OBG Management

Of the approximately 1 million benign breast biopsies obtained annually from US women, some 10% yield a diagnosis of atypical hyperplasia, microscopically classified as ductal or lobular. Atypical hyperplasia represents a “proliferation of dysplastic, mono­tonous epithelial-cell populations that include clonal subpopulations. In models of breast carcinogenesis, atypical hyperplasia occupies a transitional zone between benign and malignant disease,” write Hartmann and colleagues, the authors of a recent special report in the New England Journal of Medicine.¹

Long-term follow-up studies have found atypical hyperplasia to confer a relative risk for breast cancer of 4.0. Although these findings are well established, the cumulative absolute risk for breast cancer conferred by a diagnosis of atypical hyperplasia only recently has been described. Hartmann and colleagues note that it approaches 30% over 25 years.¹

Recommendations for clinical practice
The authors of this special report do a service to women and their clinicians by pointing out the high long-term risk of malignancy faced by women with atypical hyperplasia of the breast. They also make a number of important recommendations for practice:

Most women will not develop breast malignancy
As Hartmann and colleagues point out, all is not dire once a woman is diagnosed with atypical hyperplasia of the breast. In most of these women, breast cancer will not develop—and if it does develop, it may occur at an age when mortality from other causes is more likely than from breast cancer. In this respect, women with atypical hyperplasia of the breast are different from carriers of BRCA mutations. Although women with atypical hyperplasia as well as mutation carriers are both at high lifetime risk for breast cancer, breast malignancies occur at an earlier age in mutation carriers. Accordingly, as the authors of this special report advise, in general, a diagnosis of atypical hyperplasia should not be considered an indication for risk-reducing bilateral mastectomy.

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

Of the approximately 1 million benign breast biopsies obtained annually from US women, some 10% yield a diagnosis of atypical hyperplasia, microscopically classified as ductal or lobular. Atypical hyperplasia represents a “proliferation of dysplastic, mono­tonous epithelial-cell populations that include clonal subpopulations. In models of breast carcinogenesis, atypical hyperplasia occupies a transitional zone between benign and malignant disease,” write Hartmann and colleagues, the authors of a recent special report in the New England Journal of Medicine.¹

Long-term follow-up studies have found atypical hyperplasia to confer a relative risk for breast cancer of 4.0. Although these findings are well established, the cumulative absolute risk for breast cancer conferred by a diagnosis of atypical hyperplasia only recently has been described. Hartmann and colleagues note that it approaches 30% over 25 years.¹

Recommendations for clinical practice
The authors of this special report do a service to women and their clinicians by pointing out the high long-term risk of malignancy faced by women with atypical hyperplasia of the breast. They also make a number of important recommendations for practice:

Most women will not develop breast malignancy
As Hartmann and colleagues point out, all is not dire once a woman is diagnosed with atypical hyperplasia of the breast. In most of these women, breast cancer will not develop—and if it does develop, it may occur at an age when mortality from other causes is more likely than from breast cancer. In this respect, women with atypical hyperplasia of the breast are different from carriers of BRCA mutations. Although women with atypical hyperplasia as well as mutation carriers are both at high lifetime risk for breast cancer, breast malignancies occur at an earlier age in mutation carriers. Accordingly, as the authors of this special report advise, in general, a diagnosis of atypical hyperplasia should not be considered an indication for risk-reducing bilateral mastectomy.

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

Of the approximately 1 million benign breast biopsies obtained annually from US women, some 10% yield a diagnosis of atypical hyperplasia, microscopically classified as ductal or lobular. Atypical hyperplasia represents a “proliferation of dysplastic, mono­tonous epithelial-cell populations that include clonal subpopulations. In models of breast carcinogenesis, atypical hyperplasia occupies a transitional zone between benign and malignant disease,” write Hartmann and colleagues, the authors of a recent special report in the New England Journal of Medicine.¹

Long-term follow-up studies have found atypical hyperplasia to confer a relative risk for breast cancer of 4.0. Although these findings are well established, the cumulative absolute risk for breast cancer conferred by a diagnosis of atypical hyperplasia only recently has been described. Hartmann and colleagues note that it approaches 30% over 25 years.¹

Recommendations for clinical practice
The authors of this special report do a service to women and their clinicians by pointing out the high long-term risk of malignancy faced by women with atypical hyperplasia of the breast. They also make a number of important recommendations for practice:

Most women will not develop breast malignancy
As Hartmann and colleagues point out, all is not dire once a woman is diagnosed with atypical hyperplasia of the breast. In most of these women, breast cancer will not develop—and if it does develop, it may occur at an age when mortality from other causes is more likely than from breast cancer. In this respect, women with atypical hyperplasia of the breast are different from carriers of BRCA mutations. Although women with atypical hyperplasia as well as mutation carriers are both at high lifetime risk for breast cancer, breast malignancies occur at an earlier age in mutation carriers. Accordingly, as the authors of this special report advise, in general, a diagnosis of atypical hyperplasia should not be considered an indication for risk-reducing bilateral mastectomy.

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

As new options for managing menopausal symptoms emerge, so do data on their efficacy and safety. In this article, I highlight the following publications:

After long-term follow-up of WHI participants, a “critical window” of HT timing is revealed
Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310(13):1353–1368.

After the initial 2002 publication of findings from the WHI trial of women with an intact uterus who were randomized to conjugated equine estrogens and medroxyprogesterone acetate or placebo, prominent news headlines claimed that HT causes myocardial infarction (MI) and breast cancer. As a result, millions of women worldwide stopped taking HT. A second impact of the report: Many clinicians became reluctant to prescribe HT.

Although it generated far less media attention, an October 2013 publication from the Journal of the American Medical Association, which details 13-year follow-up of WHI HT clinical trial participants, better informs clinicians and our patients about HT’s safety profile.

During the WHI intervention phase, absolute risks were modest
Although HT was associated with a multifaceted pattern of benefits and risks in both the ­estrogen-progestin therapy (EPT) and ­estrogen-only therapy (ET) arms of the WHI, absolute risks, as reflected in an increase or decrease in the number of cases per 10,000 women treated per year, were modest.

For example, the hazard ratio (HR) for coronary heart disease (CHD) ­during the intervention phase, during which ­participants were given HT or placebo (mean 5.2 years for EPT and 6.8 years for ET) was 1.18 in the EPT arm (95% confidence interval [CI], 0.95–1.45) and 0.94 in the ET arm (95% CI, 0.78–1.14). In both arms, women given HT had reduced risks of vasomotor symptoms, hip fractures, and diabetes, and increased risks of stroke, venous thromboembolism (VTE), and gallbladder disease, compared with women receiving placebo.

The results for breast cancer differed markedly between arms. During the intervention period, an elevated risk was observed with EPT while a borderline reduced risk was observed with ET.

Among participants older than 65 years at baseline, the risk of cognitive decline was increased in the EPT arm but not in the ET arm.

Post intervention, most risks and benefits attenuated
An elevation in the risk of breast cancer persisted in the EPT arm (cumulative HR over 13 years, 1.28; 95% CI, 1.11–1.48). In contrast, in the ET arm, a significantly reduced risk of breast cancer materialized (HR, 0.79; 95% CI, 0.65–0.97) (TABLE).

To put into perspective the elevated risk of breast cancer observed among women randomly allocated to EPT, the attributable risk is less than 1 additional case of breast cancer diagnosed per 1,000 EPT users annually. Another way to frame this elevated risk: An HR of 1.28 is slightly higher than the HR conferred by consuming 1 glass of wine daily and lower than the HR noted with 2 glasses daily.¹ Overall, results tended to be more favorable for ET than for EPT. Neither type of HT affected overall mortality rates.

Age differences come to the fore
The WHI findings demonstrate a lower absolute risk of adverse events with HT in younger versus older participants. In addition, age and time since menopause appeared to affect many of the HRs observed in the trial. In the ET arm, more favorable results for all-cause mortality, MI, colorectal cancer, and the global index (CHD, invasive breast cancer, pulmonary embolism, colorectal cancer, and endometrial cancer) were observed in women aged 50 to 59 years at baseline. In the EPT arm, the risk of MI was elevated only in women more than 10 years past the onset of menopause at baseline. Both HT regimens, however, were associated with increased risks of stroke, VTE, and gallbladder disease.

EPT increased the risk of breast cancer in all age groups. However, the lower absolute risks of adverse events in younger women, together with the generally more favorable HRs for many outcomes in the younger women, resulted in substantially lower rates of adverse events attributable to HT in the younger age group, compared with older women.

As far as CHD is concerned, the impact of age (or time since menopause) on the vascular response to HT in women and in nonhuman models has generated support for a “critical window” or timing hypothesis, which postulates that estrogen reduces the development of early stages of atherosclerosis while causing plaque destabilization and other adverse effects when advanced atherosclerotic lesions are present. Recent studies from Scandinavia provide additional support for this hypothesis (see the sidebar below).
 

What this EVIDENCE means for practice
Long-term follow-up of women who participated in the WHI clarifies the benefit-risk profile of systemic HT, underscoring that the benefit-risk ratio is greatest in younger menopausal women.

Because the safety of HT is greater in women nearer the onset of menopause, as well as in those at lower baseline risk of cardiovascular disease (CVD), individualized risk assessment may improve the benefit-risk profile and safety of HT. One approach to decision-making for women with bothersome menopausal symptoms is the MenoPro app, a free mobile app from the North American Menopause Society, with modes for both clinicians and patients.

In hysterectomized women, supraphysiologic doses of testosterone improve parameters of sexual function
Huang G, Basaria S, Travison TG, et al. Testosterone dose-response relationships in hysterectomized women with or without oophorectomy: effects on sexual function, body composition, muscle performance, and physical function in a randomized trial. Menopause. 2014;21(6):612–623.

No formulation of testosterone is approved by the US Food and Drug Administration (FDA) for use in women. Nonetheless, in the United States, many menopausal women hoping to boost their sexual desire are prescribed, off-label, testosterone formulations indicated for use in men, as well as compounded formulations.²

Investigators randomly allocated women who had undergone hysterectomy to 12 weeks of transdermal estradiol followed by 24 weekly intramuscular injections of placebo or testosterone enanthate at doses of 3.0 mg, 6.0 mg, 12.5 mg, or 25.0 mg while continuing estrogen. At the outset of the trial, all women had serum free testosterone levels below the range for healthy premenopausal women.

Among the 62 women who received testosterone, serum testosterone levels increased in a dose-related fashion. Among those allocated to the highest dose, serum total testosterone levels at 24 weeks were 5 to 6 times higher than values in healthy premenopausal women. Compared with women who received placebo, those who received the highest testosterone dose had better measures of sexual desire, arousal, and frequency of sexual activity. Excess hair growth was significantly more common in women who received the 2 highest doses of testosterone.

What this EVIDENCE means for practice
Although this well-executed study was small and short-term, it confirms that, in menopausal women receiving estrogen, testosterone can enhance parameters of sexuality. It is unfortunate that the dose needed to achieve this benefit results in markedly supraphysiologic serum testosterone levels.

One important caveat raised by this trial: It did not specifically recruit participants with low sexual desire. Therefore, it remains unknown whether lower doses of testosterone might provide benefits in women with low baseline libido. Regrettably, no randomized trials have addressed the long-term benefits and risks of use of testosterone among menopausal women.

ACOG offers valuable guidance on management of menopausal symptoms
ACOG Practice Bulletin No. 141: management of menopausal symptoms. American College of Obstetricians and Gynecologists. Obstet Gynecol. 2014;123(1):202–216.

Despite findings from new studies, optimal management of menopausal symptoms remains controversial. In January 2014, ACOG issued guidance regarding conventional systemic and vaginal HT, recently approved treatments, and compounded HT.

