Mitchell D. Creinin, MD

More US women are using IUDs than ever before. With more use comes the potential for complications and more requests related to non-contraceptive benefits. New information provides contemporary insight into rare IUD complications and the use of hormonal IUDs for treatment of HMB.

The first intrauterine device (IUD) to be approved in the United States, the Lippes Loop, became available in 1964. Sixty years later, more US women are using IUDs than ever before, and numbers are trending upward (FIGURE).^1,2 Over the past year, contemporary information has become available to further inform IUD management when pregnancy occurs with an IUD in situ, as well as counseling about device breakage. Additionally, new data help clinicians expand which patients can use a levonorgestrel (LNG) 52-mg IUD for heavy menstrual bleeding (HMB) treatment.

As the total absolute number of IUD users increases, so do the absolute numbers of rare outcomes, such as pregnancy among IUD users. These highly effective contraceptives have a failure rate within the first year after placement ranging from 0.1% for the LNG 52-mg IUD to 0.8% for the copper 380-mm² IUD.³ Although the possibility for extrauterine gestation is higher when pregnancy occurs while a patient is using an IUD as compared with most other contraceptive methods, most pregnancies that occur with an IUD in situ are intrauterine.⁴

The high contraceptive efficacy of IUDs make pregnancy with a retained IUD rare; therefore, it is difficult to perform a study with a large enough population to evaluate management of pregnancy complicated by an IUD in situ. Clinical management recommendations for these situations are 20 years old and are supported by limited data from case reports and series with fewer than 200 patients.^5,6

Intrauterine device breakage is another rare event that is poorly understood due to the low absolute number of cases. Information about breakage has similarly been limited to case reports and case series.^7,8 This past year, contemporary data were published to provide more insight into both intrauterine pregnancy with an IUD in situ and IUD breakage.

Beyond contraception, hormonal IUDs have become a popular and evidence-based treatment option for patients with HMB. The initial LNG 52-mg IUD (Mirena) regulatory approval studies for HMB treatment included data limited to parous patients and users with a body mass index (BMI) less than 35 kg/m².⁹ Since that time, no studies have explored these populations. Although current practice has commonly extended use to include patients with these characteristics, we have lacked outcome data. New phase 3 data on the LNG 52-mg IUD (Liletta) included a broader range of participants and provide evidence to support this practice.

Removing retained copper 380-mm² IUDs improves pregnancy outcomes

Panchal VR, Rau AR, Mandelbaum RS, et al. Pregnancy with retained intrauterine device: national-level assessment of characteristics and outcomes. Am J Obstet Gynecol MFM. 2023;5:101056. doi:10.1016/j.ajogmf.2023.101056

Karakuş SS, Karakuş R, Akalın EE, et al. Pregnancy outcomes with a copper 380 mm2 intrauterine device in place: a retrospective cohort study in Turkey, 2011-2021. Contraception. 2023;125:110090. doi:10.1016/j.contraception.2023.110090
 

To update our understanding of outcomes of pregnancy with an IUD in situ, Panchal and colleagues performed a cross-sectional study using the Healthcare Cost and Utilization Project’s National Inpatient Sample. This data set represents 85% of US hospital discharges. The population investigated included hospital deliveries from 2016 to 2020 with an ICD-10 (International Classification of Diseases, Tenth Revision) code of retained IUD. Those without the code were assigned to the comparison non-retained IUD group.

The primary outcome studied was the incidence rate of retained IUD, patient and pregnancy characteristics, and delivery outcomes including but not limited to gestational age at delivery, placental abnormalities, intrauterine fetal demise (IUFD), preterm premature rupture of membranes (PPROM), cesarean delivery, postpartum hemorrhage, and hysterectomy.

Outcomes were worse with retained IUD, regardless of IUD removal status

The authors found that an IUD in situ was reported in 1 out of 8,307 pregnancies and was associated with PPROM, fetal malpresentation, IUFD, placental abnormalities including abruption, accreta spectrum, retained placenta, and need for manual removal (TABLE 1). About three-quarters (76.3%) of patients had a term delivery (≥37 weeks).

Retained IUD was associated with previable loss, defined as less than 22 weeks’ gestation (adjusted odds ratio [aOR], 5.49; 95% confidence interval [CI], 3.30–9.15) and periviable delivery, defined as 22 to 25 weeks’ gestation (aOR, 2.81; 95% CI, 1.63–4.85). Retained IUD was not associated with preterm delivery beyond 26 weeks’ gestation, cesarean delivery, postpartum hemorrhage, or hysterectomy.

Important limitations of this study are the lack of information on IUD type (copper vs hormonal) and the timing of removal or attempted removal in relation to measured pregnancy outcomes.

Continue to: Removal of copper IUD improves, but does not eliminate, poor pregnancy outcomes...

Karakus and colleagues conducted a retrospective cohort study of 233 patients in Turkey with pregnancies that occurred during copper 380-mm² IUD use from 2011 to 2021. The authors reported that, at the time of first contact with the health system and diagnosis of retained IUD, 18.9% of the pregnancies were ectopic, 13.2% were first trimester losses, and 67.5% were ongoing pregnancies.

The authors assessed outcomes in patients with ongoing pregnancies based on whether or not the IUD was removed or retained. Outcomes included gestational age at delivery and adverse pregnancy outcomes, assessed as a composite of preterm delivery, PPROM, chorioamnionitis, placental abruption, and postpartum hemorrhage.

Of those with ongoing pregnancies, 13.3% chose to have an abortion, leaving 137 (86.7%) with continuing pregnancy. The IUD was able to be removed in 39.4% of the sample, with an average gestational age of 7 weeks at the time of removal.

Compared with those with a retained IUD, patients in the removal group had a lower rate of pregnancy loss (33.3% vs 61.4%; P<.001) and a lower rate of the composite adverse pregnancy outcomes (53.1% vs 27.8%; P=.03). TABLE 2 shows the approximate rate of ongoing pregnancy by gestational age in patients with retained and removed copper 380-mm² IUDs. Notably, the largest change occurred periviably, with the proportion of patients with an ongoing pregnancy after 26 weeks reducing to about half for patients with a retained IUD as compared with patients with a removed IUD; this proportion of ongoing pregnancies held through the remainder of gestation.

Do national data reveal more breakage reports for copper 380-mm² or LNG IUDs?

Latack KR, Nguyen BT. Trends in copper versus hormonal intrauterine device breakage reporting within the United States’ Food and Drug Administration Adverse Event Reporting System. Contraception. 2023;118:109909. doi:10.1016/j.contraception.2022.10.011

Latack and Nguyen reviewed postmarket surveillance data of IUD adverse events in the US Food and Drug Administration’s (FDA) Adverse Event Reporting System (FAERS) from 1998 to 2022. The FAERS is a voluntary, or passive, reporting system.

Study findings

Of the approximately 170,000 IUD-related adverse events reported to the agency during the 24-year timeframe, 25.4% were for copper IUDs and 74.6% were for hormonal IUDs. Slightly more than 4,000 reports were specific for device breakage, which the authors grouped into copper (copper 380-mm²)and hormonal (LNG 52 mg, 19.5 mg, and 13.5 mg) IUDs.

The copper 380-mm² IUD was 6.19 times more likely to have a breakage report than hormonal IUDs (9.6% vs 1.7%; 95% CI, 5.87–6.53).

Continue to: Data support the LNG 52-mg IUD for HMB in nulliparous and obese patients...

Data support the LNG 52-mg IUD for HMB in nulliparous and obese patients

Creinin MD, Barnhart KT, Gawron LM, et al. Heavy menstrual bleeding treatment with a levonorgestrel 52-mg intrauterine device. Obstet Gynecol. 2023;141:971-978. doi:10.1097AOG.0000000000005137

Creinin and colleagues conducted a study for US regulatory product approval of the LNG 52-mg IUD (Liletta) for HMB. This multicenter phase 3 open-label clinical trial recruited nonpregnant participants aged 18 to 50 years with HMB at 29 clinical sites in the United States. No BMI cutoff was used.

Baseline menstrual flow data were obtained over 2 to 3 screening cycles by collection of menstrual products and quantification of blood loss using alkaline hematin measurement. Patients with 2 cycles with a blood loss exceeding 80 mL had an IUD placement, with similar flow evaluations during the third and sixth postplacement cycles.

Treatment success was defined as a reduction in blood loss by more than 50% as compared with baseline (during screening) and measured blood loss of less than 80 mL. The enrolled population (n=105) included 28% nulliparous users, with 49% and 28% of participants having a BMI of 30 kg/m² or higher and higher than 35 kg/m², respectively.

Treatment highly successful in reducing blood loss

Participants in this trial had a 93% and a 98% reduction in blood loss at the third and sixth cycles of use, respectively. Additionally, during the sixth cycle of use, 19% of users had no bleeding. Treatment success occurred in about 80% of participants overall and occurred regardless of parity or BMI.

To assess a subjective measure of success, participants were asked to evaluate their menstrual bleeding and dysmenorrhea severity, acceptability, and overall impact on quality of life at 3 time points: during prior typical menses, cycle 3, and cycle 6. At cycle 6, all participants reported significantly improved acceptability of bleeding and uterine pain and, importantly, decreased overall menstrual interference with the ability to complete daily activities (TABLE 3).

IUD expulsion and replacement rates

Although bleeding greatly decreased in all participants, 13% (n=14) discontinued before cycle 6 due to expulsion or IUD-related symptoms, with the majority citing bleeding irregularities. Expulsion occurred in 9% (n=5) of users, with the majority (2/3) occurring in the first 3 months of use and more commonly in obese and/or parous users. About half of participants with expulsion had the IUD replaced during the study. ●

More US women are using IUDs than ever before. With more use comes the potential for complications and more requests related to non-contraceptive benefits. New information provides contemporary insight into rare IUD complications and the use of hormonal IUDs for treatment of HMB.

The first intrauterine device (IUD) to be approved in the United States, the Lippes Loop, became available in 1964. Sixty years later, more US women are using IUDs than ever before, and numbers are trending upward (FIGURE).^1,2 Over the past year, contemporary information has become available to further inform IUD management when pregnancy occurs with an IUD in situ, as well as counseling about device breakage. Additionally, new data help clinicians expand which patients can use a levonorgestrel (LNG) 52-mg IUD for heavy menstrual bleeding (HMB) treatment.

As the total absolute number of IUD users increases, so do the absolute numbers of rare outcomes, such as pregnancy among IUD users. These highly effective contraceptives have a failure rate within the first year after placement ranging from 0.1% for the LNG 52-mg IUD to 0.8% for the copper 380-mm² IUD.³ Although the possibility for extrauterine gestation is higher when pregnancy occurs while a patient is using an IUD as compared with most other contraceptive methods, most pregnancies that occur with an IUD in situ are intrauterine.⁴

The high contraceptive efficacy of IUDs make pregnancy with a retained IUD rare; therefore, it is difficult to perform a study with a large enough population to evaluate management of pregnancy complicated by an IUD in situ. Clinical management recommendations for these situations are 20 years old and are supported by limited data from case reports and series with fewer than 200 patients.^5,6

Intrauterine device breakage is another rare event that is poorly understood due to the low absolute number of cases. Information about breakage has similarly been limited to case reports and case series.^7,8 This past year, contemporary data were published to provide more insight into both intrauterine pregnancy with an IUD in situ and IUD breakage.

Beyond contraception, hormonal IUDs have become a popular and evidence-based treatment option for patients with HMB. The initial LNG 52-mg IUD (Mirena) regulatory approval studies for HMB treatment included data limited to parous patients and users with a body mass index (BMI) less than 35 kg/m².⁹ Since that time, no studies have explored these populations. Although current practice has commonly extended use to include patients with these characteristics, we have lacked outcome data. New phase 3 data on the LNG 52-mg IUD (Liletta) included a broader range of participants and provide evidence to support this practice.

Removing retained copper 380-mm² IUDs improves pregnancy outcomes

Panchal VR, Rau AR, Mandelbaum RS, et al. Pregnancy with retained intrauterine device: national-level assessment of characteristics and outcomes. Am J Obstet Gynecol MFM. 2023;5:101056. doi:10.1016/j.ajogmf.2023.101056

Karakuş SS, Karakuş R, Akalın EE, et al. Pregnancy outcomes with a copper 380 mm2 intrauterine device in place: a retrospective cohort study in Turkey, 2011-2021. Contraception. 2023;125:110090. doi:10.1016/j.contraception.2023.110090
 

To update our understanding of outcomes of pregnancy with an IUD in situ, Panchal and colleagues performed a cross-sectional study using the Healthcare Cost and Utilization Project’s National Inpatient Sample. This data set represents 85% of US hospital discharges. The population investigated included hospital deliveries from 2016 to 2020 with an ICD-10 (International Classification of Diseases, Tenth Revision) code of retained IUD. Those without the code were assigned to the comparison non-retained IUD group.

The primary outcome studied was the incidence rate of retained IUD, patient and pregnancy characteristics, and delivery outcomes including but not limited to gestational age at delivery, placental abnormalities, intrauterine fetal demise (IUFD), preterm premature rupture of membranes (PPROM), cesarean delivery, postpartum hemorrhage, and hysterectomy.

Outcomes were worse with retained IUD, regardless of IUD removal status

The authors found that an IUD in situ was reported in 1 out of 8,307 pregnancies and was associated with PPROM, fetal malpresentation, IUFD, placental abnormalities including abruption, accreta spectrum, retained placenta, and need for manual removal (TABLE 1). About three-quarters (76.3%) of patients had a term delivery (≥37 weeks).

Retained IUD was associated with previable loss, defined as less than 22 weeks’ gestation (adjusted odds ratio [aOR], 5.49; 95% confidence interval [CI], 3.30–9.15) and periviable delivery, defined as 22 to 25 weeks’ gestation (aOR, 2.81; 95% CI, 1.63–4.85). Retained IUD was not associated with preterm delivery beyond 26 weeks’ gestation, cesarean delivery, postpartum hemorrhage, or hysterectomy.

Important limitations of this study are the lack of information on IUD type (copper vs hormonal) and the timing of removal or attempted removal in relation to measured pregnancy outcomes.

Continue to: Removal of copper IUD improves, but does not eliminate, poor pregnancy outcomes...

Karakus and colleagues conducted a retrospective cohort study of 233 patients in Turkey with pregnancies that occurred during copper 380-mm² IUD use from 2011 to 2021. The authors reported that, at the time of first contact with the health system and diagnosis of retained IUD, 18.9% of the pregnancies were ectopic, 13.2% were first trimester losses, and 67.5% were ongoing pregnancies.

The authors assessed outcomes in patients with ongoing pregnancies based on whether or not the IUD was removed or retained. Outcomes included gestational age at delivery and adverse pregnancy outcomes, assessed as a composite of preterm delivery, PPROM, chorioamnionitis, placental abruption, and postpartum hemorrhage.

Of those with ongoing pregnancies, 13.3% chose to have an abortion, leaving 137 (86.7%) with continuing pregnancy. The IUD was able to be removed in 39.4% of the sample, with an average gestational age of 7 weeks at the time of removal.

Compared with those with a retained IUD, patients in the removal group had a lower rate of pregnancy loss (33.3% vs 61.4%; P<.001) and a lower rate of the composite adverse pregnancy outcomes (53.1% vs 27.8%; P=.03). TABLE 2 shows the approximate rate of ongoing pregnancy by gestational age in patients with retained and removed copper 380-mm² IUDs. Notably, the largest change occurred periviably, with the proportion of patients with an ongoing pregnancy after 26 weeks reducing to about half for patients with a retained IUD as compared with patients with a removed IUD; this proportion of ongoing pregnancies held through the remainder of gestation.

Do national data reveal more breakage reports for copper 380-mm² or LNG IUDs?

Latack KR, Nguyen BT. Trends in copper versus hormonal intrauterine device breakage reporting within the United States’ Food and Drug Administration Adverse Event Reporting System. Contraception. 2023;118:109909. doi:10.1016/j.contraception.2022.10.011

Latack and Nguyen reviewed postmarket surveillance data of IUD adverse events in the US Food and Drug Administration’s (FDA) Adverse Event Reporting System (FAERS) from 1998 to 2022. The FAERS is a voluntary, or passive, reporting system.

Study findings

Of the approximately 170,000 IUD-related adverse events reported to the agency during the 24-year timeframe, 25.4% were for copper IUDs and 74.6% were for hormonal IUDs. Slightly more than 4,000 reports were specific for device breakage, which the authors grouped into copper (copper 380-mm²)and hormonal (LNG 52 mg, 19.5 mg, and 13.5 mg) IUDs.

The copper 380-mm² IUD was 6.19 times more likely to have a breakage report than hormonal IUDs (9.6% vs 1.7%; 95% CI, 5.87–6.53).

Continue to: Data support the LNG 52-mg IUD for HMB in nulliparous and obese patients...

Data support the LNG 52-mg IUD for HMB in nulliparous and obese patients

Creinin MD, Barnhart KT, Gawron LM, et al. Heavy menstrual bleeding treatment with a levonorgestrel 52-mg intrauterine device. Obstet Gynecol. 2023;141:971-978. doi:10.1097AOG.0000000000005137

Creinin and colleagues conducted a study for US regulatory product approval of the LNG 52-mg IUD (Liletta) for HMB. This multicenter phase 3 open-label clinical trial recruited nonpregnant participants aged 18 to 50 years with HMB at 29 clinical sites in the United States. No BMI cutoff was used.

Baseline menstrual flow data were obtained over 2 to 3 screening cycles by collection of menstrual products and quantification of blood loss using alkaline hematin measurement. Patients with 2 cycles with a blood loss exceeding 80 mL had an IUD placement, with similar flow evaluations during the third and sixth postplacement cycles.

Treatment success was defined as a reduction in blood loss by more than 50% as compared with baseline (during screening) and measured blood loss of less than 80 mL. The enrolled population (n=105) included 28% nulliparous users, with 49% and 28% of participants having a BMI of 30 kg/m² or higher and higher than 35 kg/m², respectively.

Treatment highly successful in reducing blood loss

Participants in this trial had a 93% and a 98% reduction in blood loss at the third and sixth cycles of use, respectively. Additionally, during the sixth cycle of use, 19% of users had no bleeding. Treatment success occurred in about 80% of participants overall and occurred regardless of parity or BMI.

To assess a subjective measure of success, participants were asked to evaluate their menstrual bleeding and dysmenorrhea severity, acceptability, and overall impact on quality of life at 3 time points: during prior typical menses, cycle 3, and cycle 6. At cycle 6, all participants reported significantly improved acceptability of bleeding and uterine pain and, importantly, decreased overall menstrual interference with the ability to complete daily activities (TABLE 3).

IUD expulsion and replacement rates

Although bleeding greatly decreased in all participants, 13% (n=14) discontinued before cycle 6 due to expulsion or IUD-related symptoms, with the majority citing bleeding irregularities. Expulsion occurred in 9% (n=5) of users, with the majority (2/3) occurring in the first 3 months of use and more commonly in obese and/or parous users. About half of participants with expulsion had the IUD replaced during the study. ●

More US women are using IUDs than ever before. With more use comes the potential for complications and more requests related to non-contraceptive benefits. New information provides contemporary insight into rare IUD complications and the use of hormonal IUDs for treatment of HMB.

The first intrauterine device (IUD) to be approved in the United States, the Lippes Loop, became available in 1964. Sixty years later, more US women are using IUDs than ever before, and numbers are trending upward (FIGURE).^1,2 Over the past year, contemporary information has become available to further inform IUD management when pregnancy occurs with an IUD in situ, as well as counseling about device breakage. Additionally, new data help clinicians expand which patients can use a levonorgestrel (LNG) 52-mg IUD for heavy menstrual bleeding (HMB) treatment.

As the total absolute number of IUD users increases, so do the absolute numbers of rare outcomes, such as pregnancy among IUD users. These highly effective contraceptives have a failure rate within the first year after placement ranging from 0.1% for the LNG 52-mg IUD to 0.8% for the copper 380-mm² IUD.³ Although the possibility for extrauterine gestation is higher when pregnancy occurs while a patient is using an IUD as compared with most other contraceptive methods, most pregnancies that occur with an IUD in situ are intrauterine.⁴

The high contraceptive efficacy of IUDs make pregnancy with a retained IUD rare; therefore, it is difficult to perform a study with a large enough population to evaluate management of pregnancy complicated by an IUD in situ. Clinical management recommendations for these situations are 20 years old and are supported by limited data from case reports and series with fewer than 200 patients.^5,6

Intrauterine device breakage is another rare event that is poorly understood due to the low absolute number of cases. Information about breakage has similarly been limited to case reports and case series.^7,8 This past year, contemporary data were published to provide more insight into both intrauterine pregnancy with an IUD in situ and IUD breakage.

Beyond contraception, hormonal IUDs have become a popular and evidence-based treatment option for patients with HMB. The initial LNG 52-mg IUD (Mirena) regulatory approval studies for HMB treatment included data limited to parous patients and users with a body mass index (BMI) less than 35 kg/m².⁹ Since that time, no studies have explored these populations. Although current practice has commonly extended use to include patients with these characteristics, we have lacked outcome data. New phase 3 data on the LNG 52-mg IUD (Liletta) included a broader range of participants and provide evidence to support this practice.

Removing retained copper 380-mm² IUDs improves pregnancy outcomes

Panchal VR, Rau AR, Mandelbaum RS, et al. Pregnancy with retained intrauterine device: national-level assessment of characteristics and outcomes. Am J Obstet Gynecol MFM. 2023;5:101056. doi:10.1016/j.ajogmf.2023.101056

Karakuş SS, Karakuş R, Akalın EE, et al. Pregnancy outcomes with a copper 380 mm2 intrauterine device in place: a retrospective cohort study in Turkey, 2011-2021. Contraception. 2023;125:110090. doi:10.1016/j.contraception.2023.110090
 

To update our understanding of outcomes of pregnancy with an IUD in situ, Panchal and colleagues performed a cross-sectional study using the Healthcare Cost and Utilization Project’s National Inpatient Sample. This data set represents 85% of US hospital discharges. The population investigated included hospital deliveries from 2016 to 2020 with an ICD-10 (International Classification of Diseases, Tenth Revision) code of retained IUD. Those without the code were assigned to the comparison non-retained IUD group.

The primary outcome studied was the incidence rate of retained IUD, patient and pregnancy characteristics, and delivery outcomes including but not limited to gestational age at delivery, placental abnormalities, intrauterine fetal demise (IUFD), preterm premature rupture of membranes (PPROM), cesarean delivery, postpartum hemorrhage, and hysterectomy.

Outcomes were worse with retained IUD, regardless of IUD removal status

The authors found that an IUD in situ was reported in 1 out of 8,307 pregnancies and was associated with PPROM, fetal malpresentation, IUFD, placental abnormalities including abruption, accreta spectrum, retained placenta, and need for manual removal (TABLE 1). About three-quarters (76.3%) of patients had a term delivery (≥37 weeks).

Retained IUD was associated with previable loss, defined as less than 22 weeks’ gestation (adjusted odds ratio [aOR], 5.49; 95% confidence interval [CI], 3.30–9.15) and periviable delivery, defined as 22 to 25 weeks’ gestation (aOR, 2.81; 95% CI, 1.63–4.85). Retained IUD was not associated with preterm delivery beyond 26 weeks’ gestation, cesarean delivery, postpartum hemorrhage, or hysterectomy.

Important limitations of this study are the lack of information on IUD type (copper vs hormonal) and the timing of removal or attempted removal in relation to measured pregnancy outcomes.

Continue to: Removal of copper IUD improves, but does not eliminate, poor pregnancy outcomes...

Karakus and colleagues conducted a retrospective cohort study of 233 patients in Turkey with pregnancies that occurred during copper 380-mm² IUD use from 2011 to 2021. The authors reported that, at the time of first contact with the health system and diagnosis of retained IUD, 18.9% of the pregnancies were ectopic, 13.2% were first trimester losses, and 67.5% were ongoing pregnancies.

The authors assessed outcomes in patients with ongoing pregnancies based on whether or not the IUD was removed or retained. Outcomes included gestational age at delivery and adverse pregnancy outcomes, assessed as a composite of preterm delivery, PPROM, chorioamnionitis, placental abruption, and postpartum hemorrhage.

Of those with ongoing pregnancies, 13.3% chose to have an abortion, leaving 137 (86.7%) with continuing pregnancy. The IUD was able to be removed in 39.4% of the sample, with an average gestational age of 7 weeks at the time of removal.

Compared with those with a retained IUD, patients in the removal group had a lower rate of pregnancy loss (33.3% vs 61.4%; P<.001) and a lower rate of the composite adverse pregnancy outcomes (53.1% vs 27.8%; P=.03). TABLE 2 shows the approximate rate of ongoing pregnancy by gestational age in patients with retained and removed copper 380-mm² IUDs. Notably, the largest change occurred periviably, with the proportion of patients with an ongoing pregnancy after 26 weeks reducing to about half for patients with a retained IUD as compared with patients with a removed IUD; this proportion of ongoing pregnancies held through the remainder of gestation.

Do national data reveal more breakage reports for copper 380-mm² or LNG IUDs?

Latack KR, Nguyen BT. Trends in copper versus hormonal intrauterine device breakage reporting within the United States’ Food and Drug Administration Adverse Event Reporting System. Contraception. 2023;118:109909. doi:10.1016/j.contraception.2022.10.011

Latack and Nguyen reviewed postmarket surveillance data of IUD adverse events in the US Food and Drug Administration’s (FDA) Adverse Event Reporting System (FAERS) from 1998 to 2022. The FAERS is a voluntary, or passive, reporting system.

Study findings

Of the approximately 170,000 IUD-related adverse events reported to the agency during the 24-year timeframe, 25.4% were for copper IUDs and 74.6% were for hormonal IUDs. Slightly more than 4,000 reports were specific for device breakage, which the authors grouped into copper (copper 380-mm²)and hormonal (LNG 52 mg, 19.5 mg, and 13.5 mg) IUDs.

The copper 380-mm² IUD was 6.19 times more likely to have a breakage report than hormonal IUDs (9.6% vs 1.7%; 95% CI, 5.87–6.53).

Continue to: Data support the LNG 52-mg IUD for HMB in nulliparous and obese patients...

Data support the LNG 52-mg IUD for HMB in nulliparous and obese patients

Creinin MD, Barnhart KT, Gawron LM, et al. Heavy menstrual bleeding treatment with a levonorgestrel 52-mg intrauterine device. Obstet Gynecol. 2023;141:971-978. doi:10.1097AOG.0000000000005137

Creinin and colleagues conducted a study for US regulatory product approval of the LNG 52-mg IUD (Liletta) for HMB. This multicenter phase 3 open-label clinical trial recruited nonpregnant participants aged 18 to 50 years with HMB at 29 clinical sites in the United States. No BMI cutoff was used.

Baseline menstrual flow data were obtained over 2 to 3 screening cycles by collection of menstrual products and quantification of blood loss using alkaline hematin measurement. Patients with 2 cycles with a blood loss exceeding 80 mL had an IUD placement, with similar flow evaluations during the third and sixth postplacement cycles.

Treatment success was defined as a reduction in blood loss by more than 50% as compared with baseline (during screening) and measured blood loss of less than 80 mL. The enrolled population (n=105) included 28% nulliparous users, with 49% and 28% of participants having a BMI of 30 kg/m² or higher and higher than 35 kg/m², respectively.

Treatment highly successful in reducing blood loss

Participants in this trial had a 93% and a 98% reduction in blood loss at the third and sixth cycles of use, respectively. Additionally, during the sixth cycle of use, 19% of users had no bleeding. Treatment success occurred in about 80% of participants overall and occurred regardless of parity or BMI.

To assess a subjective measure of success, participants were asked to evaluate their menstrual bleeding and dysmenorrhea severity, acceptability, and overall impact on quality of life at 3 time points: during prior typical menses, cycle 3, and cycle 6. At cycle 6, all participants reported significantly improved acceptability of bleeding and uterine pain and, importantly, decreased overall menstrual interference with the ability to complete daily activities (TABLE 3).

IUD expulsion and replacement rates

Although bleeding greatly decreased in all participants, 13% (n=14) discontinued before cycle 6 due to expulsion or IUD-related symptoms, with the majority citing bleeding irregularities. Expulsion occurred in 9% (n=5) of users, with the majority (2/3) occurring in the first 3 months of use and more commonly in obese and/or parous users. About half of participants with expulsion had the IUD replaced during the study. ●

On June 24, 2022, the US Supreme Court ruled in Dobbs v Jackson to overturn the landmark Roe v Wade decision, deeming that abortion is not protected by statutes that provide the right to privacy, liberty, or autonomy. With this historic ruling, other rights founded on the same principles, including the freedom to use contraception, may be called into question in the future. Clinics that provide abortion care typically play a vital role in providing contraception services. Due to abortion restriction across the country, many of these clinics are predicted to close and many have already closed. Within one month of the Dobbs decision, 43 clinics in 11 states had shut their doors to patients, reducing access to basic contraception services.¹ It is more important now than ever that clinicians address barriers and lead the effort to improve and ensure that patients have access to contraceptive services.

In this Update, we review recent evidence that may help aid patients in obtaining contraception more easily and for longer periods of time. We review strategies demonstrated to improve contraceptive access, including how to increase prescribing rates of 1-year contraceptive supplies and pharmacist-prescribed contraception. We also review new data on extended use of the levonorgestrel 52 mg intrauterine device (LNG 52 mg IUD).

One-year prescribing of  hormonal contraception  decreases an access barrier

Uhm S, Chen MJ, Cutler ED, et al. Twelve-month prescribing of contraceptive pill, patch, and ring before and after a standardized electronic medical record order change. Contraception. 2021;103:60-63.

Providing a 1-year supply of self-administered contraception can lead to higher likelihood of continued use and is associated with reduced cost, unintended pregnancy, and abortion rates.^2-4 Although some patients may not use a full year’s supply of pills, rings, or patches under such programs, the lower rates of unintended pregnancy result in significant cost savings as compared with the unused contraceptives.^2,3 Accordingly, the Centers for Disease Control and Prevention (CDC) advises dispensing a 1-year supply of self-administered hormonal contraception.⁵ Insurance coverage and providers’ prescribing practices can be barriers to patients obtaining a year’s supply of hormonal contraception. Currently, 18 states and the District of Columbia legally require insurers to cover a 12-month supply of prescription contraceptives (FIGURE 1). Despite these laws and the CDC recommendation, studies show that most people continue to receive only a 1- to 3-month supply.^6-8 One strategy to increase the number of 1-year supplies of self-administered contraception is institutional changes to default prescription orders.

Study design

In California, legislation enacted in January 2017 required commercial and medical assistance health plans to cover up to  12 months of US Food and Drug Administration (FDA)-approved self-administered hormonal contraceptives dispensed at 1 time as prescribed or requested. To better serve patients, a multidisciplinary team from the University of California Davis Health worked with the institution’s pharmacy to institute an electronic medical record (EMR) default order change from dispensing 1-month with refills to dispensing 12-month quantities for all combined and progestin-only pills, patches, and rings on formulary.

After this EMR order change in December 2019, Uhm and colleagues conducted a retrospective pre-post study using outpatient prescription data that included nearly  5,000 contraceptive pill, patch, and ring prescriptions over an 8-month period. They compared the frequency of 12-month prescriptions for each of these methods 4 months before and 4 months after the default order change. They compared the proportion of 12-month prescriptions by prescriber department affiliation and by clinic location. Department affiliation was categorized as obstetrics-gynecology or non–obstetrics-gynecology. Clinic location was categorized as medical center campus or community clinics.

Increase in 12-month prescriptions

The authors found an overall increase in 12-month prescriptions, from 11% to 27%, after the EMR order change. Prescribers at the medical center campus clinics more frequently ordered a 12-month supply compared with prescribers at community clinics both before (33% vs 4%, respectively) and after (53% vs 19%, respectively) the EMR change. The only group of providers without a significant increase in 12-month prescriptions was among obstetrics-gynecology providers at community clinics (4% before  vs 6% after).

The system EMR change modified only the standard facility order settings and did not affect individual favorite orders, which may help explain the differences in prescribing practices. While this study found an increase in 12-month prescriptions, there were no data on the actual number of supplies a patient received or  on reimbursement.

 Continue to: Pharmacist prescription of  hormonal contraception is safe and promotes continuation...

Pharmacist prescription of  hormonal contraception is safe and promotes continuation

Rodriguez MI, Skye M, Edelman AB, et al. Association of pharmacist prescription and 12-month contraceptive continuation rates. Am J Obstet Gynecol. 2021;225:647.e1-647.e9.

Patients often face difficulty obtaining both new and timely refills of self-administered contraception.^10,11 To expand contraception access, Oregon became the first state (in 2016) to enact legislation to authorize direct pharmacist prescribing of hormonal contraceptives.¹² Currently, 17 states and the District of Columbia have protocols for pharmacist prescribing privileges (FIGURE 2), and proposed legislation is pending in another  14 states.^10,12 These protocols vary, but basic processes include screening, documentation, monitoring, and referrals when necessary. Typically, protocols require a pharmacist to review a patient’s medical history, pregnancy status, medication use, and blood pressure, followed by contraceptive counseling.¹⁰ Pharmacies are generally located in the community they serve, have extended hours, and usually do not require an appointment.^8,13,14

Pharmacist prescribing increases the number of new contraceptive users, and pharmacists are more likely to prescribe a 6-month or longer supply of contraceptives compared with clinicians.^8,13,15 Also, pharmacist prescribing is safe, with adherence rates to the CDC’s US Medical Eligibility Criteria for Contraceptive Use similar to those of prescriptions provided by a clinician.¹³

Authors of a recent multi-state study further assessed the impact of pharmacist prescribing by evaluating 12-month continuation and perfect use rates.

Study design

Rodriguez and colleagues evaluated the results of a 1-year prospective cohort study conducted in 2019 that included 388 participants who sought contraception in California, Colorado, Hawaii, and Oregon. All these states had laws permitting pharmacist prescribing and 12-month supply of hormonal contraception. Participants received prescriptions directly from a pharmacist at 1 of 139 pharmacies (n = 149) or filled a prescription provided by a clinician (n = 239). The primary outcomes were continuation of an effective method and perfect use of contraception across 12 months.

Participant demographics were similar between the 2 groups except for education and insurance status. Participants who received a prescription from a clinician reported higher levels of education. A greater proportion of uninsured participants received a prescription from a pharmacist (11%) compared with from a clinician (3%).

Contraceptive continuation rates

Participants were surveyed 3 times during the 12-month study about their current contraceptive method, if they had switched methods, or if they had any missed days  of contraception. 

Overall, 340 participants (88%) completed a full 12 months of follow-up. Continuation rates were similar between the 2 groups: 89% in the clinician-prescribed and 90% in the pharmacist-prescribed group (P=.86). Participants in the 2 groups also reported similar rates of perfect use (no missed days: 54% and 47%, respectively [P=.69]).  Additionally, the authors reported that  29 participants changed from a tier 2 (pill, patch, ring, injection) to a tier 1 (intrauterine device or implant) method during follow-up, with no difference in switch rates for participants who received care from a clinician (10%) or a pharmacist (7%).

Continue to: LNG 52 mg IUD demonstrates  efficacy and safety through 8 years of use... 

LNG 52 mg IUD demonstrates  efficacy and safety through 8 years of use 

Creinin MD, Schreiber CA, Turok DK, et al. Levonorgestrel 52 mg intrauterine system efficacy and safety through 8 years of use. Am J Obstet Gynecol. 2022;S00029378(22)00366-0.

Given the potential difficulty accessing contraceptive and abortion services due to state restrictions, patients may be more motivated to maintain long-acting reversible contraceptives for maximum periods of time. The LNG 52 mg IUD was first marketed as a 5-year product, but multiple studies suggested that it had potential longer duration of efficacy and safety.^18,19 The most recent clinical trial report shows that the LNG 52 mg IUD has at least 8 years of efficacy  and safety.

Evidence supports 8 years’ use

The ACCESS IUS (A Comprehensive Contraceptive Efficacy and Safety Study of an IUS) phase 3 trial was designed to assess the safety and efficacy of a LNG 52 mg IUD (Liletta) for up to 10 years of use. The recent publication by Creinin and colleagues extends the available data from this study from 6 to 8 years.

