OBG Management

SAFER CESAREAN SCALPEL

FOR MORE INFORMATION, VISIT: www.sureglide.info

RF ENERGY TO IMPROVE SEXUAL FUNCTION

According to Viveve Medical, results of the recent Viveve I multicenter, blinded, randomized, sham controlled study showed no serious adverse effects plus improvement in arousal and/or orgasm self-reported by 9 of 10 women who noted vaginal laxity and sexual dysfunction following vaginal childbirth.

FOR MORE INFORMATION, VISIT: www.viveve.com

NEXT-GENERATION ENDOMETRIAL ABLATION

FOR MORE INFORMATION, VISIT: www.novasure.com

SAFER CESAREAN SCALPEL

FOR MORE INFORMATION, VISIT: www.sureglide.info

RF ENERGY TO IMPROVE SEXUAL FUNCTION

According to Viveve Medical, results of the recent Viveve I multicenter, blinded, randomized, sham controlled study showed no serious adverse effects plus improvement in arousal and/or orgasm self-reported by 9 of 10 women who noted vaginal laxity and sexual dysfunction following vaginal childbirth.

FOR MORE INFORMATION, VISIT: www.viveve.com

NEXT-GENERATION ENDOMETRIAL ABLATION

FOR MORE INFORMATION, VISIT: www.novasure.com

SAFER CESAREAN SCALPEL

FOR MORE INFORMATION, VISIT: www.sureglide.info

RF ENERGY TO IMPROVE SEXUAL FUNCTION

According to Viveve Medical, results of the recent Viveve I multicenter, blinded, randomized, sham controlled study showed no serious adverse effects plus improvement in arousal and/or orgasm self-reported by 9 of 10 women who noted vaginal laxity and sexual dysfunction following vaginal childbirth.

FOR MORE INFORMATION, VISIT: www.viveve.com

NEXT-GENERATION ENDOMETRIAL ABLATION

FOR MORE INFORMATION, VISIT: www.novasure.com

(A) Paratubal cyst CORRECT

Paratubal, or paraovarian, cysts typically are round or oval avascular hypoechoic cysts (long arrow) separate from the adjacent ovary (short arrow). Since they are congenital remnants of the Wolffian duct, they arise from the mesosalpinx, specifically the broad ligament or fallopian tube.^1,2 They usually are seen in close proximity to but separate from the ovary without distorting the ovary’s architecture.^1,2

A hydrosalpinx appears as an elongated C- or S-shaped, thin-walled tubular serpiginous cystic lesion separate from the ovary. It often has incomplete septations that are infolding of the tube on itself (long arrow).³ Other findings include diametrically opposed indentations (short arrows) of the wall (Waist sign) and short linear mucosal or submucosal folds (arrowhead) that when viewed in cross section appear similar to the spokes of a cogwheel (Cogwheel sign).^1–3 Prior tubal infection or gynecologic surgery represent risk factors for hydrosalpinx.

A peritoneal inclusion cyst appears as an anechoic cystic mass that conforms passively to the shape of the peritoneal cavity/pelvic sidewall (long arrow) and may contain entrapped ovaries (short arrow)  within or along the periphery of the fluid collection.^1,2 Septations within it are likely from peritoneal adhesions (arrowhead) and may show vascularity.² Prior (often multiple) gynecologic surgeries represent a risk factor for peritoneal inclusion cysts.

Dilated pelvic veins appear on sonography as a cluster of elongated and tubular cystic lesions in the adnexa along the broad ligament and demonstrate low level echoes due to sluggish flow (long arrow) and visible red blood cell rouleaux formation. This can be confirmed on color Doppler images (short arrow) and help differentiate it from hydrosalpinx.

(A) Paratubal cyst CORRECT

Paratubal, or paraovarian, cysts typically are round or oval avascular hypoechoic cysts (long arrow) separate from the adjacent ovary (short arrow). Since they are congenital remnants of the Wolffian duct, they arise from the mesosalpinx, specifically the broad ligament or fallopian tube.^1,2 They usually are seen in close proximity to but separate from the ovary without distorting the ovary’s architecture.^1,2

A hydrosalpinx appears as an elongated C- or S-shaped, thin-walled tubular serpiginous cystic lesion separate from the ovary. It often has incomplete septations that are infolding of the tube on itself (long arrow).³ Other findings include diametrically opposed indentations (short arrows) of the wall (Waist sign) and short linear mucosal or submucosal folds (arrowhead) that when viewed in cross section appear similar to the spokes of a cogwheel (Cogwheel sign).^1–3 Prior tubal infection or gynecologic surgery represent risk factors for hydrosalpinx.

A peritoneal inclusion cyst appears as an anechoic cystic mass that conforms passively to the shape of the peritoneal cavity/pelvic sidewall (long arrow) and may contain entrapped ovaries (short arrow)  within or along the periphery of the fluid collection.^1,2 Septations within it are likely from peritoneal adhesions (arrowhead) and may show vascularity.² Prior (often multiple) gynecologic surgeries represent a risk factor for peritoneal inclusion cysts.

Dilated pelvic veins appear on sonography as a cluster of elongated and tubular cystic lesions in the adnexa along the broad ligament and demonstrate low level echoes due to sluggish flow (long arrow) and visible red blood cell rouleaux formation. This can be confirmed on color Doppler images (short arrow) and help differentiate it from hydrosalpinx.

(A) Paratubal cyst CORRECT

Paratubal, or paraovarian, cysts typically are round or oval avascular hypoechoic cysts (long arrow) separate from the adjacent ovary (short arrow). Since they are congenital remnants of the Wolffian duct, they arise from the mesosalpinx, specifically the broad ligament or fallopian tube.^1,2 They usually are seen in close proximity to but separate from the ovary without distorting the ovary’s architecture.^1,2

A hydrosalpinx appears as an elongated C- or S-shaped, thin-walled tubular serpiginous cystic lesion separate from the ovary. It often has incomplete septations that are infolding of the tube on itself (long arrow).³ Other findings include diametrically opposed indentations (short arrows) of the wall (Waist sign) and short linear mucosal or submucosal folds (arrowhead) that when viewed in cross section appear similar to the spokes of a cogwheel (Cogwheel sign).^1–3 Prior tubal infection or gynecologic surgery represent risk factors for hydrosalpinx.

A peritoneal inclusion cyst appears as an anechoic cystic mass that conforms passively to the shape of the peritoneal cavity/pelvic sidewall (long arrow) and may contain entrapped ovaries (short arrow)  within or along the periphery of the fluid collection.^1,2 Septations within it are likely from peritoneal adhesions (arrowhead) and may show vascularity.² Prior (often multiple) gynecologic surgeries represent a risk factor for peritoneal inclusion cysts.

Dilated pelvic veins appear on sonography as a cluster of elongated and tubular cystic lesions in the adnexa along the broad ligament and demonstrate low level echoes due to sluggish flow (long arrow) and visible red blood cell rouleaux formation. This can be confirmed on color Doppler images (short arrow) and help differentiate it from hydrosalpinx.

Resources

• Essure permanent birth control (Bayer) instructions for use

• Essure patient information booklet

• US Food and Drug Administration. Labeling for permanent hysteroscopically-placed tubal implants intended for sterilization: guidance for industry and Food and Drug Administration staff. October 31, 2016

• Visit the companion article

Resources

• Essure permanent birth control (Bayer) instructions for use

• Essure patient information booklet

• US Food and Drug Administration. Labeling for permanent hysteroscopically-placed tubal implants intended for sterilization: guidance for industry and Food and Drug Administration staff. October 31, 2016

• Visit the companion article

Resources

• Essure permanent birth control (Bayer) instructions for use

• Essure patient information booklet

• US Food and Drug Administration. Labeling for permanent hysteroscopically-placed tubal implants intended for sterilization: guidance for industry and Food and Drug Administration staff. October 31, 2016

• Visit the companion article

Fibroids are extremely common and can be detected in 60% of African American women and 40% of white women by age 35. By age 50, more than 80% of African American women and almost 70% of white women have fibroids. Although most women with fibroids are relatively asymptomatic, women who have bothersome symptoms, such as heavy menstrual bleeding, urinary frequency, pelvic or abdominal pressure, or pain, account for nearly 30% of all gynecologic admissions in the United States. The cost of fibroid-related care, including surgery, hospital admissions, outpatient visits, and medications, is estimated at $4 to $9 billion per year.¹ In addition, each woman seeking treatment for fibroid-related symptoms incurs an expense of $4,500 to $30,000 for lost work or disability every year.¹

Many treatment options, including medical therapy and noninvasive procedures, are now available for women with symptomatic fibroids. For women who require surgical treatment, however, hysterectomy is often recommended. Fibroid-related hysterectomy currently accounts for 45% of all hysterectomies, or approximately 195,700 per year. Although the American College of Obstetricians and Gynecologists (ACOG) clinical management guidelines state that myomectomy is a safe and effective alternative to hysterectomy for treatment of women with symptomatic fibroids, only 30,000 myomectomies (abdominal, laparoscopic, and robotic-assisted approaches) are performed each year.² Why is this? One reason may be that, although many women wish to have uterus-preserving treatment, they often feel that doctors are too quick to recommend hysterectomy as the first—and sometimes only—treatment option for fibroids.³

CASE: Woman with fibroids seeks alternative to hysterectomy

A 42-year-old woman (G2P2) presents for a third opinion regarding her heavy menstrual bleeding and known uterine fibroids. She does not want to have any more children, but she wishes to avoid a hysterectomy. Both her regular gynecologist and the second gynecologist she consulted recommended hysterectomy as the first, and only, treatment option. Physical examination reveals a 16-week-sized uterus, and ultrasonography shows at least 6 fibroids, 2 of which impinge on the uterine cavity. The patient’s other gynecologists advised her that a myomectomy would be a “bloody operation,” would leave her uterus looking like Swiss cheese, and is not appropriate for women who have completed childbearing.

The patient asks if myomectomy could be considered in her situation. How would you advise her regarding myomectomy as an alternative to hysterectomy?

Organ conservation is important

In 1931, prominent British gynecologic surgeon Victor Bonney said, “Since cure without deformity or loss of function must ever be surgery’s highest ideal, the general proposition that myomectomy is a greater surgical achievement is incontestable.”⁴ As current hysterectomy and myomectomy rates indicate, however, we are not attempting organ conservation very often.

Other specialties almost never remove an entire organ for benign growths. Using breast cancer surgery as an admirable paradigm, consider that in the early 20th century the standard treatment for breast cancer was a Halsted radical mastectomy with axial lymphadenectomy. By the 1930s, this disfiguring operation was replaced by simple mastectomy and radiation, and by the 1970s, by lumpectomy and lymphadenectomy. Currently, lumpectomy and sentinel node sampling is the standard of care for early stage breast cancer. This is an excellent example of “minimally invasive surgery,” a term fostered by gynecologists. And, these organ-preservingsurgeries are performed for women with cancer, not a benign condition like fibroids.

Although our approach to hysterectomy has evolved with the increasing use of laparoscopic or robotic assistance, removal of the entire uterus nevertheless remains the surgical goal. I think this narrow view of surgical options is a disservice to our patients.

Many of us were taught that myomectomy was associated with more complications and more blood loss than hysterectomy. We were taught that the uterus had no function other than childbearing and that removing the uterus had no adverse health effects. The dogma suggested that myomectomy preserved a uterus that looked like Swiss cheese and would not heal properly and that the risk of fibroid recurrence was high. These beliefs, however, are myths, which are discussed and debunked below. In second and third installments for this series on myomectomy, I present steps for successful abdominal and laparoscopic technique.

Read myths on hysterectomy, myomectomy, and fibroids

MYTH #1: Hysterectomy is safer than myomectomy

Myomectomy is performed within the confines of the uterus and myometrium, with only infrequent occasion to operate near the ureters, uterine vessels, bowel, or bladder. Therefore, it should not be surprising that studies show that fewer complications occur with myomectomy than with hysterectomy.

A retrospective review of 197 women who had myomectomy and 197 women who underwent hysterectomy with similar uterine size (14 vs 15 weeks) reported that 13% (n = 26) of women in the hysterectomy group experienced complications, including 1 bladder injury, 1 ureteral injury, and 3 bowel injuries; 8 women had an ileus and 6 women had a pelvic abscess.⁵ Only 5% (n = 11) of the myomectomy patients had complications, including 1 bladder injury; 2 women had reoperation for small bowel obstruction, and 6 women had an ileus. The risks of febrile morbidity, unintended surgical procedure, life-threatening events, and rehospitalization were similar for both groups.

Authors of a recent systematic review of 6 studies, which included 1,520 women with uterine size up to 18 weeks, found higher rates of visceral injury and longer hospital stays for women who had a hysterectomy compared with those who had a myomectomy (TABLE 1).⁶

MYTH #2: Myomectomy is associated with more surgical blood loss than hysterectomy

In the previously cited study of 197 women treated with myomectomy and 197 women treated with hysterectomy, the estimated blood loss was greater in the hysterectomy group (484 mL) than in the myomectomy group (227 mL). When uterine size was corrected for, blood loss was no greater for myomectomy than for hysterectomy.⁵ The risk of hemorrhage (>500 mL blood loss) was greater in the hysterectomy group (14.2% vs 9.6%). Authors of the recent meta-analysis also found that the rate of transfusion was higher in the hysterectomy cohort. Tourniquets, misoprostol, vasopressin, and tranexamic acid all have been shown to significantly decrease surgical blood loss. (These treatments will be discussed in the next installment of this article series.)

MYTH #3: A uterus will look like Swiss cheese after a myomectomy

The uterus heals remarkably well after myomectomy. Three months following laparoscopic myomectomy, 3-dimensional Doppler ultrasonography demonstrated complete myometrial healing and normal blood flow to the uterus.⁷ In a study of women undergoing abdominal myomectomy, follow-up magnetic resonance imaging (MRI) with gadolinium showed complete healing of the myometrium and normal myometrial perfusion by 3 months.⁸ This study also found that, after removal of 65 g to 380 g of fibroids, the uterine volume 3 months after surgery was 65 mL, essentially equivalent to the normal volume of a uterus without fibroids (57 mL).⁸ See FIGURE for MRI scans of the uterus before and after myomectomy.

