OBG Management

There’s a cyclical lament in obstetrics, and it goes something like this: Forceps are waning and are going to fade away completely if something isn’t done about it. This lament resounds every few decades, as a look at the literature confirms:

In this, our latest cycle of lament, 4 or 5 papers have suggested that forceps in general and Kielland forceps in particular ought not be abandoned because outcomes are better than those suggested by the older literature. With the cesarean delivery rate hovering at about 31% in the United States, perhaps it is time to revisit the issue.

This Update is not intended to be a comprehensive review of the literature. Rather, it offers a snapshot of articles published within the past year—articles that highlight some new features of a very old debate:

Forceps and vacuum device placement is “suboptimal” in almost 30% of operative vaginal deliveries
Ramphul M, Kennelly MM, Burke G, Murphy DJ. Risk factors and morbidity associated with suboptimal instrument placement at instrumental delivery: observational study nested within the Instrumental Delivery & Ultrasound randomised controlled trial ISRCTN 72230496. BJOG. 2015;122(4):558–563.

Rouse DJ. Instrument placement is sub-optimal in three of ten attempted operative vaginal deliveries. BJOG. 2015;122(4):564.

Over the years, many clinicians have argued that we don’t do enough forceps deliveries to maintain our own competence with the procedure, let alone teach residents how to perform it. This observational study nested in a randomized clinical trial is intriguing because Ramphul and colleagues looked for objective evidence of clinicians’ skill at the vacuum and forceps. Specifically, they looked for evidence that the forceps or vacuum was malpositioned during attempts at operative vaginal delivery. In the process, they nicely documented the absolute rate of malpositioning of the forceps and vacuum, finding that it is much higher than expected, even in an institution that performs a lot of operative vaginal deliveries.

Details of the trial
A cohort of 478 nulliparous women at term (≥37 weeks) underwent instrumental delivery at 2 university-affiliated maternity hospitals in Ireland. Ramphul and colleagues documented fetal head position prior to application of the instrument and at delivery. The midwife or neonatologist attending each delivery examined the neonate after birth and recorded the markings of the instrument on the infant’s head to determine whether instrument placement had been optimal.

Instrument placement was considered optimal when the vacuum cup included the flexion point (3 cm anterior to the posterior fontanelle) and the posterior fontanelle, with central placement. For forceps, instrument placement was considered optimal when the blades were positioned bilaterally and symmetrically over the malar bones. Two main types of forceps were used in this study—direct-traction Neville Barnes forceps (n = 138) and rotational Kielland forceps (n = 13)—and the rates of optimal and suboptimal placement were similar between them. 

Each case was labeled as “optimal” or “suboptimal” by 2 investigators, with a third observer arbitrating when the 2 investigators differed in opinion.

Instrument placement was clearly documented in 478 deliveries, 138 of which (28.8%) involved suboptimal placement. There was a lower rate of induction of labor among deliveries with suboptimal placement (42.8% vs 53.2%; odds ratio [OR], 0.66; 95% confidence interval [CI], 0.44–0.98; P = .038). There were no differences between the optimal and suboptimal groups in terms of duration of labor, use of oxytocin, and analgesia. In addition, the seniority of obstetricians performing operative vaginal delivery was similar between groups.

Fetal malposition was more common in the suboptimal group (58.7% vs 37.4%; OR, 2.44; 95% CI, 1.62–3.66; P<.0001). Midcavity station also was more common in the suboptimal group (82.6% vs 73.8%; OR, 1.68; 95% CI, 1.02–2.78; P = .042).

Maternal and neonatal outcomes
Postpartum hemorrhage was more common in the suboptimal placement group (24.6% vs 14.4%; OR, 1.94; 95% CI, 1.19–3.17; P = .008), as was prolonged hospitalization (26.8% vs 14.7%; OR, 2.13; 95% CI, 1.31–3.44; P = .02).

In addition, the incidence of neonatal trauma was higher in the group with suboptimal placement (15.9% vs 3.9%; OR, 4.64; 95% CI, 2.25–9.58; P<.0001) and included such effects as Erb’s palsy, fracture, retinal hemorrhage, cephalhematoma, and cerebral hemorrhage.

After adjustment for potential confounding factors, including induction of labor, seniority of the obstetrician, fetal malposition, caput above +1, midcavity station, regional analgesia, and the instrument used, the association remained significant between suboptimal placement and prolonged hospitalization (adjusted OR, 2.28; 95% CI, 1.30–4.02) and neonatal trauma (adjusted OR, 4.25; 95% CI, 1.85–9.72).

Dwindling statistics for operative vaginal delivery
In an editorial accompanying the study by Ramphul and colleagues, Dwight J. Rouse, MD,points to the waning of instrumental vaginal delivery in many parts of the world, most notably the United States, where, in 2012, only 2.8% of live births involved use of a vacuum device and only 0.6% involved the forceps.⁵

“When the rate of cesarean delivery is 10 times the combined rate of vaginal vacuum and forceps delivery (as it is in the USA), it is fair to argue that operative vaginal delivery is underutilized,” Dr. Rouse writes. “So kudos to Ramphul et al for providing insight into how we might continue to perform operative vaginal delivery safely.”

What this EVIDENCE means for practice
The study by Ramphul and colleagues very clearly confirms that correct placement of the vacuum device or forceps is key to safety.

Should we continue forceps education using the apprenticeship model of training?
Kyser KL, Lu X, Santillan D, et al. Forceps delivery volumes in teaching and nonteaching hospitals: Are volumes sufficient for physicians to acquire and maintain competence? Acad Med. 2014;89(1):71–76.

Ericsson KA. Necessity is the mother of invention: ­video recording firsthand perspectives of critical medical procedures to make simulated training more effective. Acad Med. 2014;89(1):17–20.

Kyser and colleagues have provided the best current snapshot of the opportunity for teaching instrumental vaginal delivery in the United States. They conducted a retrospective cohort study using new state inpatient data from 9 states in diverse geographic locations to capture experience at large and small teaching hospitals, as well as nonteaching institutions. They demonstrated that the opportunity for hands-on experience with these difficult and technically demanding deliveries is extremely limited and probably insufficient for all practicing physicians to maintain their skills if we continue to rely on traditional ways of teaching.

Details of the study
Using State Inpatient Data from 9 states, Kyser and colleagues identified all women hospitalized for childbirth in 2008. Of 1,344,305 deliveries in 835 hospitals, the final cohort included 624,000 operative deliveries—424,224 cesarean deliveries, 174,036 vacuum extractions, 6,158 forceps deliveries, and 19,582 deliveries that required more than 1 method. Of the 835 hospitals in this study, 68 were major teaching hospitals, 130 were minor teaching facilities, and 637 were nonteaching institutions.

The mean annual volumes for cesarean delivery for major teaching, minor teaching, and nonteaching hospitals were 969.8, 757.8, and 406.9, respectively (P<.0001).

The mean annual volumes for vacuum delivery were 301.0, 304.2, and 190.4, respectively (P<.0001).

The mean annual volumes for forceps delivery were 25.2, 15.3, and 8.9, respectively (P<.0001).

Three hundred twenty hospitals (38.3% of all hospitals) failed to perform a single forceps delivery in 2008, including 11 major teaching hospitals (16.2% of major teaching hospitals), 30 minor teaching hospitals (23.1% of minor teaching hospitals), and 279 nonteaching hospitals (43.8% of nonteaching hospitals) (P<.0001).

We need to rethink the apprenticeship model
In a commentary accompanying the study by Kyser and colleagues, K. Anders ­Ericsson, PhD, revisits the “see one, do one, teach one” model that has long characterized medical education. “Both the limitations on learning opportunities available in the clinics and the restrictions on resident work hours have created a real problem for the traditional apprenticeship model for training doctors,” he writes.

Ericsson notes that other specialists, such as concert musicians, chess players, and professional athletes do not learn using an apprenticeship model. For example, chess players do not play game after game of chess to become expert. And when a game is concluded, usually after several hours have passed, they are unlikely to be aware of the specific moves that lost or won them the game (unless an observer points them out). That is why, when training, chess players focus on particular aspects of the game (often identified by a mentor) as being crucial to improve their overall performance.

In today’s chess-learning environment, Ericsson notes, the computer plays a key role and can provide accurate feedback on each move the player executes. Computer chess programs have evolved to the point that they “are far superior in skill to any human chess player. Most important, computers can provide more accurate feedback on each chess move and are available at any time for practice,” writes Ericsson.

The same is true in sports. A tennis player does not practice by playing an endless series of games—though an ability to win a game is the ultimate goal. Rather, the athlete focuses on aspects of the game—the serve, for example—that can make the difference between winning or losing. Ericsson also notes that most musicians, dancers, and athletes “spend most of their time training by themselves to get ready to exhibit their skills for the first time in front of a large audience.”

These approaches are a better model for improving performance than the apprenticeship model, Ericsson argues. In medicine, one alternative might be the video recording of medical procedures in the clinic from multiple points of view—so that later viewers get both the “big picture” and a close-up view from the point of technical performance. After the recording is digitized and stored on a server, it can serve as valuable teaching for an unlimited number of residents.

Simulator training offers another venue for education, as it makes possible the isolation of difficult aspects of a procedure, which can then be repeated by the trainee as many times as necessary. In the future, it should be possible to link video recordings directly to simulators “so trainees could focus on particular aspects of the procedures and be required to respond to prompts with recordable actions,” Ericsson writes.

What this EVIDENCE means for practice
Given the extremely limited opportunities for observing forceps deliveries in the United States, it is time for us to explore new avenues for teaching other than the traditional apprenticeship model.

Is ultrasound evidence of levator muscle “avulsion” a real anatomic entity?
Dietz HP. Forceps: toward obsolescence or revival? Acta Obstet Gynecol Scand. 2015;94(4):347–351.

Da Silva AS, Digesu GA, Dell’Utri C, Fritsch H, ­Piffarotti P, Khullar V. Do ultrasound findings of levator ani “avulsion” correlate with anatomical findings? A multicenter cadaveric study [published online ahead of print May 15, 2015]. Neurourol Urodyn. doi:10.1002 /nau.22781.

Dietz takes a new tack in the debate over cesarean versus forceps by pointing to a recently highlighted abnormality in women who deliver by forceps: levator ani muscle avulsion, or LMA—traumatic disconnection of the levator ani from the pelvic sidewall. It has long been known that forceps deliveries can increase the risk of obstetric anal sphincter injuries (OASIS). Dietz contends that OASIS occurs at a rate as high as 40% to 60% after forceps delivery. He also notes, with some consternation, that the American ­College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine have advocated forceps as a way of reducing the high cesarean delivery rate.

When a parturient has been pushing for an extended period of time and there is a positional abnormality of the fetus, such as persistent occiput posterior position, cesarean delivery is often favored as a way of protecting the rectal sphincter. Dietz argues that cesarean delivery also protects against LMA, which “has only recently been recognized as a major etiological factor in pelvic floor dysfunction.” Dietz then presents a list of studies that have produced ultrasound findings of LMA in a high percentage of women undergoing forceps delivery—percentages on the order of 10% to 40%.

Enter Da Silva and colleagues, who argue that “the only true place to visualize the 3D structure of the human body, [and] thus validate imaging findings, [is] on cadaveric or live tissue dissections.” They undertook a cadaveric study to validate—or not—some of the findings of LMA summarized by Dietz.

Details of the study
The pubovisceral muscle (PVM) anatomy of 30 female cadavers was analyzed via 3D translabial ultrasonography to confirm LMA. The cadavers were then dissected to assess the finding anatomically. Da Silva and colleagues found LMA on imaging in 11 (36.7%) cadavers. LMA was unilateral in 10 (33.3%) cadavers and bilateral in 1 (3.3%). However, no LMA was found at dissection.

When an additional 39 cadavers were dissected, no LMA was identified.

On ultrasound, LMA is strongly associated with a narrower PVM insertion depth (mean of 4.79 mm vs 6.32 mm; P = .001). Da Silva and colleagues concluded that “there is a clear difference between anatomical and ultrasonographic findings. The imaged appearance of an ‘avulsion’ does not represent a true anatomical ‘avulsion’ as confirmed on dissection.”

What this EVIDENCE means for practice
Before we prematurely adopt ultrasound evidence of LMA as a significant morbidity, we need to learn more about its true etiology, pathophysiology, and epidemiology. We don’t yet know enough to say that it’s such a bad injury, when imaged via ultrasound, that it warrants cesarean delivery to avoid it.

When deciding between cesarean and forceps, keep the risks of second-stage cesarean in mind
Pergialiotis V, Vlachos DG, Rodolakis A, Haidopoulos D, Thomakos N, Vlachos GD. First versus second stage C/S maternal and neonatal morbidity: a systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2014;175:15–24.

This expert systematic review and meta-analysis summarizes the morbidity of second-stage cesarean delivery. When an obstetrician has a patient who is arrested at persistent occiput posterior position, say, and is trying to decide on cesarean delivery versus Kielland’s rotation or other forceps delivery, it is necessary to balance the risks and benefits of the 2 options. And as all clinicians are aware, when cesarean delivery is performed late in labor and the patient has been pushing for a prolonged period of time in the second stage—cesarean can be a challenging procedure. Moreover, these late cesareans are associated with much greater risks than cesarean deliveries performed earlier in labor.

Details of the review
Pergialiotis and colleagues selected 10 studies comparing maternal and neonatal morbidity and mortality between cesarean delivery at full dilatation and cesarean delivery prior to full dilatation. These studies involved 23,104 women with a singleton fetus who underwent cesarean delivery in the first (n = 18,160) or second (n = 4,944) stage of labor.

They found that second-stage cesarean was associated with a higher rate of maternal death (OR, 7.96; 95% CI, 1.61–39.39), a higher rate of maternal admission to the intensive care unit (OR, 7.41; 95% CI, 2.47–22.5), and a higher maternal transfusion rate (OR, 2.60; 95% CI, 1.49–2.54).

The rate of neonatal death also was higher among second-stage cesareans (OR, 5.20; 95% CI, 2.49–10.85), as was admission to the neonatal intensive care unit (OR, 1.63; 95% CI, 0.91–2.91), and the 5-minute Apgar score was more likely to be less than 7 (OR, 2.77; 95% CI, 1.02–7.50).

According to the authors, this study is the “first systematic review and meta-­analysis that investigates the impact of the stage of labor on maternal and neonatal outcomes among women delivering by cesarean section.” The findings demonstrate with authority that second-stage cesareans can be a risky undertaking.

What this EVIDENCE means for practice
Cesareans performed late in the second stage of labor are distinct from those performed in the first stage, carrying much higher risks, especially for the mother. When deciding whether to proceed with cesarean, vacuum, or forceps, the added risk of second-stage cesarean is an important aspect of both the consent conversation and clinical decision making.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

There’s a cyclical lament in obstetrics, and it goes something like this: Forceps are waning and are going to fade away completely if something isn’t done about it. This lament resounds every few decades, as a look at the literature confirms:

In this, our latest cycle of lament, 4 or 5 papers have suggested that forceps in general and Kielland forceps in particular ought not be abandoned because outcomes are better than those suggested by the older literature. With the cesarean delivery rate hovering at about 31% in the United States, perhaps it is time to revisit the issue.