For the management of vasomotor symptoms, ACOG indicated that systemic HT (including oral and transdermal routes), alone or combined with a progestin, is the most effective treatment for bothersome menopausal vasomotor symptoms. The ACOG Practice Bulletin also pointed out that systemic EPT increases the risk for VTE and breast cancer and that, compared with oral estrogen, transdermal estrogen may carry a lower risk for VTE.

Some insurers deny coverage of HT for women older than 65 years
A classification of medications from the American Geriatrics Society known as “the Beers List” [the Beers Criteria for ­Potentially Inappropriate Medication Use in Older Adults] includes oral and transdermal estrogen, with or without a progestin.³ Along with many of the clinicians reading this Update, I routinely receive notices from insurance companies that, based on the Beers List, they will no longer provide reimbursement for systemic HT in patients who are older than 65 years. In this regard, I believe that one of the most important components of ACOG’s Practice Bulletin is the following text:

Three new options for menopausal HT
The ACOG Practice Bulletin describes 3 formulations for the treatment of menopausal symptoms that have recently become available:

Steer patients clear of compounded formulations
Every week I encounter patients who have recently visited physicians who prescribe and sell compounded bioidentical hormones. In addressing this issue, ACOG provides a useful service to women and their clinicians:

What this EVIDENCE means for practice
ACOG’s Practice Bulletin provides useful guidance for clinicians regarding treatment of menopausal symptoms. Besides clarifying that systemic HT should not be arbitrarily discontinued at age 65 and that FDA-approved HT is preferable to compounded HT, this publication details newer (including nonhormonal) formulations for treating menopausal symptoms as well as traditional HT formulations, including useful dosing information. 

Is menopausal HT safe in statin users?
Berglind IA, Andersen M, Citarella A, Linder M, Sundström A, Kieler H. Hormone therapy and risk of cardiovascular outcomes and mortality in women treated with statins. Menopause. 2015;22(4):369–376.

Hodis HN, Mack WJ. Hormone therapy and risk of all-cause mortality in women treated with statins [comment]. Menopause. 2015;22(4):363–364.

Since the initial publications of findings from the WHI, clinicians have been cautioned not to prescribe menopausal HT in women at elevated risk for CVD. In this study from Sweden, investigators enrolled women 40 to 74 years old who initiated statin use between 2006 and 2007 due to known CVD (secondary prevention) or in the absence of known CVD (primary prevention). Women were followed for a mean of 4 years after beginning statins until the end of 2011.

Of 40,958 statin users, 7% used HT (mean age of HT users and nonusers was 61 and 62 years, respectively). Overall, 70% of statin use was for primary prevention. Deaths from CVD occurred in 5 and 18 patients per 10,000 person-years among HT users and nonusers, respectively (HR, 0.38). All-cause mortality occurred in 33 and 87 patients per 10,000 person-years among HT users and non­users, respectively (HR, 0.53). These reduced risks of mortality noted in women who used concomitant statins achieved statistical significance. Whether statins were used for ­primary or secondary prevention, the incidence of cardiovascular events was similar in HT users and nonusers.

Why these findings diverge from those of the WHI
The findings of this large prospective cohort study are consistent with findings from other large observational studies—though they diverge from WHI findings. As Berglind and colleagues note, few WHI participants used statins at baseline. Also in contrast with the WHI, in which all HT was based on conjugated estrogen, all HT users in this Swedish study used oral or transdermal estradiol, as conjugated estrogen is not available in Sweden (and appears to be associated with an elevated risk of CVD, compared with other estrogens⁴).

What this EVIDENCE means for practice
This important study provides strong evidence that, for menopausal women with bothersome vasomotor symptoms or an elevated risk for osteoporosis, concomitant use of statins should not be considered a contraindication to HT.

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

As new options for managing menopausal symptoms emerge, so do data on their efficacy and safety. In this article, I highlight the following publications:

After long-term follow-up of WHI participants, a “critical window” of HT timing is revealed
Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310(13):1353–1368.

After the initial 2002 publication of findings from the WHI trial of women with an intact uterus who were randomized to conjugated equine estrogens and medroxyprogesterone acetate or placebo, prominent news headlines claimed that HT causes myocardial infarction (MI) and breast cancer. As a result, millions of women worldwide stopped taking HT. A second impact of the report: Many clinicians became reluctant to prescribe HT.

Although it generated far less media attention, an October 2013 publication from the Journal of the American Medical Association, which details 13-year follow-up of WHI HT clinical trial participants, better informs clinicians and our patients about HT’s safety profile.

During the WHI intervention phase, absolute risks were modest
Although HT was associated with a multifaceted pattern of benefits and risks in both the ­estrogen-progestin therapy (EPT) and ­estrogen-only therapy (ET) arms of the WHI, absolute risks, as reflected in an increase or decrease in the number of cases per 10,000 women treated per year, were modest.

For example, the hazard ratio (HR) for coronary heart disease (CHD) ­during the intervention phase, during which ­participants were given HT or placebo (mean 5.2 years for EPT and 6.8 years for ET) was 1.18 in the EPT arm (95% confidence interval [CI], 0.95–1.45) and 0.94 in the ET arm (95% CI, 0.78–1.14). In both arms, women given HT had reduced risks of vasomotor symptoms, hip fractures, and diabetes, and increased risks of stroke, venous thromboembolism (VTE), and gallbladder disease, compared with women receiving placebo.

The results for breast cancer differed markedly between arms. During the intervention period, an elevated risk was observed with EPT while a borderline reduced risk was observed with ET.

Among participants older than 65 years at baseline, the risk of cognitive decline was increased in the EPT arm but not in the ET arm.

Post intervention, most risks and benefits attenuated
An elevation in the risk of breast cancer persisted in the EPT arm (cumulative HR over 13 years, 1.28; 95% CI, 1.11–1.48). In contrast, in the ET arm, a significantly reduced risk of breast cancer materialized (HR, 0.79; 95% CI, 0.65–0.97) (TABLE).

To put into perspective the elevated risk of breast cancer observed among women randomly allocated to EPT, the attributable risk is less than 1 additional case of breast cancer diagnosed per 1,000 EPT users annually. Another way to frame this elevated risk: An HR of 1.28 is slightly higher than the HR conferred by consuming 1 glass of wine daily and lower than the HR noted with 2 glasses daily.¹ Overall, results tended to be more favorable for ET than for EPT. Neither type of HT affected overall mortality rates.

Age differences come to the fore
The WHI findings demonstrate a lower absolute risk of adverse events with HT in younger versus older participants. In addition, age and time since menopause appeared to affect many of the HRs observed in the trial. In the ET arm, more favorable results for all-cause mortality, MI, colorectal cancer, and the global index (CHD, invasive breast cancer, pulmonary embolism, colorectal cancer, and endometrial cancer) were observed in women aged 50 to 59 years at baseline. In the EPT arm, the risk of MI was elevated only in women more than 10 years past the onset of menopause at baseline. Both HT regimens, however, were associated with increased risks of stroke, VTE, and gallbladder disease.

EPT increased the risk of breast cancer in all age groups. However, the lower absolute risks of adverse events in younger women, together with the generally more favorable HRs for many outcomes in the younger women, resulted in substantially lower rates of adverse events attributable to HT in the younger age group, compared with older women.

As far as CHD is concerned, the impact of age (or time since menopause) on the vascular response to HT in women and in nonhuman models has generated support for a “critical window” or timing hypothesis, which postulates that estrogen reduces the development of early stages of atherosclerosis while causing plaque destabilization and other adverse effects when advanced atherosclerotic lesions are present. Recent studies from Scandinavia provide additional support for this hypothesis (see the sidebar below).
 

What this EVIDENCE means for practice
Long-term follow-up of women who participated in the WHI clarifies the benefit-risk profile of systemic HT, underscoring that the benefit-risk ratio is greatest in younger menopausal women.

Because the safety of HT is greater in women nearer the onset of menopause, as well as in those at lower baseline risk of cardiovascular disease (CVD), individualized risk assessment may improve the benefit-risk profile and safety of HT. One approach to decision-making for women with bothersome menopausal symptoms is the MenoPro app, a free mobile app from the North American Menopause Society, with modes for both clinicians and patients.

In hysterectomized women, supraphysiologic doses of testosterone improve parameters of sexual function
Huang G, Basaria S, Travison TG, et al. Testosterone dose-response relationships in hysterectomized women with or without oophorectomy: effects on sexual function, body composition, muscle performance, and physical function in a randomized trial. Menopause. 2014;21(6):612–623.

No formulation of testosterone is approved by the US Food and Drug Administration (FDA) for use in women. Nonetheless, in the United States, many menopausal women hoping to boost their sexual desire are prescribed, off-label, testosterone formulations indicated for use in men, as well as compounded formulations.²

Investigators randomly allocated women who had undergone hysterectomy to 12 weeks of transdermal estradiol followed by 24 weekly intramuscular injections of placebo or testosterone enanthate at doses of 3.0 mg, 6.0 mg, 12.5 mg, or 25.0 mg while continuing estrogen. At the outset of the trial, all women had serum free testosterone levels below the range for healthy premenopausal women.

Among the 62 women who received testosterone, serum testosterone levels increased in a dose-related fashion. Among those allocated to the highest dose, serum total testosterone levels at 24 weeks were 5 to 6 times higher than values in healthy premenopausal women. Compared with women who received placebo, those who received the highest testosterone dose had better measures of sexual desire, arousal, and frequency of sexual activity. Excess hair growth was significantly more common in women who received the 2 highest doses of testosterone.

What this EVIDENCE means for practice
Although this well-executed study was small and short-term, it confirms that, in menopausal women receiving estrogen, testosterone can enhance parameters of sexuality. It is unfortunate that the dose needed to achieve this benefit results in markedly supraphysiologic serum testosterone levels.

One important caveat raised by this trial: It did not specifically recruit participants with low sexual desire. Therefore, it remains unknown whether lower doses of testosterone might provide benefits in women with low baseline libido. Regrettably, no randomized trials have addressed the long-term benefits and risks of use of testosterone among menopausal women.

ACOG offers valuable guidance on management of menopausal symptoms
ACOG Practice Bulletin No. 141: management of menopausal symptoms. American College of Obstetricians and Gynecologists. Obstet Gynecol. 2014;123(1):202–216.

Despite findings from new studies, optimal management of menopausal symptoms remains controversial. In January 2014, ACOG issued guidance regarding conventional systemic and vaginal HT, recently approved treatments, and compounded HT.

For the management of vasomotor symptoms, ACOG indicated that systemic HT (including oral and transdermal routes), alone or combined with a progestin, is the most effective treatment for bothersome menopausal vasomotor symptoms. The ACOG Practice Bulletin also pointed out that systemic EPT increases the risk for VTE and breast cancer and that, compared with oral estrogen, transdermal estrogen may carry a lower risk for VTE.

Some insurers deny coverage of HT for women older than 65 years
A classification of medications from the American Geriatrics Society known as “the Beers List” [the Beers Criteria for ­Potentially Inappropriate Medication Use in Older Adults] includes oral and transdermal estrogen, with or without a progestin.³ Along with many of the clinicians reading this Update, I routinely receive notices from insurance companies that, based on the Beers List, they will no longer provide reimbursement for systemic HT in patients who are older than 65 years. In this regard, I believe that one of the most important components of ACOG’s Practice Bulletin is the following text:

Three new options for menopausal HT
The ACOG Practice Bulletin describes 3 formulations for the treatment of menopausal symptoms that have recently become available:

Steer patients clear of compounded formulations
Every week I encounter patients who have recently visited physicians who prescribe and sell compounded bioidentical hormones. In addressing this issue, ACOG provides a useful service to women and their clinicians:

What this EVIDENCE means for practice
ACOG’s Practice Bulletin provides useful guidance for clinicians regarding treatment of menopausal symptoms. Besides clarifying that systemic HT should not be arbitrarily discontinued at age 65 and that FDA-approved HT is preferable to compounded HT, this publication details newer (including nonhormonal) formulations for treating menopausal symptoms as well as traditional HT formulations, including useful dosing information. 

