OBG Management

Gyamfi-Bannerman and Son report their secondary analysis of a randomized controlled trial (RCT) conducted through the Eunice Kennedy Shriver National Institute of Child Health and Human Development’s Maternal-Fetal Medicine Units Network. The aim of the parent RCT was to determine whether antenatal administration of magnesium sulfate decreases the rate of cerebral palsy or death in children delivered preterm. More than 80% of the women enrolled in this RCT had preterm PROM. Of these women, 98% were given antenatal corticosteroids for fetal maturation, and 9% received two courses. This aspect of the RCT provided an opportunity for Gyamfi-Bannerman and Son to study the comparative effects of one course versus two courses of ACS in the setting of preterm PROM.

Background of the study
Concern about the declining efficacy of ACS when the interval between administration and delivery exceeds 7 days prompted several randomized trials exploring the safety and efficacy of multiple ACS courses. Multiple courses were ultimately deemed to be inadvisable because of an association with reduced birth weight and neonatal head circumference.^1,2 However, the unfavorable effects of ACS on anthropometrics was observed when more than three courses were administered, leaving open the possibility of giving only one additional course when needed as a “rescue” dose. Indeed, the use of a single rescue course of ACS in women with intact membranes had a favorable impact on neonatal respiratory function in two RCTs.^3,4

The best available evidence (Level 1) demonstrates that the use of a single course of ACS in preterm PROM does not increase the risk of neonatal or maternal infection even in the setting of prolonged rupture of membranes.⁵ However, pregnant women with preterm PROM were excluded from trials of repetitive ACS dosing because earlier observational studies had suggested that they would experience a substantially increased risk of infectious morbidity when three or more courses of ACS are given.^6–8 What remained debatable on a scientific level was whether a single rescue dose of ACS in women with preterm PROM would be safe and beneficial.

Findings of the analysis
Compared with a single course of ACS, exposure to two courses did not influence the rate of neonatal sepsis or chorioamnionitis. As reassuring as that finding may be, the study found no benefit for the additional course, although it was powered to do so. There was no difference in the rates of respiratory distress syndrome between the study groups.

The findings of Gyamfi-Bannerman and Son replicate those of a subgroup analysis of women in an RCT comparing weekly and single-course ACS.⁹ In that study, weekly courses of ACS in women with preterm PROM did not improve neonatal outcomes beyond what was achieved with single-course therapy. Similar findings have been reported by the Cochrane database.¹⁰

Ruptured versus intact membranes: When is the benefit of ACS greater?
The improvement in neonatal outcomes observed with ACS in pregnancies complicated by preterm PROM is not as pronounced as it is in gestations with intact membranes. In preterm PROM, fetuses reportedly are stressed by the presence of intrauterine inflammation or infection, or both, which accelerates lung maturity by encouraging the secretion of endogenous corticosteroids, resulting in the production of surfactant and eliminating the potential benefit of exogenous ACS.¹¹ This theoretical consideration has not been verified in a systematic analysis of accumulated data,⁵ and the administration of a single course of ACS in preterm PROM now has been shown clearly to improve neonatal outcomes.¹² As Gyamfi-Bannerman and Son demonstrate, the same cannot be said about the administration of a rescue dose of ACS.

Strengths and limitations of the trial
Gyamfi-Bannerman and Son did not address the same interaction as the parent study. The exposure of interest was ACS, an event that occurred in a manner unrelated to the randomization for magnesium sulfate administration. Therefore, the outcome data are no longer randomized in nature, and the study becomes a retrospective cohort analysis.

Gyamfi-Bannerman and Son recognize the limitations of such a study, especially the lack of standardization in the intervention (exact timing of intervention or type of formulation). As with any nonrandomized experiment, the potential for unintended systematic bias is present.

This study, in particular, was subject to “survivor bias,” as reflected in the significantly different intervals between membrane rupture and delivery in the two groups.  

What this evidence means for practice
We must always remain cautious about basing policy or clinical decisions on cohort studies. It has been argued that basing a change in clinical practice on the findings of subgroup analyses is a deviation from fundamental scientific truth.¹³ Such findings should be regarded as hypothesis testing only and consi­dered exploratory in nature.

This study’s abstract conclusion that there is a lack of association between a second dose of ACS and neonatal sepsis should not be regarded as justification to use a rescue course of ACS in women with preterm PROM. We recommend that such a practice be avoided outside the context of an ­approved research protocol.
— Kathleen M. Antony, MD, and Alex C. Vidaeff, MD, MPH

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

Gyamfi-Bannerman and Son report their secondary analysis of a randomized controlled trial (RCT) conducted through the Eunice Kennedy Shriver National Institute of Child Health and Human Development’s Maternal-Fetal Medicine Units Network. The aim of the parent RCT was to determine whether antenatal administration of magnesium sulfate decreases the rate of cerebral palsy or death in children delivered preterm. More than 80% of the women enrolled in this RCT had preterm PROM. Of these women, 98% were given antenatal corticosteroids for fetal maturation, and 9% received two courses. This aspect of the RCT provided an opportunity for Gyamfi-Bannerman and Son to study the comparative effects of one course versus two courses of ACS in the setting of preterm PROM.

Background of the study
Concern about the declining efficacy of ACS when the interval between administration and delivery exceeds 7 days prompted several randomized trials exploring the safety and efficacy of multiple ACS courses. Multiple courses were ultimately deemed to be inadvisable because of an association with reduced birth weight and neonatal head circumference.^1,2 However, the unfavorable effects of ACS on anthropometrics was observed when more than three courses were administered, leaving open the possibility of giving only one additional course when needed as a “rescue” dose. Indeed, the use of a single rescue course of ACS in women with intact membranes had a favorable impact on neonatal respiratory function in two RCTs.^3,4

The best available evidence (Level 1) demonstrates that the use of a single course of ACS in preterm PROM does not increase the risk of neonatal or maternal infection even in the setting of prolonged rupture of membranes.⁵ However, pregnant women with preterm PROM were excluded from trials of repetitive ACS dosing because earlier observational studies had suggested that they would experience a substantially increased risk of infectious morbidity when three or more courses of ACS are given.^6–8 What remained debatable on a scientific level was whether a single rescue dose of ACS in women with preterm PROM would be safe and beneficial.

Findings of the analysis
Compared with a single course of ACS, exposure to two courses did not influence the rate of neonatal sepsis or chorioamnionitis. As reassuring as that finding may be, the study found no benefit for the additional course, although it was powered to do so. There was no difference in the rates of respiratory distress syndrome between the study groups.

The findings of Gyamfi-Bannerman and Son replicate those of a subgroup analysis of women in an RCT comparing weekly and single-course ACS.⁹ In that study, weekly courses of ACS in women with preterm PROM did not improve neonatal outcomes beyond what was achieved with single-course therapy. Similar findings have been reported by the Cochrane database.¹⁰

Ruptured versus intact membranes: When is the benefit of ACS greater?
The improvement in neonatal outcomes observed with ACS in pregnancies complicated by preterm PROM is not as pronounced as it is in gestations with intact membranes. In preterm PROM, fetuses reportedly are stressed by the presence of intrauterine inflammation or infection, or both, which accelerates lung maturity by encouraging the secretion of endogenous corticosteroids, resulting in the production of surfactant and eliminating the potential benefit of exogenous ACS.¹¹ This theoretical consideration has not been verified in a systematic analysis of accumulated data,⁵ and the administration of a single course of ACS in preterm PROM now has been shown clearly to improve neonatal outcomes.¹² As Gyamfi-Bannerman and Son demonstrate, the same cannot be said about the administration of a rescue dose of ACS.

Strengths and limitations of the trial
Gyamfi-Bannerman and Son did not address the same interaction as the parent study. The exposure of interest was ACS, an event that occurred in a manner unrelated to the randomization for magnesium sulfate administration. Therefore, the outcome data are no longer randomized in nature, and the study becomes a retrospective cohort analysis.

Gyamfi-Bannerman and Son recognize the limitations of such a study, especially the lack of standardization in the intervention (exact timing of intervention or type of formulation). As with any nonrandomized experiment, the potential for unintended systematic bias is present.

This study, in particular, was subject to “survivor bias,” as reflected in the significantly different intervals between membrane rupture and delivery in the two groups.  

What this evidence means for practice
We must always remain cautious about basing policy or clinical decisions on cohort studies. It has been argued that basing a change in clinical practice on the findings of subgroup analyses is a deviation from fundamental scientific truth.¹³ Such findings should be regarded as hypothesis testing only and consi­dered exploratory in nature.

This study’s abstract conclusion that there is a lack of association between a second dose of ACS and neonatal sepsis should not be regarded as justification to use a rescue course of ACS in women with preterm PROM. We recommend that such a practice be avoided outside the context of an ­approved research protocol.
— Kathleen M. Antony, MD, and Alex C. Vidaeff, MD, MPH

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

Gyamfi-Bannerman and Son report their secondary analysis of a randomized controlled trial (RCT) conducted through the Eunice Kennedy Shriver National Institute of Child Health and Human Development’s Maternal-Fetal Medicine Units Network. The aim of the parent RCT was to determine whether antenatal administration of magnesium sulfate decreases the rate of cerebral palsy or death in children delivered preterm. More than 80% of the women enrolled in this RCT had preterm PROM. Of these women, 98% were given antenatal corticosteroids for fetal maturation, and 9% received two courses. This aspect of the RCT provided an opportunity for Gyamfi-Bannerman and Son to study the comparative effects of one course versus two courses of ACS in the setting of preterm PROM.

Background of the study
Concern about the declining efficacy of ACS when the interval between administration and delivery exceeds 7 days prompted several randomized trials exploring the safety and efficacy of multiple ACS courses. Multiple courses were ultimately deemed to be inadvisable because of an association with reduced birth weight and neonatal head circumference.^1,2 However, the unfavorable effects of ACS on anthropometrics was observed when more than three courses were administered, leaving open the possibility of giving only one additional course when needed as a “rescue” dose. Indeed, the use of a single rescue course of ACS in women with intact membranes had a favorable impact on neonatal respiratory function in two RCTs.^3,4

The best available evidence (Level 1) demonstrates that the use of a single course of ACS in preterm PROM does not increase the risk of neonatal or maternal infection even in the setting of prolonged rupture of membranes.⁵ However, pregnant women with preterm PROM were excluded from trials of repetitive ACS dosing because earlier observational studies had suggested that they would experience a substantially increased risk of infectious morbidity when three or more courses of ACS are given.^6–8 What remained debatable on a scientific level was whether a single rescue dose of ACS in women with preterm PROM would be safe and beneficial.

Findings of the analysis
Compared with a single course of ACS, exposure to two courses did not influence the rate of neonatal sepsis or chorioamnionitis. As reassuring as that finding may be, the study found no benefit for the additional course, although it was powered to do so. There was no difference in the rates of respiratory distress syndrome between the study groups.

The findings of Gyamfi-Bannerman and Son replicate those of a subgroup analysis of women in an RCT comparing weekly and single-course ACS.⁹ In that study, weekly courses of ACS in women with preterm PROM did not improve neonatal outcomes beyond what was achieved with single-course therapy. Similar findings have been reported by the Cochrane database.¹⁰

Ruptured versus intact membranes: When is the benefit of ACS greater?
The improvement in neonatal outcomes observed with ACS in pregnancies complicated by preterm PROM is not as pronounced as it is in gestations with intact membranes. In preterm PROM, fetuses reportedly are stressed by the presence of intrauterine inflammation or infection, or both, which accelerates lung maturity by encouraging the secretion of endogenous corticosteroids, resulting in the production of surfactant and eliminating the potential benefit of exogenous ACS.¹¹ This theoretical consideration has not been verified in a systematic analysis of accumulated data,⁵ and the administration of a single course of ACS in preterm PROM now has been shown clearly to improve neonatal outcomes.¹² As Gyamfi-Bannerman and Son demonstrate, the same cannot be said about the administration of a rescue dose of ACS.

Strengths and limitations of the trial
Gyamfi-Bannerman and Son did not address the same interaction as the parent study. The exposure of interest was ACS, an event that occurred in a manner unrelated to the randomization for magnesium sulfate administration. Therefore, the outcome data are no longer randomized in nature, and the study becomes a retrospective cohort analysis.

Gyamfi-Bannerman and Son recognize the limitations of such a study, especially the lack of standardization in the intervention (exact timing of intervention or type of formulation). As with any nonrandomized experiment, the potential for unintended systematic bias is present.

This study, in particular, was subject to “survivor bias,” as reflected in the significantly different intervals between membrane rupture and delivery in the two groups.  

What this evidence means for practice
We must always remain cautious about basing policy or clinical decisions on cohort studies. It has been argued that basing a change in clinical practice on the findings of subgroup analyses is a deviation from fundamental scientific truth.¹³ Such findings should be regarded as hypothesis testing only and consi­dered exploratory in nature.

This study’s abstract conclusion that there is a lack of association between a second dose of ACS and neonatal sepsis should not be regarded as justification to use a rescue course of ACS in women with preterm PROM. We recommend that such a practice be avoided outside the context of an ­approved research protocol.
— Kathleen M. Antony, MD, and Alex C. Vidaeff, MD, MPH

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

When laparoscopic hysterectomy was pioneered in the late 1980s, uptake among the gynecologic surgical community was slow—despite the fact that the benefits of laparoscopy soon were evident. Compared with abdominal hysterectomy, the laparoscopic approach offered less blood loss, shorter length of hospitalization, less pain, an earlier return to activity, and improved cosmesis.

Contrast this slow start with the rapid introduction of robotic assistance in gynecologic surgery. Soon after the robot was approved for gynecology in 2005, adoption of the new technology surged. In recent years, in fact, use of the robot has grown faster than use of laparoscopy for benign hysterectomy.

At the Pelvic Anatomy and Gynecologic Surgery (PAGS) Symposium in December 2014, Tommaso Falcone, MD, and Javier Magrina, MD, discussed the rapid adoption of the robot, its role in gynecologic surgery, and how it compares with traditional laparoscopy in a key domain—cost. When OBG Management asked these experts to defend their preferred route of hysterectomy, a lively discussion ensued.

Advantages of laparoscopy
OBG Management: What is your preferred approach for hysterectomy, and why do you consider it superior to other options?

Dr. Falcone: I’m a reproductive endocrinologist by training. In my practice at the Cleveland Clinic, I treat only benign disease—no cancer. For hysterectomy, I favor conventional laparoscopy for several reasons. First, it’s time-proven, with a long history of efficacy over the past 20 years. Second, apart from vaginal hysterectomy, it’s the most cost-effective approach to removal of the uterus in patients with benign disease.

Dr. Magrina: I have practiced as a gynecologic oncologist at the Mayo Clinic, Arizona, for the past 27 years, but I also do surgical procedures for benign disease. During my initial training, there were only two ways to perform a hysterectomy—either you made an incision in the abdomen, or you went through the vagina, which is a NOTES (natural orifice transluminal endoscopic surgery) procedure. Of the two, the vaginal approach is the most effective. It also is cheapest and offers the fastest recovery, but it never surpassed the abdominal approach in practice. The reason: The vaginal approach requires you to work through a small opening using specialized instruments, so it’s more difficult for the surgeon and has reduced ­visualization.

Laparoscopic hysterectomy—or, more specifically, laparoscopically assisted vaginal hysterectomy—arrived in 1989. This approach never gained popularity, but even pure laparoscopy, which came along shortly afterward, took a long time for surgeons to adopt. A main problem was that the technology made it counterintuitive for the surgeon. With the abdominal approach, the surgeon can work with his or her hands in the abdomen, with direct visualization and tactile feedback. In laparoscopy, however, the surgeon uses instruments inside of the abdomen with visualization via a camera. As a result, laparoscopy has a much steeperlearning curve, so it never replaced abdominal hysterectomy in the way that we ­expected.

When robotic surgery came along, in contrast, it quickly became an enabling technology for surgeons who could not perform conventional laparoscopy, and it has overtaken laparoscopy for that reason.

Today there are four options for hysterectomy: the abdominal approach, the vaginal approach, the laparoscopic approach, and robotic assistance. I prefer robotics for complicated surgeries—primarily gynecologic cancer and advanced endometriosis. I also prefer robotics when the patient is obese.

In our practice at Mayo Clinic, Arizona, the abdominal open option essentially doesn’t exist for benign disease. If the patient has a simple problem, such as menorrhagia, which can be corrected by removing the uterus, I would choose a vaginal approach. However, if she has pain in addition to menorrhagia—particularly if it is not cyclic pain—I would prefer a laparoscopic ­approach.

How cost comes into play
Dr. Falcone: I think that what has influenced this discussion in recent years is the cost of medicine. Both Dr. Magrina and I trained in an era when we taught ourselves laparoscopy—as no one else was using it—and then began to try to teach others. And Dr. Magrina is correct when he describes the very slow process of absorption of the new technology. Laparoscopic hysterectomy was performed at a low frequency for a long time, and then robotic technology came along—an enabling technology, to be sure—and minimally invasive surgery took off.

Now, however, cost pressures are increasing. Let’s say the robot is the “Lamborghini” of surgical technology, as it is the most expensive of all the approaches. Until a couple of years ago, we could say, “OK, you need a Lamborghini to cross the finish line, fine. We are so wealthy, you can buy that Lamborghini. I prefer the ‘Honda’ (laparoscopy) but as long as we both cross the finish line, there’s no problem.” Now we can no longer afford the Lamborghini.

The aim is not to eliminate the robot entirely. It definitely has a role in minimally invasive surgery. But doctors who need a sophisticated enabling device to perform minimally invasive surgery now may be discouraged from using the robot, owing to its higher cost. In the future, robotics cases are more likely to be performed by surgeons who can do complex procedures at a high volume. That’s already the model at the Mayo Clinic and Cleveland Clinic. More and more, we’re going to say, “You don’t do enough hysterectomies. Although you are performing the ones you do satisfactorily with the robot, you simply aren’t doing enough. So we’re going to move them into the hands of someone who can do them more cost-effectively.”

It’s the cost variable that has changed the game.

Dr. Magrina: I fully agree that we are in an era in which cost-effectiveness is imperative. At our institution, we have four gynecologic surgeons performing robotic, laparoscopic, and vaginal procedures. I happen to be in the low expensive end of the four,  particularly in robotics, largely because I limit the number of robotic instruments—two or three, one assistant, and no manipulator. I utilize a reusable probe, and I look for ways to minimize costs. For example, instead of using an additional needle holder to suture the vaginal cuff, I use one of the robotic graspers already used in the hysterectomy part.

When surgeons begin performing robotic hysterectomy, they try multiple instruments, making the approach very expensive. As surgeons gain experience and begin to watch their costs, however, the expense comes down somewhat.

Why the robot should be reserved for high-volume surgeons
Dr. Magrina: In my opinion, if you have a basic “bread and butter” practice, I don’t think you need to have a robot. The robot should be reserved for advanced surgery. And because of fixed costs with the robot, such as maintenance, you need to perform a sufficient number of cases per year to cover those expenses. At my institution, the minimum number of robotic cases per year is about 200. Our cost for robotic surgery is 8% higher than it is for laparoscopy. If we perform fewer than 200 robotic surgeries, the difference is even greater.