Five-hundred and sixty-nine participants started year 7; 478 completed year 7 and 343 completed year 8 by the time the study was discontinued. Two pregnancies occurred in year 7 and no pregnancies occurred in year 8. One of the pregnancies in year 7 was determined by ultrasound examination to have implantation on day 4 after LNG IUD removal. According to the FDA, any pregnancy that occurs within 7 days of discontinuation is included as on-treatment, whereas the European Medicines Agency (EMA) has a 2-day cutoff. Over 8 years,  11 pregnancies occurred. The cumulative life-table pregnancy rate in the primary efficacy population through year 8 was 1.32% (95% confidence interval [CI],  0.69–2.51) under FDA rules and 1.09% (95% CI,  0.56–2.13) according to EMA guidance.

Absence of bleeding/spotting rates and adverse events

Rates of absence of bleeding/spotting remained relatively stable in years 7 and 8 at around 40%, similar to the rates during years 3 to 8 (FIGURE 4). Overall, only 2.6% of participants discontinued LNG IUD use because of bleeding problems, with a total of 4 participants discontinuing for this reason in years 7 and 8. Expulsion rates remained low at a rate of approximately 0.5% in years 7 and 8. Vulvovaginal infections were the most common adverse effect during year 7–8 of use. These findings are consistent with those found at  6 years.²⁰ ●

On June 24, 2022, the US Supreme Court ruled in Dobbs v Jackson to overturn the landmark Roe v Wade decision, deeming that abortion is not protected by statutes that provide the right to privacy, liberty, or autonomy. With this historic ruling, other rights founded on the same principles, including the freedom to use contraception, may be called into question in the future. Clinics that provide abortion care typically play a vital role in providing contraception services. Due to abortion restriction across the country, many of these clinics are predicted to close and many have already closed. Within one month of the Dobbs decision, 43 clinics in 11 states had shut their doors to patients, reducing access to basic contraception services.¹ It is more important now than ever that clinicians address barriers and lead the effort to improve and ensure that patients have access to contraceptive services.

In this Update, we review recent evidence that may help aid patients in obtaining contraception more easily and for longer periods of time. We review strategies demonstrated to improve contraceptive access, including how to increase prescribing rates of 1-year contraceptive supplies and pharmacist-prescribed contraception. We also review new data on extended use of the levonorgestrel 52 mg intrauterine device (LNG 52 mg IUD).

One-year prescribing of  hormonal contraception  decreases an access barrier

Uhm S, Chen MJ, Cutler ED, et al. Twelve-month prescribing of contraceptive pill, patch, and ring before and after a standardized electronic medical record order change. Contraception. 2021;103:60-63.

Providing a 1-year supply of self-administered contraception can lead to higher likelihood of continued use and is associated with reduced cost, unintended pregnancy, and abortion rates.^2-4 Although some patients may not use a full year’s supply of pills, rings, or patches under such programs, the lower rates of unintended pregnancy result in significant cost savings as compared with the unused contraceptives.^2,3 Accordingly, the Centers for Disease Control and Prevention (CDC) advises dispensing a 1-year supply of self-administered hormonal contraception.⁵ Insurance coverage and providers’ prescribing practices can be barriers to patients obtaining a year’s supply of hormonal contraception. Currently, 18 states and the District of Columbia legally require insurers to cover a 12-month supply of prescription contraceptives (FIGURE 1). Despite these laws and the CDC recommendation, studies show that most people continue to receive only a 1- to 3-month supply.^6-8 One strategy to increase the number of 1-year supplies of self-administered contraception is institutional changes to default prescription orders.

Study design

In California, legislation enacted in January 2017 required commercial and medical assistance health plans to cover up to  12 months of US Food and Drug Administration (FDA)-approved self-administered hormonal contraceptives dispensed at 1 time as prescribed or requested. To better serve patients, a multidisciplinary team from the University of California Davis Health worked with the institution’s pharmacy to institute an electronic medical record (EMR) default order change from dispensing 1-month with refills to dispensing 12-month quantities for all combined and progestin-only pills, patches, and rings on formulary.

After this EMR order change in December 2019, Uhm and colleagues conducted a retrospective pre-post study using outpatient prescription data that included nearly  5,000 contraceptive pill, patch, and ring prescriptions over an 8-month period. They compared the frequency of 12-month prescriptions for each of these methods 4 months before and 4 months after the default order change. They compared the proportion of 12-month prescriptions by prescriber department affiliation and by clinic location. Department affiliation was categorized as obstetrics-gynecology or non–obstetrics-gynecology. Clinic location was categorized as medical center campus or community clinics.

Increase in 12-month prescriptions

The authors found an overall increase in 12-month prescriptions, from 11% to 27%, after the EMR order change. Prescribers at the medical center campus clinics more frequently ordered a 12-month supply compared with prescribers at community clinics both before (33% vs 4%, respectively) and after (53% vs 19%, respectively) the EMR change. The only group of providers without a significant increase in 12-month prescriptions was among obstetrics-gynecology providers at community clinics (4% before  vs 6% after).

The system EMR change modified only the standard facility order settings and did not affect individual favorite orders, which may help explain the differences in prescribing practices. While this study found an increase in 12-month prescriptions, there were no data on the actual number of supplies a patient received or  on reimbursement.

 Continue to: Pharmacist prescription of  hormonal contraception is safe and promotes continuation...

Pharmacist prescription of  hormonal contraception is safe and promotes continuation

Rodriguez MI, Skye M, Edelman AB, et al. Association of pharmacist prescription and 12-month contraceptive continuation rates. Am J Obstet Gynecol. 2021;225:647.e1-647.e9.

Patients often face difficulty obtaining both new and timely refills of self-administered contraception.^10,11 To expand contraception access, Oregon became the first state (in 2016) to enact legislation to authorize direct pharmacist prescribing of hormonal contraceptives.¹² Currently, 17 states and the District of Columbia have protocols for pharmacist prescribing privileges (FIGURE 2), and proposed legislation is pending in another  14 states.^10,12 These protocols vary, but basic processes include screening, documentation, monitoring, and referrals when necessary. Typically, protocols require a pharmacist to review a patient’s medical history, pregnancy status, medication use, and blood pressure, followed by contraceptive counseling.¹⁰ Pharmacies are generally located in the community they serve, have extended hours, and usually do not require an appointment.^8,13,14

Pharmacist prescribing increases the number of new contraceptive users, and pharmacists are more likely to prescribe a 6-month or longer supply of contraceptives compared with clinicians.^8,13,15 Also, pharmacist prescribing is safe, with adherence rates to the CDC’s US Medical Eligibility Criteria for Contraceptive Use similar to those of prescriptions provided by a clinician.¹³

Authors of a recent multi-state study further assessed the impact of pharmacist prescribing by evaluating 12-month continuation and perfect use rates.

Study design

Rodriguez and colleagues evaluated the results of a 1-year prospective cohort study conducted in 2019 that included 388 participants who sought contraception in California, Colorado, Hawaii, and Oregon. All these states had laws permitting pharmacist prescribing and 12-month supply of hormonal contraception. Participants received prescriptions directly from a pharmacist at 1 of 139 pharmacies (n = 149) or filled a prescription provided by a clinician (n = 239). The primary outcomes were continuation of an effective method and perfect use of contraception across 12 months.

Participant demographics were similar between the 2 groups except for education and insurance status. Participants who received a prescription from a clinician reported higher levels of education. A greater proportion of uninsured participants received a prescription from a pharmacist (11%) compared with from a clinician (3%).

Contraceptive continuation rates

Participants were surveyed 3 times during the 12-month study about their current contraceptive method, if they had switched methods, or if they had any missed days  of contraception. 

Overall, 340 participants (88%) completed a full 12 months of follow-up. Continuation rates were similar between the 2 groups: 89% in the clinician-prescribed and 90% in the pharmacist-prescribed group (P=.86). Participants in the 2 groups also reported similar rates of perfect use (no missed days: 54% and 47%, respectively [P=.69]).  Additionally, the authors reported that  29 participants changed from a tier 2 (pill, patch, ring, injection) to a tier 1 (intrauterine device or implant) method during follow-up, with no difference in switch rates for participants who received care from a clinician (10%) or a pharmacist (7%).

Continue to: LNG 52 mg IUD demonstrates  efficacy and safety through 8 years of use... 

LNG 52 mg IUD demonstrates  efficacy and safety through 8 years of use 

Creinin MD, Schreiber CA, Turok DK, et al. Levonorgestrel 52 mg intrauterine system efficacy and safety through 8 years of use. Am J Obstet Gynecol. 2022;S00029378(22)00366-0.

Given the potential difficulty accessing contraceptive and abortion services due to state restrictions, patients may be more motivated to maintain long-acting reversible contraceptives for maximum periods of time. The LNG 52 mg IUD was first marketed as a 5-year product, but multiple studies suggested that it had potential longer duration of efficacy and safety.^18,19 The most recent clinical trial report shows that the LNG 52 mg IUD has at least 8 years of efficacy  and safety.

Evidence supports 8 years’ use

The ACCESS IUS (A Comprehensive Contraceptive Efficacy and Safety Study of an IUS) phase 3 trial was designed to assess the safety and efficacy of a LNG 52 mg IUD (Liletta) for up to 10 years of use. The recent publication by Creinin and colleagues extends the available data from this study from 6 to 8 years.

Five-hundred and sixty-nine participants started year 7; 478 completed year 7 and 343 completed year 8 by the time the study was discontinued. Two pregnancies occurred in year 7 and no pregnancies occurred in year 8. One of the pregnancies in year 7 was determined by ultrasound examination to have implantation on day 4 after LNG IUD removal. According to the FDA, any pregnancy that occurs within 7 days of discontinuation is included as on-treatment, whereas the European Medicines Agency (EMA) has a 2-day cutoff. Over 8 years,  11 pregnancies occurred. The cumulative life-table pregnancy rate in the primary efficacy population through year 8 was 1.32% (95% confidence interval [CI],  0.69–2.51) under FDA rules and 1.09% (95% CI,  0.56–2.13) according to EMA guidance.

Absence of bleeding/spotting rates and adverse events

Rates of absence of bleeding/spotting remained relatively stable in years 7 and 8 at around 40%, similar to the rates during years 3 to 8 (FIGURE 4). Overall, only 2.6% of participants discontinued LNG IUD use because of bleeding problems, with a total of 4 participants discontinuing for this reason in years 7 and 8. Expulsion rates remained low at a rate of approximately 0.5% in years 7 and 8. Vulvovaginal infections were the most common adverse effect during year 7–8 of use. These findings are consistent with those found at  6 years.²⁰ ●

On June 24, 2022, the US Supreme Court ruled in Dobbs v Jackson to overturn the landmark Roe v Wade decision, deeming that abortion is not protected by statutes that provide the right to privacy, liberty, or autonomy. With this historic ruling, other rights founded on the same principles, including the freedom to use contraception, may be called into question in the future. Clinics that provide abortion care typically play a vital role in providing contraception services. Due to abortion restriction across the country, many of these clinics are predicted to close and many have already closed. Within one month of the Dobbs decision, 43 clinics in 11 states had shut their doors to patients, reducing access to basic contraception services.¹ It is more important now than ever that clinicians address barriers and lead the effort to improve and ensure that patients have access to contraceptive services.

In this Update, we review recent evidence that may help aid patients in obtaining contraception more easily and for longer periods of time. We review strategies demonstrated to improve contraceptive access, including how to increase prescribing rates of 1-year contraceptive supplies and pharmacist-prescribed contraception. We also review new data on extended use of the levonorgestrel 52 mg intrauterine device (LNG 52 mg IUD).

One-year prescribing of  hormonal contraception  decreases an access barrier

Uhm S, Chen MJ, Cutler ED, et al. Twelve-month prescribing of contraceptive pill, patch, and ring before and after a standardized electronic medical record order change. Contraception. 2021;103:60-63.

Providing a 1-year supply of self-administered contraception can lead to higher likelihood of continued use and is associated with reduced cost, unintended pregnancy, and abortion rates.^2-4 Although some patients may not use a full year’s supply of pills, rings, or patches under such programs, the lower rates of unintended pregnancy result in significant cost savings as compared with the unused contraceptives.^2,3 Accordingly, the Centers for Disease Control and Prevention (CDC) advises dispensing a 1-year supply of self-administered hormonal contraception.⁵ Insurance coverage and providers’ prescribing practices can be barriers to patients obtaining a year’s supply of hormonal contraception. Currently, 18 states and the District of Columbia legally require insurers to cover a 12-month supply of prescription contraceptives (FIGURE 1). Despite these laws and the CDC recommendation, studies show that most people continue to receive only a 1- to 3-month supply.^6-8 One strategy to increase the number of 1-year supplies of self-administered contraception is institutional changes to default prescription orders.

Study design

In California, legislation enacted in January 2017 required commercial and medical assistance health plans to cover up to  12 months of US Food and Drug Administration (FDA)-approved self-administered hormonal contraceptives dispensed at 1 time as prescribed or requested. To better serve patients, a multidisciplinary team from the University of California Davis Health worked with the institution’s pharmacy to institute an electronic medical record (EMR) default order change from dispensing 1-month with refills to dispensing 12-month quantities for all combined and progestin-only pills, patches, and rings on formulary.

After this EMR order change in December 2019, Uhm and colleagues conducted a retrospective pre-post study using outpatient prescription data that included nearly  5,000 contraceptive pill, patch, and ring prescriptions over an 8-month period. They compared the frequency of 12-month prescriptions for each of these methods 4 months before and 4 months after the default order change. They compared the proportion of 12-month prescriptions by prescriber department affiliation and by clinic location. Department affiliation was categorized as obstetrics-gynecology or non–obstetrics-gynecology. Clinic location was categorized as medical center campus or community clinics.

Increase in 12-month prescriptions

The authors found an overall increase in 12-month prescriptions, from 11% to 27%, after the EMR order change. Prescribers at the medical center campus clinics more frequently ordered a 12-month supply compared with prescribers at community clinics both before (33% vs 4%, respectively) and after (53% vs 19%, respectively) the EMR change. The only group of providers without a significant increase in 12-month prescriptions was among obstetrics-gynecology providers at community clinics (4% before  vs 6% after).

The system EMR change modified only the standard facility order settings and did not affect individual favorite orders, which may help explain the differences in prescribing practices. While this study found an increase in 12-month prescriptions, there were no data on the actual number of supplies a patient received or  on reimbursement.

 Continue to: Pharmacist prescription of  hormonal contraception is safe and promotes continuation...

Pharmacist prescription of  hormonal contraception is safe and promotes continuation

Rodriguez MI, Skye M, Edelman AB, et al. Association of pharmacist prescription and 12-month contraceptive continuation rates. Am J Obstet Gynecol. 2021;225:647.e1-647.e9.

Patients often face difficulty obtaining both new and timely refills of self-administered contraception.^10,11 To expand contraception access, Oregon became the first state (in 2016) to enact legislation to authorize direct pharmacist prescribing of hormonal contraceptives.¹² Currently, 17 states and the District of Columbia have protocols for pharmacist prescribing privileges (FIGURE 2), and proposed legislation is pending in another  14 states.^10,12 These protocols vary, but basic processes include screening, documentation, monitoring, and referrals when necessary. Typically, protocols require a pharmacist to review a patient’s medical history, pregnancy status, medication use, and blood pressure, followed by contraceptive counseling.¹⁰ Pharmacies are generally located in the community they serve, have extended hours, and usually do not require an appointment.^8,13,14

Pharmacist prescribing increases the number of new contraceptive users, and pharmacists are more likely to prescribe a 6-month or longer supply of contraceptives compared with clinicians.^8,13,15 Also, pharmacist prescribing is safe, with adherence rates to the CDC’s US Medical Eligibility Criteria for Contraceptive Use similar to those of prescriptions provided by a clinician.¹³

Authors of a recent multi-state study further assessed the impact of pharmacist prescribing by evaluating 12-month continuation and perfect use rates.

Study design

Rodriguez and colleagues evaluated the results of a 1-year prospective cohort study conducted in 2019 that included 388 participants who sought contraception in California, Colorado, Hawaii, and Oregon. All these states had laws permitting pharmacist prescribing and 12-month supply of hormonal contraception. Participants received prescriptions directly from a pharmacist at 1 of 139 pharmacies (n = 149) or filled a prescription provided by a clinician (n = 239). The primary outcomes were continuation of an effective method and perfect use of contraception across 12 months.

Participant demographics were similar between the 2 groups except for education and insurance status. Participants who received a prescription from a clinician reported higher levels of education. A greater proportion of uninsured participants received a prescription from a pharmacist (11%) compared with from a clinician (3%).

Contraceptive continuation rates

Participants were surveyed 3 times during the 12-month study about their current contraceptive method, if they had switched methods, or if they had any missed days  of contraception. 

Overall, 340 participants (88%) completed a full 12 months of follow-up. Continuation rates were similar between the 2 groups: 89% in the clinician-prescribed and 90% in the pharmacist-prescribed group (P=.86). Participants in the 2 groups also reported similar rates of perfect use (no missed days: 54% and 47%, respectively [P=.69]).  Additionally, the authors reported that  29 participants changed from a tier 2 (pill, patch, ring, injection) to a tier 1 (intrauterine device or implant) method during follow-up, with no difference in switch rates for participants who received care from a clinician (10%) or a pharmacist (7%).

Continue to: LNG 52 mg IUD demonstrates  efficacy and safety through 8 years of use... 

LNG 52 mg IUD demonstrates  efficacy and safety through 8 years of use 

Creinin MD, Schreiber CA, Turok DK, et al. Levonorgestrel 52 mg intrauterine system efficacy and safety through 8 years of use. Am J Obstet Gynecol. 2022;S00029378(22)00366-0.

Given the potential difficulty accessing contraceptive and abortion services due to state restrictions, patients may be more motivated to maintain long-acting reversible contraceptives for maximum periods of time. The LNG 52 mg IUD was first marketed as a 5-year product, but multiple studies suggested that it had potential longer duration of efficacy and safety.^18,19 The most recent clinical trial report shows that the LNG 52 mg IUD has at least 8 years of efficacy  and safety.

Evidence supports 8 years’ use

The ACCESS IUS (A Comprehensive Contraceptive Efficacy and Safety Study of an IUS) phase 3 trial was designed to assess the safety and efficacy of a LNG 52 mg IUD (Liletta) for up to 10 years of use. The recent publication by Creinin and colleagues extends the available data from this study from 6 to 8 years.

Five-hundred and sixty-nine participants started year 7; 478 completed year 7 and 343 completed year 8 by the time the study was discontinued. Two pregnancies occurred in year 7 and no pregnancies occurred in year 8. One of the pregnancies in year 7 was determined by ultrasound examination to have implantation on day 4 after LNG IUD removal. According to the FDA, any pregnancy that occurs within 7 days of discontinuation is included as on-treatment, whereas the European Medicines Agency (EMA) has a 2-day cutoff. Over 8 years,  11 pregnancies occurred. The cumulative life-table pregnancy rate in the primary efficacy population through year 8 was 1.32% (95% confidence interval [CI],  0.69–2.51) under FDA rules and 1.09% (95% CI,  0.56–2.13) according to EMA guidance.

Absence of bleeding/spotting rates and adverse events

Rates of absence of bleeding/spotting remained relatively stable in years 7 and 8 at around 40%, similar to the rates during years 3 to 8 (FIGURE 4). Overall, only 2.6% of participants discontinued LNG IUD use because of bleeding problems, with a total of 4 participants discontinuing for this reason in years 7 and 8. Expulsion rates remained low at a rate of approximately 0.5% in years 7 and 8. Vulvovaginal infections were the most common adverse effect during year 7–8 of use. These findings are consistent with those found at  6 years.²⁰ ●

A new contraceptive method should ideally provide improved access or a higher quality and safety option. Although unintended pregnancy rates in the United States are decreasing, significant disparities across race and socioeconomic status remain,¹ and these disparities actually doubled from 1994 to 2011 even though the overall unintended pregnancy rate decreased.^1-3 Specifically, people of color, those with lower income, and people with lower education levels had higher rates of unintended pregnancies than did White people with higher education and income, suggesting disparate access to contraception services.¹ Thus, as new contraceptive methods are introduced, we must assess if they have the potential to address this disparity as well as continue to provide higher quality and safer options.

In this Update, we critically review the phase 3 data on efficacy and safety for 3 new methods that were introduced to the US market over the past year to evaluate their impact on the current contraceptive landscape.

The first method, newly approved by the US Food and Drug Administration (FDA), is a combined oral contraceptive (OC) that contains a novel endogenous estrogen, estetrol, or E4 (Nextstellis). E4 is a natural estrogen produced in the fetal liver that has lower potency and a longer half-life than estradiol. Nextstellis is a monophasic 24/4 OC pill that contains E4 14.2 mg and drospirenone 3 mg in each of the 24 hormone-containing pills. Most combined hormonal contraceptives (CHCs) in the United States today contain synthetically made ethinyl estradiol (EE) due to its high potency and oral bioavailability. Outside of the reproductive system, EE upregulates the production of hepatic proteins and alters procoagulant and anticoagulant factors, which results in an overall increase in venous thromboembolic (VTE) risk among CHC users.²

After widespread use of combined oral contraceptives (COCs) started in the 1960s, data emerged regarding increased VTE risk.³ Subsequent research discovered that the type of estrogen used in CHCs directly correlates with the thrombosis risk due to the hepatic upregulation with both first- and second-pass metabolism. Although this risk was reduced as the EE dose decreased below 50 µg and concurrent VTE risk factors were contraindicated, CHC users still faced a 2-fold increase in VTE risk compared with nonusers.^4,5 EE in contraceptive formulations increases VTE risk, likely related to upregulation of procoagulant factors and decreasing anticoagulant proteins.² By contrast, a phase 2 trial of Nextstellis demonstrated more neutral effects of E4/drospirenone on hemostatic parameters compared with EE/levonorgestrel or EE/drospirenone.⁶ Furthermore, E4/drospirenone exhibited lower increases in hepatic proteins, such as angiotensinogen, triglycerides, and sex-hormone binding globulin.⁷ These findings together suggest that this novel CHC pill has a more favorable cardiovascular adverse effect profile compared with currently available CHCs.

The second contraceptive method is a new transdermal patch that contains EE and levonorgestrel (Twirla); this is in contrast to the available EE/norelgestromin contraceptive patch (Xulane). Transdermal contraceptive patches can offer some users easier adherence as compared with a daily OC.⁸ Until this past year, the only transdermal contraceptive available in the United States was Xulane, which contains a daily dose of EE 35 µg and norelgestromin 150 µg. Norelgestromin is eventually metabolized to levonorgestrel derivatives.⁹ Twirla is administered in the same manner as Xulane and contains a daily hormone exposure equivalent to a COC containing EE 30 µg and levonorgestrel 120 µg. Similar to EE/norelgestromin, the EE/levonorgestrel patch also is contraindicated in obese patients (body mass index [BMI] ≥30 kg/m²) due to decreased efficacy and increased risk for VTE. Additionally, phase 3 data demonstrated decreasing efficacy of Twirla in overweight users (BMI ≥25–30 kg/m²), perhaps further limiting the population that may benefit from this contraceptive method.¹⁰ These issues with efficacy and weight likely are related to the fact that levonorgestrel distribution is weight dependent, with evidence of lower plasma levels in obese individuals.^11-13

The third new method is a prescription vaginal contraceptive gel with lactic acid, citric acid, and potassium bitartrate (Phexxi) designed to prevent pregnancy by maintaining an acidic vaginal environment that is inhospitable to sperm. For many decades, vaginal contraceptives, including vaginal spermicidal gels, provided easy access to a nonhormonal and flexible method of moderately effective contraception for many users. Phexxi is a prescription vaginal pH regulator administered as a gel and active for 1 hour after application. All previous vaginal gels sold in the United States are applied similarly, are available over the counter, and include nonoxynol-9, which is a surfactant that damages sperm cell membranes. Recent data from a phase 3 trial demonstrated similar contraceptive effectiveness of Phexxi when compared with available nonoxynol-9 alternatives.¹⁴

Continue to: New OC with the novel estrogen E4 demonstrates good safety profile for VTE...

New OC with the novel estrogen E4 demonstrates good safety profile for VTE

Creinin MD, Westhoff CL, Bouchard C, et al. Estetrol-drospirenone combination oral contraceptive: North American phase 3 efficacy and safety results. Contraception. 2021;104:222-228.

The COC E4/drospirenone was evaluated in 2 parallel multinational studies. Here, we review the North American data that are more relevant for the US population; the European-Russian data also are published.¹⁵

Study examined 1 year’s use of E4/drospirenone

The US–Canadian trial conducted by Creinin and colleagues enrolled 1,864 participants aged 16 to 50 years to evaluate contraceptive efficacy, bleeding patterns, and adverse events with 1-year use (13 cycles) of E4/drospirenone. The primary efficacy group included 1,524 women aged 16 to 35. This study enrolled healthy, heterosexually active participants with a BMI ≤35 kg/m² and regular menses from 70 sites in the United States and 7 sites in Canada. The dropout rate was 45%, comparable to that in other contraceptive studies. Participants used E4/drospirenone cyclically, taking 1 hormone-containing pill daily for 24 days followed by 4 days of placebo pills.

Contraceptive efficacious, no VTE observed

The researchers reported efficacy as a Pearl Index (PI) of 2.65 pregnancies per 100 woman-years in participants aged 16 to 35 and an overall 13-cycle life-table pregnancy rate of 2.06%. The PI did not differ among nonobese and obese participants in multivariable analysis. Most users experienced scheduled withdrawal bleeding; only 13% to 18% reported absence of scheduled bleeding. Unscheduled bleeding was typically spotting (55.2%), and this decreased with treatment duration from 30% in cycle 1 to 15% to 20% in cycle 5 and on.

Overall, 28.9% of participants reported treatment-related adverse events (AEs), which most commonly were headache (5.0%), metrorrhagia (4.6%), and nausea (3.8%). Investigators reported a minimal change in mean (SD) BMI of 0.4 (1.7) kg/m² from baseline after 1 year of E4/drospirenone use, and only 0.5% of participants discontinued use due to weight gain. The most common reasons for AE-related treatment discontinuation included metrorrhagia (0.9%), menorrhagia (0.8%), and vaginal hemorrhage (0.5%). Importantly, no cases of VTE occurred in this study of estetrol despite 23% of participants being obese, a known risk factor for VTE.

Continue to: Efficacy of a new EE/levonorgestrel transdermal patch may be lower in overweight, obese women...

Efficacy of a new EE/levonorgestrel transdermal patch may be lower in overweight, obese women

Nelson AL, Kaunitz AM, Kroll R; SECURE Investigators. Efficacy, safety, and tolerability of a levonorgestrel/ethinyl estradiol transdermal delivery system: phase 3 clinical trial results. Contraception. 2021;103:137-143.

To assess the contraceptive efficacy, tolerability, and safety of the transdermal patch Twirla (EE/levonorgestrel) over 1 year of treatment (13 cycles), Nelson and colleagues conducted an open-label, multicenter, US-based phase 3 trial of participants aged 18 years and older with regular cycles. There were no restrictions based on BMI. On average, the study population was overweight, with a mean BMI of 28.3 kg/m² , and 35% of the population was considered obese (BMI ≥30 kg/m²).

Study design

A total of 2,032 participants enrolled in the study, with separate populations defined for specific analysis on safety, contraceptive efficacy, and cycle control. The primary efficacy group included 1,736 participants. Fifty-one percent discontinued the study, most commonly due to “women’s decision” (15%) and lost to follow-up (11%). Users received bleeding diaries and returned periodically throughout the study for evaluation for efficacy, adherence, and adverse events.

Efficacy associated with BMI

The study results demonstrated an overall PI of 5.8 pregnancies per 100 woman-years for users aged younger than 35. TABLE 2 demonstrates the overall trend of efficacy in relation to BMI.^10,15-19 Participants with a higher BMI were found to have a higher PI, revealing lower contraceptive efficacy in more overweight and obese patients. The overall cumulative pregnancy rate over 13 cycles was 5.3%

Participants reported decreasing frequency of bleeding/spotting days over the treatment duration of 13 cycles, from a mean (SD) of 6.2 (4.5) days in cycle 1 to 4.9 (3.5) days in cycle 13. Unscheduled bleeding episodes remained high throughout the study period. Initially, 60% of users reported 1 or more days of unscheduled bleeding in cycle 1, and 42% still reported unscheduled bleeding in cycle 13. In light of this, only 45 participants (2.2%) discontinued the study due to bleeding issues, suggesting perhaps that the bleeding was light. Overall, users experienced acceptable wearability of the patch, and the rate of detachment decreased over the study period from 9.9% in cycle 1 to 2.4% in cycle 13. There were also low rates (0.5%) of moderate to severe irritation. Itching at the adhesion site decreased slightly from 13.1% in cycle 2 to 9.6% in cycle 13.

In general, 27.2% of patch users experienced a study-related AE, most reported as mild to moderate. Nausea (4.1%) and headaches (3.6%) were the most common hormone-related AE. Importantly, 4 obese users experienced 5 VTEs (deep vein thrombosis, n = 2; pulmonary embolism, n = 3) between cycle 5 and 13. Three of these users had additional VTE risk factors, such as air travel and a family history of clots. No users who were of normal weight or overweight experienced VTE.

Continue to: Novel vaginal pH buffering spermicide is a new Rx-only option...

Novel vaginal pH buffering spermicide is a new Rx-only option

Thomas MA, Chappell BT, Maximos B, et al. A novel vaginal pH regulator: results from the phase 3 AMPOWER contraception clinical trial. Contracept X. 2020;2:100031.

In an open-label phase 3 study, Thomas and colleagues enrolled 1,384 participants aged 18 to 35 with regular cycles at 112 sites in the United States to assess the contraceptive efficacy, safety, and acceptability of Phexxi vaginal gel (lactic acid, citric acid, and potassium bitartrate) over 7 cycles (6 months). Participants were required to have at least 3 episodes of heterosexual vaginal intercourse per cycle and return throughout the treatment duration for study visits. Fifty-three percent of participants did not complete the study, most frequently due to loss to follow-up (18.1%) and participant withdrawal (12.3%). Most participants were White (69%) and had an average (SD) age of 27.7 (4.5) years.

Efficacy and AE rates

The investigators reported a cumulative pregnancy rate of 13.7% over 7 cycles (6 months). In this study, 45.2% of women experienced 1 AE, and most were noted to be mild (23.9%) to moderate (18.7%). The most reported AE was vulvovaginal burning (20.0%), followed by vulvovaginal pruritus (11.2%), urinary tract infection (5.7%), and vulvovaginal pain (3.8%). Less than 2% of participants discontinued the study due to an AE. Burning and itching decreased with time and with decreased frequency of use. When used twice per day compared with once per day, burning rates decreased from 4.6% to 2.1%, and itching rates decreased from 1.0% to 0.7%. Serious AEs were uncommon, occurring in 1.3% of users; only 1, cystitis, was noted to be “probably” related to the treatment. ●

A new contraceptive method should ideally provide improved access or a higher quality and safety option. Although unintended pregnancy rates in the United States are decreasing, significant disparities across race and socioeconomic status remain,¹ and these disparities actually doubled from 1994 to 2011 even though the overall unintended pregnancy rate decreased.^1-3 Specifically, people of color, those with lower income, and people with lower education levels had higher rates of unintended pregnancies than did White people with higher education and income, suggesting disparate access to contraception services.¹ Thus, as new contraceptive methods are introduced, we must assess if they have the potential to address this disparity as well as continue to provide higher quality and safer options.

In this Update, we critically review the phase 3 data on efficacy and safety for 3 new methods that were introduced to the US market over the past year to evaluate their impact on the current contraceptive landscape.

The first method, newly approved by the US Food and Drug Administration (FDA), is a combined oral contraceptive (OC) that contains a novel endogenous estrogen, estetrol, or E4 (Nextstellis). E4 is a natural estrogen produced in the fetal liver that has lower potency and a longer half-life than estradiol. Nextstellis is a monophasic 24/4 OC pill that contains E4 14.2 mg and drospirenone 3 mg in each of the 24 hormone-containing pills. Most combined hormonal contraceptives (CHCs) in the United States today contain synthetically made ethinyl estradiol (EE) due to its high potency and oral bioavailability. Outside of the reproductive system, EE upregulates the production of hepatic proteins and alters procoagulant and anticoagulant factors, which results in an overall increase in venous thromboembolic (VTE) risk among CHC users.²

After widespread use of combined oral contraceptives (COCs) started in the 1960s, data emerged regarding increased VTE risk.³ Subsequent research discovered that the type of estrogen used in CHCs directly correlates with the thrombosis risk due to the hepatic upregulation with both first- and second-pass metabolism. Although this risk was reduced as the EE dose decreased below 50 µg and concurrent VTE risk factors were contraindicated, CHC users still faced a 2-fold increase in VTE risk compared with nonusers.^4,5 EE in contraceptive formulations increases VTE risk, likely related to upregulation of procoagulant factors and decreasing anticoagulant proteins.² By contrast, a phase 2 trial of Nextstellis demonstrated more neutral effects of E4/drospirenone on hemostatic parameters compared with EE/levonorgestrel or EE/drospirenone.⁶ Furthermore, E4/drospirenone exhibited lower increases in hepatic proteins, such as angiotensinogen, triglycerides, and sex-hormone binding globulin.⁷ These findings together suggest that this novel CHC pill has a more favorable cardiovascular adverse effect profile compared with currently available CHCs.

The second contraceptive method is a new transdermal patch that contains EE and levonorgestrel (Twirla); this is in contrast to the available EE/norelgestromin contraceptive patch (Xulane). Transdermal contraceptive patches can offer some users easier adherence as compared with a daily OC.⁸ Until this past year, the only transdermal contraceptive available in the United States was Xulane, which contains a daily dose of EE 35 µg and norelgestromin 150 µg. Norelgestromin is eventually metabolized to levonorgestrel derivatives.⁹ Twirla is administered in the same manner as Xulane and contains a daily hormone exposure equivalent to a COC containing EE 30 µg and levonorgestrel 120 µg. Similar to EE/norelgestromin, the EE/levonorgestrel patch also is contraindicated in obese patients (body mass index [BMI] ≥30 kg/m²) due to decreased efficacy and increased risk for VTE. Additionally, phase 3 data demonstrated decreasing efficacy of Twirla in overweight users (BMI ≥25–30 kg/m²), perhaps further limiting the population that may benefit from this contraceptive method.¹⁰ These issues with efficacy and weight likely are related to the fact that levonorgestrel distribution is weight dependent, with evidence of lower plasma levels in obese individuals.^11-13

The third new method is a prescription vaginal contraceptive gel with lactic acid, citric acid, and potassium bitartrate (Phexxi) designed to prevent pregnancy by maintaining an acidic vaginal environment that is inhospitable to sperm. For many decades, vaginal contraceptives, including vaginal spermicidal gels, provided easy access to a nonhormonal and flexible method of moderately effective contraception for many users. Phexxi is a prescription vaginal pH regulator administered as a gel and active for 1 hour after application. All previous vaginal gels sold in the United States are applied similarly, are available over the counter, and include nonoxynol-9, which is a surfactant that damages sperm cell membranes. Recent data from a phase 3 trial demonstrated similar contraceptive effectiveness of Phexxi when compared with available nonoxynol-9 alternatives.¹⁴

Continue to: New OC with the novel estrogen E4 demonstrates good safety profile for VTE...

New OC with the novel estrogen E4 demonstrates good safety profile for VTE

Creinin MD, Westhoff CL, Bouchard C, et al. Estetrol-drospirenone combination oral contraceptive: North American phase 3 efficacy and safety results. Contraception. 2021;104:222-228.

The COC E4/drospirenone was evaluated in 2 parallel multinational studies. Here, we review the North American data that are more relevant for the US population; the European-Russian data also are published.¹⁵

Study examined 1 year’s use of E4/drospirenone

The US–Canadian trial conducted by Creinin and colleagues enrolled 1,864 participants aged 16 to 50 years to evaluate contraceptive efficacy, bleeding patterns, and adverse events with 1-year use (13 cycles) of E4/drospirenone. The primary efficacy group included 1,524 women aged 16 to 35. This study enrolled healthy, heterosexually active participants with a BMI ≤35 kg/m² and regular menses from 70 sites in the United States and 7 sites in Canada. The dropout rate was 45%, comparable to that in other contraceptive studies. Participants used E4/drospirenone cyclically, taking 1 hormone-containing pill daily for 24 days followed by 4 days of placebo pills.

