Program Chair

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.

A roundtable discussion among key thought leaders in the area of hormonal contraception was held on October 20, 2006, in New Orleans, Louisiana. These experts addressed the critical questions regarding the practical management of extended regimen oral contraceptives based on information in the medical literature.

Oral contraceptives (OCs) have been available in the United States for nearly 50 years. It is easy to forget that the introduction of reliable oral contraception—a widely available method that allows women control of their fertility—was revolutionary at that time. The decision to use a 28-day pill regimen was not a response to a physiologic need for 13 cycles per year but was dictated by the social norms and pregnancy testing technology of the day. At a time when pregnancy testing was neither easy to perform nor highly sensitive, the 7-day hormone free interval (HFI) provided a monthly reassurance to the OC user that she was not pregnant. Over the ensuing years numerous improvements in oral contraception have taken place—lowering of estrogen content due to safety concerns, confirmation of the efficacy of low-dose pills, introduction of new progestins, and phasic regimens. These changes came about due to a large number of clinical trials and other scientific assessments of OC regimens. Now with research shifted toward reducing the HFI and maximizing ovarian follicular suppression, oral contraception is undergoing a second revolution. By altering or eliminating the HFI, the goal of reducing withdrawal bleeding and minimizing hormone withdrawal can be accomplished.

Both spontaneous menstrual bleeding associated with ovulatory cycles and iatrogenically induced scheduled bleeding associated with OCs are due to endogenous or exogenous hormone withdrawal. However, the similarity ends abruptly, as menstrual bleeding fulfills a physiologic need to slough the secretory endometrium after ovulation in preparation for a new cycle and possible pregnancy. In contrast, there is no health-related reason to bleed while taking OCs. Monthly menstruation in reproductive-age women is necessary unless the patient is pregnant, using hormonal contraception, breastfeeding, or has undergone hysterectomy. A lack of cyclical menstrual bleeding in women not taking hormonal contraception is indicative of a pathologic state, whether it is the hypoestrogenic state of premature ovarian failure or the unopposed estrogen anovulatory state characteristic of women with polycystic ovarian syndrome (TABLE 1). Conversely, the recurrent ovulation and menstruation that is common among today’s post-industrial women is associated with health risks (TABLE 2).

The focus on alteration of the HFI to further improve OC therapy began with the introduction of Mircette^® in 1998.¹ This was followed by the introduction of Seasonale^®, the first extended OC regimen² and subsequently 2 OC products, Yaz^® and Loestrin^® 24 Fe, that maintained the 28-day cycle with a shortened HFI.^3-5 A recently introduced OC product, Seasonique^®, uses an extended 91-day regimen with low-dose ethinyl estradiol (EE) during the HFI, thus eliminating the HFI completely (TABLE 3).⁶

TABLE 1

Conditions Associated With Oligomenorrhea/Amenorrhea

TABLE 2

Health Risks

TABLE 3

OC Products With Extended Regimens or Altered Hormone Free Interval

Are there specific clinical advantages to extended regimen OCs?

DR LONDON: The real advantage to the extended regimens is that they do not have the disadvantages known to exist with the 21/7 regimens.

DR KAUNITZ: There are 4 advantages to extended regimens:

• improvement in contraceptive success
• therapeutic use for hormone withdrawal symptoms
• treatment of gynecologic problems such as dysmenorrhea, endometriosis, and anemia
• accommodation of lifestyle preference

Once women understand that extending combined hormone contraceptives is safe, most will prefer fewer cycles.

DR SULAK: While we need to acknowledge that the decision to introduce the first OCs in a 21/7 regimen was a wise choice nearly 50 years ago, research has shown us that the low doses of EE and the 7-day HFI creates problems—incomplete pituitary-ovarian suppression, endogenous estradiol formation, follicular development, ovarian cyst formation, risk of escape ovulation, and hormone withdrawal symptoms. It doesn’t matter whether a pill, patch, or ring is used—a 7-day HFI is too long with today’s low-dose combined hormonal contraceptives.

Spona was the first to report greater suppression of ovarian activity with a shortened HFI.⁷ By increasing the number of active pills from 21 to 23 per cycle and decreasing the HFI from 7 to 5 days, there was lower residual ovarian activity and endogenous 17β-estradiol. The study also showed that 17β-estradiol levels began to rise during the HFI but the rise was earlier and greater in women assigned to the 21-day regimen.

DR KAUNITZ: Another fundamental issue focuses on the reason our patients use OCs—effective, convenient, and reversible contraception. Unfortunately, the current 21/7 paradigm may not be optimal. The “typical” failure rate with OCs—which is what applies to our patients—is 8%.⁸ I don’t think that is acceptable.

The HFI and the first few days of a new pill pack are the time at which women are at greatest risk for contraceptive failure and unintended pregnancy. By extending the overall duration of active pills and decreasing the duration of the HFI, we are setting our patients up for better contraceptive success.

DR SULAK: There is also the issue of symptoms during the HFI. We all recognize that menstrual symptoms—breast tenderness, headache, bloating, and cramping—increase during the HFI.⁹ Although our data reported significant hormone withdrawal symptoms in women taking OCs, women experience these symptoms with all forms of combined estrogen-progestin hormonal contraceptives regardless of route of administration.

Importantly, the study showed that the symptoms occurred consistently not only in the new start patients, but also in the established users—the women who had been on the pill for more than a year. There is a reason why so many women stop their OCs in less than a year—it’s not because they are feeling wonderful. They may stop because they feel terrible during the HFI.

DR NELSON: The symptoms are real and it is astonishing how many women experience them. Women have become so accustomed to feeling lousy once a month, whether it’s due to menstrual symptoms or hormone withdrawal, that they will not mention it.

Another advantage to extended use of combination estrogen-progestin contraception is the prolonged suppression of ovulation and menstruation, like that produced by the progestin-only regimens, without the negative effects on bone. Given the multitude of problems caused by recurrent ovulation and menstruation, it may be healthier for some women not to have periods every month.

DR KAUNITZ: There are also therapeutic uses for extended regimen OCs that we should not overlook. Decreased dysmenorrhea and menorrhagia are both included in the prescribing information for all OCs. Women suffering from these disorders will likely have additive benefit from extended regimens. In the same vein, the value of extended regimens in managing endometriosis has been known for years.¹⁰

DR SULAK: A very recent paper showed that extending the regimen can improve premenstrual symptoms.¹¹ When symptomatology was compared with that recorded during a 21/7 cycle, there was a significant improvement that was especially apparent in the women who had the greatest variability in their cycles.

Another important finding was that the greatest improvement was detected in the sixth month. That is a key counseling point—you need to stick with the regimen to see the benefits.

What practical advantages does an extended regimen offer to the patient?

DR LONDON: Convenience, convenience, convenience.

MS MOORE: The worst pill to miss in any cycle is the one that is still at the pharmacy. Once your patient has already had 7 hormone-free days, her risk of pregnancy increases with each day of delay in starting a new pack of pills.

DR LONDON: With an extended regimen, that risk occurs fewer times per year. Just as the change from 50-mcg pills to low-dose pills was an improvement, the extension of the regimen beyond 28 days is a real improvement in OC therapy.

DR NELSON: Access to pills is a real issue—it’s more than having to go to the pharmacy every few weeks. A recent paper from the California Family PACT (Planning, Access, Care and Treatment) Program showed that women who were dispensed a year’s supply of OCs at their first visit were more likely to continue therapy, were more likely to receive Papanicolaou tests and Chlamydia tests, and actually had a lower annual women’s health care–related costs than women who were dispensed 3 cycles.¹²

We recently presented data that support this conclusion—hormonal method continuation rates were higher among women who received 3 pill packs than in those who received only 1. Having the supply of pills available is one more way of promoting contraceptive success.

Are there side effects that are specific to the extended regimen OCs?

DR SULAK: We are in consensus that there are no side effects that are specific to the extended regimen OCs. The only side effect found to be increased with extended regimen is unscheduled bleeding, but some studies have shown less bleeding overall.¹³ Studies have shown a decrease in many typical side effects seen with 21/7 OCs such as premenstrual syndrome and headaches.¹⁴

DR KAUNITZ: I agree. We should, however, address unscheduled bleeding and spotting. It’s something that we see with every OC, but extending the regimen changes the pattern.

A number of years ago, a randomized trial showed that addition of low-dose estrogen to the HFI provided superior cycle control to that of a 20-mcg EE OC and similar to that reported with a 35-mcg pill.¹⁵ There are more recent data that suggest that once you have passed the first cycle, addition of low-dose estrogen to the HFI also improves unscheduled bleeding in 91-day regimens.⁶

MS MOORE: Patients must understand there will be some unscheduled bleeding/spotting as their endometrium transitions from a monthly cycle or withdrawal bleed to more complete ovarian suppression, but it is manageable.

DR LONDON: Some clinicians have concerns about estrogen exposure—specifically the risk of venous thromboembolism and breast cancer. When the published data regarding extended regimens are examined in total, the safety profile is virtually the same as for 21/7. The safety of 91-day regimens have been demonstrated in both 1-year trials as well as longer-term 2-year studies.^2,6,16

The Women’s CARE (Contraceptive and Reproductive Experiences) study really put concerns about the association of OC use and breast cancer to rest.¹⁷ There was no evidence of increased risk of breast cancer in either current or past users of OCs. Given that the study included women who had taken high-dose 50-mcg EE pills, it’s very reasonable to conclude that extended OC use poses no increased risk of breast cancer.

What can be done to ensure that an extended regimen is offered to all OC-appropriate patients regardless of age or pathology?

DR KAUNITZ: We still need to work on overcoming common misconceptions. Despite more than 45 years of use, a fundamental lack of understanding of how OCs work persists among patients and health care professionals outside the field of women’s health.

MS MOORE: Many of my students are incredulous when they realize that there is no physiologic reason for the 7-day HFI and cyclical bleeding for women taking OCs.

DR LONDON: We also need to dispel the myth that women taking OCs are having periods. Remember that no women taking an OC has a period. They have withdrawal bleeding.

DR SULAK: Extended regimens set my patients up for contraceptive success and should be considered for all women who are candidates for OCs. The advantages—avoidance of monthly withdrawal symptoms, less follicular development, and, overall, less bleeding—outweigh the issues of unscheduled bleeding and spotting.

DR NELSON: We should discuss bleeding with our patients and, perhaps, it is time to turn the tables and ask her why she feels the need to bleed every month. For women considering use of OCs, it opens up the conversation to use of regimens other than 21/7. For women who are established users of OCs, asking whether they are having symptoms every month will open up the same conversation.

DR KAUNITZ: We’re not here to suggest that women should no longer menstruate or that women should no longer experience monthly bleeding.

It’s all about choice. Using hormones not only to provide safe, effective contraception but also to allow women the option of choosing when to bleed is a second revolution in contraception.

With regard to symptoms, I ask about grouchiness. “Do you get headaches or feel grouchy or down during your HFI?” If the answer is yes, it moves the conversation in the direction of extended regimens.

MS MOORE: I agree. The extended regimen has become mainstream over the past couple of years—the only reason I can see for using 21/7 is if the patient demands it or if reimbursement drives the issue.

How important is breakthrough bleeding in OC product selection?

DR KAUNITZ: Breakthrough bleeding occurs with all OC products—it’s importance becomes a matter of how well you have prepared patients for it.

MS MOORE: I like to tell my patients that it is likely they will experience some breakthrough bleeding in the early cycles. Then they are prepared and those who do not have any are pleasantly surprised.

DR SULAK: It’s inevitable and it can be managed—to me, it’s more important to focus on eliminating hormone withdrawal symptoms.

Are all combined hormonal contraceptive products appropriate for use in extended regimens?

DR NELSON: At this time there are insufficient data regarding the safety and pharmacokinetics of extended regimen use of the transdermal patch. Until studies evaluating its use in multiple extended cycles become available, we cannot recommend its use in extended regimens.¹⁸

DR KAUNITZ: Traditional 21/7 pill packs can be used in extended regimens but I find this approach often poses challenges for the patient—from remembering not to take placebo pills to reimbursement to trips to the pharmacy every 3 weeks for a new pill pack.

DR LONDON: It seems intuitive that the multiphasic pills would not be optimal for use in extended regimens. Given the paucity of data supporting their use, I would not recommend initiating an extended regimen with a mutiphasic pill. I certainly would allow a patient who is using them successfully to continue.

What are practical options to manage breakthrough bleeding in patients taking extended regimen OCs?

DR SULAK: We find that patients usually don’t begin to have unscheduled bleeding until week 4 or later. In our prospective study, we found that women who had heavier daily flow ratings during the 21/7 lead-in cycle tended to have greater daily flow ratings and earlier occurrence of unscheduled bleeding when taking an extended regimen.¹³ We also showed that a 3-day pill holiday was helpful in managing breakthrough bleeding and/or spotting that had persisted for 7 consecutive days (TABLE 4).

MS MOORE: Essentially patients have 2 options: endure the bleeding or take a brief pill holiday. I let my patients decide—some are very bothered by even the slightest amount of breakthrough bleeding while others have no issue with it. The worse thing a patient can do is to stop taking pills without a back-up plan for contraception. It is critical that they take at least 3 weeks of active pills between drug holidays.

DR LONDON: It’s also important to remember that you cannot use a 3-day pill holiday to manage breakthrough bleeding/spotting with 21/7 regimens as the increased number of hormone-free days per cycle could lead to a greater chance of escape ovulation.

DR KAUNITZ: Let’s not forget the value of counseling. Just letting women know what to expect and what to do has certainly been proven to be valuable in improving continuation rates among women on other forms of long-term contraception^19,20 and would without doubt be beneficial for women receiving extended regimens (SIDEBAR).

DR SULAK: With the low-dose OCs, it is especially important to let the patient know at the time you write the prescription that she has to take her pills at about the same time each day. I have had patients tell me that they experience bleeding if they take their pills even a few hours late.

DR NELSON: There will be patients with breakthrough bleeding/spotting who need to be examined, such as a long-term pill user who reports it for the first time. If you can establish a history of good pill taking with no illnesses or medication interaction which might alter hormone absorption, this woman should be evaluated for infection and anatomic changes like cervical or endometrial polyps.