Dr. Falcone: I agree with everything you’ve said, Dr. Magrina. But if you consider that about 120,000 of the 500,000 hysterectomies performed each year are done for abnormal uterine bleeding in women who have a normal uterus and no other complexity, there’s no need for the robot for these cases. A lot of places—certainly not the Cleveland Clinic or the Mayo Clinic, but other places—use the robot to remove that little uterus. That’s when conventional laparoscopy should be the preferred route.

When it comes to endometriosis, which accounts for another 20% of cases, the robot might break even because it’s the length of surgery that is important. Still, although the robot might allow most community surgeons to perform routine endometriosis cases, complex cases are another matter. The robot is an enabling device for simple cases for the average gynecologist but not for complex cases. For those cases, it requires a different skill set—sophisticated skills of retroperitoneal anatomy, which the robot doesn’t teach you. It requires experience working in a different space, which the robot doesn’t give you.

Dr. Magrina: That’s an important point. If a surgeon came to me and said, “Look, at my institution, if I don’t perform 35 robotic cases a year, they’ll take my privileges away,” that would indicate to me that the surgeon is performing some cases robotically that might be better done laparoscopically or vaginally. But he is doing them robotically just to maintain his privileges.

I would suggest to him that if his caseload is not that high, maybe he shouldn’t be doing any robotic cases. Another option is for him to propose to his institution that he perform the 20 well-indicated cases on the robot and the other 15 laparoscopically. Then, to maintain his robotic skills and privileges, he could log in the equivalent of 15 or more robotic cases by simulation.
 

Gynecologic surgeons have strong preferences when it comes to the route of hysterectomy for benign disease—at least among OBG Management’s Virtual Board of Editors (VBE). When they were asked to weigh in on laparoscopic hysterectomy versus robotic assistance, VBE members tended to come down firmly on one side or another, with very little “fence-sitting.”

For example, Soheil Hanjani, MD, reported that he performs approximately 95% of benign hysterectomy cases using a minimally invasive approach, preferably robotic assistance.

“In the right hands, robotics is superior,” he said, adding that it gives him “better dissection control.”

Heather Hilkowitz, MD, agreed.

“I feel like the imaging is better with robotics, such that I can really see tissue and planes better than with 2D straight-stick laparoscopy. I also appreciate the wristed instrumentation of the robot, which allows me to do more difficult cases laparoscopically that I would have had to open in the past.”

Weighing in on the other side of the equation is Noor Ahmed-Ebbiary, MB, who practices in the United Kingdom. Dr. Ahmed-Ebbiary cites expense as a major disadvantage of the robot.

“If the surgeon is experienced in both vaginal and laparoscopic surgery, he or she should be able to manage the vast majority of hysterectomies without a robot. European countries are not as rich, and most of them cannot offer or justify the price of a robot,” he added.

Raksha Joshi, MD, uses a minimally invasive approach for about 50% of the benign hysterectomies she performs, favoring the vaginal route.

“Robotic surgery for hysterectomy for benign disease is ‘overkill,’” she says. “It’s expensive, takes much longer than laparoscopic surgery or a laparoscopically assisted vaginal approach, and does not give any outcomes advantage for the patient.”

Michael Kirwin, MD, prefers total laparoscopic hysterectomy, depending on the patient’s surgical history and anticipated abdominal conditions, because it allows him to “port-hop,” offers more options for energy instrumentation, is more economical than the robot, and yields smaller incisions.

John T. Armstrong Jr., MD, MS, prefers neither total laparoscopic hysterectomy nor robotic assistance. He opts instead for a straight vaginal approach or open hysterectomy through a minilaparotomy incision.

A look to the future
OBG Management: Now that cost pressures are beginning to discourage use of the robot for straightforward, low-complexity hysterectomy cases, do you anticipate that surgeons who lack laparoscopic skills will refer patients to minimally invasive surgical experts? Or are they likely to utilize abdominal hysterectomy more than in the past? In other words, what changes do you foresee as cost pressures increase?

Dr. Falcone: I think cost pressures will ensure that surgeons will think about their approach to a surgical procedure more critically. It will add the cost of the procedure to the conversation between doctor and patient of what is best for her.

Dr. Magrina: Cost pressures will force hospitals and gynecologists to change our present modus operandi. In general, high-volume surgeons have shorter operating times, fewer complications, and lower costs—a true fact among many different surgical specialties. Hospitals will start looking at the cost of specific procedures and compare costs among surgeons. Expensive surgeons may be asked to explore ways to reduce costs, and, if they don’t, may be denied privileges for specific procedures.

I envision ObGyn groups—so-called generalists—to be composed of physicians dedicated to obstetrics and gynecologists dedicated to office practice or surgery. The days when an ObGyn surgical practice offered care that encompassed both the delivery of babies and oncologic procedures, including urogynecologic, infertility, and complex operations, should be over.  Our specialty is in need of a higher degree of focused practice.

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

Learn directly from experts Tommaso Falcone, MD, Javier Magrina, MD, and Mark Walters, MD
2015 PELVIC ANATOMY AND GYNECOLOGIC SURGERY (PAGS) SYMPOSIUM
Thursday, December 10 – Saturday December 12, 2015
At Paris in Las Vegas
Preconference hands-on workshops on laparoscopic suturing, hysteroscopy, and ultrasound on Wednesday, December 9.
Visit: www.PAGS-CME.org

When laparoscopic hysterectomy was pioneered in the late 1980s, uptake among the gynecologic surgical community was slow—despite the fact that the benefits of laparoscopy soon were evident. Compared with abdominal hysterectomy, the laparoscopic approach offered less blood loss, shorter length of hospitalization, less pain, an earlier return to activity, and improved cosmesis.

Contrast this slow start with the rapid introduction of robotic assistance in gynecologic surgery. Soon after the robot was approved for gynecology in 2005, adoption of the new technology surged. In recent years, in fact, use of the robot has grown faster than use of laparoscopy for benign hysterectomy.

At the Pelvic Anatomy and Gynecologic Surgery (PAGS) Symposium in December 2014, Tommaso Falcone, MD, and Javier Magrina, MD, discussed the rapid adoption of the robot, its role in gynecologic surgery, and how it compares with traditional laparoscopy in a key domain—cost. When OBG Management asked these experts to defend their preferred route of hysterectomy, a lively discussion ensued.

Advantages of laparoscopy
OBG Management: What is your preferred approach for hysterectomy, and why do you consider it superior to other options?

Dr. Falcone: I’m a reproductive endocrinologist by training. In my practice at the Cleveland Clinic, I treat only benign disease—no cancer. For hysterectomy, I favor conventional laparoscopy for several reasons. First, it’s time-proven, with a long history of efficacy over the past 20 years. Second, apart from vaginal hysterectomy, it’s the most cost-effective approach to removal of the uterus in patients with benign disease.

Dr. Magrina: I have practiced as a gynecologic oncologist at the Mayo Clinic, Arizona, for the past 27 years, but I also do surgical procedures for benign disease. During my initial training, there were only two ways to perform a hysterectomy—either you made an incision in the abdomen, or you went through the vagina, which is a NOTES (natural orifice transluminal endoscopic surgery) procedure. Of the two, the vaginal approach is the most effective. It also is cheapest and offers the fastest recovery, but it never surpassed the abdominal approach in practice. The reason: The vaginal approach requires you to work through a small opening using specialized instruments, so it’s more difficult for the surgeon and has reduced ­visualization.

Laparoscopic hysterectomy—or, more specifically, laparoscopically assisted vaginal hysterectomy—arrived in 1989. This approach never gained popularity, but even pure laparoscopy, which came along shortly afterward, took a long time for surgeons to adopt. A main problem was that the technology made it counterintuitive for the surgeon. With the abdominal approach, the surgeon can work with his or her hands in the abdomen, with direct visualization and tactile feedback. In laparoscopy, however, the surgeon uses instruments inside of the abdomen with visualization via a camera. As a result, laparoscopy has a much steeperlearning curve, so it never replaced abdominal hysterectomy in the way that we ­expected.

When robotic surgery came along, in contrast, it quickly became an enabling technology for surgeons who could not perform conventional laparoscopy, and it has overtaken laparoscopy for that reason.

Today there are four options for hysterectomy: the abdominal approach, the vaginal approach, the laparoscopic approach, and robotic assistance. I prefer robotics for complicated surgeries—primarily gynecologic cancer and advanced endometriosis. I also prefer robotics when the patient is obese.

In our practice at Mayo Clinic, Arizona, the abdominal open option essentially doesn’t exist for benign disease. If the patient has a simple problem, such as menorrhagia, which can be corrected by removing the uterus, I would choose a vaginal approach. However, if she has pain in addition to menorrhagia—particularly if it is not cyclic pain—I would prefer a laparoscopic ­approach.

How cost comes into play
Dr. Falcone: I think that what has influenced this discussion in recent years is the cost of medicine. Both Dr. Magrina and I trained in an era when we taught ourselves laparoscopy—as no one else was using it—and then began to try to teach others. And Dr. Magrina is correct when he describes the very slow process of absorption of the new technology. Laparoscopic hysterectomy was performed at a low frequency for a long time, and then robotic technology came along—an enabling technology, to be sure—and minimally invasive surgery took off.

Now, however, cost pressures are increasing. Let’s say the robot is the “Lamborghini” of surgical technology, as it is the most expensive of all the approaches. Until a couple of years ago, we could say, “OK, you need a Lamborghini to cross the finish line, fine. We are so wealthy, you can buy that Lamborghini. I prefer the ‘Honda’ (laparoscopy) but as long as we both cross the finish line, there’s no problem.” Now we can no longer afford the Lamborghini.

The aim is not to eliminate the robot entirely. It definitely has a role in minimally invasive surgery. But doctors who need a sophisticated enabling device to perform minimally invasive surgery now may be discouraged from using the robot, owing to its higher cost. In the future, robotics cases are more likely to be performed by surgeons who can do complex procedures at a high volume. That’s already the model at the Mayo Clinic and Cleveland Clinic. More and more, we’re going to say, “You don’t do enough hysterectomies. Although you are performing the ones you do satisfactorily with the robot, you simply aren’t doing enough. So we’re going to move them into the hands of someone who can do them more cost-effectively.”

It’s the cost variable that has changed the game.

Dr. Magrina: I fully agree that we are in an era in which cost-effectiveness is imperative. At our institution, we have four gynecologic surgeons performing robotic, laparoscopic, and vaginal procedures. I happen to be in the low expensive end of the four,  particularly in robotics, largely because I limit the number of robotic instruments—two or three, one assistant, and no manipulator. I utilize a reusable probe, and I look for ways to minimize costs. For example, instead of using an additional needle holder to suture the vaginal cuff, I use one of the robotic graspers already used in the hysterectomy part.

When surgeons begin performing robotic hysterectomy, they try multiple instruments, making the approach very expensive. As surgeons gain experience and begin to watch their costs, however, the expense comes down somewhat.

Why the robot should be reserved for high-volume surgeons
Dr. Magrina: In my opinion, if you have a basic “bread and butter” practice, I don’t think you need to have a robot. The robot should be reserved for advanced surgery. And because of fixed costs with the robot, such as maintenance, you need to perform a sufficient number of cases per year to cover those expenses. At my institution, the minimum number of robotic cases per year is about 200. Our cost for robotic surgery is 8% higher than it is for laparoscopy. If we perform fewer than 200 robotic surgeries, the difference is even greater.

Dr. Falcone: I agree with everything you’ve said, Dr. Magrina. But if you consider that about 120,000 of the 500,000 hysterectomies performed each year are done for abnormal uterine bleeding in women who have a normal uterus and no other complexity, there’s no need for the robot for these cases. A lot of places—certainly not the Cleveland Clinic or the Mayo Clinic, but other places—use the robot to remove that little uterus. That’s when conventional laparoscopy should be the preferred route.

When it comes to endometriosis, which accounts for another 20% of cases, the robot might break even because it’s the length of surgery that is important. Still, although the robot might allow most community surgeons to perform routine endometriosis cases, complex cases are another matter. The robot is an enabling device for simple cases for the average gynecologist but not for complex cases. For those cases, it requires a different skill set—sophisticated skills of retroperitoneal anatomy, which the robot doesn’t teach you. It requires experience working in a different space, which the robot doesn’t give you.

Dr. Magrina: That’s an important point. If a surgeon came to me and said, “Look, at my institution, if I don’t perform 35 robotic cases a year, they’ll take my privileges away,” that would indicate to me that the surgeon is performing some cases robotically that might be better done laparoscopically or vaginally. But he is doing them robotically just to maintain his privileges.

I would suggest to him that if his caseload is not that high, maybe he shouldn’t be doing any robotic cases. Another option is for him to propose to his institution that he perform the 20 well-indicated cases on the robot and the other 15 laparoscopically. Then, to maintain his robotic skills and privileges, he could log in the equivalent of 15 or more robotic cases by simulation.
 

Gynecologic surgeons have strong preferences when it comes to the route of hysterectomy for benign disease—at least among OBG Management’s Virtual Board of Editors (VBE). When they were asked to weigh in on laparoscopic hysterectomy versus robotic assistance, VBE members tended to come down firmly on one side or another, with very little “fence-sitting.”

For example, Soheil Hanjani, MD, reported that he performs approximately 95% of benign hysterectomy cases using a minimally invasive approach, preferably robotic assistance.

“In the right hands, robotics is superior,” he said, adding that it gives him “better dissection control.”

Heather Hilkowitz, MD, agreed.

“I feel like the imaging is better with robotics, such that I can really see tissue and planes better than with 2D straight-stick laparoscopy. I also appreciate the wristed instrumentation of the robot, which allows me to do more difficult cases laparoscopically that I would have had to open in the past.”

Weighing in on the other side of the equation is Noor Ahmed-Ebbiary, MB, who practices in the United Kingdom. Dr. Ahmed-Ebbiary cites expense as a major disadvantage of the robot.

“If the surgeon is experienced in both vaginal and laparoscopic surgery, he or she should be able to manage the vast majority of hysterectomies without a robot. European countries are not as rich, and most of them cannot offer or justify the price of a robot,” he added.

Raksha Joshi, MD, uses a minimally invasive approach for about 50% of the benign hysterectomies she performs, favoring the vaginal route.

“Robotic surgery for hysterectomy for benign disease is ‘overkill,’” she says. “It’s expensive, takes much longer than laparoscopic surgery or a laparoscopically assisted vaginal approach, and does not give any outcomes advantage for the patient.”

Michael Kirwin, MD, prefers total laparoscopic hysterectomy, depending on the patient’s surgical history and anticipated abdominal conditions, because it allows him to “port-hop,” offers more options for energy instrumentation, is more economical than the robot, and yields smaller incisions.

John T. Armstrong Jr., MD, MS, prefers neither total laparoscopic hysterectomy nor robotic assistance. He opts instead for a straight vaginal approach or open hysterectomy through a minilaparotomy incision.

A look to the future
OBG Management: Now that cost pressures are beginning to discourage use of the robot for straightforward, low-complexity hysterectomy cases, do you anticipate that surgeons who lack laparoscopic skills will refer patients to minimally invasive surgical experts? Or are they likely to utilize abdominal hysterectomy more than in the past? In other words, what changes do you foresee as cost pressures increase?

Dr. Falcone: I think cost pressures will ensure that surgeons will think about their approach to a surgical procedure more critically. It will add the cost of the procedure to the conversation between doctor and patient of what is best for her.

Dr. Magrina: Cost pressures will force hospitals and gynecologists to change our present modus operandi. In general, high-volume surgeons have shorter operating times, fewer complications, and lower costs—a true fact among many different surgical specialties. Hospitals will start looking at the cost of specific procedures and compare costs among surgeons. Expensive surgeons may be asked to explore ways to reduce costs, and, if they don’t, may be denied privileges for specific procedures.

I envision ObGyn groups—so-called generalists—to be composed of physicians dedicated to obstetrics and gynecologists dedicated to office practice or surgery. The days when an ObGyn surgical practice offered care that encompassed both the delivery of babies and oncologic procedures, including urogynecologic, infertility, and complex operations, should be over.  Our specialty is in need of a higher degree of focused practice.

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

Learn directly from experts Tommaso Falcone, MD, Javier Magrina, MD, and Mark Walters, MD
2015 PELVIC ANATOMY AND GYNECOLOGIC SURGERY (PAGS) SYMPOSIUM
Thursday, December 10 – Saturday December 12, 2015
At Paris in Las Vegas
Preconference hands-on workshops on laparoscopic suturing, hysteroscopy, and ultrasound on Wednesday, December 9.
Visit: www.PAGS-CME.org

When laparoscopic hysterectomy was pioneered in the late 1980s, uptake among the gynecologic surgical community was slow—despite the fact that the benefits of laparoscopy soon were evident. Compared with abdominal hysterectomy, the laparoscopic approach offered less blood loss, shorter length of hospitalization, less pain, an earlier return to activity, and improved cosmesis.

Contrast this slow start with the rapid introduction of robotic assistance in gynecologic surgery. Soon after the robot was approved for gynecology in 2005, adoption of the new technology surged. In recent years, in fact, use of the robot has grown faster than use of laparoscopy for benign hysterectomy.

At the Pelvic Anatomy and Gynecologic Surgery (PAGS) Symposium in December 2014, Tommaso Falcone, MD, and Javier Magrina, MD, discussed the rapid adoption of the robot, its role in gynecologic surgery, and how it compares with traditional laparoscopy in a key domain—cost. When OBG Management asked these experts to defend their preferred route of hysterectomy, a lively discussion ensued.

Advantages of laparoscopy
OBG Management: What is your preferred approach for hysterectomy, and why do you consider it superior to other options?

Dr. Falcone: I’m a reproductive endocrinologist by training. In my practice at the Cleveland Clinic, I treat only benign disease—no cancer. For hysterectomy, I favor conventional laparoscopy for several reasons. First, it’s time-proven, with a long history of efficacy over the past 20 years. Second, apart from vaginal hysterectomy, it’s the most cost-effective approach to removal of the uterus in patients with benign disease.

Dr. Magrina: I have practiced as a gynecologic oncologist at the Mayo Clinic, Arizona, for the past 27 years, but I also do surgical procedures for benign disease. During my initial training, there were only two ways to perform a hysterectomy—either you made an incision in the abdomen, or you went through the vagina, which is a NOTES (natural orifice transluminal endoscopic surgery) procedure. Of the two, the vaginal approach is the most effective. It also is cheapest and offers the fastest recovery, but it never surpassed the abdominal approach in practice. The reason: The vaginal approach requires you to work through a small opening using specialized instruments, so it’s more difficult for the surgeon and has reduced ­visualization.

Laparoscopic hysterectomy—or, more specifically, laparoscopically assisted vaginal hysterectomy—arrived in 1989. This approach never gained popularity, but even pure laparoscopy, which came along shortly afterward, took a long time for surgeons to adopt. A main problem was that the technology made it counterintuitive for the surgeon. With the abdominal approach, the surgeon can work with his or her hands in the abdomen, with direct visualization and tactile feedback. In laparoscopy, however, the surgeon uses instruments inside of the abdomen with visualization via a camera. As a result, laparoscopy has a much steeperlearning curve, so it never replaced abdominal hysterectomy in the way that we ­expected.