MYTH #4: Fibroids will just grow back after myomectomy

Once a fibroid is completely removed surgically, it does not grow back. The risk of new fibroid growth depends on the number of fibroids originally removed and the amount of time until menopause, when fibroids reduce in size and symptoms usually resolve. Given that the prevalence of fibroids is nearly 80% by age 50, studies measuring the detection of new fibroid growth of 1 cm on ultrasound imaging overstate the problem.⁹ What is likely a more important consideration for women is whether, following myomectomy, they will need another procedure for new fibroid-related symptoms.

Results of a meta-analysis of 872 women in 7 studies with 10- to 25-year follow-up indicated that 89% of women did not require another surgery.¹⁰ In another study, authors found that, over an average follow-up of 7.6 years, a second surgery occurred in 11% of the women who had 1 fibroid initially removed and for 26% of women who had multiple fibroids initially removed.¹¹ In another study of 92 women who had either abdominal or laparoscopic myomectomy after age 45and who were followed for an average of 30 months, only 1 woman (1%) required a hysterectomy for fibroid-related symptoms.¹² That patient had growth of a fibroid that was present but was not removed at her initial laparoscopic myomectomy.

Read myths 5–7 on ovarian conservation, fibroid growth, and symptom improvement

MYTH #5: Hysterectomy with ovarian conservation does not change hormone levels

Following hysterectomy with ovarian conservation, some women begin menopause earlier than age-matched women who have not undergone any surgery.¹³ Hysterectomy with ovarian conservation prior to age 50 has been associated with a significant increase in the risk of coronary heart disease, stroke, and heart failure.¹⁴ In a prospective longitudinal study, antimüllerian hormone (AMH) levels were persistently decreased following hysterectomy despite ovarian conservation.¹⁵ However, 3 months after myomectomy, no such changes in AMH levels were seen (TABLE 2).¹⁵

Early natural menopause has been associated with an increase in cardiovascular disease and death, and bilateral oophorectomy has been associated with increased risks of cardiovascular disease, all-cause mortality, lung cancer, colon cancer, anxiety, and depression. Although taking estrogen might obviate these adverse health effects, the majority of women who receive a prescription for estrogen following surgery are no longer taking it 5 years later.

MYTH #6: Fibroid growth in a premenopausal patient means cancer may be present

While most fibroids grow slowly, rapid growth of benign fibroids is very common. Using computerized analysis of a group of 72 women having serial MRI scans, investigators found that 34% of benign fibroids increased more than 20% in volume over 6 months.¹⁶ In premenopausal women, “rapid uterine growth” almost never indicates presence of uterine sarcoma. One study reported only 1 sarcoma among 371 women operated on for rapid growth of presumed fibroids.¹⁷ Using current criteria from the World Health Organization to determine the pathologic diagnosis, however, that 1 woman was determined to have had an atypical leiomyoma. Therefore, the prevalence of leiomyosarcoma in that study approached zero. In addition, in the 198 women who had a 6-week increase in uterine size over 1 year (one published definition of rapid growth), no sarcomas were found.¹⁷

Because of recent concern about leiomyosarcoma and morcellation of fibroids, some gynecologists have reverted to advising women that growing fibroids might be cancer and that hysterectomy is recommended. However, there is no evidence that fibroid growth is a sign of leiomyosarcoma in premenopausal women. Leiomyosarcoma should strongly be considered in a postmenopausal woman on no hormone therapy who has growth of a presumed fibroid.

MYTH #7: Myomectomy will not improve symptoms

Fibroid-related symptoms can be significant; women who undergo hysterectomy because of fibroid-related symptoms have significantly worse scores on the 36-Item Short-Form Survey (SF-36) quality-of-life questionnaire than women diagnosed with hypertension, heart disease, chronic lung disease, or arthritis.¹⁸

For women with fibroid-related symptoms, myomectomy has been shown to improve quality of life. A study of 72 women showed that SF-36 scores improved significantly following myomectomy (TABLE 3, page 48).¹⁹ In another study that used the European Quality of Life Five-Dimension Scale and Visual Analog Scale, 95 women had significant improvement in quality of life (P<.001) following laparoscopic myomectomy.²⁰

For some women, hysterectomy may have an impact on emotional quality of life. Some women report decreased sexual desire after hysterectomy. They worry that partners will see them as “not whole” and less desirable. Some women expect that hysterectomy will lead to depression, crying, lack of sexual desire, and vaginal dryness.²¹ No such changes have been reported for women having myomectomy.

CASE Continued: Third consult leads patient to schedule surgical procedure

After reviewing the patient’s symptoms, examination, and ultrasound results, we advise the patient that abdominal myomectomy is indeed appropriate and feasible in her case. She schedules surgery for the following month.

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

Fibroids are extremely common and can be detected in 60% of African American women and 40% of white women by age 35. By age 50, more than 80% of African American women and almost 70% of white women have fibroids. Although most women with fibroids are relatively asymptomatic, women who have bothersome symptoms, such as heavy menstrual bleeding, urinary frequency, pelvic or abdominal pressure, or pain, account for nearly 30% of all gynecologic admissions in the United States. The cost of fibroid-related care, including surgery, hospital admissions, outpatient visits, and medications, is estimated at $4 to $9 billion per year.¹ In addition, each woman seeking treatment for fibroid-related symptoms incurs an expense of $4,500 to $30,000 for lost work or disability every year.¹

Many treatment options, including medical therapy and noninvasive procedures, are now available for women with symptomatic fibroids. For women who require surgical treatment, however, hysterectomy is often recommended. Fibroid-related hysterectomy currently accounts for 45% of all hysterectomies, or approximately 195,700 per year. Although the American College of Obstetricians and Gynecologists (ACOG) clinical management guidelines state that myomectomy is a safe and effective alternative to hysterectomy for treatment of women with symptomatic fibroids, only 30,000 myomectomies (abdominal, laparoscopic, and robotic-assisted approaches) are performed each year.² Why is this? One reason may be that, although many women wish to have uterus-preserving treatment, they often feel that doctors are too quick to recommend hysterectomy as the first—and sometimes only—treatment option for fibroids.³

CASE: Woman with fibroids seeks alternative to hysterectomy

A 42-year-old woman (G2P2) presents for a third opinion regarding her heavy menstrual bleeding and known uterine fibroids. She does not want to have any more children, but she wishes to avoid a hysterectomy. Both her regular gynecologist and the second gynecologist she consulted recommended hysterectomy as the first, and only, treatment option. Physical examination reveals a 16-week-sized uterus, and ultrasonography shows at least 6 fibroids, 2 of which impinge on the uterine cavity. The patient’s other gynecologists advised her that a myomectomy would be a “bloody operation,” would leave her uterus looking like Swiss cheese, and is not appropriate for women who have completed childbearing.

The patient asks if myomectomy could be considered in her situation. How would you advise her regarding myomectomy as an alternative to hysterectomy?

Organ conservation is important

In 1931, prominent British gynecologic surgeon Victor Bonney said, “Since cure without deformity or loss of function must ever be surgery’s highest ideal, the general proposition that myomectomy is a greater surgical achievement is incontestable.”⁴ As current hysterectomy and myomectomy rates indicate, however, we are not attempting organ conservation very often.

Other specialties almost never remove an entire organ for benign growths. Using breast cancer surgery as an admirable paradigm, consider that in the early 20th century the standard treatment for breast cancer was a Halsted radical mastectomy with axial lymphadenectomy. By the 1930s, this disfiguring operation was replaced by simple mastectomy and radiation, and by the 1970s, by lumpectomy and lymphadenectomy. Currently, lumpectomy and sentinel node sampling is the standard of care for early stage breast cancer. This is an excellent example of “minimally invasive surgery,” a term fostered by gynecologists. And, these organ-preservingsurgeries are performed for women with cancer, not a benign condition like fibroids.

Although our approach to hysterectomy has evolved with the increasing use of laparoscopic or robotic assistance, removal of the entire uterus nevertheless remains the surgical goal. I think this narrow view of surgical options is a disservice to our patients.

Many of us were taught that myomectomy was associated with more complications and more blood loss than hysterectomy. We were taught that the uterus had no function other than childbearing and that removing the uterus had no adverse health effects. The dogma suggested that myomectomy preserved a uterus that looked like Swiss cheese and would not heal properly and that the risk of fibroid recurrence was high. These beliefs, however, are myths, which are discussed and debunked below. In second and third installments for this series on myomectomy, I present steps for successful abdominal and laparoscopic technique.

Read myths on hysterectomy, myomectomy, and fibroids

MYTH #1: Hysterectomy is safer than myomectomy

Myomectomy is performed within the confines of the uterus and myometrium, with only infrequent occasion to operate near the ureters, uterine vessels, bowel, or bladder. Therefore, it should not be surprising that studies show that fewer complications occur with myomectomy than with hysterectomy.

A retrospective review of 197 women who had myomectomy and 197 women who underwent hysterectomy with similar uterine size (14 vs 15 weeks) reported that 13% (n = 26) of women in the hysterectomy group experienced complications, including 1 bladder injury, 1 ureteral injury, and 3 bowel injuries; 8 women had an ileus and 6 women had a pelvic abscess.⁵ Only 5% (n = 11) of the myomectomy patients had complications, including 1 bladder injury; 2 women had reoperation for small bowel obstruction, and 6 women had an ileus. The risks of febrile morbidity, unintended surgical procedure, life-threatening events, and rehospitalization were similar for both groups.

Authors of a recent systematic review of 6 studies, which included 1,520 women with uterine size up to 18 weeks, found higher rates of visceral injury and longer hospital stays for women who had a hysterectomy compared with those who had a myomectomy (TABLE 1).⁶

MYTH #2: Myomectomy is associated with more surgical blood loss than hysterectomy

In the previously cited study of 197 women treated with myomectomy and 197 women treated with hysterectomy, the estimated blood loss was greater in the hysterectomy group (484 mL) than in the myomectomy group (227 mL). When uterine size was corrected for, blood loss was no greater for myomectomy than for hysterectomy.⁵ The risk of hemorrhage (>500 mL blood loss) was greater in the hysterectomy group (14.2% vs 9.6%). Authors of the recent meta-analysis also found that the rate of transfusion was higher in the hysterectomy cohort. Tourniquets, misoprostol, vasopressin, and tranexamic acid all have been shown to significantly decrease surgical blood loss. (These treatments will be discussed in the next installment of this article series.)

MYTH #3: A uterus will look like Swiss cheese after a myomectomy

The uterus heals remarkably well after myomectomy. Three months following laparoscopic myomectomy, 3-dimensional Doppler ultrasonography demonstrated complete myometrial healing and normal blood flow to the uterus.⁷ In a study of women undergoing abdominal myomectomy, follow-up magnetic resonance imaging (MRI) with gadolinium showed complete healing of the myometrium and normal myometrial perfusion by 3 months.⁸ This study also found that, after removal of 65 g to 380 g of fibroids, the uterine volume 3 months after surgery was 65 mL, essentially equivalent to the normal volume of a uterus without fibroids (57 mL).⁸ See FIGURE for MRI scans of the uterus before and after myomectomy.

MYTH #4: Fibroids will just grow back after myomectomy

Once a fibroid is completely removed surgically, it does not grow back. The risk of new fibroid growth depends on the number of fibroids originally removed and the amount of time until menopause, when fibroids reduce in size and symptoms usually resolve. Given that the prevalence of fibroids is nearly 80% by age 50, studies measuring the detection of new fibroid growth of 1 cm on ultrasound imaging overstate the problem.⁹ What is likely a more important consideration for women is whether, following myomectomy, they will need another procedure for new fibroid-related symptoms.

Results of a meta-analysis of 872 women in 7 studies with 10- to 25-year follow-up indicated that 89% of women did not require another surgery.¹⁰ In another study, authors found that, over an average follow-up of 7.6 years, a second surgery occurred in 11% of the women who had 1 fibroid initially removed and for 26% of women who had multiple fibroids initially removed.¹¹ In another study of 92 women who had either abdominal or laparoscopic myomectomy after age 45and who were followed for an average of 30 months, only 1 woman (1%) required a hysterectomy for fibroid-related symptoms.¹² That patient had growth of a fibroid that was present but was not removed at her initial laparoscopic myomectomy.

Read myths 5–7 on ovarian conservation, fibroid growth, and symptom improvement

MYTH #5: Hysterectomy with ovarian conservation does not change hormone levels

Following hysterectomy with ovarian conservation, some women begin menopause earlier than age-matched women who have not undergone any surgery.¹³ Hysterectomy with ovarian conservation prior to age 50 has been associated with a significant increase in the risk of coronary heart disease, stroke, and heart failure.¹⁴ In a prospective longitudinal study, antimüllerian hormone (AMH) levels were persistently decreased following hysterectomy despite ovarian conservation.¹⁵ However, 3 months after myomectomy, no such changes in AMH levels were seen (TABLE 2).¹⁵

Early natural menopause has been associated with an increase in cardiovascular disease and death, and bilateral oophorectomy has been associated with increased risks of cardiovascular disease, all-cause mortality, lung cancer, colon cancer, anxiety, and depression. Although taking estrogen might obviate these adverse health effects, the majority of women who receive a prescription for estrogen following surgery are no longer taking it 5 years later.

MYTH #6: Fibroid growth in a premenopausal patient means cancer may be present

While most fibroids grow slowly, rapid growth of benign fibroids is very common. Using computerized analysis of a group of 72 women having serial MRI scans, investigators found that 34% of benign fibroids increased more than 20% in volume over 6 months.¹⁶ In premenopausal women, “rapid uterine growth” almost never indicates presence of uterine sarcoma. One study reported only 1 sarcoma among 371 women operated on for rapid growth of presumed fibroids.¹⁷ Using current criteria from the World Health Organization to determine the pathologic diagnosis, however, that 1 woman was determined to have had an atypical leiomyoma. Therefore, the prevalence of leiomyosarcoma in that study approached zero. In addition, in the 198 women who had a 6-week increase in uterine size over 1 year (one published definition of rapid growth), no sarcomas were found.¹⁷

Because of recent concern about leiomyosarcoma and morcellation of fibroids, some gynecologists have reverted to advising women that growing fibroids might be cancer and that hysterectomy is recommended. However, there is no evidence that fibroid growth is a sign of leiomyosarcoma in premenopausal women. Leiomyosarcoma should strongly be considered in a postmenopausal woman on no hormone therapy who has growth of a presumed fibroid.