Contraceptive efficacious, no VTE observed

The researchers reported efficacy as a Pearl Index (PI) of 2.65 pregnancies per 100 woman-years in participants aged 16 to 35 and an overall 13-cycle life-table pregnancy rate of 2.06%. The PI did not differ among nonobese and obese participants in multivariable analysis. Most users experienced scheduled withdrawal bleeding; only 13% to 18% reported absence of scheduled bleeding. Unscheduled bleeding was typically spotting (55.2%), and this decreased with treatment duration from 30% in cycle 1 to 15% to 20% in cycle 5 and on.

Overall, 28.9% of participants reported treatment-related adverse events (AEs), which most commonly were headache (5.0%), metrorrhagia (4.6%), and nausea (3.8%). Investigators reported a minimal change in mean (SD) BMI of 0.4 (1.7) kg/m² from baseline after 1 year of E4/drospirenone use, and only 0.5% of participants discontinued use due to weight gain. The most common reasons for AE-related treatment discontinuation included metrorrhagia (0.9%), menorrhagia (0.8%), and vaginal hemorrhage (0.5%). Importantly, no cases of VTE occurred in this study of estetrol despite 23% of participants being obese, a known risk factor for VTE.

Continue to: Efficacy of a new EE/levonorgestrel transdermal patch may be lower in overweight, obese women...

Efficacy of a new EE/levonorgestrel transdermal patch may be lower in overweight, obese women

Nelson AL, Kaunitz AM, Kroll R; SECURE Investigators. Efficacy, safety, and tolerability of a levonorgestrel/ethinyl estradiol transdermal delivery system: phase 3 clinical trial results. Contraception. 2021;103:137-143.

To assess the contraceptive efficacy, tolerability, and safety of the transdermal patch Twirla (EE/levonorgestrel) over 1 year of treatment (13 cycles), Nelson and colleagues conducted an open-label, multicenter, US-based phase 3 trial of participants aged 18 years and older with regular cycles. There were no restrictions based on BMI. On average, the study population was overweight, with a mean BMI of 28.3 kg/m² , and 35% of the population was considered obese (BMI ≥30 kg/m²).

Study design

A total of 2,032 participants enrolled in the study, with separate populations defined for specific analysis on safety, contraceptive efficacy, and cycle control. The primary efficacy group included 1,736 participants. Fifty-one percent discontinued the study, most commonly due to “women’s decision” (15%) and lost to follow-up (11%). Users received bleeding diaries and returned periodically throughout the study for evaluation for efficacy, adherence, and adverse events.

Efficacy associated with BMI

The study results demonstrated an overall PI of 5.8 pregnancies per 100 woman-years for users aged younger than 35. TABLE 2 demonstrates the overall trend of efficacy in relation to BMI.^10,15-19 Participants with a higher BMI were found to have a higher PI, revealing lower contraceptive efficacy in more overweight and obese patients. The overall cumulative pregnancy rate over 13 cycles was 5.3%

Participants reported decreasing frequency of bleeding/spotting days over the treatment duration of 13 cycles, from a mean (SD) of 6.2 (4.5) days in cycle 1 to 4.9 (3.5) days in cycle 13. Unscheduled bleeding episodes remained high throughout the study period. Initially, 60% of users reported 1 or more days of unscheduled bleeding in cycle 1, and 42% still reported unscheduled bleeding in cycle 13. In light of this, only 45 participants (2.2%) discontinued the study due to bleeding issues, suggesting perhaps that the bleeding was light. Overall, users experienced acceptable wearability of the patch, and the rate of detachment decreased over the study period from 9.9% in cycle 1 to 2.4% in cycle 13. There were also low rates (0.5%) of moderate to severe irritation. Itching at the adhesion site decreased slightly from 13.1% in cycle 2 to 9.6% in cycle 13.

In general, 27.2% of patch users experienced a study-related AE, most reported as mild to moderate. Nausea (4.1%) and headaches (3.6%) were the most common hormone-related AE. Importantly, 4 obese users experienced 5 VTEs (deep vein thrombosis, n = 2; pulmonary embolism, n = 3) between cycle 5 and 13. Three of these users had additional VTE risk factors, such as air travel and a family history of clots. No users who were of normal weight or overweight experienced VTE.

Continue to: Novel vaginal pH buffering spermicide is a new Rx-only option...

Novel vaginal pH buffering spermicide is a new Rx-only option

Thomas MA, Chappell BT, Maximos B, et al. A novel vaginal pH regulator: results from the phase 3 AMPOWER contraception clinical trial. Contracept X. 2020;2:100031.

In an open-label phase 3 study, Thomas and colleagues enrolled 1,384 participants aged 18 to 35 with regular cycles at 112 sites in the United States to assess the contraceptive efficacy, safety, and acceptability of Phexxi vaginal gel (lactic acid, citric acid, and potassium bitartrate) over 7 cycles (6 months). Participants were required to have at least 3 episodes of heterosexual vaginal intercourse per cycle and return throughout the treatment duration for study visits. Fifty-three percent of participants did not complete the study, most frequently due to loss to follow-up (18.1%) and participant withdrawal (12.3%). Most participants were White (69%) and had an average (SD) age of 27.7 (4.5) years.

Efficacy and AE rates

The investigators reported a cumulative pregnancy rate of 13.7% over 7 cycles (6 months). In this study, 45.2% of women experienced 1 AE, and most were noted to be mild (23.9%) to moderate (18.7%). The most reported AE was vulvovaginal burning (20.0%), followed by vulvovaginal pruritus (11.2%), urinary tract infection (5.7%), and vulvovaginal pain (3.8%). Less than 2% of participants discontinued the study due to an AE. Burning and itching decreased with time and with decreased frequency of use. When used twice per day compared with once per day, burning rates decreased from 4.6% to 2.1%, and itching rates decreased from 1.0% to 0.7%. Serious AEs were uncommon, occurring in 1.3% of users; only 1, cystitis, was noted to be “probably” related to the treatment. ●

A new contraceptive method should ideally provide improved access or a higher quality and safety option. Although unintended pregnancy rates in the United States are decreasing, significant disparities across race and socioeconomic status remain,¹ and these disparities actually doubled from 1994 to 2011 even though the overall unintended pregnancy rate decreased.^1-3 Specifically, people of color, those with lower income, and people with lower education levels had higher rates of unintended pregnancies than did White people with higher education and income, suggesting disparate access to contraception services.¹ Thus, as new contraceptive methods are introduced, we must assess if they have the potential to address this disparity as well as continue to provide higher quality and safer options.

In this Update, we critically review the phase 3 data on efficacy and safety for 3 new methods that were introduced to the US market over the past year to evaluate their impact on the current contraceptive landscape.

The first method, newly approved by the US Food and Drug Administration (FDA), is a combined oral contraceptive (OC) that contains a novel endogenous estrogen, estetrol, or E4 (Nextstellis). E4 is a natural estrogen produced in the fetal liver that has lower potency and a longer half-life than estradiol. Nextstellis is a monophasic 24/4 OC pill that contains E4 14.2 mg and drospirenone 3 mg in each of the 24 hormone-containing pills. Most combined hormonal contraceptives (CHCs) in the United States today contain synthetically made ethinyl estradiol (EE) due to its high potency and oral bioavailability. Outside of the reproductive system, EE upregulates the production of hepatic proteins and alters procoagulant and anticoagulant factors, which results in an overall increase in venous thromboembolic (VTE) risk among CHC users.²

After widespread use of combined oral contraceptives (COCs) started in the 1960s, data emerged regarding increased VTE risk.³ Subsequent research discovered that the type of estrogen used in CHCs directly correlates with the thrombosis risk due to the hepatic upregulation with both first- and second-pass metabolism. Although this risk was reduced as the EE dose decreased below 50 µg and concurrent VTE risk factors were contraindicated, CHC users still faced a 2-fold increase in VTE risk compared with nonusers.^4,5 EE in contraceptive formulations increases VTE risk, likely related to upregulation of procoagulant factors and decreasing anticoagulant proteins.² By contrast, a phase 2 trial of Nextstellis demonstrated more neutral effects of E4/drospirenone on hemostatic parameters compared with EE/levonorgestrel or EE/drospirenone.⁶ Furthermore, E4/drospirenone exhibited lower increases in hepatic proteins, such as angiotensinogen, triglycerides, and sex-hormone binding globulin.⁷ These findings together suggest that this novel CHC pill has a more favorable cardiovascular adverse effect profile compared with currently available CHCs.

The second contraceptive method is a new transdermal patch that contains EE and levonorgestrel (Twirla); this is in contrast to the available EE/norelgestromin contraceptive patch (Xulane). Transdermal contraceptive patches can offer some users easier adherence as compared with a daily OC.⁸ Until this past year, the only transdermal contraceptive available in the United States was Xulane, which contains a daily dose of EE 35 µg and norelgestromin 150 µg. Norelgestromin is eventually metabolized to levonorgestrel derivatives.⁹ Twirla is administered in the same manner as Xulane and contains a daily hormone exposure equivalent to a COC containing EE 30 µg and levonorgestrel 120 µg. Similar to EE/norelgestromin, the EE/levonorgestrel patch also is contraindicated in obese patients (body mass index [BMI] ≥30 kg/m²) due to decreased efficacy and increased risk for VTE. Additionally, phase 3 data demonstrated decreasing efficacy of Twirla in overweight users (BMI ≥25–30 kg/m²), perhaps further limiting the population that may benefit from this contraceptive method.¹⁰ These issues with efficacy and weight likely are related to the fact that levonorgestrel distribution is weight dependent, with evidence of lower plasma levels in obese individuals.^11-13

The third new method is a prescription vaginal contraceptive gel with lactic acid, citric acid, and potassium bitartrate (Phexxi) designed to prevent pregnancy by maintaining an acidic vaginal environment that is inhospitable to sperm. For many decades, vaginal contraceptives, including vaginal spermicidal gels, provided easy access to a nonhormonal and flexible method of moderately effective contraception for many users. Phexxi is a prescription vaginal pH regulator administered as a gel and active for 1 hour after application. All previous vaginal gels sold in the United States are applied similarly, are available over the counter, and include nonoxynol-9, which is a surfactant that damages sperm cell membranes. Recent data from a phase 3 trial demonstrated similar contraceptive effectiveness of Phexxi when compared with available nonoxynol-9 alternatives.¹⁴

Continue to: New OC with the novel estrogen E4 demonstrates good safety profile for VTE...

New OC with the novel estrogen E4 demonstrates good safety profile for VTE

Creinin MD, Westhoff CL, Bouchard C, et al. Estetrol-drospirenone combination oral contraceptive: North American phase 3 efficacy and safety results. Contraception. 2021;104:222-228.

The COC E4/drospirenone was evaluated in 2 parallel multinational studies. Here, we review the North American data that are more relevant for the US population; the European-Russian data also are published.¹⁵

Study examined 1 year’s use of E4/drospirenone

The US–Canadian trial conducted by Creinin and colleagues enrolled 1,864 participants aged 16 to 50 years to evaluate contraceptive efficacy, bleeding patterns, and adverse events with 1-year use (13 cycles) of E4/drospirenone. The primary efficacy group included 1,524 women aged 16 to 35. This study enrolled healthy, heterosexually active participants with a BMI ≤35 kg/m² and regular menses from 70 sites in the United States and 7 sites in Canada. The dropout rate was 45%, comparable to that in other contraceptive studies. Participants used E4/drospirenone cyclically, taking 1 hormone-containing pill daily for 24 days followed by 4 days of placebo pills.

Contraceptive efficacious, no VTE observed

The researchers reported efficacy as a Pearl Index (PI) of 2.65 pregnancies per 100 woman-years in participants aged 16 to 35 and an overall 13-cycle life-table pregnancy rate of 2.06%. The PI did not differ among nonobese and obese participants in multivariable analysis. Most users experienced scheduled withdrawal bleeding; only 13% to 18% reported absence of scheduled bleeding. Unscheduled bleeding was typically spotting (55.2%), and this decreased with treatment duration from 30% in cycle 1 to 15% to 20% in cycle 5 and on.

Overall, 28.9% of participants reported treatment-related adverse events (AEs), which most commonly were headache (5.0%), metrorrhagia (4.6%), and nausea (3.8%). Investigators reported a minimal change in mean (SD) BMI of 0.4 (1.7) kg/m² from baseline after 1 year of E4/drospirenone use, and only 0.5% of participants discontinued use due to weight gain. The most common reasons for AE-related treatment discontinuation included metrorrhagia (0.9%), menorrhagia (0.8%), and vaginal hemorrhage (0.5%). Importantly, no cases of VTE occurred in this study of estetrol despite 23% of participants being obese, a known risk factor for VTE.

Continue to: Efficacy of a new EE/levonorgestrel transdermal patch may be lower in overweight, obese women...

Efficacy of a new EE/levonorgestrel transdermal patch may be lower in overweight, obese women

Nelson AL, Kaunitz AM, Kroll R; SECURE Investigators. Efficacy, safety, and tolerability of a levonorgestrel/ethinyl estradiol transdermal delivery system: phase 3 clinical trial results. Contraception. 2021;103:137-143.

To assess the contraceptive efficacy, tolerability, and safety of the transdermal patch Twirla (EE/levonorgestrel) over 1 year of treatment (13 cycles), Nelson and colleagues conducted an open-label, multicenter, US-based phase 3 trial of participants aged 18 years and older with regular cycles. There were no restrictions based on BMI. On average, the study population was overweight, with a mean BMI of 28.3 kg/m² , and 35% of the population was considered obese (BMI ≥30 kg/m²).

Study design

A total of 2,032 participants enrolled in the study, with separate populations defined for specific analysis on safety, contraceptive efficacy, and cycle control. The primary efficacy group included 1,736 participants. Fifty-one percent discontinued the study, most commonly due to “women’s decision” (15%) and lost to follow-up (11%). Users received bleeding diaries and returned periodically throughout the study for evaluation for efficacy, adherence, and adverse events.

Efficacy associated with BMI

The study results demonstrated an overall PI of 5.8 pregnancies per 100 woman-years for users aged younger than 35. TABLE 2 demonstrates the overall trend of efficacy in relation to BMI.^10,15-19 Participants with a higher BMI were found to have a higher PI, revealing lower contraceptive efficacy in more overweight and obese patients. The overall cumulative pregnancy rate over 13 cycles was 5.3%

Participants reported decreasing frequency of bleeding/spotting days over the treatment duration of 13 cycles, from a mean (SD) of 6.2 (4.5) days in cycle 1 to 4.9 (3.5) days in cycle 13. Unscheduled bleeding episodes remained high throughout the study period. Initially, 60% of users reported 1 or more days of unscheduled bleeding in cycle 1, and 42% still reported unscheduled bleeding in cycle 13. In light of this, only 45 participants (2.2%) discontinued the study due to bleeding issues, suggesting perhaps that the bleeding was light. Overall, users experienced acceptable wearability of the patch, and the rate of detachment decreased over the study period from 9.9% in cycle 1 to 2.4% in cycle 13. There were also low rates (0.5%) of moderate to severe irritation. Itching at the adhesion site decreased slightly from 13.1% in cycle 2 to 9.6% in cycle 13.

In general, 27.2% of patch users experienced a study-related AE, most reported as mild to moderate. Nausea (4.1%) and headaches (3.6%) were the most common hormone-related AE. Importantly, 4 obese users experienced 5 VTEs (deep vein thrombosis, n = 2; pulmonary embolism, n = 3) between cycle 5 and 13. Three of these users had additional VTE risk factors, such as air travel and a family history of clots. No users who were of normal weight or overweight experienced VTE.

Continue to: Novel vaginal pH buffering spermicide is a new Rx-only option...

Novel vaginal pH buffering spermicide is a new Rx-only option

Thomas MA, Chappell BT, Maximos B, et al. A novel vaginal pH regulator: results from the phase 3 AMPOWER contraception clinical trial. Contracept X. 2020;2:100031.

In an open-label phase 3 study, Thomas and colleagues enrolled 1,384 participants aged 18 to 35 with regular cycles at 112 sites in the United States to assess the contraceptive efficacy, safety, and acceptability of Phexxi vaginal gel (lactic acid, citric acid, and potassium bitartrate) over 7 cycles (6 months). Participants were required to have at least 3 episodes of heterosexual vaginal intercourse per cycle and return throughout the treatment duration for study visits. Fifty-three percent of participants did not complete the study, most frequently due to loss to follow-up (18.1%) and participant withdrawal (12.3%). Most participants were White (69%) and had an average (SD) age of 27.7 (4.5) years.

Efficacy and AE rates

The investigators reported a cumulative pregnancy rate of 13.7% over 7 cycles (6 months). In this study, 45.2% of women experienced 1 AE, and most were noted to be mild (23.9%) to moderate (18.7%). The most reported AE was vulvovaginal burning (20.0%), followed by vulvovaginal pruritus (11.2%), urinary tract infection (5.7%), and vulvovaginal pain (3.8%). Less than 2% of participants discontinued the study due to an AE. Burning and itching decreased with time and with decreased frequency of use. When used twice per day compared with once per day, burning rates decreased from 4.6% to 2.1%, and itching rates decreased from 1.0% to 0.7%. Serious AEs were uncommon, occurring in 1.3% of users; only 1, cystitis, was noted to be “probably” related to the treatment. ●

A vaginal ring that can be reused for up to 1 year and a progestin-only pill (POP) with a wider window for missed pills are 2 of the novel contraceptive products introduced to the market this year. In addition, an ongoing study of the levonorgestrel 52-mg intrauterine system (IUS) continues to provide evidence on its extended duration of use, now approved through 6 years.

The segesterone acetate (SA) and ethinyl estradiol (EE) vaginal ring (Annovera) is new among contraceptive options. Segesterone acetate is a novel progestin that can be used only via nonoral routes; it binds specifically to progesterone receptors without estrogenic or antiandrogen effects.¹ Unlike the etonogestrel and ethinyl estradiol ring (NuvaRing; for which generic products became available this past year), which is used for 1 cycle and then thrown away, the SA/EE ring is effective for 13 consecutive cycles. It does not require refrigeration when not in use.² Because a single ring can be used for 13 cycles, users in locations without laws that mandate a 12-month supply of pills, patches, and rings need less frequent visits to the pharmacy or clinic.

Progestin-only contraceptive pills are an important option for patients who desire hormonal contraception and have contraindications to estrogen, such as migraines with aura, cardiovascular risk factors, and being in the early postpartum period.³ In the United States, current POPs contain norethindrone, which has a 3-hour window for missed pills⁴; a desogestrel-only pill available outside the United States has a 12-hour window.⁵ Both are provided as a 28-day pill pack for continuous use, and both result in undesirable bleeding patterns in some users.

The prolonged half-life of drospirenone, another progestin, gives it the potential to increase reliability in the setting of missed or delayed pills and improve bleeding patterns. A new POP contraceptive contains drospirenone (Slynd) and is available in a 28-day pack with a 24-day supply of hormone and a 4-day supply of placebo; it provides a window for missed pill use similar to that for combined hormonal contraception (CHC) as well as a placebo period for a timed withdrawal bleed.^6,7

Liletta is a well-known levonorgestrel 52-mg IUS that was first approved by the US Food and Drug Administration (FDA) in 2015. An ongoing clinical trial has been the basis for approval of this IUS for use in increasing durations, from 3 years initially to 4 and then 5 years. The newest data indicate efficacy up to 6 years.⁸

Continue to: Combined hormonal vaginal system provides a year's contraception with an acceptable safety profile...

Combined hormonal vaginal system provides a year's contraception with an acceptable safety profile 

Archer DF, Merkatz RB, Bahamondes L, et al. Efficacy of the 1-year (13-cycle) segesterone acetate and ethinylestradiol contraceptive vaginal system: results of two multicentre, open-label, single-arm, phase 3 trials. Lancet Glob Health. 2019;7:e1054-e1064. 

Gemzell-Danielsson K, Sitruk-Ware R, Creinin MD, et al. Segesterone acetate/ethinyl estradiol 12-month contraceptive vaginal system safety evaluation. Contraception. 2019;99:323-328. 

Archer and colleagues reported the results of 2 pivotal multicenter, open-label, phase 3 trials, which included 2,265 users, conducted to evaluate efficacy and return to menses or pregnancy after use of the 1-year (13 cycles) SA/EE contraceptive vaginal system (CVS). 

Details of the efficacy study 

The study included 1,130 women in a US-only study and 1,135 women in an international study with sites in the United States, Australia, Brazil, Chile, Dominican Republic, Finland, Hungary, and Sweden. Participants used the CVS for 21 days followed by a 7-day use-free interval for up to 13 consecutive cycles; they were instructed not to remove the CVS for more than 2 hours during the 21 days of use. 

Primary and secondary efficacy outcomes were calculated using the Pearl Index and an intention-to-treat Kaplan-Meier life table, respectively. At the end of the study, users who desired not to continue hormonal contraception or to become pregnant were followed up for 6 months to evaluate return to menses or pregnancy. 

Year-long effectiveness 

The investigators reported an overall Pearl index of 2.98 (95% confidence interval [CI], 2.13-4.06) and a Kaplan-Meier life table cumulative efficacy rate of 97.5% (FIGURE 1), consistent with other recently approved CHC methods. Women from non-European sites, who primarily were US participants, had a Pearl Index of 3.25 (95% CI, 2.35-4.37), and participants from the European sites had a Pearl Index of 0.47 (95% CI, 0.03-2.07). Importantly, CVS removal had a significant impact on efficacy, with a Pearl Index of 5.98 (95% CI, 2.46-9.27) in users reporting CVS removals for longer than 2 hours, suggesting escape ovulation with improper use. The Pearl Index was highest in users aged 18 to 19 years and was not affected by body mass index (BMI), although 91% of users had a BMI of 29.0 kg/m² or lower. 

There was no trend for a change in pregnancy risk across 13 cycles, providing evidence of CVS efficacy throughout a full year's use. The follow-up portion of the study included 290 users who were not continuing hormonal contraception at study end; all follow-up participants reported return to menses after method discontinuation. 

Clinical safety data 

To evaluate safety outcomes from clinical studies on the CVS containing SA/EE, Gemzell-Danielsson and colleagues analyzed 9 studies. Most of the data were derived from 2 phase 3, multicenter trials (as discussed above), with supporting evidence from 7 other studies. 

Adverse events reported 

Among 2,308 CVS users in the phase 3 trials, 87% reported at least 1 adverse effect, with most of mild or moderate severity. These included headache, 26%; nausea, 18%; vaginal discharge, 10%; and metrorrhagia, 7%. Overall, 12% of CVS users discontinued use due to an adverse effect. Two percent of users experienced severe adverse effects, including venous thromboembolism (VTE), allergic reaction, gallbladder disease, and spontaneous abortion. 

In the US-only phase 3 trial, 2 VTE events occurred in the first 6 months in women with baseline BMI greater than 29.0 kg/m²; therefore, enrollment of patients with a BMI greater than 29.0 kg/m² was halted and current users meeting that criteria were discontinued. Notably, no cases of VTE occurred in studies with a segesterone acetate-only CVS; this suggests that risk can be attributed to the estrogen component. Overall, 4 nonfatal VTEs occurred, all among the 1,536 women enrolled in the phase 3 trials (4 of 1,536 [0.3%]); at least 3 of these cases occurred in users with VTE risk factors (TABLE 1). The estimated VTE rate in CVS users with a BMI greater than 29.0 kg/m2 is 10.8/10,000 women-years (95% CI, 8.9-13.1). 

Complete expulsion of the CVS occurred in 7% of cycles and partial expulsion in 19.5% of cycles; users reported expulsion more frequently in the first cycle, most (about 70%) of which were partial expulsions. Of the laboratory values and vital signs studied, including weight, users had no clinically relevant changes from baseline.

Continue to: New drospirenone pill is an effective POP option...

New drospirenone pill is an effective POP option 

Kimble T, Burke AE, Barnhart KT, et al. A 1-year prospective, open-label, single-arm, multicenter, phase 3 trial of the contraceptive efficacy and safety of the oral progestin-only pill drospirenone 4 mg using a 24/4-day regimen. Contracept X. 2020;2:100020. 

Palacios S, Colli E, Regidor PA. Multicenter, phase III trials on the contraceptive efficacy, tolerability and safety of a new drospirenone-only pill. Acta Obstet Gynecol Scand. 2019;98:1549-1557. 

In a prospective, single-arm, multicenter phase 3 trial in the United States, Kimble and colleagues evaluated the efficacy and safety of an oral drospirenone POP in a cyclic 24-day hormone/4-day placebo regimen. The trial included 1,006 users. No BMI cutoff was used, and about one-third of study participants were obese (BMI >30.0 kg/m²). Women were instructed to take a missed tablet as soon as remembered if within 24 hours or with the next scheduled dose if more than 24 hours late. 

Contraceptive effectiveness 

The Pearl Index for nonbreastfeeding users aged 35 years or younger with pregnancies confirmed by a quantitative serum ß-human chorionic gonadotropin test (915 users) was 2.9 (95% CI, 1.5-5.1). Of note, 2 out of 15 on-treatment pregnancies were excluded from this calculation because of protocol site violations, as were 3 pregnancies that were unconfirmed. In the modified full analysis set of 915 users, 36% were obese (BMI≥30 kg/m²), and the Pearl Index was noted to be unaffected by BMI (TABLE 2). 

While 61% of women reported adverse effects, more than 95% of these were mild or moderate in intensity, including headache, nausea, dysmenorrhea, metrorrhagia, and breast pain. No VTE occurred. The frequency of hyperkalemia was 0.5%, and there was no evidence of hypotension, which is significant due to the antimineralocorticoid activity of drospirenone. All cases of hyperkalemia were considered mild, and all women were asymptomatic. There were no clinically relevant changes in body weight, gynecologic exam, or other laboratory values. 

With increased cycles of use, the number of days with bleeding or spotting generally decreased and amenorrhea increased. However, in cycles 11 to 13, 41.6% of users still had unscheduled bleeding (reduced from 57.0% at cycles 2-4), and 29.0% had scheduled bleeding (decreased from 44% at cycles 2-4) (FIGURE 2). With these bleeding patterns, 86.2% of users agreed or strongly agreed that they were satisfied with the product. 

European multicenter study of drospironene 

In a European investigation, Palacios and colleagues pooled and analyzed data from 2 phase 3 multicenter trials to assess the efficacy, tolerability, and safety of the same drospirenone-only pill (24 days of drospironene 4 mg and 4 days of placebo) in 1,571 users. No BMI cutoff was used, but overall only 71 participants (4.6%) were obese. One study included desogestrel 0.075 mg (in a regimen of 28 active pills) as a comparator for safety. 

The overall Pearl Index for users 35 years or younger (1,251 users) was 1.0 (95% CI, 0.4-2.0). The "method failure Pearl Index" in users 35 years or younger, which included all pregnancies during "perfect medication cycles," was 1.3 (95% CI, 0.5-2.5). 

The most common adverse effects were acne (6.6% in study 1 and 4.4% in study 2), headache (4.5% in study 1), and irregular bleeding (4.4% in study 2). No cases of VTE occurred; there was 1 case of asymptomatic hyperkalemia. Additional laboratory values and vital signs showed no significant changes. The trend in bleeding was similar to that in the US studies, but it is interesting to note that there were significantly lower rates of unscheduled bleeding or spotting in drospirenone users than in desogestrel users (67.9% vs 86.5%, respectively; P<.001).

Continue to: Evidence supports 6 years' use of a levonorgestrel 52-mg IUS...

Westhoff CL, Keder LM, Gangestad A, et al. Six-year contraceptive efficacy and continued safety of a levonorgestrel 52-mg intrauterine system. Contraception. 2020;101:159-161. 

Two levonorgestrel 52-mg IUS products are on the market, both of which were approved for 5 years of use. The ACCESS IUS study (A Comprehensive Contraceptive Efficacy and Safety Study of an IUS) is an ongoing phase 3 trial to assess the safety and efficacy of a levonorgestrel 52-mg IUS (Liletta) for up to 10 years of use in US women. Westhoff and colleagues presented the data used for this IUS to gain approval for 6 years of use as of October 2019. The report included safety information for all users, with use exceeding 8 years in 122 participants. 

In year 6 of the ongoing trial, there were no on-treatment pregnancies with a 6-year life table pregnancy rate of 0.87 (95% CI, 0.44-1.70). Forty percent of users reported amenorrhea in the 90 days preceding the end of year 6, consistent with prior data after 3 years of use (FIGURE 3). The most common adverse effects over 6 or more years of use were bacterial vulvovaginal infections and urinary tract infections. 

Long-term IUS effectiveness 

Overall, in users aged 16 to 35 years, 72% discontinued study participation, most frequently due to an adverse event (19.2%) or to seeking pregnancy (15.5%). Through 6 or more years of use, overall discontinuation rates for expulsion (4.0%) and bleeding symptoms (2.3%) were very low, with 2 expulsions occurring in year 6 and only 1 participant discontinuing in year 6 for a bleeding symptom. These findings are consistent with those found at 5 years of IUS use and are representative of continued efficacy as well as overall low frequency of new significant events with extended use.¹¹

A vaginal ring that can be reused for up to 1 year and a progestin-only pill (POP) with a wider window for missed pills are 2 of the novel contraceptive products introduced to the market this year. In addition, an ongoing study of the levonorgestrel 52-mg intrauterine system (IUS) continues to provide evidence on its extended duration of use, now approved through 6 years.

The segesterone acetate (SA) and ethinyl estradiol (EE) vaginal ring (Annovera) is new among contraceptive options. Segesterone acetate is a novel progestin that can be used only via nonoral routes; it binds specifically to progesterone receptors without estrogenic or antiandrogen effects.¹ Unlike the etonogestrel and ethinyl estradiol ring (NuvaRing; for which generic products became available this past year), which is used for 1 cycle and then thrown away, the SA/EE ring is effective for 13 consecutive cycles. It does not require refrigeration when not in use.² Because a single ring can be used for 13 cycles, users in locations without laws that mandate a 12-month supply of pills, patches, and rings need less frequent visits to the pharmacy or clinic.

Progestin-only contraceptive pills are an important option for patients who desire hormonal contraception and have contraindications to estrogen, such as migraines with aura, cardiovascular risk factors, and being in the early postpartum period.³ In the United States, current POPs contain norethindrone, which has a 3-hour window for missed pills⁴; a desogestrel-only pill available outside the United States has a 12-hour window.⁵ Both are provided as a 28-day pill pack for continuous use, and both result in undesirable bleeding patterns in some users.

The prolonged half-life of drospirenone, another progestin, gives it the potential to increase reliability in the setting of missed or delayed pills and improve bleeding patterns. A new POP contraceptive contains drospirenone (Slynd) and is available in a 28-day pack with a 24-day supply of hormone and a 4-day supply of placebo; it provides a window for missed pill use similar to that for combined hormonal contraception (CHC) as well as a placebo period for a timed withdrawal bleed.^6,7

Liletta is a well-known levonorgestrel 52-mg IUS that was first approved by the US Food and Drug Administration (FDA) in 2015. An ongoing clinical trial has been the basis for approval of this IUS for use in increasing durations, from 3 years initially to 4 and then 5 years. The newest data indicate efficacy up to 6 years.⁸

Continue to: Combined hormonal vaginal system provides a year's contraception with an acceptable safety profile...

Combined hormonal vaginal system provides a year's contraception with an acceptable safety profile 

Archer DF, Merkatz RB, Bahamondes L, et al. Efficacy of the 1-year (13-cycle) segesterone acetate and ethinylestradiol contraceptive vaginal system: results of two multicentre, open-label, single-arm, phase 3 trials. Lancet Glob Health. 2019;7:e1054-e1064. 

Gemzell-Danielsson K, Sitruk-Ware R, Creinin MD, et al. Segesterone acetate/ethinyl estradiol 12-month contraceptive vaginal system safety evaluation. Contraception. 2019;99:323-328. 

Archer and colleagues reported the results of 2 pivotal multicenter, open-label, phase 3 trials, which included 2,265 users, conducted to evaluate efficacy and return to menses or pregnancy after use of the 1-year (13 cycles) SA/EE contraceptive vaginal system (CVS). 

Details of the efficacy study 

The study included 1,130 women in a US-only study and 1,135 women in an international study with sites in the United States, Australia, Brazil, Chile, Dominican Republic, Finland, Hungary, and Sweden. Participants used the CVS for 21 days followed by a 7-day use-free interval for up to 13 consecutive cycles; they were instructed not to remove the CVS for more than 2 hours during the 21 days of use. 

Primary and secondary efficacy outcomes were calculated using the Pearl Index and an intention-to-treat Kaplan-Meier life table, respectively. At the end of the study, users who desired not to continue hormonal contraception or to become pregnant were followed up for 6 months to evaluate return to menses or pregnancy. 

Year-long effectiveness 

The investigators reported an overall Pearl index of 2.98 (95% confidence interval [CI], 2.13-4.06) and a Kaplan-Meier life table cumulative efficacy rate of 97.5% (FIGURE 1), consistent with other recently approved CHC methods. Women from non-European sites, who primarily were US participants, had a Pearl Index of 3.25 (95% CI, 2.35-4.37), and participants from the European sites had a Pearl Index of 0.47 (95% CI, 0.03-2.07). Importantly, CVS removal had a significant impact on efficacy, with a Pearl Index of 5.98 (95% CI, 2.46-9.27) in users reporting CVS removals for longer than 2 hours, suggesting escape ovulation with improper use. The Pearl Index was highest in users aged 18 to 19 years and was not affected by body mass index (BMI), although 91% of users had a BMI of 29.0 kg/m² or lower. 

There was no trend for a change in pregnancy risk across 13 cycles, providing evidence of CVS efficacy throughout a full year's use. The follow-up portion of the study included 290 users who were not continuing hormonal contraception at study end; all follow-up participants reported return to menses after method discontinuation. 

Clinical safety data 

To evaluate safety outcomes from clinical studies on the CVS containing SA/EE, Gemzell-Danielsson and colleagues analyzed 9 studies. Most of the data were derived from 2 phase 3, multicenter trials (as discussed above), with supporting evidence from 7 other studies. 

Adverse events reported 

Among 2,308 CVS users in the phase 3 trials, 87% reported at least 1 adverse effect, with most of mild or moderate severity. These included headache, 26%; nausea, 18%; vaginal discharge, 10%; and metrorrhagia, 7%. Overall, 12% of CVS users discontinued use due to an adverse effect. Two percent of users experienced severe adverse effects, including venous thromboembolism (VTE), allergic reaction, gallbladder disease, and spontaneous abortion. 

In the US-only phase 3 trial, 2 VTE events occurred in the first 6 months in women with baseline BMI greater than 29.0 kg/m²; therefore, enrollment of patients with a BMI greater than 29.0 kg/m² was halted and current users meeting that criteria were discontinued. Notably, no cases of VTE occurred in studies with a segesterone acetate-only CVS; this suggests that risk can be attributed to the estrogen component. Overall, 4 nonfatal VTEs occurred, all among the 1,536 women enrolled in the phase 3 trials (4 of 1,536 [0.3%]); at least 3 of these cases occurred in users with VTE risk factors (TABLE 1). The estimated VTE rate in CVS users with a BMI greater than 29.0 kg/m2 is 10.8/10,000 women-years (95% CI, 8.9-13.1). 

Complete expulsion of the CVS occurred in 7% of cycles and partial expulsion in 19.5% of cycles; users reported expulsion more frequently in the first cycle, most (about 70%) of which were partial expulsions. Of the laboratory values and vital signs studied, including weight, users had no clinically relevant changes from baseline.

Continue to: New drospirenone pill is an effective POP option...

New drospirenone pill is an effective POP option 

Kimble T, Burke AE, Barnhart KT, et al. A 1-year prospective, open-label, single-arm, multicenter, phase 3 trial of the contraceptive efficacy and safety of the oral progestin-only pill drospirenone 4 mg using a 24/4-day regimen. Contracept X. 2020;2:100020. 

Palacios S, Colli E, Regidor PA. Multicenter, phase III trials on the contraceptive efficacy, tolerability and safety of a new drospirenone-only pill. Acta Obstet Gynecol Scand. 2019;98:1549-1557. 

In a prospective, single-arm, multicenter phase 3 trial in the United States, Kimble and colleagues evaluated the efficacy and safety of an oral drospirenone POP in a cyclic 24-day hormone/4-day placebo regimen. The trial included 1,006 users. No BMI cutoff was used, and about one-third of study participants were obese (BMI >30.0 kg/m²). Women were instructed to take a missed tablet as soon as remembered if within 24 hours or with the next scheduled dose if more than 24 hours late. 