Is menopausal HT safe in statin users?
Berglind IA, Andersen M, Citarella A, Linder M, Sundström A, Kieler H. Hormone therapy and risk of cardiovascular outcomes and mortality in women treated with statins. Menopause. 2015;22(4):369–376.

Hodis HN, Mack WJ. Hormone therapy and risk of all-cause mortality in women treated with statins [comment]. Menopause. 2015;22(4):363–364.

Since the initial publications of findings from the WHI, clinicians have been cautioned not to prescribe menopausal HT in women at elevated risk for CVD. In this study from Sweden, investigators enrolled women 40 to 74 years old who initiated statin use between 2006 and 2007 due to known CVD (secondary prevention) or in the absence of known CVD (primary prevention). Women were followed for a mean of 4 years after beginning statins until the end of 2011.

Of 40,958 statin users, 7% used HT (mean age of HT users and nonusers was 61 and 62 years, respectively). Overall, 70% of statin use was for primary prevention. Deaths from CVD occurred in 5 and 18 patients per 10,000 person-years among HT users and nonusers, respectively (HR, 0.38). All-cause mortality occurred in 33 and 87 patients per 10,000 person-years among HT users and non­users, respectively (HR, 0.53). These reduced risks of mortality noted in women who used concomitant statins achieved statistical significance. Whether statins were used for ­primary or secondary prevention, the incidence of cardiovascular events was similar in HT users and nonusers.

Why these findings diverge from those of the WHI
The findings of this large prospective cohort study are consistent with findings from other large observational studies—though they diverge from WHI findings. As Berglind and colleagues note, few WHI participants used statins at baseline. Also in contrast with the WHI, in which all HT was based on conjugated estrogen, all HT users in this Swedish study used oral or transdermal estradiol, as conjugated estrogen is not available in Sweden (and appears to be associated with an elevated risk of CVD, compared with other estrogens⁴).

What this EVIDENCE means for practice
This important study provides strong evidence that, for menopausal women with bothersome vasomotor symptoms or an elevated risk for osteoporosis, concomitant use of statins should not be considered a contraindication to HT.

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

As new options for managing menopausal symptoms emerge, so do data on their efficacy and safety. In this article, I highlight the following publications:

After long-term follow-up of WHI participants, a “critical window” of HT timing is revealed
Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310(13):1353–1368.

After the initial 2002 publication of findings from the WHI trial of women with an intact uterus who were randomized to conjugated equine estrogens and medroxyprogesterone acetate or placebo, prominent news headlines claimed that HT causes myocardial infarction (MI) and breast cancer. As a result, millions of women worldwide stopped taking HT. A second impact of the report: Many clinicians became reluctant to prescribe HT.

Although it generated far less media attention, an October 2013 publication from the Journal of the American Medical Association, which details 13-year follow-up of WHI HT clinical trial participants, better informs clinicians and our patients about HT’s safety profile.

During the WHI intervention phase, absolute risks were modest
Although HT was associated with a multifaceted pattern of benefits and risks in both the ­estrogen-progestin therapy (EPT) and ­estrogen-only therapy (ET) arms of the WHI, absolute risks, as reflected in an increase or decrease in the number of cases per 10,000 women treated per year, were modest.

For example, the hazard ratio (HR) for coronary heart disease (CHD) ­during the intervention phase, during which ­participants were given HT or placebo (mean 5.2 years for EPT and 6.8 years for ET) was 1.18 in the EPT arm (95% confidence interval [CI], 0.95–1.45) and 0.94 in the ET arm (95% CI, 0.78–1.14). In both arms, women given HT had reduced risks of vasomotor symptoms, hip fractures, and diabetes, and increased risks of stroke, venous thromboembolism (VTE), and gallbladder disease, compared with women receiving placebo.

The results for breast cancer differed markedly between arms. During the intervention period, an elevated risk was observed with EPT while a borderline reduced risk was observed with ET.

Among participants older than 65 years at baseline, the risk of cognitive decline was increased in the EPT arm but not in the ET arm.

Post intervention, most risks and benefits attenuated
An elevation in the risk of breast cancer persisted in the EPT arm (cumulative HR over 13 years, 1.28; 95% CI, 1.11–1.48). In contrast, in the ET arm, a significantly reduced risk of breast cancer materialized (HR, 0.79; 95% CI, 0.65–0.97) (TABLE).

To put into perspective the elevated risk of breast cancer observed among women randomly allocated to EPT, the attributable risk is less than 1 additional case of breast cancer diagnosed per 1,000 EPT users annually. Another way to frame this elevated risk: An HR of 1.28 is slightly higher than the HR conferred by consuming 1 glass of wine daily and lower than the HR noted with 2 glasses daily.¹ Overall, results tended to be more favorable for ET than for EPT. Neither type of HT affected overall mortality rates.

Age differences come to the fore
The WHI findings demonstrate a lower absolute risk of adverse events with HT in younger versus older participants. In addition, age and time since menopause appeared to affect many of the HRs observed in the trial. In the ET arm, more favorable results for all-cause mortality, MI, colorectal cancer, and the global index (CHD, invasive breast cancer, pulmonary embolism, colorectal cancer, and endometrial cancer) were observed in women aged 50 to 59 years at baseline. In the EPT arm, the risk of MI was elevated only in women more than 10 years past the onset of menopause at baseline. Both HT regimens, however, were associated with increased risks of stroke, VTE, and gallbladder disease.

EPT increased the risk of breast cancer in all age groups. However, the lower absolute risks of adverse events in younger women, together with the generally more favorable HRs for many outcomes in the younger women, resulted in substantially lower rates of adverse events attributable to HT in the younger age group, compared with older women.

As far as CHD is concerned, the impact of age (or time since menopause) on the vascular response to HT in women and in nonhuman models has generated support for a “critical window” or timing hypothesis, which postulates that estrogen reduces the development of early stages of atherosclerosis while causing plaque destabilization and other adverse effects when advanced atherosclerotic lesions are present. Recent studies from Scandinavia provide additional support for this hypothesis (see the sidebar below).
 

What this EVIDENCE means for practice
Long-term follow-up of women who participated in the WHI clarifies the benefit-risk profile of systemic HT, underscoring that the benefit-risk ratio is greatest in younger menopausal women.

Because the safety of HT is greater in women nearer the onset of menopause, as well as in those at lower baseline risk of cardiovascular disease (CVD), individualized risk assessment may improve the benefit-risk profile and safety of HT. One approach to decision-making for women with bothersome menopausal symptoms is the MenoPro app, a free mobile app from the North American Menopause Society, with modes for both clinicians and patients.

In hysterectomized women, supraphysiologic doses of testosterone improve parameters of sexual function
Huang G, Basaria S, Travison TG, et al. Testosterone dose-response relationships in hysterectomized women with or without oophorectomy: effects on sexual function, body composition, muscle performance, and physical function in a randomized trial. Menopause. 2014;21(6):612–623.

No formulation of testosterone is approved by the US Food and Drug Administration (FDA) for use in women. Nonetheless, in the United States, many menopausal women hoping to boost their sexual desire are prescribed, off-label, testosterone formulations indicated for use in men, as well as compounded formulations.²

Investigators randomly allocated women who had undergone hysterectomy to 12 weeks of transdermal estradiol followed by 24 weekly intramuscular injections of placebo or testosterone enanthate at doses of 3.0 mg, 6.0 mg, 12.5 mg, or 25.0 mg while continuing estrogen. At the outset of the trial, all women had serum free testosterone levels below the range for healthy premenopausal women.

Among the 62 women who received testosterone, serum testosterone levels increased in a dose-related fashion. Among those allocated to the highest dose, serum total testosterone levels at 24 weeks were 5 to 6 times higher than values in healthy premenopausal women. Compared with women who received placebo, those who received the highest testosterone dose had better measures of sexual desire, arousal, and frequency of sexual activity. Excess hair growth was significantly more common in women who received the 2 highest doses of testosterone.

What this EVIDENCE means for practice
Although this well-executed study was small and short-term, it confirms that, in menopausal women receiving estrogen, testosterone can enhance parameters of sexuality. It is unfortunate that the dose needed to achieve this benefit results in markedly supraphysiologic serum testosterone levels.

One important caveat raised by this trial: It did not specifically recruit participants with low sexual desire. Therefore, it remains unknown whether lower doses of testosterone might provide benefits in women with low baseline libido. Regrettably, no randomized trials have addressed the long-term benefits and risks of use of testosterone among menopausal women.

ACOG offers valuable guidance on management of menopausal symptoms
ACOG Practice Bulletin No. 141: management of menopausal symptoms. American College of Obstetricians and Gynecologists. Obstet Gynecol. 2014;123(1):202–216.

Despite findings from new studies, optimal management of menopausal symptoms remains controversial. In January 2014, ACOG issued guidance regarding conventional systemic and vaginal HT, recently approved treatments, and compounded HT.

For the management of vasomotor symptoms, ACOG indicated that systemic HT (including oral and transdermal routes), alone or combined with a progestin, is the most effective treatment for bothersome menopausal vasomotor symptoms. The ACOG Practice Bulletin also pointed out that systemic EPT increases the risk for VTE and breast cancer and that, compared with oral estrogen, transdermal estrogen may carry a lower risk for VTE.

Some insurers deny coverage of HT for women older than 65 years
A classification of medications from the American Geriatrics Society known as “the Beers List” [the Beers Criteria for ­Potentially Inappropriate Medication Use in Older Adults] includes oral and transdermal estrogen, with or without a progestin.³ Along with many of the clinicians reading this Update, I routinely receive notices from insurance companies that, based on the Beers List, they will no longer provide reimbursement for systemic HT in patients who are older than 65 years. In this regard, I believe that one of the most important components of ACOG’s Practice Bulletin is the following text:

Three new options for menopausal HT
The ACOG Practice Bulletin describes 3 formulations for the treatment of menopausal symptoms that have recently become available:

Steer patients clear of compounded formulations
Every week I encounter patients who have recently visited physicians who prescribe and sell compounded bioidentical hormones. In addressing this issue, ACOG provides a useful service to women and their clinicians:

What this EVIDENCE means for practice
ACOG’s Practice Bulletin provides useful guidance for clinicians regarding treatment of menopausal symptoms. Besides clarifying that systemic HT should not be arbitrarily discontinued at age 65 and that FDA-approved HT is preferable to compounded HT, this publication details newer (including nonhormonal) formulations for treating menopausal symptoms as well as traditional HT formulations, including useful dosing information. 

Is menopausal HT safe in statin users?
Berglind IA, Andersen M, Citarella A, Linder M, Sundström A, Kieler H. Hormone therapy and risk of cardiovascular outcomes and mortality in women treated with statins. Menopause. 2015;22(4):369–376.

Hodis HN, Mack WJ. Hormone therapy and risk of all-cause mortality in women treated with statins [comment]. Menopause. 2015;22(4):363–364.

Since the initial publications of findings from the WHI, clinicians have been cautioned not to prescribe menopausal HT in women at elevated risk for CVD. In this study from Sweden, investigators enrolled women 40 to 74 years old who initiated statin use between 2006 and 2007 due to known CVD (secondary prevention) or in the absence of known CVD (primary prevention). Women were followed for a mean of 4 years after beginning statins until the end of 2011.

Of 40,958 statin users, 7% used HT (mean age of HT users and nonusers was 61 and 62 years, respectively). Overall, 70% of statin use was for primary prevention. Deaths from CVD occurred in 5 and 18 patients per 10,000 person-years among HT users and nonusers, respectively (HR, 0.38). All-cause mortality occurred in 33 and 87 patients per 10,000 person-years among HT users and non­users, respectively (HR, 0.53). These reduced risks of mortality noted in women who used concomitant statins achieved statistical significance. Whether statins were used for ­primary or secondary prevention, the incidence of cardiovascular events was similar in HT users and nonusers.