This Update is not intended to be a comprehensive review of the literature. Rather, it offers a snapshot of articles published within the past year—articles that highlight some new features of a very old debate:

Forceps and vacuum device placement is “suboptimal” in almost 30% of operative vaginal deliveries
Ramphul M, Kennelly MM, Burke G, Murphy DJ. Risk factors and morbidity associated with suboptimal instrument placement at instrumental delivery: observational study nested within the Instrumental Delivery & Ultrasound randomised controlled trial ISRCTN 72230496. BJOG. 2015;122(4):558–563.

Rouse DJ. Instrument placement is sub-optimal in three of ten attempted operative vaginal deliveries. BJOG. 2015;122(4):564.

Over the years, many clinicians have argued that we don’t do enough forceps deliveries to maintain our own competence with the procedure, let alone teach residents how to perform it. This observational study nested in a randomized clinical trial is intriguing because Ramphul and colleagues looked for objective evidence of clinicians’ skill at the vacuum and forceps. Specifically, they looked for evidence that the forceps or vacuum was malpositioned during attempts at operative vaginal delivery. In the process, they nicely documented the absolute rate of malpositioning of the forceps and vacuum, finding that it is much higher than expected, even in an institution that performs a lot of operative vaginal deliveries.

Details of the trial
A cohort of 478 nulliparous women at term (≥37 weeks) underwent instrumental delivery at 2 university-affiliated maternity hospitals in Ireland. Ramphul and colleagues documented fetal head position prior to application of the instrument and at delivery. The midwife or neonatologist attending each delivery examined the neonate after birth and recorded the markings of the instrument on the infant’s head to determine whether instrument placement had been optimal.

Instrument placement was considered optimal when the vacuum cup included the flexion point (3 cm anterior to the posterior fontanelle) and the posterior fontanelle, with central placement. For forceps, instrument placement was considered optimal when the blades were positioned bilaterally and symmetrically over the malar bones. Two main types of forceps were used in this study—direct-traction Neville Barnes forceps (n = 138) and rotational Kielland forceps (n = 13)—and the rates of optimal and suboptimal placement were similar between them. 

Each case was labeled as “optimal” or “suboptimal” by 2 investigators, with a third observer arbitrating when the 2 investigators differed in opinion.

Instrument placement was clearly documented in 478 deliveries, 138 of which (28.8%) involved suboptimal placement. There was a lower rate of induction of labor among deliveries with suboptimal placement (42.8% vs 53.2%; odds ratio [OR], 0.66; 95% confidence interval [CI], 0.44–0.98; P = .038). There were no differences between the optimal and suboptimal groups in terms of duration of labor, use of oxytocin, and analgesia. In addition, the seniority of obstetricians performing operative vaginal delivery was similar between groups.

Fetal malposition was more common in the suboptimal group (58.7% vs 37.4%; OR, 2.44; 95% CI, 1.62–3.66; P<.0001). Midcavity station also was more common in the suboptimal group (82.6% vs 73.8%; OR, 1.68; 95% CI, 1.02–2.78; P = .042).

Maternal and neonatal outcomes
Postpartum hemorrhage was more common in the suboptimal placement group (24.6% vs 14.4%; OR, 1.94; 95% CI, 1.19–3.17; P = .008), as was prolonged hospitalization (26.8% vs 14.7%; OR, 2.13; 95% CI, 1.31–3.44; P = .02).

In addition, the incidence of neonatal trauma was higher in the group with suboptimal placement (15.9% vs 3.9%; OR, 4.64; 95% CI, 2.25–9.58; P<.0001) and included such effects as Erb’s palsy, fracture, retinal hemorrhage, cephalhematoma, and cerebral hemorrhage.

After adjustment for potential confounding factors, including induction of labor, seniority of the obstetrician, fetal malposition, caput above +1, midcavity station, regional analgesia, and the instrument used, the association remained significant between suboptimal placement and prolonged hospitalization (adjusted OR, 2.28; 95% CI, 1.30–4.02) and neonatal trauma (adjusted OR, 4.25; 95% CI, 1.85–9.72).

Dwindling statistics for operative vaginal delivery
In an editorial accompanying the study by Ramphul and colleagues, Dwight J. Rouse, MD,points to the waning of instrumental vaginal delivery in many parts of the world, most notably the United States, where, in 2012, only 2.8% of live births involved use of a vacuum device and only 0.6% involved the forceps.⁵

“When the rate of cesarean delivery is 10 times the combined rate of vaginal vacuum and forceps delivery (as it is in the USA), it is fair to argue that operative vaginal delivery is underutilized,” Dr. Rouse writes. “So kudos to Ramphul et al for providing insight into how we might continue to perform operative vaginal delivery safely.”

What this EVIDENCE means for practice
The study by Ramphul and colleagues very clearly confirms that correct placement of the vacuum device or forceps is key to safety.

Should we continue forceps education using the apprenticeship model of training?
Kyser KL, Lu X, Santillan D, et al. Forceps delivery volumes in teaching and nonteaching hospitals: Are volumes sufficient for physicians to acquire and maintain competence? Acad Med. 2014;89(1):71–76.

Ericsson KA. Necessity is the mother of invention: ­video recording firsthand perspectives of critical medical procedures to make simulated training more effective. Acad Med. 2014;89(1):17–20.

Kyser and colleagues have provided the best current snapshot of the opportunity for teaching instrumental vaginal delivery in the United States. They conducted a retrospective cohort study using new state inpatient data from 9 states in diverse geographic locations to capture experience at large and small teaching hospitals, as well as nonteaching institutions. They demonstrated that the opportunity for hands-on experience with these difficult and technically demanding deliveries is extremely limited and probably insufficient for all practicing physicians to maintain their skills if we continue to rely on traditional ways of teaching.

Details of the study
Using State Inpatient Data from 9 states, Kyser and colleagues identified all women hospitalized for childbirth in 2008. Of 1,344,305 deliveries in 835 hospitals, the final cohort included 624,000 operative deliveries—424,224 cesarean deliveries, 174,036 vacuum extractions, 6,158 forceps deliveries, and 19,582 deliveries that required more than 1 method. Of the 835 hospitals in this study, 68 were major teaching hospitals, 130 were minor teaching facilities, and 637 were nonteaching institutions.

The mean annual volumes for cesarean delivery for major teaching, minor teaching, and nonteaching hospitals were 969.8, 757.8, and 406.9, respectively (P<.0001).

The mean annual volumes for vacuum delivery were 301.0, 304.2, and 190.4, respectively (P<.0001).

The mean annual volumes for forceps delivery were 25.2, 15.3, and 8.9, respectively (P<.0001).

Three hundred twenty hospitals (38.3% of all hospitals) failed to perform a single forceps delivery in 2008, including 11 major teaching hospitals (16.2% of major teaching hospitals), 30 minor teaching hospitals (23.1% of minor teaching hospitals), and 279 nonteaching hospitals (43.8% of nonteaching hospitals) (P<.0001).

We need to rethink the apprenticeship model
In a commentary accompanying the study by Kyser and colleagues, K. Anders ­Ericsson, PhD, revisits the “see one, do one, teach one” model that has long characterized medical education. “Both the limitations on learning opportunities available in the clinics and the restrictions on resident work hours have created a real problem for the traditional apprenticeship model for training doctors,” he writes.

Ericsson notes that other specialists, such as concert musicians, chess players, and professional athletes do not learn using an apprenticeship model. For example, chess players do not play game after game of chess to become expert. And when a game is concluded, usually after several hours have passed, they are unlikely to be aware of the specific moves that lost or won them the game (unless an observer points them out). That is why, when training, chess players focus on particular aspects of the game (often identified by a mentor) as being crucial to improve their overall performance.

In today’s chess-learning environment, Ericsson notes, the computer plays a key role and can provide accurate feedback on each move the player executes. Computer chess programs have evolved to the point that they “are far superior in skill to any human chess player. Most important, computers can provide more accurate feedback on each chess move and are available at any time for practice,” writes Ericsson.

The same is true in sports. A tennis player does not practice by playing an endless series of games—though an ability to win a game is the ultimate goal. Rather, the athlete focuses on aspects of the game—the serve, for example—that can make the difference between winning or losing. Ericsson also notes that most musicians, dancers, and athletes “spend most of their time training by themselves to get ready to exhibit their skills for the first time in front of a large audience.”

These approaches are a better model for improving performance than the apprenticeship model, Ericsson argues. In medicine, one alternative might be the video recording of medical procedures in the clinic from multiple points of view—so that later viewers get both the “big picture” and a close-up view from the point of technical performance. After the recording is digitized and stored on a server, it can serve as valuable teaching for an unlimited number of residents.

Simulator training offers another venue for education, as it makes possible the isolation of difficult aspects of a procedure, which can then be repeated by the trainee as many times as necessary. In the future, it should be possible to link video recordings directly to simulators “so trainees could focus on particular aspects of the procedures and be required to respond to prompts with recordable actions,” Ericsson writes.

What this EVIDENCE means for practice
Given the extremely limited opportunities for observing forceps deliveries in the United States, it is time for us to explore new avenues for teaching other than the traditional apprenticeship model.

Is ultrasound evidence of levator muscle “avulsion” a real anatomic entity?
Dietz HP. Forceps: toward obsolescence or revival? Acta Obstet Gynecol Scand. 2015;94(4):347–351.

Da Silva AS, Digesu GA, Dell’Utri C, Fritsch H, ­Piffarotti P, Khullar V. Do ultrasound findings of levator ani “avulsion” correlate with anatomical findings? A multicenter cadaveric study [published online ahead of print May 15, 2015]. Neurourol Urodyn. doi:10.1002 /nau.22781.

Dietz takes a new tack in the debate over cesarean versus forceps by pointing to a recently highlighted abnormality in women who deliver by forceps: levator ani muscle avulsion, or LMA—traumatic disconnection of the levator ani from the pelvic sidewall. It has long been known that forceps deliveries can increase the risk of obstetric anal sphincter injuries (OASIS). Dietz contends that OASIS occurs at a rate as high as 40% to 60% after forceps delivery. He also notes, with some consternation, that the American ­College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine have advocated forceps as a way of reducing the high cesarean delivery rate.

When a parturient has been pushing for an extended period of time and there is a positional abnormality of the fetus, such as persistent occiput posterior position, cesarean delivery is often favored as a way of protecting the rectal sphincter. Dietz argues that cesarean delivery also protects against LMA, which “has only recently been recognized as a major etiological factor in pelvic floor dysfunction.” Dietz then presents a list of studies that have produced ultrasound findings of LMA in a high percentage of women undergoing forceps delivery—percentages on the order of 10% to 40%.

Enter Da Silva and colleagues, who argue that “the only true place to visualize the 3D structure of the human body, [and] thus validate imaging findings, [is] on cadaveric or live tissue dissections.” They undertook a cadaveric study to validate—or not—some of the findings of LMA summarized by Dietz.

Details of the study
The pubovisceral muscle (PVM) anatomy of 30 female cadavers was analyzed via 3D translabial ultrasonography to confirm LMA. The cadavers were then dissected to assess the finding anatomically. Da Silva and colleagues found LMA on imaging in 11 (36.7%) cadavers. LMA was unilateral in 10 (33.3%) cadavers and bilateral in 1 (3.3%). However, no LMA was found at dissection.

When an additional 39 cadavers were dissected, no LMA was identified.

On ultrasound, LMA is strongly associated with a narrower PVM insertion depth (mean of 4.79 mm vs 6.32 mm; P = .001). Da Silva and colleagues concluded that “there is a clear difference between anatomical and ultrasonographic findings. The imaged appearance of an ‘avulsion’ does not represent a true anatomical ‘avulsion’ as confirmed on dissection.”

What this EVIDENCE means for practice
Before we prematurely adopt ultrasound evidence of LMA as a significant morbidity, we need to learn more about its true etiology, pathophysiology, and epidemiology. We don’t yet know enough to say that it’s such a bad injury, when imaged via ultrasound, that it warrants cesarean delivery to avoid it.

When deciding between cesarean and forceps, keep the risks of second-stage cesarean in mind
Pergialiotis V, Vlachos DG, Rodolakis A, Haidopoulos D, Thomakos N, Vlachos GD. First versus second stage C/S maternal and neonatal morbidity: a systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2014;175:15–24.

This expert systematic review and meta-analysis summarizes the morbidity of second-stage cesarean delivery. When an obstetrician has a patient who is arrested at persistent occiput posterior position, say, and is trying to decide on cesarean delivery versus Kielland’s rotation or other forceps delivery, it is necessary to balance the risks and benefits of the 2 options. And as all clinicians are aware, when cesarean delivery is performed late in labor and the patient has been pushing for a prolonged period of time in the second stage—cesarean can be a challenging procedure. Moreover, these late cesareans are associated with much greater risks than cesarean deliveries performed earlier in labor.

Details of the review
Pergialiotis and colleagues selected 10 studies comparing maternal and neonatal morbidity and mortality between cesarean delivery at full dilatation and cesarean delivery prior to full dilatation. These studies involved 23,104 women with a singleton fetus who underwent cesarean delivery in the first (n = 18,160) or second (n = 4,944) stage of labor.

They found that second-stage cesarean was associated with a higher rate of maternal death (OR, 7.96; 95% CI, 1.61–39.39), a higher rate of maternal admission to the intensive care unit (OR, 7.41; 95% CI, 2.47–22.5), and a higher maternal transfusion rate (OR, 2.60; 95% CI, 1.49–2.54).

The rate of neonatal death also was higher among second-stage cesareans (OR, 5.20; 95% CI, 2.49–10.85), as was admission to the neonatal intensive care unit (OR, 1.63; 95% CI, 0.91–2.91), and the 5-minute Apgar score was more likely to be less than 7 (OR, 2.77; 95% CI, 1.02–7.50).

According to the authors, this study is the “first systematic review and meta-­analysis that investigates the impact of the stage of labor on maternal and neonatal outcomes among women delivering by cesarean section.” The findings demonstrate with authority that second-stage cesareans can be a risky undertaking.

What this EVIDENCE means for practice
Cesareans performed late in the second stage of labor are distinct from those performed in the first stage, carrying much higher risks, especially for the mother. When deciding whether to proceed with cesarean, vacuum, or forceps, the added risk of second-stage cesarean is an important aspect of both the consent conversation and clinical decision making.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

There’s a cyclical lament in obstetrics, and it goes something like this: Forceps are waning and are going to fade away completely if something isn’t done about it. This lament resounds every few decades, as a look at the literature confirms:

In this, our latest cycle of lament, 4 or 5 papers have suggested that forceps in general and Kielland forceps in particular ought not be abandoned because outcomes are better than those suggested by the older literature. With the cesarean delivery rate hovering at about 31% in the United States, perhaps it is time to revisit the issue.