When robotic surgery came along, in contrast, it quickly became an enabling technology for surgeons who could not perform conventional laparoscopy, and it has overtaken laparoscopy for that reason.

Today there are four options for hysterectomy: the abdominal approach, the vaginal approach, the laparoscopic approach, and robotic assistance. I prefer robotics for complicated surgeries—primarily gynecologic cancer and advanced endometriosis. I also prefer robotics when the patient is obese.

In our practice at Mayo Clinic, Arizona, the abdominal open option essentially doesn’t exist for benign disease. If the patient has a simple problem, such as menorrhagia, which can be corrected by removing the uterus, I would choose a vaginal approach. However, if she has pain in addition to menorrhagia—particularly if it is not cyclic pain—I would prefer a laparoscopic ­approach.

How cost comes into play
Dr. Falcone: I think that what has influenced this discussion in recent years is the cost of medicine. Both Dr. Magrina and I trained in an era when we taught ourselves laparoscopy—as no one else was using it—and then began to try to teach others. And Dr. Magrina is correct when he describes the very slow process of absorption of the new technology. Laparoscopic hysterectomy was performed at a low frequency for a long time, and then robotic technology came along—an enabling technology, to be sure—and minimally invasive surgery took off.

Now, however, cost pressures are increasing. Let’s say the robot is the “Lamborghini” of surgical technology, as it is the most expensive of all the approaches. Until a couple of years ago, we could say, “OK, you need a Lamborghini to cross the finish line, fine. We are so wealthy, you can buy that Lamborghini. I prefer the ‘Honda’ (laparoscopy) but as long as we both cross the finish line, there’s no problem.” Now we can no longer afford the Lamborghini.

The aim is not to eliminate the robot entirely. It definitely has a role in minimally invasive surgery. But doctors who need a sophisticated enabling device to perform minimally invasive surgery now may be discouraged from using the robot, owing to its higher cost. In the future, robotics cases are more likely to be performed by surgeons who can do complex procedures at a high volume. That’s already the model at the Mayo Clinic and Cleveland Clinic. More and more, we’re going to say, “You don’t do enough hysterectomies. Although you are performing the ones you do satisfactorily with the robot, you simply aren’t doing enough. So we’re going to move them into the hands of someone who can do them more cost-effectively.”

It’s the cost variable that has changed the game.

Dr. Magrina: I fully agree that we are in an era in which cost-effectiveness is imperative. At our institution, we have four gynecologic surgeons performing robotic, laparoscopic, and vaginal procedures. I happen to be in the low expensive end of the four,  particularly in robotics, largely because I limit the number of robotic instruments—two or three, one assistant, and no manipulator. I utilize a reusable probe, and I look for ways to minimize costs. For example, instead of using an additional needle holder to suture the vaginal cuff, I use one of the robotic graspers already used in the hysterectomy part.

When surgeons begin performing robotic hysterectomy, they try multiple instruments, making the approach very expensive. As surgeons gain experience and begin to watch their costs, however, the expense comes down somewhat.

Why the robot should be reserved for high-volume surgeons
Dr. Magrina: In my opinion, if you have a basic “bread and butter” practice, I don’t think you need to have a robot. The robot should be reserved for advanced surgery. And because of fixed costs with the robot, such as maintenance, you need to perform a sufficient number of cases per year to cover those expenses. At my institution, the minimum number of robotic cases per year is about 200. Our cost for robotic surgery is 8% higher than it is for laparoscopy. If we perform fewer than 200 robotic surgeries, the difference is even greater.

Dr. Falcone: I agree with everything you’ve said, Dr. Magrina. But if you consider that about 120,000 of the 500,000 hysterectomies performed each year are done for abnormal uterine bleeding in women who have a normal uterus and no other complexity, there’s no need for the robot for these cases. A lot of places—certainly not the Cleveland Clinic or the Mayo Clinic, but other places—use the robot to remove that little uterus. That’s when conventional laparoscopy should be the preferred route.

When it comes to endometriosis, which accounts for another 20% of cases, the robot might break even because it’s the length of surgery that is important. Still, although the robot might allow most community surgeons to perform routine endometriosis cases, complex cases are another matter. The robot is an enabling device for simple cases for the average gynecologist but not for complex cases. For those cases, it requires a different skill set—sophisticated skills of retroperitoneal anatomy, which the robot doesn’t teach you. It requires experience working in a different space, which the robot doesn’t give you.

Dr. Magrina: That’s an important point. If a surgeon came to me and said, “Look, at my institution, if I don’t perform 35 robotic cases a year, they’ll take my privileges away,” that would indicate to me that the surgeon is performing some cases robotically that might be better done laparoscopically or vaginally. But he is doing them robotically just to maintain his privileges.

I would suggest to him that if his caseload is not that high, maybe he shouldn’t be doing any robotic cases. Another option is for him to propose to his institution that he perform the 20 well-indicated cases on the robot and the other 15 laparoscopically. Then, to maintain his robotic skills and privileges, he could log in the equivalent of 15 or more robotic cases by simulation.
 

Gynecologic surgeons have strong preferences when it comes to the route of hysterectomy for benign disease—at least among OBG Management’s Virtual Board of Editors (VBE). When they were asked to weigh in on laparoscopic hysterectomy versus robotic assistance, VBE members tended to come down firmly on one side or another, with very little “fence-sitting.”

For example, Soheil Hanjani, MD, reported that he performs approximately 95% of benign hysterectomy cases using a minimally invasive approach, preferably robotic assistance.

“In the right hands, robotics is superior,” he said, adding that it gives him “better dissection control.”

Heather Hilkowitz, MD, agreed.

“I feel like the imaging is better with robotics, such that I can really see tissue and planes better than with 2D straight-stick laparoscopy. I also appreciate the wristed instrumentation of the robot, which allows me to do more difficult cases laparoscopically that I would have had to open in the past.”

Weighing in on the other side of the equation is Noor Ahmed-Ebbiary, MB, who practices in the United Kingdom. Dr. Ahmed-Ebbiary cites expense as a major disadvantage of the robot.

“If the surgeon is experienced in both vaginal and laparoscopic surgery, he or she should be able to manage the vast majority of hysterectomies without a robot. European countries are not as rich, and most of them cannot offer or justify the price of a robot,” he added.

Raksha Joshi, MD, uses a minimally invasive approach for about 50% of the benign hysterectomies she performs, favoring the vaginal route.

“Robotic surgery for hysterectomy for benign disease is ‘overkill,’” she says. “It’s expensive, takes much longer than laparoscopic surgery or a laparoscopically assisted vaginal approach, and does not give any outcomes advantage for the patient.”

Michael Kirwin, MD, prefers total laparoscopic hysterectomy, depending on the patient’s surgical history and anticipated abdominal conditions, because it allows him to “port-hop,” offers more options for energy instrumentation, is more economical than the robot, and yields smaller incisions.

John T. Armstrong Jr., MD, MS, prefers neither total laparoscopic hysterectomy nor robotic assistance. He opts instead for a straight vaginal approach or open hysterectomy through a minilaparotomy incision.

A look to the future
OBG Management: Now that cost pressures are beginning to discourage use of the robot for straightforward, low-complexity hysterectomy cases, do you anticipate that surgeons who lack laparoscopic skills will refer patients to minimally invasive surgical experts? Or are they likely to utilize abdominal hysterectomy more than in the past? In other words, what changes do you foresee as cost pressures increase?

Dr. Falcone: I think cost pressures will ensure that surgeons will think about their approach to a surgical procedure more critically. It will add the cost of the procedure to the conversation between doctor and patient of what is best for her.

Dr. Magrina: Cost pressures will force hospitals and gynecologists to change our present modus operandi. In general, high-volume surgeons have shorter operating times, fewer complications, and lower costs—a true fact among many different surgical specialties. Hospitals will start looking at the cost of specific procedures and compare costs among surgeons. Expensive surgeons may be asked to explore ways to reduce costs, and, if they don’t, may be denied privileges for specific procedures.

I envision ObGyn groups—so-called generalists—to be composed of physicians dedicated to obstetrics and gynecologists dedicated to office practice or surgery. The days when an ObGyn surgical practice offered care that encompassed both the delivery of babies and oncologic procedures, including urogynecologic, infertility, and complex operations, should be over.  Our specialty is in need of a higher degree of focused practice.

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

Learn directly from experts Tommaso Falcone, MD, Javier Magrina, MD, and Mark Walters, MD
2015 PELVIC ANATOMY AND GYNECOLOGIC SURGERY (PAGS) SYMPOSIUM
Thursday, December 10 – Saturday December 12, 2015
At Paris in Las Vegas
Preconference hands-on workshops on laparoscopic suturing, hysteroscopy, and ultrasound on Wednesday, December 9.
Visit: www.PAGS-CME.org

CASE: Pregnant patient seeks medication for her NVP

A 23-year-old G1P0 woman at 9 weeks’ gestation presents to your office with nausea and vomiting that is interfering with work. She has tried many changes in her daily habits. She has tried eating small, frequent meals; snacking on nuts and crackers; using lemon-scented products; and avoiding coffee and strong odors. Following an evaluation you diagnose nausea and vomiting of pregnancy (NVP). She asks, “Is there a medication for my nausea that is safe for my baby?”

Nausea with or without vomiting is a common problem for pregnant women between 6 and 14 weeks of gestation. In one study, nausea with or without vomiting was reported by 69% of patients and resulted in pharmacologic treatment in 15%.¹ In a Cochrane review of NVP, investigators analyzed 37 trials involving treatments such as acupressure, acustimulation, acupuncture, ginger, chamomile, lemon oil, vitamin B₆, and antiemetic medications. The authors concluded, “There is a lack of high-quality evidence to support any particular intervention.”² Clinicians are challenged to effectively treat the symptoms of NVP and simultaneously to minimize the risk that the fetus will be exposed to a teratogen during the first trimester, a vulnerable period in organ development.

In this editorial, I briefly review nonpharmacologic options for NVP, but focus on current pharmacologic treatments. Of those available to ObGyns, what is the best first-choice treatment given recent and accumulated data regarding associated congenital anomalies?

Nonpharmacologic treatment
Although the authors of the Cochrane review did not identify high-quality evidence to support nonpharmacologic interventions, results of multiple randomized trials have demonstrated that ginger is effective in reducing pregnancy-associated nausea and vomiting.³ Ginger treatment is recommended at doses of 250 mg in capsules or syrup four times daily.

First-line pharmacologic treatment: Doxylamine plus pyridoxine
The US Food and Drug Administration (FDA) has approved the combination of doxylamine plus pyridoxine (vitamin B₆) in a delayed-release formulation for treatment of NVP (­Diclegis). Doxy­lamine is an antihistamine that blocks H₁-receptor sites in the chemoreceptor trigger zone. It also diminishes vestibular stimulation and depresses labyrinthine activity through central anticholinergic activity. Its elimination half-life is 10 to 12 hours (Lexicomp). Each tablet contains doxylamine 10 mg and pyridoxine 10 mg. The starting dose is 2 tablets at bedtime.

If the woman has persistent symptoms, a third tablet is added, to be taken in the morning. If symptoms continue, a fourth tablet is recommended to be taken in the afternoon. In a large, randomized clinical trial, doxylamine-pyridoxine treatment reduced nausea, vomiting, and retching and improved perceived quality of life compared with placebo.⁴ The FDA assigned doxylamine-pyridoxine pregnancy category A because of the extensive evidence that it does not cause an increase in fetal malformations.^5,6

If the delayed-release doxylamine-pyridoxine formulation (Diclegis) is not available to the patient, alternative formulations of doxylamine and pyridoxine can be prescribed. Pyridoxine is widely available over the counter as 25-mg tablets, and one tablet can be prescribed two or three times daily. Doxylamine is available as a chewable prescription medicine in 5-mg tablets (Aldex AN) and two tablets can be prescribed two or three times daily. Doxylamine is also available as a 25-mg over-the-counter tablet in Unisom SleepTabs. One-half tablet can be prescribed two or three times daily. The patient should be alerted that Unisom SleepGels contain diphenhydramine, not doxylamine.

Second-line pharmacologic treatment
Metoclopramide Metoclopramide is a dopamine antagonist. It enhances upper gastrointestinal motility, accelerates gastric emptying, and increases lower esophageal sphincter tone. At higher doses it blocks serotonin receptors in the chemoreceptor trigger zone. Its elimination half-life is 5 to 6 hours (Lexicomp). There are no large, randomized, placebo-controlled trials of oral metoclopramide for the treatment of nausea and vomiting of early pregnancy.

I am recommending metoclopramide as a second-line treatment for NVP because it appears to be effective and is not known to be associated with an increased risk of congenital malformations. Metoclopramide is widely used to prevent and treat intraoperative and postoperative nausea associated with cesarean delivery.⁷ In addition, intravenous (IV) metoclopramide is commonly used to treat women hospitalized with hyperemesis gravidarum. Results of randomized clinical trials demonstrate that when used to treat hyperemesis gravidarum, IV metoclopramide (10 mg every 8 hours) has similar efficacy to IV ondansetron (4 mg every 8 hours)⁸ and IV promethazine (25 mg every 8 hours).⁹ When using metoclopramide as an oral treatment for NVP, 10 mg every 8 hours is a commonly recommended regimen.

The FDA has assigned metoclopramide to pregnancy category B, which indicates that there is no evidence of fetal risk. Studies from Israel and Denmark show that metoclopramide is not associated with an increased risk of congenital malformations. In the study from Israel, among 3,458 infants born to women who had filled a prescription for metoclopramide during the first trimester of pregnancy, there was no increase in major congenital malformations, low birth weight, preterm delivery, or perinatal death.¹⁰ In the study from Denmark, among 28,486 infants born to mothers who had filled a prescription for metoclopramide in the first trimester there was no increase in congenital malformations or any of 20 individual categories of malformations, including neural tube defects, transposition of the great vessels, ventricular septal defect, atrial septal defect, tetralogy of Fallot, coarctation of the aorta, cleft lip or palate, anorectal atresia/stenosis, or limb reduction.¹¹ The results of these two large studies are reassuring that metoclopramide is not associated with an increased risk of congenital malformations.

Metoclopramide can cause tardive dyskinesia, a serious movement disorder that may be irreversible with discontinuation of the drug. This risk increases with dose and length of treatment. The FDA recommends that clinicians avoid the use of metoclopramide for more than 12 weeks.

Third-line pharmacologic treatment: Ondansetron
In the United States ondansetron is commonly used to treat NVP.¹² The drug is a selective 5-HT₃ antagonist that blocks serotonin action in the central nervous system chemoreceptor trigger zone. The elimination half-life of ondansetron is 3 to 6 hours (Lexicomp).

The frequent use of ondansetron may be due, in part, to the perception that it is a very effective antiemetic. For example, in one small clinical trial, ondansetron 4 mg every 8 hours was reported to be superior to a combination of pyridoxine 25 mg every 8 hours plus doxylamine 12.5 mg every 8 hours.¹³ (Note that the pyridoxine and doxylamine tablets used in this trial were not in a combination delayed-release formulation.) I am recommending ondansetron as a third-line treatment for NVP because, although it is effective, it may be associated with an increased risk of fetal cardiac anomalies.

Is ondansetron associated with cardiac malformations?
The FDA has assigned ondansetron to pregnancy category B; however, there is concern that it may be associated with congenital heart defects. In a recent study of 1,349 infants born to Swedish women who had filled a prescription for ondansetron in early pregnancy, a significantly increased risk of cardiovascular defect (odds ratio [OR], 1.62; 95% confidence interval [CI], 1.04−2.14) and cardiac septum defect (OR, 2.05; 95% CI, 1.19−3.28) was reported.¹⁴ The cardiac anomalies were mostly atrial septal or ventricular septal defects.

In a second study, reported as an abstract, authors analyzed congenital malformations in 1,248 infants born to Danish women who filled a prescription for ondansetron in early pregnancy. These authors also found an increased risk of a congenital heart malformation (OR, 2.0; 95% CI, 1.3−3.1).¹⁵

A US case-control study showed an association between ondansetron use and cleft palate.¹ The Swedish¹⁴ and Danish¹⁵ studies reported above did not find an association between ondansetron use and cleft palate.

The FDA issued a warning in June 2012 that at a dose of 32 mg, administered intravenously, ondansetron may prolong the QT interval and result in a potentially fatal heart arrhythmia, torsades de pointes.¹⁶ In the announcement the FDA did not alter the recommendations for oral dosing because there is no strong evidence that oral dosing is associated with clinically significant arrhythmias. Authors of a recent systematic review concluded that IV administration of large doses of ondansetron may cause cardiac arrhythmias, especially in patients with cardiac disease and those taking other drugs that prolong the QT interval, but that a single oral dose of ondansetron does not have a significant risk of causing an arrhythmia.¹⁷

Health Canada¹⁸ has advised that many commonly prescribed medications increase serotonin activity. When multiple drugs that each increase serotonin activity are prescribed in combination, the risk of serotonin syndrome is increased. Serotonin syndrome results in hyperthermia, agitation, tachycardia, and muscle twitching and can be fatal. Ondansetron was specifically mentioned in the Health Canada warning, but a search of the literature revealed very few reported cases of ondansetron being implicated in the serotonin syndrome.¹⁹

My bottom-line recommendations
NVP is a common obstetric problem. When oral pharmacologic therapy is indicated, first-line treatment should be with the FDA-approved combination of doxylamine-pyridoxine because it is both effective and associated with no known increased risk of congenital malformations. An effective second-line agent is metoclopramide. Based on very limited data, metoclopramide appears effective and is not associated with an increased risk of congenital malformations. However, it is not FDA approved for treatment of NVP. Ondansetron appears to be effective but its use in early pregnancy may be associated with congenital anomalies. Consequently, ondansetron should not be used to treat NVP unless first- and second-line treatments have been ineffective to treat the patient’s symptoms. 

INSTANT POLL
Which of the following pharmacologic treatments of nausea with or without vomiting during pregnancy is your first-line medication choice?
               • Ondansetron
               • Metoclopramide
               • Doxylamine-pyridoxine
               • Meclizine Promethazine
               • Trimethobenzamide

Visit the Quick Poll on the homepage, give your answer, and then see how other ObGyns have answered.

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

CASE: Pregnant patient seeks medication for her NVP

A 23-year-old G1P0 woman at 9 weeks’ gestation presents to your office with nausea and vomiting that is interfering with work. She has tried many changes in her daily habits. She has tried eating small, frequent meals; snacking on nuts and crackers; using lemon-scented products; and avoiding coffee and strong odors. Following an evaluation you diagnose nausea and vomiting of pregnancy (NVP). She asks, “Is there a medication for my nausea that is safe for my baby?”