MYTH #7: Myomectomy will not improve symptoms

Fibroid-related symptoms can be significant; women who undergo hysterectomy because of fibroid-related symptoms have significantly worse scores on the 36-Item Short-Form Survey (SF-36) quality-of-life questionnaire than women diagnosed with hypertension, heart disease, chronic lung disease, or arthritis.¹⁸

For women with fibroid-related symptoms, myomectomy has been shown to improve quality of life. A study of 72 women showed that SF-36 scores improved significantly following myomectomy (TABLE 3, page 48).¹⁹ In another study that used the European Quality of Life Five-Dimension Scale and Visual Analog Scale, 95 women had significant improvement in quality of life (P<.001) following laparoscopic myomectomy.²⁰

For some women, hysterectomy may have an impact on emotional quality of life. Some women report decreased sexual desire after hysterectomy. They worry that partners will see them as “not whole” and less desirable. Some women expect that hysterectomy will lead to depression, crying, lack of sexual desire, and vaginal dryness.²¹ No such changes have been reported for women having myomectomy.

CASE Continued: Third consult leads patient to schedule surgical procedure

After reviewing the patient’s symptoms, examination, and ultrasound results, we advise the patient that abdominal myomectomy is indeed appropriate and feasible in her case. She schedules surgery for the following month.

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

Fibroids are extremely common and can be detected in 60% of African American women and 40% of white women by age 35. By age 50, more than 80% of African American women and almost 70% of white women have fibroids. Although most women with fibroids are relatively asymptomatic, women who have bothersome symptoms, such as heavy menstrual bleeding, urinary frequency, pelvic or abdominal pressure, or pain, account for nearly 30% of all gynecologic admissions in the United States. The cost of fibroid-related care, including surgery, hospital admissions, outpatient visits, and medications, is estimated at $4 to $9 billion per year.¹ In addition, each woman seeking treatment for fibroid-related symptoms incurs an expense of $4,500 to $30,000 for lost work or disability every year.¹

Many treatment options, including medical therapy and noninvasive procedures, are now available for women with symptomatic fibroids. For women who require surgical treatment, however, hysterectomy is often recommended. Fibroid-related hysterectomy currently accounts for 45% of all hysterectomies, or approximately 195,700 per year. Although the American College of Obstetricians and Gynecologists (ACOG) clinical management guidelines state that myomectomy is a safe and effective alternative to hysterectomy for treatment of women with symptomatic fibroids, only 30,000 myomectomies (abdominal, laparoscopic, and robotic-assisted approaches) are performed each year.² Why is this? One reason may be that, although many women wish to have uterus-preserving treatment, they often feel that doctors are too quick to recommend hysterectomy as the first—and sometimes only—treatment option for fibroids.³

CASE: Woman with fibroids seeks alternative to hysterectomy

A 42-year-old woman (G2P2) presents for a third opinion regarding her heavy menstrual bleeding and known uterine fibroids. She does not want to have any more children, but she wishes to avoid a hysterectomy. Both her regular gynecologist and the second gynecologist she consulted recommended hysterectomy as the first, and only, treatment option. Physical examination reveals a 16-week-sized uterus, and ultrasonography shows at least 6 fibroids, 2 of which impinge on the uterine cavity. The patient’s other gynecologists advised her that a myomectomy would be a “bloody operation,” would leave her uterus looking like Swiss cheese, and is not appropriate for women who have completed childbearing.

The patient asks if myomectomy could be considered in her situation. How would you advise her regarding myomectomy as an alternative to hysterectomy?

Organ conservation is important

In 1931, prominent British gynecologic surgeon Victor Bonney said, “Since cure without deformity or loss of function must ever be surgery’s highest ideal, the general proposition that myomectomy is a greater surgical achievement is incontestable.”⁴ As current hysterectomy and myomectomy rates indicate, however, we are not attempting organ conservation very often.

Other specialties almost never remove an entire organ for benign growths. Using breast cancer surgery as an admirable paradigm, consider that in the early 20th century the standard treatment for breast cancer was a Halsted radical mastectomy with axial lymphadenectomy. By the 1930s, this disfiguring operation was replaced by simple mastectomy and radiation, and by the 1970s, by lumpectomy and lymphadenectomy. Currently, lumpectomy and sentinel node sampling is the standard of care for early stage breast cancer. This is an excellent example of “minimally invasive surgery,” a term fostered by gynecologists. And, these organ-preservingsurgeries are performed for women with cancer, not a benign condition like fibroids.

Although our approach to hysterectomy has evolved with the increasing use of laparoscopic or robotic assistance, removal of the entire uterus nevertheless remains the surgical goal. I think this narrow view of surgical options is a disservice to our patients.

Many of us were taught that myomectomy was associated with more complications and more blood loss than hysterectomy. We were taught that the uterus had no function other than childbearing and that removing the uterus had no adverse health effects. The dogma suggested that myomectomy preserved a uterus that looked like Swiss cheese and would not heal properly and that the risk of fibroid recurrence was high. These beliefs, however, are myths, which are discussed and debunked below. In second and third installments for this series on myomectomy, I present steps for successful abdominal and laparoscopic technique.

Read myths on hysterectomy, myomectomy, and fibroids

MYTH #1: Hysterectomy is safer than myomectomy

Myomectomy is performed within the confines of the uterus and myometrium, with only infrequent occasion to operate near the ureters, uterine vessels, bowel, or bladder. Therefore, it should not be surprising that studies show that fewer complications occur with myomectomy than with hysterectomy.

A retrospective review of 197 women who had myomectomy and 197 women who underwent hysterectomy with similar uterine size (14 vs 15 weeks) reported that 13% (n = 26) of women in the hysterectomy group experienced complications, including 1 bladder injury, 1 ureteral injury, and 3 bowel injuries; 8 women had an ileus and 6 women had a pelvic abscess.⁵ Only 5% (n = 11) of the myomectomy patients had complications, including 1 bladder injury; 2 women had reoperation for small bowel obstruction, and 6 women had an ileus. The risks of febrile morbidity, unintended surgical procedure, life-threatening events, and rehospitalization were similar for both groups.

Authors of a recent systematic review of 6 studies, which included 1,520 women with uterine size up to 18 weeks, found higher rates of visceral injury and longer hospital stays for women who had a hysterectomy compared with those who had a myomectomy (TABLE 1).⁶

MYTH #2: Myomectomy is associated with more surgical blood loss than hysterectomy

In the previously cited study of 197 women treated with myomectomy and 197 women treated with hysterectomy, the estimated blood loss was greater in the hysterectomy group (484 mL) than in the myomectomy group (227 mL). When uterine size was corrected for, blood loss was no greater for myomectomy than for hysterectomy.⁵ The risk of hemorrhage (>500 mL blood loss) was greater in the hysterectomy group (14.2% vs 9.6%). Authors of the recent meta-analysis also found that the rate of transfusion was higher in the hysterectomy cohort. Tourniquets, misoprostol, vasopressin, and tranexamic acid all have been shown to significantly decrease surgical blood loss. (These treatments will be discussed in the next installment of this article series.)

MYTH #3: A uterus will look like Swiss cheese after a myomectomy

The uterus heals remarkably well after myomectomy. Three months following laparoscopic myomectomy, 3-dimensional Doppler ultrasonography demonstrated complete myometrial healing and normal blood flow to the uterus.⁷ In a study of women undergoing abdominal myomectomy, follow-up magnetic resonance imaging (MRI) with gadolinium showed complete healing of the myometrium and normal myometrial perfusion by 3 months.⁸ This study also found that, after removal of 65 g to 380 g of fibroids, the uterine volume 3 months after surgery was 65 mL, essentially equivalent to the normal volume of a uterus without fibroids (57 mL).⁸ See FIGURE for MRI scans of the uterus before and after myomectomy.

MYTH #4: Fibroids will just grow back after myomectomy

Once a fibroid is completely removed surgically, it does not grow back. The risk of new fibroid growth depends on the number of fibroids originally removed and the amount of time until menopause, when fibroids reduce in size and symptoms usually resolve. Given that the prevalence of fibroids is nearly 80% by age 50, studies measuring the detection of new fibroid growth of 1 cm on ultrasound imaging overstate the problem.⁹ What is likely a more important consideration for women is whether, following myomectomy, they will need another procedure for new fibroid-related symptoms.

Results of a meta-analysis of 872 women in 7 studies with 10- to 25-year follow-up indicated that 89% of women did not require another surgery.¹⁰ In another study, authors found that, over an average follow-up of 7.6 years, a second surgery occurred in 11% of the women who had 1 fibroid initially removed and for 26% of women who had multiple fibroids initially removed.¹¹ In another study of 92 women who had either abdominal or laparoscopic myomectomy after age 45and who were followed for an average of 30 months, only 1 woman (1%) required a hysterectomy for fibroid-related symptoms.¹² That patient had growth of a fibroid that was present but was not removed at her initial laparoscopic myomectomy.

Read myths 5–7 on ovarian conservation, fibroid growth, and symptom improvement

MYTH #5: Hysterectomy with ovarian conservation does not change hormone levels

Following hysterectomy with ovarian conservation, some women begin menopause earlier than age-matched women who have not undergone any surgery.¹³ Hysterectomy with ovarian conservation prior to age 50 has been associated with a significant increase in the risk of coronary heart disease, stroke, and heart failure.¹⁴ In a prospective longitudinal study, antimüllerian hormone (AMH) levels were persistently decreased following hysterectomy despite ovarian conservation.¹⁵ However, 3 months after myomectomy, no such changes in AMH levels were seen (TABLE 2).¹⁵

Early natural menopause has been associated with an increase in cardiovascular disease and death, and bilateral oophorectomy has been associated with increased risks of cardiovascular disease, all-cause mortality, lung cancer, colon cancer, anxiety, and depression. Although taking estrogen might obviate these adverse health effects, the majority of women who receive a prescription for estrogen following surgery are no longer taking it 5 years later.

MYTH #6: Fibroid growth in a premenopausal patient means cancer may be present

While most fibroids grow slowly, rapid growth of benign fibroids is very common. Using computerized analysis of a group of 72 women having serial MRI scans, investigators found that 34% of benign fibroids increased more than 20% in volume over 6 months.¹⁶ In premenopausal women, “rapid uterine growth” almost never indicates presence of uterine sarcoma. One study reported only 1 sarcoma among 371 women operated on for rapid growth of presumed fibroids.¹⁷ Using current criteria from the World Health Organization to determine the pathologic diagnosis, however, that 1 woman was determined to have had an atypical leiomyoma. Therefore, the prevalence of leiomyosarcoma in that study approached zero. In addition, in the 198 women who had a 6-week increase in uterine size over 1 year (one published definition of rapid growth), no sarcomas were found.¹⁷

Because of recent concern about leiomyosarcoma and morcellation of fibroids, some gynecologists have reverted to advising women that growing fibroids might be cancer and that hysterectomy is recommended. However, there is no evidence that fibroid growth is a sign of leiomyosarcoma in premenopausal women. Leiomyosarcoma should strongly be considered in a postmenopausal woman on no hormone therapy who has growth of a presumed fibroid.

MYTH #7: Myomectomy will not improve symptoms

Fibroid-related symptoms can be significant; women who undergo hysterectomy because of fibroid-related symptoms have significantly worse scores on the 36-Item Short-Form Survey (SF-36) quality-of-life questionnaire than women diagnosed with hypertension, heart disease, chronic lung disease, or arthritis.¹⁸

For women with fibroid-related symptoms, myomectomy has been shown to improve quality of life. A study of 72 women showed that SF-36 scores improved significantly following myomectomy (TABLE 3, page 48).¹⁹ In another study that used the European Quality of Life Five-Dimension Scale and Visual Analog Scale, 95 women had significant improvement in quality of life (P<.001) following laparoscopic myomectomy.²⁰

For some women, hysterectomy may have an impact on emotional quality of life. Some women report decreased sexual desire after hysterectomy. They worry that partners will see them as “not whole” and less desirable. Some women expect that hysterectomy will lead to depression, crying, lack of sexual desire, and vaginal dryness.²¹ No such changes have been reported for women having myomectomy.

CASE Continued: Third consult leads patient to schedule surgical procedure

After reviewing the patient’s symptoms, examination, and ultrasound results, we advise the patient that abdominal myomectomy is indeed appropriate and feasible in her case. She schedules surgery for the following month.

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

In November 2016, Bayer, the manufacturer of the permanent birth control tubal implant system (Essure), revised the Essure product labeling in accordance with a US Food and Drug Administration (FDA) guidance document.¹ The FDA developed its labeling guidance based on its examination of an increasing number of reported adverse events associated with the system’s use (such as persistent pain, perforation of the uterus and/or fallopian tubes, intra-abdominal or pelvic device migration, abnormal or irregular bleeding, and allergy or hypersensitivity reactions) and its evaluation of a trade complaint regarding allegations initially made in a Citizen Petition.

Changes to the new FDA-approved labeling for Essure include:

• the addition of a boxed warning listing adverse events that have been reported either in clinical studies or through postmarket surveillance (see Box)
• updated Instructions for Use document for clinicians and Patient Information Booklet, which contain additional information on safety (contraindications, warnings, and precautions), clinical data, and instructions^2,3
• a Patient-Doctor Discussion Checklist (included within the Patient Information Booklet), designed to support appropriate patient counseling, facilitate the patient’s understanding of birth control options, and explain the benefits and risks associated with the device and what to expect during and after the implantation procedure.³

How will these labeling changes impact clinicians and patients? OBG Managementasked Linda Bradley, MD, Professor of Surgery and Vice Chair of Obstetrics and Gynecology at the Women’s Health Institute, Cleveland Clinic, Cleveland, Ohio, to share her expertise with readers.

OBG Management: What does the new product labeling mean for clinicians who offer tubal implants as an option for permanent sterilization?

Linda D. Bradley, MD: The FDA-approved revised labeling for the Essure system means that physicians should have a very detailed, in-depth conversation with their patients who are contemplating hysteroscopic tubal insert placement for permanent sterilization. This counseling really should not differ from what doctors were doing before the label was revised. However, physicians can now use the new Patient-Doctor Discussion Checklist as a guide in reviewing the benefits of the device, its known risks and potential risks, outcomes of the insertion procedure, and the possible need for future surgical intervention if device placement–related issues arise.

For clinicians, this counseling adds just a few more minutes to the visit. The Patient-Doctor Discussion Checklist will become an inherent part of the informed consent process, aiding in the review of the device’s benefits, potential risks, and more importantly its permanence.