TABLE 4

Recommendations for Initiating Extended Regimens

Summary

DR SULAK: We are finally seeing the demise of 21/7 contraceptive regimens. Numerous studies of these regimens over the past decade have documented hormone withdrawal symptoms, inadequate pituitary-ovarian suppression, follicular development, and even ovulation. Regimens which shorten or eliminate the 7-day HFI by adding estrogen and providing greater duration of active pills will improve the side effect profile and efficacy.

Oral contraceptives first gave women control over their fertility; now, regimens that extend the cycle and eliminate the HFI give women the option of having fewer hormone withdrawal symptoms. In addition to the convenience of fewer cycles per year, women may experience further benefit from prolonged suppression of ovulation and menstruation.

While breakthrough bleeding and spotting occur with all OCs, the pattern seen with extended regimens differs. It can be managed with patient counseling and brief pill holidays. Additional strategies to manage breakthrough bleeding that should be evaluated in the future include additional estrogen only, nonsteroidal anti-inflammatory drugs, and changing the estrogen dose of the formulation (ie, increasing the dose from 20 mcg EE to 30-35 mcg EE).

Articles of interest

Anderson FD, Gibbons W, Portman D. Safety and efficacy of an extended-regimen oral contraceptive utilizing continuous low-dose ethinyl estradiol. Contraception. 2006;73:229-234.

Prospective trial of 1006 sexually active adult women of childbearing potential who received a 91-day extended regimen OC (30 mcg EE/150 mcg LNG) with continuous low-dose EE (10 mcg) during the hormone free interval. Cycle control and safety of the regimen were comparable to that reported for other OCs.

Anderson FD, Gibbons W, Portman D. Long-term safety of an extended-cycle oral contraceptive (Seasonale): a 2-year multicenter open-label extension trial. Am J Obstet Gynecol. 2006;195:92-96.

Long-term safety study of a 91-day extended cycle OC regimen. Overall rates of study discontinuation and incidence of adverse events were similar to those of an earlier Phase 3 clinical trial. The regimen was well tolerated and the numbers of reported bleeding and/or spotting days diminished during the study.

Foster DG, Parvataneni R, de Bocanegra HT, Lewis C, Bradsberry M, Darney P. Number of oral contraceptive pill packages dispensed, method continuation, and costs. Obstet Gynecol. 2006;108:1107-1114.

Evaluation of the effect of the number of cycles of OC pill packages dispensed on the method continuation, pill wastage, use of services, and health care costs among 82,319 women enrolled in the California Family PACT system. Dispensing a year’s supply of OCs during first visits was associated with a higher method continuation and lower health care costs than dispensing fewer cycles per visit.

Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and the risk of breast cancer. N Engl J Med. 2002;346:2025-2032.

A population-based, case-control study of 4575 women with breast cancer and 4682 controls to determine the risk of breast cancer among former and current users of OCs. The relative risk of breast cancer was 1.0 (95% CI, 0.8-1.3) for women who were currently using OCs and 0.9 (95% CI, 0.8-1.0) for those who had previously used them. The relative risk did not increase consistently with longer periods of use or with higher doses of estrogen. Use of OCs by women with a family history of breast cancer was not associated with an increased risk of breast cancer nor was the initiation of OC use at a young age.

Spona J, Elstein M, Feichtinger W, et al. Shorter pill-free interval in combined oral contraceptives decreases follicular development. Contraception. 1996;54:71-77.

Double-blind, randomized trial to determine the suppressive effect on ovarian activity of OCs administered for 21 or 23 days. Observed differences in 17β-estradiol levels and follicular development between a 21-day and 23-day preparation suggest that shortening the pill-free interval in combined OCs may increase the contraceptive safety margin in women on low-dose formulations.

Sulak PJ, Scow RD, Preece C, Riggs MW, Kuehl TJ. Hormone withdrawal symptoms in oral contraceptive users. Obstet Gynecol. 2000;95:261-266.

Prospective evaluation to measure the timing, frequency, and severity of hormone-related symptoms in OC users. Pelvic pain, headaches, use of pain medication, bloating or swelling, and breast tenderness occurred significantly more frequently during the 7-day hormone free interval among both current users and new start users of OCs.

Sulak PJ, Kuehl TJ, Coffee A, Willis S. Prospective analysis of occurrence and management of breakthrough bleeding during an extended oral contraceptive regimen. Am J Obstet Gynecol. 2006;195:935-941.

Single-center, prospective analysis of self-rated menstrual flow during a 21/7 regimen versus a 168-day extended OC regimen. Subjects with a heavier daily flow rating during the 21/7 day cycle tended to have greater daily flow ratings and earlier breakthrough bleeding during the 168-day extension cycle. The 168-day extended regimen had an acceptable bleeding profile with bleeding during the active pill interval effectively managed with institution of a 3-day hormone free interval.

Acknowledgment

The assistance of Kathryn Martin, PharmD, in providing background research and editorial support is acknowledged.

A roundtable discussion among key thought leaders in the area of hormonal contraception was held on October 20, 2006, in New Orleans, Louisiana. These experts addressed the critical questions regarding the practical management of extended regimen oral contraceptives based on information in the medical literature.

Oral contraceptives (OCs) have been available in the United States for nearly 50 years. It is easy to forget that the introduction of reliable oral contraception—a widely available method that allows women control of their fertility—was revolutionary at that time. The decision to use a 28-day pill regimen was not a response to a physiologic need for 13 cycles per year but was dictated by the social norms and pregnancy testing technology of the day. At a time when pregnancy testing was neither easy to perform nor highly sensitive, the 7-day hormone free interval (HFI) provided a monthly reassurance to the OC user that she was not pregnant. Over the ensuing years numerous improvements in oral contraception have taken place—lowering of estrogen content due to safety concerns, confirmation of the efficacy of low-dose pills, introduction of new progestins, and phasic regimens. These changes came about due to a large number of clinical trials and other scientific assessments of OC regimens. Now with research shifted toward reducing the HFI and maximizing ovarian follicular suppression, oral contraception is undergoing a second revolution. By altering or eliminating the HFI, the goal of reducing withdrawal bleeding and minimizing hormone withdrawal can be accomplished.

Both spontaneous menstrual bleeding associated with ovulatory cycles and iatrogenically induced scheduled bleeding associated with OCs are due to endogenous or exogenous hormone withdrawal. However, the similarity ends abruptly, as menstrual bleeding fulfills a physiologic need to slough the secretory endometrium after ovulation in preparation for a new cycle and possible pregnancy. In contrast, there is no health-related reason to bleed while taking OCs. Monthly menstruation in reproductive-age women is necessary unless the patient is pregnant, using hormonal contraception, breastfeeding, or has undergone hysterectomy. A lack of cyclical menstrual bleeding in women not taking hormonal contraception is indicative of a pathologic state, whether it is the hypoestrogenic state of premature ovarian failure or the unopposed estrogen anovulatory state characteristic of women with polycystic ovarian syndrome (TABLE 1). Conversely, the recurrent ovulation and menstruation that is common among today’s post-industrial women is associated with health risks (TABLE 2).

The focus on alteration of the HFI to further improve OC therapy began with the introduction of Mircette^® in 1998.¹ This was followed by the introduction of Seasonale^®, the first extended OC regimen² and subsequently 2 OC products, Yaz^® and Loestrin^® 24 Fe, that maintained the 28-day cycle with a shortened HFI.^3-5 A recently introduced OC product, Seasonique^®, uses an extended 91-day regimen with low-dose ethinyl estradiol (EE) during the HFI, thus eliminating the HFI completely (TABLE 3).⁶

TABLE 1

Conditions Associated With Oligomenorrhea/Amenorrhea

TABLE 2

Health Risks

TABLE 3

OC Products With Extended Regimens or Altered Hormone Free Interval

Are there specific clinical advantages to extended regimen OCs?

DR LONDON: The real advantage to the extended regimens is that they do not have the disadvantages known to exist with the 21/7 regimens.

DR KAUNITZ: There are 4 advantages to extended regimens:

• improvement in contraceptive success
• therapeutic use for hormone withdrawal symptoms
• treatment of gynecologic problems such as dysmenorrhea, endometriosis, and anemia
• accommodation of lifestyle preference

Once women understand that extending combined hormone contraceptives is safe, most will prefer fewer cycles.

DR SULAK: While we need to acknowledge that the decision to introduce the first OCs in a 21/7 regimen was a wise choice nearly 50 years ago, research has shown us that the low doses of EE and the 7-day HFI creates problems—incomplete pituitary-ovarian suppression, endogenous estradiol formation, follicular development, ovarian cyst formation, risk of escape ovulation, and hormone withdrawal symptoms. It doesn’t matter whether a pill, patch, or ring is used—a 7-day HFI is too long with today’s low-dose combined hormonal contraceptives.

Spona was the first to report greater suppression of ovarian activity with a shortened HFI.⁷ By increasing the number of active pills from 21 to 23 per cycle and decreasing the HFI from 7 to 5 days, there was lower residual ovarian activity and endogenous 17β-estradiol. The study also showed that 17β-estradiol levels began to rise during the HFI but the rise was earlier and greater in women assigned to the 21-day regimen.

DR KAUNITZ: Another fundamental issue focuses on the reason our patients use OCs—effective, convenient, and reversible contraception. Unfortunately, the current 21/7 paradigm may not be optimal. The “typical” failure rate with OCs—which is what applies to our patients—is 8%.⁸ I don’t think that is acceptable.

The HFI and the first few days of a new pill pack are the time at which women are at greatest risk for contraceptive failure and unintended pregnancy. By extending the overall duration of active pills and decreasing the duration of the HFI, we are setting our patients up for better contraceptive success.

DR SULAK: There is also the issue of symptoms during the HFI. We all recognize that menstrual symptoms—breast tenderness, headache, bloating, and cramping—increase during the HFI.⁹ Although our data reported significant hormone withdrawal symptoms in women taking OCs, women experience these symptoms with all forms of combined estrogen-progestin hormonal contraceptives regardless of route of administration.

Importantly, the study showed that the symptoms occurred consistently not only in the new start patients, but also in the established users—the women who had been on the pill for more than a year. There is a reason why so many women stop their OCs in less than a year—it’s not because they are feeling wonderful. They may stop because they feel terrible during the HFI.

DR NELSON: The symptoms are real and it is astonishing how many women experience them. Women have become so accustomed to feeling lousy once a month, whether it’s due to menstrual symptoms or hormone withdrawal, that they will not mention it.

Another advantage to extended use of combination estrogen-progestin contraception is the prolonged suppression of ovulation and menstruation, like that produced by the progestin-only regimens, without the negative effects on bone. Given the multitude of problems caused by recurrent ovulation and menstruation, it may be healthier for some women not to have periods every month.

DR KAUNITZ: There are also therapeutic uses for extended regimen OCs that we should not overlook. Decreased dysmenorrhea and menorrhagia are both included in the prescribing information for all OCs. Women suffering from these disorders will likely have additive benefit from extended regimens. In the same vein, the value of extended regimens in managing endometriosis has been known for years.¹⁰

DR SULAK: A very recent paper showed that extending the regimen can improve premenstrual symptoms.¹¹ When symptomatology was compared with that recorded during a 21/7 cycle, there was a significant improvement that was especially apparent in the women who had the greatest variability in their cycles.

Another important finding was that the greatest improvement was detected in the sixth month. That is a key counseling point—you need to stick with the regimen to see the benefits.

What practical advantages does an extended regimen offer to the patient?

DR LONDON: Convenience, convenience, convenience.

MS MOORE: The worst pill to miss in any cycle is the one that is still at the pharmacy. Once your patient has already had 7 hormone-free days, her risk of pregnancy increases with each day of delay in starting a new pack of pills.

DR LONDON: With an extended regimen, that risk occurs fewer times per year. Just as the change from 50-mcg pills to low-dose pills was an improvement, the extension of the regimen beyond 28 days is a real improvement in OC therapy.

DR NELSON: Access to pills is a real issue—it’s more than having to go to the pharmacy every few weeks. A recent paper from the California Family PACT (Planning, Access, Care and Treatment) Program showed that women who were dispensed a year’s supply of OCs at their first visit were more likely to continue therapy, were more likely to receive Papanicolaou tests and Chlamydia tests, and actually had a lower annual women’s health care–related costs than women who were dispensed 3 cycles.¹²

We recently presented data that support this conclusion—hormonal method continuation rates were higher among women who received 3 pill packs than in those who received only 1. Having the supply of pills available is one more way of promoting contraceptive success.

Are there side effects that are specific to the extended regimen OCs?

DR SULAK: We are in consensus that there are no side effects that are specific to the extended regimen OCs. The only side effect found to be increased with extended regimen is unscheduled bleeding, but some studies have shown less bleeding overall.¹³ Studies have shown a decrease in many typical side effects seen with 21/7 OCs such as premenstrual syndrome and headaches.¹⁴

DR KAUNITZ: I agree. We should, however, address unscheduled bleeding and spotting. It’s something that we see with every OC, but extending the regimen changes the pattern.

A number of years ago, a randomized trial showed that addition of low-dose estrogen to the HFI provided superior cycle control to that of a 20-mcg EE OC and similar to that reported with a 35-mcg pill.¹⁵ There are more recent data that suggest that once you have passed the first cycle, addition of low-dose estrogen to the HFI also improves unscheduled bleeding in 91-day regimens.⁶

MS MOORE: Patients must understand there will be some unscheduled bleeding/spotting as their endometrium transitions from a monthly cycle or withdrawal bleed to more complete ovarian suppression, but it is manageable.

DR LONDON: Some clinicians have concerns about estrogen exposure—specifically the risk of venous thromboembolism and breast cancer. When the published data regarding extended regimens are examined in total, the safety profile is virtually the same as for 21/7. The safety of 91-day regimens have been demonstrated in both 1-year trials as well as longer-term 2-year studies.^2,6,16

The Women’s CARE (Contraceptive and Reproductive Experiences) study really put concerns about the association of OC use and breast cancer to rest.¹⁷ There was no evidence of increased risk of breast cancer in either current or past users of OCs. Given that the study included women who had taken high-dose 50-mcg EE pills, it’s very reasonable to conclude that extended OC use poses no increased risk of breast cancer.

What can be done to ensure that an extended regimen is offered to all OC-appropriate patients regardless of age or pathology?