Nausea with or without vomiting is a common problem for pregnant women between 6 and 14 weeks of gestation. In one study, nausea with or without vomiting was reported by 69% of patients and resulted in pharmacologic treatment in 15%.¹ In a Cochrane review of NVP, investigators analyzed 37 trials involving treatments such as acupressure, acustimulation, acupuncture, ginger, chamomile, lemon oil, vitamin B₆, and antiemetic medications. The authors concluded, “There is a lack of high-quality evidence to support any particular intervention.”² Clinicians are challenged to effectively treat the symptoms of NVP and simultaneously to minimize the risk that the fetus will be exposed to a teratogen during the first trimester, a vulnerable period in organ development.

In this editorial, I briefly review nonpharmacologic options for NVP, but focus on current pharmacologic treatments. Of those available to ObGyns, what is the best first-choice treatment given recent and accumulated data regarding associated congenital anomalies?

Nonpharmacologic treatment
Although the authors of the Cochrane review did not identify high-quality evidence to support nonpharmacologic interventions, results of multiple randomized trials have demonstrated that ginger is effective in reducing pregnancy-associated nausea and vomiting.³ Ginger treatment is recommended at doses of 250 mg in capsules or syrup four times daily.

First-line pharmacologic treatment: Doxylamine plus pyridoxine
The US Food and Drug Administration (FDA) has approved the combination of doxylamine plus pyridoxine (vitamin B₆) in a delayed-release formulation for treatment of NVP (­Diclegis). Doxy­lamine is an antihistamine that blocks H₁-receptor sites in the chemoreceptor trigger zone. It also diminishes vestibular stimulation and depresses labyrinthine activity through central anticholinergic activity. Its elimination half-life is 10 to 12 hours (Lexicomp). Each tablet contains doxylamine 10 mg and pyridoxine 10 mg. The starting dose is 2 tablets at bedtime.

If the woman has persistent symptoms, a third tablet is added, to be taken in the morning. If symptoms continue, a fourth tablet is recommended to be taken in the afternoon. In a large, randomized clinical trial, doxylamine-pyridoxine treatment reduced nausea, vomiting, and retching and improved perceived quality of life compared with placebo.⁴ The FDA assigned doxylamine-pyridoxine pregnancy category A because of the extensive evidence that it does not cause an increase in fetal malformations.^5,6

If the delayed-release doxylamine-pyridoxine formulation (Diclegis) is not available to the patient, alternative formulations of doxylamine and pyridoxine can be prescribed. Pyridoxine is widely available over the counter as 25-mg tablets, and one tablet can be prescribed two or three times daily. Doxylamine is available as a chewable prescription medicine in 5-mg tablets (Aldex AN) and two tablets can be prescribed two or three times daily. Doxylamine is also available as a 25-mg over-the-counter tablet in Unisom SleepTabs. One-half tablet can be prescribed two or three times daily. The patient should be alerted that Unisom SleepGels contain diphenhydramine, not doxylamine.

Second-line pharmacologic treatment
Metoclopramide Metoclopramide is a dopamine antagonist. It enhances upper gastrointestinal motility, accelerates gastric emptying, and increases lower esophageal sphincter tone. At higher doses it blocks serotonin receptors in the chemoreceptor trigger zone. Its elimination half-life is 5 to 6 hours (Lexicomp). There are no large, randomized, placebo-controlled trials of oral metoclopramide for the treatment of nausea and vomiting of early pregnancy.

I am recommending metoclopramide as a second-line treatment for NVP because it appears to be effective and is not known to be associated with an increased risk of congenital malformations. Metoclopramide is widely used to prevent and treat intraoperative and postoperative nausea associated with cesarean delivery.⁷ In addition, intravenous (IV) metoclopramide is commonly used to treat women hospitalized with hyperemesis gravidarum. Results of randomized clinical trials demonstrate that when used to treat hyperemesis gravidarum, IV metoclopramide (10 mg every 8 hours) has similar efficacy to IV ondansetron (4 mg every 8 hours)⁸ and IV promethazine (25 mg every 8 hours).⁹ When using metoclopramide as an oral treatment for NVP, 10 mg every 8 hours is a commonly recommended regimen.

The FDA has assigned metoclopramide to pregnancy category B, which indicates that there is no evidence of fetal risk. Studies from Israel and Denmark show that metoclopramide is not associated with an increased risk of congenital malformations. In the study from Israel, among 3,458 infants born to women who had filled a prescription for metoclopramide during the first trimester of pregnancy, there was no increase in major congenital malformations, low birth weight, preterm delivery, or perinatal death.¹⁰ In the study from Denmark, among 28,486 infants born to mothers who had filled a prescription for metoclopramide in the first trimester there was no increase in congenital malformations or any of 20 individual categories of malformations, including neural tube defects, transposition of the great vessels, ventricular septal defect, atrial septal defect, tetralogy of Fallot, coarctation of the aorta, cleft lip or palate, anorectal atresia/stenosis, or limb reduction.¹¹ The results of these two large studies are reassuring that metoclopramide is not associated with an increased risk of congenital malformations.

Metoclopramide can cause tardive dyskinesia, a serious movement disorder that may be irreversible with discontinuation of the drug. This risk increases with dose and length of treatment. The FDA recommends that clinicians avoid the use of metoclopramide for more than 12 weeks.

Third-line pharmacologic treatment: Ondansetron
In the United States ondansetron is commonly used to treat NVP.¹² The drug is a selective 5-HT₃ antagonist that blocks serotonin action in the central nervous system chemoreceptor trigger zone. The elimination half-life of ondansetron is 3 to 6 hours (Lexicomp).

The frequent use of ondansetron may be due, in part, to the perception that it is a very effective antiemetic. For example, in one small clinical trial, ondansetron 4 mg every 8 hours was reported to be superior to a combination of pyridoxine 25 mg every 8 hours plus doxylamine 12.5 mg every 8 hours.¹³ (Note that the pyridoxine and doxylamine tablets used in this trial were not in a combination delayed-release formulation.) I am recommending ondansetron as a third-line treatment for NVP because, although it is effective, it may be associated with an increased risk of fetal cardiac anomalies.

Is ondansetron associated with cardiac malformations?
The FDA has assigned ondansetron to pregnancy category B; however, there is concern that it may be associated with congenital heart defects. In a recent study of 1,349 infants born to Swedish women who had filled a prescription for ondansetron in early pregnancy, a significantly increased risk of cardiovascular defect (odds ratio [OR], 1.62; 95% confidence interval [CI], 1.04−2.14) and cardiac septum defect (OR, 2.05; 95% CI, 1.19−3.28) was reported.¹⁴ The cardiac anomalies were mostly atrial septal or ventricular septal defects.

In a second study, reported as an abstract, authors analyzed congenital malformations in 1,248 infants born to Danish women who filled a prescription for ondansetron in early pregnancy. These authors also found an increased risk of a congenital heart malformation (OR, 2.0; 95% CI, 1.3−3.1).¹⁵

A US case-control study showed an association between ondansetron use and cleft palate.¹ The Swedish¹⁴ and Danish¹⁵ studies reported above did not find an association between ondansetron use and cleft palate.

The FDA issued a warning in June 2012 that at a dose of 32 mg, administered intravenously, ondansetron may prolong the QT interval and result in a potentially fatal heart arrhythmia, torsades de pointes.¹⁶ In the announcement the FDA did not alter the recommendations for oral dosing because there is no strong evidence that oral dosing is associated with clinically significant arrhythmias. Authors of a recent systematic review concluded that IV administration of large doses of ondansetron may cause cardiac arrhythmias, especially in patients with cardiac disease and those taking other drugs that prolong the QT interval, but that a single oral dose of ondansetron does not have a significant risk of causing an arrhythmia.¹⁷

Health Canada¹⁸ has advised that many commonly prescribed medications increase serotonin activity. When multiple drugs that each increase serotonin activity are prescribed in combination, the risk of serotonin syndrome is increased. Serotonin syndrome results in hyperthermia, agitation, tachycardia, and muscle twitching and can be fatal. Ondansetron was specifically mentioned in the Health Canada warning, but a search of the literature revealed very few reported cases of ondansetron being implicated in the serotonin syndrome.¹⁹

My bottom-line recommendations
NVP is a common obstetric problem. When oral pharmacologic therapy is indicated, first-line treatment should be with the FDA-approved combination of doxylamine-pyridoxine because it is both effective and associated with no known increased risk of congenital malformations. An effective second-line agent is metoclopramide. Based on very limited data, metoclopramide appears effective and is not associated with an increased risk of congenital malformations. However, it is not FDA approved for treatment of NVP. Ondansetron appears to be effective but its use in early pregnancy may be associated with congenital anomalies. Consequently, ondansetron should not be used to treat NVP unless first- and second-line treatments have been ineffective to treat the patient’s symptoms. 

INSTANT POLL
Which of the following pharmacologic treatments of nausea with or without vomiting during pregnancy is your first-line medication choice?
               • Ondansetron
               • Metoclopramide
               • Doxylamine-pyridoxine
               • Meclizine Promethazine
               • Trimethobenzamide

Visit the Quick Poll on the homepage, give your answer, and then see how other ObGyns have answered.

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

CASE: Pregnant patient seeks medication for her NVP

A 23-year-old G1P0 woman at 9 weeks’ gestation presents to your office with nausea and vomiting that is interfering with work. She has tried many changes in her daily habits. She has tried eating small, frequent meals; snacking on nuts and crackers; using lemon-scented products; and avoiding coffee and strong odors. Following an evaluation you diagnose nausea and vomiting of pregnancy (NVP). She asks, “Is there a medication for my nausea that is safe for my baby?”

Nausea with or without vomiting is a common problem for pregnant women between 6 and 14 weeks of gestation. In one study, nausea with or without vomiting was reported by 69% of patients and resulted in pharmacologic treatment in 15%.¹ In a Cochrane review of NVP, investigators analyzed 37 trials involving treatments such as acupressure, acustimulation, acupuncture, ginger, chamomile, lemon oil, vitamin B₆, and antiemetic medications. The authors concluded, “There is a lack of high-quality evidence to support any particular intervention.”² Clinicians are challenged to effectively treat the symptoms of NVP and simultaneously to minimize the risk that the fetus will be exposed to a teratogen during the first trimester, a vulnerable period in organ development.

In this editorial, I briefly review nonpharmacologic options for NVP, but focus on current pharmacologic treatments. Of those available to ObGyns, what is the best first-choice treatment given recent and accumulated data regarding associated congenital anomalies?

Nonpharmacologic treatment
Although the authors of the Cochrane review did not identify high-quality evidence to support nonpharmacologic interventions, results of multiple randomized trials have demonstrated that ginger is effective in reducing pregnancy-associated nausea and vomiting.³ Ginger treatment is recommended at doses of 250 mg in capsules or syrup four times daily.

First-line pharmacologic treatment: Doxylamine plus pyridoxine
The US Food and Drug Administration (FDA) has approved the combination of doxylamine plus pyridoxine (vitamin B₆) in a delayed-release formulation for treatment of NVP (­Diclegis). Doxy­lamine is an antihistamine that blocks H₁-receptor sites in the chemoreceptor trigger zone. It also diminishes vestibular stimulation and depresses labyrinthine activity through central anticholinergic activity. Its elimination half-life is 10 to 12 hours (Lexicomp). Each tablet contains doxylamine 10 mg and pyridoxine 10 mg. The starting dose is 2 tablets at bedtime.

If the woman has persistent symptoms, a third tablet is added, to be taken in the morning. If symptoms continue, a fourth tablet is recommended to be taken in the afternoon. In a large, randomized clinical trial, doxylamine-pyridoxine treatment reduced nausea, vomiting, and retching and improved perceived quality of life compared with placebo.⁴ The FDA assigned doxylamine-pyridoxine pregnancy category A because of the extensive evidence that it does not cause an increase in fetal malformations.^5,6

If the delayed-release doxylamine-pyridoxine formulation (Diclegis) is not available to the patient, alternative formulations of doxylamine and pyridoxine can be prescribed. Pyridoxine is widely available over the counter as 25-mg tablets, and one tablet can be prescribed two or three times daily. Doxylamine is available as a chewable prescription medicine in 5-mg tablets (Aldex AN) and two tablets can be prescribed two or three times daily. Doxylamine is also available as a 25-mg over-the-counter tablet in Unisom SleepTabs. One-half tablet can be prescribed two or three times daily. The patient should be alerted that Unisom SleepGels contain diphenhydramine, not doxylamine.

Second-line pharmacologic treatment
Metoclopramide Metoclopramide is a dopamine antagonist. It enhances upper gastrointestinal motility, accelerates gastric emptying, and increases lower esophageal sphincter tone. At higher doses it blocks serotonin receptors in the chemoreceptor trigger zone. Its elimination half-life is 5 to 6 hours (Lexicomp). There are no large, randomized, placebo-controlled trials of oral metoclopramide for the treatment of nausea and vomiting of early pregnancy.

I am recommending metoclopramide as a second-line treatment for NVP because it appears to be effective and is not known to be associated with an increased risk of congenital malformations. Metoclopramide is widely used to prevent and treat intraoperative and postoperative nausea associated with cesarean delivery.⁷ In addition, intravenous (IV) metoclopramide is commonly used to treat women hospitalized with hyperemesis gravidarum. Results of randomized clinical trials demonstrate that when used to treat hyperemesis gravidarum, IV metoclopramide (10 mg every 8 hours) has similar efficacy to IV ondansetron (4 mg every 8 hours)⁸ and IV promethazine (25 mg every 8 hours).⁹ When using metoclopramide as an oral treatment for NVP, 10 mg every 8 hours is a commonly recommended regimen.

The FDA has assigned metoclopramide to pregnancy category B, which indicates that there is no evidence of fetal risk. Studies from Israel and Denmark show that metoclopramide is not associated with an increased risk of congenital malformations. In the study from Israel, among 3,458 infants born to women who had filled a prescription for metoclopramide during the first trimester of pregnancy, there was no increase in major congenital malformations, low birth weight, preterm delivery, or perinatal death.¹⁰ In the study from Denmark, among 28,486 infants born to mothers who had filled a prescription for metoclopramide in the first trimester there was no increase in congenital malformations or any of 20 individual categories of malformations, including neural tube defects, transposition of the great vessels, ventricular septal defect, atrial septal defect, tetralogy of Fallot, coarctation of the aorta, cleft lip or palate, anorectal atresia/stenosis, or limb reduction.¹¹ The results of these two large studies are reassuring that metoclopramide is not associated with an increased risk of congenital malformations.

Metoclopramide can cause tardive dyskinesia, a serious movement disorder that may be irreversible with discontinuation of the drug. This risk increases with dose and length of treatment. The FDA recommends that clinicians avoid the use of metoclopramide for more than 12 weeks.

Third-line pharmacologic treatment: Ondansetron
In the United States ondansetron is commonly used to treat NVP.¹² The drug is a selective 5-HT₃ antagonist that blocks serotonin action in the central nervous system chemoreceptor trigger zone. The elimination half-life of ondansetron is 3 to 6 hours (Lexicomp).

The frequent use of ondansetron may be due, in part, to the perception that it is a very effective antiemetic. For example, in one small clinical trial, ondansetron 4 mg every 8 hours was reported to be superior to a combination of pyridoxine 25 mg every 8 hours plus doxylamine 12.5 mg every 8 hours.¹³ (Note that the pyridoxine and doxylamine tablets used in this trial were not in a combination delayed-release formulation.) I am recommending ondansetron as a third-line treatment for NVP because, although it is effective, it may be associated with an increased risk of fetal cardiac anomalies.

Is ondansetron associated with cardiac malformations?
The FDA has assigned ondansetron to pregnancy category B; however, there is concern that it may be associated with congenital heart defects. In a recent study of 1,349 infants born to Swedish women who had filled a prescription for ondansetron in early pregnancy, a significantly increased risk of cardiovascular defect (odds ratio [OR], 1.62; 95% confidence interval [CI], 1.04−2.14) and cardiac septum defect (OR, 2.05; 95% CI, 1.19−3.28) was reported.¹⁴ The cardiac anomalies were mostly atrial septal or ventricular septal defects.

In a second study, reported as an abstract, authors analyzed congenital malformations in 1,248 infants born to Danish women who filled a prescription for ondansetron in early pregnancy. These authors also found an increased risk of a congenital heart malformation (OR, 2.0; 95% CI, 1.3−3.1).¹⁵

A US case-control study showed an association between ondansetron use and cleft palate.¹ The Swedish¹⁴ and Danish¹⁵ studies reported above did not find an association between ondansetron use and cleft palate.

The FDA issued a warning in June 2012 that at a dose of 32 mg, administered intravenously, ondansetron may prolong the QT interval and result in a potentially fatal heart arrhythmia, torsades de pointes.¹⁶ In the announcement the FDA did not alter the recommendations for oral dosing because there is no strong evidence that oral dosing is associated with clinically significant arrhythmias. Authors of a recent systematic review concluded that IV administration of large doses of ondansetron may cause cardiac arrhythmias, especially in patients with cardiac disease and those taking other drugs that prolong the QT interval, but that a single oral dose of ondansetron does not have a significant risk of causing an arrhythmia.¹⁷

Health Canada¹⁸ has advised that many commonly prescribed medications increase serotonin activity. When multiple drugs that each increase serotonin activity are prescribed in combination, the risk of serotonin syndrome is increased. Serotonin syndrome results in hyperthermia, agitation, tachycardia, and muscle twitching and can be fatal. Ondansetron was specifically mentioned in the Health Canada warning, but a search of the literature revealed very few reported cases of ondansetron being implicated in the serotonin syndrome.¹⁹

My bottom-line recommendations
NVP is a common obstetric problem. When oral pharmacologic therapy is indicated, first-line treatment should be with the FDA-approved combination of doxylamine-pyridoxine because it is both effective and associated with no known increased risk of congenital malformations. An effective second-line agent is metoclopramide. Based on very limited data, metoclopramide appears effective and is not associated with an increased risk of congenital malformations. However, it is not FDA approved for treatment of NVP. Ondansetron appears to be effective but its use in early pregnancy may be associated with congenital anomalies. Consequently, ondansetron should not be used to treat NVP unless first- and second-line treatments have been ineffective to treat the patient’s symptoms. 

INSTANT POLL
Which of the following pharmacologic treatments of nausea with or without vomiting during pregnancy is your first-line medication choice?
               • Ondansetron
               • Metoclopramide
               • Doxylamine-pyridoxine
               • Meclizine Promethazine
               • Trimethobenzamide

Visit the Quick Poll on the homepage, give your answer, and then see how other ObGyns have answered.

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

Heavy menstrual bleeding is a common gynecologic problem and can negatively affect a woman’s quality of life.¹ Endometrial ablation is an effective treatment option.² Despite its efficacy, however, endometrial ablation has failure rates ranging from 15% to 30%.^3,4 Two consistent reasons for failure are persistent bleeding and new or worsening pain. Endometrial regrowth and intrauterine scarring are thought to be key factors in this pain process.⁵

Details of the trial
Wishall and colleagues conducted their retrospective cohort study using patient data from two large academic medical centers. The primary outcome was the development of new or worsening pain following endometrial ablation. The two most commonly used endometrial ablation devices in this study were thermal balloon ablation and bipolar radiofrequency ablation.