In the past, there was some concern that perhaps patients did not receive enough guidance for informed consent, so one of the first things listed on the checklist is confirmation—in the form of a printed line where the patient can sign her initials—that she understands that Essure is a permanent form of birth control. The checklist covers additional important issues, including that the doctor has indeed shared with the patient other options for birth control or sterilization, such as laparoscopic sterilization, vasectomy for her male partner, an intrauterine device (IUD), and birth control pills. This is an opportunity to reinforce the fact that tubal implants are a permanent form of birth control, and if the patient is uncertain about ending her fertility, the clinician can inform her about reversible options. The checklist also includes for discussion the pregnancy risk with use of the device, what the patient can expect during the implant insertion procedure and for the days afterwards (such as cramping, mild to moderate pain, nausea and vomiting), and the need for a confirmation test 3 months after device placement.

Other discussion points covered include long-term risks and benefits of the device, the potential for complications, and the possibility (due to pelvic pain) that the hysteroscopically placed devices may need to be removed with a surgical procedure requiring general anesthesia.

Incorporating the checklist into our clinical practice shows that we have listened to patients and complied with recommendations made by the FDA review panel, and we can use this document to have a more complete discussion with our patients.

OBG Management: Do you agree with some clinicians who say that physicians who place the device also should have the skills required to remove it if necessary?

Dr. Bradley: Essure placement—which is a hysteroscopic procedure—is done very differently than a laparoscopic procedure. In the past, among women who needed to have the Essure system removed, most procedures would be done laparoscopically. Since we work collaboratively in teams, someone within the team or division would have the clinical expertise to remove the devices. An ObGyn who does laparoscopy with salpingectomy and/or cornual resection would best be able to remove the devices.

The clinician who does hysteroscopy is not always the same one who does laparoscopy. Someone within the division who is interested in removing the device will develop an expertise and algorithm that suits the practice, so that person in the practice becomes the expert. This is no different from many other things that physicians do. In our clinical practice, for example, we have a pelvic pain specialist, a sexual counselor, someone interested in menopause and management, and someone interested in alternatives to hysterectomies. Those who practice their craft and their art become proficient at it. So if you do not perform a particular procedure such as a tubal implant removal, know the expert to whom you can make a referral.

OBG Management: How do you now advise your colleagues to counsel patients on permanent sterilization?

Dr. Bradley: Hysteroscopic tubal implant sterilization, a minimally invasive procedure, is an excellent and viable option for women who meet the inclusion criteria and who do not have the exclusion criteria for placement. It is overall safe and extremely effective. If a patient has issues after undergoing implant placement—just like with any other surgery or procedure—for example, if she is not feeling better or is not doing as well as anticipated, we must not forget the patient. It is important for our patients to be listened to and to be heard. Postprocedure issues are generally transient and related to pain and discomfort or abnormal bleeding. If they are persistent, then further evaluation is needed.

Tell the patient to contact you if she has questions or issues, and have a tiered approach for working up any problems that she may present with. In addition, reiterate that the patient must use another form of birth control for 3 months until she undergoes the confirmation test and until the results verify that the implants can be relied on for contraception. I am still placing the device. Before I perform the procedure, I speak with my patients—as I did before the checklist was developed—about all of the informed consent issues, the risk−benefit profile, and ruling out contraindications to use. I think this is good medical and surgical practice. The new labeling means we need to have a critical conversation with our patients, and we should be doing that for all procedures.

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

In November 2016, Bayer, the manufacturer of the permanent birth control tubal implant system (Essure), revised the Essure product labeling in accordance with a US Food and Drug Administration (FDA) guidance document.¹ The FDA developed its labeling guidance based on its examination of an increasing number of reported adverse events associated with the system’s use (such as persistent pain, perforation of the uterus and/or fallopian tubes, intra-abdominal or pelvic device migration, abnormal or irregular bleeding, and allergy or hypersensitivity reactions) and its evaluation of a trade complaint regarding allegations initially made in a Citizen Petition.

Changes to the new FDA-approved labeling for Essure include:

• the addition of a boxed warning listing adverse events that have been reported either in clinical studies or through postmarket surveillance (see Box)
• updated Instructions for Use document for clinicians and Patient Information Booklet, which contain additional information on safety (contraindications, warnings, and precautions), clinical data, and instructions^2,3
• a Patient-Doctor Discussion Checklist (included within the Patient Information Booklet), designed to support appropriate patient counseling, facilitate the patient’s understanding of birth control options, and explain the benefits and risks associated with the device and what to expect during and after the implantation procedure.³

How will these labeling changes impact clinicians and patients? OBG Managementasked Linda Bradley, MD, Professor of Surgery and Vice Chair of Obstetrics and Gynecology at the Women’s Health Institute, Cleveland Clinic, Cleveland, Ohio, to share her expertise with readers.

OBG Management: What does the new product labeling mean for clinicians who offer tubal implants as an option for permanent sterilization?

Linda D. Bradley, MD: The FDA-approved revised labeling for the Essure system means that physicians should have a very detailed, in-depth conversation with their patients who are contemplating hysteroscopic tubal insert placement for permanent sterilization. This counseling really should not differ from what doctors were doing before the label was revised. However, physicians can now use the new Patient-Doctor Discussion Checklist as a guide in reviewing the benefits of the device, its known risks and potential risks, outcomes of the insertion procedure, and the possible need for future surgical intervention if device placement–related issues arise.

For clinicians, this counseling adds just a few more minutes to the visit. The Patient-Doctor Discussion Checklist will become an inherent part of the informed consent process, aiding in the review of the device’s benefits, potential risks, and more importantly its permanence.

In the past, there was some concern that perhaps patients did not receive enough guidance for informed consent, so one of the first things listed on the checklist is confirmation—in the form of a printed line where the patient can sign her initials—that she understands that Essure is a permanent form of birth control. The checklist covers additional important issues, including that the doctor has indeed shared with the patient other options for birth control or sterilization, such as laparoscopic sterilization, vasectomy for her male partner, an intrauterine device (IUD), and birth control pills. This is an opportunity to reinforce the fact that tubal implants are a permanent form of birth control, and if the patient is uncertain about ending her fertility, the clinician can inform her about reversible options. The checklist also includes for discussion the pregnancy risk with use of the device, what the patient can expect during the implant insertion procedure and for the days afterwards (such as cramping, mild to moderate pain, nausea and vomiting), and the need for a confirmation test 3 months after device placement.

Other discussion points covered include long-term risks and benefits of the device, the potential for complications, and the possibility (due to pelvic pain) that the hysteroscopically placed devices may need to be removed with a surgical procedure requiring general anesthesia.

Incorporating the checklist into our clinical practice shows that we have listened to patients and complied with recommendations made by the FDA review panel, and we can use this document to have a more complete discussion with our patients.

OBG Management: Do you agree with some clinicians who say that physicians who place the device also should have the skills required to remove it if necessary?

Dr. Bradley: Essure placement—which is a hysteroscopic procedure—is done very differently than a laparoscopic procedure. In the past, among women who needed to have the Essure system removed, most procedures would be done laparoscopically. Since we work collaboratively in teams, someone within the team or division would have the clinical expertise to remove the devices. An ObGyn who does laparoscopy with salpingectomy and/or cornual resection would best be able to remove the devices.

The clinician who does hysteroscopy is not always the same one who does laparoscopy. Someone within the division who is interested in removing the device will develop an expertise and algorithm that suits the practice, so that person in the practice becomes the expert. This is no different from many other things that physicians do. In our clinical practice, for example, we have a pelvic pain specialist, a sexual counselor, someone interested in menopause and management, and someone interested in alternatives to hysterectomies. Those who practice their craft and their art become proficient at it. So if you do not perform a particular procedure such as a tubal implant removal, know the expert to whom you can make a referral.

OBG Management: How do you now advise your colleagues to counsel patients on permanent sterilization?

Dr. Bradley: Hysteroscopic tubal implant sterilization, a minimally invasive procedure, is an excellent and viable option for women who meet the inclusion criteria and who do not have the exclusion criteria for placement. It is overall safe and extremely effective. If a patient has issues after undergoing implant placement—just like with any other surgery or procedure—for example, if she is not feeling better or is not doing as well as anticipated, we must not forget the patient. It is important for our patients to be listened to and to be heard. Postprocedure issues are generally transient and related to pain and discomfort or abnormal bleeding. If they are persistent, then further evaluation is needed.

Tell the patient to contact you if she has questions or issues, and have a tiered approach for working up any problems that she may present with. In addition, reiterate that the patient must use another form of birth control for 3 months until she undergoes the confirmation test and until the results verify that the implants can be relied on for contraception. I am still placing the device. Before I perform the procedure, I speak with my patients—as I did before the checklist was developed—about all of the informed consent issues, the risk−benefit profile, and ruling out contraindications to use. I think this is good medical and surgical practice. The new labeling means we need to have a critical conversation with our patients, and we should be doing that for all procedures.

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

In November 2016, Bayer, the manufacturer of the permanent birth control tubal implant system (Essure), revised the Essure product labeling in accordance with a US Food and Drug Administration (FDA) guidance document.¹ The FDA developed its labeling guidance based on its examination of an increasing number of reported adverse events associated with the system’s use (such as persistent pain, perforation of the uterus and/or fallopian tubes, intra-abdominal or pelvic device migration, abnormal or irregular bleeding, and allergy or hypersensitivity reactions) and its evaluation of a trade complaint regarding allegations initially made in a Citizen Petition.

Changes to the new FDA-approved labeling for Essure include:

• the addition of a boxed warning listing adverse events that have been reported either in clinical studies or through postmarket surveillance (see Box)
• updated Instructions for Use document for clinicians and Patient Information Booklet, which contain additional information on safety (contraindications, warnings, and precautions), clinical data, and instructions^2,3
• a Patient-Doctor Discussion Checklist (included within the Patient Information Booklet), designed to support appropriate patient counseling, facilitate the patient’s understanding of birth control options, and explain the benefits and risks associated with the device and what to expect during and after the implantation procedure.³

How will these labeling changes impact clinicians and patients? OBG Managementasked Linda Bradley, MD, Professor of Surgery and Vice Chair of Obstetrics and Gynecology at the Women’s Health Institute, Cleveland Clinic, Cleveland, Ohio, to share her expertise with readers.

OBG Management: What does the new product labeling mean for clinicians who offer tubal implants as an option for permanent sterilization?

Linda D. Bradley, MD: The FDA-approved revised labeling for the Essure system means that physicians should have a very detailed, in-depth conversation with their patients who are contemplating hysteroscopic tubal insert placement for permanent sterilization. This counseling really should not differ from what doctors were doing before the label was revised. However, physicians can now use the new Patient-Doctor Discussion Checklist as a guide in reviewing the benefits of the device, its known risks and potential risks, outcomes of the insertion procedure, and the possible need for future surgical intervention if device placement–related issues arise.

For clinicians, this counseling adds just a few more minutes to the visit. The Patient-Doctor Discussion Checklist will become an inherent part of the informed consent process, aiding in the review of the device’s benefits, potential risks, and more importantly its permanence.

In the past, there was some concern that perhaps patients did not receive enough guidance for informed consent, so one of the first things listed on the checklist is confirmation—in the form of a printed line where the patient can sign her initials—that she understands that Essure is a permanent form of birth control. The checklist covers additional important issues, including that the doctor has indeed shared with the patient other options for birth control or sterilization, such as laparoscopic sterilization, vasectomy for her male partner, an intrauterine device (IUD), and birth control pills. This is an opportunity to reinforce the fact that tubal implants are a permanent form of birth control, and if the patient is uncertain about ending her fertility, the clinician can inform her about reversible options. The checklist also includes for discussion the pregnancy risk with use of the device, what the patient can expect during the implant insertion procedure and for the days afterwards (such as cramping, mild to moderate pain, nausea and vomiting), and the need for a confirmation test 3 months after device placement.

Other discussion points covered include long-term risks and benefits of the device, the potential for complications, and the possibility (due to pelvic pain) that the hysteroscopically placed devices may need to be removed with a surgical procedure requiring general anesthesia.

Incorporating the checklist into our clinical practice shows that we have listened to patients and complied with recommendations made by the FDA review panel, and we can use this document to have a more complete discussion with our patients.

OBG Management: Do you agree with some clinicians who say that physicians who place the device also should have the skills required to remove it if necessary?

Dr. Bradley: Essure placement—which is a hysteroscopic procedure—is done very differently than a laparoscopic procedure. In the past, among women who needed to have the Essure system removed, most procedures would be done laparoscopically. Since we work collaboratively in teams, someone within the team or division would have the clinical expertise to remove the devices. An ObGyn who does laparoscopy with salpingectomy and/or cornual resection would best be able to remove the devices.

The clinician who does hysteroscopy is not always the same one who does laparoscopy. Someone within the division who is interested in removing the device will develop an expertise and algorithm that suits the practice, so that person in the practice becomes the expert. This is no different from many other things that physicians do. In our clinical practice, for example, we have a pelvic pain specialist, a sexual counselor, someone interested in menopause and management, and someone interested in alternatives to hysterectomies. Those who practice their craft and their art become proficient at it. So if you do not perform a particular procedure such as a tubal implant removal, know the expert to whom you can make a referral.

OBG Management: How do you now advise your colleagues to counsel patients on permanent sterilization?

Dr. Bradley: Hysteroscopic tubal implant sterilization, a minimally invasive procedure, is an excellent and viable option for women who meet the inclusion criteria and who do not have the exclusion criteria for placement. It is overall safe and extremely effective. If a patient has issues after undergoing implant placement—just like with any other surgery or procedure—for example, if she is not feeling better or is not doing as well as anticipated, we must not forget the patient. It is important for our patients to be listened to and to be heard. Postprocedure issues are generally transient and related to pain and discomfort or abnormal bleeding. If they are persistent, then further evaluation is needed.

Tell the patient to contact you if she has questions or issues, and have a tiered approach for working up any problems that she may present with. In addition, reiterate that the patient must use another form of birth control for 3 months until she undergoes the confirmation test and until the results verify that the implants can be relied on for contraception. I am still placing the device. Before I perform the procedure, I speak with my patients—as I did before the checklist was developed—about all of the informed consent issues, the risk−benefit profile, and ruling out contraindications to use. I think this is good medical and surgical practice. The new labeling means we need to have a critical conversation with our patients, and we should be doing that for all procedures.

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

Zika virus is a serious problem. Education and infection prevention are critical to effective management, and why we chose to include Zika virus as a topic for this year’s Update. We also discuss obesity’s effects on reproduction—a very relevant concern for all ObGyns and patients alike as about half of reproductive-age women are obese. Finally, subclinical hypothyroidism can present unique management challenges, such as determining when it is present and when treatment is indicated.