DR KAUNITZ: We still need to work on overcoming common misconceptions. Despite more than 45 years of use, a fundamental lack of understanding of how OCs work persists among patients and health care professionals outside the field of women’s health.

MS MOORE: Many of my students are incredulous when they realize that there is no physiologic reason for the 7-day HFI and cyclical bleeding for women taking OCs.

DR LONDON: We also need to dispel the myth that women taking OCs are having periods. Remember that no women taking an OC has a period. They have withdrawal bleeding.

DR SULAK: Extended regimens set my patients up for contraceptive success and should be considered for all women who are candidates for OCs. The advantages—avoidance of monthly withdrawal symptoms, less follicular development, and, overall, less bleeding—outweigh the issues of unscheduled bleeding and spotting.

DR NELSON: We should discuss bleeding with our patients and, perhaps, it is time to turn the tables and ask her why she feels the need to bleed every month. For women considering use of OCs, it opens up the conversation to use of regimens other than 21/7. For women who are established users of OCs, asking whether they are having symptoms every month will open up the same conversation.

DR KAUNITZ: We’re not here to suggest that women should no longer menstruate or that women should no longer experience monthly bleeding.

It’s all about choice. Using hormones not only to provide safe, effective contraception but also to allow women the option of choosing when to bleed is a second revolution in contraception.

With regard to symptoms, I ask about grouchiness. “Do you get headaches or feel grouchy or down during your HFI?” If the answer is yes, it moves the conversation in the direction of extended regimens.

MS MOORE: I agree. The extended regimen has become mainstream over the past couple of years—the only reason I can see for using 21/7 is if the patient demands it or if reimbursement drives the issue.

How important is breakthrough bleeding in OC product selection?

DR KAUNITZ: Breakthrough bleeding occurs with all OC products—it’s importance becomes a matter of how well you have prepared patients for it.

MS MOORE: I like to tell my patients that it is likely they will experience some breakthrough bleeding in the early cycles. Then they are prepared and those who do not have any are pleasantly surprised.

DR SULAK: It’s inevitable and it can be managed—to me, it’s more important to focus on eliminating hormone withdrawal symptoms.

Are all combined hormonal contraceptive products appropriate for use in extended regimens?

DR NELSON: At this time there are insufficient data regarding the safety and pharmacokinetics of extended regimen use of the transdermal patch. Until studies evaluating its use in multiple extended cycles become available, we cannot recommend its use in extended regimens.¹⁸

DR KAUNITZ: Traditional 21/7 pill packs can be used in extended regimens but I find this approach often poses challenges for the patient—from remembering not to take placebo pills to reimbursement to trips to the pharmacy every 3 weeks for a new pill pack.

DR LONDON: It seems intuitive that the multiphasic pills would not be optimal for use in extended regimens. Given the paucity of data supporting their use, I would not recommend initiating an extended regimen with a mutiphasic pill. I certainly would allow a patient who is using them successfully to continue.

What are practical options to manage breakthrough bleeding in patients taking extended regimen OCs?

DR SULAK: We find that patients usually don’t begin to have unscheduled bleeding until week 4 or later. In our prospective study, we found that women who had heavier daily flow ratings during the 21/7 lead-in cycle tended to have greater daily flow ratings and earlier occurrence of unscheduled bleeding when taking an extended regimen.¹³ We also showed that a 3-day pill holiday was helpful in managing breakthrough bleeding and/or spotting that had persisted for 7 consecutive days (TABLE 4).

MS MOORE: Essentially patients have 2 options: endure the bleeding or take a brief pill holiday. I let my patients decide—some are very bothered by even the slightest amount of breakthrough bleeding while others have no issue with it. The worse thing a patient can do is to stop taking pills without a back-up plan for contraception. It is critical that they take at least 3 weeks of active pills between drug holidays.

DR LONDON: It’s also important to remember that you cannot use a 3-day pill holiday to manage breakthrough bleeding/spotting with 21/7 regimens as the increased number of hormone-free days per cycle could lead to a greater chance of escape ovulation.

DR KAUNITZ: Let’s not forget the value of counseling. Just letting women know what to expect and what to do has certainly been proven to be valuable in improving continuation rates among women on other forms of long-term contraception^19,20 and would without doubt be beneficial for women receiving extended regimens (SIDEBAR).

DR SULAK: With the low-dose OCs, it is especially important to let the patient know at the time you write the prescription that she has to take her pills at about the same time each day. I have had patients tell me that they experience bleeding if they take their pills even a few hours late.

DR NELSON: There will be patients with breakthrough bleeding/spotting who need to be examined, such as a long-term pill user who reports it for the first time. If you can establish a history of good pill taking with no illnesses or medication interaction which might alter hormone absorption, this woman should be evaluated for infection and anatomic changes like cervical or endometrial polyps.

TABLE 4

Recommendations for Initiating Extended Regimens

Summary

DR SULAK: We are finally seeing the demise of 21/7 contraceptive regimens. Numerous studies of these regimens over the past decade have documented hormone withdrawal symptoms, inadequate pituitary-ovarian suppression, follicular development, and even ovulation. Regimens which shorten or eliminate the 7-day HFI by adding estrogen and providing greater duration of active pills will improve the side effect profile and efficacy.

Oral contraceptives first gave women control over their fertility; now, regimens that extend the cycle and eliminate the HFI give women the option of having fewer hormone withdrawal symptoms. In addition to the convenience of fewer cycles per year, women may experience further benefit from prolonged suppression of ovulation and menstruation.

While breakthrough bleeding and spotting occur with all OCs, the pattern seen with extended regimens differs. It can be managed with patient counseling and brief pill holidays. Additional strategies to manage breakthrough bleeding that should be evaluated in the future include additional estrogen only, nonsteroidal anti-inflammatory drugs, and changing the estrogen dose of the formulation (ie, increasing the dose from 20 mcg EE to 30-35 mcg EE).

Articles of interest

Anderson FD, Gibbons W, Portman D. Safety and efficacy of an extended-regimen oral contraceptive utilizing continuous low-dose ethinyl estradiol. Contraception. 2006;73:229-234.

Prospective trial of 1006 sexually active adult women of childbearing potential who received a 91-day extended regimen OC (30 mcg EE/150 mcg LNG) with continuous low-dose EE (10 mcg) during the hormone free interval. Cycle control and safety of the regimen were comparable to that reported for other OCs.

Anderson FD, Gibbons W, Portman D. Long-term safety of an extended-cycle oral contraceptive (Seasonale): a 2-year multicenter open-label extension trial. Am J Obstet Gynecol. 2006;195:92-96.

Long-term safety study of a 91-day extended cycle OC regimen. Overall rates of study discontinuation and incidence of adverse events were similar to those of an earlier Phase 3 clinical trial. The regimen was well tolerated and the numbers of reported bleeding and/or spotting days diminished during the study.

Foster DG, Parvataneni R, de Bocanegra HT, Lewis C, Bradsberry M, Darney P. Number of oral contraceptive pill packages dispensed, method continuation, and costs. Obstet Gynecol. 2006;108:1107-1114.

Evaluation of the effect of the number of cycles of OC pill packages dispensed on the method continuation, pill wastage, use of services, and health care costs among 82,319 women enrolled in the California Family PACT system. Dispensing a year’s supply of OCs during first visits was associated with a higher method continuation and lower health care costs than dispensing fewer cycles per visit.

Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and the risk of breast cancer. N Engl J Med. 2002;346:2025-2032.

A population-based, case-control study of 4575 women with breast cancer and 4682 controls to determine the risk of breast cancer among former and current users of OCs. The relative risk of breast cancer was 1.0 (95% CI, 0.8-1.3) for women who were currently using OCs and 0.9 (95% CI, 0.8-1.0) for those who had previously used them. The relative risk did not increase consistently with longer periods of use or with higher doses of estrogen. Use of OCs by women with a family history of breast cancer was not associated with an increased risk of breast cancer nor was the initiation of OC use at a young age.

Spona J, Elstein M, Feichtinger W, et al. Shorter pill-free interval in combined oral contraceptives decreases follicular development. Contraception. 1996;54:71-77.

Double-blind, randomized trial to determine the suppressive effect on ovarian activity of OCs administered for 21 or 23 days. Observed differences in 17β-estradiol levels and follicular development between a 21-day and 23-day preparation suggest that shortening the pill-free interval in combined OCs may increase the contraceptive safety margin in women on low-dose formulations.

Sulak PJ, Scow RD, Preece C, Riggs MW, Kuehl TJ. Hormone withdrawal symptoms in oral contraceptive users. Obstet Gynecol. 2000;95:261-266.

Prospective evaluation to measure the timing, frequency, and severity of hormone-related symptoms in OC users. Pelvic pain, headaches, use of pain medication, bloating or swelling, and breast tenderness occurred significantly more frequently during the 7-day hormone free interval among both current users and new start users of OCs.

Sulak PJ, Kuehl TJ, Coffee A, Willis S. Prospective analysis of occurrence and management of breakthrough bleeding during an extended oral contraceptive regimen. Am J Obstet Gynecol. 2006;195:935-941.

Single-center, prospective analysis of self-rated menstrual flow during a 21/7 regimen versus a 168-day extended OC regimen. Subjects with a heavier daily flow rating during the 21/7 day cycle tended to have greater daily flow ratings and earlier breakthrough bleeding during the 168-day extension cycle. The 168-day extended regimen had an acceptable bleeding profile with bleeding during the active pill interval effectively managed with institution of a 3-day hormone free interval.

Acknowledgment

The assistance of Kathryn Martin, PharmD, in providing background research and editorial support is acknowledged.

A roundtable discussion among key thought leaders in the area of hormonal contraception was held on October 20, 2006, in New Orleans, Louisiana. These experts addressed the critical questions regarding the practical management of extended regimen oral contraceptives based on information in the medical literature.

Oral contraceptives (OCs) have been available in the United States for nearly 50 years. It is easy to forget that the introduction of reliable oral contraception—a widely available method that allows women control of their fertility—was revolutionary at that time. The decision to use a 28-day pill regimen was not a response to a physiologic need for 13 cycles per year but was dictated by the social norms and pregnancy testing technology of the day. At a time when pregnancy testing was neither easy to perform nor highly sensitive, the 7-day hormone free interval (HFI) provided a monthly reassurance to the OC user that she was not pregnant. Over the ensuing years numerous improvements in oral contraception have taken place—lowering of estrogen content due to safety concerns, confirmation of the efficacy of low-dose pills, introduction of new progestins, and phasic regimens. These changes came about due to a large number of clinical trials and other scientific assessments of OC regimens. Now with research shifted toward reducing the HFI and maximizing ovarian follicular suppression, oral contraception is undergoing a second revolution. By altering or eliminating the HFI, the goal of reducing withdrawal bleeding and minimizing hormone withdrawal can be accomplished.

Both spontaneous menstrual bleeding associated with ovulatory cycles and iatrogenically induced scheduled bleeding associated with OCs are due to endogenous or exogenous hormone withdrawal. However, the similarity ends abruptly, as menstrual bleeding fulfills a physiologic need to slough the secretory endometrium after ovulation in preparation for a new cycle and possible pregnancy. In contrast, there is no health-related reason to bleed while taking OCs. Monthly menstruation in reproductive-age women is necessary unless the patient is pregnant, using hormonal contraception, breastfeeding, or has undergone hysterectomy. A lack of cyclical menstrual bleeding in women not taking hormonal contraception is indicative of a pathologic state, whether it is the hypoestrogenic state of premature ovarian failure or the unopposed estrogen anovulatory state characteristic of women with polycystic ovarian syndrome (TABLE 1). Conversely, the recurrent ovulation and menstruation that is common among today’s post-industrial women is associated with health risks (TABLE 2).

The focus on alteration of the HFI to further improve OC therapy began with the introduction of Mircette^® in 1998.¹ This was followed by the introduction of Seasonale^®, the first extended OC regimen² and subsequently 2 OC products, Yaz^® and Loestrin^® 24 Fe, that maintained the 28-day cycle with a shortened HFI.^3-5 A recently introduced OC product, Seasonique^®, uses an extended 91-day regimen with low-dose ethinyl estradiol (EE) during the HFI, thus eliminating the HFI completely (TABLE 3).⁶

TABLE 1

Conditions Associated With Oligomenorrhea/Amenorrhea

TABLE 2

Health Risks

TABLE 3

OC Products With Extended Regimens or Altered Hormone Free Interval

Are there specific clinical advantages to extended regimen OCs?

DR LONDON: The real advantage to the extended regimens is that they do not have the disadvantages known to exist with the 21/7 regimens.

DR KAUNITZ: There are 4 advantages to extended regimens:

• improvement in contraceptive success
• therapeutic use for hormone withdrawal symptoms
• treatment of gynecologic problems such as dysmenorrhea, endometriosis, and anemia
• accommodation of lifestyle preference

Once women understand that extending combined hormone contraceptives is safe, most will prefer fewer cycles.

DR SULAK: While we need to acknowledge that the decision to introduce the first OCs in a 21/7 regimen was a wise choice nearly 50 years ago, research has shown us that the low doses of EE and the 7-day HFI creates problems—incomplete pituitary-ovarian suppression, endogenous estradiol formation, follicular development, ovarian cyst formation, risk of escape ovulation, and hormone withdrawal symptoms. It doesn’t matter whether a pill, patch, or ring is used—a 7-day HFI is too long with today’s low-dose combined hormonal contraceptives.

Spona was the first to report greater suppression of ovarian activity with a shortened HFI.⁷ By increasing the number of active pills from 21 to 23 per cycle and decreasing the HFI from 7 to 5 days, there was lower residual ovarian activity and endogenous 17β-estradiol. The study also showed that 17β-estradiol levels began to rise during the HFI but the rise was earlier and greater in women assigned to the 21-day regimen.

DR KAUNITZ: Another fundamental issue focuses on the reason our patients use OCs—effective, convenient, and reversible contraception. Unfortunately, the current 21/7 paradigm may not be optimal. The “typical” failure rate with OCs—which is what applies to our patients—is 8%.⁸ I don’t think that is acceptable.

The HFI and the first few days of a new pill pack are the time at which women are at greatest risk for contraceptive failure and unintended pregnancy. By extending the overall duration of active pills and decreasing the duration of the HFI, we are setting our patients up for better contraceptive success.