Twenty-three percent of patients developed new or worsening pain following the ablation, a finding in accordance with earlier studies looking specifically at pain after endometrial ablation.⁶ In addition, 19% of patients underwent hysterectomy after ablation—again, within the range commonly reported in the literature.^3,4

Risk factors for new or worsening pain after ablation included a preprocedure history of dysmenorrhea or tubal sterilization. White race was protective of postprocedure new or worsening pain (adjusted OR, 0.55; 95% CI, 0.34–0.89).

Risk factors for hysterectomy after ablation included a history of cesarean delivery (adjusted OR, 2.33; 95% CI, 1.05–5.16) and uterine abnormalities on imaging, including leiomyoma, adenomyosis, a thickened endometrial lining, and polyps (adjusted OR, 3.96; 95% CI, 1.25–12.56). When the ablation procedure was performed in an operating room, the risk of postprocedure hysterectomy decreased (adjusted OR, 0.24; 95% CI, 0.07–0.77). In histopathologic analysis of the hysterectomy specimens, leiomyomas or adenomyosis, or both, were the most common findings, consistent with other reports on pathologic findings in this setting.⁷

Placing these findings in context
Overall, the findings of Wishall and colleagues support those of other studies exploring endometrial ablation, an effective uterine-conserving procedure for the treatment of heavy menstrual bleeding. All conservative procedures have inherent failure rates and can lead to unintended adverse effects. Common reasons for failure after endometrial ablation include bleeding or pain, or both. 

Although there are discrepancies between studies in regard to some of the individual predictors of failure or development of pain, the collection of retrospective studies on this subject to date have made it clear: There are predictors of treatment failure. Future efforts should focus on model development and prospective validation of these models to improve patient selection.

What this evidence means for practice
This study reinforces the idea that patient selection for conservative procedures such as endometrial ablation is one of the most important steps in the process. In light of these findings, I recommend that women with a history of dysmenorrhea or tubal sterilization be counseled about the potential for postprocedure pain and subsequent treatment failure.
— Matthew R. Hopkins, MD

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

Heavy menstrual bleeding is a common gynecologic problem and can negatively affect a woman’s quality of life.¹ Endometrial ablation is an effective treatment option.² Despite its efficacy, however, endometrial ablation has failure rates ranging from 15% to 30%.^3,4 Two consistent reasons for failure are persistent bleeding and new or worsening pain. Endometrial regrowth and intrauterine scarring are thought to be key factors in this pain process.⁵

Details of the trial
Wishall and colleagues conducted their retrospective cohort study using patient data from two large academic medical centers. The primary outcome was the development of new or worsening pain following endometrial ablation. The two most commonly used endometrial ablation devices in this study were thermal balloon ablation and bipolar radiofrequency ablation.

Twenty-three percent of patients developed new or worsening pain following the ablation, a finding in accordance with earlier studies looking specifically at pain after endometrial ablation.⁶ In addition, 19% of patients underwent hysterectomy after ablation—again, within the range commonly reported in the literature.^3,4

Risk factors for new or worsening pain after ablation included a preprocedure history of dysmenorrhea or tubal sterilization. White race was protective of postprocedure new or worsening pain (adjusted OR, 0.55; 95% CI, 0.34–0.89).

Risk factors for hysterectomy after ablation included a history of cesarean delivery (adjusted OR, 2.33; 95% CI, 1.05–5.16) and uterine abnormalities on imaging, including leiomyoma, adenomyosis, a thickened endometrial lining, and polyps (adjusted OR, 3.96; 95% CI, 1.25–12.56). When the ablation procedure was performed in an operating room, the risk of postprocedure hysterectomy decreased (adjusted OR, 0.24; 95% CI, 0.07–0.77). In histopathologic analysis of the hysterectomy specimens, leiomyomas or adenomyosis, or both, were the most common findings, consistent with other reports on pathologic findings in this setting.⁷

Placing these findings in context
Overall, the findings of Wishall and colleagues support those of other studies exploring endometrial ablation, an effective uterine-conserving procedure for the treatment of heavy menstrual bleeding. All conservative procedures have inherent failure rates and can lead to unintended adverse effects. Common reasons for failure after endometrial ablation include bleeding or pain, or both. 

Although there are discrepancies between studies in regard to some of the individual predictors of failure or development of pain, the collection of retrospective studies on this subject to date have made it clear: There are predictors of treatment failure. Future efforts should focus on model development and prospective validation of these models to improve patient selection.

What this evidence means for practice
This study reinforces the idea that patient selection for conservative procedures such as endometrial ablation is one of the most important steps in the process. In light of these findings, I recommend that women with a history of dysmenorrhea or tubal sterilization be counseled about the potential for postprocedure pain and subsequent treatment failure.
— Matthew R. Hopkins, MD

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

Heavy menstrual bleeding is a common gynecologic problem and can negatively affect a woman’s quality of life.¹ Endometrial ablation is an effective treatment option.² Despite its efficacy, however, endometrial ablation has failure rates ranging from 15% to 30%.^3,4 Two consistent reasons for failure are persistent bleeding and new or worsening pain. Endometrial regrowth and intrauterine scarring are thought to be key factors in this pain process.⁵

Details of the trial
Wishall and colleagues conducted their retrospective cohort study using patient data from two large academic medical centers. The primary outcome was the development of new or worsening pain following endometrial ablation. The two most commonly used endometrial ablation devices in this study were thermal balloon ablation and bipolar radiofrequency ablation.

Twenty-three percent of patients developed new or worsening pain following the ablation, a finding in accordance with earlier studies looking specifically at pain after endometrial ablation.⁶ In addition, 19% of patients underwent hysterectomy after ablation—again, within the range commonly reported in the literature.^3,4

Risk factors for new or worsening pain after ablation included a preprocedure history of dysmenorrhea or tubal sterilization. White race was protective of postprocedure new or worsening pain (adjusted OR, 0.55; 95% CI, 0.34–0.89).

Risk factors for hysterectomy after ablation included a history of cesarean delivery (adjusted OR, 2.33; 95% CI, 1.05–5.16) and uterine abnormalities on imaging, including leiomyoma, adenomyosis, a thickened endometrial lining, and polyps (adjusted OR, 3.96; 95% CI, 1.25–12.56). When the ablation procedure was performed in an operating room, the risk of postprocedure hysterectomy decreased (adjusted OR, 0.24; 95% CI, 0.07–0.77). In histopathologic analysis of the hysterectomy specimens, leiomyomas or adenomyosis, or both, were the most common findings, consistent with other reports on pathologic findings in this setting.⁷

Placing these findings in context
Overall, the findings of Wishall and colleagues support those of other studies exploring endometrial ablation, an effective uterine-conserving procedure for the treatment of heavy menstrual bleeding. All conservative procedures have inherent failure rates and can lead to unintended adverse effects. Common reasons for failure after endometrial ablation include bleeding or pain, or both. 

Although there are discrepancies between studies in regard to some of the individual predictors of failure or development of pain, the collection of retrospective studies on this subject to date have made it clear: There are predictors of treatment failure. Future efforts should focus on model development and prospective validation of these models to improve patient selection.

What this evidence means for practice
This study reinforces the idea that patient selection for conservative procedures such as endometrial ablation is one of the most important steps in the process. In light of these findings, I recommend that women with a history of dysmenorrhea or tubal sterilization be counseled about the potential for postprocedure pain and subsequent treatment failure.
— Matthew R. Hopkins, MD

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

Negligence during cord blood sampling? Child has CP
A woman’s first child was treated for neonatal alloimmune thrombocytopenia (NAIT) after birth. When prenatal testing identified NAIT in her second child, the mother received twice-weekly immunoglobulin injections to increase the fetus’ platelet count.

At 33 weeks’ gestation, percutaneous umbilical blood sampling (PUBS) was undertaken by a maternal-fetal medicine (MFM) specialist to check the baby’s platelet count and inject additional platelets. During the procedure, the mother’s blood pressure dropped from 122/80 to 80/40 mm Hg. The fetal heart rate dropped from 120–130 bpm to 65 bpm. An emergency cesarean delivery was performed.

At birth, the baby had seizures and respiratory distress secondary to perinatal asphyxia. She has severe spastic quadriplegic cerebral palsy. At age 9 years, she has been hospitalized for multiple complications, underwent tendon-release procedures on both legs, and receives occupational and physical therapy. She cannot speak, needs a feeding tube, is wheelchair bound, and requires 24-hour nursing care. 

PARENTS’ CLAIM The MFM was not adequately trained to perform PUBS and did not use continuous ultrasound guidance during the procedure. She was negligent in attempting to insert the needle into the umbilical cord multiple times. She failed to recognize fetal distress. The anesthesiologist only told the MFM that the patient was hypotensive, not that the patient’s blood pressure never returned to baseline.

defendants’ DEFENSE The mother was part of a NAIT study, and the procedure was properly performed under the guidelines of that study. A sonographer constantly monitored the fetal heart rate. The anesthesiologist claimed that proper actions were taken in response to low blood pressure; there was no requirement to communicate more information to the MFM. The child’s hypoxia was due to placental abruption. The estimated cost of the life-care plan for the child is $5 to $10 million.

VERDICT A $15 million Indiana verdict was returned against the medical center that employed the anesthesiologist, but was reduced to $1,250,000 by the state cap. A defense verdict was returned for the MFM.

Woman dies from cervical cancer: $2.33M
When a woman had an abnormal Pap smear in 2001, her gynecologist did not order a repeat test, but told the patient to return in 3 months. The patient did not see the gynecologist again until 2007. At that time, her Pap smear was normal, but she was experiencing symptoms. The gynecologist did not order further testing.

In 2009, the patient was found to have advanced cervical cancer. She died 2 years later at age 48.  

ESTATE’S CLAIM The second Pap smear was incorrectly interpreted. Further testing should have been ordered in 2001 and 2007.

DEFENDANTS’ DEFENSE The laboratory and patient’s estate settled for a confidential amount before the trial commenced. The gynecologist denied negligence. He claimed the patient was at fault for not returning to see him, as recommended.

VERDICT A New Jersey jury found the gynecologist 40% at fault, the laboratory 50% at fault, and the patient 10% at fault. A gross verdict of $2.33 million was returned.

Was it HELLP syndrome?
By her prenatal visit at 33 weeks’ gestation, a mother had gained 59 lb during her pregnancy. Three days later, she went to the emergency department (ED). The fetus had died. 

PARENT’S CLAIM The ObGyn failed to intervene when the mother was gaining excessive weight. The mother had HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count); timely diagnosis could have avoided fetal demise.

DEFENDANTS’ DEFENSE Fetal demise could not have been diagnosed or prevented. The cause of the mother’s illness was never fully identified.

VERDICT A Tennessee defense verdict was returned.
 

Vesicovaginal fistula after hysterectomy
A woman underwent a hysterectomy performed by her ObGyn. A week later, during a postoperative visit, the ObGyn detected a bladder injury and related vesicovaginal fistula. He attempted a repair, but it failed. Eventually, successful repair surgery was performed by a urologist.

PATIENT’S CLAIM The ObGyn only should have used sharp dissection during the hysterectomy, as opposed to a combination of sharp and blunt dissection, due to dense adhesions that had developed after earlier abdominal surgery. Because the ObGyn had never repaired a vesicovaginal fistula before, he should have requested the assistance of a urologist or urogynecologist. A peritoneal flap should have been used during the initial repair.

PHYSICIAN’S DEFENSE Referral to a urologist or urogynecologist had been offered to the patient, but was refused (no record of this was found in the patient’s file). There was no negligence in the attempted repair.

VERDICT  A $387,000 Virginia verdict was returned.

Did she really need that hysterectomy?
A 31-year-old woman went to the ED with sudden, severe abdominal pain. The radiologist noted that the patient’s appendix could not be visualized on computed tomography (CT) because it was behind the cecum. A general surgeon interpreted the report as ruling out appendicitis, made a diagnosis of pelvic inflammatory disease, and requested a gynecologic consult. An ObGyn sent his nurse practitioner to see the patient in the ED. The patient was discharged and instructed to follow up with the ObGyn.

When the patient’s condition worsened 2 days later, she returned to the ED. The ObGyn performed laparoscopic exploratory surgery. When he could not find the appendix, he called the general surgeon. The surgeon was in his car, and told the ObGyn that it was unnecessary to visualize the appendix; the ObGyn could complete the surgery. The patient was again discharged without a firm diagnosis. She was readmitted to the hospital several hours after discharge and treated for sepsis.

She was in and out of the hospital several times during the next 7 weeks until the ObGyn told her that the only way to cure her pain was to perform a partial hysterectomy. He scheduled a concurrent prophylactic appendectomy by the general surgeon. At surgery, the surgeon found and removed a burst appendix. The ObGyn then performed a hysterectomy, although he had been present during the appendectomy.

PATIENT’S CLAIM Any general surgeon could have come into the operating room during exploratory surgery to assist in ruling out appendicitis; there were other general surgeons available at the hospital. The ObGyn was negligent in performing the hysterectomy after the surgeon had performed the appendectomy.

PHYSICIAN’S DEFENSE The general surgeon died before the case could be deposed. The ObGyn admitted that the removal of the burst appendix resolved the patient’s medical problems; her uterus had not been damaged by sepsis.

VERDICT A $350,000 Michigan settlement was reached.

Erb’s palsy: $1.7M net award
At 38 weeks’ gestation, a mother went to the local ED reporting shortness of breath. She was transferred to a university medical center where a chest x-ray revealed what was thought to be pneumonia or a pulmonary embolism. The decision was made to induce labor. During vaginal delivery, shoulder dystocia was encountered.

The 3-year-old child has Erb’s palsy and, despite treatment and therapy, does not have full use of her left arm and shoulder.  

PARENTS’ CLAIM Maneuvers undertaken to relieve shoulder dystocia were not properly performed, injuring the baby. A cesarean delivery should have been performed because of the mother’s condition.

DEFENDANTS’ DEFENSE Proper maneuvers were used. There was no medical necessity for emergency cesarean delivery.

VERDICT A $3 million Maryland verdict was returned. After state caps and recalculation of a lost-wages claim from the mother due to jury error, the net award was $1.7 million.

Was nonreassuring fetal heart rate ignored?
In her third trimester, a 20-year-old woman was admitted to the hospital for observation, which included fetal heart-rate monitoring.

After 2 days, the patient began to bleed vaginally, and the nurses called the ObGyn. When he came to the hospital, he performed emergency cesarean delivery. The fetus was stillborn.

PATIENT’S CLAIM The nurses failed to inform the ObGyn when nonreassuring fetal heart-rate monitoring results were first evident. The ObGyn did not come to the hospital immediately after being told about the vaginal bleeding. The surgical team was not ready when it was time for the cesarean delivery.

DEFENDANTS’ DEFENSE The case was tried against the hospital that employed the nurses and ObGyn. The hospital claimed that fetal demise was caused by a sudden placental abruption. The nurses’ actions were appropriate. The hospital faulted the ObGyn for not coming to the hospital when summoned by the nurses.

VERDICT A $100,000 Louisiana verdict was returned. The jury found the ObGyn 99% at fault and the hospital 1% at fault. The patient was awarded $100,000 from the Patient’s Compensation Fund; the hospital paid $1,000.

Patient says wrong ovary was removed
A woman saw her ObGyn (Dr. A) because of lower abdominal pain. Dr. A performed laparoscopic right salpingo-oophorectomy.

A tumor on the left ovary was found 5 months later, and a second operation was performed by another ObGyn (Dr. B) with Dr. A’s assistance. During this surgery, the patient’s sigmoid colon was injured; a fistula developed and a third operation was required to repair the colon. 

PATIENT’S CLAIM The initial plan was to remove the left ovary. When Dr. Aremoved the right ovary instead of the left, the patient experienced sudden onset of menopause; the left ovary was nonfunctional. Dr. B was negligent in injuring the sigmoid colon.

PHYSICIANS’ DEFENSE Dr. B was released from the case because colon injury is a known complication of the procedure. Dr. A claimed that the radiologic film of the mass was misleading, and that the ovary he removed was diseased.

VERDICT A Virginia defense verdict was returned.

Second pregnancy ends in injury after shoulder dystocia
A mother told her new ObGyn that, during the birth of her first child a few years earlier, shoulder dystocia had been encountered. Although the baby was born unharmed, her prior ObGyn had recommended that she undergo cesarean delivery for future pregnancies. During the second pregnancy, the mother and new ObGyn discussed the possibility of a trial of labor and vaginal delivery.

When the mother went into labor at 37 weeks’ gestation, the ObGyn believed the child was of normal weight and proceeded with a vaginal delivery. When shoulder dystocia was encountered, various maneuvers were performed. Birth occurred 5 minutes later using moderate traction.

The child showed no signs of life at birth; Apgar scores were 0 for more than 14 minutes. The newborn was sent to the neonatal intensive care unit and later airlifted to another hospital. He had hypoxic ischemic encephalopathy and a C5–C6 brachial plexus injury.

Additional testing revealed that he has neurocognitive deficits including attention deficit hyperactivity disorder and executive function disabilities. 

Parents’ claim The ObGyn was negligent in failing to fully explain the risks of vaginal delivery, failing to recommend cesarean delivery based on the patient’s history and prior physician’s recommendation. The ObGyn failed to perform ultrasonography when the mother was admitted to the hospital; such imaging would have revealed that the fetus was larger than her first baby, mandating cesarean delivery. The ObGyn failed to perform an episiotomy after dystocia was encountered, and he applied excessive traction during dystocial maneuvers.

PHYSICIAN’S DEFENSE The mother was extensively counseled on the risks of vaginal delivery, but the ObGyn admitted that he did not recommend a cesarean delivery. Ultrasonography would have had no benefit. The use of moderate traction was necessary to prevent severe brain damage or death. The child’s current deficits are not related to his birth.

VERDICT The hospital settled for $85,000 before the trial began. An Illinois defense verdict was returned for the ObGyn.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

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

Negligence during cord blood sampling? Child has CP
A woman’s first child was treated for neonatal alloimmune thrombocytopenia (NAIT) after birth. When prenatal testing identified NAIT in her second child, the mother received twice-weekly immunoglobulin injections to increase the fetus’ platelet count.

At 33 weeks’ gestation, percutaneous umbilical blood sampling (PUBS) was undertaken by a maternal-fetal medicine (MFM) specialist to check the baby’s platelet count and inject additional platelets. During the procedure, the mother’s blood pressure dropped from 122/80 to 80/40 mm Hg. The fetal heart rate dropped from 120–130 bpm to 65 bpm. An emergency cesarean delivery was performed.

At birth, the baby had seizures and respiratory distress secondary to perinatal asphyxia. She has severe spastic quadriplegic cerebral palsy. At age 9 years, she has been hospitalized for multiple complications, underwent tendon-release procedures on both legs, and receives occupational and physical therapy. She cannot speak, needs a feeding tube, is wheelchair bound, and requires 24-hour nursing care. 