This Update is not intended to be a comprehensive review of the literature. Rather, it offers a snapshot of articles published within the past year—articles that highlight some new features of a very old debate:

Forceps and vacuum device placement is “suboptimal” in almost 30% of operative vaginal deliveries
Ramphul M, Kennelly MM, Burke G, Murphy DJ. Risk factors and morbidity associated with suboptimal instrument placement at instrumental delivery: observational study nested within the Instrumental Delivery & Ultrasound randomised controlled trial ISRCTN 72230496. BJOG. 2015;122(4):558–563.

Rouse DJ. Instrument placement is sub-optimal in three of ten attempted operative vaginal deliveries. BJOG. 2015;122(4):564.

Over the years, many clinicians have argued that we don’t do enough forceps deliveries to maintain our own competence with the procedure, let alone teach residents how to perform it. This observational study nested in a randomized clinical trial is intriguing because Ramphul and colleagues looked for objective evidence of clinicians’ skill at the vacuum and forceps. Specifically, they looked for evidence that the forceps or vacuum was malpositioned during attempts at operative vaginal delivery. In the process, they nicely documented the absolute rate of malpositioning of the forceps and vacuum, finding that it is much higher than expected, even in an institution that performs a lot of operative vaginal deliveries.

Details of the trial
A cohort of 478 nulliparous women at term (≥37 weeks) underwent instrumental delivery at 2 university-affiliated maternity hospitals in Ireland. Ramphul and colleagues documented fetal head position prior to application of the instrument and at delivery. The midwife or neonatologist attending each delivery examined the neonate after birth and recorded the markings of the instrument on the infant’s head to determine whether instrument placement had been optimal.

Instrument placement was considered optimal when the vacuum cup included the flexion point (3 cm anterior to the posterior fontanelle) and the posterior fontanelle, with central placement. For forceps, instrument placement was considered optimal when the blades were positioned bilaterally and symmetrically over the malar bones. Two main types of forceps were used in this study—direct-traction Neville Barnes forceps (n = 138) and rotational Kielland forceps (n = 13)—and the rates of optimal and suboptimal placement were similar between them. 

Each case was labeled as “optimal” or “suboptimal” by 2 investigators, with a third observer arbitrating when the 2 investigators differed in opinion.

Instrument placement was clearly documented in 478 deliveries, 138 of which (28.8%) involved suboptimal placement. There was a lower rate of induction of labor among deliveries with suboptimal placement (42.8% vs 53.2%; odds ratio [OR], 0.66; 95% confidence interval [CI], 0.44–0.98; P = .038). There were no differences between the optimal and suboptimal groups in terms of duration of labor, use of oxytocin, and analgesia. In addition, the seniority of obstetricians performing operative vaginal delivery was similar between groups.

Fetal malposition was more common in the suboptimal group (58.7% vs 37.4%; OR, 2.44; 95% CI, 1.62–3.66; P<.0001). Midcavity station also was more common in the suboptimal group (82.6% vs 73.8%; OR, 1.68; 95% CI, 1.02–2.78; P = .042).

Maternal and neonatal outcomes
Postpartum hemorrhage was more common in the suboptimal placement group (24.6% vs 14.4%; OR, 1.94; 95% CI, 1.19–3.17; P = .008), as was prolonged hospitalization (26.8% vs 14.7%; OR, 2.13; 95% CI, 1.31–3.44; P = .02).

In addition, the incidence of neonatal trauma was higher in the group with suboptimal placement (15.9% vs 3.9%; OR, 4.64; 95% CI, 2.25–9.58; P<.0001) and included such effects as Erb’s palsy, fracture, retinal hemorrhage, cephalhematoma, and cerebral hemorrhage.

After adjustment for potential confounding factors, including induction of labor, seniority of the obstetrician, fetal malposition, caput above +1, midcavity station, regional analgesia, and the instrument used, the association remained significant between suboptimal placement and prolonged hospitalization (adjusted OR, 2.28; 95% CI, 1.30–4.02) and neonatal trauma (adjusted OR, 4.25; 95% CI, 1.85–9.72).

Dwindling statistics for operative vaginal delivery
In an editorial accompanying the study by Ramphul and colleagues, Dwight J. Rouse, MD,points to the waning of instrumental vaginal delivery in many parts of the world, most notably the United States, where, in 2012, only 2.8% of live births involved use of a vacuum device and only 0.6% involved the forceps.⁵

“When the rate of cesarean delivery is 10 times the combined rate of vaginal vacuum and forceps delivery (as it is in the USA), it is fair to argue that operative vaginal delivery is underutilized,” Dr. Rouse writes. “So kudos to Ramphul et al for providing insight into how we might continue to perform operative vaginal delivery safely.”

What this EVIDENCE means for practice
The study by Ramphul and colleagues very clearly confirms that correct placement of the vacuum device or forceps is key to safety.

Should we continue forceps education using the apprenticeship model of training?
Kyser KL, Lu X, Santillan D, et al. Forceps delivery volumes in teaching and nonteaching hospitals: Are volumes sufficient for physicians to acquire and maintain competence? Acad Med. 2014;89(1):71–76.

Ericsson KA. Necessity is the mother of invention: ­video recording firsthand perspectives of critical medical procedures to make simulated training more effective. Acad Med. 2014;89(1):17–20.

Kyser and colleagues have provided the best current snapshot of the opportunity for teaching instrumental vaginal delivery in the United States. They conducted a retrospective cohort study using new state inpatient data from 9 states in diverse geographic locations to capture experience at large and small teaching hospitals, as well as nonteaching institutions. They demonstrated that the opportunity for hands-on experience with these difficult and technically demanding deliveries is extremely limited and probably insufficient for all practicing physicians to maintain their skills if we continue to rely on traditional ways of teaching.

Details of the study
Using State Inpatient Data from 9 states, Kyser and colleagues identified all women hospitalized for childbirth in 2008. Of 1,344,305 deliveries in 835 hospitals, the final cohort included 624,000 operative deliveries—424,224 cesarean deliveries, 174,036 vacuum extractions, 6,158 forceps deliveries, and 19,582 deliveries that required more than 1 method. Of the 835 hospitals in this study, 68 were major teaching hospitals, 130 were minor teaching facilities, and 637 were nonteaching institutions.

The mean annual volumes for cesarean delivery for major teaching, minor teaching, and nonteaching hospitals were 969.8, 757.8, and 406.9, respectively (P<.0001).

The mean annual volumes for vacuum delivery were 301.0, 304.2, and 190.4, respectively (P<.0001).

The mean annual volumes for forceps delivery were 25.2, 15.3, and 8.9, respectively (P<.0001).

Three hundred twenty hospitals (38.3% of all hospitals) failed to perform a single forceps delivery in 2008, including 11 major teaching hospitals (16.2% of major teaching hospitals), 30 minor teaching hospitals (23.1% of minor teaching hospitals), and 279 nonteaching hospitals (43.8% of nonteaching hospitals) (P<.0001).

We need to rethink the apprenticeship model
In a commentary accompanying the study by Kyser and colleagues, K. Anders ­Ericsson, PhD, revisits the “see one, do one, teach one” model that has long characterized medical education. “Both the limitations on learning opportunities available in the clinics and the restrictions on resident work hours have created a real problem for the traditional apprenticeship model for training doctors,” he writes.

Ericsson notes that other specialists, such as concert musicians, chess players, and professional athletes do not learn using an apprenticeship model. For example, chess players do not play game after game of chess to become expert. And when a game is concluded, usually after several hours have passed, they are unlikely to be aware of the specific moves that lost or won them the game (unless an observer points them out). That is why, when training, chess players focus on particular aspects of the game (often identified by a mentor) as being crucial to improve their overall performance.

In today’s chess-learning environment, Ericsson notes, the computer plays a key role and can provide accurate feedback on each move the player executes. Computer chess programs have evolved to the point that they “are far superior in skill to any human chess player. Most important, computers can provide more accurate feedback on each chess move and are available at any time for practice,” writes Ericsson.

The same is true in sports. A tennis player does not practice by playing an endless series of games—though an ability to win a game is the ultimate goal. Rather, the athlete focuses on aspects of the game—the serve, for example—that can make the difference between winning or losing. Ericsson also notes that most musicians, dancers, and athletes “spend most of their time training by themselves to get ready to exhibit their skills for the first time in front of a large audience.”

These approaches are a better model for improving performance than the apprenticeship model, Ericsson argues. In medicine, one alternative might be the video recording of medical procedures in the clinic from multiple points of view—so that later viewers get both the “big picture” and a close-up view from the point of technical performance. After the recording is digitized and stored on a server, it can serve as valuable teaching for an unlimited number of residents.

Simulator training offers another venue for education, as it makes possible the isolation of difficult aspects of a procedure, which can then be repeated by the trainee as many times as necessary. In the future, it should be possible to link video recordings directly to simulators “so trainees could focus on particular aspects of the procedures and be required to respond to prompts with recordable actions,” Ericsson writes.

What this EVIDENCE means for practice
Given the extremely limited opportunities for observing forceps deliveries in the United States, it is time for us to explore new avenues for teaching other than the traditional apprenticeship model.

Is ultrasound evidence of levator muscle “avulsion” a real anatomic entity?
Dietz HP. Forceps: toward obsolescence or revival? Acta Obstet Gynecol Scand. 2015;94(4):347–351.

Da Silva AS, Digesu GA, Dell’Utri C, Fritsch H, ­Piffarotti P, Khullar V. Do ultrasound findings of levator ani “avulsion” correlate with anatomical findings? A multicenter cadaveric study [published online ahead of print May 15, 2015]. Neurourol Urodyn. doi:10.1002 /nau.22781.

Dietz takes a new tack in the debate over cesarean versus forceps by pointing to a recently highlighted abnormality in women who deliver by forceps: levator ani muscle avulsion, or LMA—traumatic disconnection of the levator ani from the pelvic sidewall. It has long been known that forceps deliveries can increase the risk of obstetric anal sphincter injuries (OASIS). Dietz contends that OASIS occurs at a rate as high as 40% to 60% after forceps delivery. He also notes, with some consternation, that the American ­College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine have advocated forceps as a way of reducing the high cesarean delivery rate.

When a parturient has been pushing for an extended period of time and there is a positional abnormality of the fetus, such as persistent occiput posterior position, cesarean delivery is often favored as a way of protecting the rectal sphincter. Dietz argues that cesarean delivery also protects against LMA, which “has only recently been recognized as a major etiological factor in pelvic floor dysfunction.” Dietz then presents a list of studies that have produced ultrasound findings of LMA in a high percentage of women undergoing forceps delivery—percentages on the order of 10% to 40%.

Enter Da Silva and colleagues, who argue that “the only true place to visualize the 3D structure of the human body, [and] thus validate imaging findings, [is] on cadaveric or live tissue dissections.” They undertook a cadaveric study to validate—or not—some of the findings of LMA summarized by Dietz.

Details of the study
The pubovisceral muscle (PVM) anatomy of 30 female cadavers was analyzed via 3D translabial ultrasonography to confirm LMA. The cadavers were then dissected to assess the finding anatomically. Da Silva and colleagues found LMA on imaging in 11 (36.7%) cadavers. LMA was unilateral in 10 (33.3%) cadavers and bilateral in 1 (3.3%). However, no LMA was found at dissection.

When an additional 39 cadavers were dissected, no LMA was identified.

On ultrasound, LMA is strongly associated with a narrower PVM insertion depth (mean of 4.79 mm vs 6.32 mm; P = .001). Da Silva and colleagues concluded that “there is a clear difference between anatomical and ultrasonographic findings. The imaged appearance of an ‘avulsion’ does not represent a true anatomical ‘avulsion’ as confirmed on dissection.”

What this EVIDENCE means for practice
Before we prematurely adopt ultrasound evidence of LMA as a significant morbidity, we need to learn more about its true etiology, pathophysiology, and epidemiology. We don’t yet know enough to say that it’s such a bad injury, when imaged via ultrasound, that it warrants cesarean delivery to avoid it.

When deciding between cesarean and forceps, keep the risks of second-stage cesarean in mind
Pergialiotis V, Vlachos DG, Rodolakis A, Haidopoulos D, Thomakos N, Vlachos GD. First versus second stage C/S maternal and neonatal morbidity: a systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2014;175:15–24.

This expert systematic review and meta-analysis summarizes the morbidity of second-stage cesarean delivery. When an obstetrician has a patient who is arrested at persistent occiput posterior position, say, and is trying to decide on cesarean delivery versus Kielland’s rotation or other forceps delivery, it is necessary to balance the risks and benefits of the 2 options. And as all clinicians are aware, when cesarean delivery is performed late in labor and the patient has been pushing for a prolonged period of time in the second stage—cesarean can be a challenging procedure. Moreover, these late cesareans are associated with much greater risks than cesarean deliveries performed earlier in labor.

Details of the review
Pergialiotis and colleagues selected 10 studies comparing maternal and neonatal morbidity and mortality between cesarean delivery at full dilatation and cesarean delivery prior to full dilatation. These studies involved 23,104 women with a singleton fetus who underwent cesarean delivery in the first (n = 18,160) or second (n = 4,944) stage of labor.

They found that second-stage cesarean was associated with a higher rate of maternal death (OR, 7.96; 95% CI, 1.61–39.39), a higher rate of maternal admission to the intensive care unit (OR, 7.41; 95% CI, 2.47–22.5), and a higher maternal transfusion rate (OR, 2.60; 95% CI, 1.49–2.54).

The rate of neonatal death also was higher among second-stage cesareans (OR, 5.20; 95% CI, 2.49–10.85), as was admission to the neonatal intensive care unit (OR, 1.63; 95% CI, 0.91–2.91), and the 5-minute Apgar score was more likely to be less than 7 (OR, 2.77; 95% CI, 1.02–7.50).

According to the authors, this study is the “first systematic review and meta-­analysis that investigates the impact of the stage of labor on maternal and neonatal outcomes among women delivering by cesarean section.” The findings demonstrate with authority that second-stage cesareans can be a risky undertaking.

What this EVIDENCE means for practice
Cesareans performed late in the second stage of labor are distinct from those performed in the first stage, carrying much higher risks, especially for the mother. When deciding whether to proceed with cesarean, vacuum, or forceps, the added risk of second-stage cesarean is an important aspect of both the consent conversation and clinical decision making.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Pelvic masses frequently are the reason for the medical evaluation of young women and girls. Regardless of what prompted the work-up that led to the mass’ discovery, the patient inevitably will be sent to a gynecologist for further evaluation, and such a practitioner should be involved whenever there is suspicion for a mass involving the reproductive tract.

While it does not happen often, it is possible that a mass diagnosed as ovarian, based on imaging, is then determined to be of another organ system at the time of surgery. Most frequently, this occurs with ruptured appendicitis, as the presence of an appendiceal abscess can mimic a complex ovarian mass or tubo-ovarian abscess (TOA).¹

The full differential diagnosis of non-gynecologic pelvic masses is extensive and includes mesenteric duplication cysts, presacral masses, pelvic kidney, peritoneal inclusion cysts, and urachal cysts (TABLE). It can be difficult to distinguish pathology as gynecologic or nongynecologic even if a thorough work-up is performed.

In this review, we offer several cases involving varying presentations of pelvic masses related to the reproductive tract.