DR SULAK: There is also the issue of symptoms during the HFI. We all recognize that menstrual symptoms—breast tenderness, headache, bloating, and cramping—increase during the HFI.⁹ Although our data reported significant hormone withdrawal symptoms in women taking OCs, women experience these symptoms with all forms of combined estrogen-progestin hormonal contraceptives regardless of route of administration.

Importantly, the study showed that the symptoms occurred consistently not only in the new start patients, but also in the established users—the women who had been on the pill for more than a year. There is a reason why so many women stop their OCs in less than a year—it’s not because they are feeling wonderful. They may stop because they feel terrible during the HFI.

DR NELSON: The symptoms are real and it is astonishing how many women experience them. Women have become so accustomed to feeling lousy once a month, whether it’s due to menstrual symptoms or hormone withdrawal, that they will not mention it.

Another advantage to extended use of combination estrogen-progestin contraception is the prolonged suppression of ovulation and menstruation, like that produced by the progestin-only regimens, without the negative effects on bone. Given the multitude of problems caused by recurrent ovulation and menstruation, it may be healthier for some women not to have periods every month.

DR KAUNITZ: There are also therapeutic uses for extended regimen OCs that we should not overlook. Decreased dysmenorrhea and menorrhagia are both included in the prescribing information for all OCs. Women suffering from these disorders will likely have additive benefit from extended regimens. In the same vein, the value of extended regimens in managing endometriosis has been known for years.¹⁰

DR SULAK: A very recent paper showed that extending the regimen can improve premenstrual symptoms.¹¹ When symptomatology was compared with that recorded during a 21/7 cycle, there was a significant improvement that was especially apparent in the women who had the greatest variability in their cycles.

Another important finding was that the greatest improvement was detected in the sixth month. That is a key counseling point—you need to stick with the regimen to see the benefits.

What practical advantages does an extended regimen offer to the patient?

DR LONDON: Convenience, convenience, convenience.

MS MOORE: The worst pill to miss in any cycle is the one that is still at the pharmacy. Once your patient has already had 7 hormone-free days, her risk of pregnancy increases with each day of delay in starting a new pack of pills.

DR LONDON: With an extended regimen, that risk occurs fewer times per year. Just as the change from 50-mcg pills to low-dose pills was an improvement, the extension of the regimen beyond 28 days is a real improvement in OC therapy.

DR NELSON: Access to pills is a real issue—it’s more than having to go to the pharmacy every few weeks. A recent paper from the California Family PACT (Planning, Access, Care and Treatment) Program showed that women who were dispensed a year’s supply of OCs at their first visit were more likely to continue therapy, were more likely to receive Papanicolaou tests and Chlamydia tests, and actually had a lower annual women’s health care–related costs than women who were dispensed 3 cycles.¹²

We recently presented data that support this conclusion—hormonal method continuation rates were higher among women who received 3 pill packs than in those who received only 1. Having the supply of pills available is one more way of promoting contraceptive success.

Are there side effects that are specific to the extended regimen OCs?

DR SULAK: We are in consensus that there are no side effects that are specific to the extended regimen OCs. The only side effect found to be increased with extended regimen is unscheduled bleeding, but some studies have shown less bleeding overall.¹³ Studies have shown a decrease in many typical side effects seen with 21/7 OCs such as premenstrual syndrome and headaches.¹⁴

DR KAUNITZ: I agree. We should, however, address unscheduled bleeding and spotting. It’s something that we see with every OC, but extending the regimen changes the pattern.

A number of years ago, a randomized trial showed that addition of low-dose estrogen to the HFI provided superior cycle control to that of a 20-mcg EE OC and similar to that reported with a 35-mcg pill.¹⁵ There are more recent data that suggest that once you have passed the first cycle, addition of low-dose estrogen to the HFI also improves unscheduled bleeding in 91-day regimens.⁶

MS MOORE: Patients must understand there will be some unscheduled bleeding/spotting as their endometrium transitions from a monthly cycle or withdrawal bleed to more complete ovarian suppression, but it is manageable.

DR LONDON: Some clinicians have concerns about estrogen exposure—specifically the risk of venous thromboembolism and breast cancer. When the published data regarding extended regimens are examined in total, the safety profile is virtually the same as for 21/7. The safety of 91-day regimens have been demonstrated in both 1-year trials as well as longer-term 2-year studies.^2,6,16

The Women’s CARE (Contraceptive and Reproductive Experiences) study really put concerns about the association of OC use and breast cancer to rest.¹⁷ There was no evidence of increased risk of breast cancer in either current or past users of OCs. Given that the study included women who had taken high-dose 50-mcg EE pills, it’s very reasonable to conclude that extended OC use poses no increased risk of breast cancer.

What can be done to ensure that an extended regimen is offered to all OC-appropriate patients regardless of age or pathology?

DR KAUNITZ: We still need to work on overcoming common misconceptions. Despite more than 45 years of use, a fundamental lack of understanding of how OCs work persists among patients and health care professionals outside the field of women’s health.

MS MOORE: Many of my students are incredulous when they realize that there is no physiologic reason for the 7-day HFI and cyclical bleeding for women taking OCs.

DR LONDON: We also need to dispel the myth that women taking OCs are having periods. Remember that no women taking an OC has a period. They have withdrawal bleeding.

DR SULAK: Extended regimens set my patients up for contraceptive success and should be considered for all women who are candidates for OCs. The advantages—avoidance of monthly withdrawal symptoms, less follicular development, and, overall, less bleeding—outweigh the issues of unscheduled bleeding and spotting.

DR NELSON: We should discuss bleeding with our patients and, perhaps, it is time to turn the tables and ask her why she feels the need to bleed every month. For women considering use of OCs, it opens up the conversation to use of regimens other than 21/7. For women who are established users of OCs, asking whether they are having symptoms every month will open up the same conversation.

DR KAUNITZ: We’re not here to suggest that women should no longer menstruate or that women should no longer experience monthly bleeding.

It’s all about choice. Using hormones not only to provide safe, effective contraception but also to allow women the option of choosing when to bleed is a second revolution in contraception.

With regard to symptoms, I ask about grouchiness. “Do you get headaches or feel grouchy or down during your HFI?” If the answer is yes, it moves the conversation in the direction of extended regimens.

MS MOORE: I agree. The extended regimen has become mainstream over the past couple of years—the only reason I can see for using 21/7 is if the patient demands it or if reimbursement drives the issue.

How important is breakthrough bleeding in OC product selection?

DR KAUNITZ: Breakthrough bleeding occurs with all OC products—it’s importance becomes a matter of how well you have prepared patients for it.

MS MOORE: I like to tell my patients that it is likely they will experience some breakthrough bleeding in the early cycles. Then they are prepared and those who do not have any are pleasantly surprised.

DR SULAK: It’s inevitable and it can be managed—to me, it’s more important to focus on eliminating hormone withdrawal symptoms.

Are all combined hormonal contraceptive products appropriate for use in extended regimens?

DR NELSON: At this time there are insufficient data regarding the safety and pharmacokinetics of extended regimen use of the transdermal patch. Until studies evaluating its use in multiple extended cycles become available, we cannot recommend its use in extended regimens.¹⁸

DR KAUNITZ: Traditional 21/7 pill packs can be used in extended regimens but I find this approach often poses challenges for the patient—from remembering not to take placebo pills to reimbursement to trips to the pharmacy every 3 weeks for a new pill pack.

DR LONDON: It seems intuitive that the multiphasic pills would not be optimal for use in extended regimens. Given the paucity of data supporting their use, I would not recommend initiating an extended regimen with a mutiphasic pill. I certainly would allow a patient who is using them successfully to continue.

What are practical options to manage breakthrough bleeding in patients taking extended regimen OCs?

DR SULAK: We find that patients usually don’t begin to have unscheduled bleeding until week 4 or later. In our prospective study, we found that women who had heavier daily flow ratings during the 21/7 lead-in cycle tended to have greater daily flow ratings and earlier occurrence of unscheduled bleeding when taking an extended regimen.¹³ We also showed that a 3-day pill holiday was helpful in managing breakthrough bleeding and/or spotting that had persisted for 7 consecutive days (TABLE 4).

MS MOORE: Essentially patients have 2 options: endure the bleeding or take a brief pill holiday. I let my patients decide—some are very bothered by even the slightest amount of breakthrough bleeding while others have no issue with it. The worse thing a patient can do is to stop taking pills without a back-up plan for contraception. It is critical that they take at least 3 weeks of active pills between drug holidays.

DR LONDON: It’s also important to remember that you cannot use a 3-day pill holiday to manage breakthrough bleeding/spotting with 21/7 regimens as the increased number of hormone-free days per cycle could lead to a greater chance of escape ovulation.

DR KAUNITZ: Let’s not forget the value of counseling. Just letting women know what to expect and what to do has certainly been proven to be valuable in improving continuation rates among women on other forms of long-term contraception^19,20 and would without doubt be beneficial for women receiving extended regimens (SIDEBAR).

DR SULAK: With the low-dose OCs, it is especially important to let the patient know at the time you write the prescription that she has to take her pills at about the same time each day. I have had patients tell me that they experience bleeding if they take their pills even a few hours late.

DR NELSON: There will be patients with breakthrough bleeding/spotting who need to be examined, such as a long-term pill user who reports it for the first time. If you can establish a history of good pill taking with no illnesses or medication interaction which might alter hormone absorption, this woman should be evaluated for infection and anatomic changes like cervical or endometrial polyps.

TABLE 4

Recommendations for Initiating Extended Regimens

Summary

DR SULAK: We are finally seeing the demise of 21/7 contraceptive regimens. Numerous studies of these regimens over the past decade have documented hormone withdrawal symptoms, inadequate pituitary-ovarian suppression, follicular development, and even ovulation. Regimens which shorten or eliminate the 7-day HFI by adding estrogen and providing greater duration of active pills will improve the side effect profile and efficacy.

Oral contraceptives first gave women control over their fertility; now, regimens that extend the cycle and eliminate the HFI give women the option of having fewer hormone withdrawal symptoms. In addition to the convenience of fewer cycles per year, women may experience further benefit from prolonged suppression of ovulation and menstruation.

While breakthrough bleeding and spotting occur with all OCs, the pattern seen with extended regimens differs. It can be managed with patient counseling and brief pill holidays. Additional strategies to manage breakthrough bleeding that should be evaluated in the future include additional estrogen only, nonsteroidal anti-inflammatory drugs, and changing the estrogen dose of the formulation (ie, increasing the dose from 20 mcg EE to 30-35 mcg EE).

Articles of interest

Anderson FD, Gibbons W, Portman D. Safety and efficacy of an extended-regimen oral contraceptive utilizing continuous low-dose ethinyl estradiol. Contraception. 2006;73:229-234.

Prospective trial of 1006 sexually active adult women of childbearing potential who received a 91-day extended regimen OC (30 mcg EE/150 mcg LNG) with continuous low-dose EE (10 mcg) during the hormone free interval. Cycle control and safety of the regimen were comparable to that reported for other OCs.

Anderson FD, Gibbons W, Portman D. Long-term safety of an extended-cycle oral contraceptive (Seasonale): a 2-year multicenter open-label extension trial. Am J Obstet Gynecol. 2006;195:92-96.

Long-term safety study of a 91-day extended cycle OC regimen. Overall rates of study discontinuation and incidence of adverse events were similar to those of an earlier Phase 3 clinical trial. The regimen was well tolerated and the numbers of reported bleeding and/or spotting days diminished during the study.

Foster DG, Parvataneni R, de Bocanegra HT, Lewis C, Bradsberry M, Darney P. Number of oral contraceptive pill packages dispensed, method continuation, and costs. Obstet Gynecol. 2006;108:1107-1114.

Evaluation of the effect of the number of cycles of OC pill packages dispensed on the method continuation, pill wastage, use of services, and health care costs among 82,319 women enrolled in the California Family PACT system. Dispensing a year’s supply of OCs during first visits was associated with a higher method continuation and lower health care costs than dispensing fewer cycles per visit.

Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and the risk of breast cancer. N Engl J Med. 2002;346:2025-2032.

A population-based, case-control study of 4575 women with breast cancer and 4682 controls to determine the risk of breast cancer among former and current users of OCs. The relative risk of breast cancer was 1.0 (95% CI, 0.8-1.3) for women who were currently using OCs and 0.9 (95% CI, 0.8-1.0) for those who had previously used them. The relative risk did not increase consistently with longer periods of use or with higher doses of estrogen. Use of OCs by women with a family history of breast cancer was not associated with an increased risk of breast cancer nor was the initiation of OC use at a young age.

Spona J, Elstein M, Feichtinger W, et al. Shorter pill-free interval in combined oral contraceptives decreases follicular development. Contraception. 1996;54:71-77.

Double-blind, randomized trial to determine the suppressive effect on ovarian activity of OCs administered for 21 or 23 days. Observed differences in 17β-estradiol levels and follicular development between a 21-day and 23-day preparation suggest that shortening the pill-free interval in combined OCs may increase the contraceptive safety margin in women on low-dose formulations.

Sulak PJ, Scow RD, Preece C, Riggs MW, Kuehl TJ. Hormone withdrawal symptoms in oral contraceptive users. Obstet Gynecol. 2000;95:261-266.

Prospective evaluation to measure the timing, frequency, and severity of hormone-related symptoms in OC users. Pelvic pain, headaches, use of pain medication, bloating or swelling, and breast tenderness occurred significantly more frequently during the 7-day hormone free interval among both current users and new start users of OCs.

Sulak PJ, Kuehl TJ, Coffee A, Willis S. Prospective analysis of occurrence and management of breakthrough bleeding during an extended oral contraceptive regimen. Am J Obstet Gynecol. 2006;195:935-941.

Single-center, prospective analysis of self-rated menstrual flow during a 21/7 regimen versus a 168-day extended OC regimen. Subjects with a heavier daily flow rating during the 21/7 day cycle tended to have greater daily flow ratings and earlier breakthrough bleeding during the 168-day extension cycle. The 168-day extended regimen had an acceptable bleeding profile with bleeding during the active pill interval effectively managed with institution of a 3-day hormone free interval.

Acknowledgment

The assistance of Kathryn Martin, PharmD, in providing background research and editorial support is acknowledged.