Why these findings diverge from those of the WHI
The findings of this large prospective cohort study are consistent with findings from other large observational studies—though they diverge from WHI findings. As Berglind and colleagues note, few WHI participants used statins at baseline. Also in contrast with the WHI, in which all HT was based on conjugated estrogen, all HT users in this Swedish study used oral or transdermal estradiol, as conjugated estrogen is not available in Sweden (and appears to be associated with an elevated risk of CVD, compared with other estrogens⁴).

What this EVIDENCE means for practice
This important study provides strong evidence that, for menopausal women with bothersome vasomotor symptoms or an elevated risk for osteoporosis, concomitant use of statins should not be considered a contraindication to HT.

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

Although endometriosis and infertility are clearly linked—in life as well as the medical literature—no causal relationship has been established. Nevertheless, data suggest that 25% to 50% of infertile women have endometriosis, and that as many as 30% to 50% of women who have endometriosis are infertile.¹

Among the mechanisms that have been proposed to explain this link are:

Recent studies by Kao and colleagues and Giudice and colleagues have led to new findings in regard to endometriosis and infertility, says Ceana Nezhat, MD.^3,4 Dr. ­Nezhat is Director of the Nezhat Medical Center in Atlanta, Georgia, and Medical Director of Training and Education at ­Northside ­Hospital in Atlanta. “These researchers have discovered that endometriosis causes changes to the endometrium that contribute to infertility.”

“There are no studies that have specifically assessed whether one anatomic site is associated with increased infertility over another,” says Tommaso Falcone, MD. “However, it is assumed that disease that involves the tubes and ovaries would impede fertility the most. Adhesive disease and endometriomas around the tubes and ovaries are associated with a worsening prognosis. Although peritoneal disease probably influences fertility solely on the basis of inflammation, disease around the tubes and ovaries is thought to have a mechanical effect as well.” Dr. Falcone is Professor and Chair of Obstetrics and Gynecology at the Cleveland Clinic in Cleveland, Ohio.

“Endometriosis is a chronic and hetero­geneous disease process,” says ­Stephanie J. Estes, MD, Director of Robotic Surgical Services and Associate Professor, Division of Reproductive Endocrinology and ­Infertility, Department of Obstetrics and Gynecology, at Penn State Hershey Medical Center in Hershey, Pennsylvania.

“It is likely that no single site is the causative factor,” Dr. Estes says. “Endometriosis alters prostaglandins, cytokines, and proteases that may adversely affect eggs, sperm, or embryo development. In addition, altered endometrial receptivity may play a role. It has been shown that, when donor oocytes from women with endometriosis are transferred to women without endometriosis, there are lower implantation rates and poorer embryo quality.”⁵

Does it follow, then, that eradication of endometriosis improves fertility?

The answer is not clear. Rather, it depends on a number of variables, including the stage of the disease, its location, the presence of symptoms, and more.

“The approach for endometiosis-­associated infertility is completely different from the approach for pain,” says Dr. Nezhat. “In a patient with pain, complete eradication of endometriosis is necessary. However, when addressing infertility, a surgeon must be cautious in the vicinity of the reproductive organs, even if a multistage approach is required. Fertility preservation is the goal.^6,7 However, thorough treatment of endometriosis improves fertility rates even in cases of failed in vitro fertilization” (IVF).⁸

In this article, the focus is on 6 critical questions concerning endometriosis and infertility, including the role of medical therapy, when surgery is indicated, and whether an endometrioma warrants removal or referral for IVF.

In Part 1 of this 3-part series, which appeared in the April 2015 issue of OBG Management, the subject was diagnosis of endometriosis. In Part 2, which appeared in May 2015, the focus was endometriosis and pain.

1. Is there a role for medical therapy?
In women who have endometriosis-related infertility, medical therapy does not appear to produce any benefit. In its committee opinion on the subject, the American Society for Reproductive Medicine (ASRM) states as much: “There is no evidence that medical treatment of endometriosis improves fertility.”²

In fact, observes Dr. Estes, trials of medical treatment, involving such medications as combined estrogen-­progestin therapy, danazol, progestins, or ­gonadotropin-releasing hormone (GnRH) agonists, may cause an unnecessary “delay in the use of more effective treatments that could result in pregnancy.”

Dr. Nezhat believes that medical therapy is effective in patients who have adenomyosis in addition to endometriosis. “Three months of treatment with a GnRH agonist will improve fertility rates in these patients,” he says.

“Medical treatments inhibit ovulation,” notes Dr. Estes. “These therapies have no role in pretreatment of patients with endometriosis prior to infertility treatment. On the other hand, medical therapy with GnRH agonists for 3 to 6 months prior to an IVF cycle does result in increased pregnancy rates.”⁹

2. What is the role of clomiphene and intrauterine insemination?
Should women who have endometriosis, open fallopian tubes, and infertility be treated with clomiphene and intrauterine insemination (IUI) prior to a cycle of IVF?

“This is a complex question,” says Dr. ­Estes, “as clinical parameters such as age, symptoms, duration of infertility, and the ability to proceed with IVF are important, as well as stage of disease.”

“Overall, in patients younger than 35 years, clomiphene-IUI is an option and has an increased pregnancy rate over timed intercourse” (9% vs 3%), she says.¹⁰ “How­ever, clearly IVF is much more successful and is the most effective treatment, with pregnancy rates of approximately 46% for women younger than 35 years (3% of whom have a ‘diagnosis’ of endometriosis, and 13% of whom have an ‘unknown’ infertility factor).¹¹ Women who are older than 35 or who have additional infertility factors, such as male factor, should consider IVF first.”

3. When is surgery indicated?
“Patients who have significant pain associated with their infertility will benefit from surgery, which offers both pain relief and an improvement in the spontaneous pregnancy rate,” says Dr. Falcone. “Patients who are infertile and desire spontaneous pregnancy without pharmacologic intervention or assisted reproductive technology (ART) also benefit from surgery.”

The benefit of surgery in asymptomatic women with minimal to mild endometriosis is unclear. In a randomized controlled trial of 341 women (aged 20–39 years) with infertility and minimal to mild endometriosis, laparoscopic resection or ablation of visible lesions resulted in pregnancy in 30.7% of women, compared with 17.7% of women who underwent diagnostic laparoscopy only.¹²

Another randomized study of 96 women with minimal to mild endometriosis who underwent resection/ablation or diagnostic laparoscopy found no difference in the birth rate at 1 year.¹³

When the results of these 2 studies are combined, the number needed to treat is 12 laparoscopies in women with endometriosis, says Dr. Falcone. “So 1 additional pregnancy would be gained from performing endometriosis surgery in 12 patients. If we assume a prevalence of 30% in asymptomatic women with infertility, then you need to perform 40 diagnostic laparoscopies to achieve an extra pregnancy.”

For women with infertility and severe endometriosis, a nonrandomized study found cumulative pregnancy rates of 45% and 63% after laparoscopy and laparotomy, respectively, in 216 women followed for up to 2 years.¹⁴ The difference in rates was not statistically significant.

“Although surgery is indicated to diagnose endometriosis, multiple repeat procedures are not an effective treatment for infertility,” says Dr. Estes. “Plus, especially for stage I and II endometriosis [according to the ASRM classification system], approximately 12 patients will need surgery for 1 additional pregnancy—and many more will have needed the procedure to even get to those who have endometriosis. While patients often want us to ‘do something’—­often a covered service such as surgery—we need to consider that surgery for early disease does not provide a significant or long-lasting enhancement to women’s ability to conceive.”

In the absence of male-factor infertility, surgical diagnosis with conservative and precise treatment of endometriosis at the same time is better than going directly to IVF, says Dr. Nezhat. Younger patients who undergo surgical treatment have a better chance of achieving more than 1 spontaneous pregnancy than they do with IVF. And older patients also will have an improved conception rate with ART when they are treated surgically, he says.⁸

Coding and reimbursement 

For endometriosis, the correct diagnostic code helps establish the medical necessity of later treatments
Several diagnostic codes are available to describe the location of endometriotic implants, but the fact remains that these codes can be reported only after a definitive diagnosis is made, which generally comes after confirmatory surgery has been performed. When the patient is in the diagnostic phase, she may present with complaints of pelvic pain, dyspareunia, dysmenorrhea, or infertility. Knowing which codes to use at the time of evaluation goes a long way toward establishing medical necessity for any later surgery or medical treatment.

In the TABLE, you will find common diagnostic codes that can be reported during evaluation of endometriosis, including both International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and ICD-10-CM equivalents. Note that, with ICD-10-CM, payers are looking for a more specific type of dysmenorrhea in the documentation. In the case of painful menstruation suspected to arise from endometriosis, the code for secondary dysmenorrhea should be reported.

Diagnostic coding in cases in which the patient first presents with a complaint of infertility in the absence of other symptoms can be problematic, as many insurers still do not cover the treatment of infertility. However, in the diagnostic stage, codes for fertility testing can be reported instead of codes that confirm infertility when no other symptoms are present. Once the clinician has verified that endometriosis is the source of the infertility and begins treatment, the primary code for the type of endometriosis would be reported, not a diagnosis of infertility.

The procedure performed to diagnose endometriosis would be diagnostic laparoscopy (Current Procedure Terminology [CPT] code 49320, Laparoscopy, abdomen, peritoneum, and omentum, diagnostic, with or without collection of specimen[s] by brushing or washing [separate procedure]) if medical treatment is being pursued. If the plan is to confirm and then immediately remove the implants, the CPT codes would be either 58662, Laparoscopy, surgical; with fulguration or excision of lesions of the ovary, pelvic viscera, or peritoneal surface by any method, or 49203–49205, Excision or destruction, open, intra-abdominal tumors, cysts or endometriomas, 1 or more peritoneal, mesenteric, or retroperitoneal primary or secondary tumors, based on the largest tumor diameter, if they are removed via an abdominal incision.

—Melanie Witt, RN, CPC, COBGC, MA

Ms. Witt is an independent coding and documentation consultant and former program manager, department of coding and nomenclature, American Congress of Obstetricians and Gynecologists.

4. Surgery or IVF for endometriomas?
When an endometrioma is present, should it be surgically treated or should the patient go straight to IVF? And does the optimal approach depend on the size of the endometrioma?

“The answer to this question ultimately depends on the skill and experience of the surgeon and the type of endometrioma,” says Dr. Nezhat, “because improper removal of an endometrioma may compromise the function of the ovary.”

“I recommend removal of the endometrioma by a skilled surgeon experienced in the management of ovarian cysts and preservation of ovarian function, especially in patients who have failed IVF,” he says.^6,15

According to the ASRM committee opinion on endometriosis and infertility, laparoscopic cystectomy for endometriomas larger than 4 cm improves fertility, compared with cyst drainage and coagulation, which is associated with a high risk of cyst recurrence.² However, no randomized trials have compared laparoscopic excision of an endometrioma to expectant management prior to IVF/intracytoplasmic sperm injection (ICSI). One case-control study found that laparoscopic cystectomy prior to IVF had no effect on fertility outcomes.¹⁶ At the same time, however, “conservative surgical treatment in symptomatic patients did not impair the success rates of IVF or ICSI,” notes the ASRM.² Therefore, “evidence suggests that surgery does not benefit asymptomatic women with an endometrioma prior to scheduled IVF/ICSI,” the ASRM concludes.²

Dr. Nezhat cautions against the practice of indiscriminate IVF in the setting of ovarian endometriomas because he has seen patients who developed tubo-ovarian abscess and infected endometriomas after transvaginal egg retrieval. He notes that there are additional case reports of similar findings from other surgeons.