Case 1: Severe pelvic pain in an 18-year-old
An 18-year-old adolescent presents to your office reporting worsening pelvic pain over the past 3 days. The pain is severe in the left lower quadrant. She reports a foul discharge and thinks she has a fever but hasn’t checked her temperature. She says she has been sexually active in the past few months with 2 different male partners. She has not been using condoms consistently and hasn’t been tested for sexually transmitted infections. Physical examination reveals a mucopurulent discharge at the cervix and copious white blood cells noted on wet mount. Bimanual examination reveals cervical motion tenderness and tenderness over the left adnexa. Ultrasound reveals a mass in the left adnexa with debris and internal echoes.
Diagnosis: Tubo-ovarian abscess.
Treatment: Admission to the hospital for intravenous antibiotic therapy.

It is important to note that TOAs can be seen in patients who have not been sexually active, as well as in cases related not to an ascending infection but rather to a history of pelvic surgery or complex structural anomaly.² The majority of the time a TOA is a result of pelvic inflammatory disease (PID). Often, patients with uncomplicated PID can be treated on an outpatient basis if they meet strict criteria, but patients with a TOA need to be treated as an inpatient due to the severity of this infection.

Clinical pearl. If a patient has an IUD in place, close clinical follow up is critical to determine response to therapy. The Centers for Disease Control and Prevention’s sexually transmitted infection treatment guidelines state that removal of the IUD is not mandatory, but if the patient is not responding to treatment removal ultimately may be necessary. The IUD should be removed if there is no improvement in the patient’s symptoms with antibiotic therapy, there is no decrease in size of the TOA with antibiotic therapy, or if there is no positive test of cure after treatment for the TOA is completed.

If a patient has progressive abdominal pain and other findings consistent with infectious etiology, consider that a ruptured appendix could have a very similar appearance to a TOA. Computed tomography can be a useful tool to aid in firm diagnosis in cases in which gastroenterologic entities must be ruled out, but ultimately the gold standard of diagnosis for both of these procedures is diagnostic laparoscopy. Diagnostic surgery can be performed if the patient does not respond to medical therapy. In an effort to avoid surgical intervention, interventional radiology may be an option to drain the TOA. If this is performed, it is useful to repeat the ultrasound to confirm resolution prior to removal of the drain.

Case 2: Acute-onset severe pelvic pain in a young adolescent
A 12-year-old girl presents to the emergency department with acute-onset right lower quadrant pain. She states that about 2 hours ago she was playing in the yard and suddenly doubled over with pain. She also has had nausea and vomiting since that time.

She is in obvious distress and is resting in the fetal position. Examination reveals normal vital signs and tenderness to palpation over the right lower pelvic quadrant. There is no palpable abdominal mass. Genital examination reveals Tanner stage 4 external genitalia with normal introitus and patent, intact, annular hymen.

An abdominal ultrasound reveals a normal appendix, and pelvic ultrasonography reveals that the right ovary is enlarged (volume = 25 mL). The left ovary shows no obvious mass and a volume of 8 mL.

She is taken to the operating room, where you perform diagnostic laparoscopy.
Diagnosis: Adnexal torsion (FIGURE 1).
Treatment: Surgical detorsion with or without cystectomy.

Ultrasonography certainly can be useful in determining the size of an adnexal mass. An adnexal volume of less than 20 mL is strong evidence against adnexal torsion in an adolescent. This information, in addition to the remainder of the clinical picture, can be used to determine if surgery is immediately necessary or can be delayed.³

Several studies have attempted to draw a link between size of an ovarian mass and risk of malignancy. Unfortunately, such attempts have been unsuccessful, especially for large and small masses.⁴ In addition, many studies have explored the use of Doppler technology to confirm a diagnosis of torsion found on sonography. Studies have shown, however, that diminished or absent Doppler flow is not a reliable finding and that ovarian blood flow can be preserved in cases of surgically confirmed adnexal torsion.⁵

Torsion ultimately is a clinical diagnosis, and medical history and physical examination are critical in the decision-making process. The decision to go to the operating room for further evaluation never should be made based on ultrasound findings alone, as not all ovarian torsions result in a mass greater than 20 mL.

Clinical pearl. In the setting of a known adnexal cyst, it is important to impress upon patients and their parents the warning signs of torsion and the need to proceed directly to the emergency center if acute pelvic pain occurs.

Historically, adnexal torsion is correlated with oophorectomy, but recent studies indicate that ovarian function can be preserved in the majority of cases with detorsion and cystectomy alone.^6,7 In cases in which no cyst is present, detorsion is therapeutic.

In addition, studies have shown that the appearance of the ovary is not indicative of damage to the ovary. Regardless of “necrotic” appearance, the adnexa should be preserved.^8,9 Ovarian function after detorsion also has been assessed in a case series that showed normal follicular development on ultrasonography in more than 90% of patients after detorsion. In this group, 6 of 102 patients with torsion eventually underwent in vitro fertilization and, in all 6 patients, oocytes retrieved from the ischemic ovary were fertilized.¹⁰

Case 3: 15-year-old girl with nontender, palpable abdominal mass
A 15-year-old adolescent comes to your office for a well woman exam and to establish gynecologic care. Abdominal examination reveals a mass below the umbilicus that is nontender to palpation. The remainder of the examination is normal, and the patient is sent for ultrasonography. Results reveal a complex-appearing mass in the left ovary that measures 8 cm x 7 cm x 8 cm. The report states that the mass shows areas of fat and calcifications. There are no other abnormalities noted in the abdomen or pelvis.
Diagnosis: Dermoid cyst.
Treatment: Surgical intervention versus expectant management.

Germ cell ovarian tumors are a diverse category of tumors that include both benign and malignant disease. The ovarian teratoma (“dermoid”) is the most common and perhaps best-known example of a benign ovarian germ cell tumor (FIGURE 2). While the incidence in the general population is unknown, dermoids account for approximately 65% of adnexal masses in pediatric patients presenting for treatment.¹¹ Most of the time, patients with ovarian dermoids will be asymptomatic; however, pain is the most common presenting symptom.

The spectrum of sonographic features includes:

The notation of internal vascularity is concerning for malignancy.¹²

Fortunately, malignant ovarian germ cell tumors are much less common than benign lesions. Of these, the most common pediatric ovarian germ cell tumor is dysgerminoma (FIGURE 3).¹³

Clinical pearl. A unique consideration in patients with dysgerminoma or choriocarcinoma is the possible diagnosis of XY gonadal dysgenesis, or Swyer syndrome.^14,15 This may be seen in young girls with female external genitalia and primary amenorrhea. Depending on the level of concern, obtaining a karyotype also may be beneficial.¹³

Sex cord−stromal tumors also are relatively common in the pediatric population.¹⁶ Of these, granulosa cell tumors are the most common and account for 2% to 5% of ovarian malignancies regardless of age at diagnosis. Juvenile-type granulosa ovarian cancers occur mainly in premenarchal girls and comprise roughly 5% of all granulosa cell tumors.¹⁷ The presenting problem usually is precocious puberty. Therefore, in any situation in which a prepubertal girl is developing too early and peripheral precocious puberty is suspected, sonography should be obtained to rule out a hormone-producing ovarian mass. Tumor markers most helpful in this situation include estradiol, testosterone, and inhibin B.¹⁷

When an adolescent is diagnosed with ovarian cancer, it is ideal to perform a fertility-sparing procedure whenever it is reasonable.¹⁸ While dermoid cysts can look concerning on sonography because of their heterogeneous appearance, the vast majority can be safely and effectively resected without oophorectomy in order to preserve fertility, as in most cases they are benign. Nonetheless, cystectomy does have a small, theoretic risk of cyst rupture, with the potential for pelvic peritonitis from dermoid content spillage.¹⁹ In the vast majority of cases in which a benign adnexal mass is identified, ovarian cystectomy is appropriate and oophorectomy is not indicated.²⁰

Another very rare presentation of mature cystic teratoma can include acute neurologic decline in cases of paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis. Frequently, these teratomas will be small in size and discovered only incidentally during the work-up of a patient with altered mental status. Resection is indicated as soon as possible to stop the neurologic decline.²¹

Case 4: Cyclic pelvic pain and a pelvic mass in a 16-year-old
A 16-year-old adolescent presents to your office for evaluation of cyclic pelvic pain. She states that menarche occurred at age 12 years and menses have been irregular ever since, occurring every few months and associated with significant pain with the onset of bleeding.

Physical examination reveals Tanner stage 4 breasts and Tanner stage 4 external genitalia. The introitus is normal with a visible intact, annular hymen. A mildly tender palpable mass at the level of the umbilicus is noted. The patient consents to having a Q-tip placed in the vagina, which reveals a bulge in the left vaginal wall that is nontender and fluctuant. Pelvic ultrasonography reveals uterine didelphys and an obstructed left hemivagina. A renal ultrasound reveals an absent left kidney.
Diagnosis: OHVIRA (obstructed hemivagina and ipsilateral renal anomaly) syndrome.
Treatment: Surgical resection of the vaginal septum.

Masses that appear complex on imaging can be deceiving, as they also can be related to obstructive reproductive tract anomalies. “Pelvic mass” is often the working diagnosis in cases of imperforate hymen, vaginal atresia, cervical agenesis, and uterine didelphys with obstructed hemivagina. This underscores the importance of taking an accurate menstrual history as well as performing a thorough physical examination. Usually this does not require an internal vaginal examination if the patient is unable to tolerate one, but a rectal examination can provide similar information in a patient presenting with a “pelvic mass” who will consent to this portion of the exam.

Clinical pearl. If a patient is not comfortable consenting to a rectal exam, a lubricated Q-tip can be used to palpate the vagina to minimize patient discomfort.

Before performing surgery…
Vaginal surgery can be corrective in the majority of these cases; however, magnetic resonance imaging is the gold standard for diagnosis and should be performed prior to surgical planning to further characterize the anomaly.²² Because Müllerian anomalies are associated with renal malformation such as absent kidney, pelvic kidney, collecting system duplication, or ectopic ureteral insertion around 40% of the time, imaging studies to assess for these structures is important prior to surgical intervention.²³ If the patient is symptomatic and surgery cannot be performed immediately in a safe manner, she may require admission for pain control and placement of a Foley catheter (if the mass is obstructing urinary flow) until surgery can be performed safely.

A comprehensive review of Müllerian anomalies is beyond the scope of this article; it is important to note that these clinical scenarios are always unique and treatment should be individualized.

Conclusion
There are many sources of pelvic masses in children, adolescents, and young women; not all sources will be gynecologic. To avoid unnecessary surgical intervention, it is important to obtain as much information as possible from the patient’s history, physical examination, and laboratory and imaging studies.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Pelvic masses frequently are the reason for the medical evaluation of young women and girls. Regardless of what prompted the work-up that led to the mass’ discovery, the patient inevitably will be sent to a gynecologist for further evaluation, and such a practitioner should be involved whenever there is suspicion for a mass involving the reproductive tract.

While it does not happen often, it is possible that a mass diagnosed as ovarian, based on imaging, is then determined to be of another organ system at the time of surgery. Most frequently, this occurs with ruptured appendicitis, as the presence of an appendiceal abscess can mimic a complex ovarian mass or tubo-ovarian abscess (TOA).¹

The full differential diagnosis of non-gynecologic pelvic masses is extensive and includes mesenteric duplication cysts, presacral masses, pelvic kidney, peritoneal inclusion cysts, and urachal cysts (TABLE). It can be difficult to distinguish pathology as gynecologic or nongynecologic even if a thorough work-up is performed.

In this review, we offer several cases involving varying presentations of pelvic masses related to the reproductive tract.

Case 1: Severe pelvic pain in an 18-year-old
An 18-year-old adolescent presents to your office reporting worsening pelvic pain over the past 3 days. The pain is severe in the left lower quadrant. She reports a foul discharge and thinks she has a fever but hasn’t checked her temperature. She says she has been sexually active in the past few months with 2 different male partners. She has not been using condoms consistently and hasn’t been tested for sexually transmitted infections. Physical examination reveals a mucopurulent discharge at the cervix and copious white blood cells noted on wet mount. Bimanual examination reveals cervical motion tenderness and tenderness over the left adnexa. Ultrasound reveals a mass in the left adnexa with debris and internal echoes.
Diagnosis: Tubo-ovarian abscess.
Treatment: Admission to the hospital for intravenous antibiotic therapy.

It is important to note that TOAs can be seen in patients who have not been sexually active, as well as in cases related not to an ascending infection but rather to a history of pelvic surgery or complex structural anomaly.² The majority of the time a TOA is a result of pelvic inflammatory disease (PID). Often, patients with uncomplicated PID can be treated on an outpatient basis if they meet strict criteria, but patients with a TOA need to be treated as an inpatient due to the severity of this infection.

Clinical pearl. If a patient has an IUD in place, close clinical follow up is critical to determine response to therapy. The Centers for Disease Control and Prevention’s sexually transmitted infection treatment guidelines state that removal of the IUD is not mandatory, but if the patient is not responding to treatment removal ultimately may be necessary. The IUD should be removed if there is no improvement in the patient’s symptoms with antibiotic therapy, there is no decrease in size of the TOA with antibiotic therapy, or if there is no positive test of cure after treatment for the TOA is completed.

If a patient has progressive abdominal pain and other findings consistent with infectious etiology, consider that a ruptured appendix could have a very similar appearance to a TOA. Computed tomography can be a useful tool to aid in firm diagnosis in cases in which gastroenterologic entities must be ruled out, but ultimately the gold standard of diagnosis for both of these procedures is diagnostic laparoscopy. Diagnostic surgery can be performed if the patient does not respond to medical therapy. In an effort to avoid surgical intervention, interventional radiology may be an option to drain the TOA. If this is performed, it is useful to repeat the ultrasound to confirm resolution prior to removal of the drain.

Case 2: Acute-onset severe pelvic pain in a young adolescent
A 12-year-old girl presents to the emergency department with acute-onset right lower quadrant pain. She states that about 2 hours ago she was playing in the yard and suddenly doubled over with pain. She also has had nausea and vomiting since that time.

She is in obvious distress and is resting in the fetal position. Examination reveals normal vital signs and tenderness to palpation over the right lower pelvic quadrant. There is no palpable abdominal mass. Genital examination reveals Tanner stage 4 external genitalia with normal introitus and patent, intact, annular hymen.

An abdominal ultrasound reveals a normal appendix, and pelvic ultrasonography reveals that the right ovary is enlarged (volume = 25 mL). The left ovary shows no obvious mass and a volume of 8 mL.

She is taken to the operating room, where you perform diagnostic laparoscopy.
Diagnosis: Adnexal torsion (FIGURE 1).
Treatment: Surgical detorsion with or without cystectomy.