Read about counseling patients about Zika virus

Managing attempted pregnancy in the era of Zika virus

Oduyebo T, Igbinosa I, Petersen EE, et al. Update: interim guidance for health care providers caring for pregnant women with possible Zika virus exposure--United States, July 2016. MMWR Morb Mortal Wkly Rep. 2016;65(29):739-744.

Petersen EE, Meaney-Delman D, Neblett-Fanfair R, et al. Update: interim guidance for preconception counseling and prevention of sexual transmission of Zika virus for persons with possible Zika virus exposure--United States, September 2016. MMWR Morb Mortal Wkly Rep. 2016;65(39):1077-1081.

US Food and Drug Administration. Donor Screening Recommendations to Reduce the Risk of Transmission of Zika Virus by Human Cells, Tissues, and Cellular and Tissue-Based Products. http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Tissue/UCM488582.pdf. Published March 2016. Accessed January 12, 2017.

National Institutes of Health. Zika: Overview. https://www.nichd.nih.gov/health/topics/zika/Pages/default.aspx. Accessed January 12, 2017.

World Health Organization. Prevention of sexual transmission of Zika virus interim guidance. WHO reference number: WHO/ZIKV/MOC/16. 1 Rev. 3, September 6, 2016. 

Zika Virus Guidance Task Force of the American Society for Reproductive Medicine. Rev. 13, September 2016.  

Zika virus presents unique challenges to physicians managing the care of patients attempting pregnancy, with or without fertility treatment. Neonatal Zika virus infection sequelae only recently have been appreciated; microcephaly was associated with Zika virus in October 2015, followed by other neurologic conditions including brain abnormalities, neural tube defects, and eye abnormalities. Results of recent studies involving the US Zika Pregnancy Registry show that 6% of women with Zika at any time in pregnancy had affected babies, but 11% of those who contracted the disease in the first trimester were affected. 

Diagnosis is difficult because symptoms are generally mild, with 80% of affected patients asymptomatic. Possible Zika virus exposure is defined as travel to or residence in an area of active Zika virus transmission, or sex without a condom with a partner who traveled to or lived in an area of active transmission. Much is unknown about the interval from exposure to symptoms. Testing availability is limited and variable, and much is unknown about sensitivity and specificity of direct viral RNA testing, appearance and disappearance of detectable immunoglobulin (Ig) M and IgG antibodies that affect false positive and false negative test results, duration of infectious phase, risk of transmission, and numerous other factors.

Positive serum viral testing likely indicates virus in semen or other bodily fluids, but a negative serum viral test cannot definitively preclude virus in other bodily fluids. Zika virus likely can be passed from any combination of semen and vaginal and cervical fluids, but validating tests for these fluids are not yet available. It is not known if sperm preparation and assisted reproductive technology (ART) procedures that minimize risk of HIV transmission are effective against Zika virus or whether or not cryopreservation can destroy the virus. 

Pregnancy timing

The Centers for Disease Control and Prevention now recommends that all men with possible Zika virus exposure who are considering attempting pregnancy with their partner wait to get pregnant until at least 6 months after symptom onset (if symptomatic) or last possible Zika virus exposure (if asymptomatic). Women with possible Zika virus exposure are recommended to wait to get pregnant until at least 8 weeks after symptom onset (if symptomatic) or last possible Zika virus exposure (if asymptomatic).

Women and men with possible exposure to Zika virus but without clinical symptoms of illness should consider testing for Zika viral RNA within 2 weeks of suspected exposure and wait at least 8 weeks after the last date of exposure before being re-tested. If direct viral testing (using rRT-PCR) results initially are negative, ideally, antibody testing would be obtained, if available, at 8 weeks. However, no testing paradigm will absolutely guarantee lack of Zika virus infectivity.

Virus management problems are dramatically compounded in areas endemic for Zika. Women and men who have had Zika virus disease should wait at least 6 months after illness onset to attempt reproduction. The temporal relationship between the presence of viral RNA and infectivity is not known definitively, and so the absolute duration of time to wait before attempting pregnancy is unknown. Male and female partners who become infected should avoid all forms of intimate sexual conduct or use condoms for the same 6 months. There is no evidence Zika will cause congenital infection in pregnancies initiated after resolution of maternal Zika viremia. However, any testing performed at a time other than the time of treatment might not reflect true viral status, particularly in areas of active Zika virus transmission.

Prevention

Women and men, especially those residing in areas of active Zika virus transmission, should talk with their physicians regarding pregnancy plans and avoid mosquito bites using the usual precautions: avoid mosquito areas, drain standing water, use mosquito repellent containing DEET, and use mosquito netting. Some people have gone so far as to relocate to nonendemic areas.

Those contemplating pregnancy should be advised to consider what they would do if they become exposed to or have suspected or confirmed Zika virus during pregnancy. Additional considerations are gamete or embryo cryopreservation and quarantine until a subsequent rRT-PCR test result is negative in both the male and female and at least 8 weeks have passed from gamete collection.

Patient counseling essentials

Counsel patients considering reproduction  about:  

• Zika virus as a new reproductive hazard  
• the significance of the hazard to the fetus if infected
• the areas of active transmission, and that they are constantly changing
• avoidance of Zika areas if possible
• methods of transmission through mosquito bites or sex
• avoidance of mosquito bites
• symptoms of Zika infection
• safe sex practices
• testing limitations and knowledge deficiency about Zika.

Not uncommonly, clinical situations require complex individualized management decisions regarding trade-offs of risks, especially in older patients with decreased ovarian reserve. Consultation with infectious disease and reproductive specialists should be obtained when complicated and consequential decisions have to be made.

All practitioners should inform their patients, especially those undergoing fertility treatments, about Zika, and develop language in their informed consent that conveys the gap in knowledge to these patients.

Read how obesity specifically affects reproduction in an adverse way

Obesity adversely affects reproduction, but how specifically?

Practice Committee of the American Society for Reproductive Medicine. Obesity and Reproduction: A committee opinion. Fertil Steril. 2015;104(5):1116-1126.

The prevalence of obesity has increased substantially over the past 2 decades. Almost two-thirds of women and three-fourths of men in the United States are overweight or obese (defined as a body mass index [BMI] ≥25 kg/m² and BMI ≥30 kg/m², respectively; TABLE). Nearly 50% of reproductive-age women are obese.

A disease of excess body fat and insulin resistance, obesity increases the risks of hypertension, diabetes, dyslipidemia, cardiovascular disease, sleep apnea, respiratory problems, and cancer as well as other serious health problems. While not all individuals with obesity will have infertility, obesity is associated with impaired reproduction in both women and men, adverse obstetric outcomes, and health problems in offspring. The American Society for Reproductive Medicine (ASRM) reviewed this important issue in a recent practice committee opinion.  

Menstrual cycle and ovulatory dysfunction

Menstrual cycle abnormalities are more common in women with obesity. Elevated levels of insulin in obese women suppress sex hormone−binding globulin (SHBG) which in turn reduces gonadotropin secretion due to increased production of estrogen from conversion of androgens by adipose aromatase.¹ Adipose tissue produces adipokines, which directly can suppress ovarian function.²

Ovulatory dysfunction is common among obese women; the relative risk of such dysfunction is 3.1 (95% confidence interval [CI], 2.2−4.4) among women with BMI levels >27 kg/m² versus BMI levels 20.0 to 24.9 kg/m².^3,4  Obesity decreases fecundity even in women with normal menstrual cycles.⁵ This may in part be due to altered ovulatory dynamics with reduced early follicular luteinizing hormone pulse amplitude accompanied by prolonged folliculogenesis and reduced luteal progesterone levels.⁶

Compared with normal-weight women, obese women have a lower chance of conception within 1 year of stopping contraception; about 66% of obese women conceive within 1 year of stopping contraception, compared with about 81% of women with normal weight.⁷ Results of a Dutch study of 3,029 women with regular ovulation, at least one patent tube, and a partner with a normal semen analysis indicated a direct correlation between obesity and delayed conception, with a 4% lower spontaneous pregnancy rate per kg/m2 increase in women with a BMI >29 kg/m² versus a BMI of 21 to 29 kg/m² (hazard ratio, 0.96; 95% CI, 0.91−0.99).⁸  

Assisted reproduction

Assisted reproduction in women with obesity is associated with lower success rates than in women with normal weight. A systematic review of 27 in vitro fertilization (IVF) studies (23 of which were retrospective) reveals  10% lower live-birth rate in overweight (BMI >25 kg/m²) versus normal-weight women (BMI <25 kg/m²) undergoing IVF (odds ratio [OR], 0.90; 95% CI, 0.82−1.0).⁹ Data from a meta-analysis of 33 IVF studies, including 47,967 cycles, show that, compared with women with a BMI <25 kg/m², overweight or obese women have significantly reduced rates of clinical pregnancy (relative risk [RR], 0.90; P<.0001) and live birth (RR, 0.84; P = .0002).¹⁰

Results of a retrospective study of 4,609 women undergoing first IVF or IVF/intracytoplasmic sperm injection cycles revealed impaired embryo implantation (controlling for embryo quality and transfer day), reducing the age-adjusted odds of live birth in a BMI-dependent manner by 37% (BMI, 30.0−34.9 kg/m²), 61% (BMI, 35.0−39.9 kg/m2), and 68% (BMI, >40 kg/m²) compared with women with a BMI of 18.5 to 24.9 kg/m².¹¹ In a study of 12,566 Danish couples undergoing assisted reproduction, overweight and obese ovulatory women had a 12% (95% CI, 0.79−0.99) and 25% (95% CI, 0.63−0.90) reduction in IVF-related live birth rate, respectively (referent BMI, 18.5−24.9 kg/m²), with a 2% (95% CI, 0.97−0.99) decrease in live-birth rate for every one-unit increase in BMI.¹² Putative mechanisms for these findings include altered oocyte morphology and reduced fertilization in eggs from obese women,¹³ and impaired embryo quality in women less than age 35.¹⁴ Oocytes from women with a BMI >25 kg/m² are smaller and less likely to complete development postfertilization, with embryos arrested prior to blastulation containing more triglyceride than those forming blastocysts.¹⁵

Blastocysts developed from oocytes of high-BMI women are smaller, contain fewer cells and have a higher content of triglycerides, lower glucose consumption, and altered amino acid metabolism compared with embryos of normal-weight women (BMI <24.9 kg/m2).¹⁵ Obesity may alter endometrial receptivity during IVF given the finding that third-party surrogate women with a BMI >35 kg/m² have a lower live-birth rate (25%) compared with women with a BMI <35 kg/m² (49%; P<.05).¹⁶

Pregnancy outcomes

Obesity is linked to an increased risk of miscarriage. Results of a meta-analysis of 33 IVF studies including 47,967 cycles indicated that overweight or obese women have a higher rate of miscarriage (RR, 1.31; P<.0001) than normal-weight women (BMI <25 kg/m2).¹⁷ Maternal and perinatal morbid obesity are strongly associated with obstetric and perinatal complications, including gestational diabetes, hypertension, preeclampsia, preterm delivery, shoulder dystocia, fetal distress, early neonatal death, and small- as well as large-for-gestational age infants.

Obese women who conceive by IVF are at increased risk for preeclampsia, gestational diabetes, preterm delivery, and cesarean delivery.¹³ Authors of a meta-analysis of 18 observational studies concluded that obese mothers were at increased odds of pregnancies affected by such birth defects as neural tube defects, cardiovascular anomalies, and cleft lip and palate, among others.¹⁸

In addition to being the cause of these fetal abnormalities, maternal metabolic dysfunction is linked to promoting obesity in offspring, thereby perpetuating a cycle of obesity and adverse health outcomes that include an increased risk of premature death in adult offspring in subsequent generations.¹³

Treatment for obesity

Lifestyle modification is the first-line treatment for obesity.  
Pre-fertility therapy and pregnancy goals. Targets for pregnancy should include:  

• preconception weight loss to a BMI of 35 kg/m2
• prevention of excess weight gain in pregnancy
• long-term reduction in weight.

For all obese individuals, lifestyle modifications should include a weight loss of 7% of body weight and increased physical activity to at least 150 minutes of moderate activity, such as walking, per week. Calorie restriction should be emphasized. A 500 to 1,000 kcal/day decrease from usual dietary intake is expected to result in a 1- to 2-lb weight loss per week. A low-calorie diet of 1,000 to 1,200 kcal/day can lead to an average 10% decrease in total body weight over 6 months.

Adjunct supervised medical therapy or bariatric surgery can play an important role in successful weight loss prepregnancy but are not appropriate for women actively attempting conception. Importantly, pregnancy should be deferred for a minimum of 1 year after bariatric surgery. The decision to postpone pregnancy to achieve weight loss must be balanced against the risk of declining fertility with advancing age of the woman. 

Read about when to treat subclinical hypothyroidism

Optimal management of subclinical hypothyroidism in women with infertility

Practice Committee of the American Society for Reproductive Medicine. Subclinical hypothyroidism in the infertile female population: a guideline. Fertil Steril. 2015;104(3):545-553.

Thyroid disorders long have been associated with the potential for adverse reproductive outcomes. While overt hypothyroidism has been linked to infertility, increased miscarriage risk, and poor maternal and fetal outcomes, controversy has existed regarding the association between subclinical hypothyroidism (SCH) and reproductive problems. The ASRM recently published a guideline on the role of SCH in the infertile female population.  

How is subclinical hypothyroidism defined?

SCH is classically defined as a thyrotropin (TSH) level above the upper limit of normal range (4.5−5.0 mIU/L) with normal free thyroxine (FT4) levels. The National Health and Nutrition Examination Survey (NHANES III) population has been used to establish normative data for TSH for a disease-free population. These include a median serum level for TSH of 1.5 mIU/L, with the corresponding 2.5 and 97.5 percentiles of 0.41 and 6.10, respectively.¹⁹ Data from the National Academy of Clinical Biochemistry, however, reveal that 95% of individuals without evidence of thyroid disease have a TSH level <2.5 mIU/L, and that the normal reference range is skewed to the right.20 Adjusting the upper limit of the normal range to 2.5 mIU/L would result in an additional 11.8% to 14.2% of the United States population (22 to 28 million individuals) being diagnosed with hypothyroidism.

This information raises several important questions.

1. Should nonpregnant women be treated for SCH?

No. There is no benefit from the standpoint of lipid profile or alteration of cardiovascular risk in the treatment of TSH levels between 5 and 10 mIU/L and, therefore, treatment of individuals with TSH <5 mIU/L is questionable. Furthermore, the risk of overtreatment resulting in bone loss is a concern. The Endocrine Society does not recommend changing the current normal TSH range for nonpregnant women.