As far as excision versus ablation is concerned, all studies have shown some effect on ovarian function after excision, says Dr. Falcone. “The studies assessed this parameter using several endpoints, such as the number of oocytes retrieved at IVF. Recently, anti-Müllerian hormone has been used and has confirmed this observation. The decreased ovarian reserve is especially problematic with bilateral ovarian disease. The extent of the decreased ovarian function is dependent on several parameters, especially how much energy is used to achieve hemostasis. Several techniques have been proposed to reduce damage, including less traumatic ways of achieving hemostasis in the ovarian hilus.”

“The dilemma is that, if we excise the disease, the pregnancy rates are better than with ablation, but if we excise, there is more damage to the ovary. In my practice, I excise if there is minimal associated disease, such as adhesions, because the pregnancy rate after surgery is good. If, however, there are extensive adhesions with a low chance of spontaneous pregnancy, I minimize excision,” Dr. Falcone says.

As for going straight to IVF, “many patients cannot afford IVF; therefore, surgery is their only option. Furthermore, many patients have severe associated pain; therefore, surgery is required to improve quality of life. However, if the decision is made to proceed to IVF, there is no evidence that cystectomy prior to treatment with ART improves the pregnancy rate,” Dr. Falcone says.

“Basically, if a woman has no pain and no endometrioma, and infertility alone is the issue, I treat her in the same manner as I would a patient with idiopathic infertility—no surgery,” Dr. Falcone says. “If a patient has severe pain and infertility, I treat her surgically but conservatively, especially when an endometrioma is present. The patient will get pain relief but also derive fertility benefit. If a patient has had previous surgery for ­endometriosis-associated infertility, additional surgery is not the next step—as our study has shown that pregnancy rates are better with IVF than repeat surgery.”¹⁷

5. Is surgery ever effective after failed IVF?
To answer this question, Dr. Nezhat points to a retrospective case series by Littman and colleagues in which 29 women with a history of failed IVF underwent laparoscopic evaluation and treatment of endometriosis (by the same surgeon).⁸ Of 29 patients, 22 conceived after laparoscopic treatment of ­endometriosis, including 15 “non-IVF” pregnancies and 7 IVF pregnancies, the study results show.⁸

“It is not unusual for patients and health care providers to perceive IVF as the final treatment for infertility,” Littman and colleagues write. “When this definitive therapy fails repeatedly, clinicians and patients may be inclined to pursue oocyte donation or elect to forego further treatment altogether. This is especially true in women of advanced age and in patients with borderline embryo quality. Presently, as a result of our clinical observation in patients with failed IVF, before egg donation or adoption, we offer the option to have meticulous laparoscopic evaluation and treatment by a skilled surgeon. Furthermore, we would not classify an infertility condition as unexplained without confirming the absence of endometriosis by a thorough laparoscopy. In our experience, patients under 35 years old with unexplained infertility who are found to have endometriosis at the time of laparoscopy have an excellent chance of pregnancy following surgical treatment without ART.”⁸

6. Is repeat surgery ever helpful?
In the treatment of endometriosis-­associated infertility, repeat surgery should be avoided if no symptoms are present, says Dr. Estes. “In women with continued symptoms, the benefits of repeat surgery are small, with known risks, including the potential for adhesive disease and the iatro­genic detrimental effect on ovarian ­function—often in a setting of already-present decreased ovarian reserve.”

Dr. Nezhat agrees that multiple surgeries carry the potential for harm. “However, there is one caveat,” he says. “What was done at the previous surgery and how? The skill and experience of the surgeon and proper technique are of paramount importance to the surgical outcome.”

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

Although endometriosis and infertility are clearly linked—in life as well as the medical literature—no causal relationship has been established. Nevertheless, data suggest that 25% to 50% of infertile women have endometriosis, and that as many as 30% to 50% of women who have endometriosis are infertile.¹

Among the mechanisms that have been proposed to explain this link are:

Recent studies by Kao and colleagues and Giudice and colleagues have led to new findings in regard to endometriosis and infertility, says Ceana Nezhat, MD.^3,4 Dr. ­Nezhat is Director of the Nezhat Medical Center in Atlanta, Georgia, and Medical Director of Training and Education at ­Northside ­Hospital in Atlanta. “These researchers have discovered that endometriosis causes changes to the endometrium that contribute to infertility.”

“There are no studies that have specifically assessed whether one anatomic site is associated with increased infertility over another,” says Tommaso Falcone, MD. “However, it is assumed that disease that involves the tubes and ovaries would impede fertility the most. Adhesive disease and endometriomas around the tubes and ovaries are associated with a worsening prognosis. Although peritoneal disease probably influences fertility solely on the basis of inflammation, disease around the tubes and ovaries is thought to have a mechanical effect as well.” Dr. Falcone is Professor and Chair of Obstetrics and Gynecology at the Cleveland Clinic in Cleveland, Ohio.

“Endometriosis is a chronic and hetero­geneous disease process,” says ­Stephanie J. Estes, MD, Director of Robotic Surgical Services and Associate Professor, Division of Reproductive Endocrinology and ­Infertility, Department of Obstetrics and Gynecology, at Penn State Hershey Medical Center in Hershey, Pennsylvania.

“It is likely that no single site is the causative factor,” Dr. Estes says. “Endometriosis alters prostaglandins, cytokines, and proteases that may adversely affect eggs, sperm, or embryo development. In addition, altered endometrial receptivity may play a role. It has been shown that, when donor oocytes from women with endometriosis are transferred to women without endometriosis, there are lower implantation rates and poorer embryo quality.”⁵

Does it follow, then, that eradication of endometriosis improves fertility?

The answer is not clear. Rather, it depends on a number of variables, including the stage of the disease, its location, the presence of symptoms, and more.

“The approach for endometiosis-­associated infertility is completely different from the approach for pain,” says Dr. Nezhat. “In a patient with pain, complete eradication of endometriosis is necessary. However, when addressing infertility, a surgeon must be cautious in the vicinity of the reproductive organs, even if a multistage approach is required. Fertility preservation is the goal.^6,7 However, thorough treatment of endometriosis improves fertility rates even in cases of failed in vitro fertilization” (IVF).⁸

In this article, the focus is on 6 critical questions concerning endometriosis and infertility, including the role of medical therapy, when surgery is indicated, and whether an endometrioma warrants removal or referral for IVF.

In Part 1 of this 3-part series, which appeared in the April 2015 issue of OBG Management, the subject was diagnosis of endometriosis. In Part 2, which appeared in May 2015, the focus was endometriosis and pain.

1. Is there a role for medical therapy?
In women who have endometriosis-related infertility, medical therapy does not appear to produce any benefit. In its committee opinion on the subject, the American Society for Reproductive Medicine (ASRM) states as much: “There is no evidence that medical treatment of endometriosis improves fertility.”²

In fact, observes Dr. Estes, trials of medical treatment, involving such medications as combined estrogen-­progestin therapy, danazol, progestins, or ­gonadotropin-releasing hormone (GnRH) agonists, may cause an unnecessary “delay in the use of more effective treatments that could result in pregnancy.”

Dr. Nezhat believes that medical therapy is effective in patients who have adenomyosis in addition to endometriosis. “Three months of treatment with a GnRH agonist will improve fertility rates in these patients,” he says.

“Medical treatments inhibit ovulation,” notes Dr. Estes. “These therapies have no role in pretreatment of patients with endometriosis prior to infertility treatment. On the other hand, medical therapy with GnRH agonists for 3 to 6 months prior to an IVF cycle does result in increased pregnancy rates.”⁹

2. What is the role of clomiphene and intrauterine insemination?
Should women who have endometriosis, open fallopian tubes, and infertility be treated with clomiphene and intrauterine insemination (IUI) prior to a cycle of IVF?

“This is a complex question,” says Dr. ­Estes, “as clinical parameters such as age, symptoms, duration of infertility, and the ability to proceed with IVF are important, as well as stage of disease.”

“Overall, in patients younger than 35 years, clomiphene-IUI is an option and has an increased pregnancy rate over timed intercourse” (9% vs 3%), she says.¹⁰ “How­ever, clearly IVF is much more successful and is the most effective treatment, with pregnancy rates of approximately 46% for women younger than 35 years (3% of whom have a ‘diagnosis’ of endometriosis, and 13% of whom have an ‘unknown’ infertility factor).¹¹ Women who are older than 35 or who have additional infertility factors, such as male factor, should consider IVF first.”

3. When is surgery indicated?
“Patients who have significant pain associated with their infertility will benefit from surgery, which offers both pain relief and an improvement in the spontaneous pregnancy rate,” says Dr. Falcone. “Patients who are infertile and desire spontaneous pregnancy without pharmacologic intervention or assisted reproductive technology (ART) also benefit from surgery.”

The benefit of surgery in asymptomatic women with minimal to mild endometriosis is unclear. In a randomized controlled trial of 341 women (aged 20–39 years) with infertility and minimal to mild endometriosis, laparoscopic resection or ablation of visible lesions resulted in pregnancy in 30.7% of women, compared with 17.7% of women who underwent diagnostic laparoscopy only.¹²

Another randomized study of 96 women with minimal to mild endometriosis who underwent resection/ablation or diagnostic laparoscopy found no difference in the birth rate at 1 year.¹³

When the results of these 2 studies are combined, the number needed to treat is 12 laparoscopies in women with endometriosis, says Dr. Falcone. “So 1 additional pregnancy would be gained from performing endometriosis surgery in 12 patients. If we assume a prevalence of 30% in asymptomatic women with infertility, then you need to perform 40 diagnostic laparoscopies to achieve an extra pregnancy.”

For women with infertility and severe endometriosis, a nonrandomized study found cumulative pregnancy rates of 45% and 63% after laparoscopy and laparotomy, respectively, in 216 women followed for up to 2 years.¹⁴ The difference in rates was not statistically significant.

“Although surgery is indicated to diagnose endometriosis, multiple repeat procedures are not an effective treatment for infertility,” says Dr. Estes. “Plus, especially for stage I and II endometriosis [according to the ASRM classification system], approximately 12 patients will need surgery for 1 additional pregnancy—and many more will have needed the procedure to even get to those who have endometriosis. While patients often want us to ‘do something’—­often a covered service such as surgery—we need to consider that surgery for early disease does not provide a significant or long-lasting enhancement to women’s ability to conceive.”

In the absence of male-factor infertility, surgical diagnosis with conservative and precise treatment of endometriosis at the same time is better than going directly to IVF, says Dr. Nezhat. Younger patients who undergo surgical treatment have a better chance of achieving more than 1 spontaneous pregnancy than they do with IVF. And older patients also will have an improved conception rate with ART when they are treated surgically, he says.⁸

Coding and reimbursement 

For endometriosis, the correct diagnostic code helps establish the medical necessity of later treatments
Several diagnostic codes are available to describe the location of endometriotic implants, but the fact remains that these codes can be reported only after a definitive diagnosis is made, which generally comes after confirmatory surgery has been performed. When the patient is in the diagnostic phase, she may present with complaints of pelvic pain, dyspareunia, dysmenorrhea, or infertility. Knowing which codes to use at the time of evaluation goes a long way toward establishing medical necessity for any later surgery or medical treatment.

In the TABLE, you will find common diagnostic codes that can be reported during evaluation of endometriosis, including both International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and ICD-10-CM equivalents. Note that, with ICD-10-CM, payers are looking for a more specific type of dysmenorrhea in the documentation. In the case of painful menstruation suspected to arise from endometriosis, the code for secondary dysmenorrhea should be reported.

Diagnostic coding in cases in which the patient first presents with a complaint of infertility in the absence of other symptoms can be problematic, as many insurers still do not cover the treatment of infertility. However, in the diagnostic stage, codes for fertility testing can be reported instead of codes that confirm infertility when no other symptoms are present. Once the clinician has verified that endometriosis is the source of the infertility and begins treatment, the primary code for the type of endometriosis would be reported, not a diagnosis of infertility.