A roundtable discussion among key thought leaders in the area of hormonal contraception was held on October 20, 2006, in New Orleans, Louisiana. These experts addressed the critical questions regarding the practical management of extended regimen oral contraceptives based on information in the medical literature.

Oral contraceptives (OCs) have been available in the United States for nearly 50 years. It is easy to forget that the introduction of reliable oral contraception—a widely available method that allows women control of their fertility—was revolutionary at that time. The decision to use a 28-day pill regimen was not a response to a physiologic need for 13 cycles per year but was dictated by the social norms and pregnancy testing technology of the day. At a time when pregnancy testing was neither easy to perform nor highly sensitive, the 7-day hormone free interval (HFI) provided a monthly reassurance to the OC user that she was not pregnant. Over the ensuing years numerous improvements in oral contraception have taken place—lowering of estrogen content due to safety concerns, confirmation of the efficacy of low-dose pills, introduction of new progestins, and phasic regimens. These changes came about due to a large number of clinical trials and other scientific assessments of OC regimens. Now with research shifted toward reducing the HFI and maximizing ovarian follicular suppression, oral contraception is undergoing a second revolution. By altering or eliminating the HFI, the goal of reducing withdrawal bleeding and minimizing hormone withdrawal can be accomplished.

Both spontaneous menstrual bleeding associated with ovulatory cycles and iatrogenically induced scheduled bleeding associated with OCs are due to endogenous or exogenous hormone withdrawal. However, the similarity ends abruptly, as menstrual bleeding fulfills a physiologic need to slough the secretory endometrium after ovulation in preparation for a new cycle and possible pregnancy. In contrast, there is no health-related reason to bleed while taking OCs. Monthly menstruation in reproductive-age women is necessary unless the patient is pregnant, using hormonal contraception, breastfeeding, or has undergone hysterectomy. A lack of cyclical menstrual bleeding in women not taking hormonal contraception is indicative of a pathologic state, whether it is the hypoestrogenic state of premature ovarian failure or the unopposed estrogen anovulatory state characteristic of women with polycystic ovarian syndrome (TABLE 1). Conversely, the recurrent ovulation and menstruation that is common among today’s post-industrial women is associated with health risks (TABLE 2).

The focus on alteration of the HFI to further improve OC therapy began with the introduction of Mircette^® in 1998.¹ This was followed by the introduction of Seasonale^®, the first extended OC regimen² and subsequently 2 OC products, Yaz^® and Loestrin^® 24 Fe, that maintained the 28-day cycle with a shortened HFI.^3-5 A recently introduced OC product, Seasonique^®, uses an extended 91-day regimen with low-dose ethinyl estradiol (EE) during the HFI, thus eliminating the HFI completely (TABLE 3).⁶

TABLE 1

Conditions Associated With Oligomenorrhea/Amenorrhea

TABLE 2

Health Risks

TABLE 3

OC Products With Extended Regimens or Altered Hormone Free Interval

Are there specific clinical advantages to extended regimen OCs?

DR LONDON: The real advantage to the extended regimens is that they do not have the disadvantages known to exist with the 21/7 regimens.

DR KAUNITZ: There are 4 advantages to extended regimens:

• improvement in contraceptive success
• therapeutic use for hormone withdrawal symptoms
• treatment of gynecologic problems such as dysmenorrhea, endometriosis, and anemia
• accommodation of lifestyle preference

Once women understand that extending combined hormone contraceptives is safe, most will prefer fewer cycles.

DR SULAK: While we need to acknowledge that the decision to introduce the first OCs in a 21/7 regimen was a wise choice nearly 50 years ago, research has shown us that the low doses of EE and the 7-day HFI creates problems—incomplete pituitary-ovarian suppression, endogenous estradiol formation, follicular development, ovarian cyst formation, risk of escape ovulation, and hormone withdrawal symptoms. It doesn’t matter whether a pill, patch, or ring is used—a 7-day HFI is too long with today’s low-dose combined hormonal contraceptives.

Spona was the first to report greater suppression of ovarian activity with a shortened HFI.⁷ By increasing the number of active pills from 21 to 23 per cycle and decreasing the HFI from 7 to 5 days, there was lower residual ovarian activity and endogenous 17β-estradiol. The study also showed that 17β-estradiol levels began to rise during the HFI but the rise was earlier and greater in women assigned to the 21-day regimen.

DR KAUNITZ: Another fundamental issue focuses on the reason our patients use OCs—effective, convenient, and reversible contraception. Unfortunately, the current 21/7 paradigm may not be optimal. The “typical” failure rate with OCs—which is what applies to our patients—is 8%.⁸ I don’t think that is acceptable.

The HFI and the first few days of a new pill pack are the time at which women are at greatest risk for contraceptive failure and unintended pregnancy. By extending the overall duration of active pills and decreasing the duration of the HFI, we are setting our patients up for better contraceptive success.

DR SULAK: There is also the issue of symptoms during the HFI. We all recognize that menstrual symptoms—breast tenderness, headache, bloating, and cramping—increase during the HFI.⁹ Although our data reported significant hormone withdrawal symptoms in women taking OCs, women experience these symptoms with all forms of combined estrogen-progestin hormonal contraceptives regardless of route of administration.

Importantly, the study showed that the symptoms occurred consistently not only in the new start patients, but also in the established users—the women who had been on the pill for more than a year. There is a reason why so many women stop their OCs in less than a year—it’s not because they are feeling wonderful. They may stop because they feel terrible during the HFI.

DR NELSON: The symptoms are real and it is astonishing how many women experience them. Women have become so accustomed to feeling lousy once a month, whether it’s due to menstrual symptoms or hormone withdrawal, that they will not mention it.

Another advantage to extended use of combination estrogen-progestin contraception is the prolonged suppression of ovulation and menstruation, like that produced by the progestin-only regimens, without the negative effects on bone. Given the multitude of problems caused by recurrent ovulation and menstruation, it may be healthier for some women not to have periods every month.

DR KAUNITZ: There are also therapeutic uses for extended regimen OCs that we should not overlook. Decreased dysmenorrhea and menorrhagia are both included in the prescribing information for all OCs. Women suffering from these disorders will likely have additive benefit from extended regimens. In the same vein, the value of extended regimens in managing endometriosis has been known for years.¹⁰

DR SULAK: A very recent paper showed that extending the regimen can improve premenstrual symptoms.¹¹ When symptomatology was compared with that recorded during a 21/7 cycle, there was a significant improvement that was especially apparent in the women who had the greatest variability in their cycles.

Another important finding was that the greatest improvement was detected in the sixth month. That is a key counseling point—you need to stick with the regimen to see the benefits.

What practical advantages does an extended regimen offer to the patient?

DR LONDON: Convenience, convenience, convenience.

MS MOORE: The worst pill to miss in any cycle is the one that is still at the pharmacy. Once your patient has already had 7 hormone-free days, her risk of pregnancy increases with each day of delay in starting a new pack of pills.

DR LONDON: With an extended regimen, that risk occurs fewer times per year. Just as the change from 50-mcg pills to low-dose pills was an improvement, the extension of the regimen beyond 28 days is a real improvement in OC therapy.

DR NELSON: Access to pills is a real issue—it’s more than having to go to the pharmacy every few weeks. A recent paper from the California Family PACT (Planning, Access, Care and Treatment) Program showed that women who were dispensed a year’s supply of OCs at their first visit were more likely to continue therapy, were more likely to receive Papanicolaou tests and Chlamydia tests, and actually had a lower annual women’s health care–related costs than women who were dispensed 3 cycles.¹²

We recently presented data that support this conclusion—hormonal method continuation rates were higher among women who received 3 pill packs than in those who received only 1. Having the supply of pills available is one more way of promoting contraceptive success.

Are there side effects that are specific to the extended regimen OCs?

DR SULAK: We are in consensus that there are no side effects that are specific to the extended regimen OCs. The only side effect found to be increased with extended regimen is unscheduled bleeding, but some studies have shown less bleeding overall.¹³ Studies have shown a decrease in many typical side effects seen with 21/7 OCs such as premenstrual syndrome and headaches.¹⁴

DR KAUNITZ: I agree. We should, however, address unscheduled bleeding and spotting. It’s something that we see with every OC, but extending the regimen changes the pattern.

A number of years ago, a randomized trial showed that addition of low-dose estrogen to the HFI provided superior cycle control to that of a 20-mcg EE OC and similar to that reported with a 35-mcg pill.¹⁵ There are more recent data that suggest that once you have passed the first cycle, addition of low-dose estrogen to the HFI also improves unscheduled bleeding in 91-day regimens.⁶

MS MOORE: Patients must understand there will be some unscheduled bleeding/spotting as their endometrium transitions from a monthly cycle or withdrawal bleed to more complete ovarian suppression, but it is manageable.

DR LONDON: Some clinicians have concerns about estrogen exposure—specifically the risk of venous thromboembolism and breast cancer. When the published data regarding extended regimens are examined in total, the safety profile is virtually the same as for 21/7. The safety of 91-day regimens have been demonstrated in both 1-year trials as well as longer-term 2-year studies.^2,6,16

The Women’s CARE (Contraceptive and Reproductive Experiences) study really put concerns about the association of OC use and breast cancer to rest.¹⁷ There was no evidence of increased risk of breast cancer in either current or past users of OCs. Given that the study included women who had taken high-dose 50-mcg EE pills, it’s very reasonable to conclude that extended OC use poses no increased risk of breast cancer.

What can be done to ensure that an extended regimen is offered to all OC-appropriate patients regardless of age or pathology?

DR KAUNITZ: We still need to work on overcoming common misconceptions. Despite more than 45 years of use, a fundamental lack of understanding of how OCs work persists among patients and health care professionals outside the field of women’s health.

MS MOORE: Many of my students are incredulous when they realize that there is no physiologic reason for the 7-day HFI and cyclical bleeding for women taking OCs.

DR LONDON: We also need to dispel the myth that women taking OCs are having periods. Remember that no women taking an OC has a period. They have withdrawal bleeding.

DR SULAK: Extended regimens set my patients up for contraceptive success and should be considered for all women who are candidates for OCs. The advantages—avoidance of monthly withdrawal symptoms, less follicular development, and, overall, less bleeding—outweigh the issues of unscheduled bleeding and spotting.

DR NELSON: We should discuss bleeding with our patients and, perhaps, it is time to turn the tables and ask her why she feels the need to bleed every month. For women considering use of OCs, it opens up the conversation to use of regimens other than 21/7. For women who are established users of OCs, asking whether they are having symptoms every month will open up the same conversation.

DR KAUNITZ: We’re not here to suggest that women should no longer menstruate or that women should no longer experience monthly bleeding.

It’s all about choice. Using hormones not only to provide safe, effective contraception but also to allow women the option of choosing when to bleed is a second revolution in contraception.

With regard to symptoms, I ask about grouchiness. “Do you get headaches or feel grouchy or down during your HFI?” If the answer is yes, it moves the conversation in the direction of extended regimens.

MS MOORE: I agree. The extended regimen has become mainstream over the past couple of years—the only reason I can see for using 21/7 is if the patient demands it or if reimbursement drives the issue.

How important is breakthrough bleeding in OC product selection?

DR KAUNITZ: Breakthrough bleeding occurs with all OC products—it’s importance becomes a matter of how well you have prepared patients for it.

MS MOORE: I like to tell my patients that it is likely they will experience some breakthrough bleeding in the early cycles. Then they are prepared and those who do not have any are pleasantly surprised.

DR SULAK: It’s inevitable and it can be managed—to me, it’s more important to focus on eliminating hormone withdrawal symptoms.

Are all combined hormonal contraceptive products appropriate for use in extended regimens?

DR NELSON: At this time there are insufficient data regarding the safety and pharmacokinetics of extended regimen use of the transdermal patch. Until studies evaluating its use in multiple extended cycles become available, we cannot recommend its use in extended regimens.¹⁸

DR KAUNITZ: Traditional 21/7 pill packs can be used in extended regimens but I find this approach often poses challenges for the patient—from remembering not to take placebo pills to reimbursement to trips to the pharmacy every 3 weeks for a new pill pack.

DR LONDON: It seems intuitive that the multiphasic pills would not be optimal for use in extended regimens. Given the paucity of data supporting their use, I would not recommend initiating an extended regimen with a mutiphasic pill. I certainly would allow a patient who is using them successfully to continue.

What are practical options to manage breakthrough bleeding in patients taking extended regimen OCs?

DR SULAK: We find that patients usually don’t begin to have unscheduled bleeding until week 4 or later. In our prospective study, we found that women who had heavier daily flow ratings during the 21/7 lead-in cycle tended to have greater daily flow ratings and earlier occurrence of unscheduled bleeding when taking an extended regimen.¹³ We also showed that a 3-day pill holiday was helpful in managing breakthrough bleeding and/or spotting that had persisted for 7 consecutive days (TABLE 4).

MS MOORE: Essentially patients have 2 options: endure the bleeding or take a brief pill holiday. I let my patients decide—some are very bothered by even the slightest amount of breakthrough bleeding while others have no issue with it. The worse thing a patient can do is to stop taking pills without a back-up plan for contraception. It is critical that they take at least 3 weeks of active pills between drug holidays.

DR LONDON: It’s also important to remember that you cannot use a 3-day pill holiday to manage breakthrough bleeding/spotting with 21/7 regimens as the increased number of hormone-free days per cycle could lead to a greater chance of escape ovulation.

DR KAUNITZ: Let’s not forget the value of counseling. Just letting women know what to expect and what to do has certainly been proven to be valuable in improving continuation rates among women on other forms of long-term contraception^19,20 and would without doubt be beneficial for women receiving extended regimens (SIDEBAR).

DR SULAK: With the low-dose OCs, it is especially important to let the patient know at the time you write the prescription that she has to take her pills at about the same time each day. I have had patients tell me that they experience bleeding if they take their pills even a few hours late.

DR NELSON: There will be patients with breakthrough bleeding/spotting who need to be examined, such as a long-term pill user who reports it for the first time. If you can establish a history of good pill taking with no illnesses or medication interaction which might alter hormone absorption, this woman should be evaluated for infection and anatomic changes like cervical or endometrial polyps.