PARENTS’ CLAIM The MFM was not adequately trained to perform PUBS and did not use continuous ultrasound guidance during the procedure. She was negligent in attempting to insert the needle into the umbilical cord multiple times. She failed to recognize fetal distress. The anesthesiologist only told the MFM that the patient was hypotensive, not that the patient’s blood pressure never returned to baseline.

defendants’ DEFENSE The mother was part of a NAIT study, and the procedure was properly performed under the guidelines of that study. A sonographer constantly monitored the fetal heart rate. The anesthesiologist claimed that proper actions were taken in response to low blood pressure; there was no requirement to communicate more information to the MFM. The child’s hypoxia was due to placental abruption. The estimated cost of the life-care plan for the child is $5 to $10 million.

VERDICT A $15 million Indiana verdict was returned against the medical center that employed the anesthesiologist, but was reduced to $1,250,000 by the state cap. A defense verdict was returned for the MFM.

Woman dies from cervical cancer: $2.33M
When a woman had an abnormal Pap smear in 2001, her gynecologist did not order a repeat test, but told the patient to return in 3 months. The patient did not see the gynecologist again until 2007. At that time, her Pap smear was normal, but she was experiencing symptoms. The gynecologist did not order further testing.

In 2009, the patient was found to have advanced cervical cancer. She died 2 years later at age 48.  

ESTATE’S CLAIM The second Pap smear was incorrectly interpreted. Further testing should have been ordered in 2001 and 2007.

DEFENDANTS’ DEFENSE The laboratory and patient’s estate settled for a confidential amount before the trial commenced. The gynecologist denied negligence. He claimed the patient was at fault for not returning to see him, as recommended.

VERDICT A New Jersey jury found the gynecologist 40% at fault, the laboratory 50% at fault, and the patient 10% at fault. A gross verdict of $2.33 million was returned.

Was it HELLP syndrome?
By her prenatal visit at 33 weeks’ gestation, a mother had gained 59 lb during her pregnancy. Three days later, she went to the emergency department (ED). The fetus had died. 

PARENT’S CLAIM The ObGyn failed to intervene when the mother was gaining excessive weight. The mother had HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count); timely diagnosis could have avoided fetal demise.

DEFENDANTS’ DEFENSE Fetal demise could not have been diagnosed or prevented. The cause of the mother’s illness was never fully identified.

VERDICT A Tennessee defense verdict was returned.
 

Vesicovaginal fistula after hysterectomy
A woman underwent a hysterectomy performed by her ObGyn. A week later, during a postoperative visit, the ObGyn detected a bladder injury and related vesicovaginal fistula. He attempted a repair, but it failed. Eventually, successful repair surgery was performed by a urologist.

PATIENT’S CLAIM The ObGyn only should have used sharp dissection during the hysterectomy, as opposed to a combination of sharp and blunt dissection, due to dense adhesions that had developed after earlier abdominal surgery. Because the ObGyn had never repaired a vesicovaginal fistula before, he should have requested the assistance of a urologist or urogynecologist. A peritoneal flap should have been used during the initial repair.

PHYSICIAN’S DEFENSE Referral to a urologist or urogynecologist had been offered to the patient, but was refused (no record of this was found in the patient’s file). There was no negligence in the attempted repair.

VERDICT  A $387,000 Virginia verdict was returned.

Did she really need that hysterectomy?
A 31-year-old woman went to the ED with sudden, severe abdominal pain. The radiologist noted that the patient’s appendix could not be visualized on computed tomography (CT) because it was behind the cecum. A general surgeon interpreted the report as ruling out appendicitis, made a diagnosis of pelvic inflammatory disease, and requested a gynecologic consult. An ObGyn sent his nurse practitioner to see the patient in the ED. The patient was discharged and instructed to follow up with the ObGyn.

When the patient’s condition worsened 2 days later, she returned to the ED. The ObGyn performed laparoscopic exploratory surgery. When he could not find the appendix, he called the general surgeon. The surgeon was in his car, and told the ObGyn that it was unnecessary to visualize the appendix; the ObGyn could complete the surgery. The patient was again discharged without a firm diagnosis. She was readmitted to the hospital several hours after discharge and treated for sepsis.

She was in and out of the hospital several times during the next 7 weeks until the ObGyn told her that the only way to cure her pain was to perform a partial hysterectomy. He scheduled a concurrent prophylactic appendectomy by the general surgeon. At surgery, the surgeon found and removed a burst appendix. The ObGyn then performed a hysterectomy, although he had been present during the appendectomy.

PATIENT’S CLAIM Any general surgeon could have come into the operating room during exploratory surgery to assist in ruling out appendicitis; there were other general surgeons available at the hospital. The ObGyn was negligent in performing the hysterectomy after the surgeon had performed the appendectomy.

PHYSICIAN’S DEFENSE The general surgeon died before the case could be deposed. The ObGyn admitted that the removal of the burst appendix resolved the patient’s medical problems; her uterus had not been damaged by sepsis.

VERDICT A $350,000 Michigan settlement was reached.

Erb’s palsy: $1.7M net award
At 38 weeks’ gestation, a mother went to the local ED reporting shortness of breath. She was transferred to a university medical center where a chest x-ray revealed what was thought to be pneumonia or a pulmonary embolism. The decision was made to induce labor. During vaginal delivery, shoulder dystocia was encountered.

The 3-year-old child has Erb’s palsy and, despite treatment and therapy, does not have full use of her left arm and shoulder.  

PARENTS’ CLAIM Maneuvers undertaken to relieve shoulder dystocia were not properly performed, injuring the baby. A cesarean delivery should have been performed because of the mother’s condition.

DEFENDANTS’ DEFENSE Proper maneuvers were used. There was no medical necessity for emergency cesarean delivery.

VERDICT A $3 million Maryland verdict was returned. After state caps and recalculation of a lost-wages claim from the mother due to jury error, the net award was $1.7 million.

Was nonreassuring fetal heart rate ignored?
In her third trimester, a 20-year-old woman was admitted to the hospital for observation, which included fetal heart-rate monitoring.

After 2 days, the patient began to bleed vaginally, and the nurses called the ObGyn. When he came to the hospital, he performed emergency cesarean delivery. The fetus was stillborn.

PATIENT’S CLAIM The nurses failed to inform the ObGyn when nonreassuring fetal heart-rate monitoring results were first evident. The ObGyn did not come to the hospital immediately after being told about the vaginal bleeding. The surgical team was not ready when it was time for the cesarean delivery.

DEFENDANTS’ DEFENSE The case was tried against the hospital that employed the nurses and ObGyn. The hospital claimed that fetal demise was caused by a sudden placental abruption. The nurses’ actions were appropriate. The hospital faulted the ObGyn for not coming to the hospital when summoned by the nurses.

VERDICT A $100,000 Louisiana verdict was returned. The jury found the ObGyn 99% at fault and the hospital 1% at fault. The patient was awarded $100,000 from the Patient’s Compensation Fund; the hospital paid $1,000.

Patient says wrong ovary was removed
A woman saw her ObGyn (Dr. A) because of lower abdominal pain. Dr. A performed laparoscopic right salpingo-oophorectomy.

A tumor on the left ovary was found 5 months later, and a second operation was performed by another ObGyn (Dr. B) with Dr. A’s assistance. During this surgery, the patient’s sigmoid colon was injured; a fistula developed and a third operation was required to repair the colon. 

PATIENT’S CLAIM The initial plan was to remove the left ovary. When Dr. Aremoved the right ovary instead of the left, the patient experienced sudden onset of menopause; the left ovary was nonfunctional. Dr. B was negligent in injuring the sigmoid colon.

PHYSICIANS’ DEFENSE Dr. B was released from the case because colon injury is a known complication of the procedure. Dr. A claimed that the radiologic film of the mass was misleading, and that the ovary he removed was diseased.

VERDICT A Virginia defense verdict was returned.

Second pregnancy ends in injury after shoulder dystocia
A mother told her new ObGyn that, during the birth of her first child a few years earlier, shoulder dystocia had been encountered. Although the baby was born unharmed, her prior ObGyn had recommended that she undergo cesarean delivery for future pregnancies. During the second pregnancy, the mother and new ObGyn discussed the possibility of a trial of labor and vaginal delivery.

When the mother went into labor at 37 weeks’ gestation, the ObGyn believed the child was of normal weight and proceeded with a vaginal delivery. When shoulder dystocia was encountered, various maneuvers were performed. Birth occurred 5 minutes later using moderate traction.

The child showed no signs of life at birth; Apgar scores were 0 for more than 14 minutes. The newborn was sent to the neonatal intensive care unit and later airlifted to another hospital. He had hypoxic ischemic encephalopathy and a C5–C6 brachial plexus injury.

Additional testing revealed that he has neurocognitive deficits including attention deficit hyperactivity disorder and executive function disabilities. 

Parents’ claim The ObGyn was negligent in failing to fully explain the risks of vaginal delivery, failing to recommend cesarean delivery based on the patient’s history and prior physician’s recommendation. The ObGyn failed to perform ultrasonography when the mother was admitted to the hospital; such imaging would have revealed that the fetus was larger than her first baby, mandating cesarean delivery. The ObGyn failed to perform an episiotomy after dystocia was encountered, and he applied excessive traction during dystocial maneuvers.

PHYSICIAN’S DEFENSE The mother was extensively counseled on the risks of vaginal delivery, but the ObGyn admitted that he did not recommend a cesarean delivery. Ultrasonography would have had no benefit. The use of moderate traction was necessary to prevent severe brain damage or death. The child’s current deficits are not related to his birth.

VERDICT The hospital settled for $85,000 before the trial began. An Illinois defense verdict was returned for the ObGyn.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

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

Negligence during cord blood sampling? Child has CP
A woman’s first child was treated for neonatal alloimmune thrombocytopenia (NAIT) after birth. When prenatal testing identified NAIT in her second child, the mother received twice-weekly immunoglobulin injections to increase the fetus’ platelet count.

At 33 weeks’ gestation, percutaneous umbilical blood sampling (PUBS) was undertaken by a maternal-fetal medicine (MFM) specialist to check the baby’s platelet count and inject additional platelets. During the procedure, the mother’s blood pressure dropped from 122/80 to 80/40 mm Hg. The fetal heart rate dropped from 120–130 bpm to 65 bpm. An emergency cesarean delivery was performed.

At birth, the baby had seizures and respiratory distress secondary to perinatal asphyxia. She has severe spastic quadriplegic cerebral palsy. At age 9 years, she has been hospitalized for multiple complications, underwent tendon-release procedures on both legs, and receives occupational and physical therapy. She cannot speak, needs a feeding tube, is wheelchair bound, and requires 24-hour nursing care. 

PARENTS’ CLAIM The MFM was not adequately trained to perform PUBS and did not use continuous ultrasound guidance during the procedure. She was negligent in attempting to insert the needle into the umbilical cord multiple times. She failed to recognize fetal distress. The anesthesiologist only told the MFM that the patient was hypotensive, not that the patient’s blood pressure never returned to baseline.

defendants’ DEFENSE The mother was part of a NAIT study, and the procedure was properly performed under the guidelines of that study. A sonographer constantly monitored the fetal heart rate. The anesthesiologist claimed that proper actions were taken in response to low blood pressure; there was no requirement to communicate more information to the MFM. The child’s hypoxia was due to placental abruption. The estimated cost of the life-care plan for the child is $5 to $10 million.

VERDICT A $15 million Indiana verdict was returned against the medical center that employed the anesthesiologist, but was reduced to $1,250,000 by the state cap. A defense verdict was returned for the MFM.

Woman dies from cervical cancer: $2.33M
When a woman had an abnormal Pap smear in 2001, her gynecologist did not order a repeat test, but told the patient to return in 3 months. The patient did not see the gynecologist again until 2007. At that time, her Pap smear was normal, but she was experiencing symptoms. The gynecologist did not order further testing.

In 2009, the patient was found to have advanced cervical cancer. She died 2 years later at age 48.  

ESTATE’S CLAIM The second Pap smear was incorrectly interpreted. Further testing should have been ordered in 2001 and 2007.

DEFENDANTS’ DEFENSE The laboratory and patient’s estate settled for a confidential amount before the trial commenced. The gynecologist denied negligence. He claimed the patient was at fault for not returning to see him, as recommended.

VERDICT A New Jersey jury found the gynecologist 40% at fault, the laboratory 50% at fault, and the patient 10% at fault. A gross verdict of $2.33 million was returned.

Was it HELLP syndrome?
By her prenatal visit at 33 weeks’ gestation, a mother had gained 59 lb during her pregnancy. Three days later, she went to the emergency department (ED). The fetus had died. 

PARENT’S CLAIM The ObGyn failed to intervene when the mother was gaining excessive weight. The mother had HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count); timely diagnosis could have avoided fetal demise.

DEFENDANTS’ DEFENSE Fetal demise could not have been diagnosed or prevented. The cause of the mother’s illness was never fully identified.

VERDICT A Tennessee defense verdict was returned.
 

Vesicovaginal fistula after hysterectomy
A woman underwent a hysterectomy performed by her ObGyn. A week later, during a postoperative visit, the ObGyn detected a bladder injury and related vesicovaginal fistula. He attempted a repair, but it failed. Eventually, successful repair surgery was performed by a urologist.

PATIENT’S CLAIM The ObGyn only should have used sharp dissection during the hysterectomy, as opposed to a combination of sharp and blunt dissection, due to dense adhesions that had developed after earlier abdominal surgery. Because the ObGyn had never repaired a vesicovaginal fistula before, he should have requested the assistance of a urologist or urogynecologist. A peritoneal flap should have been used during the initial repair.

PHYSICIAN’S DEFENSE Referral to a urologist or urogynecologist had been offered to the patient, but was refused (no record of this was found in the patient’s file). There was no negligence in the attempted repair.

VERDICT  A $387,000 Virginia verdict was returned.

Did she really need that hysterectomy?
A 31-year-old woman went to the ED with sudden, severe abdominal pain. The radiologist noted that the patient’s appendix could not be visualized on computed tomography (CT) because it was behind the cecum. A general surgeon interpreted the report as ruling out appendicitis, made a diagnosis of pelvic inflammatory disease, and requested a gynecologic consult. An ObGyn sent his nurse practitioner to see the patient in the ED. The patient was discharged and instructed to follow up with the ObGyn.

When the patient’s condition worsened 2 days later, she returned to the ED. The ObGyn performed laparoscopic exploratory surgery. When he could not find the appendix, he called the general surgeon. The surgeon was in his car, and told the ObGyn that it was unnecessary to visualize the appendix; the ObGyn could complete the surgery. The patient was again discharged without a firm diagnosis. She was readmitted to the hospital several hours after discharge and treated for sepsis.

She was in and out of the hospital several times during the next 7 weeks until the ObGyn told her that the only way to cure her pain was to perform a partial hysterectomy. He scheduled a concurrent prophylactic appendectomy by the general surgeon. At surgery, the surgeon found and removed a burst appendix. The ObGyn then performed a hysterectomy, although he had been present during the appendectomy.

PATIENT’S CLAIM Any general surgeon could have come into the operating room during exploratory surgery to assist in ruling out appendicitis; there were other general surgeons available at the hospital. The ObGyn was negligent in performing the hysterectomy after the surgeon had performed the appendectomy.

PHYSICIAN’S DEFENSE The general surgeon died before the case could be deposed. The ObGyn admitted that the removal of the burst appendix resolved the patient’s medical problems; her uterus had not been damaged by sepsis.

VERDICT A $350,000 Michigan settlement was reached.

Erb’s palsy: $1.7M net award
At 38 weeks’ gestation, a mother went to the local ED reporting shortness of breath. She was transferred to a university medical center where a chest x-ray revealed what was thought to be pneumonia or a pulmonary embolism. The decision was made to induce labor. During vaginal delivery, shoulder dystocia was encountered.

The 3-year-old child has Erb’s palsy and, despite treatment and therapy, does not have full use of her left arm and shoulder.  

PARENTS’ CLAIM Maneuvers undertaken to relieve shoulder dystocia were not properly performed, injuring the baby. A cesarean delivery should have been performed because of the mother’s condition.

DEFENDANTS’ DEFENSE Proper maneuvers were used. There was no medical necessity for emergency cesarean delivery.

VERDICT A $3 million Maryland verdict was returned. After state caps and recalculation of a lost-wages claim from the mother due to jury error, the net award was $1.7 million.

Was nonreassuring fetal heart rate ignored?
In her third trimester, a 20-year-old woman was admitted to the hospital for observation, which included fetal heart-rate monitoring.

After 2 days, the patient began to bleed vaginally, and the nurses called the ObGyn. When he came to the hospital, he performed emergency cesarean delivery. The fetus was stillborn.

PATIENT’S CLAIM The nurses failed to inform the ObGyn when nonreassuring fetal heart-rate monitoring results were first evident. The ObGyn did not come to the hospital immediately after being told about the vaginal bleeding. The surgical team was not ready when it was time for the cesarean delivery.

DEFENDANTS’ DEFENSE The case was tried against the hospital that employed the nurses and ObGyn. The hospital claimed that fetal demise was caused by a sudden placental abruption. The nurses’ actions were appropriate. The hospital faulted the ObGyn for not coming to the hospital when summoned by the nurses.

VERDICT A $100,000 Louisiana verdict was returned. The jury found the ObGyn 99% at fault and the hospital 1% at fault. The patient was awarded $100,000 from the Patient’s Compensation Fund; the hospital paid $1,000.

Patient says wrong ovary was removed
A woman saw her ObGyn (Dr. A) because of lower abdominal pain. Dr. A performed laparoscopic right salpingo-oophorectomy.

A tumor on the left ovary was found 5 months later, and a second operation was performed by another ObGyn (Dr. B) with Dr. A’s assistance. During this surgery, the patient’s sigmoid colon was injured; a fistula developed and a third operation was required to repair the colon. 

PATIENT’S CLAIM The initial plan was to remove the left ovary. When Dr. Aremoved the right ovary instead of the left, the patient experienced sudden onset of menopause; the left ovary was nonfunctional. Dr. B was negligent in injuring the sigmoid colon.

PHYSICIANS’ DEFENSE Dr. B was released from the case because colon injury is a known complication of the procedure. Dr. A claimed that the radiologic film of the mass was misleading, and that the ovary he removed was diseased.

VERDICT A Virginia defense verdict was returned.

Second pregnancy ends in injury after shoulder dystocia
A mother told her new ObGyn that, during the birth of her first child a few years earlier, shoulder dystocia had been encountered. Although the baby was born unharmed, her prior ObGyn had recommended that she undergo cesarean delivery for future pregnancies. During the second pregnancy, the mother and new ObGyn discussed the possibility of a trial of labor and vaginal delivery.

When the mother went into labor at 37 weeks’ gestation, the ObGyn believed the child was of normal weight and proceeded with a vaginal delivery. When shoulder dystocia was encountered, various maneuvers were performed. Birth occurred 5 minutes later using moderate traction.

The child showed no signs of life at birth; Apgar scores were 0 for more than 14 minutes. The newborn was sent to the neonatal intensive care unit and later airlifted to another hospital. He had hypoxic ischemic encephalopathy and a C5–C6 brachial plexus injury.

Additional testing revealed that he has neurocognitive deficits including attention deficit hyperactivity disorder and executive function disabilities. 