The procedure performed to diagnose endometriosis would be diagnostic laparoscopy (Current Procedure Terminology [CPT] code 49320, Laparoscopy, abdomen, peritoneum, and omentum, diagnostic, with or without collection of specimen[s] by brushing or washing [separate procedure]) if medical treatment is being pursued. If the plan is to confirm and then immediately remove the implants, the CPT codes would be either 58662, Laparoscopy, surgical; with fulguration or excision of lesions of the ovary, pelvic viscera, or peritoneal surface by any method, or 49203–49205, Excision or destruction, open, intra-abdominal tumors, cysts or endometriomas, 1 or more peritoneal, mesenteric, or retroperitoneal primary or secondary tumors, based on the largest tumor diameter, if they are removed via an abdominal incision.

—Melanie Witt, RN, CPC, COBGC, MA

Ms. Witt is an independent coding and documentation consultant and former program manager, department of coding and nomenclature, American Congress of Obstetricians and Gynecologists.

4. Surgery or IVF for endometriomas?
When an endometrioma is present, should it be surgically treated or should the patient go straight to IVF? And does the optimal approach depend on the size of the endometrioma?

“The answer to this question ultimately depends on the skill and experience of the surgeon and the type of endometrioma,” says Dr. Nezhat, “because improper removal of an endometrioma may compromise the function of the ovary.”

“I recommend removal of the endometrioma by a skilled surgeon experienced in the management of ovarian cysts and preservation of ovarian function, especially in patients who have failed IVF,” he says.^6,15

According to the ASRM committee opinion on endometriosis and infertility, laparoscopic cystectomy for endometriomas larger than 4 cm improves fertility, compared with cyst drainage and coagulation, which is associated with a high risk of cyst recurrence.² However, no randomized trials have compared laparoscopic excision of an endometrioma to expectant management prior to IVF/intracytoplasmic sperm injection (ICSI). One case-control study found that laparoscopic cystectomy prior to IVF had no effect on fertility outcomes.¹⁶ At the same time, however, “conservative surgical treatment in symptomatic patients did not impair the success rates of IVF or ICSI,” notes the ASRM.² Therefore, “evidence suggests that surgery does not benefit asymptomatic women with an endometrioma prior to scheduled IVF/ICSI,” the ASRM concludes.²

Dr. Nezhat cautions against the practice of indiscriminate IVF in the setting of ovarian endometriomas because he has seen patients who developed tubo-ovarian abscess and infected endometriomas after transvaginal egg retrieval. He notes that there are additional case reports of similar findings from other surgeons.

As far as excision versus ablation is concerned, all studies have shown some effect on ovarian function after excision, says Dr. Falcone. “The studies assessed this parameter using several endpoints, such as the number of oocytes retrieved at IVF. Recently, anti-Müllerian hormone has been used and has confirmed this observation. The decreased ovarian reserve is especially problematic with bilateral ovarian disease. The extent of the decreased ovarian function is dependent on several parameters, especially how much energy is used to achieve hemostasis. Several techniques have been proposed to reduce damage, including less traumatic ways of achieving hemostasis in the ovarian hilus.”

“The dilemma is that, if we excise the disease, the pregnancy rates are better than with ablation, but if we excise, there is more damage to the ovary. In my practice, I excise if there is minimal associated disease, such as adhesions, because the pregnancy rate after surgery is good. If, however, there are extensive adhesions with a low chance of spontaneous pregnancy, I minimize excision,” Dr. Falcone says.

As for going straight to IVF, “many patients cannot afford IVF; therefore, surgery is their only option. Furthermore, many patients have severe associated pain; therefore, surgery is required to improve quality of life. However, if the decision is made to proceed to IVF, there is no evidence that cystectomy prior to treatment with ART improves the pregnancy rate,” Dr. Falcone says.

“Basically, if a woman has no pain and no endometrioma, and infertility alone is the issue, I treat her in the same manner as I would a patient with idiopathic infertility—no surgery,” Dr. Falcone says. “If a patient has severe pain and infertility, I treat her surgically but conservatively, especially when an endometrioma is present. The patient will get pain relief but also derive fertility benefit. If a patient has had previous surgery for ­endometriosis-associated infertility, additional surgery is not the next step—as our study has shown that pregnancy rates are better with IVF than repeat surgery.”¹⁷

5. Is surgery ever effective after failed IVF?
To answer this question, Dr. Nezhat points to a retrospective case series by Littman and colleagues in which 29 women with a history of failed IVF underwent laparoscopic evaluation and treatment of endometriosis (by the same surgeon).⁸ Of 29 patients, 22 conceived after laparoscopic treatment of ­endometriosis, including 15 “non-IVF” pregnancies and 7 IVF pregnancies, the study results show.⁸

“It is not unusual for patients and health care providers to perceive IVF as the final treatment for infertility,” Littman and colleagues write. “When this definitive therapy fails repeatedly, clinicians and patients may be inclined to pursue oocyte donation or elect to forego further treatment altogether. This is especially true in women of advanced age and in patients with borderline embryo quality. Presently, as a result of our clinical observation in patients with failed IVF, before egg donation or adoption, we offer the option to have meticulous laparoscopic evaluation and treatment by a skilled surgeon. Furthermore, we would not classify an infertility condition as unexplained without confirming the absence of endometriosis by a thorough laparoscopy. In our experience, patients under 35 years old with unexplained infertility who are found to have endometriosis at the time of laparoscopy have an excellent chance of pregnancy following surgical treatment without ART.”⁸

6. Is repeat surgery ever helpful?
In the treatment of endometriosis-­associated infertility, repeat surgery should be avoided if no symptoms are present, says Dr. Estes. “In women with continued symptoms, the benefits of repeat surgery are small, with known risks, including the potential for adhesive disease and the iatro­genic detrimental effect on ovarian ­function—often in a setting of already-present decreased ovarian reserve.”

Dr. Nezhat agrees that multiple surgeries carry the potential for harm. “However, there is one caveat,” he says. “What was done at the previous surgery and how? The skill and experience of the surgeon and proper technique are of paramount importance to the surgical outcome.”

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

Although endometriosis and infertility are clearly linked—in life as well as the medical literature—no causal relationship has been established. Nevertheless, data suggest that 25% to 50% of infertile women have endometriosis, and that as many as 30% to 50% of women who have endometriosis are infertile.¹

Among the mechanisms that have been proposed to explain this link are:

Recent studies by Kao and colleagues and Giudice and colleagues have led to new findings in regard to endometriosis and infertility, says Ceana Nezhat, MD.^3,4 Dr. ­Nezhat is Director of the Nezhat Medical Center in Atlanta, Georgia, and Medical Director of Training and Education at ­Northside ­Hospital in Atlanta. “These researchers have discovered that endometriosis causes changes to the endometrium that contribute to infertility.”

“There are no studies that have specifically assessed whether one anatomic site is associated with increased infertility over another,” says Tommaso Falcone, MD. “However, it is assumed that disease that involves the tubes and ovaries would impede fertility the most. Adhesive disease and endometriomas around the tubes and ovaries are associated with a worsening prognosis. Although peritoneal disease probably influences fertility solely on the basis of inflammation, disease around the tubes and ovaries is thought to have a mechanical effect as well.” Dr. Falcone is Professor and Chair of Obstetrics and Gynecology at the Cleveland Clinic in Cleveland, Ohio.

“Endometriosis is a chronic and hetero­geneous disease process,” says ­Stephanie J. Estes, MD, Director of Robotic Surgical Services and Associate Professor, Division of Reproductive Endocrinology and ­Infertility, Department of Obstetrics and Gynecology, at Penn State Hershey Medical Center in Hershey, Pennsylvania.

“It is likely that no single site is the causative factor,” Dr. Estes says. “Endometriosis alters prostaglandins, cytokines, and proteases that may adversely affect eggs, sperm, or embryo development. In addition, altered endometrial receptivity may play a role. It has been shown that, when donor oocytes from women with endometriosis are transferred to women without endometriosis, there are lower implantation rates and poorer embryo quality.”⁵

Does it follow, then, that eradication of endometriosis improves fertility?

The answer is not clear. Rather, it depends on a number of variables, including the stage of the disease, its location, the presence of symptoms, and more.

“The approach for endometiosis-­associated infertility is completely different from the approach for pain,” says Dr. Nezhat. “In a patient with pain, complete eradication of endometriosis is necessary. However, when addressing infertility, a surgeon must be cautious in the vicinity of the reproductive organs, even if a multistage approach is required. Fertility preservation is the goal.^6,7 However, thorough treatment of endometriosis improves fertility rates even in cases of failed in vitro fertilization” (IVF).⁸

In this article, the focus is on 6 critical questions concerning endometriosis and infertility, including the role of medical therapy, when surgery is indicated, and whether an endometrioma warrants removal or referral for IVF.

In Part 1 of this 3-part series, which appeared in the April 2015 issue of OBG Management, the subject was diagnosis of endometriosis. In Part 2, which appeared in May 2015, the focus was endometriosis and pain.

1. Is there a role for medical therapy?
In women who have endometriosis-related infertility, medical therapy does not appear to produce any benefit. In its committee opinion on the subject, the American Society for Reproductive Medicine (ASRM) states as much: “There is no evidence that medical treatment of endometriosis improves fertility.”²

In fact, observes Dr. Estes, trials of medical treatment, involving such medications as combined estrogen-­progestin therapy, danazol, progestins, or ­gonadotropin-releasing hormone (GnRH) agonists, may cause an unnecessary “delay in the use of more effective treatments that could result in pregnancy.”

Dr. Nezhat believes that medical therapy is effective in patients who have adenomyosis in addition to endometriosis. “Three months of treatment with a GnRH agonist will improve fertility rates in these patients,” he says.

“Medical treatments inhibit ovulation,” notes Dr. Estes. “These therapies have no role in pretreatment of patients with endometriosis prior to infertility treatment. On the other hand, medical therapy with GnRH agonists for 3 to 6 months prior to an IVF cycle does result in increased pregnancy rates.”⁹

2. What is the role of clomiphene and intrauterine insemination?
Should women who have endometriosis, open fallopian tubes, and infertility be treated with clomiphene and intrauterine insemination (IUI) prior to a cycle of IVF?

“This is a complex question,” says Dr. ­Estes, “as clinical parameters such as age, symptoms, duration of infertility, and the ability to proceed with IVF are important, as well as stage of disease.”

“Overall, in patients younger than 35 years, clomiphene-IUI is an option and has an increased pregnancy rate over timed intercourse” (9% vs 3%), she says.¹⁰ “How­ever, clearly IVF is much more successful and is the most effective treatment, with pregnancy rates of approximately 46% for women younger than 35 years (3% of whom have a ‘diagnosis’ of endometriosis, and 13% of whom have an ‘unknown’ infertility factor).¹¹ Women who are older than 35 or who have additional infertility factors, such as male factor, should consider IVF first.”

3. When is surgery indicated?
“Patients who have significant pain associated with their infertility will benefit from surgery, which offers both pain relief and an improvement in the spontaneous pregnancy rate,” says Dr. Falcone. “Patients who are infertile and desire spontaneous pregnancy without pharmacologic intervention or assisted reproductive technology (ART) also benefit from surgery.”

The benefit of surgery in asymptomatic women with minimal to mild endometriosis is unclear. In a randomized controlled trial of 341 women (aged 20–39 years) with infertility and minimal to mild endometriosis, laparoscopic resection or ablation of visible lesions resulted in pregnancy in 30.7% of women, compared with 17.7% of women who underwent diagnostic laparoscopy only.¹²

Another randomized study of 96 women with minimal to mild endometriosis who underwent resection/ablation or diagnostic laparoscopy found no difference in the birth rate at 1 year.¹³

When the results of these 2 studies are combined, the number needed to treat is 12 laparoscopies in women with endometriosis, says Dr. Falcone. “So 1 additional pregnancy would be gained from performing endometriosis surgery in 12 patients. If we assume a prevalence of 30% in asymptomatic women with infertility, then you need to perform 40 diagnostic laparoscopies to achieve an extra pregnancy.”