2. What are normal TSH levels in pregnant women?

Because human chorionic gonadotropin (hCG) can bind to and affect the TSH receptor, thereby influencing TSH values, the normal range for TSH is modified in pregnancy. The Endocrine Society recommends the following pregnancy trimester guidelines for TSH levels: 2.5 mIU/L is the recommended upper limit of normal in the first trimester, 3.0 mIU/L in the second trimester, and 3.5 mIU/L in the third trimester.

3. Is untreated SCH associated with miscarriage?

There is fair evidence that SCH, defined as a TSH level >4 mIU/L during pregnancy, is associated with miscarriage, but there is insufficient evidence that TSH levels between 2.5 and 4 mIU/L are associated with miscarriage.

4. Is untreated SCH associated with infertility?

Limited data are available to assess the effect of SCH on infertility. While a few studies show an association between SCH on unexplained infertility and ovulatory disorders, SCH does not appear to be increased in other causes of infertility.

5. Is SCH associated with adverse obstetric outcomes?

Available data reveal that SCH with TSH levels outside the normal pregnancy range are associated with an increased risk of such obstetric complications as placental abruption, preterm birth, fetal death, and preterm premature rupture of membranes (PPROM). However, it is unclear if prepregnancy TSH levels between 2.5 and 4 mIU/L are associated with adverse obstetric outcomes.

6. Does untreated SCH affect developmental outcomes in children?

The fetus is solely dependent on maternal thyroid hormone in early pregnancy because the fetal thyroid does not produce thyroid hormone before 10 to 13 weeks of gestation. Significant evidence has associated untreated maternal hypothyroidism with delayed fetal neurologic development, impaired school performance, and lower intelligence quotient (IQ) among offspring.21 There is fair evidence that SCH diagnosed in pregnancy is associated with adverse neurologic development. There is no evidence that SCH prior to pregnancy is associated with adverse neurodevelopmental outcomes. It should be noted that only one study has examined whether treatment of SCH improves developmental outcomes (measured by IQ scored at age 3 years) and no significant differences were observed in women with SCH who were treated with levothyroxine versus those who were not.²²

7. Does treatment of SCH improve miscarriage rates, live-birth rates, and/or clinical pregnancy rates?

Small randomized controlled studies of women undergoing infertility treatment and a few observational studies in the general population yield good evidence that levothyroxine treatment in women with SCH defined as TSH >4.0 mIU/L is associated with improvement in pregnancy, live birth, and miscarriage rates. There are no randomized trials assessing whether levothyroxine treatment in women with TSH levels between 2.5 and 4 mIU/L would yield similar benefits to those observed in women with TSH levels above 4 mIU/L.

8. Are thyroid antibodies associated with infertility or adverse reproductive outcomes?

There is good evidence that the thyroid autoimmunity, or the presence of TPO-Ab, is associated with miscarriage and fair evidence that it is associated with infertility. Treatment with levothyroxine may improve pregnancy outcomes especially if the TSH level is above 2.5 mIU/L.

9. Should there be universal screening for hypothyroidism in the first trimester of pregnancy?

Current evidence does not reveal a benefit of universal screening at this time. The American College of Obstetricians and Gynecologists does not recommend routine screening for hypothyroidism in pregnancy unless women have risk factors for thyroid disease, including a personal or family history of thyroid disease, physical findings or symptoms of goiter or hypothyroidism, type 1 diabetes mellitus, infertility, history of miscarriage or preterm delivery, and/or personal or family history of autoimmune disease.

The bottom line

SCH, defined as a TSH level greater than the upper limit of normal range (4.5&#8722;5.0 mIU/L)with normal FT4 levels, is associated with adverse reproductive outcomes including miscarriage, pregnancy complications, and delayed fetal neurodevelopment. Thyroid supplementation is beneficial; however, treatment has not been shown to improve long-term neurologic developmental outcomes in offspring. Data are limited on whether TSH values between 2.5 mIU/L and the upper range of normal are associated with adverse pregnancy outcomes and therefore treatment in this group remains controversial. Although available evidence is weak, there may be a benefit in some subgroups, and because risk is minimal, it may be reasonable to treat or to monitor levels and treat above nonpregnant and pregnancy ranges. There is fair evidence that thyroid autoimmunity (positive thyroid antibody) is associated with miscarriage and infertility. Levothyroxine therapy may improve pregnancy outcomes especially if the TSH level is above 2.5 mIU/L. While universal screening of thyroid function in pregnancy is not recommended, women at high risk for thyroid disease should be screened.23

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

Zika virus is a serious problem. Education and infection prevention are critical to effective management, and why we chose to include Zika virus as a topic for this year’s Update. We also discuss obesity’s effects on reproduction—a very relevant concern for all ObGyns and patients alike as about half of reproductive-age women are obese. Finally, subclinical hypothyroidism can present unique management challenges, such as determining when it is present and when treatment is indicated.

Read about counseling patients about Zika virus

Managing attempted pregnancy in the era of Zika virus

Oduyebo T, Igbinosa I, Petersen EE, et al. Update: interim guidance for health care providers caring for pregnant women with possible Zika virus exposure--United States, July 2016. MMWR Morb Mortal Wkly Rep. 2016;65(29):739-744.

Petersen EE, Meaney-Delman D, Neblett-Fanfair R, et al. Update: interim guidance for preconception counseling and prevention of sexual transmission of Zika virus for persons with possible Zika virus exposure--United States, September 2016. MMWR Morb Mortal Wkly Rep. 2016;65(39):1077-1081.

US Food and Drug Administration. Donor Screening Recommendations to Reduce the Risk of Transmission of Zika Virus by Human Cells, Tissues, and Cellular and Tissue-Based Products. http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Tissue/UCM488582.pdf. Published March 2016. Accessed January 12, 2017.

National Institutes of Health. Zika: Overview. https://www.nichd.nih.gov/health/topics/zika/Pages/default.aspx. Accessed January 12, 2017.

World Health Organization. Prevention of sexual transmission of Zika virus interim guidance. WHO reference number: WHO/ZIKV/MOC/16. 1 Rev. 3, September 6, 2016. 

Zika Virus Guidance Task Force of the American Society for Reproductive Medicine. Rev. 13, September 2016.  

Zika virus presents unique challenges to physicians managing the care of patients attempting pregnancy, with or without fertility treatment. Neonatal Zika virus infection sequelae only recently have been appreciated; microcephaly was associated with Zika virus in October 2015, followed by other neurologic conditions including brain abnormalities, neural tube defects, and eye abnormalities. Results of recent studies involving the US Zika Pregnancy Registry show that 6% of women with Zika at any time in pregnancy had affected babies, but 11% of those who contracted the disease in the first trimester were affected. 

Diagnosis is difficult because symptoms are generally mild, with 80% of affected patients asymptomatic. Possible Zika virus exposure is defined as travel to or residence in an area of active Zika virus transmission, or sex without a condom with a partner who traveled to or lived in an area of active transmission. Much is unknown about the interval from exposure to symptoms. Testing availability is limited and variable, and much is unknown about sensitivity and specificity of direct viral RNA testing, appearance and disappearance of detectable immunoglobulin (Ig) M and IgG antibodies that affect false positive and false negative test results, duration of infectious phase, risk of transmission, and numerous other factors.

Positive serum viral testing likely indicates virus in semen or other bodily fluids, but a negative serum viral test cannot definitively preclude virus in other bodily fluids. Zika virus likely can be passed from any combination of semen and vaginal and cervical fluids, but validating tests for these fluids are not yet available. It is not known if sperm preparation and assisted reproductive technology (ART) procedures that minimize risk of HIV transmission are effective against Zika virus or whether or not cryopreservation can destroy the virus. 

Pregnancy timing

The Centers for Disease Control and Prevention now recommends that all men with possible Zika virus exposure who are considering attempting pregnancy with their partner wait to get pregnant until at least 6 months after symptom onset (if symptomatic) or last possible Zika virus exposure (if asymptomatic). Women with possible Zika virus exposure are recommended to wait to get pregnant until at least 8 weeks after symptom onset (if symptomatic) or last possible Zika virus exposure (if asymptomatic).

Women and men with possible exposure to Zika virus but without clinical symptoms of illness should consider testing for Zika viral RNA within 2 weeks of suspected exposure and wait at least 8 weeks after the last date of exposure before being re-tested. If direct viral testing (using rRT-PCR) results initially are negative, ideally, antibody testing would be obtained, if available, at 8 weeks. However, no testing paradigm will absolutely guarantee lack of Zika virus infectivity.

Virus management problems are dramatically compounded in areas endemic for Zika. Women and men who have had Zika virus disease should wait at least 6 months after illness onset to attempt reproduction. The temporal relationship between the presence of viral RNA and infectivity is not known definitively, and so the absolute duration of time to wait before attempting pregnancy is unknown. Male and female partners who become infected should avoid all forms of intimate sexual conduct or use condoms for the same 6 months. There is no evidence Zika will cause congenital infection in pregnancies initiated after resolution of maternal Zika viremia. However, any testing performed at a time other than the time of treatment might not reflect true viral status, particularly in areas of active Zika virus transmission.

Prevention

Women and men, especially those residing in areas of active Zika virus transmission, should talk with their physicians regarding pregnancy plans and avoid mosquito bites using the usual precautions: avoid mosquito areas, drain standing water, use mosquito repellent containing DEET, and use mosquito netting. Some people have gone so far as to relocate to nonendemic areas.

Those contemplating pregnancy should be advised to consider what they would do if they become exposed to or have suspected or confirmed Zika virus during pregnancy. Additional considerations are gamete or embryo cryopreservation and quarantine until a subsequent rRT-PCR test result is negative in both the male and female and at least 8 weeks have passed from gamete collection.

Patient counseling essentials

Counsel patients considering reproduction  about:  

• Zika virus as a new reproductive hazard  
• the significance of the hazard to the fetus if infected
• the areas of active transmission, and that they are constantly changing
• avoidance of Zika areas if possible
• methods of transmission through mosquito bites or sex
• avoidance of mosquito bites
• symptoms of Zika infection
• safe sex practices
• testing limitations and knowledge deficiency about Zika.

Not uncommonly, clinical situations require complex individualized management decisions regarding trade-offs of risks, especially in older patients with decreased ovarian reserve. Consultation with infectious disease and reproductive specialists should be obtained when complicated and consequential decisions have to be made.

All practitioners should inform their patients, especially those undergoing fertility treatments, about Zika, and develop language in their informed consent that conveys the gap in knowledge to these patients.

Read how obesity specifically affects reproduction in an adverse way

Obesity adversely affects reproduction, but how specifically?

Practice Committee of the American Society for Reproductive Medicine. Obesity and Reproduction: A committee opinion. Fertil Steril. 2015;104(5):1116-1126.

The prevalence of obesity has increased substantially over the past 2 decades. Almost two-thirds of women and three-fourths of men in the United States are overweight or obese (defined as a body mass index [BMI] ≥25 kg/m² and BMI ≥30 kg/m², respectively; TABLE). Nearly 50% of reproductive-age women are obese.

A disease of excess body fat and insulin resistance, obesity increases the risks of hypertension, diabetes, dyslipidemia, cardiovascular disease, sleep apnea, respiratory problems, and cancer as well as other serious health problems. While not all individuals with obesity will have infertility, obesity is associated with impaired reproduction in both women and men, adverse obstetric outcomes, and health problems in offspring. The American Society for Reproductive Medicine (ASRM) reviewed this important issue in a recent practice committee opinion.  

Menstrual cycle and ovulatory dysfunction

Menstrual cycle abnormalities are more common in women with obesity. Elevated levels of insulin in obese women suppress sex hormone−binding globulin (SHBG) which in turn reduces gonadotropin secretion due to increased production of estrogen from conversion of androgens by adipose aromatase.¹ Adipose tissue produces adipokines, which directly can suppress ovarian function.²

Ovulatory dysfunction is common among obese women; the relative risk of such dysfunction is 3.1 (95% confidence interval [CI], 2.2−4.4) among women with BMI levels >27 kg/m² versus BMI levels 20.0 to 24.9 kg/m².^3,4  Obesity decreases fecundity even in women with normal menstrual cycles.⁵ This may in part be due to altered ovulatory dynamics with reduced early follicular luteinizing hormone pulse amplitude accompanied by prolonged folliculogenesis and reduced luteal progesterone levels.⁶

Compared with normal-weight women, obese women have a lower chance of conception within 1 year of stopping contraception; about 66% of obese women conceive within 1 year of stopping contraception, compared with about 81% of women with normal weight.⁷ Results of a Dutch study of 3,029 women with regular ovulation, at least one patent tube, and a partner with a normal semen analysis indicated a direct correlation between obesity and delayed conception, with a 4% lower spontaneous pregnancy rate per kg/m2 increase in women with a BMI >29 kg/m² versus a BMI of 21 to 29 kg/m² (hazard ratio, 0.96; 95% CI, 0.91−0.99).⁸  

Assisted reproduction

Assisted reproduction in women with obesity is associated with lower success rates than in women with normal weight. A systematic review of 27 in vitro fertilization (IVF) studies (23 of which were retrospective) reveals  10% lower live-birth rate in overweight (BMI >25 kg/m²) versus normal-weight women (BMI <25 kg/m²) undergoing IVF (odds ratio [OR], 0.90; 95% CI, 0.82−1.0).⁹ Data from a meta-analysis of 33 IVF studies, including 47,967 cycles, show that, compared with women with a BMI <25 kg/m², overweight or obese women have significantly reduced rates of clinical pregnancy (relative risk [RR], 0.90; P<.0001) and live birth (RR, 0.84; P = .0002).¹⁰

Results of a retrospective study of 4,609 women undergoing first IVF or IVF/intracytoplasmic sperm injection cycles revealed impaired embryo implantation (controlling for embryo quality and transfer day), reducing the age-adjusted odds of live birth in a BMI-dependent manner by 37% (BMI, 30.0−34.9 kg/m²), 61% (BMI, 35.0−39.9 kg/m2), and 68% (BMI, >40 kg/m²) compared with women with a BMI of 18.5 to 24.9 kg/m².¹¹ In a study of 12,566 Danish couples undergoing assisted reproduction, overweight and obese ovulatory women had a 12% (95% CI, 0.79−0.99) and 25% (95% CI, 0.63−0.90) reduction in IVF-related live birth rate, respectively (referent BMI, 18.5−24.9 kg/m²), with a 2% (95% CI, 0.97−0.99) decrease in live-birth rate for every one-unit increase in BMI.¹² Putative mechanisms for these findings include altered oocyte morphology and reduced fertilization in eggs from obese women,¹³ and impaired embryo quality in women less than age 35.¹⁴ Oocytes from women with a BMI >25 kg/m² are smaller and less likely to complete development postfertilization, with embryos arrested prior to blastulation containing more triglyceride than those forming blastocysts.¹⁵

Blastocysts developed from oocytes of high-BMI women are smaller, contain fewer cells and have a higher content of triglycerides, lower glucose consumption, and altered amino acid metabolism compared with embryos of normal-weight women (BMI <24.9 kg/m2).¹⁵ Obesity may alter endometrial receptivity during IVF given the finding that third-party surrogate women with a BMI >35 kg/m² have a lower live-birth rate (25%) compared with women with a BMI <35 kg/m² (49%; P<.05).¹⁶

Pregnancy outcomes

Obesity is linked to an increased risk of miscarriage. Results of a meta-analysis of 33 IVF studies including 47,967 cycles indicated that overweight or obese women have a higher rate of miscarriage (RR, 1.31; P<.0001) than normal-weight women (BMI <25 kg/m2).¹⁷ Maternal and perinatal morbid obesity are strongly associated with obstetric and perinatal complications, including gestational diabetes, hypertension, preeclampsia, preterm delivery, shoulder dystocia, fetal distress, early neonatal death, and small- as well as large-for-gestational age infants.

