE) and 0.15 mg desogestrel, 2 placebo days, and 5 days of 10 mcg EE pills. Comparing Mircette with a 21/7 regimen of the same hormones, researchers found that women experienced greater ovarian suppression and less follicular development when a 10 mcg EE pill replaced the last 5 placebo pills.⁴

Interestingly, even though Mircette is a 20 mcg EE pill, its bleeding profile is comparable to many OCs with 30 mcg EE.^5,6 Adding that low dose of estrogen suppresses the ovary and prevents “rebound” FSH and estrogen production; it is the production of endogenous estrogen that interferes with the next cycle and causes breakthrough bleeding.^6,7

All of the OCs that have been approved since 2003 feature modifications of the 21/7 regimen. Seasonale extended the OC regimen to 84 days of active pills followed by 7 days off. Loestrin 24 and Yaz shortened the HFI of a 28-day regimen and demonstrated that 20 mcg EE pills can have a good bleeding profile if the HFI is decreased.

Seasonique (84 days of levonorgestrel, 0.15 mg, and EE, 30 mcg; followed by 7 days of EE, 10 mcg) was developed when it became apparent that after prolonged suppression, FSH rises very quickly and the ovary is even more responsive; a 7-day HFI could lead to escape ovulation and other problems.^2,3,8 The most recently approved OC regimen is Lybrel, a continuous ultra-low-dose regimen of EE and levonorgestrel.

DR LIU: So the modifications to the HFI have been made based on our understanding of how follicular development can be suppressed and why escape ovulation occurs. Altering the HFI can address some of these problems. The use of a very-low-dose estrogen in place of the placebo suppresses the pituitary and attenuates the rise of FSH and inhibin B, so that a new crop of follicles does not begin to develop.⁹

Importance of correct, consistent use

DR LIU: For patients using an OC with an HFI, during which days of the regimen is missing a pill most likely to cause contraceptive failure?

DR SULAK: The first pill is the most important one in the pack! Particularly with low-dose OCs, it’s especially a problem if a patient misses a pill during the first week after a 7-day HFI.

DR LIU: I tell patients that it takes several tablets to suppress FSH; no single tablet will maintain a persistent effect. Missing a pill during the first 5 days is probably more risky than missing 1 or more in the second or third week.

DR SULAK: The rise in FSH and 17-beta estradiol during the 7-day HFI continues into the first week of active pills and takes 5 to 7 days to decrease significantly.²

Reducing hormone withdrawal symptoms

DR LIU: Clinicians started extending OC regimens for patients with endometriosis or suspected endometriosis, whose pelvic pain flared up with the onset of bleeding.

DR SULAK: Then we realized that the benefits of extended regimens went beyond endometriosis and could help patients with menstrual migraine headaches or severe premenstrual syndrome. With extended regimens, we have shown reductions in mood swings, pain, headaches, bloating, and swelling.^6,10-12

With a low-dose regimen and a 7-day HFI, we were actually creating estrogen-withdrawal headaches, cramps, bloating, and other symptoms.¹³ In our prospective randomized trial of Seasonale vs Seasonique, we observed a tendency toward fewer headaches during the estrogen-supplemented week.⁷ And we weren’t even looking at headaches in that study! Adding estrogen during that typical week off may have the potential to decrease some of these withdrawal symptoms, but this needs further study.

Bleeding and spotting: Managing expectations

DR LIU: When a patient begins an extended-regimen OC, how do you manage her expectations about spotting and bleeding?

DR SULAK: Any patient on an extended-regimen OC has to be a great pill-taker, so I suggest that she put her pills somewhere she’ll see them at about the same time everyday. I tell patients that particularly during that first cycle, there is a high incidence of unscheduled bleeding. When I prescribe an OC regimen that substitutes a low-dose estrogen pill for the traditional placebo week, I explain that the patient will have a progestin withdrawal bleed during the estrogen-only pills. I also mention that in subsequent packs, the unscheduled bleeding is greatly reduced.^14,15

Conclusions

DR LIU: The modifications to the HFI that we’ve seen in recently approved OCs represent an incremental advance in our understanding of the physiology of ovarian follicle development. Experience and studies have shown how altering the HFI can optimize patient outcomes.

DR SULAK: We do need to see the demise of the 7-day HFI. Practitioners should realize that these changes in OCs are not arbitrary. They are substantiated by real science and will mean a true improvement in the symptoms and quality of life our patients experience.