Ultrasonography certainly can be useful in determining the size of an adnexal mass. An adnexal volume of less than 20 mL is strong evidence against adnexal torsion in an adolescent. This information, in addition to the remainder of the clinical picture, can be used to determine if surgery is immediately necessary or can be delayed.³

Several studies have attempted to draw a link between size of an ovarian mass and risk of malignancy. Unfortunately, such attempts have been unsuccessful, especially for large and small masses.⁴ In addition, many studies have explored the use of Doppler technology to confirm a diagnosis of torsion found on sonography. Studies have shown, however, that diminished or absent Doppler flow is not a reliable finding and that ovarian blood flow can be preserved in cases of surgically confirmed adnexal torsion.⁵

Torsion ultimately is a clinical diagnosis, and medical history and physical examination are critical in the decision-making process. The decision to go to the operating room for further evaluation never should be made based on ultrasound findings alone, as not all ovarian torsions result in a mass greater than 20 mL.

Clinical pearl. In the setting of a known adnexal cyst, it is important to impress upon patients and their parents the warning signs of torsion and the need to proceed directly to the emergency center if acute pelvic pain occurs.

Historically, adnexal torsion is correlated with oophorectomy, but recent studies indicate that ovarian function can be preserved in the majority of cases with detorsion and cystectomy alone.^6,7 In cases in which no cyst is present, detorsion is therapeutic.

In addition, studies have shown that the appearance of the ovary is not indicative of damage to the ovary. Regardless of “necrotic” appearance, the adnexa should be preserved.^8,9 Ovarian function after detorsion also has been assessed in a case series that showed normal follicular development on ultrasonography in more than 90% of patients after detorsion. In this group, 6 of 102 patients with torsion eventually underwent in vitro fertilization and, in all 6 patients, oocytes retrieved from the ischemic ovary were fertilized.¹⁰

Case 3: 15-year-old girl with nontender, palpable abdominal mass
A 15-year-old adolescent comes to your office for a well woman exam and to establish gynecologic care. Abdominal examination reveals a mass below the umbilicus that is nontender to palpation. The remainder of the examination is normal, and the patient is sent for ultrasonography. Results reveal a complex-appearing mass in the left ovary that measures 8 cm x 7 cm x 8 cm. The report states that the mass shows areas of fat and calcifications. There are no other abnormalities noted in the abdomen or pelvis.
Diagnosis: Dermoid cyst.
Treatment: Surgical intervention versus expectant management.

Germ cell ovarian tumors are a diverse category of tumors that include both benign and malignant disease. The ovarian teratoma (“dermoid”) is the most common and perhaps best-known example of a benign ovarian germ cell tumor (FIGURE 2). While the incidence in the general population is unknown, dermoids account for approximately 65% of adnexal masses in pediatric patients presenting for treatment.¹¹ Most of the time, patients with ovarian dermoids will be asymptomatic; however, pain is the most common presenting symptom.

The spectrum of sonographic features includes:

The notation of internal vascularity is concerning for malignancy.¹²

Fortunately, malignant ovarian germ cell tumors are much less common than benign lesions. Of these, the most common pediatric ovarian germ cell tumor is dysgerminoma (FIGURE 3).¹³

Clinical pearl. A unique consideration in patients with dysgerminoma or choriocarcinoma is the possible diagnosis of XY gonadal dysgenesis, or Swyer syndrome.^14,15 This may be seen in young girls with female external genitalia and primary amenorrhea. Depending on the level of concern, obtaining a karyotype also may be beneficial.¹³

Sex cord−stromal tumors also are relatively common in the pediatric population.¹⁶ Of these, granulosa cell tumors are the most common and account for 2% to 5% of ovarian malignancies regardless of age at diagnosis. Juvenile-type granulosa ovarian cancers occur mainly in premenarchal girls and comprise roughly 5% of all granulosa cell tumors.¹⁷ The presenting problem usually is precocious puberty. Therefore, in any situation in which a prepubertal girl is developing too early and peripheral precocious puberty is suspected, sonography should be obtained to rule out a hormone-producing ovarian mass. Tumor markers most helpful in this situation include estradiol, testosterone, and inhibin B.¹⁷

When an adolescent is diagnosed with ovarian cancer, it is ideal to perform a fertility-sparing procedure whenever it is reasonable.¹⁸ While dermoid cysts can look concerning on sonography because of their heterogeneous appearance, the vast majority can be safely and effectively resected without oophorectomy in order to preserve fertility, as in most cases they are benign. Nonetheless, cystectomy does have a small, theoretic risk of cyst rupture, with the potential for pelvic peritonitis from dermoid content spillage.¹⁹ In the vast majority of cases in which a benign adnexal mass is identified, ovarian cystectomy is appropriate and oophorectomy is not indicated.²⁰

Another very rare presentation of mature cystic teratoma can include acute neurologic decline in cases of paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis. Frequently, these teratomas will be small in size and discovered only incidentally during the work-up of a patient with altered mental status. Resection is indicated as soon as possible to stop the neurologic decline.²¹

Case 4: Cyclic pelvic pain and a pelvic mass in a 16-year-old
A 16-year-old adolescent presents to your office for evaluation of cyclic pelvic pain. She states that menarche occurred at age 12 years and menses have been irregular ever since, occurring every few months and associated with significant pain with the onset of bleeding.

Physical examination reveals Tanner stage 4 breasts and Tanner stage 4 external genitalia. The introitus is normal with a visible intact, annular hymen. A mildly tender palpable mass at the level of the umbilicus is noted. The patient consents to having a Q-tip placed in the vagina, which reveals a bulge in the left vaginal wall that is nontender and fluctuant. Pelvic ultrasonography reveals uterine didelphys and an obstructed left hemivagina. A renal ultrasound reveals an absent left kidney.
Diagnosis: OHVIRA (obstructed hemivagina and ipsilateral renal anomaly) syndrome.
Treatment: Surgical resection of the vaginal septum.

Masses that appear complex on imaging can be deceiving, as they also can be related to obstructive reproductive tract anomalies. “Pelvic mass” is often the working diagnosis in cases of imperforate hymen, vaginal atresia, cervical agenesis, and uterine didelphys with obstructed hemivagina. This underscores the importance of taking an accurate menstrual history as well as performing a thorough physical examination. Usually this does not require an internal vaginal examination if the patient is unable to tolerate one, but a rectal examination can provide similar information in a patient presenting with a “pelvic mass” who will consent to this portion of the exam.

Clinical pearl. If a patient is not comfortable consenting to a rectal exam, a lubricated Q-tip can be used to palpate the vagina to minimize patient discomfort.

Before performing surgery…
Vaginal surgery can be corrective in the majority of these cases; however, magnetic resonance imaging is the gold standard for diagnosis and should be performed prior to surgical planning to further characterize the anomaly.²² Because Müllerian anomalies are associated with renal malformation such as absent kidney, pelvic kidney, collecting system duplication, or ectopic ureteral insertion around 40% of the time, imaging studies to assess for these structures is important prior to surgical intervention.²³ If the patient is symptomatic and surgery cannot be performed immediately in a safe manner, she may require admission for pain control and placement of a Foley catheter (if the mass is obstructing urinary flow) until surgery can be performed safely.

A comprehensive review of Müllerian anomalies is beyond the scope of this article; it is important to note that these clinical scenarios are always unique and treatment should be individualized.

Conclusion
There are many sources of pelvic masses in children, adolescents, and young women; not all sources will be gynecologic. To avoid unnecessary surgical intervention, it is important to obtain as much information as possible from the patient’s history, physical examination, and laboratory and imaging studies.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Pelvic masses frequently are the reason for the medical evaluation of young women and girls. Regardless of what prompted the work-up that led to the mass’ discovery, the patient inevitably will be sent to a gynecologist for further evaluation, and such a practitioner should be involved whenever there is suspicion for a mass involving the reproductive tract.

While it does not happen often, it is possible that a mass diagnosed as ovarian, based on imaging, is then determined to be of another organ system at the time of surgery. Most frequently, this occurs with ruptured appendicitis, as the presence of an appendiceal abscess can mimic a complex ovarian mass or tubo-ovarian abscess (TOA).¹

The full differential diagnosis of non-gynecologic pelvic masses is extensive and includes mesenteric duplication cysts, presacral masses, pelvic kidney, peritoneal inclusion cysts, and urachal cysts (TABLE). It can be difficult to distinguish pathology as gynecologic or nongynecologic even if a thorough work-up is performed.

In this review, we offer several cases involving varying presentations of pelvic masses related to the reproductive tract.

Case 1: Severe pelvic pain in an 18-year-old
An 18-year-old adolescent presents to your office reporting worsening pelvic pain over the past 3 days. The pain is severe in the left lower quadrant. She reports a foul discharge and thinks she has a fever but hasn’t checked her temperature. She says she has been sexually active in the past few months with 2 different male partners. She has not been using condoms consistently and hasn’t been tested for sexually transmitted infections. Physical examination reveals a mucopurulent discharge at the cervix and copious white blood cells noted on wet mount. Bimanual examination reveals cervical motion tenderness and tenderness over the left adnexa. Ultrasound reveals a mass in the left adnexa with debris and internal echoes.
Diagnosis: Tubo-ovarian abscess.
Treatment: Admission to the hospital for intravenous antibiotic therapy.

It is important to note that TOAs can be seen in patients who have not been sexually active, as well as in cases related not to an ascending infection but rather to a history of pelvic surgery or complex structural anomaly.² The majority of the time a TOA is a result of pelvic inflammatory disease (PID). Often, patients with uncomplicated PID can be treated on an outpatient basis if they meet strict criteria, but patients with a TOA need to be treated as an inpatient due to the severity of this infection.

Clinical pearl. If a patient has an IUD in place, close clinical follow up is critical to determine response to therapy. The Centers for Disease Control and Prevention’s sexually transmitted infection treatment guidelines state that removal of the IUD is not mandatory, but if the patient is not responding to treatment removal ultimately may be necessary. The IUD should be removed if there is no improvement in the patient’s symptoms with antibiotic therapy, there is no decrease in size of the TOA with antibiotic therapy, or if there is no positive test of cure after treatment for the TOA is completed.

If a patient has progressive abdominal pain and other findings consistent with infectious etiology, consider that a ruptured appendix could have a very similar appearance to a TOA. Computed tomography can be a useful tool to aid in firm diagnosis in cases in which gastroenterologic entities must be ruled out, but ultimately the gold standard of diagnosis for both of these procedures is diagnostic laparoscopy. Diagnostic surgery can be performed if the patient does not respond to medical therapy. In an effort to avoid surgical intervention, interventional radiology may be an option to drain the TOA. If this is performed, it is useful to repeat the ultrasound to confirm resolution prior to removal of the drain.

Case 2: Acute-onset severe pelvic pain in a young adolescent
A 12-year-old girl presents to the emergency department with acute-onset right lower quadrant pain. She states that about 2 hours ago she was playing in the yard and suddenly doubled over with pain. She also has had nausea and vomiting since that time.

She is in obvious distress and is resting in the fetal position. Examination reveals normal vital signs and tenderness to palpation over the right lower pelvic quadrant. There is no palpable abdominal mass. Genital examination reveals Tanner stage 4 external genitalia with normal introitus and patent, intact, annular hymen.

An abdominal ultrasound reveals a normal appendix, and pelvic ultrasonography reveals that the right ovary is enlarged (volume = 25 mL). The left ovary shows no obvious mass and a volume of 8 mL.

She is taken to the operating room, where you perform diagnostic laparoscopy.
Diagnosis: Adnexal torsion (FIGURE 1).
Treatment: Surgical detorsion with or without cystectomy.

Ultrasonography certainly can be useful in determining the size of an adnexal mass. An adnexal volume of less than 20 mL is strong evidence against adnexal torsion in an adolescent. This information, in addition to the remainder of the clinical picture, can be used to determine if surgery is immediately necessary or can be delayed.³

Several studies have attempted to draw a link between size of an ovarian mass and risk of malignancy. Unfortunately, such attempts have been unsuccessful, especially for large and small masses.⁴ In addition, many studies have explored the use of Doppler technology to confirm a diagnosis of torsion found on sonography. Studies have shown, however, that diminished or absent Doppler flow is not a reliable finding and that ovarian blood flow can be preserved in cases of surgically confirmed adnexal torsion.⁵

Torsion ultimately is a clinical diagnosis, and medical history and physical examination are critical in the decision-making process. The decision to go to the operating room for further evaluation never should be made based on ultrasound findings alone, as not all ovarian torsions result in a mass greater than 20 mL.

Clinical pearl. In the setting of a known adnexal cyst, it is important to impress upon patients and their parents the warning signs of torsion and the need to proceed directly to the emergency center if acute pelvic pain occurs.

Historically, adnexal torsion is correlated with oophorectomy, but recent studies indicate that ovarian function can be preserved in the majority of cases with detorsion and cystectomy alone.^6,7 In cases in which no cyst is present, detorsion is therapeutic.

In addition, studies have shown that the appearance of the ovary is not indicative of damage to the ovary. Regardless of “necrotic” appearance, the adnexa should be preserved.^8,9 Ovarian function after detorsion also has been assessed in a case series that showed normal follicular development on ultrasonography in more than 90% of patients after detorsion. In this group, 6 of 102 patients with torsion eventually underwent in vitro fertilization and, in all 6 patients, oocytes retrieved from the ischemic ovary were fertilized.¹⁰

Case 3: 15-year-old girl with nontender, palpable abdominal mass
A 15-year-old adolescent comes to your office for a well woman exam and to establish gynecologic care. Abdominal examination reveals a mass below the umbilicus that is nontender to palpation. The remainder of the examination is normal, and the patient is sent for ultrasonography. Results reveal a complex-appearing mass in the left ovary that measures 8 cm x 7 cm x 8 cm. The report states that the mass shows areas of fat and calcifications. There are no other abnormalities noted in the abdomen or pelvis.
Diagnosis: Dermoid cyst.
Treatment: Surgical intervention versus expectant management.

Germ cell ovarian tumors are a diverse category of tumors that include both benign and malignant disease. The ovarian teratoma (“dermoid”) is the most common and perhaps best-known example of a benign ovarian germ cell tumor (FIGURE 2). While the incidence in the general population is unknown, dermoids account for approximately 65% of adnexal masses in pediatric patients presenting for treatment.¹¹ Most of the time, patients with ovarian dermoids will be asymptomatic; however, pain is the most common presenting symptom.