Contraceptive effectiveness 

The Pearl Index for nonbreastfeeding users aged 35 years or younger with pregnancies confirmed by a quantitative serum ß-human chorionic gonadotropin test (915 users) was 2.9 (95% CI, 1.5-5.1). Of note, 2 out of 15 on-treatment pregnancies were excluded from this calculation because of protocol site violations, as were 3 pregnancies that were unconfirmed. In the modified full analysis set of 915 users, 36% were obese (BMI≥30 kg/m²), and the Pearl Index was noted to be unaffected by BMI (TABLE 2). 

While 61% of women reported adverse effects, more than 95% of these were mild or moderate in intensity, including headache, nausea, dysmenorrhea, metrorrhagia, and breast pain. No VTE occurred. The frequency of hyperkalemia was 0.5%, and there was no evidence of hypotension, which is significant due to the antimineralocorticoid activity of drospirenone. All cases of hyperkalemia were considered mild, and all women were asymptomatic. There were no clinically relevant changes in body weight, gynecologic exam, or other laboratory values. 

With increased cycles of use, the number of days with bleeding or spotting generally decreased and amenorrhea increased. However, in cycles 11 to 13, 41.6% of users still had unscheduled bleeding (reduced from 57.0% at cycles 2-4), and 29.0% had scheduled bleeding (decreased from 44% at cycles 2-4) (FIGURE 2). With these bleeding patterns, 86.2% of users agreed or strongly agreed that they were satisfied with the product. 

European multicenter study of drospironene 

In a European investigation, Palacios and colleagues pooled and analyzed data from 2 phase 3 multicenter trials to assess the efficacy, tolerability, and safety of the same drospirenone-only pill (24 days of drospironene 4 mg and 4 days of placebo) in 1,571 users. No BMI cutoff was used, but overall only 71 participants (4.6%) were obese. One study included desogestrel 0.075 mg (in a regimen of 28 active pills) as a comparator for safety. 

The overall Pearl Index for users 35 years or younger (1,251 users) was 1.0 (95% CI, 0.4-2.0). The "method failure Pearl Index" in users 35 years or younger, which included all pregnancies during "perfect medication cycles," was 1.3 (95% CI, 0.5-2.5). 

The most common adverse effects were acne (6.6% in study 1 and 4.4% in study 2), headache (4.5% in study 1), and irregular bleeding (4.4% in study 2). No cases of VTE occurred; there was 1 case of asymptomatic hyperkalemia. Additional laboratory values and vital signs showed no significant changes. The trend in bleeding was similar to that in the US studies, but it is interesting to note that there were significantly lower rates of unscheduled bleeding or spotting in drospirenone users than in desogestrel users (67.9% vs 86.5%, respectively; P<.001).

Continue to: Evidence supports 6 years' use of a levonorgestrel 52-mg IUS...

Westhoff CL, Keder LM, Gangestad A, et al. Six-year contraceptive efficacy and continued safety of a levonorgestrel 52-mg intrauterine system. Contraception. 2020;101:159-161. 

Two levonorgestrel 52-mg IUS products are on the market, both of which were approved for 5 years of use. The ACCESS IUS study (A Comprehensive Contraceptive Efficacy and Safety Study of an IUS) is an ongoing phase 3 trial to assess the safety and efficacy of a levonorgestrel 52-mg IUS (Liletta) for up to 10 years of use in US women. Westhoff and colleagues presented the data used for this IUS to gain approval for 6 years of use as of October 2019. The report included safety information for all users, with use exceeding 8 years in 122 participants. 

In year 6 of the ongoing trial, there were no on-treatment pregnancies with a 6-year life table pregnancy rate of 0.87 (95% CI, 0.44-1.70). Forty percent of users reported amenorrhea in the 90 days preceding the end of year 6, consistent with prior data after 3 years of use (FIGURE 3). The most common adverse effects over 6 or more years of use were bacterial vulvovaginal infections and urinary tract infections. 

Long-term IUS effectiveness 

Overall, in users aged 16 to 35 years, 72% discontinued study participation, most frequently due to an adverse event (19.2%) or to seeking pregnancy (15.5%). Through 6 or more years of use, overall discontinuation rates for expulsion (4.0%) and bleeding symptoms (2.3%) were very low, with 2 expulsions occurring in year 6 and only 1 participant discontinuing in year 6 for a bleeding symptom. These findings are consistent with those found at 5 years of IUS use and are representative of continued efficacy as well as overall low frequency of new significant events with extended use.¹¹

A vaginal ring that can be reused for up to 1 year and a progestin-only pill (POP) with a wider window for missed pills are 2 of the novel contraceptive products introduced to the market this year. In addition, an ongoing study of the levonorgestrel 52-mg intrauterine system (IUS) continues to provide evidence on its extended duration of use, now approved through 6 years.

The segesterone acetate (SA) and ethinyl estradiol (EE) vaginal ring (Annovera) is new among contraceptive options. Segesterone acetate is a novel progestin that can be used only via nonoral routes; it binds specifically to progesterone receptors without estrogenic or antiandrogen effects.¹ Unlike the etonogestrel and ethinyl estradiol ring (NuvaRing; for which generic products became available this past year), which is used for 1 cycle and then thrown away, the SA/EE ring is effective for 13 consecutive cycles. It does not require refrigeration when not in use.² Because a single ring can be used for 13 cycles, users in locations without laws that mandate a 12-month supply of pills, patches, and rings need less frequent visits to the pharmacy or clinic.

Progestin-only contraceptive pills are an important option for patients who desire hormonal contraception and have contraindications to estrogen, such as migraines with aura, cardiovascular risk factors, and being in the early postpartum period.³ In the United States, current POPs contain norethindrone, which has a 3-hour window for missed pills⁴; a desogestrel-only pill available outside the United States has a 12-hour window.⁵ Both are provided as a 28-day pill pack for continuous use, and both result in undesirable bleeding patterns in some users.

The prolonged half-life of drospirenone, another progestin, gives it the potential to increase reliability in the setting of missed or delayed pills and improve bleeding patterns. A new POP contraceptive contains drospirenone (Slynd) and is available in a 28-day pack with a 24-day supply of hormone and a 4-day supply of placebo; it provides a window for missed pill use similar to that for combined hormonal contraception (CHC) as well as a placebo period for a timed withdrawal bleed.^6,7

Liletta is a well-known levonorgestrel 52-mg IUS that was first approved by the US Food and Drug Administration (FDA) in 2015. An ongoing clinical trial has been the basis for approval of this IUS for use in increasing durations, from 3 years initially to 4 and then 5 years. The newest data indicate efficacy up to 6 years.⁸

Continue to: Combined hormonal vaginal system provides a year's contraception with an acceptable safety profile...

Combined hormonal vaginal system provides a year's contraception with an acceptable safety profile 

Archer DF, Merkatz RB, Bahamondes L, et al. Efficacy of the 1-year (13-cycle) segesterone acetate and ethinylestradiol contraceptive vaginal system: results of two multicentre, open-label, single-arm, phase 3 trials. Lancet Glob Health. 2019;7:e1054-e1064. 

Gemzell-Danielsson K, Sitruk-Ware R, Creinin MD, et al. Segesterone acetate/ethinyl estradiol 12-month contraceptive vaginal system safety evaluation. Contraception. 2019;99:323-328. 

Archer and colleagues reported the results of 2 pivotal multicenter, open-label, phase 3 trials, which included 2,265 users, conducted to evaluate efficacy and return to menses or pregnancy after use of the 1-year (13 cycles) SA/EE contraceptive vaginal system (CVS). 

Details of the efficacy study 

The study included 1,130 women in a US-only study and 1,135 women in an international study with sites in the United States, Australia, Brazil, Chile, Dominican Republic, Finland, Hungary, and Sweden. Participants used the CVS for 21 days followed by a 7-day use-free interval for up to 13 consecutive cycles; they were instructed not to remove the CVS for more than 2 hours during the 21 days of use. 

Primary and secondary efficacy outcomes were calculated using the Pearl Index and an intention-to-treat Kaplan-Meier life table, respectively. At the end of the study, users who desired not to continue hormonal contraception or to become pregnant were followed up for 6 months to evaluate return to menses or pregnancy. 

Year-long effectiveness 

The investigators reported an overall Pearl index of 2.98 (95% confidence interval [CI], 2.13-4.06) and a Kaplan-Meier life table cumulative efficacy rate of 97.5% (FIGURE 1), consistent with other recently approved CHC methods. Women from non-European sites, who primarily were US participants, had a Pearl Index of 3.25 (95% CI, 2.35-4.37), and participants from the European sites had a Pearl Index of 0.47 (95% CI, 0.03-2.07). Importantly, CVS removal had a significant impact on efficacy, with a Pearl Index of 5.98 (95% CI, 2.46-9.27) in users reporting CVS removals for longer than 2 hours, suggesting escape ovulation with improper use. The Pearl Index was highest in users aged 18 to 19 years and was not affected by body mass index (BMI), although 91% of users had a BMI of 29.0 kg/m² or lower. 

There was no trend for a change in pregnancy risk across 13 cycles, providing evidence of CVS efficacy throughout a full year's use. The follow-up portion of the study included 290 users who were not continuing hormonal contraception at study end; all follow-up participants reported return to menses after method discontinuation. 

Clinical safety data 

To evaluate safety outcomes from clinical studies on the CVS containing SA/EE, Gemzell-Danielsson and colleagues analyzed 9 studies. Most of the data were derived from 2 phase 3, multicenter trials (as discussed above), with supporting evidence from 7 other studies. 

Adverse events reported 

Among 2,308 CVS users in the phase 3 trials, 87% reported at least 1 adverse effect, with most of mild or moderate severity. These included headache, 26%; nausea, 18%; vaginal discharge, 10%; and metrorrhagia, 7%. Overall, 12% of CVS users discontinued use due to an adverse effect. Two percent of users experienced severe adverse effects, including venous thromboembolism (VTE), allergic reaction, gallbladder disease, and spontaneous abortion. 

In the US-only phase 3 trial, 2 VTE events occurred in the first 6 months in women with baseline BMI greater than 29.0 kg/m²; therefore, enrollment of patients with a BMI greater than 29.0 kg/m² was halted and current users meeting that criteria were discontinued. Notably, no cases of VTE occurred in studies with a segesterone acetate-only CVS; this suggests that risk can be attributed to the estrogen component. Overall, 4 nonfatal VTEs occurred, all among the 1,536 women enrolled in the phase 3 trials (4 of 1,536 [0.3%]); at least 3 of these cases occurred in users with VTE risk factors (TABLE 1). The estimated VTE rate in CVS users with a BMI greater than 29.0 kg/m2 is 10.8/10,000 women-years (95% CI, 8.9-13.1). 

Complete expulsion of the CVS occurred in 7% of cycles and partial expulsion in 19.5% of cycles; users reported expulsion more frequently in the first cycle, most (about 70%) of which were partial expulsions. Of the laboratory values and vital signs studied, including weight, users had no clinically relevant changes from baseline.

Continue to: New drospirenone pill is an effective POP option...

New drospirenone pill is an effective POP option 

Kimble T, Burke AE, Barnhart KT, et al. A 1-year prospective, open-label, single-arm, multicenter, phase 3 trial of the contraceptive efficacy and safety of the oral progestin-only pill drospirenone 4 mg using a 24/4-day regimen. Contracept X. 2020;2:100020. 

Palacios S, Colli E, Regidor PA. Multicenter, phase III trials on the contraceptive efficacy, tolerability and safety of a new drospirenone-only pill. Acta Obstet Gynecol Scand. 2019;98:1549-1557. 

In a prospective, single-arm, multicenter phase 3 trial in the United States, Kimble and colleagues evaluated the efficacy and safety of an oral drospirenone POP in a cyclic 24-day hormone/4-day placebo regimen. The trial included 1,006 users. No BMI cutoff was used, and about one-third of study participants were obese (BMI >30.0 kg/m²). Women were instructed to take a missed tablet as soon as remembered if within 24 hours or with the next scheduled dose if more than 24 hours late. 

Contraceptive effectiveness 

The Pearl Index for nonbreastfeeding users aged 35 years or younger with pregnancies confirmed by a quantitative serum ß-human chorionic gonadotropin test (915 users) was 2.9 (95% CI, 1.5-5.1). Of note, 2 out of 15 on-treatment pregnancies were excluded from this calculation because of protocol site violations, as were 3 pregnancies that were unconfirmed. In the modified full analysis set of 915 users, 36% were obese (BMI≥30 kg/m²), and the Pearl Index was noted to be unaffected by BMI (TABLE 2). 

While 61% of women reported adverse effects, more than 95% of these were mild or moderate in intensity, including headache, nausea, dysmenorrhea, metrorrhagia, and breast pain. No VTE occurred. The frequency of hyperkalemia was 0.5%, and there was no evidence of hypotension, which is significant due to the antimineralocorticoid activity of drospirenone. All cases of hyperkalemia were considered mild, and all women were asymptomatic. There were no clinically relevant changes in body weight, gynecologic exam, or other laboratory values. 

With increased cycles of use, the number of days with bleeding or spotting generally decreased and amenorrhea increased. However, in cycles 11 to 13, 41.6% of users still had unscheduled bleeding (reduced from 57.0% at cycles 2-4), and 29.0% had scheduled bleeding (decreased from 44% at cycles 2-4) (FIGURE 2). With these bleeding patterns, 86.2% of users agreed or strongly agreed that they were satisfied with the product. 

European multicenter study of drospironene 

In a European investigation, Palacios and colleagues pooled and analyzed data from 2 phase 3 multicenter trials to assess the efficacy, tolerability, and safety of the same drospirenone-only pill (24 days of drospironene 4 mg and 4 days of placebo) in 1,571 users. No BMI cutoff was used, but overall only 71 participants (4.6%) were obese. One study included desogestrel 0.075 mg (in a regimen of 28 active pills) as a comparator for safety. 

The overall Pearl Index for users 35 years or younger (1,251 users) was 1.0 (95% CI, 0.4-2.0). The "method failure Pearl Index" in users 35 years or younger, which included all pregnancies during "perfect medication cycles," was 1.3 (95% CI, 0.5-2.5). 

The most common adverse effects were acne (6.6% in study 1 and 4.4% in study 2), headache (4.5% in study 1), and irregular bleeding (4.4% in study 2). No cases of VTE occurred; there was 1 case of asymptomatic hyperkalemia. Additional laboratory values and vital signs showed no significant changes. The trend in bleeding was similar to that in the US studies, but it is interesting to note that there were significantly lower rates of unscheduled bleeding or spotting in drospirenone users than in desogestrel users (67.9% vs 86.5%, respectively; P<.001).

Continue to: Evidence supports 6 years' use of a levonorgestrel 52-mg IUS...

Westhoff CL, Keder LM, Gangestad A, et al. Six-year contraceptive efficacy and continued safety of a levonorgestrel 52-mg intrauterine system. Contraception. 2020;101:159-161. 

Two levonorgestrel 52-mg IUS products are on the market, both of which were approved for 5 years of use. The ACCESS IUS study (A Comprehensive Contraceptive Efficacy and Safety Study of an IUS) is an ongoing phase 3 trial to assess the safety and efficacy of a levonorgestrel 52-mg IUS (Liletta) for up to 10 years of use in US women. Westhoff and colleagues presented the data used for this IUS to gain approval for 6 years of use as of October 2019. The report included safety information for all users, with use exceeding 8 years in 122 participants. 

In year 6 of the ongoing trial, there were no on-treatment pregnancies with a 6-year life table pregnancy rate of 0.87 (95% CI, 0.44-1.70). Forty percent of users reported amenorrhea in the 90 days preceding the end of year 6, consistent with prior data after 3 years of use (FIGURE 3). The most common adverse effects over 6 or more years of use were bacterial vulvovaginal infections and urinary tract infections. 

Long-term IUS effectiveness 

Overall, in users aged 16 to 35 years, 72% discontinued study participation, most frequently due to an adverse event (19.2%) or to seeking pregnancy (15.5%). Through 6 or more years of use, overall discontinuation rates for expulsion (4.0%) and bleeding symptoms (2.3%) were very low, with 2 expulsions occurring in year 6 and only 1 participant discontinuing in year 6 for a bleeding symptom. These findings are consistent with those found at 5 years of IUS use and are representative of continued efficacy as well as overall low frequency of new significant events with extended use.¹¹

Long-acting reversible contraception (LARC) use continues to increase in the United States. According to the most recent estimates from 2014, 14% of women use either an intrauterine device (IUD) or the etonogestrel implant.¹ Forms of LARC currently available in the United States include:

• 4 hormone-releasing IUDs
• 1 nonhormonal copper IUD, and
• 1 hormonal subdermal implant.

The hormone-releasing IUDs all contain levonorgestrel (LNG). These include two 52-mg LNG products and a 19.5-mg LNG IUD, which are currently approved by the US Food and Drug Administration (FDA) for contraception for 5 continuous years of use. In addition, a 13.5-mg LNG IUD is FDA-approved for 3 years of use. The hormonal subdermal implant, which contains etonogestrel, is FDA-approved for 3 years of use. Although major complications with IUDs (perforation, expulsion, intrauterine infection)and implants (subfascial implantation, distant migration) are rare, adverse effects that can affect continuation—such as irregular bleeding—are more common.^2,3

Contraceptive discontinuation due to bleeding concerns occurs more frequently with the etonogestrel implant than with LNG IUDs (TABLE 1). In a large prospective study in the United States, 13% of women discontinued the implant during 3 years of follow-up due to bleeding pattern changes.⁴ In comparison, the 3-year discontinuation rate for bleeding complaints with the 52-mg LNG IUD is 1.5%.⁵ The 3-year discontinuation rate is higher with the 19.5-mg and 13.5-mg LNG IUDs (4.9% and 4.7%, respectively).⁶ The discontinuation rate for bleeding complaints within 5 years of use remains higher for the 19.5-mg LNG IUD (5.2%) compared with the 52-mg LNG IUD (2.2%).^7,8

Notably, it is important to use standardized definitions to understand and compare bleeding concerns with LARC use. The Belsey criteria of the World Health Organization (WHO), a standard used for decades, describe bleeding patterns using 90-day reference periods or intervals (TABLE 2).⁹ Bleeding patterns that decrease flow (amenorrhea, infrequent bleeding) often are considered favorable, and those that increase bleeding or irregularity often are considered unfavorable. These criteria are commonly used in package labeling to describe bleeding patterns with extended use.

In this Update, we examine recent data evaluating differences in bleeding patterns with the 3 doses of the LNG IUD, predictors of abnormal bleeding with the etonogestrel implant, and the impact of timing on postpartum etonogestrel implant placement.

Continue to: Bleeding patterns with progestin-containing IUDs vary according to the LNG dose...

Bleeding patterns with progestin-containing IUDs vary according to the LNG dose 

Goldthwaite LM, Creinin MD. Comparing bleeding patterns for the levonorgestrel 52 mg, 19.5 mg, and 13.5 mg intrauterine systems. Contraception. 2019;100:128-131. 

Counseling on IUDs' different hormonal doses requires an understanding of patients' desires for contraceptive efficacy and bleeding expectations. A recent study provides guidance on what patients typically can expect for their bleeding patterns over the first few years with the 3 different doses of LNG IUDs. 

Goldthwaite and Creinin used existing published or publicly available data to analyze differences in bleeding patterns associated with the 52-mg, 19.5-mg, and 13.5-mg LNG IUDs. Although two 52-mg LNG IUDs are available, published data using the WHO Belsey criteria are available only for one (Liletta; Allergan, Medicines360). The 2 products have been shown previously to have similar drug-release rates and LNG levels over 5 years.⁸ 

Comparing favorable bleeding patterns: Amenorrhea and infrequent bleeding 

Among favorable bleeding patterns, amenorrhea was uncommon in the first 90 days and increased over time for all 3 IUDs. However, starting as soon as the second 90-day reference period, amenorrhea rates were significantly higher with the 52-mg LNG IUD compared with both of the lower-LNG dose IUDs, and this difference increased through 3 years of use (FIGURE 1). 

Similarly, the 19.5-mg LNG IUD users had significantly higher rates of amenorrhea than the 13.5-mg LNG IUD users for all periods starting with the second 90-day reference period. At 3 years, 36% of women using the 52-mg LNG IUD had amenorrhea compared with 20% of those using the 19.5-mg LNG IUD (P<.0001) and 12% of those using the 13.5-mg LNG IUD (P<.0001). 

Infrequent bleeding was similar for all 3 LNG IUDs in the first 90-day period, and it then increased most rapidly in the 52-mg LNG IUD users. At the end of year 1, 30% of the 52-mg LNG IUD users had infrequent bleeding compared with 26% of the 19.5-mg users (P = .01) and 20% of the 13.5-mg users (P<.0001). Although there was no difference in infrequent bleeding rates between the 52-mg and the 19.5-mg LNG IUD users at the end of year 1, those using a 52-mg LNG IUD had significantly higher rates of infrequent bleeding compared with the 13.5-mg LNG IUD at all time points. 

Comparing unfavorable bleeding patterns: Frequent, prolonged, and irregular bleeding 

Frequent and prolonged bleeding were uncommon with all LNG doses. Irregular bleeding rates declined for users of the 3 IUDs over time. However, significantly fewer users of the 52-mg LNG IUD reported irregular bleeding at 1 year (6%) compared with users of the 19.5-mg (16.5%, P<.0001) and 13.5-mg (23%, P<.0001) LNG IUD (FIGURE 2). 

Study limitations 

Comparing the data from different studies has limitations. For example, the data were collected from different populations, with the lower-dose LNG products tested in women who had a lower body mass index (BMI) and higher parity. However, prior analysis of the data on the 52-mg LNG IUD demonstrated that bleeding pattern changes did not vary based on these factors.¹⁰

Continue to: Predicting long-term bleeding patterns after etonogestrel implant insertion...

Mansour D, Fraser IS, Edelman A, et al. Can initial vaginal bleeding patterns in etonogestrel implant users predict subsequent bleeding in the first two years of use? Contraception. 2019. doi: 10.1016/j.contraception.2019.05.017. 

Data from 2014 indicate that the etonogestrel implant was used by nearly 1 million women in the United States and by 3% of women using contraception.¹ The primary reason women discontinue implant use is because of changes in bleeding patterns. Given the high prevalence of bleeding concerns with the etonogestrel implant, we need more data to help counsel our patients on how they can expect their bleeding to change with implant use. 

Etonogestral implant and bleeding pattern trends 

Mansour and colleagues completed a secondary analysis of 12 phase 3 studies to evaluate the correlation between bleeding patterns early after placement of the etonogestrel implant (days 29-118) compared with bleeding patterns through 90-day intervals during the rest of the first year of use. To account for differences in timing of etonogestrel implant placement relative to the menstrual cycle and discontinuation of other methods like oral contraceptives, bleeding outcomes on days 0-28 were excluded. They also sought to investigate the correlation between bleeding patterns in year 1 compared with those in year 2. 

Overall, these studies included 923 individuals across 11 countries; however, for the current analysis, the researchers excluded women from Asian countries who comprised more than 28% of the study population. These women report significantly fewer bleeding/spotting days with the etonogestrel implant and have a lower average body weight compared with European and American women.¹² 

A prior analysis of the same data set looked at the number of bleeding/spotting days in groups of users rather than trends in individual patients, and, as mentioned, it also included Asian women, which diluted the overall number of bleeding days.¹² In this new analysis, Mansour and colleagues used the Belsey criteria to analyze individual bleeding patterns as favorable (amenorrhea, infrequent bleeding, normal bleeding) or unfavorable (prolonged and/or frequent bleeding) from a patient perspective. In this way, we can understand trends in bleeding patterns for each patient over time, rather than seeing a static (cross-sectional) report of bleeding patterns at one point in time. Data were analyzed from 537 women in year 1 and 428 women in year 2. During the first 90-day reference period (days 29-118 after implant insertion), 61% of women reported favorable bleeding, and 39% reported unfavorable bleeding. 

Favorable bleeding correlates with favorable patterns later 

A favorable bleeding pattern in this first reference period correlated with favorable bleeding patterns through year 1, with 85%, 80%, and 80% of these women having a favorable pattern in reference periods 2, 3, and 4, respectively. Overall, 61% of women with a favorable pattern in reference period 1 had favorable bleeding throughout the entire first year of use. Only 3.7% of women with favorable bleeding in the first reference period discontinued the implant for bleeding in year 1. Further, women with favorable bleeding at year 1 commonly continued to have favorable bleeding in year 2, with a low discontinuation rate (2.5%) in year 2. 

Initial unfavorable bleeding portends less favorable patterns later 

Women who had an unfavorable bleeding pattern initially, however, had a less predictable course over the first year. For those with an initial unfavorable pattern, only 37%, 47%, and 51% reported a favorable pattern in reference periods 2, 3, and 4. Despite these relatively low rates of favorable bleeding, only 13% of the women with an initial unfavorable bleeding pattern discontinued implant use for a bleeding complaint by the end of year 1; this rate was significantly higher than that for women with a favorable initial bleeding pattern (P<.0001). The discontinuation rate for bleeding complaints also remained higher in year 2, at 16.5%. 

Limitations and strengths to consider 

Although the etonogestrel implant is FDA-approved for 3 years of use, the bleeding data from the combined trials included information for only up to 2 years after placement. The studies included also did not uniformly assess BMI, which makes it difficult to find correlations between bleeding patterns and BMI. Importantly, the studies did not include women who were more than 30% above their ideal body weight, so these assessments do not apply to obese users.¹² Exclusion of women from Southeast Asia in this analysis makes this study's findings more generalizable to populations in the United States and Europe. 
 

Continue to: Early versus delayed postpartum etonogestrel implant insertion...

Early versus delayed postpartum etonogestrel implant insertion: Similar impacts on 12-month bleeding patterns 

Vieira CS, de Nadai MN, de Melo Pereira do Carmo LS, et al. Timing of postpartum etonogestrel-releasing implant insertion and bleeding patterns, weight change, 12-month continuation and satisfaction rates: a randomized controlled trial. Contraception. 2019. doi:10.1016/j.contraception.2019.05.007. 

Initiation of a desired LARC method shortly after delivery is associated with significant reductions in short interpregnancy intervals.¹⁴ With that goal in mind, Vieira and colleagues compared bleeding patterns in women who received an etonogestrel implant within 48 hours of delivery with those who received an implant at 6 weeks postdelivery. 

The study was a secondary analysis of data from a randomized controlled trial of early versus delayed postpartum insertion of the etonogestrel implant conducted in Sao Paulo, Brazil. That primary trial's goal was to examine the impact of early versus delayed implant insertion on infant growth (100 women were randomly assigned to the 2 implant groups); no difference in infant growth at 12 months was seen in the 2 groups.¹⁵ In the secondary analysis, bleeding patterns and BMI were evaluated every 90 days for 12 months. The mean BMI at enrollment postpartum was 29.4 kg/m² in the early-insertion group and 30.2 kg/m² for the delayed-insertion group. 

Bleeding patterns with early or delayed implant insertion were similar 

Vieira and colleagues found similar bleeding patterns between the groups over 12 months of follow-up. Amenorrhea was reported by 56% of the early-insertion group in the first 90 days and by 62% in the delayed-insertion group. During the last 90 days of the year, 52% of the early-insertion and 46% of the delayed-insertion group reported amenorrhea. Amenorrhea rates did not differ between women who were exclusively breastfeeding and those nonexclusively breastfeeding. 

Continuation rates were high at 1 year 

Prolonged bleeding episodes were uncommon in both groups, with only 2% of women reporting prolonged bleeding in any given reference period. Twelve-month implant continuation rates were high in both groups: 98% in the early- and 100% in the delayed-insertion group. Additionally, the investigators found that both groups experienced a BMI decrease, with no difference between groups (10.3% and 11% in the early- and delayed-insertion groups, respectively). 

Study limitations and strengths 

This study included a larger number of participants than prior randomized, controlled trials that evaluated bleeding patterns with postpartum etonogestrel implant insertion, and it had very low rates of loss to follow-up. The study's low rate of 12-month implant discontinuation (2%) is lower than that of other studies that reported rates of 6% to 14%.^16,17 Although the authors stated that this low rate may be due to thorough anticipatory counseling prior to placement, it is also possible that this study population does not reflect all populations. Regardless, the data clearly show that placing an etonogestrel implant prior to hospital discharge, compared with waiting for later placement, does not impact bleeding patterns over the ensuing year. 

Long-acting reversible contraception (LARC) use continues to increase in the United States. According to the most recent estimates from 2014, 14% of women use either an intrauterine device (IUD) or the etonogestrel implant.¹ Forms of LARC currently available in the United States include:

• 4 hormone-releasing IUDs
• 1 nonhormonal copper IUD, and
• 1 hormonal subdermal implant.

The hormone-releasing IUDs all contain levonorgestrel (LNG). These include two 52-mg LNG products and a 19.5-mg LNG IUD, which are currently approved by the US Food and Drug Administration (FDA) for contraception for 5 continuous years of use. In addition, a 13.5-mg LNG IUD is FDA-approved for 3 years of use. The hormonal subdermal implant, which contains etonogestrel, is FDA-approved for 3 years of use. Although major complications with IUDs (perforation, expulsion, intrauterine infection)and implants (subfascial implantation, distant migration) are rare, adverse effects that can affect continuation—such as irregular bleeding—are more common.^2,3

Contraceptive discontinuation due to bleeding concerns occurs more frequently with the etonogestrel implant than with LNG IUDs (TABLE 1). In a large prospective study in the United States, 13% of women discontinued the implant during 3 years of follow-up due to bleeding pattern changes.⁴ In comparison, the 3-year discontinuation rate for bleeding complaints with the 52-mg LNG IUD is 1.5%.⁵ The 3-year discontinuation rate is higher with the 19.5-mg and 13.5-mg LNG IUDs (4.9% and 4.7%, respectively).⁶ The discontinuation rate for bleeding complaints within 5 years of use remains higher for the 19.5-mg LNG IUD (5.2%) compared with the 52-mg LNG IUD (2.2%).^7,8

Notably, it is important to use standardized definitions to understand and compare bleeding concerns with LARC use. The Belsey criteria of the World Health Organization (WHO), a standard used for decades, describe bleeding patterns using 90-day reference periods or intervals (TABLE 2).⁹ Bleeding patterns that decrease flow (amenorrhea, infrequent bleeding) often are considered favorable, and those that increase bleeding or irregularity often are considered unfavorable. These criteria are commonly used in package labeling to describe bleeding patterns with extended use.

In this Update, we examine recent data evaluating differences in bleeding patterns with the 3 doses of the LNG IUD, predictors of abnormal bleeding with the etonogestrel implant, and the impact of timing on postpartum etonogestrel implant placement.

Continue to: Bleeding patterns with progestin-containing IUDs vary according to the LNG dose...

Bleeding patterns with progestin-containing IUDs vary according to the LNG dose 

Goldthwaite LM, Creinin MD. Comparing bleeding patterns for the levonorgestrel 52 mg, 19.5 mg, and 13.5 mg intrauterine systems. Contraception. 2019;100:128-131. 

Counseling on IUDs' different hormonal doses requires an understanding of patients' desires for contraceptive efficacy and bleeding expectations. A recent study provides guidance on what patients typically can expect for their bleeding patterns over the first few years with the 3 different doses of LNG IUDs. 

Goldthwaite and Creinin used existing published or publicly available data to analyze differences in bleeding patterns associated with the 52-mg, 19.5-mg, and 13.5-mg LNG IUDs. Although two 52-mg LNG IUDs are available, published data using the WHO Belsey criteria are available only for one (Liletta; Allergan, Medicines360). The 2 products have been shown previously to have similar drug-release rates and LNG levels over 5 years.⁸ 

Comparing favorable bleeding patterns: Amenorrhea and infrequent bleeding 

Among favorable bleeding patterns, amenorrhea was uncommon in the first 90 days and increased over time for all 3 IUDs. However, starting as soon as the second 90-day reference period, amenorrhea rates were significantly higher with the 52-mg LNG IUD compared with both of the lower-LNG dose IUDs, and this difference increased through 3 years of use (FIGURE 1). 

Similarly, the 19.5-mg LNG IUD users had significantly higher rates of amenorrhea than the 13.5-mg LNG IUD users for all periods starting with the second 90-day reference period. At 3 years, 36% of women using the 52-mg LNG IUD had amenorrhea compared with 20% of those using the 19.5-mg LNG IUD (P<.0001) and 12% of those using the 13.5-mg LNG IUD (P<.0001). 

Infrequent bleeding was similar for all 3 LNG IUDs in the first 90-day period, and it then increased most rapidly in the 52-mg LNG IUD users. At the end of year 1, 30% of the 52-mg LNG IUD users had infrequent bleeding compared with 26% of the 19.5-mg users (P = .01) and 20% of the 13.5-mg users (P<.0001). Although there was no difference in infrequent bleeding rates between the 52-mg and the 19.5-mg LNG IUD users at the end of year 1, those using a 52-mg LNG IUD had significantly higher rates of infrequent bleeding compared with the 13.5-mg LNG IUD at all time points. 

Comparing unfavorable bleeding patterns: Frequent, prolonged, and irregular bleeding 

Frequent and prolonged bleeding were uncommon with all LNG doses. Irregular bleeding rates declined for users of the 3 IUDs over time. However, significantly fewer users of the 52-mg LNG IUD reported irregular bleeding at 1 year (6%) compared with users of the 19.5-mg (16.5%, P<.0001) and 13.5-mg (23%, P<.0001) LNG IUD (FIGURE 2). 

Study limitations 

Comparing the data from different studies has limitations. For example, the data were collected from different populations, with the lower-dose LNG products tested in women who had a lower body mass index (BMI) and higher parity. However, prior analysis of the data on the 52-mg LNG IUD demonstrated that bleeding pattern changes did not vary based on these factors.¹⁰

Continue to: Predicting long-term bleeding patterns after etonogestrel implant insertion...

Mansour D, Fraser IS, Edelman A, et al. Can initial vaginal bleeding patterns in etonogestrel implant users predict subsequent bleeding in the first two years of use? Contraception. 2019. doi: 10.1016/j.contraception.2019.05.017. 

Data from 2014 indicate that the etonogestrel implant was used by nearly 1 million women in the United States and by 3% of women using contraception.¹ The primary reason women discontinue implant use is because of changes in bleeding patterns. Given the high prevalence of bleeding concerns with the etonogestrel implant, we need more data to help counsel our patients on how they can expect their bleeding to change with implant use. 

Etonogestral implant and bleeding pattern trends 

Mansour and colleagues completed a secondary analysis of 12 phase 3 studies to evaluate the correlation between bleeding patterns early after placement of the etonogestrel implant (days 29-118) compared with bleeding patterns through 90-day intervals during the rest of the first year of use. To account for differences in timing of etonogestrel implant placement relative to the menstrual cycle and discontinuation of other methods like oral contraceptives, bleeding outcomes on days 0-28 were excluded. They also sought to investigate the correlation between bleeding patterns in year 1 compared with those in year 2. 

Overall, these studies included 923 individuals across 11 countries; however, for the current analysis, the researchers excluded women from Asian countries who comprised more than 28% of the study population. These women report significantly fewer bleeding/spotting days with the etonogestrel implant and have a lower average body weight compared with European and American women.¹² 

A prior analysis of the same data set looked at the number of bleeding/spotting days in groups of users rather than trends in individual patients, and, as mentioned, it also included Asian women, which diluted the overall number of bleeding days.¹² In this new analysis, Mansour and colleagues used the Belsey criteria to analyze individual bleeding patterns as favorable (amenorrhea, infrequent bleeding, normal bleeding) or unfavorable (prolonged and/or frequent bleeding) from a patient perspective. In this way, we can understand trends in bleeding patterns for each patient over time, rather than seeing a static (cross-sectional) report of bleeding patterns at one point in time. Data were analyzed from 537 women in year 1 and 428 women in year 2. During the first 90-day reference period (days 29-118 after implant insertion), 61% of women reported favorable bleeding, and 39% reported unfavorable bleeding. 

Favorable bleeding correlates with favorable patterns later 

A favorable bleeding pattern in this first reference period correlated with favorable bleeding patterns through year 1, with 85%, 80%, and 80% of these women having a favorable pattern in reference periods 2, 3, and 4, respectively. Overall, 61% of women with a favorable pattern in reference period 1 had favorable bleeding throughout the entire first year of use. Only 3.7% of women with favorable bleeding in the first reference period discontinued the implant for bleeding in year 1. Further, women with favorable bleeding at year 1 commonly continued to have favorable bleeding in year 2, with a low discontinuation rate (2.5%) in year 2. 