DR SULAK: The estrogen and progestin doses in oral contraceptives (OCs) have steadily decreased since the 1960s; however, until recently, we’ve kept the same 21/7-day regimen. Due to the high doses in the first-generation OCs, the hormones lingered into the week off. With the low-dose pills and a 7-day hormone-free interval (HFI), we have seen problems such as ovulation, estrogen withdrawal symptoms, and unscheduled bleeding (ie, breakthrough bleeding or spotting).

DR LIU: The physiology of ovarian follicle development explains why many of these problems occur. In the normal menstrual cycle, follicle-stimulating hormone (FSH) levels increase dramatically during the first 2 days of menses, driving the development of as many as 10 early (primordial) follicles. As estrogen and inhibin B levels increase and suppress FSH, only the follicle with the greatest ability to generate FSH receptors within itself survives this low-FSH environment to become the “egg of the month.”

During the HFI of an OC regimen, FSH begins to rebound just as it does in a normal menstrual cycle. With very-low-dose estrogen/progestin OCs, this rebound occurs rapidly and follicles begin to develop. If the follicle develops to a critical stage—which might be as small as 14 mm—escape ovulation may occur, despite the resumption of active OC pills and dampening of FSH.¹ In fact, up to 30% of women may ovulate on OCs when the HFI is increased.¹

DR SULAK: It is amazing how rapidly the pituitary wakes up and starts producing FSH—and how responsive the ovary is! Studies have shown that the dramatic rise in FSH occurs around the fourth day of a 7-day HFI, followed rapidly by the rise in 17-beta estradiol from the ovarian follicles.^2,3 We reported a 500% increase in estradiol, from 10 pg to almost 60 pg—and that was using a 30 mcg pill.²

I am amazed that more people taking OCs do not conceive. The reason failure rates are not higher is due in large part to the “backup mechanisms” of the pill, such as cervical mucous thickening and thinning of the endometrial lining.

Development of extended-regimen OCs

DR LIU: Starting in 1998 with the approval of Mircette, we’ve begun to see a number of modifications to the 21/7 regimen.

DR SULAK: Mircette is a regimen of 21 days of 20 mcg ethinyl estradiol (EE) and 0.15 mg desogestrel, 2 placebo days, and 5 days of 10 mcg EE pills. Comparing Mircette with a 21/7 regimen of the same hormones, researchers found that women experienced greater ovarian suppression and less follicular development when a 10 mcg EE pill replaced the last 5 placebo pills.⁴

Interestingly, even though Mircette is a 20 mcg EE pill, its bleeding profile is comparable to many OCs with 30 mcg EE.^5,6 Adding that low dose of estrogen suppresses the ovary and prevents “rebound” FSH and estrogen production; it is the production of endogenous estrogen that interferes with the next cycle and causes breakthrough bleeding.^6,7

All of the OCs that have been approved since 2003 feature modifications of the 21/7 regimen. Seasonale extended the OC regimen to 84 days of active pills followed by 7 days off. Loestrin 24 and Yaz shortened the HFI of a 28-day regimen and demonstrated that 20 mcg EE pills can have a good bleeding profile if the HFI is decreased.

Seasonique (84 days of levonorgestrel, 0.15 mg, and EE, 30 mcg; followed by 7 days of EE, 10 mcg) was developed when it became apparent that after prolonged suppression, FSH rises very quickly and the ovary is even more responsive; a 7-day HFI could lead to escape ovulation and other problems.^2,3,8 The most recently approved OC regimen is Lybrel, a continuous ultra-low-dose regimen of EE and levonorgestrel.

DR LIU: So the modifications to the HFI have been made based on our understanding of how follicular development can be suppressed and why escape ovulation occurs. Altering the HFI can address some of these problems. The use of a very-low-dose estrogen in place of the placebo suppresses the pituitary and attenuates the rise of FSH and inhibin B, so that a new crop of follicles does not begin to develop.⁹

Importance of correct, consistent use

DR LIU: For patients using an OC with an HFI, during which days of the regimen is missing a pill most likely to cause contraceptive failure?

DR SULAK: The first pill is the most important one in the pack! Particularly with low-dose OCs, it’s especially a problem if a patient misses a pill during the first week after a 7-day HFI.

DR LIU: I tell patients that it takes several tablets to suppress FSH; no single tablet will maintain a persistent effect. Missing a pill during the first 5 days is probably more risky than missing 1 or more in the second or third week.