TABLE 4

Recommendations for Initiating Extended Regimens

Summary

DR SULAK: We are finally seeing the demise of 21/7 contraceptive regimens. Numerous studies of these regimens over the past decade have documented hormone withdrawal symptoms, inadequate pituitary-ovarian suppression, follicular development, and even ovulation. Regimens which shorten or eliminate the 7-day HFI by adding estrogen and providing greater duration of active pills will improve the side effect profile and efficacy.

Oral contraceptives first gave women control over their fertility; now, regimens that extend the cycle and eliminate the HFI give women the option of having fewer hormone withdrawal symptoms. In addition to the convenience of fewer cycles per year, women may experience further benefit from prolonged suppression of ovulation and menstruation.

While breakthrough bleeding and spotting occur with all OCs, the pattern seen with extended regimens differs. It can be managed with patient counseling and brief pill holidays. Additional strategies to manage breakthrough bleeding that should be evaluated in the future include additional estrogen only, nonsteroidal anti-inflammatory drugs, and changing the estrogen dose of the formulation (ie, increasing the dose from 20 mcg EE to 30-35 mcg EE).

Articles of interest

Anderson FD, Gibbons W, Portman D. Safety and efficacy of an extended-regimen oral contraceptive utilizing continuous low-dose ethinyl estradiol. Contraception. 2006;73:229-234.

Prospective trial of 1006 sexually active adult women of childbearing potential who received a 91-day extended regimen OC (30 mcg EE/150 mcg LNG) with continuous low-dose EE (10 mcg) during the hormone free interval. Cycle control and safety of the regimen were comparable to that reported for other OCs.

Anderson FD, Gibbons W, Portman D. Long-term safety of an extended-cycle oral contraceptive (Seasonale): a 2-year multicenter open-label extension trial. Am J Obstet Gynecol. 2006;195:92-96.

Long-term safety study of a 91-day extended cycle OC regimen. Overall rates of study discontinuation and incidence of adverse events were similar to those of an earlier Phase 3 clinical trial. The regimen was well tolerated and the numbers of reported bleeding and/or spotting days diminished during the study.

Foster DG, Parvataneni R, de Bocanegra HT, Lewis C, Bradsberry M, Darney P. Number of oral contraceptive pill packages dispensed, method continuation, and costs. Obstet Gynecol. 2006;108:1107-1114.

Evaluation of the effect of the number of cycles of OC pill packages dispensed on the method continuation, pill wastage, use of services, and health care costs among 82,319 women enrolled in the California Family PACT system. Dispensing a year’s supply of OCs during first visits was associated with a higher method continuation and lower health care costs than dispensing fewer cycles per visit.

Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and the risk of breast cancer. N Engl J Med. 2002;346:2025-2032.

A population-based, case-control study of 4575 women with breast cancer and 4682 controls to determine the risk of breast cancer among former and current users of OCs. The relative risk of breast cancer was 1.0 (95% CI, 0.8-1.3) for women who were currently using OCs and 0.9 (95% CI, 0.8-1.0) for those who had previously used them. The relative risk did not increase consistently with longer periods of use or with higher doses of estrogen. Use of OCs by women with a family history of breast cancer was not associated with an increased risk of breast cancer nor was the initiation of OC use at a young age.

Spona J, Elstein M, Feichtinger W, et al. Shorter pill-free interval in combined oral contraceptives decreases follicular development. Contraception. 1996;54:71-77.

Double-blind, randomized trial to determine the suppressive effect on ovarian activity of OCs administered for 21 or 23 days. Observed differences in 17β-estradiol levels and follicular development between a 21-day and 23-day preparation suggest that shortening the pill-free interval in combined OCs may increase the contraceptive safety margin in women on low-dose formulations.

Sulak PJ, Scow RD, Preece C, Riggs MW, Kuehl TJ. Hormone withdrawal symptoms in oral contraceptive users. Obstet Gynecol. 2000;95:261-266.

Prospective evaluation to measure the timing, frequency, and severity of hormone-related symptoms in OC users. Pelvic pain, headaches, use of pain medication, bloating or swelling, and breast tenderness occurred significantly more frequently during the 7-day hormone free interval among both current users and new start users of OCs.

Sulak PJ, Kuehl TJ, Coffee A, Willis S. Prospective analysis of occurrence and management of breakthrough bleeding during an extended oral contraceptive regimen. Am J Obstet Gynecol. 2006;195:935-941.

Single-center, prospective analysis of self-rated menstrual flow during a 21/7 regimen versus a 168-day extended OC regimen. Subjects with a heavier daily flow rating during the 21/7 day cycle tended to have greater daily flow ratings and earlier breakthrough bleeding during the 168-day extension cycle. The 168-day extended regimen had an acceptable bleeding profile with bleeding during the active pill interval effectively managed with institution of a 3-day hormone free interval.

Acknowledgment

The assistance of Kathryn Martin, PharmD, in providing background research and editorial support is acknowledged.

A roundtable discussion among key thought leaders in the area of hormonal contraception was held on October 20, 2006, in New Orleans, Louisiana. These experts addressed the critical questions regarding the practical management of extended regimen oral contraceptives based on information in the medical literature.

Oral contraceptives (OCs) have been available in the United States for nearly 50 years. It is easy to forget that the introduction of reliable oral contraception—a widely available method that allows women control of their fertility—was revolutionary at that time. The decision to use a 28-day pill regimen was not a response to a physiologic need for 13 cycles per year but was dictated by the social norms and pregnancy testing technology of the day. At a time when pregnancy testing was neither easy to perform nor highly sensitive, the 7-day hormone free interval (HFI) provided a monthly reassurance to the OC user that she was not pregnant. Over the ensuing years numerous improvements in oral contraception have taken place—lowering of estrogen content due to safety concerns, confirmation of the efficacy of low-dose pills, introduction of new progestins, and phasic regimens. These changes came about due to a large number of clinical trials and other scientific assessments of OC regimens. Now with research shifted toward reducing the HFI and maximizing ovarian follicular suppression, oral contraception is undergoing a second revolution. By altering or eliminating the HFI, the goal of reducing withdrawal bleeding and minimizing hormone withdrawal can be accomplished.

Both spontaneous menstrual bleeding associated with ovulatory cycles and iatrogenically induced scheduled bleeding associated with OCs are due to endogenous or exogenous hormone withdrawal. However, the similarity ends abruptly, as menstrual bleeding fulfills a physiologic need to slough the secretory endometrium after ovulation in preparation for a new cycle and possible pregnancy. In contrast, there is no health-related reason to bleed while taking OCs. Monthly menstruation in reproductive-age women is necessary unless the patient is pregnant, using hormonal contraception, breastfeeding, or has undergone hysterectomy. A lack of cyclical menstrual bleeding in women not taking hormonal contraception is indicative of a pathologic state, whether it is the hypoestrogenic state of premature ovarian failure or the unopposed estrogen anovulatory state characteristic of women with polycystic ovarian syndrome (TABLE 1). Conversely, the recurrent ovulation and menstruation that is common among today’s post-industrial women is associated with health risks (TABLE 2).

The focus on alteration of the HFI to further improve OC therapy began with the introduction of Mircette^® in 1998.¹ This was followed by the introduction of Seasonale^®, the first extended OC regimen² and subsequently 2 OC products, Yaz^® and Loestrin^® 24 Fe, that maintained the 28-day cycle with a shortened HFI.^3-5 A recently introduced OC product, Seasonique^®, uses an extended 91-day regimen with low-dose ethinyl estradiol (EE) during the HFI, thus eliminating the HFI completely (TABLE 3).⁶

TABLE 1

Conditions Associated With Oligomenorrhea/Amenorrhea

TABLE 2

Health Risks

TABLE 3

OC Products With Extended Regimens or Altered Hormone Free Interval

Are there specific clinical advantages to extended regimen OCs?

DR LONDON: The real advantage to the extended regimens is that they do not have the disadvantages known to exist with the 21/7 regimens.

DR KAUNITZ: There are 4 advantages to extended regimens:

• improvement in contraceptive success
• therapeutic use for hormone withdrawal symptoms
• treatment of gynecologic problems such as dysmenorrhea, endometriosis, and anemia
• accommodation of lifestyle preference

Once women understand that extending combined hormone contraceptives is safe, most will prefer fewer cycles.

DR SULAK: While we need to acknowledge that the decision to introduce the first OCs in a 21/7 regimen was a wise choice nearly 50 years ago, research has shown us that the low doses of EE and the 7-day HFI creates problems—incomplete pituitary-ovarian suppression, endogenous estradiol formation, follicular development, ovarian cyst formation, risk of escape ovulation, and hormone withdrawal symptoms. It doesn’t matter whether a pill, patch, or ring is used—a 7-day HFI is too long with today’s low-dose combined hormonal contraceptives.

Spona was the first to report greater suppression of ovarian activity with a shortened HFI.⁷ By increasing the number of active pills from 21 to 23 per cycle and decreasing the HFI from 7 to 5 days, there was lower residual ovarian activity and endogenous 17β-estradiol. The study also showed that 17β-estradiol levels began to rise during the HFI but the rise was earlier and greater in women assigned to the 21-day regimen.

DR KAUNITZ: Another fundamental issue focuses on the reason our patients use OCs—effective, convenient, and reversible contraception. Unfortunately, the current 21/7 paradigm may not be optimal. The “typical” failure rate with OCs—which is what applies to our patients—is 8%.⁸ I don’t think that is acceptable.

The HFI and the first few days of a new pill pack are the time at which women are at greatest risk for contraceptive failure and unintended pregnancy. By extending the overall duration of active pills and decreasing the duration of the HFI, we are setting our patients up for better contraceptive success.

DR SULAK: There is also the issue of symptoms during the HFI. We all recognize that menstrual symptoms—breast tenderness, headache, bloating, and cramping—increase during the HFI.⁹ Although our data reported significant hormone withdrawal symptoms in women taking OCs, women experience these symptoms with all forms of combined estrogen-progestin hormonal contraceptives regardless of route of administration.

Importantly, the study showed that the symptoms occurred consistently not only in the new start patients, but also in the established users—the women who had been on the pill for more than a year. There is a reason why so many women stop their OCs in less than a year—it’s not because they are feeling wonderful. They may stop because they feel terrible during the HFI.

DR NELSON: The symptoms are real and it is astonishing how many women experience them. Women have become so accustomed to feeling lousy once a month, whether it’s due to menstrual symptoms or hormone withdrawal, that they will not mention it.

Another advantage to extended use of combination estrogen-progestin contraception is the prolonged suppression of ovulation and menstruation, like that produced by the progestin-only regimens, without the negative effects on bone. Given the multitude of problems caused by recurrent ovulation and menstruation, it may be healthier for some women not to have periods every month.

DR KAUNITZ: There are also therapeutic uses for extended regimen OCs that we should not overlook. Decreased dysmenorrhea and menorrhagia are both included in the prescribing information for all OCs. Women suffering from these disorders will likely have additive benefit from extended regimens. In the same vein, the value of extended regimens in managing endometriosis has been known for years.¹⁰

DR SULAK: A very recent paper showed that extending the regimen can improve premenstrual symptoms.¹¹ When symptomatology was compared with that recorded during a 21/7 cycle, there was a significant improvement that was especially apparent in the women who had the greatest variability in their cycles.

Another important finding was that the greatest improvement was detected in the sixth month. That is a key counseling point—you need to stick with the regimen to see the benefits.

What practical advantages does an extended regimen offer to the patient?

DR LONDON: Convenience, convenience, convenience.

MS MOORE: The worst pill to miss in any cycle is the one that is still at the pharmacy. Once your patient has already had 7 hormone-free days, her risk of pregnancy increases with each day of delay in starting a new pack of pills.

DR LONDON: With an extended regimen, that risk occurs fewer times per year. Just as the change from 50-mcg pills to low-dose pills was an improvement, the extension of the regimen beyond 28 days is a real improvement in OC therapy.

DR NELSON: Access to pills is a real issue—it’s more than having to go to the pharmacy every few weeks. A recent paper from the California Family PACT (Planning, Access, Care and Treatment) Program showed that women who were dispensed a year’s supply of OCs at their first visit were more likely to continue therapy, were more likely to receive Papanicolaou tests and Chlamydia tests, and actually had a lower annual women’s health care–related costs than women who were dispensed 3 cycles.¹²

We recently presented data that support this conclusion—hormonal method continuation rates were higher among women who received 3 pill packs than in those who received only 1. Having the supply of pills available is one more way of promoting contraceptive success.

Are there side effects that are specific to the extended regimen OCs?

DR SULAK: We are in consensus that there are no side effects that are specific to the extended regimen OCs. The only side effect found to be increased with extended regimen is unscheduled bleeding, but some studies have shown less bleeding overall.¹³ Studies have shown a decrease in many typical side effects seen with 21/7 OCs such as premenstrual syndrome and headaches.¹⁴

DR KAUNITZ: I agree. We should, however, address unscheduled bleeding and spotting. It’s something that we see with every OC, but extending the regimen changes the pattern.

A number of years ago, a randomized trial showed that addition of low-dose estrogen to the HFI provided superior cycle control to that of a 20-mcg EE OC and similar to that reported with a 35-mcg pill.¹⁵ There are more recent data that suggest that once you have passed the first cycle, addition of low-dose estrogen to the HFI also improves unscheduled bleeding in 91-day regimens.⁶

MS MOORE: Patients must understand there will be some unscheduled bleeding/spotting as their endometrium transitions from a monthly cycle or withdrawal bleed to more complete ovarian suppression, but it is manageable.

DR LONDON: Some clinicians have concerns about estrogen exposure—specifically the risk of venous thromboembolism and breast cancer. When the published data regarding extended regimens are examined in total, the safety profile is virtually the same as for 21/7. The safety of 91-day regimens have been demonstrated in both 1-year trials as well as longer-term 2-year studies.^2,6,16

The Women’s CARE (Contraceptive and Reproductive Experiences) study really put concerns about the association of OC use and breast cancer to rest.¹⁷ There was no evidence of increased risk of breast cancer in either current or past users of OCs. Given that the study included women who had taken high-dose 50-mcg EE pills, it’s very reasonable to conclude that extended OC use poses no increased risk of breast cancer.

What can be done to ensure that an extended regimen is offered to all OC-appropriate patients regardless of age or pathology?