Parents’ claim The ObGyn was negligent in failing to fully explain the risks of vaginal delivery, failing to recommend cesarean delivery based on the patient’s history and prior physician’s recommendation. The ObGyn failed to perform ultrasonography when the mother was admitted to the hospital; such imaging would have revealed that the fetus was larger than her first baby, mandating cesarean delivery. The ObGyn failed to perform an episiotomy after dystocia was encountered, and he applied excessive traction during dystocial maneuvers.

PHYSICIAN’S DEFENSE The mother was extensively counseled on the risks of vaginal delivery, but the ObGyn admitted that he did not recommend a cesarean delivery. Ultrasonography would have had no benefit. The use of moderate traction was necessary to prevent severe brain damage or death. The child’s current deficits are not related to his birth.

VERDICT The hospital settled for $85,000 before the trial began. An Illinois defense verdict was returned for the ObGyn.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

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

“THE FDA’S REVIEW OF THE DATA ON OPEN POWER MORCELLATION WAS INADEQUATE”
WILLIAM H. PARKER, MD (AUDIO; NOVEMBER 2014)

Why is traditional open myomectomy acceptable if power morcellation isn’t?
The actions taken by the US Food and Drug Administration (FDA) and medical device companies to limit use of power morcellation have effectively led to a halt in the use of minimally invasive surgery for removal of large uterine fibroids. This would seem to leave open laparotomy as the only viable choice for the conservative removal of these benign tumors in women who choose to retain their uterus for personal, cultural, or childbearing reasons. Or does it?

Any open myomectomy of an intramural or subserosal myoma involves an incision into the uterine serosa and muscularis, thus exposing the surface of the tumor to the peritoneal environment. The mass is then grasped with penetrating instruments and manipulated free of its myometrial attachments with other instruments such as forceps, scissors, and electrocautery devices. Suction instruments are freely employed over the operative field. The gloved digits of the surgeon are frequently used to bluntly dissect the tumor from the surrounding myometrial bed.

Because of the desire to maximize future fertility potential by minimizing adhesions, frequent irrigation is considered by most reproductive surgeons to be a necessary part of good surgical technique. Irrigation hydrates the tissues and carries away blood, but it can be counted on to disperse countless cells from the exposed surface of the tumor. After resection, the tumor is removed from the operative field and handed off, usually to the gloved hand of an assistant who will be handling all of the tools that are used from that point forward. If an abscess is a “dirty case” from the standpoint of the spread of infection, then any myomectomy is a potentially “dirty case” from the standpoint of the spread of neoplasia. Given the fundamental nature of this procedure, there seems to be no way to do a “clean” myomectomy. 

Since any form of myomectomy involves at least as much manipulation of the tumor mass as morcellation, it should be at least as likely as morcellation to spread aberrant cells. An inadvertent exposure of the unprotected surface of a leiomyosarcoma at the time of a traditional open myomectomy is not different in any essential way from the exposure of the surface of the same tumor at the time of a myomectomy followed by any type of morcellation. 

It is logical then that if morcellation can be proscribed by regulation and litigation, myomectomy itself will be proscribed on the exact same lines of reasoning.

Despite the widespread use of either abdominal or minimally invasive myomectomy over the last 75 years, disseminated uterine leiomyosarcoma is now and always has been a rare disease. This fact has always been accounted for in our risk assessments of leiomyoma surgeries. In addition, there is no scientific evidence that power morcellation, nonpowered morcellation, or abdominal myomectomy without morcellation has ever been causative in the spread of even one patient’s leiomyosarcoma. Leiomyosarcoma is by definition capable of disseminating by itself.

No medical authority would recommend total hysterectomy for every patient with any myoma, based on the possibility that any individual patient might be harboring a uterine cancer that can spread. This is, however, the exact evolutionary endpoint of the reasoning of the FDA and our legal system. The device companies are to be the deep pockets of the morcellation lawsuits and physicians will be the deep pockets of future myomectomy lawsuits. Gynecologists have always considered risk/reward factors in decisions regarding myomectomy and morcellation. We have an obligation to defend the reproductive rights of our patients. Lawyers, regulators, and even the corporations that dominate the medical device market are motivated by other concerns.

The practice of modern medicine aggressively challenges clinical decision-making based solely on anecdotal evidence. It has done so for well over a century now. It is one of the few standards that still unites good doctors under the battered and tattered umbrella of our professionalism. Our challenge as modern physicians is to stand fast against our new regulatory masters (as well as their former and future law partners) with their grave misunderstandings of the very character of gynecologic decision-making.
Michael C. Doody, MD, PhD
Knoxville, Tennessee
 

“THE EXTRACORPOREAL C-INCISION TISSUE EXTRACTION (EXCITE) TECHNIQUE”
MIREILLE D. TRUONG, MD, AND ARNOLD P. ADVINCULA, MD (VIDEO; NOVEMBER 2014)

Awesome video!
I tried this technique as outlined in the video—totally awesome! It worked really well! Thanks to the surgeons who came up with it!
Ravindhra Mamilla, MD
Thief River Falls, Minnesota
 

“HOW USEFUL IS RANDOM BIOPSY WHEN NO COLPOSCOPIC LESIONS ARE SEEN?”
ANDREW M. KAUNITZ, MD (EXAMINING THE EVIDENCE; OCTOBER 2014)

Additional clarification would be appreciated
According to Dr. Kaunitz’s summary of the findings of Huh and colleagues,¹ the population group included women with low-grade squamous intraepithelial lesions (LSIL) or high-grade squamous intraepithelial lesions (HSIL) (ie, anything above atypical cells of undetermined significance [ASCUS]), along with women who tested positive for human papillomavirus (HPV) 16/18, regardless of cytology.

It would have been useful to have the LSIL and HSIL populations (independent or dependent of HPV status) broken down into subgroups.

The expert commentary does not indicate whether the 2.7% of biopsy-proven cervical ­intraepithelial neoplasia (CIN) 2 and CIN 3 were predominantly confined to women with HSIL or equally prevalent in the LSIL population.

Without this information, I am not convinced that LSIL requires a random biopsy when colposcopy is adequate and normal, regardless of HPV status.
Jonathan Kew
Maitland, New South Wales, Australia

Reference
1. Huh WK, Sideri M, Stoler M, Zhang G, Feldman R, Behrens CM. Relevance of random biopsy at the transformation zone when colposcopy is negative. Obstet Gynecol. 2014;124(4):670–678.

Are we reverting to past practices?
For someone who has done colposcopy for about 35 years, I find the conclusions of Huh and colleagues nonsensical. If the squamocolumnar junction is visible and an endocervical curettage is done, this is adequate. Performing random biopsies takes us back to the days before we had the colposcope. I was there, and I’m not proud of how we handled abnormal Pap results.

Another issue: If you find severe dysplasia on random biopsy in a 40-year-old woman, how and what do you treat? Is this a case of treating the lab and not the patient? Or is this a case of inadequately trained gynecologists and/or pathologists?
Anton Strocel, MD
Grand Blanc, Michigan
 

Dr. Kaunitz responds
I thank Dr. Kew and Dr. Strocel for their interest in this commentary on the value of random biopsies during colposcopy when lesions are not visualized. Dr. Kew is correct that the authors did not separate findings in women with low-grade versus high-grade intraepithelial cytology. Dr. Strocel refers to the value of ­clinical experience when performing colposcopy. Both the current article by Huh and colleagues,¹ as well an earlier high-quality report by Gage and colleagues,² point out that, even in skilled hands, colposcopy is not as sensitive in detecting CIN as we have believed in the past. These reports present convincing evidence that, regardless of clinical experience, when no lesion is seen at the time of colposcopy, performing one or two random biopsies substantially increases diagnostic yield of clinically actionable (CIN 2 or worse) disease. 

References
1. Huh WK, Sideri M, Stoler M, Zhang G, Feldman R, Behrens CM. Relevance of random biopsy at the transformation zone when colposcopy is negative. Obstet Gynecol. 2014;124(4):670–678.

2. Gage JC, Hanson VW, Abbey K, et al. Number of cervical biopsies and sensitivity of colposcopy. Obstet Gynecol. 2006;108(2):264–272.
 

“CONJUGATED ESTROGEN PLUS BAZEDOXIFENE—A NEW APPROACH TO ESTROGEN THERAPY”
ANNE A. MOORE, DNP, APN (CASES IN MENOPAUSE; OCTOBER 2014)

Why not encourage soy intake?
Thanks for an interesting discussion on conjugated estrogen/bazedoxifene (CE/BZA; Duavee). I note that:

• CE/BZA is manufactured by Pfizer
• Dr. JoAnn Pinkerton, who is interviewed by Anne Moore, DNP, APN, is affiliated with Pfizer, and
• CE/BZA costs $120 per month.

Since menopausal symptoms are caused by the decreased production of ovarian estradiol, why not prescribe estradiol 0.5–1 mg, which costs only $4 monthly?

Another point to consider: Over several decades of providing care to ethnically diverse women, my observation is that Japanese/Korean and Latina women report far fewer hot flushes than their white sisters.

I believe that it is because of their soy and yam intake. I personally eat about 0.25 lb of tofu per week. It can be diced for salad or soup or served with soy sauce, ginger, and bonito (fish) flakes. It can also be crushed and mixed with lean ground beef, pork, chicken, or turkey to make lean, healthy meatloaf.

Tofu is rich in phytoestrogens, lowers cholesterol, and promotes local soy farmers—a win-win situation.
Yasuo Ishida, MD
St. Louis, Missouri
 

‡‡Dr. Barbieri responds
Dr. Ishida raises an important issue of managing conflicts of interest in medical publications. Dr. Ishida notes that, in the past, Dr. Pinkerton was supported by Pfizer, the company that manufactures (CE/BZA, Duavee). Dr. Ishida also points out that, in a recent OBG Management article, Dr. Pinkerton provided her clinical perspective on the use of CE/BZA in practice.

Often, with a new medication, the physicians with the most expertise in using it have helped with key clinical trials. The results of these trials provide the basis for FDA approval of the medication. Prior to FDA approval of a drug, only experts involved in the clinical trial have first-hand experience with the new treatment.

Dr. Pinkerton is an internationally respected expert in the field and provided a balanced overview of CE/BZA and how it might be used in practice. Dr. Pinkerton disclosed that she personally receives no current support from Pfizer, but that she was supported by Pfizer years ago.

This potential conflict of interest was reported in the article.

Dr. Pinkerton responds
I am proud to serve as a key researcher, consultant, and writer for publications exploring the newest hormonal option for menopausal women—CE/BZA. All of my contracting and fees for my research and consulting with Pfizer have been paid through the University of Virginia, not to me personally. This allows me to be involved in innovative women’s health research and disseminate results without the same conflicts as those who receive reimbursements directly from Pfizer. My relationship to any pharmaceutical company with which I am involved is always through my university and disclosed on every paper, presentation, and talk that I give.

The best way to learn about the pros and cons of a product is to be involved in the sentinel research, to have access to all data, including adverse effects, and to be able to evaluate who might be the best candidates for a new product in women’s health.

Although oral estradiol is inexpensive, women with a uterus also need a progestogen to protect against uterine cancer. It appears that the combination of estrogen and synthetic progestins carry a greater risk of breast cancer than estrogen alone. Estradiol is also available as a patch, gel, lotion, and ring but, again, needs to be paired with a progestogen if a woman has a uterus.

This new drug is well established in published randomized clinical trial data as an effective alternative to traditional estrogen-progestogen therapy (EPT) in symptomatic postmenopausal women with a uterus. Results from Selective Estrogens, Menopause, and Response to Therapy (SMART)¹ randomized controlled trials (RCTs) have shown improvements in symptoms similar to those seen with EPT. These include a reduction in hot flash frequency and severity; a reduction in night sweats, with fewer sleep disruptions; and bone loss prevention. The effects on total cholesterol (an increase in triglycerides) and the drug’s mild effect on vulvovaginal atrophy (VVA) also are similar to those observed with EPT. The drug has a neutral effect on breast tenderness, breast density, and the risk of breast cancer.^1,2 It also protects against endometrial hyperplasia and cancer and increases amenorrhea rates. VTE and stroke risks are expected to be similar to traditional oral hormone therapy (HT). The major benefit of CE/BZA, compared with traditional EPT, is the lack of significant breast tenderness and changes in breast density or vaginal bleeding often seen with traditional EPT.³ 

As for the benefits of soy for menopausal women, clinical data imply that phytoestrogens and soy foods may be of benefit for postmenopausal women. According to a recent review article by Messina⁴ (an international authority on phytoestrogens), isoflavone supplements relieve menopausal hot flashes if they have enough of the isoflavone genistein. Soy has shown benefits with regard to ischemic heart disease—by lowering low-density lipoprotein (LDL) levels and providing a source of omega fatty acids. However, no clear effect has been seen with soy for the prevention of bone loss. The effect on breast cancer risk is unclear. Soy binds to estrogen receptors, which could be harmful. However, soy may bind preferentially to estrogen-receptor beta, thus acting more SERM-like or protective, particularly if given during childhood or adolescence.

For any woman, the decision about using a food source, such as tofu, or isoflavone-rich supplements, such as one containing equol, should be based on a discussion with her clinician regarding her individual needs and the risks and benefits of all options.

In our Midlife Clinic at University of Virginia, we discuss over-the-counter products, lifestyle and dietary changes, and nonhormonal and hormonal options with our patients to help them identify the best choices.

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

“THE FDA’S REVIEW OF THE DATA ON OPEN POWER MORCELLATION WAS INADEQUATE”
WILLIAM H. PARKER, MD (AUDIO; NOVEMBER 2014)

Why is traditional open myomectomy acceptable if power morcellation isn’t?
The actions taken by the US Food and Drug Administration (FDA) and medical device companies to limit use of power morcellation have effectively led to a halt in the use of minimally invasive surgery for removal of large uterine fibroids. This would seem to leave open laparotomy as the only viable choice for the conservative removal of these benign tumors in women who choose to retain their uterus for personal, cultural, or childbearing reasons. Or does it?

Any open myomectomy of an intramural or subserosal myoma involves an incision into the uterine serosa and muscularis, thus exposing the surface of the tumor to the peritoneal environment. The mass is then grasped with penetrating instruments and manipulated free of its myometrial attachments with other instruments such as forceps, scissors, and electrocautery devices. Suction instruments are freely employed over the operative field. The gloved digits of the surgeon are frequently used to bluntly dissect the tumor from the surrounding myometrial bed.

Because of the desire to maximize future fertility potential by minimizing adhesions, frequent irrigation is considered by most reproductive surgeons to be a necessary part of good surgical technique. Irrigation hydrates the tissues and carries away blood, but it can be counted on to disperse countless cells from the exposed surface of the tumor. After resection, the tumor is removed from the operative field and handed off, usually to the gloved hand of an assistant who will be handling all of the tools that are used from that point forward. If an abscess is a “dirty case” from the standpoint of the spread of infection, then any myomectomy is a potentially “dirty case” from the standpoint of the spread of neoplasia. Given the fundamental nature of this procedure, there seems to be no way to do a “clean” myomectomy. 

Since any form of myomectomy involves at least as much manipulation of the tumor mass as morcellation, it should be at least as likely as morcellation to spread aberrant cells. An inadvertent exposure of the unprotected surface of a leiomyosarcoma at the time of a traditional open myomectomy is not different in any essential way from the exposure of the surface of the same tumor at the time of a myomectomy followed by any type of morcellation. 

It is logical then that if morcellation can be proscribed by regulation and litigation, myomectomy itself will be proscribed on the exact same lines of reasoning.

Despite the widespread use of either abdominal or minimally invasive myomectomy over the last 75 years, disseminated uterine leiomyosarcoma is now and always has been a rare disease. This fact has always been accounted for in our risk assessments of leiomyoma surgeries. In addition, there is no scientific evidence that power morcellation, nonpowered morcellation, or abdominal myomectomy without morcellation has ever been causative in the spread of even one patient’s leiomyosarcoma. Leiomyosarcoma is by definition capable of disseminating by itself.

No medical authority would recommend total hysterectomy for every patient with any myoma, based on the possibility that any individual patient might be harboring a uterine cancer that can spread. This is, however, the exact evolutionary endpoint of the reasoning of the FDA and our legal system. The device companies are to be the deep pockets of the morcellation lawsuits and physicians will be the deep pockets of future myomectomy lawsuits. Gynecologists have always considered risk/reward factors in decisions regarding myomectomy and morcellation. We have an obligation to defend the reproductive rights of our patients. Lawyers, regulators, and even the corporations that dominate the medical device market are motivated by other concerns.

The practice of modern medicine aggressively challenges clinical decision-making based solely on anecdotal evidence. It has done so for well over a century now. It is one of the few standards that still unites good doctors under the battered and tattered umbrella of our professionalism. Our challenge as modern physicians is to stand fast against our new regulatory masters (as well as their former and future law partners) with their grave misunderstandings of the very character of gynecologic decision-making.
Michael C. Doody, MD, PhD
Knoxville, Tennessee
 

“THE EXTRACORPOREAL C-INCISION TISSUE EXTRACTION (EXCITE) TECHNIQUE”
MIREILLE D. TRUONG, MD, AND ARNOLD P. ADVINCULA, MD (VIDEO; NOVEMBER 2014)

Awesome video!
I tried this technique as outlined in the video—totally awesome! It worked really well! Thanks to the surgeons who came up with it!
Ravindhra Mamilla, MD
Thief River Falls, Minnesota
 

“HOW USEFUL IS RANDOM BIOPSY WHEN NO COLPOSCOPIC LESIONS ARE SEEN?”
ANDREW M. KAUNITZ, MD (EXAMINING THE EVIDENCE; OCTOBER 2014)

Additional clarification would be appreciated
According to Dr. Kaunitz’s summary of the findings of Huh and colleagues,¹ the population group included women with low-grade squamous intraepithelial lesions (LSIL) or high-grade squamous intraepithelial lesions (HSIL) (ie, anything above atypical cells of undetermined significance [ASCUS]), along with women who tested positive for human papillomavirus (HPV) 16/18, regardless of cytology.

It would have been useful to have the LSIL and HSIL populations (independent or dependent of HPV status) broken down into subgroups.

The expert commentary does not indicate whether the 2.7% of biopsy-proven cervical ­intraepithelial neoplasia (CIN) 2 and CIN 3 were predominantly confined to women with HSIL or equally prevalent in the LSIL population.

Without this information, I am not convinced that LSIL requires a random biopsy when colposcopy is adequate and normal, regardless of HPV status.
Jonathan Kew
Maitland, New South Wales, Australia

Reference
1. Huh WK, Sideri M, Stoler M, Zhang G, Feldman R, Behrens CM. Relevance of random biopsy at the transformation zone when colposcopy is negative. Obstet Gynecol. 2014;124(4):670–678.

Are we reverting to past practices?
For someone who has done colposcopy for about 35 years, I find the conclusions of Huh and colleagues nonsensical. If the squamocolumnar junction is visible and an endocervical curettage is done, this is adequate. Performing random biopsies takes us back to the days before we had the colposcope. I was there, and I’m not proud of how we handled abnormal Pap results.