For women with infertility and severe endometriosis, a nonrandomized study found cumulative pregnancy rates of 45% and 63% after laparoscopy and laparotomy, respectively, in 216 women followed for up to 2 years.¹⁴ The difference in rates was not statistically significant.

“Although surgery is indicated to diagnose endometriosis, multiple repeat procedures are not an effective treatment for infertility,” says Dr. Estes. “Plus, especially for stage I and II endometriosis [according to the ASRM classification system], approximately 12 patients will need surgery for 1 additional pregnancy—and many more will have needed the procedure to even get to those who have endometriosis. While patients often want us to ‘do something’—­often a covered service such as surgery—we need to consider that surgery for early disease does not provide a significant or long-lasting enhancement to women’s ability to conceive.”

In the absence of male-factor infertility, surgical diagnosis with conservative and precise treatment of endometriosis at the same time is better than going directly to IVF, says Dr. Nezhat. Younger patients who undergo surgical treatment have a better chance of achieving more than 1 spontaneous pregnancy than they do with IVF. And older patients also will have an improved conception rate with ART when they are treated surgically, he says.⁸

Coding and reimbursement 

For endometriosis, the correct diagnostic code helps establish the medical necessity of later treatments
Several diagnostic codes are available to describe the location of endometriotic implants, but the fact remains that these codes can be reported only after a definitive diagnosis is made, which generally comes after confirmatory surgery has been performed. When the patient is in the diagnostic phase, she may present with complaints of pelvic pain, dyspareunia, dysmenorrhea, or infertility. Knowing which codes to use at the time of evaluation goes a long way toward establishing medical necessity for any later surgery or medical treatment.

In the TABLE, you will find common diagnostic codes that can be reported during evaluation of endometriosis, including both International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and ICD-10-CM equivalents. Note that, with ICD-10-CM, payers are looking for a more specific type of dysmenorrhea in the documentation. In the case of painful menstruation suspected to arise from endometriosis, the code for secondary dysmenorrhea should be reported.

Diagnostic coding in cases in which the patient first presents with a complaint of infertility in the absence of other symptoms can be problematic, as many insurers still do not cover the treatment of infertility. However, in the diagnostic stage, codes for fertility testing can be reported instead of codes that confirm infertility when no other symptoms are present. Once the clinician has verified that endometriosis is the source of the infertility and begins treatment, the primary code for the type of endometriosis would be reported, not a diagnosis of infertility.

The procedure performed to diagnose endometriosis would be diagnostic laparoscopy (Current Procedure Terminology [CPT] code 49320, Laparoscopy, abdomen, peritoneum, and omentum, diagnostic, with or without collection of specimen[s] by brushing or washing [separate procedure]) if medical treatment is being pursued. If the plan is to confirm and then immediately remove the implants, the CPT codes would be either 58662, Laparoscopy, surgical; with fulguration or excision of lesions of the ovary, pelvic viscera, or peritoneal surface by any method, or 49203–49205, Excision or destruction, open, intra-abdominal tumors, cysts or endometriomas, 1 or more peritoneal, mesenteric, or retroperitoneal primary or secondary tumors, based on the largest tumor diameter, if they are removed via an abdominal incision.

—Melanie Witt, RN, CPC, COBGC, MA

Ms. Witt is an independent coding and documentation consultant and former program manager, department of coding and nomenclature, American Congress of Obstetricians and Gynecologists.

4. Surgery or IVF for endometriomas?
When an endometrioma is present, should it be surgically treated or should the patient go straight to IVF? And does the optimal approach depend on the size of the endometrioma?

“The answer to this question ultimately depends on the skill and experience of the surgeon and the type of endometrioma,” says Dr. Nezhat, “because improper removal of an endometrioma may compromise the function of the ovary.”

“I recommend removal of the endometrioma by a skilled surgeon experienced in the management of ovarian cysts and preservation of ovarian function, especially in patients who have failed IVF,” he says.^6,15

According to the ASRM committee opinion on endometriosis and infertility, laparoscopic cystectomy for endometriomas larger than 4 cm improves fertility, compared with cyst drainage and coagulation, which is associated with a high risk of cyst recurrence.² However, no randomized trials have compared laparoscopic excision of an endometrioma to expectant management prior to IVF/intracytoplasmic sperm injection (ICSI). One case-control study found that laparoscopic cystectomy prior to IVF had no effect on fertility outcomes.¹⁶ At the same time, however, “conservative surgical treatment in symptomatic patients did not impair the success rates of IVF or ICSI,” notes the ASRM.² Therefore, “evidence suggests that surgery does not benefit asymptomatic women with an endometrioma prior to scheduled IVF/ICSI,” the ASRM concludes.²

Dr. Nezhat cautions against the practice of indiscriminate IVF in the setting of ovarian endometriomas because he has seen patients who developed tubo-ovarian abscess and infected endometriomas after transvaginal egg retrieval. He notes that there are additional case reports of similar findings from other surgeons.

As far as excision versus ablation is concerned, all studies have shown some effect on ovarian function after excision, says Dr. Falcone. “The studies assessed this parameter using several endpoints, such as the number of oocytes retrieved at IVF. Recently, anti-Müllerian hormone has been used and has confirmed this observation. The decreased ovarian reserve is especially problematic with bilateral ovarian disease. The extent of the decreased ovarian function is dependent on several parameters, especially how much energy is used to achieve hemostasis. Several techniques have been proposed to reduce damage, including less traumatic ways of achieving hemostasis in the ovarian hilus.”

“The dilemma is that, if we excise the disease, the pregnancy rates are better than with ablation, but if we excise, there is more damage to the ovary. In my practice, I excise if there is minimal associated disease, such as adhesions, because the pregnancy rate after surgery is good. If, however, there are extensive adhesions with a low chance of spontaneous pregnancy, I minimize excision,” Dr. Falcone says.

As for going straight to IVF, “many patients cannot afford IVF; therefore, surgery is their only option. Furthermore, many patients have severe associated pain; therefore, surgery is required to improve quality of life. However, if the decision is made to proceed to IVF, there is no evidence that cystectomy prior to treatment with ART improves the pregnancy rate,” Dr. Falcone says.

“Basically, if a woman has no pain and no endometrioma, and infertility alone is the issue, I treat her in the same manner as I would a patient with idiopathic infertility—no surgery,” Dr. Falcone says. “If a patient has severe pain and infertility, I treat her surgically but conservatively, especially when an endometrioma is present. The patient will get pain relief but also derive fertility benefit. If a patient has had previous surgery for ­endometriosis-associated infertility, additional surgery is not the next step—as our study has shown that pregnancy rates are better with IVF than repeat surgery.”¹⁷

5. Is surgery ever effective after failed IVF?
To answer this question, Dr. Nezhat points to a retrospective case series by Littman and colleagues in which 29 women with a history of failed IVF underwent laparoscopic evaluation and treatment of endometriosis (by the same surgeon).⁸ Of 29 patients, 22 conceived after laparoscopic treatment of ­endometriosis, including 15 “non-IVF” pregnancies and 7 IVF pregnancies, the study results show.⁸

“It is not unusual for patients and health care providers to perceive IVF as the final treatment for infertility,” Littman and colleagues write. “When this definitive therapy fails repeatedly, clinicians and patients may be inclined to pursue oocyte donation or elect to forego further treatment altogether. This is especially true in women of advanced age and in patients with borderline embryo quality. Presently, as a result of our clinical observation in patients with failed IVF, before egg donation or adoption, we offer the option to have meticulous laparoscopic evaluation and treatment by a skilled surgeon. Furthermore, we would not classify an infertility condition as unexplained without confirming the absence of endometriosis by a thorough laparoscopy. In our experience, patients under 35 years old with unexplained infertility who are found to have endometriosis at the time of laparoscopy have an excellent chance of pregnancy following surgical treatment without ART.”⁸

6. Is repeat surgery ever helpful?
In the treatment of endometriosis-­associated infertility, repeat surgery should be avoided if no symptoms are present, says Dr. Estes. “In women with continued symptoms, the benefits of repeat surgery are small, with known risks, including the potential for adhesive disease and the iatro­genic detrimental effect on ovarian ­function—often in a setting of already-present decreased ovarian reserve.”

Dr. Nezhat agrees that multiple surgeries carry the potential for harm. “However, there is one caveat,” he says. “What was done at the previous surgery and how? The skill and experience of the surgeon and proper technique are of paramount importance to the surgical outcome.”

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

“[Pregnant patients infected with the Ebola virus in West Africa] aren’t given preferential treatment...They aren’t even given beds.…They are assumed to die. Priority is given to the patients whom the health-care workers believe they can save. In effect, pregnant women are being triaged last.”

—Joshua Lang¹

Ebola is a rare and potentially deadly disease caused by infection with a strain of the Ebola virus. First described in 1967,² the Ebola virus has caused significant morbidity and mortality in many parts of sub-Saharan Africa. Awareness about this disease has increased dramatically in the United States as a result of the largest Ebola epidemic in history, which broke out in West Africa in 2014. The 3 countries most widely affected include Sierra Leone, Liberia, and Guinea. As of May 15, 2015, there were 26,798 cases of Ebola in this epidemic (with 14,971 laboratory confirmed), of whom 11,089 have died.³ There have been a total of 868 confirmed health care worker infections reported in Guinea, Liberia, and Sierra Leone since the start of the outbreak, with 507 reported deaths.⁴

It is highly unlikely that an Ebola epidemic of similar proportion will break out in any developed nation. However, isolated cases of Ebola have been identified among high-risk individuals in the United States (such as those who had recently served as medical volunteers in West Africa), which has raised concern about Ebola infection prevention and management in this country.

Little is known about Ebola infection in pregnancy. The few reports available suggest that pregnant women who become infected are highly contagious, with a maternal and perinatal mortality rate near 100%.⁵ Significant efforts were put in place in hospitals around the United States, including in labor and delivery units, to care for potentially or actively infected individuals, to protect health care workers, and to contain the spread of any new infections. It is important that clinicians be aware of the efforts and the recommended protocols—especially for the unique circumstance of infection during pregnancy. We review these protocols, as well as provide details on viral transmission and treatment.

What is Ebola virus and why are humans affected?

Ebola virus is a single-stranded RNA filovirus (FIGURE) with 5 independently identified species named after the countries or regions in which they were identified. Four of these are known to cause disease in humans, including Zaire Ebola virus, Sudan virus, Tai Forest virus (isolated in Ivory Coast), and Bundibugyo virus.¹ Zaire Ebola virus is the most virulent species and has been responsible for most of the outbreaks in sub-Saharan Africa, with an overall mortality rate of around 70%.² Sudan virus was responsible for outbreaks in the 1970s, 2000, and 2004; Bundibugyo virus caused a single outbreak in 2007, which had a lower mortality rate of around 30%. The fifth virus, Reston virus, does not appear to cause infection in humans, but does infect pigs and nonhuman primates.¹

The natural reservoir of the Ebola virus is not known. It is unlikely to be primates, since the virus typically kills its primate host within a matter of days. Recent studies suggest that the natural host may be bats.³ Initial infections in humans may result from preparing and eating infected bush meat or from exposure to infected bat droppings during such activities as mining and spelunking.