Obese women who conceive by IVF are at increased risk for preeclampsia, gestational diabetes, preterm delivery, and cesarean delivery.¹³ Authors of a meta-analysis of 18 observational studies concluded that obese mothers were at increased odds of pregnancies affected by such birth defects as neural tube defects, cardiovascular anomalies, and cleft lip and palate, among others.¹⁸

In addition to being the cause of these fetal abnormalities, maternal metabolic dysfunction is linked to promoting obesity in offspring, thereby perpetuating a cycle of obesity and adverse health outcomes that include an increased risk of premature death in adult offspring in subsequent generations.¹³

Treatment for obesity

Lifestyle modification is the first-line treatment for obesity.  
Pre-fertility therapy and pregnancy goals. Targets for pregnancy should include:  

• preconception weight loss to a BMI of 35 kg/m2
• prevention of excess weight gain in pregnancy
• long-term reduction in weight.

For all obese individuals, lifestyle modifications should include a weight loss of 7% of body weight and increased physical activity to at least 150 minutes of moderate activity, such as walking, per week. Calorie restriction should be emphasized. A 500 to 1,000 kcal/day decrease from usual dietary intake is expected to result in a 1- to 2-lb weight loss per week. A low-calorie diet of 1,000 to 1,200 kcal/day can lead to an average 10% decrease in total body weight over 6 months.

Adjunct supervised medical therapy or bariatric surgery can play an important role in successful weight loss prepregnancy but are not appropriate for women actively attempting conception. Importantly, pregnancy should be deferred for a minimum of 1 year after bariatric surgery. The decision to postpone pregnancy to achieve weight loss must be balanced against the risk of declining fertility with advancing age of the woman. 

Read about when to treat subclinical hypothyroidism

Optimal management of subclinical hypothyroidism in women with infertility

Practice Committee of the American Society for Reproductive Medicine. Subclinical hypothyroidism in the infertile female population: a guideline. Fertil Steril. 2015;104(3):545-553.

Thyroid disorders long have been associated with the potential for adverse reproductive outcomes. While overt hypothyroidism has been linked to infertility, increased miscarriage risk, and poor maternal and fetal outcomes, controversy has existed regarding the association between subclinical hypothyroidism (SCH) and reproductive problems. The ASRM recently published a guideline on the role of SCH in the infertile female population.  

How is subclinical hypothyroidism defined?

SCH is classically defined as a thyrotropin (TSH) level above the upper limit of normal range (4.5−5.0 mIU/L) with normal free thyroxine (FT4) levels. The National Health and Nutrition Examination Survey (NHANES III) population has been used to establish normative data for TSH for a disease-free population. These include a median serum level for TSH of 1.5 mIU/L, with the corresponding 2.5 and 97.5 percentiles of 0.41 and 6.10, respectively.¹⁹ Data from the National Academy of Clinical Biochemistry, however, reveal that 95% of individuals without evidence of thyroid disease have a TSH level <2.5 mIU/L, and that the normal reference range is skewed to the right.20 Adjusting the upper limit of the normal range to 2.5 mIU/L would result in an additional 11.8% to 14.2% of the United States population (22 to 28 million individuals) being diagnosed with hypothyroidism.

This information raises several important questions.

1. Should nonpregnant women be treated for SCH?

No. There is no benefit from the standpoint of lipid profile or alteration of cardiovascular risk in the treatment of TSH levels between 5 and 10 mIU/L and, therefore, treatment of individuals with TSH <5 mIU/L is questionable. Furthermore, the risk of overtreatment resulting in bone loss is a concern. The Endocrine Society does not recommend changing the current normal TSH range for nonpregnant women.

2. What are normal TSH levels in pregnant women?

Because human chorionic gonadotropin (hCG) can bind to and affect the TSH receptor, thereby influencing TSH values, the normal range for TSH is modified in pregnancy. The Endocrine Society recommends the following pregnancy trimester guidelines for TSH levels: 2.5 mIU/L is the recommended upper limit of normal in the first trimester, 3.0 mIU/L in the second trimester, and 3.5 mIU/L in the third trimester.

3. Is untreated SCH associated with miscarriage?

There is fair evidence that SCH, defined as a TSH level >4 mIU/L during pregnancy, is associated with miscarriage, but there is insufficient evidence that TSH levels between 2.5 and 4 mIU/L are associated with miscarriage.

4. Is untreated SCH associated with infertility?

Limited data are available to assess the effect of SCH on infertility. While a few studies show an association between SCH on unexplained infertility and ovulatory disorders, SCH does not appear to be increased in other causes of infertility.

5. Is SCH associated with adverse obstetric outcomes?

Available data reveal that SCH with TSH levels outside the normal pregnancy range are associated with an increased risk of such obstetric complications as placental abruption, preterm birth, fetal death, and preterm premature rupture of membranes (PPROM). However, it is unclear if prepregnancy TSH levels between 2.5 and 4 mIU/L are associated with adverse obstetric outcomes.

6. Does untreated SCH affect developmental outcomes in children?

The fetus is solely dependent on maternal thyroid hormone in early pregnancy because the fetal thyroid does not produce thyroid hormone before 10 to 13 weeks of gestation. Significant evidence has associated untreated maternal hypothyroidism with delayed fetal neurologic development, impaired school performance, and lower intelligence quotient (IQ) among offspring.21 There is fair evidence that SCH diagnosed in pregnancy is associated with adverse neurologic development. There is no evidence that SCH prior to pregnancy is associated with adverse neurodevelopmental outcomes. It should be noted that only one study has examined whether treatment of SCH improves developmental outcomes (measured by IQ scored at age 3 years) and no significant differences were observed in women with SCH who were treated with levothyroxine versus those who were not.²²

7. Does treatment of SCH improve miscarriage rates, live-birth rates, and/or clinical pregnancy rates?

Small randomized controlled studies of women undergoing infertility treatment and a few observational studies in the general population yield good evidence that levothyroxine treatment in women with SCH defined as TSH >4.0 mIU/L is associated with improvement in pregnancy, live birth, and miscarriage rates. There are no randomized trials assessing whether levothyroxine treatment in women with TSH levels between 2.5 and 4 mIU/L would yield similar benefits to those observed in women with TSH levels above 4 mIU/L.

8. Are thyroid antibodies associated with infertility or adverse reproductive outcomes?

There is good evidence that the thyroid autoimmunity, or the presence of TPO-Ab, is associated with miscarriage and fair evidence that it is associated with infertility. Treatment with levothyroxine may improve pregnancy outcomes especially if the TSH level is above 2.5 mIU/L.

9. Should there be universal screening for hypothyroidism in the first trimester of pregnancy?

Current evidence does not reveal a benefit of universal screening at this time. The American College of Obstetricians and Gynecologists does not recommend routine screening for hypothyroidism in pregnancy unless women have risk factors for thyroid disease, including a personal or family history of thyroid disease, physical findings or symptoms of goiter or hypothyroidism, type 1 diabetes mellitus, infertility, history of miscarriage or preterm delivery, and/or personal or family history of autoimmune disease.

The bottom line

SCH, defined as a TSH level greater than the upper limit of normal range (4.5&#8722;5.0 mIU/L)with normal FT4 levels, is associated with adverse reproductive outcomes including miscarriage, pregnancy complications, and delayed fetal neurodevelopment. Thyroid supplementation is beneficial; however, treatment has not been shown to improve long-term neurologic developmental outcomes in offspring. Data are limited on whether TSH values between 2.5 mIU/L and the upper range of normal are associated with adverse pregnancy outcomes and therefore treatment in this group remains controversial. Although available evidence is weak, there may be a benefit in some subgroups, and because risk is minimal, it may be reasonable to treat or to monitor levels and treat above nonpregnant and pregnancy ranges. There is fair evidence that thyroid autoimmunity (positive thyroid antibody) is associated with miscarriage and infertility. Levothyroxine therapy may improve pregnancy outcomes especially if the TSH level is above 2.5 mIU/L. While universal screening of thyroid function in pregnancy is not recommended, women at high risk for thyroid disease should be screened.23

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

Zika virus is a serious problem. Education and infection prevention are critical to effective management, and why we chose to include Zika virus as a topic for this year’s Update. We also discuss obesity’s effects on reproduction—a very relevant concern for all ObGyns and patients alike as about half of reproductive-age women are obese. Finally, subclinical hypothyroidism can present unique management challenges, such as determining when it is present and when treatment is indicated.

Read about counseling patients about Zika virus

Managing attempted pregnancy in the era of Zika virus

Oduyebo T, Igbinosa I, Petersen EE, et al. Update: interim guidance for health care providers caring for pregnant women with possible Zika virus exposure--United States, July 2016. MMWR Morb Mortal Wkly Rep. 2016;65(29):739-744.

Petersen EE, Meaney-Delman D, Neblett-Fanfair R, et al. Update: interim guidance for preconception counseling and prevention of sexual transmission of Zika virus for persons with possible Zika virus exposure--United States, September 2016. MMWR Morb Mortal Wkly Rep. 2016;65(39):1077-1081.

US Food and Drug Administration. Donor Screening Recommendations to Reduce the Risk of Transmission of Zika Virus by Human Cells, Tissues, and Cellular and Tissue-Based Products. http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Tissue/UCM488582.pdf. Published March 2016. Accessed January 12, 2017.

National Institutes of Health. Zika: Overview. https://www.nichd.nih.gov/health/topics/zika/Pages/default.aspx. Accessed January 12, 2017.

World Health Organization. Prevention of sexual transmission of Zika virus interim guidance. WHO reference number: WHO/ZIKV/MOC/16. 1 Rev. 3, September 6, 2016. 

Zika Virus Guidance Task Force of the American Society for Reproductive Medicine. Rev. 13, September 2016.  

Zika virus presents unique challenges to physicians managing the care of patients attempting pregnancy, with or without fertility treatment. Neonatal Zika virus infection sequelae only recently have been appreciated; microcephaly was associated with Zika virus in October 2015, followed by other neurologic conditions including brain abnormalities, neural tube defects, and eye abnormalities. Results of recent studies involving the US Zika Pregnancy Registry show that 6% of women with Zika at any time in pregnancy had affected babies, but 11% of those who contracted the disease in the first trimester were affected. 

Diagnosis is difficult because symptoms are generally mild, with 80% of affected patients asymptomatic. Possible Zika virus exposure is defined as travel to or residence in an area of active Zika virus transmission, or sex without a condom with a partner who traveled to or lived in an area of active transmission. Much is unknown about the interval from exposure to symptoms. Testing availability is limited and variable, and much is unknown about sensitivity and specificity of direct viral RNA testing, appearance and disappearance of detectable immunoglobulin (Ig) M and IgG antibodies that affect false positive and false negative test results, duration of infectious phase, risk of transmission, and numerous other factors.

Positive serum viral testing likely indicates virus in semen or other bodily fluids, but a negative serum viral test cannot definitively preclude virus in other bodily fluids. Zika virus likely can be passed from any combination of semen and vaginal and cervical fluids, but validating tests for these fluids are not yet available. It is not known if sperm preparation and assisted reproductive technology (ART) procedures that minimize risk of HIV transmission are effective against Zika virus or whether or not cryopreservation can destroy the virus. 

Pregnancy timing

The Centers for Disease Control and Prevention now recommends that all men with possible Zika virus exposure who are considering attempting pregnancy with their partner wait to get pregnant until at least 6 months after symptom onset (if symptomatic) or last possible Zika virus exposure (if asymptomatic). Women with possible Zika virus exposure are recommended to wait to get pregnant until at least 8 weeks after symptom onset (if symptomatic) or last possible Zika virus exposure (if asymptomatic).

Women and men with possible exposure to Zika virus but without clinical symptoms of illness should consider testing for Zika viral RNA within 2 weeks of suspected exposure and wait at least 8 weeks after the last date of exposure before being re-tested. If direct viral testing (using rRT-PCR) results initially are negative, ideally, antibody testing would be obtained, if available, at 8 weeks. However, no testing paradigm will absolutely guarantee lack of Zika virus infectivity.

Virus management problems are dramatically compounded in areas endemic for Zika. Women and men who have had Zika virus disease should wait at least 6 months after illness onset to attempt reproduction. The temporal relationship between the presence of viral RNA and infectivity is not known definitively, and so the absolute duration of time to wait before attempting pregnancy is unknown. Male and female partners who become infected should avoid all forms of intimate sexual conduct or use condoms for the same 6 months. There is no evidence Zika will cause congenital infection in pregnancies initiated after resolution of maternal Zika viremia. However, any testing performed at a time other than the time of treatment might not reflect true viral status, particularly in areas of active Zika virus transmission.

Prevention

Women and men, especially those residing in areas of active Zika virus transmission, should talk with their physicians regarding pregnancy plans and avoid mosquito bites using the usual precautions: avoid mosquito areas, drain standing water, use mosquito repellent containing DEET, and use mosquito netting. Some people have gone so far as to relocate to nonendemic areas.