Initial unfavorable bleeding portends less favorable patterns later 

Women who had an unfavorable bleeding pattern initially, however, had a less predictable course over the first year. For those with an initial unfavorable pattern, only 37%, 47%, and 51% reported a favorable pattern in reference periods 2, 3, and 4. Despite these relatively low rates of favorable bleeding, only 13% of the women with an initial unfavorable bleeding pattern discontinued implant use for a bleeding complaint by the end of year 1; this rate was significantly higher than that for women with a favorable initial bleeding pattern (P<.0001). The discontinuation rate for bleeding complaints also remained higher in year 2, at 16.5%. 

Limitations and strengths to consider 

Although the etonogestrel implant is FDA-approved for 3 years of use, the bleeding data from the combined trials included information for only up to 2 years after placement. The studies included also did not uniformly assess BMI, which makes it difficult to find correlations between bleeding patterns and BMI. Importantly, the studies did not include women who were more than 30% above their ideal body weight, so these assessments do not apply to obese users.¹² Exclusion of women from Southeast Asia in this analysis makes this study's findings more generalizable to populations in the United States and Europe. 
 

Continue to: Early versus delayed postpartum etonogestrel implant insertion...

Early versus delayed postpartum etonogestrel implant insertion: Similar impacts on 12-month bleeding patterns 

Vieira CS, de Nadai MN, de Melo Pereira do Carmo LS, et al. Timing of postpartum etonogestrel-releasing implant insertion and bleeding patterns, weight change, 12-month continuation and satisfaction rates: a randomized controlled trial. Contraception. 2019. doi:10.1016/j.contraception.2019.05.007. 

Initiation of a desired LARC method shortly after delivery is associated with significant reductions in short interpregnancy intervals.¹⁴ With that goal in mind, Vieira and colleagues compared bleeding patterns in women who received an etonogestrel implant within 48 hours of delivery with those who received an implant at 6 weeks postdelivery. 

The study was a secondary analysis of data from a randomized controlled trial of early versus delayed postpartum insertion of the etonogestrel implant conducted in Sao Paulo, Brazil. That primary trial's goal was to examine the impact of early versus delayed implant insertion on infant growth (100 women were randomly assigned to the 2 implant groups); no difference in infant growth at 12 months was seen in the 2 groups.¹⁵ In the secondary analysis, bleeding patterns and BMI were evaluated every 90 days for 12 months. The mean BMI at enrollment postpartum was 29.4 kg/m² in the early-insertion group and 30.2 kg/m² for the delayed-insertion group. 

Bleeding patterns with early or delayed implant insertion were similar 

Vieira and colleagues found similar bleeding patterns between the groups over 12 months of follow-up. Amenorrhea was reported by 56% of the early-insertion group in the first 90 days and by 62% in the delayed-insertion group. During the last 90 days of the year, 52% of the early-insertion and 46% of the delayed-insertion group reported amenorrhea. Amenorrhea rates did not differ between women who were exclusively breastfeeding and those nonexclusively breastfeeding. 

Continuation rates were high at 1 year 

Prolonged bleeding episodes were uncommon in both groups, with only 2% of women reporting prolonged bleeding in any given reference period. Twelve-month implant continuation rates were high in both groups: 98% in the early- and 100% in the delayed-insertion group. Additionally, the investigators found that both groups experienced a BMI decrease, with no difference between groups (10.3% and 11% in the early- and delayed-insertion groups, respectively). 

Study limitations and strengths 

This study included a larger number of participants than prior randomized, controlled trials that evaluated bleeding patterns with postpartum etonogestrel implant insertion, and it had very low rates of loss to follow-up. The study's low rate of 12-month implant discontinuation (2%) is lower than that of other studies that reported rates of 6% to 14%.^16,17 Although the authors stated that this low rate may be due to thorough anticipatory counseling prior to placement, it is also possible that this study population does not reflect all populations. Regardless, the data clearly show that placing an etonogestrel implant prior to hospital discharge, compared with waiting for later placement, does not impact bleeding patterns over the ensuing year. 

Long-acting reversible contraception (LARC) use continues to increase in the United States. According to the most recent estimates from 2014, 14% of women use either an intrauterine device (IUD) or the etonogestrel implant.¹ Forms of LARC currently available in the United States include:

• 4 hormone-releasing IUDs
• 1 nonhormonal copper IUD, and
• 1 hormonal subdermal implant.

The hormone-releasing IUDs all contain levonorgestrel (LNG). These include two 52-mg LNG products and a 19.5-mg LNG IUD, which are currently approved by the US Food and Drug Administration (FDA) for contraception for 5 continuous years of use. In addition, a 13.5-mg LNG IUD is FDA-approved for 3 years of use. The hormonal subdermal implant, which contains etonogestrel, is FDA-approved for 3 years of use. Although major complications with IUDs (perforation, expulsion, intrauterine infection)and implants (subfascial implantation, distant migration) are rare, adverse effects that can affect continuation—such as irregular bleeding—are more common.^2,3

Contraceptive discontinuation due to bleeding concerns occurs more frequently with the etonogestrel implant than with LNG IUDs (TABLE 1). In a large prospective study in the United States, 13% of women discontinued the implant during 3 years of follow-up due to bleeding pattern changes.⁴ In comparison, the 3-year discontinuation rate for bleeding complaints with the 52-mg LNG IUD is 1.5%.⁵ The 3-year discontinuation rate is higher with the 19.5-mg and 13.5-mg LNG IUDs (4.9% and 4.7%, respectively).⁶ The discontinuation rate for bleeding complaints within 5 years of use remains higher for the 19.5-mg LNG IUD (5.2%) compared with the 52-mg LNG IUD (2.2%).^7,8

Notably, it is important to use standardized definitions to understand and compare bleeding concerns with LARC use. The Belsey criteria of the World Health Organization (WHO), a standard used for decades, describe bleeding patterns using 90-day reference periods or intervals (TABLE 2).⁹ Bleeding patterns that decrease flow (amenorrhea, infrequent bleeding) often are considered favorable, and those that increase bleeding or irregularity often are considered unfavorable. These criteria are commonly used in package labeling to describe bleeding patterns with extended use.

In this Update, we examine recent data evaluating differences in bleeding patterns with the 3 doses of the LNG IUD, predictors of abnormal bleeding with the etonogestrel implant, and the impact of timing on postpartum etonogestrel implant placement.

Continue to: Bleeding patterns with progestin-containing IUDs vary according to the LNG dose...

Bleeding patterns with progestin-containing IUDs vary according to the LNG dose 

Goldthwaite LM, Creinin MD. Comparing bleeding patterns for the levonorgestrel 52 mg, 19.5 mg, and 13.5 mg intrauterine systems. Contraception. 2019;100:128-131. 

Counseling on IUDs' different hormonal doses requires an understanding of patients' desires for contraceptive efficacy and bleeding expectations. A recent study provides guidance on what patients typically can expect for their bleeding patterns over the first few years with the 3 different doses of LNG IUDs. 

Goldthwaite and Creinin used existing published or publicly available data to analyze differences in bleeding patterns associated with the 52-mg, 19.5-mg, and 13.5-mg LNG IUDs. Although two 52-mg LNG IUDs are available, published data using the WHO Belsey criteria are available only for one (Liletta; Allergan, Medicines360). The 2 products have been shown previously to have similar drug-release rates and LNG levels over 5 years.⁸ 

Comparing favorable bleeding patterns: Amenorrhea and infrequent bleeding 

Among favorable bleeding patterns, amenorrhea was uncommon in the first 90 days and increased over time for all 3 IUDs. However, starting as soon as the second 90-day reference period, amenorrhea rates were significantly higher with the 52-mg LNG IUD compared with both of the lower-LNG dose IUDs, and this difference increased through 3 years of use (FIGURE 1). 

Similarly, the 19.5-mg LNG IUD users had significantly higher rates of amenorrhea than the 13.5-mg LNG IUD users for all periods starting with the second 90-day reference period. At 3 years, 36% of women using the 52-mg LNG IUD had amenorrhea compared with 20% of those using the 19.5-mg LNG IUD (P<.0001) and 12% of those using the 13.5-mg LNG IUD (P<.0001). 

Infrequent bleeding was similar for all 3 LNG IUDs in the first 90-day period, and it then increased most rapidly in the 52-mg LNG IUD users. At the end of year 1, 30% of the 52-mg LNG IUD users had infrequent bleeding compared with 26% of the 19.5-mg users (P = .01) and 20% of the 13.5-mg users (P<.0001). Although there was no difference in infrequent bleeding rates between the 52-mg and the 19.5-mg LNG IUD users at the end of year 1, those using a 52-mg LNG IUD had significantly higher rates of infrequent bleeding compared with the 13.5-mg LNG IUD at all time points. 

Comparing unfavorable bleeding patterns: Frequent, prolonged, and irregular bleeding 

Frequent and prolonged bleeding were uncommon with all LNG doses. Irregular bleeding rates declined for users of the 3 IUDs over time. However, significantly fewer users of the 52-mg LNG IUD reported irregular bleeding at 1 year (6%) compared with users of the 19.5-mg (16.5%, P<.0001) and 13.5-mg (23%, P<.0001) LNG IUD (FIGURE 2). 

Study limitations 

Comparing the data from different studies has limitations. For example, the data were collected from different populations, with the lower-dose LNG products tested in women who had a lower body mass index (BMI) and higher parity. However, prior analysis of the data on the 52-mg LNG IUD demonstrated that bleeding pattern changes did not vary based on these factors.¹⁰

Continue to: Predicting long-term bleeding patterns after etonogestrel implant insertion...

Mansour D, Fraser IS, Edelman A, et al. Can initial vaginal bleeding patterns in etonogestrel implant users predict subsequent bleeding in the first two years of use? Contraception. 2019. doi: 10.1016/j.contraception.2019.05.017. 

Data from 2014 indicate that the etonogestrel implant was used by nearly 1 million women in the United States and by 3% of women using contraception.¹ The primary reason women discontinue implant use is because of changes in bleeding patterns. Given the high prevalence of bleeding concerns with the etonogestrel implant, we need more data to help counsel our patients on how they can expect their bleeding to change with implant use. 

Etonogestral implant and bleeding pattern trends 

Mansour and colleagues completed a secondary analysis of 12 phase 3 studies to evaluate the correlation between bleeding patterns early after placement of the etonogestrel implant (days 29-118) compared with bleeding patterns through 90-day intervals during the rest of the first year of use. To account for differences in timing of etonogestrel implant placement relative to the menstrual cycle and discontinuation of other methods like oral contraceptives, bleeding outcomes on days 0-28 were excluded. They also sought to investigate the correlation between bleeding patterns in year 1 compared with those in year 2. 

Overall, these studies included 923 individuals across 11 countries; however, for the current analysis, the researchers excluded women from Asian countries who comprised more than 28% of the study population. These women report significantly fewer bleeding/spotting days with the etonogestrel implant and have a lower average body weight compared with European and American women.¹² 

A prior analysis of the same data set looked at the number of bleeding/spotting days in groups of users rather than trends in individual patients, and, as mentioned, it also included Asian women, which diluted the overall number of bleeding days.¹² In this new analysis, Mansour and colleagues used the Belsey criteria to analyze individual bleeding patterns as favorable (amenorrhea, infrequent bleeding, normal bleeding) or unfavorable (prolonged and/or frequent bleeding) from a patient perspective. In this way, we can understand trends in bleeding patterns for each patient over time, rather than seeing a static (cross-sectional) report of bleeding patterns at one point in time. Data were analyzed from 537 women in year 1 and 428 women in year 2. During the first 90-day reference period (days 29-118 after implant insertion), 61% of women reported favorable bleeding, and 39% reported unfavorable bleeding. 

Favorable bleeding correlates with favorable patterns later 

A favorable bleeding pattern in this first reference period correlated with favorable bleeding patterns through year 1, with 85%, 80%, and 80% of these women having a favorable pattern in reference periods 2, 3, and 4, respectively. Overall, 61% of women with a favorable pattern in reference period 1 had favorable bleeding throughout the entire first year of use. Only 3.7% of women with favorable bleeding in the first reference period discontinued the implant for bleeding in year 1. Further, women with favorable bleeding at year 1 commonly continued to have favorable bleeding in year 2, with a low discontinuation rate (2.5%) in year 2. 

Initial unfavorable bleeding portends less favorable patterns later 

Women who had an unfavorable bleeding pattern initially, however, had a less predictable course over the first year. For those with an initial unfavorable pattern, only 37%, 47%, and 51% reported a favorable pattern in reference periods 2, 3, and 4. Despite these relatively low rates of favorable bleeding, only 13% of the women with an initial unfavorable bleeding pattern discontinued implant use for a bleeding complaint by the end of year 1; this rate was significantly higher than that for women with a favorable initial bleeding pattern (P<.0001). The discontinuation rate for bleeding complaints also remained higher in year 2, at 16.5%. 

Limitations and strengths to consider 

Although the etonogestrel implant is FDA-approved for 3 years of use, the bleeding data from the combined trials included information for only up to 2 years after placement. The studies included also did not uniformly assess BMI, which makes it difficult to find correlations between bleeding patterns and BMI. Importantly, the studies did not include women who were more than 30% above their ideal body weight, so these assessments do not apply to obese users.¹² Exclusion of women from Southeast Asia in this analysis makes this study's findings more generalizable to populations in the United States and Europe. 
 

Continue to: Early versus delayed postpartum etonogestrel implant insertion...

Early versus delayed postpartum etonogestrel implant insertion: Similar impacts on 12-month bleeding patterns 

Vieira CS, de Nadai MN, de Melo Pereira do Carmo LS, et al. Timing of postpartum etonogestrel-releasing implant insertion and bleeding patterns, weight change, 12-month continuation and satisfaction rates: a randomized controlled trial. Contraception. 2019. doi:10.1016/j.contraception.2019.05.007. 

Initiation of a desired LARC method shortly after delivery is associated with significant reductions in short interpregnancy intervals.¹⁴ With that goal in mind, Vieira and colleagues compared bleeding patterns in women who received an etonogestrel implant within 48 hours of delivery with those who received an implant at 6 weeks postdelivery. 

The study was a secondary analysis of data from a randomized controlled trial of early versus delayed postpartum insertion of the etonogestrel implant conducted in Sao Paulo, Brazil. That primary trial's goal was to examine the impact of early versus delayed implant insertion on infant growth (100 women were randomly assigned to the 2 implant groups); no difference in infant growth at 12 months was seen in the 2 groups.¹⁵ In the secondary analysis, bleeding patterns and BMI were evaluated every 90 days for 12 months. The mean BMI at enrollment postpartum was 29.4 kg/m² in the early-insertion group and 30.2 kg/m² for the delayed-insertion group. 

Bleeding patterns with early or delayed implant insertion were similar 

Vieira and colleagues found similar bleeding patterns between the groups over 12 months of follow-up. Amenorrhea was reported by 56% of the early-insertion group in the first 90 days and by 62% in the delayed-insertion group. During the last 90 days of the year, 52% of the early-insertion and 46% of the delayed-insertion group reported amenorrhea. Amenorrhea rates did not differ between women who were exclusively breastfeeding and those nonexclusively breastfeeding. 

Continuation rates were high at 1 year 

Prolonged bleeding episodes were uncommon in both groups, with only 2% of women reporting prolonged bleeding in any given reference period. Twelve-month implant continuation rates were high in both groups: 98% in the early- and 100% in the delayed-insertion group. Additionally, the investigators found that both groups experienced a BMI decrease, with no difference between groups (10.3% and 11% in the early- and delayed-insertion groups, respectively). 

Study limitations and strengths 

This study included a larger number of participants than prior randomized, controlled trials that evaluated bleeding patterns with postpartum etonogestrel implant insertion, and it had very low rates of loss to follow-up. The study's low rate of 12-month implant discontinuation (2%) is lower than that of other studies that reported rates of 6% to 14%.^16,17 Although the authors stated that this low rate may be due to thorough anticipatory counseling prior to placement, it is also possible that this study population does not reflect all populations. Regardless, the data clearly show that placing an etonogestrel implant prior to hospital discharge, compared with waiting for later placement, does not impact bleeding patterns over the ensuing year. 

Female permanent contraception is among the most widely used contraceptive methods worldwide. In the United States, more than 640,000 procedures are performed each year and it is used by 25% of women who use contraception.^1–4 Female permanent contraception is achieved via salpingectomy, tubal interruption, or hysteroscopic techniques.

Essure, the only currently available hysteroscopic permanent contraception device, approved by the US Food and Drug Administration (FDA) in 2002,^5,6 has been implanted in more than 750,000 women worldwide.⁷ Essure was developed by Conceptus Inc, a small medical device company that was acquired by Bayer in 2013. The greatest uptake has been in the United States, which accounts for approximately 80% of procedures worldwide.^7,8

Essure placement involves insertion of a nickel-titanium alloy coil with a stainless-steel inner coil, polyethylene terephthalate fibers, platinum marker bands, and silver-tin solder.⁹ The insert is approximately 4 cm in length and expands to 2 mm in diameter once deployed.⁹

Potential advantages of a hysteroscopic approach are that intra-abdominal surgery can be avoided and the procedure can be performed in an office without the need for general anesthesia.⁷ Due to these potential benefits, hysteroscopic permanent contraception with Essure underwent expedited review and received FDA approval without any comparative trials.^1,5,10 However, there also are disadvantages: the method is not always successfully placed on first attempt and it is not immediately effective. Successful placement rates range between 60% and 98%, most commonly around 90%.^11–15 Additionally, if placement is successful, alternative contraception must be used until a confirmatory radiologic test is performed at least 3 months after the procedure.^9,11 Initially, hysterosalpingography was required to demonstrate a satisfactory insert location and successful tubal occlusion.^11,16 Compliance with this testing is variable, ranging in studies from 13% to 71%.¹¹ As of 2015, transvaginal ultrasonography showing insert retention and location has been approved as an alternative confirmatory method.^9,11,16,17 Evidence suggests that the less invasive ultrasound option increases follow-up rates; while limited, one study noted an increase in follow-up rates from 77.5% for hysterosalpingogram to 88% (P = .008) for transvaginal ultrasound.¹⁸

Recent concerns about potential medical and safety issues have impacted approval status and marketing of hysteroscopic permanent contraception worldwide. In response to safety concerns, the FDA added a boxed safety warning and patient decision checklist in 2016.¹⁹ Bayer withdrew the device from all markets outside of the United States as of May 2017.^20–22 In April 2018, the FDA restricted Essure sales in the United States only to providers and facilities who utilized an FDA-approved checklist to ensure the device met standards for safety and effectiveness.¹⁹ Most recently, Bayer announced that Essure would no longer be sold or distributed in the United States after December 31, 2018 (See “FDA Press Release”).²³

So how did we get here? How did the promise of a “less invasive” approach for female permanent contraception get off course?

A search of the Manufacturer and User Facility Device Experience (MAUDE) database from Essure’s approval date in 2002 to December 2017 revealed 26,773 medical device reports, with more than 90% of those received in 2017 related to device removal.¹⁹ As more complications and complaints have been reported, the lack of comparative data has presented a problem for understanding the relative risk of the procedure as compared with laparoscopic techniques. Additionally, the approval studies lacked information about what happened to women who had an unsuccessful attempted hysteroscopic procedure. Without robust data sets or large trials, early research used evidence-based Markov modeling; findings suggested that hysteroscopic permanent contraception resulted in fewer women achieving successful permanent contraception and that the hysteroscopic procedure was not as effective as laparoscopic occlusion procedures with “typical” use.^24,25

Over the past year, more clinical data have been published comparing hysteroscopic with laparoscopic permanent contraception procedures. In this article, we evaluate this information to help us better understand the relative efficacy and safety of the different permanent contraception methods and review recent articles describing removal techniques to further assist clinicians and patients considering such procedures.

Hysteroscopic versus laparoscopic procedures for permanent contraception

Bouillon K, Bertrand M, Bader G, et al. Association of hysteroscopic vs laparoscopic sterilization with procedural, gynecological, and medical outcomes. JAMA. 2018:319(4):375-387.

Antoun L, Smith P, Gupta J, et al. The feasibility, safety, and effectiveness of hysteroscopic sterilization compared with laparoscopic sterilization. Am J of Obstet Gynecol. 2017;217(5):570.e1-570.e6. doi:10.1016/j.ajog.2017.07.011.

Jokinen E, Heino A, Karipohja T, et al. Safety and effectiveness of female tubal sterilisation by hysteroscopy, laparoscopy, or laparotomy: a register based study. BJOG. 2017;124(12):1851-1857.

In this section, we present 3 recent studies that evaluate pregnancy outcomes and complications including reoperation or second permanent contraception procedure rates.

Data from France measure up to 3-year differences in adverse outcomes

Bouillon and colleagues aimed to identify differences in adverse outcome rates between hysteroscopic and laparoscopic permanent contraceptive methods. Utilizing national hospital discharge data in France, the researchers conducted a large database study review of records from more than 105,000 women aged 30 to 54 years receiving hysteroscopic or laparoscopic permanent contraception between 2010 and 2014. The database contains details based on the ICD-10 codes for all public and private hospitals in France, representing approximately 75% of the total population. Procedures were performed at 831 hospitals in 26 regions.

Adverse outcomes were divided into surgical, medical, and gynecologic complications (TABLE 1) and were assessed at 3 timepoints: at the time of procedure and at 1 and 3 years postprocedure.

Overall, 71,303 women (67.7%) underwent hysteroscopic permanent contraception procedures and 34,054 women (32.3%) underwent laparoscopic permanent contraception procedures. Immediate surgical and medical complications were significantly less common for women having hysteroscopic compared with laparoscopic procedures. Surgical complications at the time of the procedure occurred in 96 (0.13%) and 265 (0.78%) women, respectively (adjusted odds ratio [aOR], 0.18; 95% confidence interval [CI], 0.14-0.23). Medical complications at the time of procedure occurred in 41 (0.06%) and 39 (0.11%) women, respectively (aOR, 0.51; 95% CI, 0.30-0.89).

However, gynecologic outcomes, including need for a second surgery to provide permanent contraception and overall failure rates (need for salpingectomy, a second permanent contraception procedure, or pregnancy) were significantly more common for women having hysteroscopic procedures. By 1 year after the procedure, 2,955 women (4.10%) who initially had a hysteroscopic procedure, and 56 women (0.16%) who had a laparoscopic procedure required a second permanent contraception surgery (adjusted hazard ratio [aHR], 25.99; 95% CI, 17.84-37.86). By the third year, additional procedures were performed in 3,230 (4.5%) and 97 (0.28%) women, respectively (aHR, 16.63; 95% CI, 12.50-22.20). Most (65%) of the repeat procedures were performed laparoscopically. Although pregnancy rates were significantly lower at 1 year among women who initially chose a hysteroscopic procedure (0.24% vs 0.41%; aHR, 0.70; 95% CI, 0.53-0.92), the rates did not differ at 3 years (0.48% vs 0.57%, respectively; aHR, 1.04; 95% CI, 0.83-1.30).

Most importantly, overall procedure failure rates were significantly higher at 1 year in women initially choosing a hysteroscopic approach compared with laparoscopic approach (3,446 [4.83%] vs 235 [0.69%] women; aHR, 7.11; 95% CI, 5.92-8.54). This difference persisted through 3 years (4,098 [5.75%] vs 438 [1.29%] women, respectively; aHR, 4.66; 95% CI, 4.06-5.34).

UK data indicate high reoperation rate for hysteroscopic procedures

Antoun and colleagues aimed to compare pregnancy rates, radiologic imaging follow-up rates, reoperations, and 30-day adverse outcomes, between hysteroscopic and laparoscopic permanent contraception methods. Conducted at a single teaching hospital in the United Kingdom, this study included 3,497 women who underwent procedures between 2005 and 2015. The data were collected prospectively for the 1,085 women who underwent hysteroscopic procedures and retrospectively for 2,412 women who had laparoscopic permanent contraception procedures with the Filshie clip.

Over the 10-year study period, hysteroscopic permanent contraception increased from 14.2% (40 of 280) of procedures in 2005 to 40.5% (150 of 350) of procedures in 2015 (P<.001). Overall, 2,400 women (99.5%) underwent successful laparoscopic permanent contraception, compared with 992 women (91.4%) in the hysteroscopic group (OR, 18.8; 95% CI, 10.2-34.4).

In the hysteroscopic group, 958 women (97%) returned for confirmatory testing, of whom 902 (91% of women with successful placement) underwent satisfactory confirmatory testing. There were 93 (8.6%) unsuccessful placements that were due to inability to visualize ostia or tubal stenosis (n = 72 [77.4%]), patient intolerance to procedure (n = 15 [16.1%]), or device failure (n = 6 [6.5%]).

The odds for reoperation were 6 times greater in the hysteroscopic group by 1 year after surgery (22 [2%] vs 8 [0.3%] women; OR, 6.2; 95% CI, 2.8-14.0). However, the 1-year pregnancy risk was similar between the 2 groups, with 3 reported pregnancies after hysteroscopic permanent contraception and 5 reported pregnancies after laparoscopic permanent contraception (OR, 1.3; 95% CI, 0.3-5.6).

Finnish researchers also find high reoperation rate

Jokinen and colleagues used linked national database registries in Finland to capture data on pregnancy rate and reoperations among 16,272 women who underwent permanent contraception procedures between 2009 and 2014. The authors compared outcomes following hysteroscopic (Essure), laparoscopic (Filshie clip), and postpartum minilaparotomy (Pomeroy) permanent contraception techniques. According to the investigators, the latter method was almost exclusively performed at the time of cesarean delivery. While there was no difference in pregnancy rates, second permanent contraception procedures were significantly greater in the hysteroscopic group compared with the laparoscopic group (TABLE 2).

Technique for hysteroscopic permanent contraception insert removal

Johal T, Kuruba N, Sule M, et al. Laparoscopic salpingectomy and removal of Essure hysteroscopic sterilisation device: a case series. Eur J Contracept Reprod Health Care. 2018;23(3):227-230.

Lazorwitz A, Tocce K. A case series of removal of nickel-titanium sterilization microinserts from the uterine cornua using laparoscopic electrocautery for salpingectomy. Contraception. 2017;96(2):96-98.

As reports of complications and concerns with hysteroscopic permanent contraception increase, there has been a rise in device removal procedures. We present 2 recent articles that review laparoscopic techniques for the removal of hysteroscopic permanent contraception devices and describe subsequent outcomes.

Laparoscopic salpingectomy without insert transection

In this descriptive retrospective study, Johal and colleagues reviewed hysteroscopic permanent contraception insert removal in 8 women between 2015 and 2017. The authors described their laparoscopic salpingectomy approach and perioperative complications. Overall safety and feasibility with laparoscopic salpingectomy were evaluated by identifying the number of procedures requiring intraoperative conversion to laparotomy, cornuectomy, or hysterectomy. The authors also measured operative time, estimated blood loss, length of stay, and incidence of implant fracture.

Indications for insert removal included pain (n = 4), dyspareunia (n = 2), abnormal uterine bleeding (n = 1), and unsuccessful placement or evidence of tubal occlusion failure during confirmatory imaging (n = 4). The surgeons divided the mesosalpinx and then transected the fallopian tube approximately 1 cm distal to the cornua exposing the permanent contraception insert while avoiding direct electrosurgical application to the insert. The inserts were then removed intact with gentle traction. All 8 women underwent laparoscopic removal with salpingectomy. One patient had a surgical complication of serosal bowel injury due to laparoscopic entry that was repaired in the usual fashion. Operative time averaged 65 minutes (range, 30 to 100 minutes), blood loss was minimal, and there were no implant fractures.

Laparoscopic salpingectomy with insert transection

In this case series, Lazorwitz and Tocce described the use of laparoscopic salpingectomy for hysteroscopic permanent contraception insert removal in 20 women between 2011 and 2017. The authors described their surgical technique, which included division of the mesosalpinx followed by transection of the fallopian tube about 0.5 to 1 cm distal to the cornua. This process often resulted in transection of the insert, and the remaining insert was grasped and removed with gentle traction. If removal of the insert was incomplete, hysteroscopy was performed to identify remaining parts.

Indications for removal included pelvic pain (n = 14), abnormal uterine bleeding (n = 2), rash (n = 1), and unsuccessful placement or evidence of tubal occlusion failure during confirmatory imaging (n = 6). Three women underwent additional diagnostic hysteroscopy for retained implant fragments after laparoscopic salpingectomy. Fragments in all 3 women were 1 to 3 mm in size and left in situ as they were unable to be removed or located hysteroscopically. There were no reported postoperative complications including injury, infection, or readmission within 30 days of salpingectomy.

Shift in method use

Hysteroscopic permanent contraception procedures have low immediate surgical and medical complication rates but result in a high rate of reoperation to achieve the desired outcome.  Notably, the largest available comparative trials are from Europe, which may affect the generalizability to US providers, patients, and health care systems.

Importantly, since the introduction of hysteroscopic permanent contraception in 2002, the landscape of contraception has changed in the United States. Contraception use has shifted to fewer permanent procedures and more high-efficacy reversible options. Overall, reliance on female permanent contraception has been declining in the United States, accounting for 17.8% of contracepting women in 1995 and 15.5% in 2013.^27,28 Permanent contraception has begun shifting from tubal interruption to salpingectomy as mounting evidence has demonstrated up to a 65% reduction in a woman's lifetime risk of ovarian cancer.^29-32 A recent study from a large Northern California integrated health system reported an increase in salpingectomy for permanent contraception from 1% of interval procedures in 2011 to 78% in 2016.³³

Long-acting reversible contraceptive (LARC) methods are also becoming more prevalent and are used by 7.2% of women using contraception in the United States.^28,34 Typical use pregnancy rates with the levonorgestrel 52-mg intrauterine system, etonogestrel implant, and copper T380A intrauterine device are 0.2%, 0.2%, and 0.4% in the first year, respectively.^35,37 These rates are about the same as those reported for Essure in the articles presented here.^13,26 Because these methods are easily placed in the office and are immediately effective, their increased availability over the past decade changes demand for a permanent contraceptive procedure.

Essure underwent expedited FDA review because it had the potential to fill a contraceptive void--it was considered permanent, highly efficacious, low risk, and accessible to women regardless of health comorbidities or access to hospital operating rooms. The removal of Essure from the market is not only the result of a collection of problem reports (relatively small given the overall number of women who have used the device) but also the aggregate result of a changing marketplace and the differential needs of pharmaceutical companies and patients.

For a hysteroscopic permanent contraception insert to survive as a marketed product, the company needs high volume use. However, the increase in LARC provision and permanent contraceptive procedures using opportunistic salpingectomy have matured the market away from the presently available hysteroscopic method. This technology, in its current form, is ideal for women desiring permanent contraception but who have a contraindication to laparoscopic surgery, or for women who can access an office procedure in their community but lack access to a hospital-based procedure. For a pharmaceutical company, that smaller market may not be enough. However, the technology itself is still vital, and future development should focus on what we have learned; the ideal product should be immediately effective, not require a follow-up confirmation test, and not leave permanent foreign body within the uterus or tube.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Female permanent contraception is among the most widely used contraceptive methods worldwide. In the United States, more than 640,000 procedures are performed each year and it is used by 25% of women who use contraception.^1–4 Female permanent contraception is achieved via salpingectomy, tubal interruption, or hysteroscopic techniques.

Essure, the only currently available hysteroscopic permanent contraception device, approved by the US Food and Drug Administration (FDA) in 2002,^5,6 has been implanted in more than 750,000 women worldwide.⁷ Essure was developed by Conceptus Inc, a small medical device company that was acquired by Bayer in 2013. The greatest uptake has been in the United States, which accounts for approximately 80% of procedures worldwide.^7,8

Essure placement involves insertion of a nickel-titanium alloy coil with a stainless-steel inner coil, polyethylene terephthalate fibers, platinum marker bands, and silver-tin solder.⁹ The insert is approximately 4 cm in length and expands to 2 mm in diameter once deployed.⁹

Potential advantages of a hysteroscopic approach are that intra-abdominal surgery can be avoided and the procedure can be performed in an office without the need for general anesthesia.⁷ Due to these potential benefits, hysteroscopic permanent contraception with Essure underwent expedited review and received FDA approval without any comparative trials.^1,5,10 However, there also are disadvantages: the method is not always successfully placed on first attempt and it is not immediately effective. Successful placement rates range between 60% and 98%, most commonly around 90%.^11–15 Additionally, if placement is successful, alternative contraception must be used until a confirmatory radiologic test is performed at least 3 months after the procedure.^9,11 Initially, hysterosalpingography was required to demonstrate a satisfactory insert location and successful tubal occlusion.^11,16 Compliance with this testing is variable, ranging in studies from 13% to 71%.¹¹ As of 2015, transvaginal ultrasonography showing insert retention and location has been approved as an alternative confirmatory method.^9,11,16,17 Evidence suggests that the less invasive ultrasound option increases follow-up rates; while limited, one study noted an increase in follow-up rates from 77.5% for hysterosalpingogram to 88% (P = .008) for transvaginal ultrasound.¹⁸

Recent concerns about potential medical and safety issues have impacted approval status and marketing of hysteroscopic permanent contraception worldwide. In response to safety concerns, the FDA added a boxed safety warning and patient decision checklist in 2016.¹⁹ Bayer withdrew the device from all markets outside of the United States as of May 2017.^20–22 In April 2018, the FDA restricted Essure sales in the United States only to providers and facilities who utilized an FDA-approved checklist to ensure the device met standards for safety and effectiveness.¹⁹ Most recently, Bayer announced that Essure would no longer be sold or distributed in the United States after December 31, 2018 (See “FDA Press Release”).²³

So how did we get here? How did the promise of a “less invasive” approach for female permanent contraception get off course?

A search of the Manufacturer and User Facility Device Experience (MAUDE) database from Essure’s approval date in 2002 to December 2017 revealed 26,773 medical device reports, with more than 90% of those received in 2017 related to device removal.¹⁹ As more complications and complaints have been reported, the lack of comparative data has presented a problem for understanding the relative risk of the procedure as compared with laparoscopic techniques. Additionally, the approval studies lacked information about what happened to women who had an unsuccessful attempted hysteroscopic procedure. Without robust data sets or large trials, early research used evidence-based Markov modeling; findings suggested that hysteroscopic permanent contraception resulted in fewer women achieving successful permanent contraception and that the hysteroscopic procedure was not as effective as laparoscopic occlusion procedures with “typical” use.^24,25

Over the past year, more clinical data have been published comparing hysteroscopic with laparoscopic permanent contraception procedures. In this article, we evaluate this information to help us better understand the relative efficacy and safety of the different permanent contraception methods and review recent articles describing removal techniques to further assist clinicians and patients considering such procedures.

Hysteroscopic versus laparoscopic procedures for permanent contraception

Bouillon K, Bertrand M, Bader G, et al. Association of hysteroscopic vs laparoscopic sterilization with procedural, gynecological, and medical outcomes. JAMA. 2018:319(4):375-387.

Antoun L, Smith P, Gupta J, et al. The feasibility, safety, and effectiveness of hysteroscopic sterilization compared with laparoscopic sterilization. Am J of Obstet Gynecol. 2017;217(5):570.e1-570.e6. doi:10.1016/j.ajog.2017.07.011.

Jokinen E, Heino A, Karipohja T, et al. Safety and effectiveness of female tubal sterilisation by hysteroscopy, laparoscopy, or laparotomy: a register based study. BJOG. 2017;124(12):1851-1857.

In this section, we present 3 recent studies that evaluate pregnancy outcomes and complications including reoperation or second permanent contraception procedure rates.

Data from France measure up to 3-year differences in adverse outcomes

Bouillon and colleagues aimed to identify differences in adverse outcome rates between hysteroscopic and laparoscopic permanent contraceptive methods. Utilizing national hospital discharge data in France, the researchers conducted a large database study review of records from more than 105,000 women aged 30 to 54 years receiving hysteroscopic or laparoscopic permanent contraception between 2010 and 2014. The database contains details based on the ICD-10 codes for all public and private hospitals in France, representing approximately 75% of the total population. Procedures were performed at 831 hospitals in 26 regions.

Adverse outcomes were divided into surgical, medical, and gynecologic complications (TABLE 1) and were assessed at 3 timepoints: at the time of procedure and at 1 and 3 years postprocedure.