References

1. Bray M. Filoviridae. In: Clinical Virology, 2nd ed. Richman DD, Whitley RJ, Hayden FG, eds. Washington, DC: ASM Press; 2002:875.
2. WHO Ebola Response Team. Ebola virus disease in West Africa—the first 9 months of the epidemic and forward projections. N Engl J Med. 2014;371:1481–1495.
3. Centers for Disease Control and Prevention. Epidemiologic risk factors to consider when evaluating a person for exposure to Ebola virus. http://www.cdc.gov/vhf/ebola/exposure/risk-factors-when-evaluating-person-for-exposure.html. Updated May 1, 2015. Accessed May 14, 2015.

Transmission and clinical presentation
Ebola is not spread through air, water supply, food, or by mosquitoes.⁶ The Ebola virus is spread from person to person through direct contact with blood or bodily fluids from an infected individual who has developed disease symptoms. It is generally accepted that asymptomatic individuals are not infectious, likely due to their low circulating viral load. The incubation period is between 2 and 21 days.^6,7

Sexual transmission. The Centers for Disease Control and Prevention (CDC) now recommends that contact with semen from male Ebola survivors be avoided “until more information regarding the duration and infectiousness of viral shedding in body fluids is known.” They recommend a condom be used (correctly and consistently) when male survivors have oral, vaginal, or anal sex.⁸

Following the initial inoculation, the virus spreads rapidly throughout the body, infecting many cell types, although it primarily targets macrophages (including the Kupffer cells of the liver), dendritic cells, and endothelial cells. Infected cells die and release more viral particles as well as proinflammatory mediators (tumor-necrosis-factor−a, interleukins, nitric oxide) leading to a massive systemic inflammatory response. Impaired dendritic cells are unable to mount an effective immune response to fight the infection.⁹

Symptoms develop rapidly, starting with fever and malaise, and progressing within a few days to vomiting, diarrhea, loss of appetite, abdominal pain, and rash. Signs include hypotension (due to vasodilation and increased vascular permeability), shock, multisystem organ failure, and coagulopathy (which occurs in 20% of cases due to activation of tissue factor). Leukopenia, thrombocytopenia, transaminitis, coagulation abnormalities, proteinuria, renal failure, and electrolyte abnormalities are commonly seen on laboratory analysis.^10,11 Interestingly, the Ebola virus gains entry into human cells using the Niemann-Pick C1 cholesterol transporter, and cells from patients with Niemann-Pick type C disease are immune to infection with the Ebola virus.¹²

Ebola in pregnancy
Information about the true incidence and complications of Ebola disease is limited. Most infected patients have been cared for in community-based health care facilities in Africa with little access to diagnostic testing and unreliable medical records. The data we do have about risks factors, disease transmission, and mortality rates come mainly from epidemiologic studies conducted in the midst of an Ebola epidemic or from studies in nonhuman primates. Data on Ebola infection in pregnancy are even more limited.

Pregnant women are more vulnerable to and may have more complications as a result of certain infections, including malaria, varicella, and seasonal influenza. While data are limited, pregnant women and their fetuses infected with the Ebola virus also appear to have worse outcomes, with a maternal and perinatal mortality rate that approaches 100%.⁵ Under normal conditions, pregnant women are given priority within the medical system. However, given the overall poor prognosis, their increased infectivity, and concerns about the well-being of health care providers, many pregnant women infected with the Ebola virus during the recent epidemic were set aside and denied basic health care needs, including hospital admission. Whether improved infection control and more intensive medical care would improve the survival rate of infected pregnant women is not clear.

Most of what we know about Ebola infection in pregnancy comes from the 1995 epidemic in the Kikwit area of the Democratic Republic of the Congo (Zaire). Of the 202 people infected during that epidemic, 105 were women and 15 were pregnant (4 in the first trimester, 6 in the second trimester, and 5 in the third trimester). Pregnant women presented with vaginal bleeding and occasionally bleeding from other sites, including gum bleeding, hematemesis, hematuria, and melena. Of note, the diagnosis of Ebola during the Kikwit epidemic was based on clinical examination alone.⁵ Fourteen of these 15 women died, giving a mortality rate of 93.3%, with death occurring within 10 days in all instances. One woman delivered a live-born child, but both she and the baby died within 3 days. The woman who did survivehad a miscarriage in the first trimester.⁵

In the 1976 epidemic centered in Yambuku, Zaire, pregnant women fared slightly better, with a mortality rate of 89% (73/82), which was similar to the mortality rate for the population as a whole of 88%.⁵ Nineteen women (23%) had a spontaneous abortion. Ten women (12%) delivered live-born babies, but all died within 19 days. It is assumed that these infants contracted the Ebola virus, but whether this was indeed the case and when and how they contracted the infection is not known. The combined perinatal and infant mortality rate in these 2 epidemics was 100%.

During the recent epidemic in Guinea, there were 2 pregnant patients, both of whom presented with fetal demise in the third trimester. Their labors were induced and both mothers survived.¹³ During the height of the recent Liberian epidemic (between August and October 2014), 700 infected patients were admitted to the largest treatment center. Four women were pregnant, all in the latter half of gestation. Of these, 3 died (75% mortality rate). The remaining woman survived, but her fetus died.⁹ Taken together, the prevailing evidence suggests that maternal and perinatal outcomes of pregnant women infected with the Ebola virus are dismal, with mortality rates approaching 100%.

Protecting health care workers
Transmission of the Ebola virus to health care workers has emerged as a major concern during the most recent outbreak in West Africa. Frontline health care workers are usually the first to see such patients and are at high risk of exposure to infected bodily fluids. This is especially true of health care professionals working on labor and delivery units, where exposure to blood and amniotic fluid is commonplace at the time of delivery.

Contaminated needles and syringes also may play a role in transmission.^14,15 And, in Africa, a large number of transmissions have been attributed to ritual washing of the body at funerals, since viral load is maximal at the time of death, but this is unlikely to play a significant role in transmission of the virus in developed countries. Ebola virus has been isolated from breast milk.¹⁶ While direct transmission of the virus through breastfeeding has not been documented, breast milk from infected individuals should be disposed of carefully.

Prophylaxis
Is a vaccine on the way?
Development of an Ebola vaccine is under way. The most promising vaccine to date is cAd3-ZEBOV (GlaxoSmithKline, Brentford, London, United Kingdom). This vaccine is derived from a chimpanzee adenovirus, called Chimp Adenovirus type 3 (ChAd3), which has been genetically engineered to express proteins from both the Zaire and Sudan species of Ebola virus to provoke an immune response against them. Phase 1 trials of this vaccine began in September 2014.¹⁷

Appropriate precautions
Until an effective vaccine is available, a number of recommendations have been put in place in an effort to prevent Ebola infection:

Classifying risk and risk-associated protocols
If an at-risk patient is identified, she should be placed in isolation and consultation with an infectious disease specialist should occur. Using appropriate personal protective equipment (PPE), a detailed history and physical examination should be performed, and the patient should be classified according to risk14,15:

When should a patient be tested for Ebola, and what does that testing entail?
Patients found to be at no risk should not be tested or monitored, regardless of whether or not they are symptomatic. Asymptomatic patients with risk factors should not be tested for the Ebola virus. However, they do need to be followed for signs and symptoms of infection. At this time, the CDC has decided that it will take on the responsibility of monitoring all such patients until they are out of the 21-day window.^14,15

Symptomatic patients with risk factors should be tested for the Ebola virus, regardless of whether they are designated as being at low, moderate, or high risk of infection. Strict infection control precautions should be followed for such patients, and local/state health departments should be notified. Laboratory testing includes RT-PCR or Ebola immunoassay. A negative RT-PCR test result obtained more than 72 hours after the onset of symptoms effectively rules out Ebola ­infection. In general, patients can be discharged from the hospital if they are ­asymptomatic and have 2 negative RT-PCR test results within 48 hours.^14,15

Other diagnoses that should be considered in these patients include influenza, malaria, Lassa fever, meningococcal infection, and typhoid. If a patient is asymptomatic but at risk, all nonemergent medical care should be deferred until they are out of the 21-day window. Repeat testing may be warranted in certain clinical scenarios.

Management of infected patients in a maternity ward
While no pregnant patient has yet been diagnosed with Ebola infection in the United States, it remains a possibility, and clinicians should be aware of appropriate management actions. Once the diagnosis is confirmed, patients and their families should be placed in strict isolation. In some states, specific regional centers have been designated to care for these patients. They should be cared for by a small, dedicated team of clinicians dressed in state-of-the-art PPE and fully trained in the technique of donning and doffing the gear. Some institutions have mandated that no medical students or residents be involved directly in the care of these patients. Infectious disease specialists should be actively involved. All medical equipment (such as stethoscopes, blood pressure cuffs, thermometers, and fetal heart rate monitors) should be dedicated to the care of this patient alone and should remain in the room, as the virus can remain viable on surfaces for “a few hours or days.”¹⁸

Treatment itself is largely supportive, with significant intravascular expansion and treatment of fever, nausea, vomiting, and diarrhea. Patients typically require 5 to 10 L of fluid replacement each day, along with regular electrolyte repletion. The development of coagulopathy is a real concern and should be carefully monitored for and corrected as needed. Since blood is highly infectious, every effort should be made to perform only critical blood tests and to do so at the bedside, if possible. Mobile devices are available that can be stationed in the room and provide basic hematologic and electrolyte measurements, thereby avoiding the need to transport the blood and the risk of potentially contaminating laboratory equipment. Dedicated staff should be trained on the use of such equipment. In all likelihood, radiologic imaging will not be available and management decisions will need to be made on the basis of clinical examination alone.

Treatment of the virus and the conditions it can cause
A number of experimental treatments are under investigation. These include some antiviral agents (such as the CMV antiviral drug brincidofovir and the influenza antiviral favipiravir), immune sera from Ebola survivors, and RNA interference agents (such as TKM-Ebola). Zmapp, a cocktail of 3 anti-Ebola monoclonal antibodies, has been shown to be protective in macaque monkeys in the late stages of the disease and has been given to 4 infected patients in the United States, with variable results.¹⁹ All of these options should be considered on an individual basis.

Some patients may experience renal or respiratory failure requiring advanced life support measures such as dialysis, mechanical ventilation, or cardiorespiratory resuscitation (CPR). The decision of whether or not to proceed with such interventions should be left to the discretion of the attending physician staff. Given the extremely poor prognosis for the patient and the attendant risks to the health care staff and potentially to subsequent patients using these same pieces of medical equipment, it would seem reasonable to withhold such interventions.

Unique considerations during pregnancy. In pregnant patients with Ebola, it may be reasonable to withhold the option of cesarean and offer only vaginal delivery in the event of labor. This is not just a theoretic concern. In 1 case in Zaire in 1995, an entire surgical team was infected after operating on an infected patient, with the infection spreading to outside hospital staff and family members.²⁰

Survival rates are dismal
Reported survival rates are extremely low, especially for pregnant women. Patients who are younger, have lower viral loads, and do not have diarrhea or severe dehydration have a higher likelihood of surviving. Whether survival rates are higher in developed countries with more health care resources has yet to be confirmed. If patients do survive, the recovery period is long, with prolonged weakness, fatigue, and weight loss. While sexual transmission of the Ebola virus has not been documented, the CDC has recommended sexual abstinence for at least 3 months after recovery.^14,15 Ebola survivors are thought to be immune to subsequent infections.

Education is the most important factor for most of us
In November 2014, the American College of Obstetricians and Gynecologists (ACOG) published a practice advisory on the care of obstetric patients during an Ebola virus outbreak.²¹ While the number of Ebola cases in the United States has been, and likely will continue to be low, especially among pregnant women, we should continue to focus on education and screening. Only providers who have undergone Ebola training and have proper PPE should be involved in the care of potentially infected or confirmed cases. The greatest potential for harm is suboptimal obstetric care leading to an adverse event in a patient suspected of having Ebola who subsequently tests negative. Once an Ebola infection has been confirmed, patients—regardless of whether or not they are pregnant—should be hospitalized in institutions with the requisite resources, protocols, and expertise to deal with such highly infectious patients.

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