DR KAUNITZ: We still need to work on overcoming common misconceptions. Despite more than 45 years of use, a fundamental lack of understanding of how OCs work persists among patients and health care professionals outside the field of women’s health.

MS MOORE: Many of my students are incredulous when they realize that there is no physiologic reason for the 7-day HFI and cyclical bleeding for women taking OCs.

DR LONDON: We also need to dispel the myth that women taking OCs are having periods. Remember that no women taking an OC has a period. They have withdrawal bleeding.

DR SULAK: Extended regimens set my patients up for contraceptive success and should be considered for all women who are candidates for OCs. The advantages—avoidance of monthly withdrawal symptoms, less follicular development, and, overall, less bleeding—outweigh the issues of unscheduled bleeding and spotting.

DR NELSON: We should discuss bleeding with our patients and, perhaps, it is time to turn the tables and ask her why she feels the need to bleed every month. For women considering use of OCs, it opens up the conversation to use of regimens other than 21/7. For women who are established users of OCs, asking whether they are having symptoms every month will open up the same conversation.

DR KAUNITZ: We’re not here to suggest that women should no longer menstruate or that women should no longer experience monthly bleeding.

It’s all about choice. Using hormones not only to provide safe, effective contraception but also to allow women the option of choosing when to bleed is a second revolution in contraception.

With regard to symptoms, I ask about grouchiness. “Do you get headaches or feel grouchy or down during your HFI?” If the answer is yes, it moves the conversation in the direction of extended regimens.

MS MOORE: I agree. The extended regimen has become mainstream over the past couple of years—the only reason I can see for using 21/7 is if the patient demands it or if reimbursement drives the issue.

How important is breakthrough bleeding in OC product selection?

DR KAUNITZ: Breakthrough bleeding occurs with all OC products—it’s importance becomes a matter of how well you have prepared patients for it.

MS MOORE: I like to tell my patients that it is likely they will experience some breakthrough bleeding in the early cycles. Then they are prepared and those who do not have any are pleasantly surprised.

DR SULAK: It’s inevitable and it can be managed—to me, it’s more important to focus on eliminating hormone withdrawal symptoms.

Are all combined hormonal contraceptive products appropriate for use in extended regimens?

DR NELSON: At this time there are insufficient data regarding the safety and pharmacokinetics of extended regimen use of the transdermal patch. Until studies evaluating its use in multiple extended cycles become available, we cannot recommend its use in extended regimens.¹⁸

DR KAUNITZ: Traditional 21/7 pill packs can be used in extended regimens but I find this approach often poses challenges for the patient—from remembering not to take placebo pills to reimbursement to trips to the pharmacy every 3 weeks for a new pill pack.

DR LONDON: It seems intuitive that the multiphasic pills would not be optimal for use in extended regimens. Given the paucity of data supporting their use, I would not recommend initiating an extended regimen with a mutiphasic pill. I certainly would allow a patient who is using them successfully to continue.

What are practical options to manage breakthrough bleeding in patients taking extended regimen OCs?

DR SULAK: We find that patients usually don’t begin to have unscheduled bleeding until week 4 or later. In our prospective study, we found that women who had heavier daily flow ratings during the 21/7 lead-in cycle tended to have greater daily flow ratings and earlier occurrence of unscheduled bleeding when taking an extended regimen.¹³ We also showed that a 3-day pill holiday was helpful in managing breakthrough bleeding and/or spotting that had persisted for 7 consecutive days (TABLE 4).

MS MOORE: Essentially patients have 2 options: endure the bleeding or take a brief pill holiday. I let my patients decide—some are very bothered by even the slightest amount of breakthrough bleeding while others have no issue with it. The worse thing a patient can do is to stop taking pills without a back-up plan for contraception. It is critical that they take at least 3 weeks of active pills between drug holidays.

DR LONDON: It’s also important to remember that you cannot use a 3-day pill holiday to manage breakthrough bleeding/spotting with 21/7 regimens as the increased number of hormone-free days per cycle could lead to a greater chance of escape ovulation.

DR KAUNITZ: Let’s not forget the value of counseling. Just letting women know what to expect and what to do has certainly been proven to be valuable in improving continuation rates among women on other forms of long-term contraception^19,20 and would without doubt be beneficial for women receiving extended regimens (SIDEBAR).

DR SULAK: With the low-dose OCs, it is especially important to let the patient know at the time you write the prescription that she has to take her pills at about the same time each day. I have had patients tell me that they experience bleeding if they take their pills even a few hours late.

DR NELSON: There will be patients with breakthrough bleeding/spotting who need to be examined, such as a long-term pill user who reports it for the first time. If you can establish a history of good pill taking with no illnesses or medication interaction which might alter hormone absorption, this woman should be evaluated for infection and anatomic changes like cervical or endometrial polyps.

TABLE 4

Recommendations for Initiating Extended Regimens

Summary

DR SULAK: We are finally seeing the demise of 21/7 contraceptive regimens. Numerous studies of these regimens over the past decade have documented hormone withdrawal symptoms, inadequate pituitary-ovarian suppression, follicular development, and even ovulation. Regimens which shorten or eliminate the 7-day HFI by adding estrogen and providing greater duration of active pills will improve the side effect profile and efficacy.

Oral contraceptives first gave women control over their fertility; now, regimens that extend the cycle and eliminate the HFI give women the option of having fewer hormone withdrawal symptoms. In addition to the convenience of fewer cycles per year, women may experience further benefit from prolonged suppression of ovulation and menstruation.

While breakthrough bleeding and spotting occur with all OCs, the pattern seen with extended regimens differs. It can be managed with patient counseling and brief pill holidays. Additional strategies to manage breakthrough bleeding that should be evaluated in the future include additional estrogen only, nonsteroidal anti-inflammatory drugs, and changing the estrogen dose of the formulation (ie, increasing the dose from 20 mcg EE to 30-35 mcg EE).

Articles of interest

Anderson FD, Gibbons W, Portman D. Safety and efficacy of an extended-regimen oral contraceptive utilizing continuous low-dose ethinyl estradiol. Contraception. 2006;73:229-234.

Prospective trial of 1006 sexually active adult women of childbearing potential who received a 91-day extended regimen OC (30 mcg EE/150 mcg LNG) with continuous low-dose EE (10 mcg) during the hormone free interval. Cycle control and safety of the regimen were comparable to that reported for other OCs.

Anderson FD, Gibbons W, Portman D. Long-term safety of an extended-cycle oral contraceptive (Seasonale): a 2-year multicenter open-label extension trial. Am J Obstet Gynecol. 2006;195:92-96.

Long-term safety study of a 91-day extended cycle OC regimen. Overall rates of study discontinuation and incidence of adverse events were similar to those of an earlier Phase 3 clinical trial. The regimen was well tolerated and the numbers of reported bleeding and/or spotting days diminished during the study.

Foster DG, Parvataneni R, de Bocanegra HT, Lewis C, Bradsberry M, Darney P. Number of oral contraceptive pill packages dispensed, method continuation, and costs. Obstet Gynecol. 2006;108:1107-1114.

Evaluation of the effect of the number of cycles of OC pill packages dispensed on the method continuation, pill wastage, use of services, and health care costs among 82,319 women enrolled in the California Family PACT system. Dispensing a year’s supply of OCs during first visits was associated with a higher method continuation and lower health care costs than dispensing fewer cycles per visit.

Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and the risk of breast cancer. N Engl J Med. 2002;346:2025-2032.

A population-based, case-control study of 4575 women with breast cancer and 4682 controls to determine the risk of breast cancer among former and current users of OCs. The relative risk of breast cancer was 1.0 (95% CI, 0.8-1.3) for women who were currently using OCs and 0.9 (95% CI, 0.8-1.0) for those who had previously used them. The relative risk did not increase consistently with longer periods of use or with higher doses of estrogen. Use of OCs by women with a family history of breast cancer was not associated with an increased risk of breast cancer nor was the initiation of OC use at a young age.

Spona J, Elstein M, Feichtinger W, et al. Shorter pill-free interval in combined oral contraceptives decreases follicular development. Contraception. 1996;54:71-77.

Double-blind, randomized trial to determine the suppressive effect on ovarian activity of OCs administered for 21 or 23 days. Observed differences in 17β-estradiol levels and follicular development between a 21-day and 23-day preparation suggest that shortening the pill-free interval in combined OCs may increase the contraceptive safety margin in women on low-dose formulations.

Sulak PJ, Scow RD, Preece C, Riggs MW, Kuehl TJ. Hormone withdrawal symptoms in oral contraceptive users. Obstet Gynecol. 2000;95:261-266.

Prospective evaluation to measure the timing, frequency, and severity of hormone-related symptoms in OC users. Pelvic pain, headaches, use of pain medication, bloating or swelling, and breast tenderness occurred significantly more frequently during the 7-day hormone free interval among both current users and new start users of OCs.

Sulak PJ, Kuehl TJ, Coffee A, Willis S. Prospective analysis of occurrence and management of breakthrough bleeding during an extended oral contraceptive regimen. Am J Obstet Gynecol. 2006;195:935-941.

Single-center, prospective analysis of self-rated menstrual flow during a 21/7 regimen versus a 168-day extended OC regimen. Subjects with a heavier daily flow rating during the 21/7 day cycle tended to have greater daily flow ratings and earlier breakthrough bleeding during the 168-day extension cycle. The 168-day extended regimen had an acceptable bleeding profile with bleeding during the active pill interval effectively managed with institution of a 3-day hormone free interval.

Acknowledgment

The assistance of Kathryn Martin, PharmD, in providing background research and editorial support is acknowledged.

A roundtable discussion among key thought leaders in the area of hormonal contraception was held on October 20, 2006, in New Orleans, Louisiana. These experts addressed the critical questions regarding the practical management of extended regimen oral contraceptives based on information in the medical literature.

Oral contraceptives (OCs) have been available in the United States for nearly 50 years. It is easy to forget that the introduction of reliable oral contraception—a widely available method that allows women control of their fertility—was revolutionary at that time. The decision to use a 28-day pill regimen was not a response to a physiologic need for 13 cycles per year but was dictated by the social norms and pregnancy testing technology of the day. At a time when pregnancy testing was neither easy to perform nor highly sensitive, the 7-day hormone free interval (HFI) provided a monthly reassurance to the OC user that she was not pregnant. Over the ensuing years numerous improvements in oral contraception have taken place—lowering of estrogen content due to safety concerns, confirmation of the efficacy of low-dose pills, introduction of new progestins, and phasic regimens. These changes came about due to a large number of clinical trials and other scientific assessments of OC regimens. Now with research shifted toward reducing the HFI and maximizing ovarian follicular suppression, oral contraception is undergoing a second revolution. By altering or eliminating the HFI, the goal of reducing withdrawal bleeding and minimizing hormone withdrawal can be accomplished.

Both spontaneous menstrual bleeding associated with ovulatory cycles and iatrogenically induced scheduled bleeding associated with OCs are due to endogenous or exogenous hormone withdrawal. However, the similarity ends abruptly, as menstrual bleeding fulfills a physiologic need to slough the secretory endometrium after ovulation in preparation for a new cycle and possible pregnancy. In contrast, there is no health-related reason to bleed while taking OCs. Monthly menstruation in reproductive-age women is necessary unless the patient is pregnant, using hormonal contraception, breastfeeding, or has undergone hysterectomy. A lack of cyclical menstrual bleeding in women not taking hormonal contraception is indicative of a pathologic state, whether it is the hypoestrogenic state of premature ovarian failure or the unopposed estrogen anovulatory state characteristic of women with polycystic ovarian syndrome (TABLE 1). Conversely, the recurrent ovulation and menstruation that is common among today’s post-industrial women is associated with health risks (TABLE 2).

The focus on alteration of the HFI to further improve OC therapy began with the introduction of Mircette^® in 1998.¹ This was followed by the introduction of Seasonale^®, the first extended OC regimen² and subsequently 2 OC products, Yaz^® and Loestrin^® 24 Fe, that maintained the 28-day cycle with a shortened HFI.^3-5 A recently introduced OC product, Seasonique^®, uses an extended 91-day regimen with low-dose ethinyl estradiol (EE) during the HFI, thus eliminating the HFI completely (TABLE 3).⁶

TABLE 1

Conditions Associated With Oligomenorrhea/Amenorrhea

TABLE 2

Health Risks

TABLE 3

OC Products With Extended Regimens or Altered Hormone Free Interval

Are there specific clinical advantages to extended regimen OCs?

DR LONDON: The real advantage to the extended regimens is that they do not have the disadvantages known to exist with the 21/7 regimens.

DR KAUNITZ: There are 4 advantages to extended regimens:

• improvement in contraceptive success
• therapeutic use for hormone withdrawal symptoms
• treatment of gynecologic problems such as dysmenorrhea, endometriosis, and anemia
• accommodation of lifestyle preference

Once women understand that extending combined hormone contraceptives is safe, most will prefer fewer cycles.

DR SULAK: While we need to acknowledge that the decision to introduce the first OCs in a 21/7 regimen was a wise choice nearly 50 years ago, research has shown us that the low doses of EE and the 7-day HFI creates problems—incomplete pituitary-ovarian suppression, endogenous estradiol formation, follicular development, ovarian cyst formation, risk of escape ovulation, and hormone withdrawal symptoms. It doesn’t matter whether a pill, patch, or ring is used—a 7-day HFI is too long with today’s low-dose combined hormonal contraceptives.

Spona was the first to report greater suppression of ovarian activity with a shortened HFI.⁷ By increasing the number of active pills from 21 to 23 per cycle and decreasing the HFI from 7 to 5 days, there was lower residual ovarian activity and endogenous 17β-estradiol. The study also showed that 17β-estradiol levels began to rise during the HFI but the rise was earlier and greater in women assigned to the 21-day regimen.

DR KAUNITZ: Another fundamental issue focuses on the reason our patients use OCs—effective, convenient, and reversible contraception. Unfortunately, the current 21/7 paradigm may not be optimal. The “typical” failure rate with OCs—which is what applies to our patients—is 8%.⁸ I don’t think that is acceptable.

The HFI and the first few days of a new pill pack are the time at which women are at greatest risk for contraceptive failure and unintended pregnancy. By extending the overall duration of active pills and decreasing the duration of the HFI, we are setting our patients up for better contraceptive success.