Overall, 71,303 women (67.7%) underwent hysteroscopic permanent contraception procedures and 34,054 women (32.3%) underwent laparoscopic permanent contraception procedures. Immediate surgical and medical complications were significantly less common for women having hysteroscopic compared with laparoscopic procedures. Surgical complications at the time of the procedure occurred in 96 (0.13%) and 265 (0.78%) women, respectively (adjusted odds ratio [aOR], 0.18; 95% confidence interval [CI], 0.14-0.23). Medical complications at the time of procedure occurred in 41 (0.06%) and 39 (0.11%) women, respectively (aOR, 0.51; 95% CI, 0.30-0.89).

However, gynecologic outcomes, including need for a second surgery to provide permanent contraception and overall failure rates (need for salpingectomy, a second permanent contraception procedure, or pregnancy) were significantly more common for women having hysteroscopic procedures. By 1 year after the procedure, 2,955 women (4.10%) who initially had a hysteroscopic procedure, and 56 women (0.16%) who had a laparoscopic procedure required a second permanent contraception surgery (adjusted hazard ratio [aHR], 25.99; 95% CI, 17.84-37.86). By the third year, additional procedures were performed in 3,230 (4.5%) and 97 (0.28%) women, respectively (aHR, 16.63; 95% CI, 12.50-22.20). Most (65%) of the repeat procedures were performed laparoscopically. Although pregnancy rates were significantly lower at 1 year among women who initially chose a hysteroscopic procedure (0.24% vs 0.41%; aHR, 0.70; 95% CI, 0.53-0.92), the rates did not differ at 3 years (0.48% vs 0.57%, respectively; aHR, 1.04; 95% CI, 0.83-1.30).

Most importantly, overall procedure failure rates were significantly higher at 1 year in women initially choosing a hysteroscopic approach compared with laparoscopic approach (3,446 [4.83%] vs 235 [0.69%] women; aHR, 7.11; 95% CI, 5.92-8.54). This difference persisted through 3 years (4,098 [5.75%] vs 438 [1.29%] women, respectively; aHR, 4.66; 95% CI, 4.06-5.34).

UK data indicate high reoperation rate for hysteroscopic procedures

Antoun and colleagues aimed to compare pregnancy rates, radiologic imaging follow-up rates, reoperations, and 30-day adverse outcomes, between hysteroscopic and laparoscopic permanent contraception methods. Conducted at a single teaching hospital in the United Kingdom, this study included 3,497 women who underwent procedures between 2005 and 2015. The data were collected prospectively for the 1,085 women who underwent hysteroscopic procedures and retrospectively for 2,412 women who had laparoscopic permanent contraception procedures with the Filshie clip.

Over the 10-year study period, hysteroscopic permanent contraception increased from 14.2% (40 of 280) of procedures in 2005 to 40.5% (150 of 350) of procedures in 2015 (P<.001). Overall, 2,400 women (99.5%) underwent successful laparoscopic permanent contraception, compared with 992 women (91.4%) in the hysteroscopic group (OR, 18.8; 95% CI, 10.2-34.4).

In the hysteroscopic group, 958 women (97%) returned for confirmatory testing, of whom 902 (91% of women with successful placement) underwent satisfactory confirmatory testing. There were 93 (8.6%) unsuccessful placements that were due to inability to visualize ostia or tubal stenosis (n = 72 [77.4%]), patient intolerance to procedure (n = 15 [16.1%]), or device failure (n = 6 [6.5%]).

The odds for reoperation were 6 times greater in the hysteroscopic group by 1 year after surgery (22 [2%] vs 8 [0.3%] women; OR, 6.2; 95% CI, 2.8-14.0). However, the 1-year pregnancy risk was similar between the 2 groups, with 3 reported pregnancies after hysteroscopic permanent contraception and 5 reported pregnancies after laparoscopic permanent contraception (OR, 1.3; 95% CI, 0.3-5.6).

Finnish researchers also find high reoperation rate

Jokinen and colleagues used linked national database registries in Finland to capture data on pregnancy rate and reoperations among 16,272 women who underwent permanent contraception procedures between 2009 and 2014. The authors compared outcomes following hysteroscopic (Essure), laparoscopic (Filshie clip), and postpartum minilaparotomy (Pomeroy) permanent contraception techniques. According to the investigators, the latter method was almost exclusively performed at the time of cesarean delivery. While there was no difference in pregnancy rates, second permanent contraception procedures were significantly greater in the hysteroscopic group compared with the laparoscopic group (TABLE 2).

Technique for hysteroscopic permanent contraception insert removal

Johal T, Kuruba N, Sule M, et al. Laparoscopic salpingectomy and removal of Essure hysteroscopic sterilisation device: a case series. Eur J Contracept Reprod Health Care. 2018;23(3):227-230.

Lazorwitz A, Tocce K. A case series of removal of nickel-titanium sterilization microinserts from the uterine cornua using laparoscopic electrocautery for salpingectomy. Contraception. 2017;96(2):96-98.

As reports of complications and concerns with hysteroscopic permanent contraception increase, there has been a rise in device removal procedures. We present 2 recent articles that review laparoscopic techniques for the removal of hysteroscopic permanent contraception devices and describe subsequent outcomes.

Laparoscopic salpingectomy without insert transection

In this descriptive retrospective study, Johal and colleagues reviewed hysteroscopic permanent contraception insert removal in 8 women between 2015 and 2017. The authors described their laparoscopic salpingectomy approach and perioperative complications. Overall safety and feasibility with laparoscopic salpingectomy were evaluated by identifying the number of procedures requiring intraoperative conversion to laparotomy, cornuectomy, or hysterectomy. The authors also measured operative time, estimated blood loss, length of stay, and incidence of implant fracture.

Indications for insert removal included pain (n = 4), dyspareunia (n = 2), abnormal uterine bleeding (n = 1), and unsuccessful placement or evidence of tubal occlusion failure during confirmatory imaging (n = 4). The surgeons divided the mesosalpinx and then transected the fallopian tube approximately 1 cm distal to the cornua exposing the permanent contraception insert while avoiding direct electrosurgical application to the insert. The inserts were then removed intact with gentle traction. All 8 women underwent laparoscopic removal with salpingectomy. One patient had a surgical complication of serosal bowel injury due to laparoscopic entry that was repaired in the usual fashion. Operative time averaged 65 minutes (range, 30 to 100 minutes), blood loss was minimal, and there were no implant fractures.

Laparoscopic salpingectomy with insert transection

In this case series, Lazorwitz and Tocce described the use of laparoscopic salpingectomy for hysteroscopic permanent contraception insert removal in 20 women between 2011 and 2017. The authors described their surgical technique, which included division of the mesosalpinx followed by transection of the fallopian tube about 0.5 to 1 cm distal to the cornua. This process often resulted in transection of the insert, and the remaining insert was grasped and removed with gentle traction. If removal of the insert was incomplete, hysteroscopy was performed to identify remaining parts.

Indications for removal included pelvic pain (n = 14), abnormal uterine bleeding (n = 2), rash (n = 1), and unsuccessful placement or evidence of tubal occlusion failure during confirmatory imaging (n = 6). Three women underwent additional diagnostic hysteroscopy for retained implant fragments after laparoscopic salpingectomy. Fragments in all 3 women were 1 to 3 mm in size and left in situ as they were unable to be removed or located hysteroscopically. There were no reported postoperative complications including injury, infection, or readmission within 30 days of salpingectomy.

Shift in method use

Hysteroscopic permanent contraception procedures have low immediate surgical and medical complication rates but result in a high rate of reoperation to achieve the desired outcome.  Notably, the largest available comparative trials are from Europe, which may affect the generalizability to US providers, patients, and health care systems.

Importantly, since the introduction of hysteroscopic permanent contraception in 2002, the landscape of contraception has changed in the United States. Contraception use has shifted to fewer permanent procedures and more high-efficacy reversible options. Overall, reliance on female permanent contraception has been declining in the United States, accounting for 17.8% of contracepting women in 1995 and 15.5% in 2013.^27,28 Permanent contraception has begun shifting from tubal interruption to salpingectomy as mounting evidence has demonstrated up to a 65% reduction in a woman's lifetime risk of ovarian cancer.^29-32 A recent study from a large Northern California integrated health system reported an increase in salpingectomy for permanent contraception from 1% of interval procedures in 2011 to 78% in 2016.³³

Long-acting reversible contraceptive (LARC) methods are also becoming more prevalent and are used by 7.2% of women using contraception in the United States.^28,34 Typical use pregnancy rates with the levonorgestrel 52-mg intrauterine system, etonogestrel implant, and copper T380A intrauterine device are 0.2%, 0.2%, and 0.4% in the first year, respectively.^35,37 These rates are about the same as those reported for Essure in the articles presented here.^13,26 Because these methods are easily placed in the office and are immediately effective, their increased availability over the past decade changes demand for a permanent contraceptive procedure.

Essure underwent expedited FDA review because it had the potential to fill a contraceptive void--it was considered permanent, highly efficacious, low risk, and accessible to women regardless of health comorbidities or access to hospital operating rooms. The removal of Essure from the market is not only the result of a collection of problem reports (relatively small given the overall number of women who have used the device) but also the aggregate result of a changing marketplace and the differential needs of pharmaceutical companies and patients.

For a hysteroscopic permanent contraception insert to survive as a marketed product, the company needs high volume use. However, the increase in LARC provision and permanent contraceptive procedures using opportunistic salpingectomy have matured the market away from the presently available hysteroscopic method. This technology, in its current form, is ideal for women desiring permanent contraception but who have a contraindication to laparoscopic surgery, or for women who can access an office procedure in their community but lack access to a hospital-based procedure. For a pharmaceutical company, that smaller market may not be enough. However, the technology itself is still vital, and future development should focus on what we have learned; the ideal product should be immediately effective, not require a follow-up confirmation test, and not leave permanent foreign body within the uterus or tube.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Female permanent contraception is among the most widely used contraceptive methods worldwide. In the United States, more than 640,000 procedures are performed each year and it is used by 25% of women who use contraception.^1–4 Female permanent contraception is achieved via salpingectomy, tubal interruption, or hysteroscopic techniques.

Essure, the only currently available hysteroscopic permanent contraception device, approved by the US Food and Drug Administration (FDA) in 2002,^5,6 has been implanted in more than 750,000 women worldwide.⁷ Essure was developed by Conceptus Inc, a small medical device company that was acquired by Bayer in 2013. The greatest uptake has been in the United States, which accounts for approximately 80% of procedures worldwide.^7,8

Essure placement involves insertion of a nickel-titanium alloy coil with a stainless-steel inner coil, polyethylene terephthalate fibers, platinum marker bands, and silver-tin solder.⁹ The insert is approximately 4 cm in length and expands to 2 mm in diameter once deployed.⁹

Potential advantages of a hysteroscopic approach are that intra-abdominal surgery can be avoided and the procedure can be performed in an office without the need for general anesthesia.⁷ Due to these potential benefits, hysteroscopic permanent contraception with Essure underwent expedited review and received FDA approval without any comparative trials.^1,5,10 However, there also are disadvantages: the method is not always successfully placed on first attempt and it is not immediately effective. Successful placement rates range between 60% and 98%, most commonly around 90%.^11–15 Additionally, if placement is successful, alternative contraception must be used until a confirmatory radiologic test is performed at least 3 months after the procedure.^9,11 Initially, hysterosalpingography was required to demonstrate a satisfactory insert location and successful tubal occlusion.^11,16 Compliance with this testing is variable, ranging in studies from 13% to 71%.¹¹ As of 2015, transvaginal ultrasonography showing insert retention and location has been approved as an alternative confirmatory method.^9,11,16,17 Evidence suggests that the less invasive ultrasound option increases follow-up rates; while limited, one study noted an increase in follow-up rates from 77.5% for hysterosalpingogram to 88% (P = .008) for transvaginal ultrasound.¹⁸

Recent concerns about potential medical and safety issues have impacted approval status and marketing of hysteroscopic permanent contraception worldwide. In response to safety concerns, the FDA added a boxed safety warning and patient decision checklist in 2016.¹⁹ Bayer withdrew the device from all markets outside of the United States as of May 2017.^20–22 In April 2018, the FDA restricted Essure sales in the United States only to providers and facilities who utilized an FDA-approved checklist to ensure the device met standards for safety and effectiveness.¹⁹ Most recently, Bayer announced that Essure would no longer be sold or distributed in the United States after December 31, 2018 (See “FDA Press Release”).²³

So how did we get here? How did the promise of a “less invasive” approach for female permanent contraception get off course?

A search of the Manufacturer and User Facility Device Experience (MAUDE) database from Essure’s approval date in 2002 to December 2017 revealed 26,773 medical device reports, with more than 90% of those received in 2017 related to device removal.¹⁹ As more complications and complaints have been reported, the lack of comparative data has presented a problem for understanding the relative risk of the procedure as compared with laparoscopic techniques. Additionally, the approval studies lacked information about what happened to women who had an unsuccessful attempted hysteroscopic procedure. Without robust data sets or large trials, early research used evidence-based Markov modeling; findings suggested that hysteroscopic permanent contraception resulted in fewer women achieving successful permanent contraception and that the hysteroscopic procedure was not as effective as laparoscopic occlusion procedures with “typical” use.^24,25

Over the past year, more clinical data have been published comparing hysteroscopic with laparoscopic permanent contraception procedures. In this article, we evaluate this information to help us better understand the relative efficacy and safety of the different permanent contraception methods and review recent articles describing removal techniques to further assist clinicians and patients considering such procedures.

Hysteroscopic versus laparoscopic procedures for permanent contraception

Bouillon K, Bertrand M, Bader G, et al. Association of hysteroscopic vs laparoscopic sterilization with procedural, gynecological, and medical outcomes. JAMA. 2018:319(4):375-387.

Antoun L, Smith P, Gupta J, et al. The feasibility, safety, and effectiveness of hysteroscopic sterilization compared with laparoscopic sterilization. Am J of Obstet Gynecol. 2017;217(5):570.e1-570.e6. doi:10.1016/j.ajog.2017.07.011.

Jokinen E, Heino A, Karipohja T, et al. Safety and effectiveness of female tubal sterilisation by hysteroscopy, laparoscopy, or laparotomy: a register based study. BJOG. 2017;124(12):1851-1857.

In this section, we present 3 recent studies that evaluate pregnancy outcomes and complications including reoperation or second permanent contraception procedure rates.

Data from France measure up to 3-year differences in adverse outcomes

Bouillon and colleagues aimed to identify differences in adverse outcome rates between hysteroscopic and laparoscopic permanent contraceptive methods. Utilizing national hospital discharge data in France, the researchers conducted a large database study review of records from more than 105,000 women aged 30 to 54 years receiving hysteroscopic or laparoscopic permanent contraception between 2010 and 2014. The database contains details based on the ICD-10 codes for all public and private hospitals in France, representing approximately 75% of the total population. Procedures were performed at 831 hospitals in 26 regions.

Adverse outcomes were divided into surgical, medical, and gynecologic complications (TABLE 1) and were assessed at 3 timepoints: at the time of procedure and at 1 and 3 years postprocedure.

Overall, 71,303 women (67.7%) underwent hysteroscopic permanent contraception procedures and 34,054 women (32.3%) underwent laparoscopic permanent contraception procedures. Immediate surgical and medical complications were significantly less common for women having hysteroscopic compared with laparoscopic procedures. Surgical complications at the time of the procedure occurred in 96 (0.13%) and 265 (0.78%) women, respectively (adjusted odds ratio [aOR], 0.18; 95% confidence interval [CI], 0.14-0.23). Medical complications at the time of procedure occurred in 41 (0.06%) and 39 (0.11%) women, respectively (aOR, 0.51; 95% CI, 0.30-0.89).

However, gynecologic outcomes, including need for a second surgery to provide permanent contraception and overall failure rates (need for salpingectomy, a second permanent contraception procedure, or pregnancy) were significantly more common for women having hysteroscopic procedures. By 1 year after the procedure, 2,955 women (4.10%) who initially had a hysteroscopic procedure, and 56 women (0.16%) who had a laparoscopic procedure required a second permanent contraception surgery (adjusted hazard ratio [aHR], 25.99; 95% CI, 17.84-37.86). By the third year, additional procedures were performed in 3,230 (4.5%) and 97 (0.28%) women, respectively (aHR, 16.63; 95% CI, 12.50-22.20). Most (65%) of the repeat procedures were performed laparoscopically. Although pregnancy rates were significantly lower at 1 year among women who initially chose a hysteroscopic procedure (0.24% vs 0.41%; aHR, 0.70; 95% CI, 0.53-0.92), the rates did not differ at 3 years (0.48% vs 0.57%, respectively; aHR, 1.04; 95% CI, 0.83-1.30).

Most importantly, overall procedure failure rates were significantly higher at 1 year in women initially choosing a hysteroscopic approach compared with laparoscopic approach (3,446 [4.83%] vs 235 [0.69%] women; aHR, 7.11; 95% CI, 5.92-8.54). This difference persisted through 3 years (4,098 [5.75%] vs 438 [1.29%] women, respectively; aHR, 4.66; 95% CI, 4.06-5.34).

UK data indicate high reoperation rate for hysteroscopic procedures

Antoun and colleagues aimed to compare pregnancy rates, radiologic imaging follow-up rates, reoperations, and 30-day adverse outcomes, between hysteroscopic and laparoscopic permanent contraception methods. Conducted at a single teaching hospital in the United Kingdom, this study included 3,497 women who underwent procedures between 2005 and 2015. The data were collected prospectively for the 1,085 women who underwent hysteroscopic procedures and retrospectively for 2,412 women who had laparoscopic permanent contraception procedures with the Filshie clip.

Over the 10-year study period, hysteroscopic permanent contraception increased from 14.2% (40 of 280) of procedures in 2005 to 40.5% (150 of 350) of procedures in 2015 (P<.001). Overall, 2,400 women (99.5%) underwent successful laparoscopic permanent contraception, compared with 992 women (91.4%) in the hysteroscopic group (OR, 18.8; 95% CI, 10.2-34.4).

In the hysteroscopic group, 958 women (97%) returned for confirmatory testing, of whom 902 (91% of women with successful placement) underwent satisfactory confirmatory testing. There were 93 (8.6%) unsuccessful placements that were due to inability to visualize ostia or tubal stenosis (n = 72 [77.4%]), patient intolerance to procedure (n = 15 [16.1%]), or device failure (n = 6 [6.5%]).

The odds for reoperation were 6 times greater in the hysteroscopic group by 1 year after surgery (22 [2%] vs 8 [0.3%] women; OR, 6.2; 95% CI, 2.8-14.0). However, the 1-year pregnancy risk was similar between the 2 groups, with 3 reported pregnancies after hysteroscopic permanent contraception and 5 reported pregnancies after laparoscopic permanent contraception (OR, 1.3; 95% CI, 0.3-5.6).

Finnish researchers also find high reoperation rate

Jokinen and colleagues used linked national database registries in Finland to capture data on pregnancy rate and reoperations among 16,272 women who underwent permanent contraception procedures between 2009 and 2014. The authors compared outcomes following hysteroscopic (Essure), laparoscopic (Filshie clip), and postpartum minilaparotomy (Pomeroy) permanent contraception techniques. According to the investigators, the latter method was almost exclusively performed at the time of cesarean delivery. While there was no difference in pregnancy rates, second permanent contraception procedures were significantly greater in the hysteroscopic group compared with the laparoscopic group (TABLE 2).

Technique for hysteroscopic permanent contraception insert removal

Johal T, Kuruba N, Sule M, et al. Laparoscopic salpingectomy and removal of Essure hysteroscopic sterilisation device: a case series. Eur J Contracept Reprod Health Care. 2018;23(3):227-230.

Lazorwitz A, Tocce K. A case series of removal of nickel-titanium sterilization microinserts from the uterine cornua using laparoscopic electrocautery for salpingectomy. Contraception. 2017;96(2):96-98.

As reports of complications and concerns with hysteroscopic permanent contraception increase, there has been a rise in device removal procedures. We present 2 recent articles that review laparoscopic techniques for the removal of hysteroscopic permanent contraception devices and describe subsequent outcomes.

Laparoscopic salpingectomy without insert transection

In this descriptive retrospective study, Johal and colleagues reviewed hysteroscopic permanent contraception insert removal in 8 women between 2015 and 2017. The authors described their laparoscopic salpingectomy approach and perioperative complications. Overall safety and feasibility with laparoscopic salpingectomy were evaluated by identifying the number of procedures requiring intraoperative conversion to laparotomy, cornuectomy, or hysterectomy. The authors also measured operative time, estimated blood loss, length of stay, and incidence of implant fracture.

Indications for insert removal included pain (n = 4), dyspareunia (n = 2), abnormal uterine bleeding (n = 1), and unsuccessful placement or evidence of tubal occlusion failure during confirmatory imaging (n = 4). The surgeons divided the mesosalpinx and then transected the fallopian tube approximately 1 cm distal to the cornua exposing the permanent contraception insert while avoiding direct electrosurgical application to the insert. The inserts were then removed intact with gentle traction. All 8 women underwent laparoscopic removal with salpingectomy. One patient had a surgical complication of serosal bowel injury due to laparoscopic entry that was repaired in the usual fashion. Operative time averaged 65 minutes (range, 30 to 100 minutes), blood loss was minimal, and there were no implant fractures.

Laparoscopic salpingectomy with insert transection

In this case series, Lazorwitz and Tocce described the use of laparoscopic salpingectomy for hysteroscopic permanent contraception insert removal in 20 women between 2011 and 2017. The authors described their surgical technique, which included division of the mesosalpinx followed by transection of the fallopian tube about 0.5 to 1 cm distal to the cornua. This process often resulted in transection of the insert, and the remaining insert was grasped and removed with gentle traction. If removal of the insert was incomplete, hysteroscopy was performed to identify remaining parts.

Indications for removal included pelvic pain (n = 14), abnormal uterine bleeding (n = 2), rash (n = 1), and unsuccessful placement or evidence of tubal occlusion failure during confirmatory imaging (n = 6). Three women underwent additional diagnostic hysteroscopy for retained implant fragments after laparoscopic salpingectomy. Fragments in all 3 women were 1 to 3 mm in size and left in situ as they were unable to be removed or located hysteroscopically. There were no reported postoperative complications including injury, infection, or readmission within 30 days of salpingectomy.

Shift in method use

Hysteroscopic permanent contraception procedures have low immediate surgical and medical complication rates but result in a high rate of reoperation to achieve the desired outcome.  Notably, the largest available comparative trials are from Europe, which may affect the generalizability to US providers, patients, and health care systems.

Importantly, since the introduction of hysteroscopic permanent contraception in 2002, the landscape of contraception has changed in the United States. Contraception use has shifted to fewer permanent procedures and more high-efficacy reversible options. Overall, reliance on female permanent contraception has been declining in the United States, accounting for 17.8% of contracepting women in 1995 and 15.5% in 2013.^27,28 Permanent contraception has begun shifting from tubal interruption to salpingectomy as mounting evidence has demonstrated up to a 65% reduction in a woman's lifetime risk of ovarian cancer.^29-32 A recent study from a large Northern California integrated health system reported an increase in salpingectomy for permanent contraception from 1% of interval procedures in 2011 to 78% in 2016.³³

Long-acting reversible contraceptive (LARC) methods are also becoming more prevalent and are used by 7.2% of women using contraception in the United States.^28,34 Typical use pregnancy rates with the levonorgestrel 52-mg intrauterine system, etonogestrel implant, and copper T380A intrauterine device are 0.2%, 0.2%, and 0.4% in the first year, respectively.^35,37 These rates are about the same as those reported for Essure in the articles presented here.^13,26 Because these methods are easily placed in the office and are immediately effective, their increased availability over the past decade changes demand for a permanent contraceptive procedure.

Essure underwent expedited FDA review because it had the potential to fill a contraceptive void--it was considered permanent, highly efficacious, low risk, and accessible to women regardless of health comorbidities or access to hospital operating rooms. The removal of Essure from the market is not only the result of a collection of problem reports (relatively small given the overall number of women who have used the device) but also the aggregate result of a changing marketplace and the differential needs of pharmaceutical companies and patients.

For a hysteroscopic permanent contraception insert to survive as a marketed product, the company needs high volume use. However, the increase in LARC provision and permanent contraceptive procedures using opportunistic salpingectomy have matured the market away from the presently available hysteroscopic method. This technology, in its current form, is ideal for women desiring permanent contraception but who have a contraindication to laparoscopic surgery, or for women who can access an office procedure in their community but lack access to a hospital-based procedure. For a pharmaceutical company, that smaller market may not be enough. However, the technology itself is still vital, and future development should focus on what we have learned; the ideal product should be immediately effective, not require a follow-up confirmation test, and not leave permanent foreign body within the uterus or tube.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

According to the most recent data (2011–2013), 62% of women of childbearing age (15–44 years) use some method of contraception. Of these “contracepting” women, about 25% reported relying on permanent contraception, making it one of the most common methods of contraception used by women in the United States (FIGURE 1).^1,2 Women either can choose to have a permanent contraception procedure performed immediately postpartum, which occurs after approximately 9% of all hospital deliveries in the United States,³ or at a time separate from pregnancy.

The most common methods of permanent contraception include partial salpingectomy at the time of cesarean delivery or within 24 hours after vaginal delivery and laparoscopic occlusive procedures at a time unrelated to the postpartum period.³ Hysteroscopic occlusion of the tubal ostia is a newer option, introduced in 2002; its worldwide use is concentrated in the United States, which accounts for 80% of sales based on revenue.⁴

Historically, for procedures remote from pregnancy, the laparoscopic approach evolved with less sophisticated laparoscopic equipment and limited visualization, which resulted in efficiency and safety being the primary goals of the procedure.⁵ Accordingly, rapid occlusive procedures were commonplace. However, advancement of laparoscopic technology related to insufflation systems, surgical equipment, and video capabilities did not change this practice.

Recent literature has suggested that complete fallopian tube removal provides additional benefits. With increasing knowledge about the origin of ovarian cancer, as well as increasing data to support the hypothesis that complete tubal excision results in increased ovarian cancer protection when compared with occlusive or partial salpingectomies, both the American College of Obstetricians and Gynecologists (ACOG)⁶ and the Society of Gynecologic Oncology (SGO)⁷ recommend discussing bilateral total salpingectomy with patients desiring permanent contraception. Although occlusive procedures decrease a woman’s lifetime risk of ovarian cancer by 24% to 34%,^8,9 total salpingectomy likely reduces this risk by 49% to 65%.^10,11

With this new evidence, McAlpine and colleagues initiated an educational campaign, targeting all ObGyns in British Columbia, which outlined the role of the fallopian tube in ovarian cancer and urged the consideration of total salpingectomy for permanent contraception in place of occlusive or partial salpingectomy procedures. They found that this one-time targeted education increased the use of total salpingectomy for permanent contraception from 0.5% at 2 years before the intervention to 33.3% by 2 years afterwards.¹² On average, laparoscopic bilateral salpingectomy took 10 minutes longer to complete than occlusive procedures. Most importantly, they found no significant differences in complication rates, including hospital readmissions or blood transfusions.

Although our community can be applauded for the rapid uptake of concomitant bilateral salpingectomy at the time of benign hysterectomy,^12,13 offering total salpingectomy for permanent contraception is far from common practice. Similarly, while multiple studies have been published to support the practice of opportunistic salpingectomy at the time of hysterectomy, little has been published about the use of bilateral salpingectomy for permanent contraception until this past year.

In this article, we review some of the first publications to focus specifically on the feasibility and safety profile of performing either immediate postpartum total salpingectomy or interval total salpingectomy in women desiring permanent contraception.

Read about a total salpingectomy at delivery

Total salpingectomy: A viable option for permanent contraception after vaginal or at cesarean delivery

Shinar S, Blecher Y, Alpern S, et al. Total bilateral salpingectomy versus partial bilateral salpingectomy for permanent sterilization during cesarean delivery. Arch Gynecol Obstet. 2017;295(5):1185-1189.

Danis RB, Della Badia CR, Richard SD. Postpartum permanent sterilization: could bilateral salpingectomy replace bilateral tubal ligation? J Minim Invasive Gynecol. 2016;23(6):928-932.

Shinar and colleagues presented a retrospective case series that included women undergoing permanent contraception procedures during cesarean delivery at a single tertiary medical center. The authors evaluated outcomes before and after a global hospital policy changed the preferred permanent contraception procedure from partial to total salpingectomy.

Details of the Shinar technique and outcomes

Of the 149 women included, 99 underwent partial salpingectomy via the modified Pomeroy technique and 50 underwent total salpingectomy using an electrothermal bipolar tissue-sealing instrument (Ligasure). The authors found no difference in operative times and similar rates of complications. Composite adverse outcomes, defined as surgery duration greater than 45 minutes, hemoglobin decline greater than 1.2 g/dL, need for blood transfusion, prolonged hospitalization, ICU admission, or re-laparotomy, were comparable and were reported as 30.3% and 36.0% in the partial and total salpingectomy groups, respectively, (P = .57).One major complication occurred in the total salpingectomy cohort; postoperatively the patient had hemodynamic instability and was found to have hemoperitoneum requiring exploratory laparotomy. Significant bleeding from the bilateral mesosalpinges was discovered, presumably directly related to the total salpingectomy.

Related article:
Hysteroscopic tubal occlusion: How new product labeling can be a resource for patient counseling

Details of Danis et al

Intuitively, performing salpingectomy at the time of cesarean delivery does not seem as significant a change in practice as would performing salpingectomy through a small periumbilical incision after vaginal delivery. However, Danis and colleagues did just that; they published a retrospective case series of total salpingectomy performed within 24 hours after a vaginal delivery at an urban, academic institution. They included all women admitted for full-term vaginal deliveries who desired permanent contraception, with no exclusion criteria related to body mass index (BMI). The authors reported on 80 women, including 64 (80%) who underwent partial salpingectomy via the modified Pomeroy or Parkland technique and 16 (20%) who underwent total salpingectomy. Most women had a BMI of less than 30 kg/m²; less than 15% of the women in each group had a BMI greater than 40 kg/m².

The technique for total salpingectomy involved a 2- to 3-cm vertical incision at the level of the umbilicus, elevation of the entire fallopian tube with 2 Babcock clamps, followed by the development of 2 to 3 windows with monopolar electrocautery in the mesosalpinx and subsequent suture ligation with polyglactin 910 (Vicryl, Ethicon).

Major findings included slightly longer operative time in the total salpingectomy compared with the partial salpingectomy group (a finding consistent with other studies^12,14,15) and no difference in complication rates. The average (SD) surgical time in the partial salpingectomy group was 59 (16) minutes, compared with 71 (6) minutes in the total salpingectomy group (P = .003). The authors reported 4 (6.3%) complications in the partial salpingectomy group--ileus, excessive bleeding from mesosalpinx, and incisional site hematoma--and no complications in the total salpingectomy group (P = .58).

Read about interval permanent contraception

Feasibility of interval laparoscopic permanent contraception via bilateral salpingectomy 

Westberg J, Scott F, Creinin MD. Safety outcomes of female sterilization by salpingectomy and tubal occlusion. Contraception. 2017;95(5):505-508.

In this retrospective study, authors used billing data to identify women undergoing interval laparoscopic permanent contraception at a single academic medical center. They educated physicians and patients about the potential benefits to ovarian cancer risk with total salpingectomy (similar to the educational initiative done in British Columbia) and discussed the requirement for the extra incision and more time for the surgery. From 2013 to 2015 use of salpingectomy for permanent contraception changed from 45% of the procedures to 85%, a fairly dramatic trend.¹⁸ With these data, the authors compared outcomes between the women receiving tubal occlusive procedures and women receiving bilateral salpingectomy.

Related article:
Risk-reducing salpingectomy at benign hysterectomy: Have surgeons embraced this practice?

Details of surgical time and complications

Tubal occlusion procedures were performed through 2 abdominal ports, and device placement was at the discretion of the provider. Bilateral salpingectomies were performed through 3 abdominal port sites with an electrothermal bipolar tissue-sealing instrument. A total of 149 procedures were identified, 68 tubal occlusions (19% Falope rings, 32% bipolar cautery, and 47% Filshie clips) and 81 bilateral salpingectomies.

The surgical time average (SD) was 6 minutes longer for the salpingectomies (44 [13] minutes vs 38 [15] minutes; P = .018). As would be expected, more experienced residents had shorter surgical times when compared with less experienced residents for both procedures (FIGURE 2).¹⁵ Similar rates of both immediate and short-term surgical complications were noted. One immediate complication was reported in each group, both of which were secondary to anesthesia issues.

Interestingly, short-term complications were lower in the salpingectomy group (4.9%) versus the tubal occlusion group (14.7%), although this difference was barely not statistically significant (P = .051). These complications included 1 incisional site infection requiring oral antibiotics and 3 cases of increased pain in the salpingectomy group and 4 incisional site infections with 6 patients reporting increased pain in the tubal occlusion group.

Read about tube removal and ovarian reserve

Does total removal of the tubes affect ovarian reserve?

Ganer Herman H, Gluck O, Keidar R, et al. Ovarian reserve following cesarean section with salpingectomy vs tubal ligation: a randomized trial. Am J Obstet Gynecol. 2017;doi: 10.1016/j.ajog.2017.04.028.

As acceptability of total salpingectomy for permanent contraception increases, one concern is that complete removal may alter blood supply to the ovary, resulting in decreased ovarian reserve and, subsequently, earlier menopause. Several studies have addressed the potential effect of salpingectomy on ovarian function when performed at the time of hysterectomy, most of which have noted no difference in anti-Müllerian hormone (AMH) levels and sonographic parameters following surgery.¹⁹ However, very little has been published to assess this same question when the salpingectomy is performed for the purpose of permanent contraception.

Ganer Herman and colleagues aimed to assess short-term ovarian reserve by measuring AMH levels preoperatively and 6 to 8 weeks postoperatively in patients undergoing partial or total salpingectomy at the time of elective cesarean delivery.

Related article:
Salpingectomy after vaginal hysterectomy: Technique, tips, and pearls

Details of the study

The study included women aged 18 to 45 who presented for elective cesarean delivery and who requested permanent contraception. Exclusion criteria included previous tubal surgery, emergent cesarean delivery, personal history of breast carcinoma, familial history of ovarian carcinoma, and BRCA carriage.

Women were randomly assigned at a 1:1 ratio to bilateral total salpingectomy or bilateral partial salpingectomy. A complete blood count and AMH level were drawn the night prior to surgery. Intraoperatively, after delivery and hysterotomy closure, partial salpingectomy, via the Parkland technique, or total salpingectomy, using a suture ligation technique, was performed.

Of the 46 women enrolled, follow-up was completed by 16 of 22 women (72%) in the total salpingectomy group and 18 of 24 women (75%) in the partial salpingectomy group. Patients in the total salpingectomy group were slightly older (mean age, 37 vs 34 years; P = .02), but otherwise all demographic and obstetric characteristics were comparable.

No differences were noted in preoperative and postoperative AMH levels between groups, with an average (SD) increase of 0.58 (0.98) ng/mL versus 0.39 (0.41) ng/mL in the total salpingectomy and partial salpingectomy groups, respectively (P = .45), consistent with known postpartum AMH level trends.

Other findings included an average 13-minute increase in operative time in the total salpingectomy cases, similar safety profile of the 2 methods as there were no postoperative complications during the study period, and no differences in postoperative hemoglobin levels.

Conclusion

The studies reviewed in this article are some of the first to evaluate the feasibility and safety of opportunistic, or total, salpingectomy for permanent contraception since the ACOG and SGO recommendations were published. Just as our community has adopted the common practice of opportunistic salpingectomy at the time of hysterectomy, we should continue to advocate for a similar practice when discussing permanent contraception. Additionally, the Westberg study provides good evidence that educational initiatives can influence provider practices, which upholds the data published by McAlpine and colleagues in British Columbia. This information is promising and valuable.

Our universal goal as ObGyns is to provide the best reproductive health care possible based on the most recent evidence available. Continuing to advocate for opportunistic salpingectomy for permanent contraception purposes meets this goal and potentially provides significant noncontraceptive benefits.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

According to the most recent data (2011–2013), 62% of women of childbearing age (15–44 years) use some method of contraception. Of these “contracepting” women, about 25% reported relying on permanent contraception, making it one of the most common methods of contraception used by women in the United States (FIGURE 1).^1,2 Women either can choose to have a permanent contraception procedure performed immediately postpartum, which occurs after approximately 9% of all hospital deliveries in the United States,³ or at a time separate from pregnancy.