DR SULAK: The rise in FSH and 17-beta estradiol during the 7-day HFI continues into the first week of active pills and takes 5 to 7 days to decrease significantly.²

Reducing hormone withdrawal symptoms

DR LIU: Clinicians started extending OC regimens for patients with endometriosis or suspected endometriosis, whose pelvic pain flared up with the onset of bleeding.

DR SULAK: Then we realized that the benefits of extended regimens went beyond endometriosis and could help patients with menstrual migraine headaches or severe premenstrual syndrome. With extended regimens, we have shown reductions in mood swings, pain, headaches, bloating, and swelling.^6,10-12

With a low-dose regimen and a 7-day HFI, we were actually creating estrogen-withdrawal headaches, cramps, bloating, and other symptoms.¹³ In our prospective randomized trial of Seasonale vs Seasonique, we observed a tendency toward fewer headaches during the estrogen-supplemented week.⁷ And we weren’t even looking at headaches in that study! Adding estrogen during that typical week off may have the potential to decrease some of these withdrawal symptoms, but this needs further study.

Bleeding and spotting: Managing expectations

DR LIU: When a patient begins an extended-regimen OC, how do you manage her expectations about spotting and bleeding?

DR SULAK: Any patient on an extended-regimen OC has to be a great pill-taker, so I suggest that she put her pills somewhere she’ll see them at about the same time everyday. I tell patients that particularly during that first cycle, there is a high incidence of unscheduled bleeding. When I prescribe an OC regimen that substitutes a low-dose estrogen pill for the traditional placebo week, I explain that the patient will have a progestin withdrawal bleed during the estrogen-only pills. I also mention that in subsequent packs, the unscheduled bleeding is greatly reduced.^14,15

Conclusions

DR LIU: The modifications to the HFI that we’ve seen in recently approved OCs represent an incremental advance in our understanding of the physiology of ovarian follicle development. Experience and studies have shown how altering the HFI can optimize patient outcomes.

DR SULAK: We do need to see the demise of the 7-day HFI. Practitioners should realize that these changes in OCs are not arbitrary. They are substantiated by real science and will mean a true improvement in the symptoms and quality of life our patients experience.

DR SULAK: The estrogen and progestin doses in oral contraceptives (OCs) have steadily decreased since the 1960s; however, until recently, we’ve kept the same 21/7-day regimen. Due to the high doses in the first-generation OCs, the hormones lingered into the week off. With the low-dose pills and a 7-day hormone-free interval (HFI), we have seen problems such as ovulation, estrogen withdrawal symptoms, and unscheduled bleeding (ie, breakthrough bleeding or spotting).

DR LIU: The physiology of ovarian follicle development explains why many of these problems occur. In the normal menstrual cycle, follicle-stimulating hormone (FSH) levels increase dramatically during the first 2 days of menses, driving the development of as many as 10 early (primordial) follicles. As estrogen and inhibin B levels increase and suppress FSH, only the follicle with the greatest ability to generate FSH receptors within itself survives this low-FSH environment to become the “egg of the month.”

During the HFI of an OC regimen, FSH begins to rebound just as it does in a normal menstrual cycle. With very-low-dose estrogen/progestin OCs, this rebound occurs rapidly and follicles begin to develop. If the follicle develops to a critical stage—which might be as small as 14 mm—escape ovulation may occur, despite the resumption of active OC pills and dampening of FSH.¹ In fact, up to 30% of women may ovulate on OCs when the HFI is increased.¹

DR SULAK: It is amazing how rapidly the pituitary wakes up and starts producing FSH—and how responsive the ovary is! Studies have shown that the dramatic rise in FSH occurs around the fourth day of a 7-day HFI, followed rapidly by the rise in 17-beta estradiol from the ovarian follicles.^2,3 We reported a 500% increase in estradiol, from 10 pg to almost 60 pg—and that was using a 30 mcg pill.²

I am amazed that more people taking OCs do not conceive. The reason failure rates are not higher is due in large part to the “backup mechanisms” of the pill, such as cervical mucous thickening and thinning of the endometrial lining.

Development of extended-regimen OCs

DR LIU: Starting in 1998 with the approval of Mircette, we’ve begun to see a number of modifications to the 21/7 regimen.