DR SULAK: There is also the issue of symptoms during the HFI. We all recognize that menstrual symptoms—breast tenderness, headache, bloating, and cramping—increase during the HFI.⁹ Although our data reported significant hormone withdrawal symptoms in women taking OCs, women experience these symptoms with all forms of combined estrogen-progestin hormonal contraceptives regardless of route of administration.

Importantly, the study showed that the symptoms occurred consistently not only in the new start patients, but also in the established users—the women who had been on the pill for more than a year. There is a reason why so many women stop their OCs in less than a year—it’s not because they are feeling wonderful. They may stop because they feel terrible during the HFI.

DR NELSON: The symptoms are real and it is astonishing how many women experience them. Women have become so accustomed to feeling lousy once a month, whether it’s due to menstrual symptoms or hormone withdrawal, that they will not mention it.

Another advantage to extended use of combination estrogen-progestin contraception is the prolonged suppression of ovulation and menstruation, like that produced by the progestin-only regimens, without the negative effects on bone. Given the multitude of problems caused by recurrent ovulation and menstruation, it may be healthier for some women not to have periods every month.

DR KAUNITZ: There are also therapeutic uses for extended regimen OCs that we should not overlook. Decreased dysmenorrhea and menorrhagia are both included in the prescribing information for all OCs. Women suffering from these disorders will likely have additive benefit from extended regimens. In the same vein, the value of extended regimens in managing endometriosis has been known for years.¹⁰

DR SULAK: A very recent paper showed that extending the regimen can improve premenstrual symptoms.¹¹ When symptomatology was compared with that recorded during a 21/7 cycle, there was a significant improvement that was especially apparent in the women who had the greatest variability in their cycles.

Another important finding was that the greatest improvement was detected in the sixth month. That is a key counseling point—you need to stick with the regimen to see the benefits.

What practical advantages does an extended regimen offer to the patient?

DR LONDON: Convenience, convenience, convenience.

MS MOORE: The worst pill to miss in any cycle is the one that is still at the pharmacy. Once your patient has already had 7 hormone-free days, her risk of pregnancy increases with each day of delay in starting a new pack of pills.

DR LONDON: With an extended regimen, that risk occurs fewer times per year. Just as the change from 50-mcg pills to low-dose pills was an improvement, the extension of the regimen beyond 28 days is a real improvement in OC therapy.

DR NELSON: Access to pills is a real issue—it’s more than having to go to the pharmacy every few weeks. A recent paper from the California Family PACT (Planning, Access, Care and Treatment) Program showed that women who were dispensed a year’s supply of OCs at their first visit were more likely to continue therapy, were more likely to receive Papanicolaou tests and Chlamydia tests, and actually had a lower annual women’s health care–related costs than women who were dispensed 3 cycles.¹²

We recently presented data that support this conclusion—hormonal method continuation rates were higher among women who received 3 pill packs than in those who received only 1. Having the supply of pills available is one more way of promoting contraceptive success.

Are there side effects that are specific to the extended regimen OCs?

DR SULAK: We are in consensus that there are no side effects that are specific to the extended regimen OCs. The only side effect found to be increased with extended regimen is unscheduled bleeding, but some studies have shown less bleeding overall.¹³ Studies have shown a decrease in many typical side effects seen with 21/7 OCs such as premenstrual syndrome and headaches.¹⁴

DR KAUNITZ: I agree. We should, however, address unscheduled bleeding and spotting. It’s something that we see with every OC, but extending the regimen changes the pattern.

A number of years ago, a randomized trial showed that addition of low-dose estrogen to the HFI provided superior cycle control to that of a 20-mcg EE OC and similar to that reported with a 35-mcg pill.¹⁵ There are more recent data that suggest that once you have passed the first cycle, addition of low-dose estrogen to the HFI also improves unscheduled bleeding in 91-day regimens.⁶

MS MOORE: Patients must understand there will be some unscheduled bleeding/spotting as their endometrium transitions from a monthly cycle or withdrawal bleed to more complete ovarian suppression, but it is manageable.

DR LONDON: Some clinicians have concerns about estrogen exposure—specifically the risk of venous thromboembolism and breast cancer. When the published data regarding extended regimens are examined in total, the safety profile is virtually the same as for 21/7. The safety of 91-day regimens have been demonstrated in both 1-year trials as well as longer-term 2-year studies.^2,6,16

The Women’s CARE (Contraceptive and Reproductive Experiences) study really put concerns about the association of OC use and breast cancer to rest.¹⁷ There was no evidence of increased risk of breast cancer in either current or past users of OCs. Given that the study included women who had taken high-dose 50-mcg EE pills, it’s very reasonable to conclude that extended OC use poses no increased risk of breast cancer.

What can be done to ensure that an extended regimen is offered to all OC-appropriate patients regardless of age or pathology?

DR KAUNITZ: We still need to work on overcoming common misconceptions. Despite more than 45 years of use, a fundamental lack of understanding of how OCs work persists among patients and health care professionals outside the field of women’s health.

MS MOORE: Many of my students are incredulous when they realize that there is no physiologic reason for the 7-day HFI and cyclical bleeding for women taking OCs.

DR LONDON: We also need to dispel the myth that women taking OCs are having periods. Remember that no women taking an OC has a period. They have withdrawal bleeding.

DR SULAK: Extended regimens set my patients up for contraceptive success and should be considered for all women who are candidates for OCs. The advantages—avoidance of monthly withdrawal symptoms, less follicular development, and, overall, less bleeding—outweigh the issues of unscheduled bleeding and spotting.

DR NELSON: We should discuss bleeding with our patients and, perhaps, it is time to turn the tables and ask her why she feels the need to bleed every month. For women considering use of OCs, it opens up the conversation to use of regimens other than 21/7. For women who are established users of OCs, asking whether they are having symptoms every month will open up the same conversation.

DR KAUNITZ: We’re not here to suggest that women should no longer menstruate or that women should no longer experience monthly bleeding.

It’s all about choice. Using hormones not only to provide safe, effective contraception but also to allow women the option of choosing when to bleed is a second revolution in contraception.

With regard to symptoms, I ask about grouchiness. “Do you get headaches or feel grouchy or down during your HFI?” If the answer is yes, it moves the conversation in the direction of extended regimens.

MS MOORE: I agree. The extended regimen has become mainstream over the past couple of years—the only reason I can see for using 21/7 is if the patient demands it or if reimbursement drives the issue.

How important is breakthrough bleeding in OC product selection?

DR KAUNITZ: Breakthrough bleeding occurs with all OC products—it’s importance becomes a matter of how well you have prepared patients for it.

MS MOORE: I like to tell my patients that it is likely they will experience some breakthrough bleeding in the early cycles. Then they are prepared and those who do not have any are pleasantly surprised.

DR SULAK: It’s inevitable and it can be managed—to me, it’s more important to focus on eliminating hormone withdrawal symptoms.

Are all combined hormonal contraceptive products appropriate for use in extended regimens?

DR NELSON: At this time there are insufficient data regarding the safety and pharmacokinetics of extended regimen use of the transdermal patch. Until studies evaluating its use in multiple extended cycles become available, we cannot recommend its use in extended regimens.¹⁸

DR KAUNITZ: Traditional 21/7 pill packs can be used in extended regimens but I find this approach often poses challenges for the patient—from remembering not to take placebo pills to reimbursement to trips to the pharmacy every 3 weeks for a new pill pack.

DR LONDON: It seems intuitive that the multiphasic pills would not be optimal for use in extended regimens. Given the paucity of data supporting their use, I would not recommend initiating an extended regimen with a mutiphasic pill. I certainly would allow a patient who is using them successfully to continue.

What are practical options to manage breakthrough bleeding in patients taking extended regimen OCs?

DR SULAK: We find that patients usually don’t begin to have unscheduled bleeding until week 4 or later. In our prospective study, we found that women who had heavier daily flow ratings during the 21/7 lead-in cycle tended to have greater daily flow ratings and earlier occurrence of unscheduled bleeding when taking an extended regimen.¹³ We also showed that a 3-day pill holiday was helpful in managing breakthrough bleeding and/or spotting that had persisted for 7 consecutive days (TABLE 4).

MS MOORE: Essentially patients have 2 options: endure the bleeding or take a brief pill holiday. I let my patients decide—some are very bothered by even the slightest amount of breakthrough bleeding while others have no issue with it. The worse thing a patient can do is to stop taking pills without a back-up plan for contraception. It is critical that they take at least 3 weeks of active pills between drug holidays.

DR LONDON: It’s also important to remember that you cannot use a 3-day pill holiday to manage breakthrough bleeding/spotting with 21/7 regimens as the increased number of hormone-free days per cycle could lead to a greater chance of escape ovulation.

DR KAUNITZ: Let’s not forget the value of counseling. Just letting women know what to expect and what to do has certainly been proven to be valuable in improving continuation rates among women on other forms of long-term contraception^19,20 and would without doubt be beneficial for women receiving extended regimens (SIDEBAR).

DR SULAK: With the low-dose OCs, it is especially important to let the patient know at the time you write the prescription that she has to take her pills at about the same time each day. I have had patients tell me that they experience bleeding if they take their pills even a few hours late.

DR NELSON: There will be patients with breakthrough bleeding/spotting who need to be examined, such as a long-term pill user who reports it for the first time. If you can establish a history of good pill taking with no illnesses or medication interaction which might alter hormone absorption, this woman should be evaluated for infection and anatomic changes like cervical or endometrial polyps.

TABLE 4

Recommendations for Initiating Extended Regimens

Summary

DR SULAK: We are finally seeing the demise of 21/7 contraceptive regimens. Numerous studies of these regimens over the past decade have documented hormone withdrawal symptoms, inadequate pituitary-ovarian suppression, follicular development, and even ovulation. Regimens which shorten or eliminate the 7-day HFI by adding estrogen and providing greater duration of active pills will improve the side effect profile and efficacy.

Oral contraceptives first gave women control over their fertility; now, regimens that extend the cycle and eliminate the HFI give women the option of having fewer hormone withdrawal symptoms. In addition to the convenience of fewer cycles per year, women may experience further benefit from prolonged suppression of ovulation and menstruation.

While breakthrough bleeding and spotting occur with all OCs, the pattern seen with extended regimens differs. It can be managed with patient counseling and brief pill holidays. Additional strategies to manage breakthrough bleeding that should be evaluated in the future include additional estrogen only, nonsteroidal anti-inflammatory drugs, and changing the estrogen dose of the formulation (ie, increasing the dose from 20 mcg EE to 30-35 mcg EE).

Articles of interest

Anderson FD, Gibbons W, Portman D. Safety and efficacy of an extended-regimen oral contraceptive utilizing continuous low-dose ethinyl estradiol. Contraception. 2006;73:229-234.

Prospective trial of 1006 sexually active adult women of childbearing potential who received a 91-day extended regimen OC (30 mcg EE/150 mcg LNG) with continuous low-dose EE (10 mcg) during the hormone free interval. Cycle control and safety of the regimen were comparable to that reported for other OCs.

Anderson FD, Gibbons W, Portman D. Long-term safety of an extended-cycle oral contraceptive (Seasonale): a 2-year multicenter open-label extension trial. Am J Obstet Gynecol. 2006;195:92-96.

Long-term safety study of a 91-day extended cycle OC regimen. Overall rates of study discontinuation and incidence of adverse events were similar to those of an earlier Phase 3 clinical trial. The regimen was well tolerated and the numbers of reported bleeding and/or spotting days diminished during the study.

Foster DG, Parvataneni R, de Bocanegra HT, Lewis C, Bradsberry M, Darney P. Number of oral contraceptive pill packages dispensed, method continuation, and costs. Obstet Gynecol. 2006;108:1107-1114.

Evaluation of the effect of the number of cycles of OC pill packages dispensed on the method continuation, pill wastage, use of services, and health care costs among 82,319 women enrolled in the California Family PACT system. Dispensing a year’s supply of OCs during first visits was associated with a higher method continuation and lower health care costs than dispensing fewer cycles per visit.

Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and the risk of breast cancer. N Engl J Med. 2002;346:2025-2032.

A population-based, case-control study of 4575 women with breast cancer and 4682 controls to determine the risk of breast cancer among former and current users of OCs. The relative risk of breast cancer was 1.0 (95% CI, 0.8-1.3) for women who were currently using OCs and 0.9 (95% CI, 0.8-1.0) for those who had previously used them. The relative risk did not increase consistently with longer periods of use or with higher doses of estrogen. Use of OCs by women with a family history of breast cancer was not associated with an increased risk of breast cancer nor was the initiation of OC use at a young age.

Spona J, Elstein M, Feichtinger W, et al. Shorter pill-free interval in combined oral contraceptives decreases follicular development. Contraception. 1996;54:71-77.

Double-blind, randomized trial to determine the suppressive effect on ovarian activity of OCs administered for 21 or 23 days. Observed differences in 17β-estradiol levels and follicular development between a 21-day and 23-day preparation suggest that shortening the pill-free interval in combined OCs may increase the contraceptive safety margin in women on low-dose formulations.

Sulak PJ, Scow RD, Preece C, Riggs MW, Kuehl TJ. Hormone withdrawal symptoms in oral contraceptive users. Obstet Gynecol. 2000;95:261-266.

Prospective evaluation to measure the timing, frequency, and severity of hormone-related symptoms in OC users. Pelvic pain, headaches, use of pain medication, bloating or swelling, and breast tenderness occurred significantly more frequently during the 7-day hormone free interval among both current users and new start users of OCs.

Sulak PJ, Kuehl TJ, Coffee A, Willis S. Prospective analysis of occurrence and management of breakthrough bleeding during an extended oral contraceptive regimen. Am J Obstet Gynecol. 2006;195:935-941.

Single-center, prospective analysis of self-rated menstrual flow during a 21/7 regimen versus a 168-day extended OC regimen. Subjects with a heavier daily flow rating during the 21/7 day cycle tended to have greater daily flow ratings and earlier breakthrough bleeding during the 168-day extension cycle. The 168-day extended regimen had an acceptable bleeding profile with bleeding during the active pill interval effectively managed with institution of a 3-day hormone free interval.

Acknowledgment

The assistance of Kathryn Martin, PharmD, in providing background research and editorial support is acknowledged.