The most common methods of permanent contraception include partial salpingectomy at the time of cesarean delivery or within 24 hours after vaginal delivery and laparoscopic occlusive procedures at a time unrelated to the postpartum period.³ Hysteroscopic occlusion of the tubal ostia is a newer option, introduced in 2002; its worldwide use is concentrated in the United States, which accounts for 80% of sales based on revenue.⁴

Historically, for procedures remote from pregnancy, the laparoscopic approach evolved with less sophisticated laparoscopic equipment and limited visualization, which resulted in efficiency and safety being the primary goals of the procedure.⁵ Accordingly, rapid occlusive procedures were commonplace. However, advancement of laparoscopic technology related to insufflation systems, surgical equipment, and video capabilities did not change this practice.

Recent literature has suggested that complete fallopian tube removal provides additional benefits. With increasing knowledge about the origin of ovarian cancer, as well as increasing data to support the hypothesis that complete tubal excision results in increased ovarian cancer protection when compared with occlusive or partial salpingectomies, both the American College of Obstetricians and Gynecologists (ACOG)⁶ and the Society of Gynecologic Oncology (SGO)⁷ recommend discussing bilateral total salpingectomy with patients desiring permanent contraception. Although occlusive procedures decrease a woman’s lifetime risk of ovarian cancer by 24% to 34%,^8,9 total salpingectomy likely reduces this risk by 49% to 65%.^10,11

With this new evidence, McAlpine and colleagues initiated an educational campaign, targeting all ObGyns in British Columbia, which outlined the role of the fallopian tube in ovarian cancer and urged the consideration of total salpingectomy for permanent contraception in place of occlusive or partial salpingectomy procedures. They found that this one-time targeted education increased the use of total salpingectomy for permanent contraception from 0.5% at 2 years before the intervention to 33.3% by 2 years afterwards.¹² On average, laparoscopic bilateral salpingectomy took 10 minutes longer to complete than occlusive procedures. Most importantly, they found no significant differences in complication rates, including hospital readmissions or blood transfusions.

Although our community can be applauded for the rapid uptake of concomitant bilateral salpingectomy at the time of benign hysterectomy,^12,13 offering total salpingectomy for permanent contraception is far from common practice. Similarly, while multiple studies have been published to support the practice of opportunistic salpingectomy at the time of hysterectomy, little has been published about the use of bilateral salpingectomy for permanent contraception until this past year.

In this article, we review some of the first publications to focus specifically on the feasibility and safety profile of performing either immediate postpartum total salpingectomy or interval total salpingectomy in women desiring permanent contraception.

Read about a total salpingectomy at delivery

Total salpingectomy: A viable option for permanent contraception after vaginal or at cesarean delivery

Shinar S, Blecher Y, Alpern S, et al. Total bilateral salpingectomy versus partial bilateral salpingectomy for permanent sterilization during cesarean delivery. Arch Gynecol Obstet. 2017;295(5):1185-1189.

Danis RB, Della Badia CR, Richard SD. Postpartum permanent sterilization: could bilateral salpingectomy replace bilateral tubal ligation? J Minim Invasive Gynecol. 2016;23(6):928-932.

Shinar and colleagues presented a retrospective case series that included women undergoing permanent contraception procedures during cesarean delivery at a single tertiary medical center. The authors evaluated outcomes before and after a global hospital policy changed the preferred permanent contraception procedure from partial to total salpingectomy.

Details of the Shinar technique and outcomes

Of the 149 women included, 99 underwent partial salpingectomy via the modified Pomeroy technique and 50 underwent total salpingectomy using an electrothermal bipolar tissue-sealing instrument (Ligasure). The authors found no difference in operative times and similar rates of complications. Composite adverse outcomes, defined as surgery duration greater than 45 minutes, hemoglobin decline greater than 1.2 g/dL, need for blood transfusion, prolonged hospitalization, ICU admission, or re-laparotomy, were comparable and were reported as 30.3% and 36.0% in the partial and total salpingectomy groups, respectively, (P = .57).One major complication occurred in the total salpingectomy cohort; postoperatively the patient had hemodynamic instability and was found to have hemoperitoneum requiring exploratory laparotomy. Significant bleeding from the bilateral mesosalpinges was discovered, presumably directly related to the total salpingectomy.

Related article:
Hysteroscopic tubal occlusion: How new product labeling can be a resource for patient counseling

Details of Danis et al

Intuitively, performing salpingectomy at the time of cesarean delivery does not seem as significant a change in practice as would performing salpingectomy through a small periumbilical incision after vaginal delivery. However, Danis and colleagues did just that; they published a retrospective case series of total salpingectomy performed within 24 hours after a vaginal delivery at an urban, academic institution. They included all women admitted for full-term vaginal deliveries who desired permanent contraception, with no exclusion criteria related to body mass index (BMI). The authors reported on 80 women, including 64 (80%) who underwent partial salpingectomy via the modified Pomeroy or Parkland technique and 16 (20%) who underwent total salpingectomy. Most women had a BMI of less than 30 kg/m²; less than 15% of the women in each group had a BMI greater than 40 kg/m².

The technique for total salpingectomy involved a 2- to 3-cm vertical incision at the level of the umbilicus, elevation of the entire fallopian tube with 2 Babcock clamps, followed by the development of 2 to 3 windows with monopolar electrocautery in the mesosalpinx and subsequent suture ligation with polyglactin 910 (Vicryl, Ethicon).

Major findings included slightly longer operative time in the total salpingectomy compared with the partial salpingectomy group (a finding consistent with other studies^12,14,15) and no difference in complication rates. The average (SD) surgical time in the partial salpingectomy group was 59 (16) minutes, compared with 71 (6) minutes in the total salpingectomy group (P = .003). The authors reported 4 (6.3%) complications in the partial salpingectomy group--ileus, excessive bleeding from mesosalpinx, and incisional site hematoma--and no complications in the total salpingectomy group (P = .58).

Read about interval permanent contraception

Feasibility of interval laparoscopic permanent contraception via bilateral salpingectomy 

Westberg J, Scott F, Creinin MD. Safety outcomes of female sterilization by salpingectomy and tubal occlusion. Contraception. 2017;95(5):505-508.

In this retrospective study, authors used billing data to identify women undergoing interval laparoscopic permanent contraception at a single academic medical center. They educated physicians and patients about the potential benefits to ovarian cancer risk with total salpingectomy (similar to the educational initiative done in British Columbia) and discussed the requirement for the extra incision and more time for the surgery. From 2013 to 2015 use of salpingectomy for permanent contraception changed from 45% of the procedures to 85%, a fairly dramatic trend.¹⁸ With these data, the authors compared outcomes between the women receiving tubal occlusive procedures and women receiving bilateral salpingectomy.

Related article:
Risk-reducing salpingectomy at benign hysterectomy: Have surgeons embraced this practice?

Details of surgical time and complications

Tubal occlusion procedures were performed through 2 abdominal ports, and device placement was at the discretion of the provider. Bilateral salpingectomies were performed through 3 abdominal port sites with an electrothermal bipolar tissue-sealing instrument. A total of 149 procedures were identified, 68 tubal occlusions (19% Falope rings, 32% bipolar cautery, and 47% Filshie clips) and 81 bilateral salpingectomies.

The surgical time average (SD) was 6 minutes longer for the salpingectomies (44 [13] minutes vs 38 [15] minutes; P = .018). As would be expected, more experienced residents had shorter surgical times when compared with less experienced residents for both procedures (FIGURE 2).¹⁵ Similar rates of both immediate and short-term surgical complications were noted. One immediate complication was reported in each group, both of which were secondary to anesthesia issues.

Interestingly, short-term complications were lower in the salpingectomy group (4.9%) versus the tubal occlusion group (14.7%), although this difference was barely not statistically significant (P = .051). These complications included 1 incisional site infection requiring oral antibiotics and 3 cases of increased pain in the salpingectomy group and 4 incisional site infections with 6 patients reporting increased pain in the tubal occlusion group.

Read about tube removal and ovarian reserve

Does total removal of the tubes affect ovarian reserve?

Ganer Herman H, Gluck O, Keidar R, et al. Ovarian reserve following cesarean section with salpingectomy vs tubal ligation: a randomized trial. Am J Obstet Gynecol. 2017;doi: 10.1016/j.ajog.2017.04.028.

As acceptability of total salpingectomy for permanent contraception increases, one concern is that complete removal may alter blood supply to the ovary, resulting in decreased ovarian reserve and, subsequently, earlier menopause. Several studies have addressed the potential effect of salpingectomy on ovarian function when performed at the time of hysterectomy, most of which have noted no difference in anti-Müllerian hormone (AMH) levels and sonographic parameters following surgery.¹⁹ However, very little has been published to assess this same question when the salpingectomy is performed for the purpose of permanent contraception.

Ganer Herman and colleagues aimed to assess short-term ovarian reserve by measuring AMH levels preoperatively and 6 to 8 weeks postoperatively in patients undergoing partial or total salpingectomy at the time of elective cesarean delivery.

Related article:
Salpingectomy after vaginal hysterectomy: Technique, tips, and pearls

Details of the study

The study included women aged 18 to 45 who presented for elective cesarean delivery and who requested permanent contraception. Exclusion criteria included previous tubal surgery, emergent cesarean delivery, personal history of breast carcinoma, familial history of ovarian carcinoma, and BRCA carriage.

Women were randomly assigned at a 1:1 ratio to bilateral total salpingectomy or bilateral partial salpingectomy. A complete blood count and AMH level were drawn the night prior to surgery. Intraoperatively, after delivery and hysterotomy closure, partial salpingectomy, via the Parkland technique, or total salpingectomy, using a suture ligation technique, was performed.

Of the 46 women enrolled, follow-up was completed by 16 of 22 women (72%) in the total salpingectomy group and 18 of 24 women (75%) in the partial salpingectomy group. Patients in the total salpingectomy group were slightly older (mean age, 37 vs 34 years; P = .02), but otherwise all demographic and obstetric characteristics were comparable.

No differences were noted in preoperative and postoperative AMH levels between groups, with an average (SD) increase of 0.58 (0.98) ng/mL versus 0.39 (0.41) ng/mL in the total salpingectomy and partial salpingectomy groups, respectively (P = .45), consistent with known postpartum AMH level trends.

Other findings included an average 13-minute increase in operative time in the total salpingectomy cases, similar safety profile of the 2 methods as there were no postoperative complications during the study period, and no differences in postoperative hemoglobin levels.

Conclusion

The studies reviewed in this article are some of the first to evaluate the feasibility and safety of opportunistic, or total, salpingectomy for permanent contraception since the ACOG and SGO recommendations were published. Just as our community has adopted the common practice of opportunistic salpingectomy at the time of hysterectomy, we should continue to advocate for a similar practice when discussing permanent contraception. Additionally, the Westberg study provides good evidence that educational initiatives can influence provider practices, which upholds the data published by McAlpine and colleagues in British Columbia. This information is promising and valuable.

Our universal goal as ObGyns is to provide the best reproductive health care possible based on the most recent evidence available. Continuing to advocate for opportunistic salpingectomy for permanent contraception purposes meets this goal and potentially provides significant noncontraceptive benefits.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

According to the most recent data (2011–2013), 62% of women of childbearing age (15–44 years) use some method of contraception. Of these “contracepting” women, about 25% reported relying on permanent contraception, making it one of the most common methods of contraception used by women in the United States (FIGURE 1).^1,2 Women either can choose to have a permanent contraception procedure performed immediately postpartum, which occurs after approximately 9% of all hospital deliveries in the United States,³ or at a time separate from pregnancy.

The most common methods of permanent contraception include partial salpingectomy at the time of cesarean delivery or within 24 hours after vaginal delivery and laparoscopic occlusive procedures at a time unrelated to the postpartum period.³ Hysteroscopic occlusion of the tubal ostia is a newer option, introduced in 2002; its worldwide use is concentrated in the United States, which accounts for 80% of sales based on revenue.⁴

Historically, for procedures remote from pregnancy, the laparoscopic approach evolved with less sophisticated laparoscopic equipment and limited visualization, which resulted in efficiency and safety being the primary goals of the procedure.⁵ Accordingly, rapid occlusive procedures were commonplace. However, advancement of laparoscopic technology related to insufflation systems, surgical equipment, and video capabilities did not change this practice.

Recent literature has suggested that complete fallopian tube removal provides additional benefits. With increasing knowledge about the origin of ovarian cancer, as well as increasing data to support the hypothesis that complete tubal excision results in increased ovarian cancer protection when compared with occlusive or partial salpingectomies, both the American College of Obstetricians and Gynecologists (ACOG)⁶ and the Society of Gynecologic Oncology (SGO)⁷ recommend discussing bilateral total salpingectomy with patients desiring permanent contraception. Although occlusive procedures decrease a woman’s lifetime risk of ovarian cancer by 24% to 34%,^8,9 total salpingectomy likely reduces this risk by 49% to 65%.^10,11

With this new evidence, McAlpine and colleagues initiated an educational campaign, targeting all ObGyns in British Columbia, which outlined the role of the fallopian tube in ovarian cancer and urged the consideration of total salpingectomy for permanent contraception in place of occlusive or partial salpingectomy procedures. They found that this one-time targeted education increased the use of total salpingectomy for permanent contraception from 0.5% at 2 years before the intervention to 33.3% by 2 years afterwards.¹² On average, laparoscopic bilateral salpingectomy took 10 minutes longer to complete than occlusive procedures. Most importantly, they found no significant differences in complication rates, including hospital readmissions or blood transfusions.

Although our community can be applauded for the rapid uptake of concomitant bilateral salpingectomy at the time of benign hysterectomy,^12,13 offering total salpingectomy for permanent contraception is far from common practice. Similarly, while multiple studies have been published to support the practice of opportunistic salpingectomy at the time of hysterectomy, little has been published about the use of bilateral salpingectomy for permanent contraception until this past year.

In this article, we review some of the first publications to focus specifically on the feasibility and safety profile of performing either immediate postpartum total salpingectomy or interval total salpingectomy in women desiring permanent contraception.

Read about a total salpingectomy at delivery

Total salpingectomy: A viable option for permanent contraception after vaginal or at cesarean delivery

Shinar S, Blecher Y, Alpern S, et al. Total bilateral salpingectomy versus partial bilateral salpingectomy for permanent sterilization during cesarean delivery. Arch Gynecol Obstet. 2017;295(5):1185-1189.

Danis RB, Della Badia CR, Richard SD. Postpartum permanent sterilization: could bilateral salpingectomy replace bilateral tubal ligation? J Minim Invasive Gynecol. 2016;23(6):928-932.

Shinar and colleagues presented a retrospective case series that included women undergoing permanent contraception procedures during cesarean delivery at a single tertiary medical center. The authors evaluated outcomes before and after a global hospital policy changed the preferred permanent contraception procedure from partial to total salpingectomy.

Details of the Shinar technique and outcomes

Of the 149 women included, 99 underwent partial salpingectomy via the modified Pomeroy technique and 50 underwent total salpingectomy using an electrothermal bipolar tissue-sealing instrument (Ligasure). The authors found no difference in operative times and similar rates of complications. Composite adverse outcomes, defined as surgery duration greater than 45 minutes, hemoglobin decline greater than 1.2 g/dL, need for blood transfusion, prolonged hospitalization, ICU admission, or re-laparotomy, were comparable and were reported as 30.3% and 36.0% in the partial and total salpingectomy groups, respectively, (P = .57).One major complication occurred in the total salpingectomy cohort; postoperatively the patient had hemodynamic instability and was found to have hemoperitoneum requiring exploratory laparotomy. Significant bleeding from the bilateral mesosalpinges was discovered, presumably directly related to the total salpingectomy.

Related article:
Hysteroscopic tubal occlusion: How new product labeling can be a resource for patient counseling

Details of Danis et al

Intuitively, performing salpingectomy at the time of cesarean delivery does not seem as significant a change in practice as would performing salpingectomy through a small periumbilical incision after vaginal delivery. However, Danis and colleagues did just that; they published a retrospective case series of total salpingectomy performed within 24 hours after a vaginal delivery at an urban, academic institution. They included all women admitted for full-term vaginal deliveries who desired permanent contraception, with no exclusion criteria related to body mass index (BMI). The authors reported on 80 women, including 64 (80%) who underwent partial salpingectomy via the modified Pomeroy or Parkland technique and 16 (20%) who underwent total salpingectomy. Most women had a BMI of less than 30 kg/m²; less than 15% of the women in each group had a BMI greater than 40 kg/m².

The technique for total salpingectomy involved a 2- to 3-cm vertical incision at the level of the umbilicus, elevation of the entire fallopian tube with 2 Babcock clamps, followed by the development of 2 to 3 windows with monopolar electrocautery in the mesosalpinx and subsequent suture ligation with polyglactin 910 (Vicryl, Ethicon).

Major findings included slightly longer operative time in the total salpingectomy compared with the partial salpingectomy group (a finding consistent with other studies^12,14,15) and no difference in complication rates. The average (SD) surgical time in the partial salpingectomy group was 59 (16) minutes, compared with 71 (6) minutes in the total salpingectomy group (P = .003). The authors reported 4 (6.3%) complications in the partial salpingectomy group--ileus, excessive bleeding from mesosalpinx, and incisional site hematoma--and no complications in the total salpingectomy group (P = .58).

Read about interval permanent contraception

Feasibility of interval laparoscopic permanent contraception via bilateral salpingectomy 

Westberg J, Scott F, Creinin MD. Safety outcomes of female sterilization by salpingectomy and tubal occlusion. Contraception. 2017;95(5):505-508.

In this retrospective study, authors used billing data to identify women undergoing interval laparoscopic permanent contraception at a single academic medical center. They educated physicians and patients about the potential benefits to ovarian cancer risk with total salpingectomy (similar to the educational initiative done in British Columbia) and discussed the requirement for the extra incision and more time for the surgery. From 2013 to 2015 use of salpingectomy for permanent contraception changed from 45% of the procedures to 85%, a fairly dramatic trend.¹⁸ With these data, the authors compared outcomes between the women receiving tubal occlusive procedures and women receiving bilateral salpingectomy.

Related article:
Risk-reducing salpingectomy at benign hysterectomy: Have surgeons embraced this practice?

Details of surgical time and complications

Tubal occlusion procedures were performed through 2 abdominal ports, and device placement was at the discretion of the provider. Bilateral salpingectomies were performed through 3 abdominal port sites with an electrothermal bipolar tissue-sealing instrument. A total of 149 procedures were identified, 68 tubal occlusions (19% Falope rings, 32% bipolar cautery, and 47% Filshie clips) and 81 bilateral salpingectomies.

The surgical time average (SD) was 6 minutes longer for the salpingectomies (44 [13] minutes vs 38 [15] minutes; P = .018). As would be expected, more experienced residents had shorter surgical times when compared with less experienced residents for both procedures (FIGURE 2).¹⁵ Similar rates of both immediate and short-term surgical complications were noted. One immediate complication was reported in each group, both of which were secondary to anesthesia issues.

Interestingly, short-term complications were lower in the salpingectomy group (4.9%) versus the tubal occlusion group (14.7%), although this difference was barely not statistically significant (P = .051). These complications included 1 incisional site infection requiring oral antibiotics and 3 cases of increased pain in the salpingectomy group and 4 incisional site infections with 6 patients reporting increased pain in the tubal occlusion group.

Read about tube removal and ovarian reserve

Does total removal of the tubes affect ovarian reserve?

Ganer Herman H, Gluck O, Keidar R, et al. Ovarian reserve following cesarean section with salpingectomy vs tubal ligation: a randomized trial. Am J Obstet Gynecol. 2017;doi: 10.1016/j.ajog.2017.04.028.

As acceptability of total salpingectomy for permanent contraception increases, one concern is that complete removal may alter blood supply to the ovary, resulting in decreased ovarian reserve and, subsequently, earlier menopause. Several studies have addressed the potential effect of salpingectomy on ovarian function when performed at the time of hysterectomy, most of which have noted no difference in anti-Müllerian hormone (AMH) levels and sonographic parameters following surgery.¹⁹ However, very little has been published to assess this same question when the salpingectomy is performed for the purpose of permanent contraception.

Ganer Herman and colleagues aimed to assess short-term ovarian reserve by measuring AMH levels preoperatively and 6 to 8 weeks postoperatively in patients undergoing partial or total salpingectomy at the time of elective cesarean delivery.

Related article:
Salpingectomy after vaginal hysterectomy: Technique, tips, and pearls

Details of the study

The study included women aged 18 to 45 who presented for elective cesarean delivery and who requested permanent contraception. Exclusion criteria included previous tubal surgery, emergent cesarean delivery, personal history of breast carcinoma, familial history of ovarian carcinoma, and BRCA carriage.

Women were randomly assigned at a 1:1 ratio to bilateral total salpingectomy or bilateral partial salpingectomy. A complete blood count and AMH level were drawn the night prior to surgery. Intraoperatively, after delivery and hysterotomy closure, partial salpingectomy, via the Parkland technique, or total salpingectomy, using a suture ligation technique, was performed.

Of the 46 women enrolled, follow-up was completed by 16 of 22 women (72%) in the total salpingectomy group and 18 of 24 women (75%) in the partial salpingectomy group. Patients in the total salpingectomy group were slightly older (mean age, 37 vs 34 years; P = .02), but otherwise all demographic and obstetric characteristics were comparable.

No differences were noted in preoperative and postoperative AMH levels between groups, with an average (SD) increase of 0.58 (0.98) ng/mL versus 0.39 (0.41) ng/mL in the total salpingectomy and partial salpingectomy groups, respectively (P = .45), consistent with known postpartum AMH level trends.

Other findings included an average 13-minute increase in operative time in the total salpingectomy cases, similar safety profile of the 2 methods as there were no postoperative complications during the study period, and no differences in postoperative hemoglobin levels.

Conclusion

The studies reviewed in this article are some of the first to evaluate the feasibility and safety of opportunistic, or total, salpingectomy for permanent contraception since the ACOG and SGO recommendations were published. Just as our community has adopted the common practice of opportunistic salpingectomy at the time of hysterectomy, we should continue to advocate for a similar practice when discussing permanent contraception. Additionally, the Westberg study provides good evidence that educational initiatives can influence provider practices, which upholds the data published by McAlpine and colleagues in British Columbia. This information is promising and valuable.

Our universal goal as ObGyns is to provide the best reproductive health care possible based on the most recent evidence available. Continuing to advocate for opportunistic salpingectomy for permanent contraception purposes meets this goal and potentially provides significant noncontraceptive benefits.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

A new single-handed inserter (SHI) for placement of Liletta has been introduced and is currently available (FIGURE 1). Liletta is a levonorgestrel 52-mg intrauterine system (IUS) that is currently approved for 3 years of use as a contraceptive in the United States. The same product in Europe, known as Levosert, is approved for both contraception and the treatment of heavy menstrual bleeding. Liletta, as a branded contraceptive, is being studied through a large Phase 3 clinical trial called ACCESS IUS, which will continue to evaluate the contraceptive efficacy of Liletta for at least 7 years of use.¹ A recent publication from the study showed that the levonorgestrel release rates from Liletta are almost identical to the rates reported for the other levonorgestrel 52-mg IUS on the market (Mirena) through 5 years and supports the continued study of the IUS for at least 7 years.²

Image copyright Medicines360.

Related article:
Benefit of self-administered vaginal lidocaine gel in IUD placement

The initial marketing and distribution of Liletta used a two-handed inserter that allowed for successful placement but required multiple steps. The SHI will make loading and placement of Liletta easier for all clinicians. Features of the new SHI include:

• A double-slider mechanism in which the first slider moves into the second slider during IUS placement, providing a tactile sense for the user during the insertion process
• The ability to reload the inserter if needed before placement
• A firm but bendable tube (that is 2 cm longer than other IUS inserters on the market). This length can be helpful for obese patients or postprocedure placements.
• Depth markings to 12 cm on both sides of the insertion tube.

Related article:
2016 Update on contraception

Liletta is an important and unique product in the US market. For most public sector providers and clinics, Liletta costs only $50, significantly less than other long-acting reversible contraceptives. The price of the IUS is only one aspect of its overall cost, however, as women still need to pay for any office visit or insertion fees. Liletta is unique in its pricing. Sales of Liletta in the private sector support the low price in the public sector. As a health care community, even if we do not directly care for women in public-sector settings, we all can help poor women access affordable, effective contraception. For providers, Liletta is a highly effective and lower-cost alternative to currently available hormonal IUS products.

How to insert Liletta

Insertion can be performed using a no-touch technique. The loading and placement technique outlined below should occur after speculum and tenaculum placement, sounding of the uterus, and vaginal preparation as would be performed for any intrauterine contraceptive insertion. Never force the uterine sound or insertion tube through the cervix; if necessary, stop and dilate the cervical canal. The steps below are the main points for successful Liletta placement; see the full product label for more details.³

Related article:
In which clinical situations can the use of the 52-mg levonorgestrel-releasing IUD (Mirena) and the TCu380A copper-IUD (ParaGard) be extended?

The key steps to remember are firm-gentle-firm

1. Load the device. While pushing forward firmly on the blue slider (with the number 1), load Liletta by pulling down evenly on the threads. The IUS should be laid on a flat surface in the sterile tray to keep the arms parallel to the floor while pulling on the threads. Once loaded, the threads can be pulled up or down to be locked in the cleft. The tip of the IUS will form a hemispheric dome at the top of the insertion tube.
2. Adjust the flange to the measured uterine depth based on sounding using the notch in the tray.
3. Place inserter into the cervix. Apply gentle traction on the tenaculum to align the cervical canal and uterine cavity. While still holding firm forward pressure on the blue slider, place the tube through the cervical canal until the flange is approximately 1.5 to 2 cm from the cervix. (FIGURE 2.) Gently slide the blue slider downward until it is flush with the green slider (with the number 2; FIGURE 3). This step will allow the IUS arms to open in the lower uterine segment; wait 10 to 15 seconds for the arms to fully unfold. By sliding gently, you will feel when to stop moving the slider.
   

   

   Image copyright Medicines360.

   
   

   

   Image copyright Medicines360.

4. Advance the inserter. While holding traction on the tenaculum, advance the inserter to the fundus. You will feel slight resistance when the IUS is at the fundus and the flange should be flush against the cervix.
5. Firmly slide both sliders together downward until a click is heard (FIGURE 4). A green indicator will be visible at the bottom of the handle to show that the threads have been ejected from the cleft.
   

   

   Image copyright Medicines360.

6. Withdraw the inserter from the uterus and cut the threads with blunt tipped scissors approximately 3 cm from the cervical os.

Technique video

Allergan and Medicines360 offer a video demonstrating proper Liletta insertion technique at www.lilettahcp.com. The video includes proper loading of the inserter as well as correct uterine depth measurement and release of Liletta from the inserter. Clinicians are reminded to use aseptic technique during the entire insertion procedure.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

A new single-handed inserter (SHI) for placement of Liletta has been introduced and is currently available (FIGURE 1). Liletta is a levonorgestrel 52-mg intrauterine system (IUS) that is currently approved for 3 years of use as a contraceptive in the United States. The same product in Europe, known as Levosert, is approved for both contraception and the treatment of heavy menstrual bleeding. Liletta, as a branded contraceptive, is being studied through a large Phase 3 clinical trial called ACCESS IUS, which will continue to evaluate the contraceptive efficacy of Liletta for at least 7 years of use.¹ A recent publication from the study showed that the levonorgestrel release rates from Liletta are almost identical to the rates reported for the other levonorgestrel 52-mg IUS on the market (Mirena) through 5 years and supports the continued study of the IUS for at least 7 years.²

Image copyright Medicines360.

Related article:
Benefit of self-administered vaginal lidocaine gel in IUD placement

The initial marketing and distribution of Liletta used a two-handed inserter that allowed for successful placement but required multiple steps. The SHI will make loading and placement of Liletta easier for all clinicians. Features of the new SHI include:

• A double-slider mechanism in which the first slider moves into the second slider during IUS placement, providing a tactile sense for the user during the insertion process
• The ability to reload the inserter if needed before placement
• A firm but bendable tube (that is 2 cm longer than other IUS inserters on the market). This length can be helpful for obese patients or postprocedure placements.
• Depth markings to 12 cm on both sides of the insertion tube.

Related article:
2016 Update on contraception

Liletta is an important and unique product in the US market. For most public sector providers and clinics, Liletta costs only $50, significantly less than other long-acting reversible contraceptives. The price of the IUS is only one aspect of its overall cost, however, as women still need to pay for any office visit or insertion fees. Liletta is unique in its pricing. Sales of Liletta in the private sector support the low price in the public sector. As a health care community, even if we do not directly care for women in public-sector settings, we all can help poor women access affordable, effective contraception. For providers, Liletta is a highly effective and lower-cost alternative to currently available hormonal IUS products.

How to insert Liletta

Insertion can be performed using a no-touch technique. The loading and placement technique outlined below should occur after speculum and tenaculum placement, sounding of the uterus, and vaginal preparation as would be performed for any intrauterine contraceptive insertion. Never force the uterine sound or insertion tube through the cervix; if necessary, stop and dilate the cervical canal. The steps below are the main points for successful Liletta placement; see the full product label for more details.³

Related article:
In which clinical situations can the use of the 52-mg levonorgestrel-releasing IUD (Mirena) and the TCu380A copper-IUD (ParaGard) be extended?

The key steps to remember are firm-gentle-firm

1. Load the device. While pushing forward firmly on the blue slider (with the number 1), load Liletta by pulling down evenly on the threads. The IUS should be laid on a flat surface in the sterile tray to keep the arms parallel to the floor while pulling on the threads. Once loaded, the threads can be pulled up or down to be locked in the cleft. The tip of the IUS will form a hemispheric dome at the top of the insertion tube.
2. Adjust the flange to the measured uterine depth based on sounding using the notch in the tray.
3. Place inserter into the cervix. Apply gentle traction on the tenaculum to align the cervical canal and uterine cavity. While still holding firm forward pressure on the blue slider, place the tube through the cervical canal until the flange is approximately 1.5 to 2 cm from the cervix. (FIGURE 2.) Gently slide the blue slider downward until it is flush with the green slider (with the number 2; FIGURE 3). This step will allow the IUS arms to open in the lower uterine segment; wait 10 to 15 seconds for the arms to fully unfold. By sliding gently, you will feel when to stop moving the slider.
   

   

   Image copyright Medicines360.

   
   

   

   Image copyright Medicines360.

4. Advance the inserter. While holding traction on the tenaculum, advance the inserter to the fundus. You will feel slight resistance when the IUS is at the fundus and the flange should be flush against the cervix.
5. Firmly slide both sliders together downward until a click is heard (FIGURE 4). A green indicator will be visible at the bottom of the handle to show that the threads have been ejected from the cleft.
   

   

   Image copyright Medicines360.

6. Withdraw the inserter from the uterus and cut the threads with blunt tipped scissors approximately 3 cm from the cervical os.

Technique video

Allergan and Medicines360 offer a video demonstrating proper Liletta insertion technique at www.lilettahcp.com. The video includes proper loading of the inserter as well as correct uterine depth measurement and release of Liletta from the inserter. Clinicians are reminded to use aseptic technique during the entire insertion procedure.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

A new single-handed inserter (SHI) for placement of Liletta has been introduced and is currently available (FIGURE 1). Liletta is a levonorgestrel 52-mg intrauterine system (IUS) that is currently approved for 3 years of use as a contraceptive in the United States. The same product in Europe, known as Levosert, is approved for both contraception and the treatment of heavy menstrual bleeding. Liletta, as a branded contraceptive, is being studied through a large Phase 3 clinical trial called ACCESS IUS, which will continue to evaluate the contraceptive efficacy of Liletta for at least 7 years of use.¹ A recent publication from the study showed that the levonorgestrel release rates from Liletta are almost identical to the rates reported for the other levonorgestrel 52-mg IUS on the market (Mirena) through 5 years and supports the continued study of the IUS for at least 7 years.²

Image copyright Medicines360.

Related article:
Benefit of self-administered vaginal lidocaine gel in IUD placement

The initial marketing and distribution of Liletta used a two-handed inserter that allowed for successful placement but required multiple steps. The SHI will make loading and placement of Liletta easier for all clinicians. Features of the new SHI include:

• A double-slider mechanism in which the first slider moves into the second slider during IUS placement, providing a tactile sense for the user during the insertion process
• The ability to reload the inserter if needed before placement
• A firm but bendable tube (that is 2 cm longer than other IUS inserters on the market). This length can be helpful for obese patients or postprocedure placements.
• Depth markings to 12 cm on both sides of the insertion tube.

Related article:
2016 Update on contraception

Liletta is an important and unique product in the US market. For most public sector providers and clinics, Liletta costs only $50, significantly less than other long-acting reversible contraceptives. The price of the IUS is only one aspect of its overall cost, however, as women still need to pay for any office visit or insertion fees. Liletta is unique in its pricing. Sales of Liletta in the private sector support the low price in the public sector. As a health care community, even if we do not directly care for women in public-sector settings, we all can help poor women access affordable, effective contraception. For providers, Liletta is a highly effective and lower-cost alternative to currently available hormonal IUS products.

How to insert Liletta

Insertion can be performed using a no-touch technique. The loading and placement technique outlined below should occur after speculum and tenaculum placement, sounding of the uterus, and vaginal preparation as would be performed for any intrauterine contraceptive insertion. Never force the uterine sound or insertion tube through the cervix; if necessary, stop and dilate the cervical canal. The steps below are the main points for successful Liletta placement; see the full product label for more details.³

Related article:
In which clinical situations can the use of the 52-mg levonorgestrel-releasing IUD (Mirena) and the TCu380A copper-IUD (ParaGard) be extended?

The key steps to remember are firm-gentle-firm

1. Load the device. While pushing forward firmly on the blue slider (with the number 1), load Liletta by pulling down evenly on the threads. The IUS should be laid on a flat surface in the sterile tray to keep the arms parallel to the floor while pulling on the threads. Once loaded, the threads can be pulled up or down to be locked in the cleft. The tip of the IUS will form a hemispheric dome at the top of the insertion tube.
2. Adjust the flange to the measured uterine depth based on sounding using the notch in the tray.
3. Place inserter into the cervix. Apply gentle traction on the tenaculum to align the cervical canal and uterine cavity. While still holding firm forward pressure on the blue slider, place the tube through the cervical canal until the flange is approximately 1.5 to 2 cm from the cervix. (FIGURE 2.) Gently slide the blue slider downward until it is flush with the green slider (with the number 2; FIGURE 3). This step will allow the IUS arms to open in the lower uterine segment; wait 10 to 15 seconds for the arms to fully unfold. By sliding gently, you will feel when to stop moving the slider.
   

   

   Image copyright Medicines360.

   
   

   

   Image copyright Medicines360.

4. Advance the inserter. While holding traction on the tenaculum, advance the inserter to the fundus. You will feel slight resistance when the IUS is at the fundus and the flange should be flush against the cervix.
5. Firmly slide both sliders together downward until a click is heard (FIGURE 4). A green indicator will be visible at the bottom of the handle to show that the threads have been ejected from the cleft.
   

   

   Image copyright Medicines360.

6. Withdraw the inserter from the uterus and cut the threads with blunt tipped scissors approximately 3 cm from the cervical os.

Technique video

Allergan and Medicines360 offer a video demonstrating proper Liletta insertion technique at www.lilettahcp.com. The video includes proper loading of the inserter as well as correct uterine depth measurement and release of Liletta from the inserter. Clinicians are reminded to use aseptic technique during the entire insertion procedure.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Contraception is an important tool that allows patients to carry out their reproductive-life plans. In the United States, the average woman desires 2 children.¹ To achieve this goal, she will spend more than 30 years of her reproductive life avoiding pregnancy.¹ The most effective reversible contraceptive methods, the intrauterine device (IUD) and the contraceptive implant, offer an efficient way to cover this significant period. Currently, American women more commonly choose an IUD than an implant by a factor 8 to 1.² Between 2002 and 2012, the percentage of US contraceptive users aged 15 to 44 using the IUD rose from 2% to 10%.²

Significant barriers to contraceptive access still exist, however. Although widespread reports have lauded the decrease in unintended pregnancies in the United States, improvement only has been marginal for women who live below the poverty level. In fact, for unintended pregnancy the gap between women above and below the poverty level has increased from a 2.6-fold difference in 1994 to a 5.6-fold difference in 2011 (FIGURE).³⁻⁵ Since the decrease in the unintended pregnancy rate is most likely related to an increase in contraceptive use, particularly the IUD, we are not providing equal contraceptive access to all women.⁵

Both the copper IUD and the 3 available levonorgestrel (LNG)-releasing intrauterine system (IUS) products provide safe and effective contraception. As IUD research expands, it is imperative for providers to stay up to date so patients can have full access to these devices.

In this article, we present important updates regarding IUD use that will help break down some continuing barriers to contraceptive access, including:

WHO study demonstrates LNG 52-mg IUS is highly effective for up to 7 years of use

Rowe P, Farley T, Peregoudov A, et al; IUD Research Group of the UNDP/UNFPA/WHO/World Bank Special Programme of Research; Development and Research Training in Human Reproduction. Safety and efficacy in parous women of a 52-mg levonorgestrel-medicated intrauterine device: a 7-year randomized comparative study with the TCu380A. Contraception. 2016;93(6):498−506.

Currently, the 2 LNG 52-mg IUS products (Liletta, Mirena) approved by the US Food and Drug Administration (FDA) are available for use for 3 and 5 years, respectively. The pivotal approval trial for Liletta is still ongoing and is planned to continue for up to 7 years.⁶ The TCu380A (ParaGard) copper IUD is FDA approved for up to 10 years of use; however, this product initially was approved for only 4 years. The duration of use was expanded to 10 years based on continued clinical trials.

Based on current data, we will not need to wait for the Liletta pivotal trial to have clinical evidence of a longer duration of efficacy for the LNG 52-mg IUS. A collaborative group as part of the UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction performed a multicenter, open-label randomized controlled trial to evaluate outcomes through 7 years of use of the LNG 52-mg IUS and the TCu380A IUD.

Details of the study

A total of 3,836 women were enrolled at 20 centers in Europe, Asia, South America, and China and were randomly assigned to one of the 2 products. Eligible women were aged 16 to 40 years, parous, and without known leiomyoma or recent pelvic infection. After excluding 15 failed IUD insertions, 1,910 women received an LNG 52-mg IUS and 1,911 received a TCu380A. Ultimately, 398 women in the LNG 52-mg IUS group and 682 in the TCu380A group completed 7-year follow-up with the IUD in place. Women were surveyed regarding pregnancy and method discontinuation.

Lower pregnancy rate, higher discontinuation with LNG IUS

The cumulative 7-year pregnancy rate among LNG 52-mg IUS users was significantly lower than among TCu380A users (0.53 per 100 women vs 2.45 per 100 women, respectively). All pregnancies in the LNG 52-mg IUS group occurred in the first 5 years of study follow-up--with no pregnancies in years 6 through 7 (TABLE). The cumulative pregnancy rate in the TCu380A group in this study is consistent with that in a previous long-term trial of this IUD.⁷

Early removal was significantly higher in the LNG 52-mg IUS group, with a cumulative discontinuation rate of 70.6 per 100 women, compared with 40.8 per 100 women in the TCu380A group. Significant cultural variation existed when it came to both rate and reason for discontinuation. Most women at Chinese centers cited amenorrhea and decreased bleeding as the primary reason for discontinuation, and they did so at twice the rate of women at non-Chinese centers.

The patterns of method discontinuation in this study were different from those found among US women. By comparison, a recent study in the United States had lower overall discontinuation rates and did not find decreased bleeding to be among the main reasons for LNG 52-mg IUS removal.⁷ In fact, most women who discontinued the LNG 52-mg IUS cited concerns about upcoming expiration as their reason for removal.

The results of this large study also generally corroborated the low-risk profile of IUDs. Only 1 reported IUD perforation occurred, for a rate of 0.03 per 1,000 women. Device expulsion rates were similar between the IUDs and were uncommon overall with 7-year rates of 8 to 9 per 100 women. Pelvic infection was cited as reason for removal in only 7 women (0.18 per 100 women) over 7 years.

What this evidence means for practiceThis exciting study is the first large-scale clinical trial demonstrating continued high efficacy with LNG 52-mg IUS use through 7 years. This information affords women extended contraceptive coverage. While additional research will be welcome, particularly in younger women who will maintain greater fertility across the IUS’s 7-year life span, we are confident in extending the 7-year duration for this IUS to our patients.

Additionally, the method discontinuation findings in this study highlight the importance of discussing the expected menstrual changes of hormonal IUS use with women prior to insertion so they can determine if the potential changes would be satisfactory. As the acceptability of medical menstrual suppression may be new to many women, providers should frame the adverse effects in this context. Providers can use this opportunity to review the noncontraceptive benefits of the hormonal IUS as well.

Novel combination of LNG 52-mg IUS and oral LNG 1.5 mg is promising for emergency contraception

Turok DK, Sanders JN, Thompson IS, Royer PA, Eggebroten J, Gawron LM. Preference for and efficacy of oral levonorgestrel for emergency contraception with concomitant placement of a levonorgestrel IUD: a prospective cohort study. Contraception. 2016;93(6):526−532.

The copper IUD is superior for EC relative to oral agents and has the added benefit of providing ongoing highly effective contraception after placement.⁸ Despite this strong evidence, the copper IUD remains underutilized for this indication. Turok and colleagues noted that women in their clinic seeking IUDs for non-EC purposes preferred the LNG 52-mg IUS over the copper IUD. It is understandable that women might carry these preferences into EC encounters as well. Thus, the investigators devised a novel combination of LNG 52-mg IUS and oral LNG 1.5 mg, which provided both known EC benefit and same-day access to a more popular contraceptive device.

Details of the study

Women presenting for EC who desired same-day IUD placement were enrolled in the prospective cohort study. Eligible women had a negative urine pregnancy test, known last menstrual period (LMP), regular menstrual cycle, and reported unprotected intercourse within 120 hours prior to presentation. Importantly, women with multiple episodes of unprotected intercourse in the weeks prior to presentation were also included to provide a population more comparable to that encountered clinically. The women were then offered the choice of a TCu380A copper IUD or oral LNG EC with LNG 52-mg IUS placement. They were counseled on the potential increased risk of pregnancy with the novel oral LNG EC plus LNG IUS combination compared with the copper IUD. Participants were given a home pregnancy test that they were to complete in 2 weeks and then report the results to the clinic.

Of the 1,004 women presenting to the clinic for EC over the 16-month study period, 188 (18%) desired same-day IUD insertion. Of these, more opted for the oral LNG EC plus LNG IUS combination (n = 121, 64%) than the copper IUD (n = 67, 36%), demonstrating that women were often willing to accept a possible decrease in EC efficacy with the goal of obtaining their preferred lUD type.

Excluding failed insertion, undiagnosed uterine didelphys, and patient withdrawal, 110 women received the oral LNG EC plus LNG IUS and 66 received the copper IUD. Demographics were comparable between groups except for body mass index (BMI). Of note, more than half (61%) of the women who opted for the oral LNG EC plus LNG IUS combination were overweight or obese.

Both EC methods are effective, broadening options

All women who received the copper IUD followed up at 2 weeks, and no pregnancies were reported. Of the women who received oral LNG EC plus the LNG IUS, 107 (97%) had follow-up at 2 weeks. In this group, there was 1 reported ectopic pregnancy that ultimately required surgical management. However, further review of the patient's coital history suggested that conception occurred prior to IUD insertion, and the case was not classified by the investigators as an EC failure.

Although this study was not powered to detect pregnancy rate differences between the traditional copper IUD and the oral LNG EC plus LNG IUS combination, the results are promising. An important strength of this study is the presence of 2 high-risk groups for EC failure in the oral LNG EC plus LNG IUS group (elevated BMI and multiple episodes of unprotected intercourse).

What this evidence means for practiceEncounters for EC are important opportunities in which to discuss a woman’s reproductive goals. For women who are interested in an IUD, this study opens up the option of same-day placement of the LNG 52-mg IUS. While larger trials need to be conducted to obtain more information regarding pregnancy rates with an oral EC plus LNG IUS combination versus the TCu380A, offering such a combination is reasonable. Given that ulipristal acetate (UPA) is a more effective EC product, especially for women who are overweight or obese,⁹ offering a UPA EC plus LNG IUS combination may be a better alternative.

It is time to remove the STI screening barrier to same-day IUD insertion

Turok DK, Eisenberg DL, Teal SB, Keder LM, Creinin MD. A prospective assessment of pelvic infection risk following same-day sexually transmitted infection testing and levonorgestrel intrauterine system placement [published online ahead of print May 12, 2016]. Am J Obstet Gynecol. doi:10.1016/j.ajog.2016.05017.

Provider concerns regarding the presence of pelvic infection remain a significant barrier to same-day IUD insertion. Older studies suggested a higher risk of pelvic infection in the first 20 days after IUD placement and extrapolated that pelvic infection was related to inserting an IUD in a woman at risk for STI.¹⁰ As a result, patients may be restricted from same-day IUD insertion by providers who think that obtaining results of STI testing is required prior to placement. Recently, a systematic review suggested, based on limited evidence, that IUD placement does not increase the risk of pelvic infection in asymptomatic women compared with those without an IUD.¹¹

Turok and colleagues (including M.D.C., coauthor of this article) reported results from a planned secondary analysis of A Comprehensive Contraceptive Efficacy and Safety Study of an IUS (ACCESS IUS), a component of the regulatory approval of the Liletta LNG 52-mg IUS. This analysis represents the first large-scale prospective investigation of pelvic infection rates during the first 2 years after IUD placement in US women.

Details of the study

Of the 1,751 women enrolled in the study, 1,714 had successful IUS insertions. Infection was assessed via baseline pelvic visual and bimanual examination and Chlamydia testing in all women. Gonorrhea testing was also performed in women who had not been tested with their current sexual partner. STI test results were not required for IUS insertion. Participants were assessed in person at 1, 3, 6, 12, and 24 months after insertion. Additional pelvic exams were performed as needed based on reported symptoms. At 6 months, 1 year, and 2 years, IUS continuation was reported in 1,553 (90.6%), 1,401 (81.7%), and 1,157 (67.3%) women, respectively.

Nearly all women received baseline STI testing (98.4%); however, results were not available prior to same-day IUS insertion for 79.6% of participants. Twenty-nine (1.7%) women had positive baseline STI tests (25 for Chlamydia, 3 for gonorrhea, 1 for both). Of these, only 6 women had results available prior to IUS placement. All women with a positive STI test were treated, and the IUS was left in place. Importantly, none of these women developed pelvic infection in the subsequent 2 years of follow-up and none requested IUS removal.

Infection risk is low with IUD placement

Among women with negative baseline STI tests, there were only 9 (0.5%) clinical diagnoses of pelvic infections over the first 2 years of follow-up. Diagnosis was typically made based on physical examination findings. Most women underwent repeat Chlamydia and gonorrhea testing at the time of pelvic infection diagnosis, and none had positive results. There were no medically recommended IUS removals; 2 women with pelvic infection requested IUS removal per their preference.

Three of the 9 women with pelvic infections were diagnosed within 1 week of IUS placement, 1 at 39 days after placement, and the remaining 5 more than 6 months after placement, suggesting that pelvic infection is not temporally related to IUS placement. Most women were successfully treated as outpatients.

What this evidence means for practiceThis study provides further reassurance regarding the low risk of pelvic infection among women with an LNG IUS. Insertion of an IUS should not be delayed to await results of Chlamydia or gonorrhea testing in a woman without clinical evidence of pelvic infection. Risk-based, as opposed to universal testing, is imperative.¹² These recommendations are in agreement with current recommendations of the Centers for Disease Control and Prevention and the American College of Obstetricians and Gynecologists.^13,14 Practices that employ 2-visit protocols unnecessarily limit women’s access to the IUS, as research has shown that nearly half of women desiring an IUD do not return for device placement if a second encounter is required.¹⁵

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Contraception is an important tool that allows patients to carry out their reproductive-life plans. In the United States, the average woman desires 2 children.¹ To achieve this goal, she will spend more than 30 years of her reproductive life avoiding pregnancy.¹ The most effective reversible contraceptive methods, the intrauterine device (IUD) and the contraceptive implant, offer an efficient way to cover this significant period. Currently, American women more commonly choose an IUD than an implant by a factor 8 to 1.² Between 2002 and 2012, the percentage of US contraceptive users aged 15 to 44 using the IUD rose from 2% to 10%.²

Significant barriers to contraceptive access still exist, however. Although widespread reports have lauded the decrease in unintended pregnancies in the United States, improvement only has been marginal for women who live below the poverty level. In fact, for unintended pregnancy the gap between women above and below the poverty level has increased from a 2.6-fold difference in 1994 to a 5.6-fold difference in 2011 (FIGURE).³⁻⁵ Since the decrease in the unintended pregnancy rate is most likely related to an increase in contraceptive use, particularly the IUD, we are not providing equal contraceptive access to all women.⁵

Both the copper IUD and the 3 available levonorgestrel (LNG)-releasing intrauterine system (IUS) products provide safe and effective contraception. As IUD research expands, it is imperative for providers to stay up to date so patients can have full access to these devices.

In this article, we present important updates regarding IUD use that will help break down some continuing barriers to contraceptive access, including:

WHO study demonstrates LNG 52-mg IUS is highly effective for up to 7 years of use

Rowe P, Farley T, Peregoudov A, et al; IUD Research Group of the UNDP/UNFPA/WHO/World Bank Special Programme of Research; Development and Research Training in Human Reproduction. Safety and efficacy in parous women of a 52-mg levonorgestrel-medicated intrauterine device: a 7-year randomized comparative study with the TCu380A. Contraception. 2016;93(6):498−506.

Currently, the 2 LNG 52-mg IUS products (Liletta, Mirena) approved by the US Food and Drug Administration (FDA) are available for use for 3 and 5 years, respectively. The pivotal approval trial for Liletta is still ongoing and is planned to continue for up to 7 years.⁶ The TCu380A (ParaGard) copper IUD is FDA approved for up to 10 years of use; however, this product initially was approved for only 4 years. The duration of use was expanded to 10 years based on continued clinical trials.

Based on current data, we will not need to wait for the Liletta pivotal trial to have clinical evidence of a longer duration of efficacy for the LNG 52-mg IUS. A collaborative group as part of the UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction performed a multicenter, open-label randomized controlled trial to evaluate outcomes through 7 years of use of the LNG 52-mg IUS and the TCu380A IUD.

Details of the study

A total of 3,836 women were enrolled at 20 centers in Europe, Asia, South America, and China and were randomly assigned to one of the 2 products. Eligible women were aged 16 to 40 years, parous, and without known leiomyoma or recent pelvic infection. After excluding 15 failed IUD insertions, 1,910 women received an LNG 52-mg IUS and 1,911 received a TCu380A. Ultimately, 398 women in the LNG 52-mg IUS group and 682 in the TCu380A group completed 7-year follow-up with the IUD in place. Women were surveyed regarding pregnancy and method discontinuation.

Lower pregnancy rate, higher discontinuation with LNG IUS

The cumulative 7-year pregnancy rate among LNG 52-mg IUS users was significantly lower than among TCu380A users (0.53 per 100 women vs 2.45 per 100 women, respectively). All pregnancies in the LNG 52-mg IUS group occurred in the first 5 years of study follow-up--with no pregnancies in years 6 through 7 (TABLE). The cumulative pregnancy rate in the TCu380A group in this study is consistent with that in a previous long-term trial of this IUD.⁷

Early removal was significantly higher in the LNG 52-mg IUS group, with a cumulative discontinuation rate of 70.6 per 100 women, compared with 40.8 per 100 women in the TCu380A group. Significant cultural variation existed when it came to both rate and reason for discontinuation. Most women at Chinese centers cited amenorrhea and decreased bleeding as the primary reason for discontinuation, and they did so at twice the rate of women at non-Chinese centers.

The patterns of method discontinuation in this study were different from those found among US women. By comparison, a recent study in the United States had lower overall discontinuation rates and did not find decreased bleeding to be among the main reasons for LNG 52-mg IUS removal.⁷ In fact, most women who discontinued the LNG 52-mg IUS cited concerns about upcoming expiration as their reason for removal.

The results of this large study also generally corroborated the low-risk profile of IUDs. Only 1 reported IUD perforation occurred, for a rate of 0.03 per 1,000 women. Device expulsion rates were similar between the IUDs and were uncommon overall with 7-year rates of 8 to 9 per 100 women. Pelvic infection was cited as reason for removal in only 7 women (0.18 per 100 women) over 7 years.

What this evidence means for practiceThis exciting study is the first large-scale clinical trial demonstrating continued high efficacy with LNG 52-mg IUS use through 7 years. This information affords women extended contraceptive coverage. While additional research will be welcome, particularly in younger women who will maintain greater fertility across the IUS’s 7-year life span, we are confident in extending the 7-year duration for this IUS to our patients.

Additionally, the method discontinuation findings in this study highlight the importance of discussing the expected menstrual changes of hormonal IUS use with women prior to insertion so they can determine if the potential changes would be satisfactory. As the acceptability of medical menstrual suppression may be new to many women, providers should frame the adverse effects in this context. Providers can use this opportunity to review the noncontraceptive benefits of the hormonal IUS as well.

Novel combination of LNG 52-mg IUS and oral LNG 1.5 mg is promising for emergency contraception

Turok DK, Sanders JN, Thompson IS, Royer PA, Eggebroten J, Gawron LM. Preference for and efficacy of oral levonorgestrel for emergency contraception with concomitant placement of a levonorgestrel IUD: a prospective cohort study. Contraception. 2016;93(6):526−532.

The copper IUD is superior for EC relative to oral agents and has the added benefit of providing ongoing highly effective contraception after placement.⁸ Despite this strong evidence, the copper IUD remains underutilized for this indication. Turok and colleagues noted that women in their clinic seeking IUDs for non-EC purposes preferred the LNG 52-mg IUS over the copper IUD. It is understandable that women might carry these preferences into EC encounters as well. Thus, the investigators devised a novel combination of LNG 52-mg IUS and oral LNG 1.5 mg, which provided both known EC benefit and same-day access to a more popular contraceptive device.

Details of the study

Women presenting for EC who desired same-day IUD placement were enrolled in the prospective cohort study. Eligible women had a negative urine pregnancy test, known last menstrual period (LMP), regular menstrual cycle, and reported unprotected intercourse within 120 hours prior to presentation. Importantly, women with multiple episodes of unprotected intercourse in the weeks prior to presentation were also included to provide a population more comparable to that encountered clinically. The women were then offered the choice of a TCu380A copper IUD or oral LNG EC with LNG 52-mg IUS placement. They were counseled on the potential increased risk of pregnancy with the novel oral LNG EC plus LNG IUS combination compared with the copper IUD. Participants were given a home pregnancy test that they were to complete in 2 weeks and then report the results to the clinic.

Of the 1,004 women presenting to the clinic for EC over the 16-month study period, 188 (18%) desired same-day IUD insertion. Of these, more opted for the oral LNG EC plus LNG IUS combination (n = 121, 64%) than the copper IUD (n = 67, 36%), demonstrating that women were often willing to accept a possible decrease in EC efficacy with the goal of obtaining their preferred lUD type.

Excluding failed insertion, undiagnosed uterine didelphys, and patient withdrawal, 110 women received the oral LNG EC plus LNG IUS and 66 received the copper IUD. Demographics were comparable between groups except for body mass index (BMI). Of note, more than half (61%) of the women who opted for the oral LNG EC plus LNG IUS combination were overweight or obese.

Both EC methods are effective, broadening options

All women who received the copper IUD followed up at 2 weeks, and no pregnancies were reported. Of the women who received oral LNG EC plus the LNG IUS, 107 (97%) had follow-up at 2 weeks. In this group, there was 1 reported ectopic pregnancy that ultimately required surgical management. However, further review of the patient's coital history suggested that conception occurred prior to IUD insertion, and the case was not classified by the investigators as an EC failure.

Although this study was not powered to detect pregnancy rate differences between the traditional copper IUD and the oral LNG EC plus LNG IUS combination, the results are promising. An important strength of this study is the presence of 2 high-risk groups for EC failure in the oral LNG EC plus LNG IUS group (elevated BMI and multiple episodes of unprotected intercourse).

What this evidence means for practiceEncounters for EC are important opportunities in which to discuss a woman’s reproductive goals. For women who are interested in an IUD, this study opens up the option of same-day placement of the LNG 52-mg IUS. While larger trials need to be conducted to obtain more information regarding pregnancy rates with an oral EC plus LNG IUS combination versus the TCu380A, offering such a combination is reasonable. Given that ulipristal acetate (UPA) is a more effective EC product, especially for women who are overweight or obese,⁹ offering a UPA EC plus LNG IUS combination may be a better alternative.

It is time to remove the STI screening barrier to same-day IUD insertion

Turok DK, Eisenberg DL, Teal SB, Keder LM, Creinin MD. A prospective assessment of pelvic infection risk following same-day sexually transmitted infection testing and levonorgestrel intrauterine system placement [published online ahead of print May 12, 2016]. Am J Obstet Gynecol. doi:10.1016/j.ajog.2016.05017.

Provider concerns regarding the presence of pelvic infection remain a significant barrier to same-day IUD insertion. Older studies suggested a higher risk of pelvic infection in the first 20 days after IUD placement and extrapolated that pelvic infection was related to inserting an IUD in a woman at risk for STI.¹⁰ As a result, patients may be restricted from same-day IUD insertion by providers who think that obtaining results of STI testing is required prior to placement. Recently, a systematic review suggested, based on limited evidence, that IUD placement does not increase the risk of pelvic infection in asymptomatic women compared with those without an IUD.¹¹

Turok and colleagues (including M.D.C., coauthor of this article) reported results from a planned secondary analysis of A Comprehensive Contraceptive Efficacy and Safety Study of an IUS (ACCESS IUS), a component of the regulatory approval of the Liletta LNG 52-mg IUS. This analysis represents the first large-scale prospective investigation of pelvic infection rates during the first 2 years after IUD placement in US women.

Details of the study

Of the 1,751 women enrolled in the study, 1,714 had successful IUS insertions. Infection was assessed via baseline pelvic visual and bimanual examination and Chlamydia testing in all women. Gonorrhea testing was also performed in women who had not been tested with their current sexual partner. STI test results were not required for IUS insertion. Participants were assessed in person at 1, 3, 6, 12, and 24 months after insertion. Additional pelvic exams were performed as needed based on reported symptoms. At 6 months, 1 year, and 2 years, IUS continuation was reported in 1,553 (90.6%), 1,401 (81.7%), and 1,157 (67.3%) women, respectively.

Nearly all women received baseline STI testing (98.4%); however, results were not available prior to same-day IUS insertion for 79.6% of participants. Twenty-nine (1.7%) women had positive baseline STI tests (25 for Chlamydia, 3 for gonorrhea, 1 for both). Of these, only 6 women had results available prior to IUS placement. All women with a positive STI test were treated, and the IUS was left in place. Importantly, none of these women developed pelvic infection in the subsequent 2 years of follow-up and none requested IUS removal.

Infection risk is low with IUD placement

Among women with negative baseline STI tests, there were only 9 (0.5%) clinical diagnoses of pelvic infections over the first 2 years of follow-up. Diagnosis was typically made based on physical examination findings. Most women underwent repeat Chlamydia and gonorrhea testing at the time of pelvic infection diagnosis, and none had positive results. There were no medically recommended IUS removals; 2 women with pelvic infection requested IUS removal per their preference.

Three of the 9 women with pelvic infections were diagnosed within 1 week of IUS placement, 1 at 39 days after placement, and the remaining 5 more than 6 months after placement, suggesting that pelvic infection is not temporally related to IUS placement. Most women were successfully treated as outpatients.

What this evidence means for practiceThis study provides further reassurance regarding the low risk of pelvic infection among women with an LNG IUS. Insertion of an IUS should not be delayed to await results of Chlamydia or gonorrhea testing in a woman without clinical evidence of pelvic infection. Risk-based, as opposed to universal testing, is imperative.¹² These recommendations are in agreement with current recommendations of the Centers for Disease Control and Prevention and the American College of Obstetricians and Gynecologists.^13,14 Practices that employ 2-visit protocols unnecessarily limit women’s access to the IUS, as research has shown that nearly half of women desiring an IUD do not return for device placement if a second encounter is required.¹⁵

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Contraception is an important tool that allows patients to carry out their reproductive-life plans. In the United States, the average woman desires 2 children.¹ To achieve this goal, she will spend more than 30 years of her reproductive life avoiding pregnancy.¹ The most effective reversible contraceptive methods, the intrauterine device (IUD) and the contraceptive implant, offer an efficient way to cover this significant period. Currently, American women more commonly choose an IUD than an implant by a factor 8 to 1.² Between 2002 and 2012, the percentage of US contraceptive users aged 15 to 44 using the IUD rose from 2% to 10%.²

Significant barriers to contraceptive access still exist, however. Although widespread reports have lauded the decrease in unintended pregnancies in the United States, improvement only has been marginal for women who live below the poverty level. In fact, for unintended pregnancy the gap between women above and below the poverty level has increased from a 2.6-fold difference in 1994 to a 5.6-fold difference in 2011 (FIGURE).³⁻⁵ Since the decrease in the unintended pregnancy rate is most likely related to an increase in contraceptive use, particularly the IUD, we are not providing equal contraceptive access to all women.⁵

Both the copper IUD and the 3 available levonorgestrel (LNG)-releasing intrauterine system (IUS) products provide safe and effective contraception. As IUD research expands, it is imperative for providers to stay up to date so patients can have full access to these devices.

In this article, we present important updates regarding IUD use that will help break down some continuing barriers to contraceptive access, including:

WHO study demonstrates LNG 52-mg IUS is highly effective for up to 7 years of use

Rowe P, Farley T, Peregoudov A, et al; IUD Research Group of the UNDP/UNFPA/WHO/World Bank Special Programme of Research; Development and Research Training in Human Reproduction. Safety and efficacy in parous women of a 52-mg levonorgestrel-medicated intrauterine device: a 7-year randomized comparative study with the TCu380A. Contraception. 2016;93(6):498−506.

Currently, the 2 LNG 52-mg IUS products (Liletta, Mirena) approved by the US Food and Drug Administration (FDA) are available for use for 3 and 5 years, respectively. The pivotal approval trial for Liletta is still ongoing and is planned to continue for up to 7 years.⁶ The TCu380A (ParaGard) copper IUD is FDA approved for up to 10 years of use; however, this product initially was approved for only 4 years. The duration of use was expanded to 10 years based on continued clinical trials.

Based on current data, we will not need to wait for the Liletta pivotal trial to have clinical evidence of a longer duration of efficacy for the LNG 52-mg IUS. A collaborative group as part of the UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction performed a multicenter, open-label randomized controlled trial to evaluate outcomes through 7 years of use of the LNG 52-mg IUS and the TCu380A IUD.

Details of the study

A total of 3,836 women were enrolled at 20 centers in Europe, Asia, South America, and China and were randomly assigned to one of the 2 products. Eligible women were aged 16 to 40 years, parous, and without known leiomyoma or recent pelvic infection. After excluding 15 failed IUD insertions, 1,910 women received an LNG 52-mg IUS and 1,911 received a TCu380A. Ultimately, 398 women in the LNG 52-mg IUS group and 682 in the TCu380A group completed 7-year follow-up with the IUD in place. Women were surveyed regarding pregnancy and method discontinuation.

Lower pregnancy rate, higher discontinuation with LNG IUS

The cumulative 7-year pregnancy rate among LNG 52-mg IUS users was significantly lower than among TCu380A users (0.53 per 100 women vs 2.45 per 100 women, respectively). All pregnancies in the LNG 52-mg IUS group occurred in the first 5 years of study follow-up--with no pregnancies in years 6 through 7 (TABLE). The cumulative pregnancy rate in the TCu380A group in this study is consistent with that in a previous long-term trial of this IUD.⁷

Early removal was significantly higher in the LNG 52-mg IUS group, with a cumulative discontinuation rate of 70.6 per 100 women, compared with 40.8 per 100 women in the TCu380A group. Significant cultural variation existed when it came to both rate and reason for discontinuation. Most women at Chinese centers cited amenorrhea and decreased bleeding as the primary reason for discontinuation, and they did so at twice the rate of women at non-Chinese centers.

The patterns of method discontinuation in this study were different from those found among US women. By comparison, a recent study in the United States had lower overall discontinuation rates and did not find decreased bleeding to be among the main reasons for LNG 52-mg IUS removal.⁷ In fact, most women who discontinued the LNG 52-mg IUS cited concerns about upcoming expiration as their reason for removal.

The results of this large study also generally corroborated the low-risk profile of IUDs. Only 1 reported IUD perforation occurred, for a rate of 0.03 per 1,000 women. Device expulsion rates were similar between the IUDs and were uncommon overall with 7-year rates of 8 to 9 per 100 women. Pelvic infection was cited as reason for removal in only 7 women (0.18 per 100 women) over 7 years.

What this evidence means for practiceThis exciting study is the first large-scale clinical trial demonstrating continued high efficacy with LNG 52-mg IUS use through 7 years. This information affords women extended contraceptive coverage. While additional research will be welcome, particularly in younger women who will maintain greater fertility across the IUS’s 7-year life span, we are confident in extending the 7-year duration for this IUS to our patients.

Additionally, the method discontinuation findings in this study highlight the importance of discussing the expected menstrual changes of hormonal IUS use with women prior to insertion so they can determine if the potential changes would be satisfactory. As the acceptability of medical menstrual suppression may be new to many women, providers should frame the adverse effects in this context. Providers can use this opportunity to review the noncontraceptive benefits of the hormonal IUS as well.

Novel combination of LNG 52-mg IUS and oral LNG 1.5 mg is promising for emergency contraception

Turok DK, Sanders JN, Thompson IS, Royer PA, Eggebroten J, Gawron LM. Preference for and efficacy of oral levonorgestrel for emergency contraception with concomitant placement of a levonorgestrel IUD: a prospective cohort study. Contraception. 2016;93(6):526−532.

The copper IUD is superior for EC relative to oral agents and has the added benefit of providing ongoing highly effective contraception after placement.⁸ Despite this strong evidence, the copper IUD remains underutilized for this indication. Turok and colleagues noted that women in their clinic seeking IUDs for non-EC purposes preferred the LNG 52-mg IUS over the copper IUD. It is understandable that women might carry these preferences into EC encounters as well. Thus, the investigators devised a novel combination of LNG 52-mg IUS and oral LNG 1.5 mg, which provided both known EC benefit and same-day access to a more popular contraceptive device.

Details of the study

Women presenting for EC who desired same-day IUD placement were enrolled in the prospective cohort study. Eligible women had a negative urine pregnancy test, known last menstrual period (LMP), regular menstrual cycle, and reported unprotected intercourse within 120 hours prior to presentation. Importantly, women with multiple episodes of unprotected intercourse in the weeks prior to presentation were also included to provide a population more comparable to that encountered clinically. The women were then offered the choice of a TCu380A copper IUD or oral LNG EC with LNG 52-mg IUS placement. They were counseled on the potential increased risk of pregnancy with the novel oral LNG EC plus LNG IUS combination compared with the copper IUD. Participants were given a home pregnancy test that they were to complete in 2 weeks and then report the results to the clinic.

Of the 1,004 women presenting to the clinic for EC over the 16-month study period, 188 (18%) desired same-day IUD insertion. Of these, more opted for the oral LNG EC plus LNG IUS combination (n = 121, 64%) than the copper IUD (n = 67, 36%), demonstrating that women were often willing to accept a possible decrease in EC efficacy with the goal of obtaining their preferred lUD type.

Excluding failed insertion, undiagnosed uterine didelphys, and patient withdrawal, 110 women received the oral LNG EC plus LNG IUS and 66 received the copper IUD. Demographics were comparable between groups except for body mass index (BMI). Of note, more than half (61%) of the women who opted for the oral LNG EC plus LNG IUS combination were overweight or obese.

Both EC methods are effective, broadening options

All women who received the copper IUD followed up at 2 weeks, and no pregnancies were reported. Of the women who received oral LNG EC plus the LNG IUS, 107 (97%) had follow-up at 2 weeks. In this group, there was 1 reported ectopic pregnancy that ultimately required surgical management. However, further review of the patient's coital history suggested that conception occurred prior to IUD insertion, and the case was not classified by the investigators as an EC failure.

Although this study was not powered to detect pregnancy rate differences between the traditional copper IUD and the oral LNG EC plus LNG IUS combination, the results are promising. An important strength of this study is the presence of 2 high-risk groups for EC failure in the oral LNG EC plus LNG IUS group (elevated BMI and multiple episodes of unprotected intercourse).

What this evidence means for practiceEncounters for EC are important opportunities in which to discuss a woman’s reproductive goals. For women who are interested in an IUD, this study opens up the option of same-day placement of the LNG 52-mg IUS. While larger trials need to be conducted to obtain more information regarding pregnancy rates with an oral EC plus LNG IUS combination versus the TCu380A, offering such a combination is reasonable. Given that ulipristal acetate (UPA) is a more effective EC product, especially for women who are overweight or obese,⁹ offering a UPA EC plus LNG IUS combination may be a better alternative.

It is time to remove the STI screening barrier to same-day IUD insertion

Turok DK, Eisenberg DL, Teal SB, Keder LM, Creinin MD. A prospective assessment of pelvic infection risk following same-day sexually transmitted infection testing and levonorgestrel intrauterine system placement [published online ahead of print May 12, 2016]. Am J Obstet Gynecol. doi:10.1016/j.ajog.2016.05017.

Provider concerns regarding the presence of pelvic infection remain a significant barrier to same-day IUD insertion. Older studies suggested a higher risk of pelvic infection in the first 20 days after IUD placement and extrapolated that pelvic infection was related to inserting an IUD in a woman at risk for STI.¹⁰ As a result, patients may be restricted from same-day IUD insertion by providers who think that obtaining results of STI testing is required prior to placement. Recently, a systematic review suggested, based on limited evidence, that IUD placement does not increase the risk of pelvic infection in asymptomatic women compared with those without an IUD.¹¹

Turok and colleagues (including M.D.C., coauthor of this article) reported results from a planned secondary analysis of A Comprehensive Contraceptive Efficacy and Safety Study of an IUS (ACCESS IUS), a component of the regulatory approval of the Liletta LNG 52-mg IUS. This analysis represents the first large-scale prospective investigation of pelvic infection rates during the first 2 years after IUD placement in US women.

Details of the study

Of the 1,751 women enrolled in the study, 1,714 had successful IUS insertions. Infection was assessed via baseline pelvic visual and bimanual examination and Chlamydia testing in all women. Gonorrhea testing was also performed in women who had not been tested with their current sexual partner. STI test results were not required for IUS insertion. Participants were assessed in person at 1, 3, 6, 12, and 24 months after insertion. Additional pelvic exams were performed as needed based on reported symptoms. At 6 months, 1 year, and 2 years, IUS continuation was reported in 1,553 (90.6%), 1,401 (81.7%), and 1,157 (67.3%) women, respectively.

Nearly all women received baseline STI testing (98.4%); however, results were not available prior to same-day IUS insertion for 79.6% of participants. Twenty-nine (1.7%) women had positive baseline STI tests (25 for Chlamydia, 3 for gonorrhea, 1 for both). Of these, only 6 women had results available prior to IUS placement. All women with a positive STI test were treated, and the IUS was left in place. Importantly, none of these women developed pelvic infection in the subsequent 2 years of follow-up and none requested IUS removal.

Infection risk is low with IUD placement

Among women with negative baseline STI tests, there were only 9 (0.5%) clinical diagnoses of pelvic infections over the first 2 years of follow-up. Diagnosis was typically made based on physical examination findings. Most women underwent repeat Chlamydia and gonorrhea testing at the time of pelvic infection diagnosis, and none had positive results. There were no medically recommended IUS removals; 2 women with pelvic infection requested IUS removal per their preference.

Three of the 9 women with pelvic infections were diagnosed within 1 week of IUS placement, 1 at 39 days after placement, and the remaining 5 more than 6 months after placement, suggesting that pelvic infection is not temporally related to IUS placement. Most women were successfully treated as outpatients.

What this evidence means for practiceThis study provides further reassurance regarding the low risk of pelvic infection among women with an LNG IUS. Insertion of an IUS should not be delayed to await results of Chlamydia or gonorrhea testing in a woman without clinical evidence of pelvic infection. Risk-based, as opposed to universal testing, is imperative.¹² These recommendations are in agreement with current recommendations of the Centers for Disease Control and Prevention and the American College of Obstetricians and Gynecologists.^13,14 Practices that employ 2-visit protocols unnecessarily limit women’s access to the IUS, as research has shown that nearly half of women desiring an IUD do not return for device placement if a second encounter is required.¹⁵

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.