The spectrum of sonographic features includes:

The notation of internal vascularity is concerning for malignancy.¹²

Fortunately, malignant ovarian germ cell tumors are much less common than benign lesions. Of these, the most common pediatric ovarian germ cell tumor is dysgerminoma (FIGURE 3).¹³

Clinical pearl. A unique consideration in patients with dysgerminoma or choriocarcinoma is the possible diagnosis of XY gonadal dysgenesis, or Swyer syndrome.^14,15 This may be seen in young girls with female external genitalia and primary amenorrhea. Depending on the level of concern, obtaining a karyotype also may be beneficial.¹³

Sex cord−stromal tumors also are relatively common in the pediatric population.¹⁶ Of these, granulosa cell tumors are the most common and account for 2% to 5% of ovarian malignancies regardless of age at diagnosis. Juvenile-type granulosa ovarian cancers occur mainly in premenarchal girls and comprise roughly 5% of all granulosa cell tumors.¹⁷ The presenting problem usually is precocious puberty. Therefore, in any situation in which a prepubertal girl is developing too early and peripheral precocious puberty is suspected, sonography should be obtained to rule out a hormone-producing ovarian mass. Tumor markers most helpful in this situation include estradiol, testosterone, and inhibin B.¹⁷

When an adolescent is diagnosed with ovarian cancer, it is ideal to perform a fertility-sparing procedure whenever it is reasonable.¹⁸ While dermoid cysts can look concerning on sonography because of their heterogeneous appearance, the vast majority can be safely and effectively resected without oophorectomy in order to preserve fertility, as in most cases they are benign. Nonetheless, cystectomy does have a small, theoretic risk of cyst rupture, with the potential for pelvic peritonitis from dermoid content spillage.¹⁹ In the vast majority of cases in which a benign adnexal mass is identified, ovarian cystectomy is appropriate and oophorectomy is not indicated.²⁰

Another very rare presentation of mature cystic teratoma can include acute neurologic decline in cases of paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis. Frequently, these teratomas will be small in size and discovered only incidentally during the work-up of a patient with altered mental status. Resection is indicated as soon as possible to stop the neurologic decline.²¹

Case 4: Cyclic pelvic pain and a pelvic mass in a 16-year-old
A 16-year-old adolescent presents to your office for evaluation of cyclic pelvic pain. She states that menarche occurred at age 12 years and menses have been irregular ever since, occurring every few months and associated with significant pain with the onset of bleeding.

Physical examination reveals Tanner stage 4 breasts and Tanner stage 4 external genitalia. The introitus is normal with a visible intact, annular hymen. A mildly tender palpable mass at the level of the umbilicus is noted. The patient consents to having a Q-tip placed in the vagina, which reveals a bulge in the left vaginal wall that is nontender and fluctuant. Pelvic ultrasonography reveals uterine didelphys and an obstructed left hemivagina. A renal ultrasound reveals an absent left kidney.
Diagnosis: OHVIRA (obstructed hemivagina and ipsilateral renal anomaly) syndrome.
Treatment: Surgical resection of the vaginal septum.

Masses that appear complex on imaging can be deceiving, as they also can be related to obstructive reproductive tract anomalies. “Pelvic mass” is often the working diagnosis in cases of imperforate hymen, vaginal atresia, cervical agenesis, and uterine didelphys with obstructed hemivagina. This underscores the importance of taking an accurate menstrual history as well as performing a thorough physical examination. Usually this does not require an internal vaginal examination if the patient is unable to tolerate one, but a rectal examination can provide similar information in a patient presenting with a “pelvic mass” who will consent to this portion of the exam.

Clinical pearl. If a patient is not comfortable consenting to a rectal exam, a lubricated Q-tip can be used to palpate the vagina to minimize patient discomfort.

Before performing surgery…
Vaginal surgery can be corrective in the majority of these cases; however, magnetic resonance imaging is the gold standard for diagnosis and should be performed prior to surgical planning to further characterize the anomaly.²² Because Müllerian anomalies are associated with renal malformation such as absent kidney, pelvic kidney, collecting system duplication, or ectopic ureteral insertion around 40% of the time, imaging studies to assess for these structures is important prior to surgical intervention.²³ If the patient is symptomatic and surgery cannot be performed immediately in a safe manner, she may require admission for pain control and placement of a Foley catheter (if the mass is obstructing urinary flow) until surgery can be performed safely.

A comprehensive review of Müllerian anomalies is beyond the scope of this article; it is important to note that these clinical scenarios are always unique and treatment should be individualized.

Conclusion
There are many sources of pelvic masses in children, adolescents, and young women; not all sources will be gynecologic. To avoid unnecessary surgical intervention, it is important to obtain as much information as possible from the patient’s history, physical examination, and laboratory and imaging studies.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Women’s sexual health took a step forward last month when an advisory panel to the US Food and Drug Administration (FDA) recommended approval of the drug flibanserin for the treatment of hypoactive sexual desire disorder (HSDD) in premenopausal women. The approval came with some reservations regarding safety (use with certain medications and alcohol). And it’s worthwhile to note that the FDA had on hand its own Drug Safety and Risk Management Committee during deliberations. However, assuming the agency follows the recommendations of the Bone, Reproductive, and Urologic Drugs Advisory Committee, women will soon have available the first agent for sexual dysfunction—aside from a medication for intercourse-associated pain—developed specifically for them.

Had the panel voted down the approval, it would have set a dangerous precedent that likely would have led to a standstill in new drug development in all therapeutic classes of women’s sexual health for the next decade.

Why do I say that—and state it so emphatically? 

To answer that question, let’s review the approval process for flibanserin, as well as for the 2 testosterone products that preceded its appearance before the FDA.

Hypoactive sexual desire disorder (HSDD) is the most common sexual dysfunction in women. Few interventions have proven to be effective for the treatment of HSDD. Education, counseling, and psychotherapy may be helpful in some women. Exogenous testosterone has been reported to be effective in the treatment of low sexual desire in postmenopausal women taking estrogen, but this treatment is not approved by the US Food and Drug Administration (FDA), and the long-term safety of exogenous testosterone in women is not established. Clinicians who treat women with sexual desire disorders are frustrated by their inability to prescribe an effective treatment for this common problem. An FDA advisory panel recently voted to support the approval of flibanserin for the treatment of HSDD in premenopausal women. In this month’s editorial, Dr. James Simon provides a history of the FDA review process for medications designed to treat HSDD, including the decision to not approve testosterone and the vote of the FDA advisory panel to support the approval of flibanserin. Readers of OBG Management should be aware that Dr. Simon, as is apparent in this piece and fully disclosed, has served as Medical Director and an advisor to Sprout Pharmaceuticals, the company with the rights to flibanserin. As editors we have concluded that Dr. Simon’s unique perspective, knowledge, and insights about the history of the FDA review of treatments of HSDD, including testosterone, would be of great interest to our readers.
—Robert L. Barbieri, MD, Editor in Chief
—Lila O’Connor, Editor

A tale of 2 products: The testosterone story
In 2004, Procter & Gamble filed a new drug application (NDA) for a testosterone patch (Intrinsa) developed for the treatment of female sexual dysfunction. Specifically, the patch was created for the treatment of HSDD in surgically menopausal women (those who had undergone bilateral oophorectomy) who were receiving concomitant estrogen therapy.

Both the FDA and the advisory committee considering the NDA agreed that the patch was effective. The question was whether its efficacy outweighed its risks. Recall that this discussion was taking place only 2 years after the initial publication of findings from the Women’s Health Initiative (WHI) estrogen-progestin arm. That arm had been halted prematurely because the risk of breast cancer exceeded the prespecified stopping boundary. In addition, the global index summarizing the balance of risks and benefits showed that risks outweighed benefits in ­regard to breast cancer, coronary heart disease, stroke, and pulmonary embolism.¹ As a result, the safety of all forms of hormone therapy was being closely scrutinized.

The FDA was also on “high alert” for safety as rofecoxib (Vioxx) had just been removed from the market due to unforeseen risks, with much media fanfare and large numbers of lawsuits.

After consideration of the NDA for the testosterone patch, the FDA advised Procter & Gamble to ­undertake an adequately designed and powered safety study to confirm that it would not increase the risks of coronary heart disease or breast cancer among users, since testosterone can be converted to estradiol in women.

Procter & Gamble ultimately withdrew its NDA. Such a safety study would have taken an additional 5 years to complete and cost upwards of $300 million. And because testosterone is not a patentable compound, a study that long and costly didn’t seem like a smart business proposition. Shortly after the NDA was withdrawn, the European Medicines Agency—the European counterpart of the FDA—approved the Intrinsa testosterone patch for the same indication as proposed in the United States.

Next up, BioSante Pharmaceuticals filed its NDA for LibiGel, a testosterone gel formulated specifically for postmenopausal women with HSDD. In its efficacy study, LibiGel failed to demonstrate superiority above and beyond placebo. The manufacturer, which was concurrently conducting a large, long-term safety study to satisfy the FDA’s concerns, ran out of money shortly thereafter, and that was the end of that.

Flibanserin’s focus: premenopausal women
In contrast to the 2 testosterone products, flibanserin was developed for premenopausal women. Although preliminary data on flibanserin use among postmenopausal women are available,² the drug was studied primarily in premenopausal women with HSDD, the indication sought at this time.

In the premenopausal population, problems such as pain with intercourse or hypoestrogenism aren’t typically present, simplifying the identification of HSDD. (See the sidebar below, “What is HSDD and how is it diagnosed?”) In clinical trials of the drug, HSDD was secondary, generalized, and acquired—that is, it followed a period of normal sexual function. And it didn’t come and go but was present regardless of location and circumstance. Study participants had had a normal sex drive before their desire “turned off,” an occurrence they found distressing.^3–6
 

In the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), hypoactive sexual desire disorder (HSDD) is described as having the following characteristics:

In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V), published in 2013, HSDD was folded with female sexual arousal disorder into a new diagnosis, female sexual interest and arousal disorder. This is somewhat confusing in that the physiologies of these 2 disorders are quite separate and distinct.

In clinical practice, HSDD is easily identified using the Decreased Sexual Desire Screener (DSDS), a simple screening test that asks 4 yes/no questions:

A “yes” response to each of these questions is required. In addition, a fifth question asks whether a number of conditions, drugs, or circumstances might be responsible for the decreased desire or interest:

Boehringer Ingelheim, a German concern, developed flibanserin and filed the initial NDA in 2009. In clinical trials, that company ran into problems because the electronic diary it was using to measure desire failed to demonstrate efficacy for flibanserin. It turns out that, if you ask women who are distressed about having low desire to report their level of desire every single day, they quickly get turned off by the question and eventually stop answering altogether. Such changes in behavior play havoc with the validity of the instrument to assess desire.

After flibanserin failed the electronic diary desire domain—one of the study’s endpoints—the ­company substituted a different measure, the Female Sexual Function Index (FSFI) desire domain. Although the FSFI showed statistically significantly greater efficacy for flibanserin than placebo, the FDA argued that it was unreasonable for the company to change the rules to fit the outcome. For that and other reasons, it turned down the NDA.

In response, Boehringer Ingelheim went back to the drawing board and undertook a new study intended to achieve several goals:

About the time this study was drawing to a conclusion, the company got cold feet and decided to shelve its plans for the drug.

Sprout steps in
I was among the delegation of medical and pharmaceutical professionals who visited Boehringer Ingelheim in 2011 to explore the possibility of Sprout Pharmaceuticals acquiring flibanserin. Boehringer Ingelheim agreed to the deal, and Sprout took over drug development, resubmitting the NDA to the FDA in 2013 with the additional study and other data. The FDA again denied the application. In response, Sprout filed a request for a dispute resolution, a formal procedure convened when the sponsor of an NDA cannot reach agreement with the FDA. In the course of this procedure, the FDA asked for additional analyses, as well as some pharmacogenomics and a driving study.

Around this time, the FDA had determined that the sleep aid zolpidem (Ambien) is metabolized differently in women than in men and that, in some of these women, there is a significant cognitive deficit carried over to the next day when the drug is taken as prescribed at bedtime. Because flibanserin came on the heels of this determination and was known to cause drowsiness, the FDA requested the driving study. It also requested a drug-drug interaction study to determine whether flibanserin is metabolized differently in some women with genetically different medication metabolism.

Sprout conducted those studies, both of which came back “clean.” Armed with this new data, the FDA scheduled a meeting of its advisory committee on June 4, 2015. And the rest, as they say, is history.

Flibanserin vs placebo
During the advisory committee’s deliberations on June 4, discussion focused, in part, on how flibanserin performed in comparison with placebo. It was ­noted that flibanserin increased the number of satisfying sexual events (SSEs) by only 1 per month, compared with placebo. But that conclusion doesn’t accurately convey the findings of the efficacy studies.

First, even without flibanserin, women in the trials reported that they continued to have sex with their partners 2 to 3 times per month. That established a baseline number of SSEs of approximately 2.5. The consent form for the flibanserin trial contained a clause stating that the woman would agree to try and have sex at least 1 additional time per month. This requirement, independent of any treatment, was bound to increase the placebo effect because, regardless of the drug given (flibanserin or placebo), the participant was going to try to have sex at least 1 more time per month.

In the flibanserin trials, the placebo effect was 1.5 additional SSEs per month. Add that to the baseline number of SSEs and you have a total of 4 SSEs per month. Among flibanserin users, the number of SSEs per month was about 5. And even though that’s only 1 more time per month than the placebo group, those 5 events were more desired events. That means that the baseline of 2.5 SSEs, among flibanserin users, had a different character by the end of the study period.

There is also a ceiling effect in play. Consider that the participants in the flibanserin trials were women who had been married an average of 10 years, with an average age of approximately 36 years. How much more sex is likely even possible in this population?

This isn’t to say that women are incapable of having more sex. It is merely a reflection of the data, which show that, among married women aged 30 to 39 years, only roughly 25% have sex more often than weekly, and only 5.1% have sex 4 or more times per week.⁷ If women were shown to be having sex more than 5 times per month, a likely criticism would have been that the drug was making them hypersexual or even abnormal.

Also keep in mind that the drug doesn’t work in every woman, just as antidepressants are not effective in every person. So when the responders and nonresponders were lumped together, the magnitude of the drug’s response in the combined group was smaller. In reality, approximately 25% of women in the flibanserin trials experienced an increase of 4 or more SSEs per month, compared with 15% among placebo users.
 

Flibanserin is indicated for the treatment of hypoactive sexual desire disorder in premenopausal women. It is taken daily in a 100-mg tablet. Bedtime dosing is preferred to mitigate potential side effects such as drowsiness, hypotension, and syncope. These effects can occur with flibanserin alone, in combination with certain drugs, or in combination with alcohol.

Significant drug-drug interactions have been documented for flibanserin in combination with moderate and strong CYP3A4 inhibitors such as fluconazole and ketoconazole. Package labeling for flibanserin will detail this risk.

Why now?
As I stated earlier, a failure to approve flibanserin would set a dangerous precedent. Why? Because the company did everything the FDA asked it to do, and the results came out statistically significantly better than placebo—which was the desired endpoint. If the FDA were to deny approval of the drug, it would be saying, in effect, that it can change its mind in the middle of the argument—something it faulted Boehringer Ingelheim for in earlier deliberations (switching the insensitive electronic diary for the statistically significant FSFI).

In reality, the FDA is likely to say yes to approval, but with restrictions, as that is what its advisory committee recommended. What those restrictions will be remains to be determined, but they are likely to resemble those of other drugs in the class, such as selective serotonin reuptake inhibitors (SSRIs), including a warning to be careful using flibanserin with alcohol until the drug’s effects are clear.

Opposition to flibanserin misses the mark
During the public hearing portion of the advisory committee meeting, most of the testimony came from women seeking approval of the drug. However, there were some naysayers. Their arguments against approval boiled down to 4 perspectives:

There is also the sociological view that HSDD is a normal variant of healthy sexual function. Its adherents argue that women with HSDD feel distress because their male partners are forcing them to feel inadequate. But I have yet to hear a single critical voice from a physician who actually treats women and who can prescribe drugs. The opposition to flibanserin, such as it is, flows from people who don’t see patients and can’t prescribe medications.