DR SULAK: Mircette is a regimen of 21 days of 20 mcg ethinyl estradiol (EE) and 0.15 mg desogestrel, 2 placebo days, and 5 days of 10 mcg EE pills. Comparing Mircette with a 21/7 regimen of the same hormones, researchers found that women experienced greater ovarian suppression and less follicular development when a 10 mcg EE pill replaced the last 5 placebo pills.⁴

Interestingly, even though Mircette is a 20 mcg EE pill, its bleeding profile is comparable to many OCs with 30 mcg EE.^5,6 Adding that low dose of estrogen suppresses the ovary and prevents “rebound” FSH and estrogen production; it is the production of endogenous estrogen that interferes with the next cycle and causes breakthrough bleeding.^6,7

All of the OCs that have been approved since 2003 feature modifications of the 21/7 regimen. Seasonale extended the OC regimen to 84 days of active pills followed by 7 days off. Loestrin 24 and Yaz shortened the HFI of a 28-day regimen and demonstrated that 20 mcg EE pills can have a good bleeding profile if the HFI is decreased.

Seasonique (84 days of levonorgestrel, 0.15 mg, and EE, 30 mcg; followed by 7 days of EE, 10 mcg) was developed when it became apparent that after prolonged suppression, FSH rises very quickly and the ovary is even more responsive; a 7-day HFI could lead to escape ovulation and other problems.^2,3,8 The most recently approved OC regimen is Lybrel, a continuous ultra-low-dose regimen of EE and levonorgestrel.

DR LIU: So the modifications to the HFI have been made based on our understanding of how follicular development can be suppressed and why escape ovulation occurs. Altering the HFI can address some of these problems. The use of a very-low-dose estrogen in place of the placebo suppresses the pituitary and attenuates the rise of FSH and inhibin B, so that a new crop of follicles does not begin to develop.⁹

Importance of correct, consistent use

DR LIU: For patients using an OC with an HFI, during which days of the regimen is missing a pill most likely to cause contraceptive failure?

DR SULAK: The first pill is the most important one in the pack! Particularly with low-dose OCs, it’s especially a problem if a patient misses a pill during the first week after a 7-day HFI.

DR LIU: I tell patients that it takes several tablets to suppress FSH; no single tablet will maintain a persistent effect. Missing a pill during the first 5 days is probably more risky than missing 1 or more in the second or third week.

DR SULAK: The rise in FSH and 17-beta estradiol during the 7-day HFI continues into the first week of active pills and takes 5 to 7 days to decrease significantly.²

Reducing hormone withdrawal symptoms

DR LIU: Clinicians started extending OC regimens for patients with endometriosis or suspected endometriosis, whose pelvic pain flared up with the onset of bleeding.

DR SULAK: Then we realized that the benefits of extended regimens went beyond endometriosis and could help patients with menstrual migraine headaches or severe premenstrual syndrome. With extended regimens, we have shown reductions in mood swings, pain, headaches, bloating, and swelling.^6,10-12

With a low-dose regimen and a 7-day HFI, we were actually creating estrogen-withdrawal headaches, cramps, bloating, and other symptoms.¹³ In our prospective randomized trial of Seasonale vs Seasonique, we observed a tendency toward fewer headaches during the estrogen-supplemented week.⁷ And we weren’t even looking at headaches in that study! Adding estrogen during that typical week off may have the potential to decrease some of these withdrawal symptoms, but this needs further study.

Bleeding and spotting: Managing expectations

DR LIU: When a patient begins an extended-regimen OC, how do you manage her expectations about spotting and bleeding?

DR SULAK: Any patient on an extended-regimen OC has to be a great pill-taker, so I suggest that she put her pills somewhere she’ll see them at about the same time everyday. I tell patients that particularly during that first cycle, there is a high incidence of unscheduled bleeding. When I prescribe an OC regimen that substitutes a low-dose estrogen pill for the traditional placebo week, I explain that the patient will have a progestin withdrawal bleed during the estrogen-only pills. I also mention that in subsequent packs, the unscheduled bleeding is greatly reduced.^14,15

Conclusions

DR LIU: The modifications to the HFI that we’ve seen in recently approved OCs represent an incremental advance in our understanding of the physiology of ovarian follicle development. Experience and studies have shown how altering the HFI can optimize patient outcomes.

DR SULAK: We do need to see the demise of the 7-day HFI. Practitioners should realize that these changes in OCs are not arbitrary. They are substantiated by real science and will mean a true improvement in the symptoms and quality of life our patients experience.

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.