Those contemplating pregnancy should be advised to consider what they would do if they become exposed to or have suspected or confirmed Zika virus during pregnancy. Additional considerations are gamete or embryo cryopreservation and quarantine until a subsequent rRT-PCR test result is negative in both the male and female and at least 8 weeks have passed from gamete collection.

Patient counseling essentials

Counsel patients considering reproduction  about:  

• Zika virus as a new reproductive hazard  
• the significance of the hazard to the fetus if infected
• the areas of active transmission, and that they are constantly changing
• avoidance of Zika areas if possible
• methods of transmission through mosquito bites or sex
• avoidance of mosquito bites
• symptoms of Zika infection
• safe sex practices
• testing limitations and knowledge deficiency about Zika.

Not uncommonly, clinical situations require complex individualized management decisions regarding trade-offs of risks, especially in older patients with decreased ovarian reserve. Consultation with infectious disease and reproductive specialists should be obtained when complicated and consequential decisions have to be made.

All practitioners should inform their patients, especially those undergoing fertility treatments, about Zika, and develop language in their informed consent that conveys the gap in knowledge to these patients.

Read how obesity specifically affects reproduction in an adverse way

Obesity adversely affects reproduction, but how specifically?

Practice Committee of the American Society for Reproductive Medicine. Obesity and Reproduction: A committee opinion. Fertil Steril. 2015;104(5):1116-1126.

The prevalence of obesity has increased substantially over the past 2 decades. Almost two-thirds of women and three-fourths of men in the United States are overweight or obese (defined as a body mass index [BMI] ≥25 kg/m² and BMI ≥30 kg/m², respectively; TABLE). Nearly 50% of reproductive-age women are obese.

A disease of excess body fat and insulin resistance, obesity increases the risks of hypertension, diabetes, dyslipidemia, cardiovascular disease, sleep apnea, respiratory problems, and cancer as well as other serious health problems. While not all individuals with obesity will have infertility, obesity is associated with impaired reproduction in both women and men, adverse obstetric outcomes, and health problems in offspring. The American Society for Reproductive Medicine (ASRM) reviewed this important issue in a recent practice committee opinion.  

Menstrual cycle and ovulatory dysfunction

Menstrual cycle abnormalities are more common in women with obesity. Elevated levels of insulin in obese women suppress sex hormone−binding globulin (SHBG) which in turn reduces gonadotropin secretion due to increased production of estrogen from conversion of androgens by adipose aromatase.¹ Adipose tissue produces adipokines, which directly can suppress ovarian function.²

Ovulatory dysfunction is common among obese women; the relative risk of such dysfunction is 3.1 (95% confidence interval [CI], 2.2−4.4) among women with BMI levels >27 kg/m² versus BMI levels 20.0 to 24.9 kg/m².^3,4  Obesity decreases fecundity even in women with normal menstrual cycles.⁵ This may in part be due to altered ovulatory dynamics with reduced early follicular luteinizing hormone pulse amplitude accompanied by prolonged folliculogenesis and reduced luteal progesterone levels.⁶

Compared with normal-weight women, obese women have a lower chance of conception within 1 year of stopping contraception; about 66% of obese women conceive within 1 year of stopping contraception, compared with about 81% of women with normal weight.⁷ Results of a Dutch study of 3,029 women with regular ovulation, at least one patent tube, and a partner with a normal semen analysis indicated a direct correlation between obesity and delayed conception, with a 4% lower spontaneous pregnancy rate per kg/m2 increase in women with a BMI >29 kg/m² versus a BMI of 21 to 29 kg/m² (hazard ratio, 0.96; 95% CI, 0.91−0.99).⁸  

Assisted reproduction

Assisted reproduction in women with obesity is associated with lower success rates than in women with normal weight. A systematic review of 27 in vitro fertilization (IVF) studies (23 of which were retrospective) reveals  10% lower live-birth rate in overweight (BMI >25 kg/m²) versus normal-weight women (BMI <25 kg/m²) undergoing IVF (odds ratio [OR], 0.90; 95% CI, 0.82−1.0).⁹ Data from a meta-analysis of 33 IVF studies, including 47,967 cycles, show that, compared with women with a BMI <25 kg/m², overweight or obese women have significantly reduced rates of clinical pregnancy (relative risk [RR], 0.90; P<.0001) and live birth (RR, 0.84; P = .0002).¹⁰

Results of a retrospective study of 4,609 women undergoing first IVF or IVF/intracytoplasmic sperm injection cycles revealed impaired embryo implantation (controlling for embryo quality and transfer day), reducing the age-adjusted odds of live birth in a BMI-dependent manner by 37% (BMI, 30.0−34.9 kg/m²), 61% (BMI, 35.0−39.9 kg/m2), and 68% (BMI, >40 kg/m²) compared with women with a BMI of 18.5 to 24.9 kg/m².¹¹ In a study of 12,566 Danish couples undergoing assisted reproduction, overweight and obese ovulatory women had a 12% (95% CI, 0.79−0.99) and 25% (95% CI, 0.63−0.90) reduction in IVF-related live birth rate, respectively (referent BMI, 18.5−24.9 kg/m²), with a 2% (95% CI, 0.97−0.99) decrease in live-birth rate for every one-unit increase in BMI.¹² Putative mechanisms for these findings include altered oocyte morphology and reduced fertilization in eggs from obese women,¹³ and impaired embryo quality in women less than age 35.¹⁴ Oocytes from women with a BMI >25 kg/m² are smaller and less likely to complete development postfertilization, with embryos arrested prior to blastulation containing more triglyceride than those forming blastocysts.¹⁵

Blastocysts developed from oocytes of high-BMI women are smaller, contain fewer cells and have a higher content of triglycerides, lower glucose consumption, and altered amino acid metabolism compared with embryos of normal-weight women (BMI <24.9 kg/m2).¹⁵ Obesity may alter endometrial receptivity during IVF given the finding that third-party surrogate women with a BMI >35 kg/m² have a lower live-birth rate (25%) compared with women with a BMI <35 kg/m² (49%; P<.05).¹⁶

Pregnancy outcomes

Obesity is linked to an increased risk of miscarriage. Results of a meta-analysis of 33 IVF studies including 47,967 cycles indicated that overweight or obese women have a higher rate of miscarriage (RR, 1.31; P<.0001) than normal-weight women (BMI <25 kg/m2).¹⁷ Maternal and perinatal morbid obesity are strongly associated with obstetric and perinatal complications, including gestational diabetes, hypertension, preeclampsia, preterm delivery, shoulder dystocia, fetal distress, early neonatal death, and small- as well as large-for-gestational age infants.

Obese women who conceive by IVF are at increased risk for preeclampsia, gestational diabetes, preterm delivery, and cesarean delivery.¹³ Authors of a meta-analysis of 18 observational studies concluded that obese mothers were at increased odds of pregnancies affected by such birth defects as neural tube defects, cardiovascular anomalies, and cleft lip and palate, among others.¹⁸

In addition to being the cause of these fetal abnormalities, maternal metabolic dysfunction is linked to promoting obesity in offspring, thereby perpetuating a cycle of obesity and adverse health outcomes that include an increased risk of premature death in adult offspring in subsequent generations.¹³

Treatment for obesity

Lifestyle modification is the first-line treatment for obesity.  
Pre-fertility therapy and pregnancy goals. Targets for pregnancy should include:  

• preconception weight loss to a BMI of 35 kg/m2
• prevention of excess weight gain in pregnancy
• long-term reduction in weight.

For all obese individuals, lifestyle modifications should include a weight loss of 7% of body weight and increased physical activity to at least 150 minutes of moderate activity, such as walking, per week. Calorie restriction should be emphasized. A 500 to 1,000 kcal/day decrease from usual dietary intake is expected to result in a 1- to 2-lb weight loss per week. A low-calorie diet of 1,000 to 1,200 kcal/day can lead to an average 10% decrease in total body weight over 6 months.

Adjunct supervised medical therapy or bariatric surgery can play an important role in successful weight loss prepregnancy but are not appropriate for women actively attempting conception. Importantly, pregnancy should be deferred for a minimum of 1 year after bariatric surgery. The decision to postpone pregnancy to achieve weight loss must be balanced against the risk of declining fertility with advancing age of the woman. 

Read about when to treat subclinical hypothyroidism

Optimal management of subclinical hypothyroidism in women with infertility

Practice Committee of the American Society for Reproductive Medicine. Subclinical hypothyroidism in the infertile female population: a guideline. Fertil Steril. 2015;104(3):545-553.

Thyroid disorders long have been associated with the potential for adverse reproductive outcomes. While overt hypothyroidism has been linked to infertility, increased miscarriage risk, and poor maternal and fetal outcomes, controversy has existed regarding the association between subclinical hypothyroidism (SCH) and reproductive problems. The ASRM recently published a guideline on the role of SCH in the infertile female population.  

How is subclinical hypothyroidism defined?

SCH is classically defined as a thyrotropin (TSH) level above the upper limit of normal range (4.5−5.0 mIU/L) with normal free thyroxine (FT4) levels. The National Health and Nutrition Examination Survey (NHANES III) population has been used to establish normative data for TSH for a disease-free population. These include a median serum level for TSH of 1.5 mIU/L, with the corresponding 2.5 and 97.5 percentiles of 0.41 and 6.10, respectively.¹⁹ Data from the National Academy of Clinical Biochemistry, however, reveal that 95% of individuals without evidence of thyroid disease have a TSH level <2.5 mIU/L, and that the normal reference range is skewed to the right.20 Adjusting the upper limit of the normal range to 2.5 mIU/L would result in an additional 11.8% to 14.2% of the United States population (22 to 28 million individuals) being diagnosed with hypothyroidism.

This information raises several important questions.

1. Should nonpregnant women be treated for SCH?

No. There is no benefit from the standpoint of lipid profile or alteration of cardiovascular risk in the treatment of TSH levels between 5 and 10 mIU/L and, therefore, treatment of individuals with TSH <5 mIU/L is questionable. Furthermore, the risk of overtreatment resulting in bone loss is a concern. The Endocrine Society does not recommend changing the current normal TSH range for nonpregnant women.

2. What are normal TSH levels in pregnant women?

Because human chorionic gonadotropin (hCG) can bind to and affect the TSH receptor, thereby influencing TSH values, the normal range for TSH is modified in pregnancy. The Endocrine Society recommends the following pregnancy trimester guidelines for TSH levels: 2.5 mIU/L is the recommended upper limit of normal in the first trimester, 3.0 mIU/L in the second trimester, and 3.5 mIU/L in the third trimester.

3. Is untreated SCH associated with miscarriage?

There is fair evidence that SCH, defined as a TSH level >4 mIU/L during pregnancy, is associated with miscarriage, but there is insufficient evidence that TSH levels between 2.5 and 4 mIU/L are associated with miscarriage.

4. Is untreated SCH associated with infertility?

Limited data are available to assess the effect of SCH on infertility. While a few studies show an association between SCH on unexplained infertility and ovulatory disorders, SCH does not appear to be increased in other causes of infertility.

5. Is SCH associated with adverse obstetric outcomes?

Available data reveal that SCH with TSH levels outside the normal pregnancy range are associated with an increased risk of such obstetric complications as placental abruption, preterm birth, fetal death, and preterm premature rupture of membranes (PPROM). However, it is unclear if prepregnancy TSH levels between 2.5 and 4 mIU/L are associated with adverse obstetric outcomes.

6. Does untreated SCH affect developmental outcomes in children?

The fetus is solely dependent on maternal thyroid hormone in early pregnancy because the fetal thyroid does not produce thyroid hormone before 10 to 13 weeks of gestation. Significant evidence has associated untreated maternal hypothyroidism with delayed fetal neurologic development, impaired school performance, and lower intelligence quotient (IQ) among offspring.21 There is fair evidence that SCH diagnosed in pregnancy is associated with adverse neurologic development. There is no evidence that SCH prior to pregnancy is associated with adverse neurodevelopmental outcomes. It should be noted that only one study has examined whether treatment of SCH improves developmental outcomes (measured by IQ scored at age 3 years) and no significant differences were observed in women with SCH who were treated with levothyroxine versus those who were not.²²

7. Does treatment of SCH improve miscarriage rates, live-birth rates, and/or clinical pregnancy rates?

Small randomized controlled studies of women undergoing infertility treatment and a few observational studies in the general population yield good evidence that levothyroxine treatment in women with SCH defined as TSH >4.0 mIU/L is associated with improvement in pregnancy, live birth, and miscarriage rates. There are no randomized trials assessing whether levothyroxine treatment in women with TSH levels between 2.5 and 4 mIU/L would yield similar benefits to those observed in women with TSH levels above 4 mIU/L.

8. Are thyroid antibodies associated with infertility or adverse reproductive outcomes?

There is good evidence that the thyroid autoimmunity, or the presence of TPO-Ab, is associated with miscarriage and fair evidence that it is associated with infertility. Treatment with levothyroxine may improve pregnancy outcomes especially if the TSH level is above 2.5 mIU/L.

9. Should there be universal screening for hypothyroidism in the first trimester of pregnancy?

Current evidence does not reveal a benefit of universal screening at this time. The American College of Obstetricians and Gynecologists does not recommend routine screening for hypothyroidism in pregnancy unless women have risk factors for thyroid disease, including a personal or family history of thyroid disease, physical findings or symptoms of goiter or hypothyroidism, type 1 diabetes mellitus, infertility, history of miscarriage or preterm delivery, and/or personal or family history of autoimmune disease.

The bottom line

SCH, defined as a TSH level greater than the upper limit of normal range (4.5&#8722;5.0 mIU/L)with normal FT4 levels, is associated with adverse reproductive outcomes including miscarriage, pregnancy complications, and delayed fetal neurodevelopment. Thyroid supplementation is beneficial; however, treatment has not been shown to improve long-term neurologic developmental outcomes in offspring. Data are limited on whether TSH values between 2.5 mIU/L and the upper range of normal are associated with adverse pregnancy outcomes and therefore treatment in this group remains controversial. Although available evidence is weak, there may be a benefit in some subgroups, and because risk is minimal, it may be reasonable to treat or to monitor levels and treat above nonpregnant and pregnancy ranges. There is fair evidence that thyroid autoimmunity (positive thyroid antibody) is associated with miscarriage and infertility. Levothyroxine therapy may improve pregnancy outcomes especially if the TSH level is above 2.5 mIU/L. While universal screening of thyroid function in pregnancy is not recommended, women at high risk for thyroid disease should be screened.23

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