Another issue: If you find severe dysplasia on random biopsy in a 40-year-old woman, how and what do you treat? Is this a case of treating the lab and not the patient? Or is this a case of inadequately trained gynecologists and/or pathologists?
Anton Strocel, MD
Grand Blanc, Michigan
 

Dr. Kaunitz responds
I thank Dr. Kew and Dr. Strocel for their interest in this commentary on the value of random biopsies during colposcopy when lesions are not visualized. Dr. Kew is correct that the authors did not separate findings in women with low-grade versus high-grade intraepithelial cytology. Dr. Strocel refers to the value of ­clinical experience when performing colposcopy. Both the current article by Huh and colleagues,¹ as well an earlier high-quality report by Gage and colleagues,² point out that, even in skilled hands, colposcopy is not as sensitive in detecting CIN as we have believed in the past. These reports present convincing evidence that, regardless of clinical experience, when no lesion is seen at the time of colposcopy, performing one or two random biopsies substantially increases diagnostic yield of clinically actionable (CIN 2 or worse) disease. 

References
1. Huh WK, Sideri M, Stoler M, Zhang G, Feldman R, Behrens CM. Relevance of random biopsy at the transformation zone when colposcopy is negative. Obstet Gynecol. 2014;124(4):670–678.

2. Gage JC, Hanson VW, Abbey K, et al. Number of cervical biopsies and sensitivity of colposcopy. Obstet Gynecol. 2006;108(2):264–272.
 

“CONJUGATED ESTROGEN PLUS BAZEDOXIFENE—A NEW APPROACH TO ESTROGEN THERAPY”
ANNE A. MOORE, DNP, APN (CASES IN MENOPAUSE; OCTOBER 2014)

Why not encourage soy intake?
Thanks for an interesting discussion on conjugated estrogen/bazedoxifene (CE/BZA; Duavee). I note that:

• CE/BZA is manufactured by Pfizer
• Dr. JoAnn Pinkerton, who is interviewed by Anne Moore, DNP, APN, is affiliated with Pfizer, and
• CE/BZA costs $120 per month.

Since menopausal symptoms are caused by the decreased production of ovarian estradiol, why not prescribe estradiol 0.5–1 mg, which costs only $4 monthly?

Another point to consider: Over several decades of providing care to ethnically diverse women, my observation is that Japanese/Korean and Latina women report far fewer hot flushes than their white sisters.

I believe that it is because of their soy and yam intake. I personally eat about 0.25 lb of tofu per week. It can be diced for salad or soup or served with soy sauce, ginger, and bonito (fish) flakes. It can also be crushed and mixed with lean ground beef, pork, chicken, or turkey to make lean, healthy meatloaf.

Tofu is rich in phytoestrogens, lowers cholesterol, and promotes local soy farmers—a win-win situation.
Yasuo Ishida, MD
St. Louis, Missouri
 

‡‡Dr. Barbieri responds
Dr. Ishida raises an important issue of managing conflicts of interest in medical publications. Dr. Ishida notes that, in the past, Dr. Pinkerton was supported by Pfizer, the company that manufactures (CE/BZA, Duavee). Dr. Ishida also points out that, in a recent OBG Management article, Dr. Pinkerton provided her clinical perspective on the use of CE/BZA in practice.

Often, with a new medication, the physicians with the most expertise in using it have helped with key clinical trials. The results of these trials provide the basis for FDA approval of the medication. Prior to FDA approval of a drug, only experts involved in the clinical trial have first-hand experience with the new treatment.

Dr. Pinkerton is an internationally respected expert in the field and provided a balanced overview of CE/BZA and how it might be used in practice. Dr. Pinkerton disclosed that she personally receives no current support from Pfizer, but that she was supported by Pfizer years ago.

This potential conflict of interest was reported in the article.

Dr. Pinkerton responds
I am proud to serve as a key researcher, consultant, and writer for publications exploring the newest hormonal option for menopausal women—CE/BZA. All of my contracting and fees for my research and consulting with Pfizer have been paid through the University of Virginia, not to me personally. This allows me to be involved in innovative women’s health research and disseminate results without the same conflicts as those who receive reimbursements directly from Pfizer. My relationship to any pharmaceutical company with which I am involved is always through my university and disclosed on every paper, presentation, and talk that I give.

The best way to learn about the pros and cons of a product is to be involved in the sentinel research, to have access to all data, including adverse effects, and to be able to evaluate who might be the best candidates for a new product in women’s health.

Although oral estradiol is inexpensive, women with a uterus also need a progestogen to protect against uterine cancer. It appears that the combination of estrogen and synthetic progestins carry a greater risk of breast cancer than estrogen alone. Estradiol is also available as a patch, gel, lotion, and ring but, again, needs to be paired with a progestogen if a woman has a uterus.

This new drug is well established in published randomized clinical trial data as an effective alternative to traditional estrogen-progestogen therapy (EPT) in symptomatic postmenopausal women with a uterus. Results from Selective Estrogens, Menopause, and Response to Therapy (SMART)¹ randomized controlled trials (RCTs) have shown improvements in symptoms similar to those seen with EPT. These include a reduction in hot flash frequency and severity; a reduction in night sweats, with fewer sleep disruptions; and bone loss prevention. The effects on total cholesterol (an increase in triglycerides) and the drug’s mild effect on vulvovaginal atrophy (VVA) also are similar to those observed with EPT. The drug has a neutral effect on breast tenderness, breast density, and the risk of breast cancer.^1,2 It also protects against endometrial hyperplasia and cancer and increases amenorrhea rates. VTE and stroke risks are expected to be similar to traditional oral hormone therapy (HT). The major benefit of CE/BZA, compared with traditional EPT, is the lack of significant breast tenderness and changes in breast density or vaginal bleeding often seen with traditional EPT.³ 

As for the benefits of soy for menopausal women, clinical data imply that phytoestrogens and soy foods may be of benefit for postmenopausal women. According to a recent review article by Messina⁴ (an international authority on phytoestrogens), isoflavone supplements relieve menopausal hot flashes if they have enough of the isoflavone genistein. Soy has shown benefits with regard to ischemic heart disease—by lowering low-density lipoprotein (LDL) levels and providing a source of omega fatty acids. However, no clear effect has been seen with soy for the prevention of bone loss. The effect on breast cancer risk is unclear. Soy binds to estrogen receptors, which could be harmful. However, soy may bind preferentially to estrogen-receptor beta, thus acting more SERM-like or protective, particularly if given during childhood or adolescence.

For any woman, the decision about using a food source, such as tofu, or isoflavone-rich supplements, such as one containing equol, should be based on a discussion with her clinician regarding her individual needs and the risks and benefits of all options.

In our Midlife Clinic at University of Virginia, we discuss over-the-counter products, lifestyle and dietary changes, and nonhormonal and hormonal options with our patients to help them identify the best choices.

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

“THE FDA’S REVIEW OF THE DATA ON OPEN POWER MORCELLATION WAS INADEQUATE”
WILLIAM H. PARKER, MD (AUDIO; NOVEMBER 2014)

Why is traditional open myomectomy acceptable if power morcellation isn’t?
The actions taken by the US Food and Drug Administration (FDA) and medical device companies to limit use of power morcellation have effectively led to a halt in the use of minimally invasive surgery for removal of large uterine fibroids. This would seem to leave open laparotomy as the only viable choice for the conservative removal of these benign tumors in women who choose to retain their uterus for personal, cultural, or childbearing reasons. Or does it?

Any open myomectomy of an intramural or subserosal myoma involves an incision into the uterine serosa and muscularis, thus exposing the surface of the tumor to the peritoneal environment. The mass is then grasped with penetrating instruments and manipulated free of its myometrial attachments with other instruments such as forceps, scissors, and electrocautery devices. Suction instruments are freely employed over the operative field. The gloved digits of the surgeon are frequently used to bluntly dissect the tumor from the surrounding myometrial bed.

Because of the desire to maximize future fertility potential by minimizing adhesions, frequent irrigation is considered by most reproductive surgeons to be a necessary part of good surgical technique. Irrigation hydrates the tissues and carries away blood, but it can be counted on to disperse countless cells from the exposed surface of the tumor. After resection, the tumor is removed from the operative field and handed off, usually to the gloved hand of an assistant who will be handling all of the tools that are used from that point forward. If an abscess is a “dirty case” from the standpoint of the spread of infection, then any myomectomy is a potentially “dirty case” from the standpoint of the spread of neoplasia. Given the fundamental nature of this procedure, there seems to be no way to do a “clean” myomectomy. 

Since any form of myomectomy involves at least as much manipulation of the tumor mass as morcellation, it should be at least as likely as morcellation to spread aberrant cells. An inadvertent exposure of the unprotected surface of a leiomyosarcoma at the time of a traditional open myomectomy is not different in any essential way from the exposure of the surface of the same tumor at the time of a myomectomy followed by any type of morcellation. 

It is logical then that if morcellation can be proscribed by regulation and litigation, myomectomy itself will be proscribed on the exact same lines of reasoning.

Despite the widespread use of either abdominal or minimally invasive myomectomy over the last 75 years, disseminated uterine leiomyosarcoma is now and always has been a rare disease. This fact has always been accounted for in our risk assessments of leiomyoma surgeries. In addition, there is no scientific evidence that power morcellation, nonpowered morcellation, or abdominal myomectomy without morcellation has ever been causative in the spread of even one patient’s leiomyosarcoma. Leiomyosarcoma is by definition capable of disseminating by itself.

No medical authority would recommend total hysterectomy for every patient with any myoma, based on the possibility that any individual patient might be harboring a uterine cancer that can spread. This is, however, the exact evolutionary endpoint of the reasoning of the FDA and our legal system. The device companies are to be the deep pockets of the morcellation lawsuits and physicians will be the deep pockets of future myomectomy lawsuits. Gynecologists have always considered risk/reward factors in decisions regarding myomectomy and morcellation. We have an obligation to defend the reproductive rights of our patients. Lawyers, regulators, and even the corporations that dominate the medical device market are motivated by other concerns.

The practice of modern medicine aggressively challenges clinical decision-making based solely on anecdotal evidence. It has done so for well over a century now. It is one of the few standards that still unites good doctors under the battered and tattered umbrella of our professionalism. Our challenge as modern physicians is to stand fast against our new regulatory masters (as well as their former and future law partners) with their grave misunderstandings of the very character of gynecologic decision-making.
Michael C. Doody, MD, PhD
Knoxville, Tennessee
 

“THE EXTRACORPOREAL C-INCISION TISSUE EXTRACTION (EXCITE) TECHNIQUE”
MIREILLE D. TRUONG, MD, AND ARNOLD P. ADVINCULA, MD (VIDEO; NOVEMBER 2014)

Awesome video!
I tried this technique as outlined in the video—totally awesome! It worked really well! Thanks to the surgeons who came up with it!
Ravindhra Mamilla, MD
Thief River Falls, Minnesota
 

“HOW USEFUL IS RANDOM BIOPSY WHEN NO COLPOSCOPIC LESIONS ARE SEEN?”
ANDREW M. KAUNITZ, MD (EXAMINING THE EVIDENCE; OCTOBER 2014)

Additional clarification would be appreciated
According to Dr. Kaunitz’s summary of the findings of Huh and colleagues,¹ the population group included women with low-grade squamous intraepithelial lesions (LSIL) or high-grade squamous intraepithelial lesions (HSIL) (ie, anything above atypical cells of undetermined significance [ASCUS]), along with women who tested positive for human papillomavirus (HPV) 16/18, regardless of cytology.

It would have been useful to have the LSIL and HSIL populations (independent or dependent of HPV status) broken down into subgroups.

The expert commentary does not indicate whether the 2.7% of biopsy-proven cervical ­intraepithelial neoplasia (CIN) 2 and CIN 3 were predominantly confined to women with HSIL or equally prevalent in the LSIL population.

Without this information, I am not convinced that LSIL requires a random biopsy when colposcopy is adequate and normal, regardless of HPV status.
Jonathan Kew
Maitland, New South Wales, Australia

Reference
1. Huh WK, Sideri M, Stoler M, Zhang G, Feldman R, Behrens CM. Relevance of random biopsy at the transformation zone when colposcopy is negative. Obstet Gynecol. 2014;124(4):670–678.

Are we reverting to past practices?
For someone who has done colposcopy for about 35 years, I find the conclusions of Huh and colleagues nonsensical. If the squamocolumnar junction is visible and an endocervical curettage is done, this is adequate. Performing random biopsies takes us back to the days before we had the colposcope. I was there, and I’m not proud of how we handled abnormal Pap results.

Another issue: If you find severe dysplasia on random biopsy in a 40-year-old woman, how and what do you treat? Is this a case of treating the lab and not the patient? Or is this a case of inadequately trained gynecologists and/or pathologists?
Anton Strocel, MD
Grand Blanc, Michigan
 

Dr. Kaunitz responds
I thank Dr. Kew and Dr. Strocel for their interest in this commentary on the value of random biopsies during colposcopy when lesions are not visualized. Dr. Kew is correct that the authors did not separate findings in women with low-grade versus high-grade intraepithelial cytology. Dr. Strocel refers to the value of ­clinical experience when performing colposcopy. Both the current article by Huh and colleagues,¹ as well an earlier high-quality report by Gage and colleagues,² point out that, even in skilled hands, colposcopy is not as sensitive in detecting CIN as we have believed in the past. These reports present convincing evidence that, regardless of clinical experience, when no lesion is seen at the time of colposcopy, performing one or two random biopsies substantially increases diagnostic yield of clinically actionable (CIN 2 or worse) disease. 

References
1. Huh WK, Sideri M, Stoler M, Zhang G, Feldman R, Behrens CM. Relevance of random biopsy at the transformation zone when colposcopy is negative. Obstet Gynecol. 2014;124(4):670–678.

2. Gage JC, Hanson VW, Abbey K, et al. Number of cervical biopsies and sensitivity of colposcopy. Obstet Gynecol. 2006;108(2):264–272.
 

“CONJUGATED ESTROGEN PLUS BAZEDOXIFENE—A NEW APPROACH TO ESTROGEN THERAPY”
ANNE A. MOORE, DNP, APN (CASES IN MENOPAUSE; OCTOBER 2014)

Why not encourage soy intake?
Thanks for an interesting discussion on conjugated estrogen/bazedoxifene (CE/BZA; Duavee). I note that:

• CE/BZA is manufactured by Pfizer
• Dr. JoAnn Pinkerton, who is interviewed by Anne Moore, DNP, APN, is affiliated with Pfizer, and
• CE/BZA costs $120 per month.

Since menopausal symptoms are caused by the decreased production of ovarian estradiol, why not prescribe estradiol 0.5–1 mg, which costs only $4 monthly?

Another point to consider: Over several decades of providing care to ethnically diverse women, my observation is that Japanese/Korean and Latina women report far fewer hot flushes than their white sisters.

I believe that it is because of their soy and yam intake. I personally eat about 0.25 lb of tofu per week. It can be diced for salad or soup or served with soy sauce, ginger, and bonito (fish) flakes. It can also be crushed and mixed with lean ground beef, pork, chicken, or turkey to make lean, healthy meatloaf.

Tofu is rich in phytoestrogens, lowers cholesterol, and promotes local soy farmers—a win-win situation.
Yasuo Ishida, MD
St. Louis, Missouri
 

‡‡Dr. Barbieri responds
Dr. Ishida raises an important issue of managing conflicts of interest in medical publications. Dr. Ishida notes that, in the past, Dr. Pinkerton was supported by Pfizer, the company that manufactures (CE/BZA, Duavee). Dr. Ishida also points out that, in a recent OBG Management article, Dr. Pinkerton provided her clinical perspective on the use of CE/BZA in practice.

Often, with a new medication, the physicians with the most expertise in using it have helped with key clinical trials. The results of these trials provide the basis for FDA approval of the medication. Prior to FDA approval of a drug, only experts involved in the clinical trial have first-hand experience with the new treatment.

Dr. Pinkerton is an internationally respected expert in the field and provided a balanced overview of CE/BZA and how it might be used in practice. Dr. Pinkerton disclosed that she personally receives no current support from Pfizer, but that she was supported by Pfizer years ago.

This potential conflict of interest was reported in the article.

Dr. Pinkerton responds
I am proud to serve as a key researcher, consultant, and writer for publications exploring the newest hormonal option for menopausal women—CE/BZA. All of my contracting and fees for my research and consulting with Pfizer have been paid through the University of Virginia, not to me personally. This allows me to be involved in innovative women’s health research and disseminate results without the same conflicts as those who receive reimbursements directly from Pfizer. My relationship to any pharmaceutical company with which I am involved is always through my university and disclosed on every paper, presentation, and talk that I give.

The best way to learn about the pros and cons of a product is to be involved in the sentinel research, to have access to all data, including adverse effects, and to be able to evaluate who might be the best candidates for a new product in women’s health.

Although oral estradiol is inexpensive, women with a uterus also need a progestogen to protect against uterine cancer. It appears that the combination of estrogen and synthetic progestins carry a greater risk of breast cancer than estrogen alone. Estradiol is also available as a patch, gel, lotion, and ring but, again, needs to be paired with a progestogen if a woman has a uterus.

This new drug is well established in published randomized clinical trial data as an effective alternative to traditional estrogen-progestogen therapy (EPT) in symptomatic postmenopausal women with a uterus. Results from Selective Estrogens, Menopause, and Response to Therapy (SMART)¹ randomized controlled trials (RCTs) have shown improvements in symptoms similar to those seen with EPT. These include a reduction in hot flash frequency and severity; a reduction in night sweats, with fewer sleep disruptions; and bone loss prevention. The effects on total cholesterol (an increase in triglycerides) and the drug’s mild effect on vulvovaginal atrophy (VVA) also are similar to those observed with EPT. The drug has a neutral effect on breast tenderness, breast density, and the risk of breast cancer.^1,2 It also protects against endometrial hyperplasia and cancer and increases amenorrhea rates. VTE and stroke risks are expected to be similar to traditional oral hormone therapy (HT). The major benefit of CE/BZA, compared with traditional EPT, is the lack of significant breast tenderness and changes in breast density or vaginal bleeding often seen with traditional EPT.³ 

As for the benefits of soy for menopausal women, clinical data imply that phytoestrogens and soy foods may be of benefit for postmenopausal women. According to a recent review article by Messina⁴ (an international authority on phytoestrogens), isoflavone supplements relieve menopausal hot flashes if they have enough of the isoflavone genistein. Soy has shown benefits with regard to ischemic heart disease—by lowering low-density lipoprotein (LDL) levels and providing a source of omega fatty acids. However, no clear effect has been seen with soy for the prevention of bone loss. The effect on breast cancer risk is unclear. Soy binds to estrogen receptors, which could be harmful. However, soy may bind preferentially to estrogen-receptor beta, thus acting more SERM-like or protective, particularly if given during childhood or adolescence.

For any woman, the decision about using a food source, such as tofu, or isoflavone-rich supplements, such as one containing equol, should be based on a discussion with her clinician regarding her individual needs and the risks and benefits of all options.

In our Midlife Clinic at University of Virginia, we discuss over-the-counter products, lifestyle and dietary changes, and nonhormonal and hormonal options with our patients to help them identify the best choices.

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