These naysayers are negative in a theoretical vacuum. It’s very easy to fall into that trap when you don’t have to look across the consultation desk to a patient who is asking you for a remedy—a woman who’s been suffering for 25 years, say—and have to tell her you have nothing to offer. You might mention testosterone, explaining that it was approved for men but you’ll try to prescribe an appropriate dose. But be sure to include discussion of its many side effects.

A long and winding road
Flibanserin’s journey from inception to probable approval has been long and eventful, and you can be sure that the pharmaceutical industry has been paying attention. Hundreds of millions of dollars in funding for drug development hang in the balance. That women deserve remedies developed specifically for their needs and metabolism is a given. The approval of flibanserin will send a hopeful signal to them as well as to industry—that the FDA takes them seriously and seeks to identify effective remedies. In this case, it seems likely, the agency will end up on the right side of history.
 

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Women’s sexual health took a step forward last month when an advisory panel to the US Food and Drug Administration (FDA) recommended approval of the drug flibanserin for the treatment of hypoactive sexual desire disorder (HSDD) in premenopausal women. The approval came with some reservations regarding safety (use with certain medications and alcohol). And it’s worthwhile to note that the FDA had on hand its own Drug Safety and Risk Management Committee during deliberations. However, assuming the agency follows the recommendations of the Bone, Reproductive, and Urologic Drugs Advisory Committee, women will soon have available the first agent for sexual dysfunction—aside from a medication for intercourse-associated pain—developed specifically for them.

Had the panel voted down the approval, it would have set a dangerous precedent that likely would have led to a standstill in new drug development in all therapeutic classes of women’s sexual health for the next decade.

Why do I say that—and state it so emphatically? 

To answer that question, let’s review the approval process for flibanserin, as well as for the 2 testosterone products that preceded its appearance before the FDA.

Hypoactive sexual desire disorder (HSDD) is the most common sexual dysfunction in women. Few interventions have proven to be effective for the treatment of HSDD. Education, counseling, and psychotherapy may be helpful in some women. Exogenous testosterone has been reported to be effective in the treatment of low sexual desire in postmenopausal women taking estrogen, but this treatment is not approved by the US Food and Drug Administration (FDA), and the long-term safety of exogenous testosterone in women is not established. Clinicians who treat women with sexual desire disorders are frustrated by their inability to prescribe an effective treatment for this common problem. An FDA advisory panel recently voted to support the approval of flibanserin for the treatment of HSDD in premenopausal women. In this month’s editorial, Dr. James Simon provides a history of the FDA review process for medications designed to treat HSDD, including the decision to not approve testosterone and the vote of the FDA advisory panel to support the approval of flibanserin. Readers of OBG Management should be aware that Dr. Simon, as is apparent in this piece and fully disclosed, has served as Medical Director and an advisor to Sprout Pharmaceuticals, the company with the rights to flibanserin. As editors we have concluded that Dr. Simon’s unique perspective, knowledge, and insights about the history of the FDA review of treatments of HSDD, including testosterone, would be of great interest to our readers.
—Robert L. Barbieri, MD, Editor in Chief
—Lila O’Connor, Editor

A tale of 2 products: The testosterone story
In 2004, Procter & Gamble filed a new drug application (NDA) for a testosterone patch (Intrinsa) developed for the treatment of female sexual dysfunction. Specifically, the patch was created for the treatment of HSDD in surgically menopausal women (those who had undergone bilateral oophorectomy) who were receiving concomitant estrogen therapy.

Both the FDA and the advisory committee considering the NDA agreed that the patch was effective. The question was whether its efficacy outweighed its risks. Recall that this discussion was taking place only 2 years after the initial publication of findings from the Women’s Health Initiative (WHI) estrogen-progestin arm. That arm had been halted prematurely because the risk of breast cancer exceeded the prespecified stopping boundary. In addition, the global index summarizing the balance of risks and benefits showed that risks outweighed benefits in ­regard to breast cancer, coronary heart disease, stroke, and pulmonary embolism.¹ As a result, the safety of all forms of hormone therapy was being closely scrutinized.

The FDA was also on “high alert” for safety as rofecoxib (Vioxx) had just been removed from the market due to unforeseen risks, with much media fanfare and large numbers of lawsuits.

After consideration of the NDA for the testosterone patch, the FDA advised Procter & Gamble to ­undertake an adequately designed and powered safety study to confirm that it would not increase the risks of coronary heart disease or breast cancer among users, since testosterone can be converted to estradiol in women.

Procter & Gamble ultimately withdrew its NDA. Such a safety study would have taken an additional 5 years to complete and cost upwards of $300 million. And because testosterone is not a patentable compound, a study that long and costly didn’t seem like a smart business proposition. Shortly after the NDA was withdrawn, the European Medicines Agency—the European counterpart of the FDA—approved the Intrinsa testosterone patch for the same indication as proposed in the United States.

Next up, BioSante Pharmaceuticals filed its NDA for LibiGel, a testosterone gel formulated specifically for postmenopausal women with HSDD. In its efficacy study, LibiGel failed to demonstrate superiority above and beyond placebo. The manufacturer, which was concurrently conducting a large, long-term safety study to satisfy the FDA’s concerns, ran out of money shortly thereafter, and that was the end of that.

Flibanserin’s focus: premenopausal women
In contrast to the 2 testosterone products, flibanserin was developed for premenopausal women. Although preliminary data on flibanserin use among postmenopausal women are available,² the drug was studied primarily in premenopausal women with HSDD, the indication sought at this time.

In the premenopausal population, problems such as pain with intercourse or hypoestrogenism aren’t typically present, simplifying the identification of HSDD. (See the sidebar below, “What is HSDD and how is it diagnosed?”) In clinical trials of the drug, HSDD was secondary, generalized, and acquired—that is, it followed a period of normal sexual function. And it didn’t come and go but was present regardless of location and circumstance. Study participants had had a normal sex drive before their desire “turned off,” an occurrence they found distressing.^3–6
 

In the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), hypoactive sexual desire disorder (HSDD) is described as having the following characteristics:

In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V), published in 2013, HSDD was folded with female sexual arousal disorder into a new diagnosis, female sexual interest and arousal disorder. This is somewhat confusing in that the physiologies of these 2 disorders are quite separate and distinct.

In clinical practice, HSDD is easily identified using the Decreased Sexual Desire Screener (DSDS), a simple screening test that asks 4 yes/no questions:

A “yes” response to each of these questions is required. In addition, a fifth question asks whether a number of conditions, drugs, or circumstances might be responsible for the decreased desire or interest:

Boehringer Ingelheim, a German concern, developed flibanserin and filed the initial NDA in 2009. In clinical trials, that company ran into problems because the electronic diary it was using to measure desire failed to demonstrate efficacy for flibanserin. It turns out that, if you ask women who are distressed about having low desire to report their level of desire every single day, they quickly get turned off by the question and eventually stop answering altogether. Such changes in behavior play havoc with the validity of the instrument to assess desire.

After flibanserin failed the electronic diary desire domain—one of the study’s endpoints—the ­company substituted a different measure, the Female Sexual Function Index (FSFI) desire domain. Although the FSFI showed statistically significantly greater efficacy for flibanserin than placebo, the FDA argued that it was unreasonable for the company to change the rules to fit the outcome. For that and other reasons, it turned down the NDA.

In response, Boehringer Ingelheim went back to the drawing board and undertook a new study intended to achieve several goals:

About the time this study was drawing to a conclusion, the company got cold feet and decided to shelve its plans for the drug.

Sprout steps in
I was among the delegation of medical and pharmaceutical professionals who visited Boehringer Ingelheim in 2011 to explore the possibility of Sprout Pharmaceuticals acquiring flibanserin. Boehringer Ingelheim agreed to the deal, and Sprout took over drug development, resubmitting the NDA to the FDA in 2013 with the additional study and other data. The FDA again denied the application. In response, Sprout filed a request for a dispute resolution, a formal procedure convened when the sponsor of an NDA cannot reach agreement with the FDA. In the course of this procedure, the FDA asked for additional analyses, as well as some pharmacogenomics and a driving study.

Around this time, the FDA had determined that the sleep aid zolpidem (Ambien) is metabolized differently in women than in men and that, in some of these women, there is a significant cognitive deficit carried over to the next day when the drug is taken as prescribed at bedtime. Because flibanserin came on the heels of this determination and was known to cause drowsiness, the FDA requested the driving study. It also requested a drug-drug interaction study to determine whether flibanserin is metabolized differently in some women with genetically different medication metabolism.

Sprout conducted those studies, both of which came back “clean.” Armed with this new data, the FDA scheduled a meeting of its advisory committee on June 4, 2015. And the rest, as they say, is history.

Flibanserin vs placebo
During the advisory committee’s deliberations on June 4, discussion focused, in part, on how flibanserin performed in comparison with placebo. It was ­noted that flibanserin increased the number of satisfying sexual events (SSEs) by only 1 per month, compared with placebo. But that conclusion doesn’t accurately convey the findings of the efficacy studies.

First, even without flibanserin, women in the trials reported that they continued to have sex with their partners 2 to 3 times per month. That established a baseline number of SSEs of approximately 2.5. The consent form for the flibanserin trial contained a clause stating that the woman would agree to try and have sex at least 1 additional time per month. This requirement, independent of any treatment, was bound to increase the placebo effect because, regardless of the drug given (flibanserin or placebo), the participant was going to try to have sex at least 1 more time per month.

In the flibanserin trials, the placebo effect was 1.5 additional SSEs per month. Add that to the baseline number of SSEs and you have a total of 4 SSEs per month. Among flibanserin users, the number of SSEs per month was about 5. And even though that’s only 1 more time per month than the placebo group, those 5 events were more desired events. That means that the baseline of 2.5 SSEs, among flibanserin users, had a different character by the end of the study period.

There is also a ceiling effect in play. Consider that the participants in the flibanserin trials were women who had been married an average of 10 years, with an average age of approximately 36 years. How much more sex is likely even possible in this population?

This isn’t to say that women are incapable of having more sex. It is merely a reflection of the data, which show that, among married women aged 30 to 39 years, only roughly 25% have sex more often than weekly, and only 5.1% have sex 4 or more times per week.⁷ If women were shown to be having sex more than 5 times per month, a likely criticism would have been that the drug was making them hypersexual or even abnormal.

Also keep in mind that the drug doesn’t work in every woman, just as antidepressants are not effective in every person. So when the responders and nonresponders were lumped together, the magnitude of the drug’s response in the combined group was smaller. In reality, approximately 25% of women in the flibanserin trials experienced an increase of 4 or more SSEs per month, compared with 15% among placebo users.
 

Flibanserin is indicated for the treatment of hypoactive sexual desire disorder in premenopausal women. It is taken daily in a 100-mg tablet. Bedtime dosing is preferred to mitigate potential side effects such as drowsiness, hypotension, and syncope. These effects can occur with flibanserin alone, in combination with certain drugs, or in combination with alcohol.

Significant drug-drug interactions have been documented for flibanserin in combination with moderate and strong CYP3A4 inhibitors such as fluconazole and ketoconazole. Package labeling for flibanserin will detail this risk.

Why now?
As I stated earlier, a failure to approve flibanserin would set a dangerous precedent. Why? Because the company did everything the FDA asked it to do, and the results came out statistically significantly better than placebo—which was the desired endpoint. If the FDA were to deny approval of the drug, it would be saying, in effect, that it can change its mind in the middle of the argument—something it faulted Boehringer Ingelheim for in earlier deliberations (switching the insensitive electronic diary for the statistically significant FSFI).

In reality, the FDA is likely to say yes to approval, but with restrictions, as that is what its advisory committee recommended. What those restrictions will be remains to be determined, but they are likely to resemble those of other drugs in the class, such as selective serotonin reuptake inhibitors (SSRIs), including a warning to be careful using flibanserin with alcohol until the drug’s effects are clear.

Opposition to flibanserin misses the mark
During the public hearing portion of the advisory committee meeting, most of the testimony came from women seeking approval of the drug. However, there were some naysayers. Their arguments against approval boiled down to 4 perspectives:

There is also the sociological view that HSDD is a normal variant of healthy sexual function. Its adherents argue that women with HSDD feel distress because their male partners are forcing them to feel inadequate. But I have yet to hear a single critical voice from a physician who actually treats women and who can prescribe drugs. The opposition to flibanserin, such as it is, flows from people who don’t see patients and can’t prescribe medications.

These naysayers are negative in a theoretical vacuum. It’s very easy to fall into that trap when you don’t have to look across the consultation desk to a patient who is asking you for a remedy—a woman who’s been suffering for 25 years, say—and have to tell her you have nothing to offer. You might mention testosterone, explaining that it was approved for men but you’ll try to prescribe an appropriate dose. But be sure to include discussion of its many side effects.

A long and winding road
Flibanserin’s journey from inception to probable approval has been long and eventful, and you can be sure that the pharmaceutical industry has been paying attention. Hundreds of millions of dollars in funding for drug development hang in the balance. That women deserve remedies developed specifically for their needs and metabolism is a given. The approval of flibanserin will send a hopeful signal to them as well as to industry—that the FDA takes them seriously and seeks to identify effective remedies. In this case, it seems likely, the agency will end up on the right side of history.
 

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Women’s sexual health took a step forward last month when an advisory panel to the US Food and Drug Administration (FDA) recommended approval of the drug flibanserin for the treatment of hypoactive sexual desire disorder (HSDD) in premenopausal women. The approval came with some reservations regarding safety (use with certain medications and alcohol). And it’s worthwhile to note that the FDA had on hand its own Drug Safety and Risk Management Committee during deliberations. However, assuming the agency follows the recommendations of the Bone, Reproductive, and Urologic Drugs Advisory Committee, women will soon have available the first agent for sexual dysfunction—aside from a medication for intercourse-associated pain—developed specifically for them.

Had the panel voted down the approval, it would have set a dangerous precedent that likely would have led to a standstill in new drug development in all therapeutic classes of women’s sexual health for the next decade.

Why do I say that—and state it so emphatically? 

To answer that question, let’s review the approval process for flibanserin, as well as for the 2 testosterone products that preceded its appearance before the FDA.

Hypoactive sexual desire disorder (HSDD) is the most common sexual dysfunction in women. Few interventions have proven to be effective for the treatment of HSDD. Education, counseling, and psychotherapy may be helpful in some women. Exogenous testosterone has been reported to be effective in the treatment of low sexual desire in postmenopausal women taking estrogen, but this treatment is not approved by the US Food and Drug Administration (FDA), and the long-term safety of exogenous testosterone in women is not established. Clinicians who treat women with sexual desire disorders are frustrated by their inability to prescribe an effective treatment for this common problem. An FDA advisory panel recently voted to support the approval of flibanserin for the treatment of HSDD in premenopausal women. In this month’s editorial, Dr. James Simon provides a history of the FDA review process for medications designed to treat HSDD, including the decision to not approve testosterone and the vote of the FDA advisory panel to support the approval of flibanserin. Readers of OBG Management should be aware that Dr. Simon, as is apparent in this piece and fully disclosed, has served as Medical Director and an advisor to Sprout Pharmaceuticals, the company with the rights to flibanserin. As editors we have concluded that Dr. Simon’s unique perspective, knowledge, and insights about the history of the FDA review of treatments of HSDD, including testosterone, would be of great interest to our readers.
—Robert L. Barbieri, MD, Editor in Chief
—Lila O’Connor, Editor

A tale of 2 products: The testosterone story
In 2004, Procter & Gamble filed a new drug application (NDA) for a testosterone patch (Intrinsa) developed for the treatment of female sexual dysfunction. Specifically, the patch was created for the treatment of HSDD in surgically menopausal women (those who had undergone bilateral oophorectomy) who were receiving concomitant estrogen therapy.

Both the FDA and the advisory committee considering the NDA agreed that the patch was effective. The question was whether its efficacy outweighed its risks. Recall that this discussion was taking place only 2 years after the initial publication of findings from the Women’s Health Initiative (WHI) estrogen-progestin arm. That arm had been halted prematurely because the risk of breast cancer exceeded the prespecified stopping boundary. In addition, the global index summarizing the balance of risks and benefits showed that risks outweighed benefits in ­regard to breast cancer, coronary heart disease, stroke, and pulmonary embolism.¹ As a result, the safety of all forms of hormone therapy was being closely scrutinized.

The FDA was also on “high alert” for safety as rofecoxib (Vioxx) had just been removed from the market due to unforeseen risks, with much media fanfare and large numbers of lawsuits.

After consideration of the NDA for the testosterone patch, the FDA advised Procter & Gamble to ­undertake an adequately designed and powered safety study to confirm that it would not increase the risks of coronary heart disease or breast cancer among users, since testosterone can be converted to estradiol in women.

Procter & Gamble ultimately withdrew its NDA. Such a safety study would have taken an additional 5 years to complete and cost upwards of $300 million. And because testosterone is not a patentable compound, a study that long and costly didn’t seem like a smart business proposition. Shortly after the NDA was withdrawn, the European Medicines Agency—the European counterpart of the FDA—approved the Intrinsa testosterone patch for the same indication as proposed in the United States.

Next up, BioSante Pharmaceuticals filed its NDA for LibiGel, a testosterone gel formulated specifically for postmenopausal women with HSDD. In its efficacy study, LibiGel failed to demonstrate superiority above and beyond placebo. The manufacturer, which was concurrently conducting a large, long-term safety study to satisfy the FDA’s concerns, ran out of money shortly thereafter, and that was the end of that.

Flibanserin’s focus: premenopausal women
In contrast to the 2 testosterone products, flibanserin was developed for premenopausal women. Although preliminary data on flibanserin use among postmenopausal women are available,² the drug was studied primarily in premenopausal women with HSDD, the indication sought at this time.

In the premenopausal population, problems such as pain with intercourse or hypoestrogenism aren’t typically present, simplifying the identification of HSDD. (See the sidebar below, “What is HSDD and how is it diagnosed?”) In clinical trials of the drug, HSDD was secondary, generalized, and acquired—that is, it followed a period of normal sexual function. And it didn’t come and go but was present regardless of location and circumstance. Study participants had had a normal sex drive before their desire “turned off,” an occurrence they found distressing.^3–6
 

In the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), hypoactive sexual desire disorder (HSDD) is described as having the following characteristics:

In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V), published in 2013, HSDD was folded with female sexual arousal disorder into a new diagnosis, female sexual interest and arousal disorder. This is somewhat confusing in that the physiologies of these 2 disorders are quite separate and distinct.

In clinical practice, HSDD is easily identified using the Decreased Sexual Desire Screener (DSDS), a simple screening test that asks 4 yes/no questions:

A “yes” response to each of these questions is required. In addition, a fifth question asks whether a number of conditions, drugs, or circumstances might be responsible for the decreased desire or interest:

Boehringer Ingelheim, a German concern, developed flibanserin and filed the initial NDA in 2009. In clinical trials, that company ran into problems because the electronic diary it was using to measure desire failed to demonstrate efficacy for flibanserin. It turns out that, if you ask women who are distressed about having low desire to report their level of desire every single day, they quickly get turned off by the question and eventually stop answering altogether. Such changes in behavior play havoc with the validity of the instrument to assess desire.

After flibanserin failed the electronic diary desire domain—one of the study’s endpoints—the ­company substituted a different measure, the Female Sexual Function Index (FSFI) desire domain. Although the FSFI showed statistically significantly greater efficacy for flibanserin than placebo, the FDA argued that it was unreasonable for the company to change the rules to fit the outcome. For that and other reasons, it turned down the NDA.

In response, Boehringer Ingelheim went back to the drawing board and undertook a new study intended to achieve several goals:

About the time this study was drawing to a conclusion, the company got cold feet and decided to shelve its plans for the drug.

Sprout steps in
I was among the delegation of medical and pharmaceutical professionals who visited Boehringer Ingelheim in 2011 to explore the possibility of Sprout Pharmaceuticals acquiring flibanserin. Boehringer Ingelheim agreed to the deal, and Sprout took over drug development, resubmitting the NDA to the FDA in 2013 with the additional study and other data. The FDA again denied the application. In response, Sprout filed a request for a dispute resolution, a formal procedure convened when the sponsor of an NDA cannot reach agreement with the FDA. In the course of this procedure, the FDA asked for additional analyses, as well as some pharmacogenomics and a driving study.

Around this time, the FDA had determined that the sleep aid zolpidem (Ambien) is metabolized differently in women than in men and that, in some of these women, there is a significant cognitive deficit carried over to the next day when the drug is taken as prescribed at bedtime. Because flibanserin came on the heels of this determination and was known to cause drowsiness, the FDA requested the driving study. It also requested a drug-drug interaction study to determine whether flibanserin is metabolized differently in some women with genetically different medication metabolism.

Sprout conducted those studies, both of which came back “clean.” Armed with this new data, the FDA scheduled a meeting of its advisory committee on June 4, 2015. And the rest, as they say, is history.

Flibanserin vs placebo
During the advisory committee’s deliberations on June 4, discussion focused, in part, on how flibanserin performed in comparison with placebo. It was ­noted that flibanserin increased the number of satisfying sexual events (SSEs) by only 1 per month, compared with placebo. But that conclusion doesn’t accurately convey the findings of the efficacy studies.

First, even without flibanserin, women in the trials reported that they continued to have sex with their partners 2 to 3 times per month. That established a baseline number of SSEs of approximately 2.5. The consent form for the flibanserin trial contained a clause stating that the woman would agree to try and have sex at least 1 additional time per month. This requirement, independent of any treatment, was bound to increase the placebo effect because, regardless of the drug given (flibanserin or placebo), the participant was going to try to have sex at least 1 more time per month.

In the flibanserin trials, the placebo effect was 1.5 additional SSEs per month. Add that to the baseline number of SSEs and you have a total of 4 SSEs per month. Among flibanserin users, the number of SSEs per month was about 5. And even though that’s only 1 more time per month than the placebo group, those 5 events were more desired events. That means that the baseline of 2.5 SSEs, among flibanserin users, had a different character by the end of the study period.

There is also a ceiling effect in play. Consider that the participants in the flibanserin trials were women who had been married an average of 10 years, with an average age of approximately 36 years. How much more sex is likely even possible in this population?

This isn’t to say that women are incapable of having more sex. It is merely a reflection of the data, which show that, among married women aged 30 to 39 years, only roughly 25% have sex more often than weekly, and only 5.1% have sex 4 or more times per week.⁷ If women were shown to be having sex more than 5 times per month, a likely criticism would have been that the drug was making them hypersexual or even abnormal.

Also keep in mind that the drug doesn’t work in every woman, just as antidepressants are not effective in every person. So when the responders and nonresponders were lumped together, the magnitude of the drug’s response in the combined group was smaller. In reality, approximately 25% of women in the flibanserin trials experienced an increase of 4 or more SSEs per month, compared with 15% among placebo users.
 

Flibanserin is indicated for the treatment of hypoactive sexual desire disorder in premenopausal women. It is taken daily in a 100-mg tablet. Bedtime dosing is preferred to mitigate potential side effects such as drowsiness, hypotension, and syncope. These effects can occur with flibanserin alone, in combination with certain drugs, or in combination with alcohol.

Significant drug-drug interactions have been documented for flibanserin in combination with moderate and strong CYP3A4 inhibitors such as fluconazole and ketoconazole. Package labeling for flibanserin will detail this risk.

Why now?
As I stated earlier, a failure to approve flibanserin would set a dangerous precedent. Why? Because the company did everything the FDA asked it to do, and the results came out statistically significantly better than placebo—which was the desired endpoint. If the FDA were to deny approval of the drug, it would be saying, in effect, that it can change its mind in the middle of the argument—something it faulted Boehringer Ingelheim for in earlier deliberations (switching the insensitive electronic diary for the statistically significant FSFI).

In reality, the FDA is likely to say yes to approval, but with restrictions, as that is what its advisory committee recommended. What those restrictions will be remains to be determined, but they are likely to resemble those of other drugs in the class, such as selective serotonin reuptake inhibitors (SSRIs), including a warning to be careful using flibanserin with alcohol until the drug’s effects are clear.

Opposition to flibanserin misses the mark
During the public hearing portion of the advisory committee meeting, most of the testimony came from women seeking approval of the drug. However, there were some naysayers. Their arguments against approval boiled down to 4 perspectives:

There is also the sociological view that HSDD is a normal variant of healthy sexual function. Its adherents argue that women with HSDD feel distress because their male partners are forcing them to feel inadequate. But I have yet to hear a single critical voice from a physician who actually treats women and who can prescribe drugs. The opposition to flibanserin, such as it is, flows from people who don’t see patients and can’t prescribe medications.

These naysayers are negative in a theoretical vacuum. It’s very easy to fall into that trap when you don’t have to look across the consultation desk to a patient who is asking you for a remedy—a woman who’s been suffering for 25 years, say—and have to tell her you have nothing to offer. You might mention testosterone, explaining that it was approved for men but you’ll try to prescribe an appropriate dose. But be sure to include discussion of its many side effects.

A long and winding road
Flibanserin’s journey from inception to probable approval has been long and eventful, and you can be sure that the pharmaceutical industry has been paying attention. Hundreds of millions of dollars in funding for drug development hang in the balance. That women deserve remedies developed specifically for their needs and metabolism is a given. The approval of flibanserin will send a hopeful signal to them as well as to industry—that the FDA takes them seriously and seeks to identify effective remedies. In this case, it seems likely, the agency will end up on the right side of history.
 

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

The number of states that require notification to a woman who is identified on mammography as having heterogeneous (Breast Imaging-Reporting and Data System [BI-RADS] C) or extremely dense breasts (BI-RADS D) is growing. In fact, Michigan became the 22nd state to require such notification when its law went into effect on June 1, 2015. How do we advise our patients who come to us wondering what they should do with the new-found information?

Since supplemental imaging after normal mammography findings can result in false positives and potentially unnecessary biopsies or treatment, Kerlikowski and colleagues investigated for which patients supplemental screening could be beneficial. In other words, which patients are at highest risk for interval cancer (invasive cancer diagnosed within 12 months of a normal mammogram), as these women would be most likely to benefit from supplemental imaging that could potentially detect a tumor not identified on digital screening mammography.

Details of the study
The researchers included 831,455 digital screening mammography examinations performed among 365,426 women aged 40 to 74 years who did not have a history of breast cancer or breast implants and had complete information on demographic and breast health history. To calculate breast cancer risk, they used the Breast Cancer Surveillance Consortium (BCSC) 5-year risk model, which requires 5 risk factors: first-degree relatives with history of breast cancer, history of breast biopsy, BI-RADS breast density, and race/ethnicity. They used breast density to stratify women by risk for interval cancer within the next year and to identify women at increased 5-year risk for breast cancer.

In which patient populations are cases of interval cancer highest?
The authors found the interval cancer rates to exceed 1 case per 1,000 mammography examinations among:

The authors point out that, together, these 2 latter groups represent 24% of women aged 40 to 74 years with dense breasts, or 12% of women having screening mammography.

For women aged 40 to 49 years, interval cancer rates were less than 1 case per 1,000 examinations for all density categories. For 51% of these women with heterogeneously dense breasts, the 5-year risk of breast cancer was low to average (0% to 1.66%), with interval cancer rates of 0.58 to 0.63 per 1,000 examinations. For 52.5% of 40- to 49-year-old women with extremely dense breasts, the 5-year risk of breast cancer was low to average, with interval cancer rates of 0.72 to 0.89 cases per 1,000 examinations.

The interval cancer rate for women with scattered fibroglandular densities (BI-RADS B) and 5-year risk of 2.50% or greater was 0.90 cases per 1,000 mammography examinations.

Kerlikowski and colleagues conclude that breast density should not be the sole criterion for deciding whether supplemental imaging is justified because not all women with dense breasts have high interval cancer rates. 

What this evidence means for practice
BCSC 5-year risk combined with BI-RADS breast density can identify women at high risk for interval cancer to inform patient–provider discussions about alternative screening strategies, as the study authors state. However, there remains a huge gap in our knowledge about whether supplemental imaging in any of these risk groups improved stage of diagnosis or breast cancer–specific mortality.

Nearly all national guidelines groups (US Preventive Services Task Force,¹ American College of Obstetricians and Gynecologists,² National Comprehensive Cancer Network,³ and the American Cancer Society⁴) concur that supplemental breast imaging should not be performed on women with dense breasts until there are reasonable data that demonstrate an improvement in stage of diagnosis or breast cancer mortality.
—Mark D. Pearlman, MD

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

The number of states that require notification to a woman who is identified on mammography as having heterogeneous (Breast Imaging-Reporting and Data System [BI-RADS] C) or extremely dense breasts (BI-RADS D) is growing. In fact, Michigan became the 22nd state to require such notification when its law went into effect on June 1, 2015. How do we advise our patients who come to us wondering what they should do with the new-found information?

Since supplemental imaging after normal mammography findings can result in false positives and potentially unnecessary biopsies or treatment, Kerlikowski and colleagues investigated for which patients supplemental screening could be beneficial. In other words, which patients are at highest risk for interval cancer (invasive cancer diagnosed within 12 months of a normal mammogram), as these women would be most likely to benefit from supplemental imaging that could potentially detect a tumor not identified on digital screening mammography.

Details of the study
The researchers included 831,455 digital screening mammography examinations performed among 365,426 women aged 40 to 74 years who did not have a history of breast cancer or breast implants and had complete information on demographic and breast health history. To calculate breast cancer risk, they used the Breast Cancer Surveillance Consortium (BCSC) 5-year risk model, which requires 5 risk factors: first-degree relatives with history of breast cancer, history of breast biopsy, BI-RADS breast density, and race/ethnicity. They used breast density to stratify women by risk for interval cancer within the next year and to identify women at increased 5-year risk for breast cancer.

In which patient populations are cases of interval cancer highest?
The authors found the interval cancer rates to exceed 1 case per 1,000 mammography examinations among: