OBG Management

Ospemifene was FDA-approved in 2013 to treat moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy (VVA) due to menopause. This nonestrogenenic drug has tissue selective agonist/antagonist effects—a selective estrogen-receptor modulator (SERM). Tamoxifen, a first-generation SERM, increases the risk of endometrial cancer. However, the second-generation SERM raloxifene is not associated with this increased risk. In preclinical studies and clinical trials, ospemifene has been shown to exert positive effects on the vaginal epithelium and minimal effects on the endometrium.

Steven R. Goldstein, MD, from New York University School of Medicine, and colleagues set out to determine the endometrial safety of ospemifene in six Phase 2/3 clinical trials of postemenopausal women with up to 52 weeks of exposure to ospemifene 60 mg/day versus placebo.

Endometrial safety of the study drug was assessed in a total of 1,349 women with an intact uterus (851 in the ospemifene group vs 543 in the placebo group).

Results
Endometrial biopsies obtained at 52 weeks revealed a rate of endometrial hyperplasia of 0.3%.

Of 342 biopsied women, “there was a single case of a woman with simple hyperplasia,” says Dr. Goldstein. “She was 52 years old, had become menopausal at age 49 and had been taking hormone therapy for about 2 years before entering the trial. After 4 months of ospemifene, she had an episode of bleeding and was diagnosed with proliferative endometrium. The study drug was stopped with a plan to follow up in 3 months; 89 days later she had another episode of bleeding and was diagnosed with simple hyperplasia. She was treated with a single course of progestogen, the hyperplasia resolved, and then she was noted to have a benign polyp.”

No complex hyperplasias or carcinomas were found.

Ospemifene participants with histologic findings other than inactive, atrophic, or insufficient was 3.5% at 52 weeks, and this finding was similar to baseline endometrial biopsy results for placebo (4.0%).

The incidence of active and disordered type endometrial proliferation was less than 1% of participants treated with ospemifene. The vaginal bleeding incidence was similar in the treatment and placebo groups.

“This data tells me that this drug is clearly acting like its cousin raloxifene in the uterus, with virtually no active proliferation and no true hyperplasia. The FDA guidance for any of these products is less than 1% hyperplasia in 1 year, and there was a single case out of 342 biopsies, says Dr. Goldstein.

MORE NEWS and HIGHLIGHTS from ACOG's 2014 ANNUAL CLINICAL MEETING
Survey: Most average-risk pregnant women preferred NIPT to invasive testing

Adding infertility assessment and treatment to your practice

Delivery notes after shoulder dystocia often lack critical elements

Why it’s important to open the sexual health dialogue

Ospemifene was FDA-approved in 2013 to treat moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy (VVA) due to menopause. This nonestrogenenic drug has tissue selective agonist/antagonist effects—a selective estrogen-receptor modulator (SERM). Tamoxifen, a first-generation SERM, increases the risk of endometrial cancer. However, the second-generation SERM raloxifene is not associated with this increased risk. In preclinical studies and clinical trials, ospemifene has been shown to exert positive effects on the vaginal epithelium and minimal effects on the endometrium.

Steven R. Goldstein, MD, from New York University School of Medicine, and colleagues set out to determine the endometrial safety of ospemifene in six Phase 2/3 clinical trials of postemenopausal women with up to 52 weeks of exposure to ospemifene 60 mg/day versus placebo.

Endometrial safety of the study drug was assessed in a total of 1,349 women with an intact uterus (851 in the ospemifene group vs 543 in the placebo group).

Results
Endometrial biopsies obtained at 52 weeks revealed a rate of endometrial hyperplasia of 0.3%.

Of 342 biopsied women, “there was a single case of a woman with simple hyperplasia,” says Dr. Goldstein. “She was 52 years old, had become menopausal at age 49 and had been taking hormone therapy for about 2 years before entering the trial. After 4 months of ospemifene, she had an episode of bleeding and was diagnosed with proliferative endometrium. The study drug was stopped with a plan to follow up in 3 months; 89 days later she had another episode of bleeding and was diagnosed with simple hyperplasia. She was treated with a single course of progestogen, the hyperplasia resolved, and then she was noted to have a benign polyp.”

No complex hyperplasias or carcinomas were found.

Ospemifene participants with histologic findings other than inactive, atrophic, or insufficient was 3.5% at 52 weeks, and this finding was similar to baseline endometrial biopsy results for placebo (4.0%).

The incidence of active and disordered type endometrial proliferation was less than 1% of participants treated with ospemifene. The vaginal bleeding incidence was similar in the treatment and placebo groups.

“This data tells me that this drug is clearly acting like its cousin raloxifene in the uterus, with virtually no active proliferation and no true hyperplasia. The FDA guidance for any of these products is less than 1% hyperplasia in 1 year, and there was a single case out of 342 biopsies, says Dr. Goldstein.

MORE NEWS and HIGHLIGHTS from ACOG's 2014 ANNUAL CLINICAL MEETING
Survey: Most average-risk pregnant women preferred NIPT to invasive testing

Adding infertility assessment and treatment to your practice

Delivery notes after shoulder dystocia often lack critical elements

Why it’s important to open the sexual health dialogue

Ospemifene was FDA-approved in 2013 to treat moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy (VVA) due to menopause. This nonestrogenenic drug has tissue selective agonist/antagonist effects—a selective estrogen-receptor modulator (SERM). Tamoxifen, a first-generation SERM, increases the risk of endometrial cancer. However, the second-generation SERM raloxifene is not associated with this increased risk. In preclinical studies and clinical trials, ospemifene has been shown to exert positive effects on the vaginal epithelium and minimal effects on the endometrium.

Steven R. Goldstein, MD, from New York University School of Medicine, and colleagues set out to determine the endometrial safety of ospemifene in six Phase 2/3 clinical trials of postemenopausal women with up to 52 weeks of exposure to ospemifene 60 mg/day versus placebo.

Endometrial safety of the study drug was assessed in a total of 1,349 women with an intact uterus (851 in the ospemifene group vs 543 in the placebo group).

Results
Endometrial biopsies obtained at 52 weeks revealed a rate of endometrial hyperplasia of 0.3%.

Of 342 biopsied women, “there was a single case of a woman with simple hyperplasia,” says Dr. Goldstein. “She was 52 years old, had become menopausal at age 49 and had been taking hormone therapy for about 2 years before entering the trial. After 4 months of ospemifene, she had an episode of bleeding and was diagnosed with proliferative endometrium. The study drug was stopped with a plan to follow up in 3 months; 89 days later she had another episode of bleeding and was diagnosed with simple hyperplasia. She was treated with a single course of progestogen, the hyperplasia resolved, and then she was noted to have a benign polyp.”

No complex hyperplasias or carcinomas were found.

Ospemifene participants with histologic findings other than inactive, atrophic, or insufficient was 3.5% at 52 weeks, and this finding was similar to baseline endometrial biopsy results for placebo (4.0%).

The incidence of active and disordered type endometrial proliferation was less than 1% of participants treated with ospemifene. The vaginal bleeding incidence was similar in the treatment and placebo groups.

“This data tells me that this drug is clearly acting like its cousin raloxifene in the uterus, with virtually no active proliferation and no true hyperplasia. The FDA guidance for any of these products is less than 1% hyperplasia in 1 year, and there was a single case out of 342 biopsies, says Dr. Goldstein.

MORE NEWS and HIGHLIGHTS from ACOG's 2014 ANNUAL CLINICAL MEETING
Survey: Most average-risk pregnant women preferred NIPT to invasive testing

Adding infertility assessment and treatment to your practice

Delivery notes after shoulder dystocia often lack critical elements

Why it’s important to open the sexual health dialogue

The use of power morcellation to remove the uterus or uterine tumors during hysterectomy and myomectomy may be riskier than many have thought. That’s the conclusion reached by the US Food and Drug Administration (FDA) in a safety communication issued April 17, 2014. In its communication, the FDA “discouraged” use of power morcellation during hysterectomy and myomectomy. Shortly afterward, Brigham and Women’s and Massachusetts General hospitals in Boston banned power morcellation in all hysterectomy and myomectomy procedures. The hospitals may resume power morcellation at some future date using a containment system, pending guidance from the Institutional Review Board.

Robert L. Barbieri, MD, who is chair of obstetrics and gynecology at Brigham and Women’s Hospital, recently wrote about this concern for OBG Management in his capacity as editor in chief of the journal.

“When used to treat tumors presumed to be fibroids, open power morcellation [without a containment system] is associated with an increased risk of disper­sing benign myoma tissue and occult malignant leiomyosarcoma tissue throughout the abdominal cavity,” he wrote.¹ “Dispersion of benign myoma tissue may result in the growth of fibroids on the peritoneal surface, omentum, and bowel, causing abdominal and pelvic pain and necessitating reoperation. Dispersion of leiomyosarcoma tissue throughout the abdominal cavity may result in a Stage I cancer being upstaged to a Stage IV malignancy, requiring additional surgery and chemotherapy. In cases in which open power morcellation causes the upstaging of a leiomyosarcoma, the death rate is increased.”¹

The two Boston hospitals are not the only institutions reconsidering the use of power morcellation. Temple University Hospital in Philadelphia banned use of the procedure without a containment system in late February 2014.

And in December 2013, the Society of Gynecologic Oncology issued a position statement on the issue, which said, “power morcellation or other techniques that cut up the uterus in the abdomen have the potential to disseminate an otherwise contained malignancy throughout the abdominal cavity. For this reason, the Society of Gynecologic Oncology (SGO) asserts that it is generally contraindicated in the presence of documented or highly suspected malignancy, and may be inadvisable in premalignant conditions or risk-reducing surgery.”²

For its part, at the time of this writing, the AAGL, previously known as the American Association of Gynecologic Laparoscopists, “is reviewing the scientific evidence and best practices reported by our members,” stated an article in its Association News. “We recognize that, in rare cases, the use of power morcellators can lead to the dissemination of an occult malignancy of endometrial or myometrial origin, and also to dissemination of benign morcellated tissues. We encourage our members to fully research and understand the risks of power morcellation and to learn more about when alternative methods of tissue extraction may be appropriate.”³

FDA STOPS SHORT OF A BAN
In laying out its concerns, the FDA stopped short of an outright ban on power morcellation. Instead, it stated that, “based on currently available information, the FDA discourages the use of laparoscopic power morcellation during hysterectomy or myomectomy for uterine fibroids.”⁴

It also noted that approximately 1 in 350 women “undergoing hysterectomy or myomectomy for the treatment of fibroids is found to have an unsuspected uterine sarcoma.”⁴

Among its recommendations for health-care providers:

• avoid laparoscopic uterine power morcellation in women with suspected or known uterine cancer
• carefully consider all available treatment options for women with symptomatic uterine fibroids
• thoroughly discuss the benefits and risks of all treatments with patients.⁴

The FDA also noted that “some clinicians and medical institutions now advocate using a specimen ‘bag’ during morcellation in an attempt to contain the uterine tissue and minimize the risk of spread in the abdomen and pelvis.”⁴

ACOG HAS YET TO WEIGH IN
At the time of this writing, the most recent committee opinion on choosing a hysterectomy route from the American College of Obstetricians and Gynecologists (ACOG) to touch on the issue states that, “the decision to perform a hysterectomy via [minimally invasive surgery] (with or without morcellation) is based on a patient evaluation, including the patient’s history and general health, tests, and procedures, such as pre-surgery biopsies. The evaluation and diagnostic process also provides an opportunity to identify any cautions or contraindications, such as finding a gynecological cancer.”⁵

FILLING THE TECHNOLOGY GAP
Now that power morcellation appears to be receding as an option for minimally invasive gynecologic surgeons, what is the best approach?

In its position statement, the SGO recommends that, “Patients being considered for minimally invasive surgery performed by laparoscopic or robotic techniques who might require intracorporeal morcellation should be appropriately evaluated for the possibility of coexisting uterine or cervical malignancy. Other options to intracorporeal morcellation include removing the uterus through a mini-laparotomy or morcellating the uterus inside a laparoscopic bag.”²

K. Anthony Shibley, MD, a Minneapolis-area ObGyn, has developed a novel strategy to prevent tissue dissemination during open power morcellation, which is demonstrated in a video at obgmanagement.com. Similarly, Ceana Nezhat, MD, and Erica Dun, MD, demonstrate enclosed vaginal morcellation of a large uterus. Click here to access these and other features in the Morcellation Topic Collection.

WE WANT TO HEAR FROM YOU!
Drop us a line and let us know what you think about this or other current articles, which topics you'd like to see covered in future issues, and what challenges you face in daily practice. Tell us what you think by emailing us at: [email protected] Please include your name, and the city and state in which you practice.

The use of power morcellation to remove the uterus or uterine tumors during hysterectomy and myomectomy may be riskier than many have thought. That’s the conclusion reached by the US Food and Drug Administration (FDA) in a safety communication issued April 17, 2014. In its communication, the FDA “discouraged” use of power morcellation during hysterectomy and myomectomy. Shortly afterward, Brigham and Women’s and Massachusetts General hospitals in Boston banned power morcellation in all hysterectomy and myomectomy procedures. The hospitals may resume power morcellation at some future date using a containment system, pending guidance from the Institutional Review Board.

Robert L. Barbieri, MD, who is chair of obstetrics and gynecology at Brigham and Women’s Hospital, recently wrote about this concern for OBG Management in his capacity as editor in chief of the journal.

“When used to treat tumors presumed to be fibroids, open power morcellation [without a containment system] is associated with an increased risk of disper­sing benign myoma tissue and occult malignant leiomyosarcoma tissue throughout the abdominal cavity,” he wrote.¹ “Dispersion of benign myoma tissue may result in the growth of fibroids on the peritoneal surface, omentum, and bowel, causing abdominal and pelvic pain and necessitating reoperation. Dispersion of leiomyosarcoma tissue throughout the abdominal cavity may result in a Stage I cancer being upstaged to a Stage IV malignancy, requiring additional surgery and chemotherapy. In cases in which open power morcellation causes the upstaging of a leiomyosarcoma, the death rate is increased.”¹

The two Boston hospitals are not the only institutions reconsidering the use of power morcellation. Temple University Hospital in Philadelphia banned use of the procedure without a containment system in late February 2014.

And in December 2013, the Society of Gynecologic Oncology issued a position statement on the issue, which said, “power morcellation or other techniques that cut up the uterus in the abdomen have the potential to disseminate an otherwise contained malignancy throughout the abdominal cavity. For this reason, the Society of Gynecologic Oncology (SGO) asserts that it is generally contraindicated in the presence of documented or highly suspected malignancy, and may be inadvisable in premalignant conditions or risk-reducing surgery.”²

For its part, at the time of this writing, the AAGL, previously known as the American Association of Gynecologic Laparoscopists, “is reviewing the scientific evidence and best practices reported by our members,” stated an article in its Association News. “We recognize that, in rare cases, the use of power morcellators can lead to the dissemination of an occult malignancy of endometrial or myometrial origin, and also to dissemination of benign morcellated tissues. We encourage our members to fully research and understand the risks of power morcellation and to learn more about when alternative methods of tissue extraction may be appropriate.”³

FDA STOPS SHORT OF A BAN
In laying out its concerns, the FDA stopped short of an outright ban on power morcellation. Instead, it stated that, “based on currently available information, the FDA discourages the use of laparoscopic power morcellation during hysterectomy or myomectomy for uterine fibroids.”⁴

It also noted that approximately 1 in 350 women “undergoing hysterectomy or myomectomy for the treatment of fibroids is found to have an unsuspected uterine sarcoma.”⁴

Among its recommendations for health-care providers:

• avoid laparoscopic uterine power morcellation in women with suspected or known uterine cancer
• carefully consider all available treatment options for women with symptomatic uterine fibroids
• thoroughly discuss the benefits and risks of all treatments with patients.⁴

The FDA also noted that “some clinicians and medical institutions now advocate using a specimen ‘bag’ during morcellation in an attempt to contain the uterine tissue and minimize the risk of spread in the abdomen and pelvis.”⁴

ACOG HAS YET TO WEIGH IN
At the time of this writing, the most recent committee opinion on choosing a hysterectomy route from the American College of Obstetricians and Gynecologists (ACOG) to touch on the issue states that, “the decision to perform a hysterectomy via [minimally invasive surgery] (with or without morcellation) is based on a patient evaluation, including the patient’s history and general health, tests, and procedures, such as pre-surgery biopsies. The evaluation and diagnostic process also provides an opportunity to identify any cautions or contraindications, such as finding a gynecological cancer.”⁵

FILLING THE TECHNOLOGY GAP
Now that power morcellation appears to be receding as an option for minimally invasive gynecologic surgeons, what is the best approach?

In its position statement, the SGO recommends that, “Patients being considered for minimally invasive surgery performed by laparoscopic or robotic techniques who might require intracorporeal morcellation should be appropriately evaluated for the possibility of coexisting uterine or cervical malignancy. Other options to intracorporeal morcellation include removing the uterus through a mini-laparotomy or morcellating the uterus inside a laparoscopic bag.”²

K. Anthony Shibley, MD, a Minneapolis-area ObGyn, has developed a novel strategy to prevent tissue dissemination during open power morcellation, which is demonstrated in a video at obgmanagement.com. Similarly, Ceana Nezhat, MD, and Erica Dun, MD, demonstrate enclosed vaginal morcellation of a large uterus. Click here to access these and other features in the Morcellation Topic Collection.

WE WANT TO HEAR FROM YOU!
Drop us a line and let us know what you think about this or other current articles, which topics you'd like to see covered in future issues, and what challenges you face in daily practice. Tell us what you think by emailing us at: [email protected] Please include your name, and the city and state in which you practice.

The use of power morcellation to remove the uterus or uterine tumors during hysterectomy and myomectomy may be riskier than many have thought. That’s the conclusion reached by the US Food and Drug Administration (FDA) in a safety communication issued April 17, 2014. In its communication, the FDA “discouraged” use of power morcellation during hysterectomy and myomectomy. Shortly afterward, Brigham and Women’s and Massachusetts General hospitals in Boston banned power morcellation in all hysterectomy and myomectomy procedures. The hospitals may resume power morcellation at some future date using a containment system, pending guidance from the Institutional Review Board.

Robert L. Barbieri, MD, who is chair of obstetrics and gynecology at Brigham and Women’s Hospital, recently wrote about this concern for OBG Management in his capacity as editor in chief of the journal.

“When used to treat tumors presumed to be fibroids, open power morcellation [without a containment system] is associated with an increased risk of disper­sing benign myoma tissue and occult malignant leiomyosarcoma tissue throughout the abdominal cavity,” he wrote.¹ “Dispersion of benign myoma tissue may result in the growth of fibroids on the peritoneal surface, omentum, and bowel, causing abdominal and pelvic pain and necessitating reoperation. Dispersion of leiomyosarcoma tissue throughout the abdominal cavity may result in a Stage I cancer being upstaged to a Stage IV malignancy, requiring additional surgery and chemotherapy. In cases in which open power morcellation causes the upstaging of a leiomyosarcoma, the death rate is increased.”¹

The two Boston hospitals are not the only institutions reconsidering the use of power morcellation. Temple University Hospital in Philadelphia banned use of the procedure without a containment system in late February 2014.

And in December 2013, the Society of Gynecologic Oncology issued a position statement on the issue, which said, “power morcellation or other techniques that cut up the uterus in the abdomen have the potential to disseminate an otherwise contained malignancy throughout the abdominal cavity. For this reason, the Society of Gynecologic Oncology (SGO) asserts that it is generally contraindicated in the presence of documented or highly suspected malignancy, and may be inadvisable in premalignant conditions or risk-reducing surgery.”²

For its part, at the time of this writing, the AAGL, previously known as the American Association of Gynecologic Laparoscopists, “is reviewing the scientific evidence and best practices reported by our members,” stated an article in its Association News. “We recognize that, in rare cases, the use of power morcellators can lead to the dissemination of an occult malignancy of endometrial or myometrial origin, and also to dissemination of benign morcellated tissues. We encourage our members to fully research and understand the risks of power morcellation and to learn more about when alternative methods of tissue extraction may be appropriate.”³

FDA STOPS SHORT OF A BAN
In laying out its concerns, the FDA stopped short of an outright ban on power morcellation. Instead, it stated that, “based on currently available information, the FDA discourages the use of laparoscopic power morcellation during hysterectomy or myomectomy for uterine fibroids.”⁴

It also noted that approximately 1 in 350 women “undergoing hysterectomy or myomectomy for the treatment of fibroids is found to have an unsuspected uterine sarcoma.”⁴

Among its recommendations for health-care providers:

• avoid laparoscopic uterine power morcellation in women with suspected or known uterine cancer
• carefully consider all available treatment options for women with symptomatic uterine fibroids
• thoroughly discuss the benefits and risks of all treatments with patients.⁴

The FDA also noted that “some clinicians and medical institutions now advocate using a specimen ‘bag’ during morcellation in an attempt to contain the uterine tissue and minimize the risk of spread in the abdomen and pelvis.”⁴

ACOG HAS YET TO WEIGH IN
At the time of this writing, the most recent committee opinion on choosing a hysterectomy route from the American College of Obstetricians and Gynecologists (ACOG) to touch on the issue states that, “the decision to perform a hysterectomy via [minimally invasive surgery] (with or without morcellation) is based on a patient evaluation, including the patient’s history and general health, tests, and procedures, such as pre-surgery biopsies. The evaluation and diagnostic process also provides an opportunity to identify any cautions or contraindications, such as finding a gynecological cancer.”⁵

FILLING THE TECHNOLOGY GAP
Now that power morcellation appears to be receding as an option for minimally invasive gynecologic surgeons, what is the best approach?

In its position statement, the SGO recommends that, “Patients being considered for minimally invasive surgery performed by laparoscopic or robotic techniques who might require intracorporeal morcellation should be appropriately evaluated for the possibility of coexisting uterine or cervical malignancy. Other options to intracorporeal morcellation include removing the uterus through a mini-laparotomy or morcellating the uterus inside a laparoscopic bag.”²

K. Anthony Shibley, MD, a Minneapolis-area ObGyn, has developed a novel strategy to prevent tissue dissemination during open power morcellation, which is demonstrated in a video at obgmanagement.com. Similarly, Ceana Nezhat, MD, and Erica Dun, MD, demonstrate enclosed vaginal morcellation of a large uterus. Click here to access these and other features in the Morcellation Topic Collection.

WE WANT TO HEAR FROM YOU!
Drop us a line and let us know what you think about this or other current articles, which topics you'd like to see covered in future issues, and what challenges you face in daily practice. Tell us what you think by emailing us at: [email protected] Please include your name, and the city and state in which you practice.

Advances in cervical cancer screening continue apace. We are fortunate that these advances are based on a substantial amount of high-quality prospective evidence. Many of these advances are designed to target the women who have clinically relevant disease while minimizing harm and anxiety caused by unnecessary procedures related to cervical screening test abnormalities that have little clinical relevance.

With clinicians being regularly judged on performance and outcomes, adoption of advances and new guidelines should be ­considered relatively quickly by women’s health providers.

In this article, I focus on two significant advances of the past (and coming) year:

• recent application and unanimous approval by a Food and Drug Administration (FDA) expert panel for the use of the cobas human papillomavirus (HPV) DNA test as a primary cervical cancer screen
• the latest update of guidelines on the management of abnormal cervical screening tests from the American Society for Colposcopy and Cervical Pathology (ASCCP).

cobas HPV TEST IS POISED FOR FDA APPROVAL AS A PRIMARY SCREEN FOR CERVICAL CANCER

Wright TC Jr, Stoler MH, Behrens CM, Apple R, Derion T, Wright TL. The ATHENA human papillomavirus study: design, methods, and baseline results. Am J Obstet Gynecol. 2012;206(1):46.e1–e11.

An FDA expert panel unanimously approved the cobas (Roche Molecular Diagnostics; Pleasanton, California) HPV DNA test on March 12, 2014. The FDA will decide on potential approval within the coming months. Although the FDA sometimes reaches a different decision from one of its advisory committees when it comes to a final vote on a product or device, most often the FDA concurs with the committee’s judgment. Therefore, approval of the cobas HPV test as a primary screen is likely.

Related article: FDA Advisory Committee recommends HPV test as primary screening tool for cervical cancer  Deborah Reale (News for your Practice, March 2014)

The cobas HPV test yields a pooled result for 12 high-risk HPV types (hrHPV 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68), as well as individual results for types 16 and 18; it also has an internal control for specimen adequacy. HPV 16 and 18 account for roughly 70% of all cases of cervical cancer, and infection with both types are known to place women at high risk for having clinically relevant disease—more so than the other hrHPV types.

COMMITTEE REVIEWED DATA FROM ATHENA IN VOTING FOR APPROVAL
In considering the cobas HPV test, the advisory committee reviewed data from the Addressing the Need for Advanced HPV Diagnostics (ATHENA) trial, a prospective, multicenter, US-based study of 47,208 women aged 21 and older. These women were recruited at the time of undergoing routine screening for cervical cancer; only 2.6% had been vaccinated against HPV. All were screened by liquid-based cytology and an HPV test. Those who had abnormal cytology or a positive test for a high-risk HPV type underwent colposcopy, as did a randomly selected group of women aged 25 or older who tested negative on both tests.

The prevalence of abnormal findings was:

• 7.1% for liquid-based cytology
• 12.6% for pooled high-risk HPV
• 2.8% for HPV 16
• 1.0% for HPV 18.

As expected, cytologic abnormalities and infection with high-risk HPV types declined with increasing age. The adjusted prevalence of cervical intraepithelial neoplasia (CIN) grade 2 or higher in women aged 25 to 34 years was 2.3%; it declined to 1.5% among women older than age 34. Of note, approximately 500,000 US women are given a diagnosis of CIN 2 or CIN 3 each year in the United States.

WHY ATHENA IS IMPORTANT
This US-based trial was designed to assess the medical utility of pooled high-risk HPV DNA in addition to genotyping for HPV 16 and 18 in three populations:

• women aged 21 and older with a cytologic finding of atypical squamous cells of undetermined significance (ASC-US)
• women aged 30 and older with normal cytology
• women aged 25 and older in the overall screening population with any cytologic finding.

Investigators were particularly interested in the use of the HPV test as:

• a triage for women with abnormal cytologic findings
• an adjunct to guide clinical management of women with negative cytology results
• a potential front-line test in the screening of women aged 25 and older.

Related article: Endometrial cancer update: The move toward personalized cancer care  Lindsay M. Kuroki, MD, and David G. Mutch, MD (October 2013)

The participants of the ATHENA trial were representative of women undergoing screening for cervical cancer in the United States—both in terms of demographics and in the distribution of cytologic findings. For example, recent US census data indicate that the female population is 79% white, 13% black, and 16% Hispanic or Latino—figures comparable to the breakdown of race/ethnicity in the ATHENA trial.

The trial was conducted in a baseline phase (published in 2012) and a 3-year follow-up phase (not yet published). The 3-year data were reviewed by the FDA advisory committee during its consideration of the cobas HPV test as a primary screen.

DESPITE PROBABLE APPROVAL, INCREMENTAL CHANGE IS LIKELY
Although a move to the HPV test as the primary screen is a definite paradigm shift for what has been cytology-based screening since the initiation of cervical cancer screening, the changeover from primary cytology to primary HPV testing likely will be slow. It will require education of clinicians as well as patients, and a shift in many internal procedures for pathology laboratories.

The ATHENA trial also leaves some intriguing questions unanswered:

• How do we transition women into the new screening strategy? Many women today still undergo cytology screening with reflex HPV testing, as appropriate, and an increasing number of women aged 30 and older undergo cotesting with both cytology and HPV testing. When should they begin screening in a primary HPV testing setting? And what screening intervals will be recommended? If a woman already has been screened with cytology, how should she transition into and at what interval should she begin primary HPV screening?
• How should we manage women’s care after the first round of primary HPV testing? The ATHENA trial so far only has outcomes data after one round of HPV testing. While some data are available from Europe, we do not know what happens after two or three rounds of screening with primary HPV testing in a large US-based cohort. We clearly will be identifying and treating many women with preinvasive disease from screening after one round of testing, at a rate likely higher than with cytology alone—a good thing. We also likely will be reducing the number of unnecessary colposcopies for cytology that are not related to hrHPV.

What this EVIDENCE means for practice
Screening women using the cobas HPV test as a primary screen will require considerable education of providers and patients to explain how this change will affect how a woman will be managed after being screened for cervical cancer. Though much remains to be determined about this new cervical cancer screening paradigm (eg, logistics, timing, use of secondary tests), it should reduce the number of screening tests and colposcopies necessary to detect clinically relevant disease.

UPDATED ASCCP GUIDELINES EMPHASIZE EQUAL MANAGEMENT FOR EQUAL RISK

Massad LS, Einstein MH, Huh WK, et al; 2012 ASCCP Consensus Guidelines Conference. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis. 2013;17(5 Suppl 1):S1–S27.

In formulating this latest set of guidelines for the management of abnormal cervical cancer screening tests and cancer precursors, the ASCCP led a conference consisting of scientific stakeholders to perform a comprehensive review of the literature. Also, with study investigators at Kaiser Permanente Northern California (KPNC) and the National Cancer Institute, the guidelines panel also modeled and assessed data on risk after abnormal tests from almost 1.4 million women followed over 8 years in the KPNC Medical Care Plan—this cohort has provided us with “big data.”

The sheer size of the Kaiser Permanente population made it possible for the ASCCP-led panel to validate its previous guidelines or to modify them, where needed. It also made risk-based stratification possible for even rare abnormalities and clinical outcomes.

Although findings from the KPNC population may not be fully generalizable to the US population as a whole, they enhance our understanding of the optimal management of abnormal cervical cancer screening tests and cancer precursors. More widely dispersed study cohorts on a similar scale in the United States are unlikely in the near future.

Related article: Update on cervical disease  Mark H. Einstein, MD, MS, and J. Thomas Cox, MD (May 2013)

SEVERAL SIGNIFICANT MODIFICATIONS
Although the ASCCP reaffirmed most elements of its 2006 consensus management guidelines, it did make a number of changes:

• Women who have ASC-US cytology but test HPV-negative now should be followed with cotesting at 3 years rather than 5 years before they return to routine screening.
• Women near age 65 who have a negative finding on ASC-US cytology and HPV testing should not exit screening.
• Women who have ASC-US cytology and test HPV-positive should go to immediate colposcopy, regardless of hrHPV results, including genotyping.
• Women who test positive for HPV 16 or 18 but have negative cytology should undergo immediate colposcopy.
• Women aged 21 to 24 years should be managed as conservatively and minimally invasively as possible, especially when an abnormality is minor.
• Endocervical curettage reported as CIN 1 should be managed as CIN 1, not as a positive endocervical curettage.
• When a cytologic sample is unsatisfactory, sampling usually should be repeated, even when HPV cotesting results are known. However, negative cytology that lacks sufficient endocervical cells or a transformation zone component usually can be managed without frequent follow-up.

Related article: New cervical Ca screening guidelines recommend less frequent assessment  Janelle Yates (News for your Practice; April 2012)

EQUAL MANAGEMENT SHOULD BE PERFORMED FOR ABNORMAL TESTS THAT INDICATE EQUAL RISK
The ASCCP-led management panel unanimously agreed to several basic assumptions in formulating the updated guidelines. For example, they concurred that achieving zero risk for cancer is impossible and that attempts to achieve zero risk (which typically means more frequent testing) may cause harm. They also cited the 2011 American Cancer Society/ASCCP/American Society for Clinical Pathology consensus screening document, which stated: “Optimal prevention strategies should identify those HPV-related abnormalities likely to progress to invasive cancers while avoiding destructive treatment of abnormalities not destined to become cancerous.”¹

The panel also agreed that CIN 3+ is a “reasonable proxy for cancer risk.” When ­calculating risk, the KPNC data were modeled for all combinations of cytology and HPV testing, using CIN 3+ for many of the outcomes, and when outcomes were rare, using CIN 2+. The theme of equal management for equal risk was the rationale behind the management approaches detailed in the TABLE. Risks were deemed to be low and return to normal screening was recommended when the risks were similar to the rate of CIN 3+ 3 years after negative cytology or 5 years after negative cotesting. However, immediate colposcopy was recommended when the 5-year risk of CIN 3+ for the combination of cytology and hrHPV testing, when indicated, exceeded 5%. A 6-month to 12-month return (intermediate risk) is indicated with a risk of CIN3+ of 2% to 5%.

An emphasis on avoiding harms
Abnormal findings at the time of cervical cancer screening can lead to a number of harms for the patient, including anxiety and emotional distress, particularly when colposcopy is necessary, as well as time lost from home and work life. For this reason, the guidelines panel emphasized that colposcopy and other interventions should be avoided when the risk of CIN 3+ is low and when the cervical screening abnormalities are likely to resolve without treatment.

However, women who experience postcoital bleeding, unexplained abnormal vaginal bleeding, pelvic pain, abnormal discharge, or a visible lesion should be managed promptly on an individualized basis.

Long-term effects of HPV vaccination are unknown
Among the areas that remain to be addressed are the unknown effects of widespread prophylactic HPV vaccination over the long term. We also lack full understanding of whether and how HPV vaccination will alter the incidence and management of cytologic and histologic abnormalities. Given the low rates of vaccination against HPV in the United States at present, this will need to be re-evaluated in the future.

What this EVIDENCE means for practice
The updated ASCCP guidelines are inherently complex, but their complexity arises from a large body of high-quality prospective data from a large population of women. Equal risk should result in equal management of cervical screening test abnormalities. Practitioners need not feel obligated to memorize the guidelines, owing to the availability of algorithms for specific findings in specific populations at the ASCCP Web site (www.asccp.org/consensus2012). Apps also are available for the iPhone, iPad, and Android.

WE WANT TO HEAR FROM YOU!
Share your thoughts on this article or on any topic relevant to ObGyns and women’s health practitioners. Tell us which topics you’d like to see covered in future issues, and what challenges you face in daily practice. We will consider publishing your letter and in a future issue. Send your letter to: [email protected] Please include the city and state in which you practice. Stay in touch! Your feedback is important to us!

Advances in cervical cancer screening continue apace. We are fortunate that these advances are based on a substantial amount of high-quality prospective evidence. Many of these advances are designed to target the women who have clinically relevant disease while minimizing harm and anxiety caused by unnecessary procedures related to cervical screening test abnormalities that have little clinical relevance.

With clinicians being regularly judged on performance and outcomes, adoption of advances and new guidelines should be ­considered relatively quickly by women’s health providers.

In this article, I focus on two significant advances of the past (and coming) year:

• recent application and unanimous approval by a Food and Drug Administration (FDA) expert panel for the use of the cobas human papillomavirus (HPV) DNA test as a primary cervical cancer screen
• the latest update of guidelines on the management of abnormal cervical screening tests from the American Society for Colposcopy and Cervical Pathology (ASCCP).

cobas HPV TEST IS POISED FOR FDA APPROVAL AS A PRIMARY SCREEN FOR CERVICAL CANCER

Wright TC Jr, Stoler MH, Behrens CM, Apple R, Derion T, Wright TL. The ATHENA human papillomavirus study: design, methods, and baseline results. Am J Obstet Gynecol. 2012;206(1):46.e1–e11.

An FDA expert panel unanimously approved the cobas (Roche Molecular Diagnostics; Pleasanton, California) HPV DNA test on March 12, 2014. The FDA will decide on potential approval within the coming months. Although the FDA sometimes reaches a different decision from one of its advisory committees when it comes to a final vote on a product or device, most often the FDA concurs with the committee’s judgment. Therefore, approval of the cobas HPV test as a primary screen is likely.

Related article: FDA Advisory Committee recommends HPV test as primary screening tool for cervical cancer  Deborah Reale (News for your Practice, March 2014)

The cobas HPV test yields a pooled result for 12 high-risk HPV types (hrHPV 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68), as well as individual results for types 16 and 18; it also has an internal control for specimen adequacy. HPV 16 and 18 account for roughly 70% of all cases of cervical cancer, and infection with both types are known to place women at high risk for having clinically relevant disease—more so than the other hrHPV types.

COMMITTEE REVIEWED DATA FROM ATHENA IN VOTING FOR APPROVAL
In considering the cobas HPV test, the advisory committee reviewed data from the Addressing the Need for Advanced HPV Diagnostics (ATHENA) trial, a prospective, multicenter, US-based study of 47,208 women aged 21 and older. These women were recruited at the time of undergoing routine screening for cervical cancer; only 2.6% had been vaccinated against HPV. All were screened by liquid-based cytology and an HPV test. Those who had abnormal cytology or a positive test for a high-risk HPV type underwent colposcopy, as did a randomly selected group of women aged 25 or older who tested negative on both tests.

The prevalence of abnormal findings was:

• 7.1% for liquid-based cytology
• 12.6% for pooled high-risk HPV
• 2.8% for HPV 16
• 1.0% for HPV 18.

As expected, cytologic abnormalities and infection with high-risk HPV types declined with increasing age. The adjusted prevalence of cervical intraepithelial neoplasia (CIN) grade 2 or higher in women aged 25 to 34 years was 2.3%; it declined to 1.5% among women older than age 34. Of note, approximately 500,000 US women are given a diagnosis of CIN 2 or CIN 3 each year in the United States.

WHY ATHENA IS IMPORTANT
This US-based trial was designed to assess the medical utility of pooled high-risk HPV DNA in addition to genotyping for HPV 16 and 18 in three populations:

• women aged 21 and older with a cytologic finding of atypical squamous cells of undetermined significance (ASC-US)
• women aged 30 and older with normal cytology
• women aged 25 and older in the overall screening population with any cytologic finding.

Investigators were particularly interested in the use of the HPV test as:

• a triage for women with abnormal cytologic findings
• an adjunct to guide clinical management of women with negative cytology results
• a potential front-line test in the screening of women aged 25 and older.

Related article: Endometrial cancer update: The move toward personalized cancer care  Lindsay M. Kuroki, MD, and David G. Mutch, MD (October 2013)

The participants of the ATHENA trial were representative of women undergoing screening for cervical cancer in the United States—both in terms of demographics and in the distribution of cytologic findings. For example, recent US census data indicate that the female population is 79% white, 13% black, and 16% Hispanic or Latino—figures comparable to the breakdown of race/ethnicity in the ATHENA trial.

The trial was conducted in a baseline phase (published in 2012) and a 3-year follow-up phase (not yet published). The 3-year data were reviewed by the FDA advisory committee during its consideration of the cobas HPV test as a primary screen.

DESPITE PROBABLE APPROVAL, INCREMENTAL CHANGE IS LIKELY
Although a move to the HPV test as the primary screen is a definite paradigm shift for what has been cytology-based screening since the initiation of cervical cancer screening, the changeover from primary cytology to primary HPV testing likely will be slow. It will require education of clinicians as well as patients, and a shift in many internal procedures for pathology laboratories.

The ATHENA trial also leaves some intriguing questions unanswered:

• How do we transition women into the new screening strategy? Many women today still undergo cytology screening with reflex HPV testing, as appropriate, and an increasing number of women aged 30 and older undergo cotesting with both cytology and HPV testing. When should they begin screening in a primary HPV testing setting? And what screening intervals will be recommended? If a woman already has been screened with cytology, how should she transition into and at what interval should she begin primary HPV screening?
• How should we manage women’s care after the first round of primary HPV testing? The ATHENA trial so far only has outcomes data after one round of HPV testing. While some data are available from Europe, we do not know what happens after two or three rounds of screening with primary HPV testing in a large US-based cohort. We clearly will be identifying and treating many women with preinvasive disease from screening after one round of testing, at a rate likely higher than with cytology alone—a good thing. We also likely will be reducing the number of unnecessary colposcopies for cytology that are not related to hrHPV.

What this EVIDENCE means for practice
Screening women using the cobas HPV test as a primary screen will require considerable education of providers and patients to explain how this change will affect how a woman will be managed after being screened for cervical cancer. Though much remains to be determined about this new cervical cancer screening paradigm (eg, logistics, timing, use of secondary tests), it should reduce the number of screening tests and colposcopies necessary to detect clinically relevant disease.

UPDATED ASCCP GUIDELINES EMPHASIZE EQUAL MANAGEMENT FOR EQUAL RISK

Massad LS, Einstein MH, Huh WK, et al; 2012 ASCCP Consensus Guidelines Conference. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis. 2013;17(5 Suppl 1):S1–S27.

In formulating this latest set of guidelines for the management of abnormal cervical cancer screening tests and cancer precursors, the ASCCP led a conference consisting of scientific stakeholders to perform a comprehensive review of the literature. Also, with study investigators at Kaiser Permanente Northern California (KPNC) and the National Cancer Institute, the guidelines panel also modeled and assessed data on risk after abnormal tests from almost 1.4 million women followed over 8 years in the KPNC Medical Care Plan—this cohort has provided us with “big data.”

The sheer size of the Kaiser Permanente population made it possible for the ASCCP-led panel to validate its previous guidelines or to modify them, where needed. It also made risk-based stratification possible for even rare abnormalities and clinical outcomes.

Although findings from the KPNC population may not be fully generalizable to the US population as a whole, they enhance our understanding of the optimal management of abnormal cervical cancer screening tests and cancer precursors. More widely dispersed study cohorts on a similar scale in the United States are unlikely in the near future.

Related article: Update on cervical disease  Mark H. Einstein, MD, MS, and J. Thomas Cox, MD (May 2013)

SEVERAL SIGNIFICANT MODIFICATIONS
Although the ASCCP reaffirmed most elements of its 2006 consensus management guidelines, it did make a number of changes:

• Women who have ASC-US cytology but test HPV-negative now should be followed with cotesting at 3 years rather than 5 years before they return to routine screening.
• Women near age 65 who have a negative finding on ASC-US cytology and HPV testing should not exit screening.
• Women who have ASC-US cytology and test HPV-positive should go to immediate colposcopy, regardless of hrHPV results, including genotyping.
• Women who test positive for HPV 16 or 18 but have negative cytology should undergo immediate colposcopy.
• Women aged 21 to 24 years should be managed as conservatively and minimally invasively as possible, especially when an abnormality is minor.
• Endocervical curettage reported as CIN 1 should be managed as CIN 1, not as a positive endocervical curettage.
• When a cytologic sample is unsatisfactory, sampling usually should be repeated, even when HPV cotesting results are known. However, negative cytology that lacks sufficient endocervical cells or a transformation zone component usually can be managed without frequent follow-up.

Related article: New cervical Ca screening guidelines recommend less frequent assessment  Janelle Yates (News for your Practice; April 2012)

EQUAL MANAGEMENT SHOULD BE PERFORMED FOR ABNORMAL TESTS THAT INDICATE EQUAL RISK
The ASCCP-led management panel unanimously agreed to several basic assumptions in formulating the updated guidelines. For example, they concurred that achieving zero risk for cancer is impossible and that attempts to achieve zero risk (which typically means more frequent testing) may cause harm. They also cited the 2011 American Cancer Society/ASCCP/American Society for Clinical Pathology consensus screening document, which stated: “Optimal prevention strategies should identify those HPV-related abnormalities likely to progress to invasive cancers while avoiding destructive treatment of abnormalities not destined to become cancerous.”¹

The panel also agreed that CIN 3+ is a “reasonable proxy for cancer risk.” When ­calculating risk, the KPNC data were modeled for all combinations of cytology and HPV testing, using CIN 3+ for many of the outcomes, and when outcomes were rare, using CIN 2+. The theme of equal management for equal risk was the rationale behind the management approaches detailed in the TABLE. Risks were deemed to be low and return to normal screening was recommended when the risks were similar to the rate of CIN 3+ 3 years after negative cytology or 5 years after negative cotesting. However, immediate colposcopy was recommended when the 5-year risk of CIN 3+ for the combination of cytology and hrHPV testing, when indicated, exceeded 5%. A 6-month to 12-month return (intermediate risk) is indicated with a risk of CIN3+ of 2% to 5%.

An emphasis on avoiding harms
Abnormal findings at the time of cervical cancer screening can lead to a number of harms for the patient, including anxiety and emotional distress, particularly when colposcopy is necessary, as well as time lost from home and work life. For this reason, the guidelines panel emphasized that colposcopy and other interventions should be avoided when the risk of CIN 3+ is low and when the cervical screening abnormalities are likely to resolve without treatment.

However, women who experience postcoital bleeding, unexplained abnormal vaginal bleeding, pelvic pain, abnormal discharge, or a visible lesion should be managed promptly on an individualized basis.

Long-term effects of HPV vaccination are unknown
Among the areas that remain to be addressed are the unknown effects of widespread prophylactic HPV vaccination over the long term. We also lack full understanding of whether and how HPV vaccination will alter the incidence and management of cytologic and histologic abnormalities. Given the low rates of vaccination against HPV in the United States at present, this will need to be re-evaluated in the future.

What this EVIDENCE means for practice
The updated ASCCP guidelines are inherently complex, but their complexity arises from a large body of high-quality prospective data from a large population of women. Equal risk should result in equal management of cervical screening test abnormalities. Practitioners need not feel obligated to memorize the guidelines, owing to the availability of algorithms for specific findings in specific populations at the ASCCP Web site (www.asccp.org/consensus2012). Apps also are available for the iPhone, iPad, and Android.

WE WANT TO HEAR FROM YOU!
Share your thoughts on this article or on any topic relevant to ObGyns and women’s health practitioners. Tell us which topics you’d like to see covered in future issues, and what challenges you face in daily practice. We will consider publishing your letter and in a future issue. Send your letter to: [email protected] Please include the city and state in which you practice. Stay in touch! Your feedback is important to us!

Advances in cervical cancer screening continue apace. We are fortunate that these advances are based on a substantial amount of high-quality prospective evidence. Many of these advances are designed to target the women who have clinically relevant disease while minimizing harm and anxiety caused by unnecessary procedures related to cervical screening test abnormalities that have little clinical relevance.

With clinicians being regularly judged on performance and outcomes, adoption of advances and new guidelines should be ­considered relatively quickly by women’s health providers.

In this article, I focus on two significant advances of the past (and coming) year:

• recent application and unanimous approval by a Food and Drug Administration (FDA) expert panel for the use of the cobas human papillomavirus (HPV) DNA test as a primary cervical cancer screen
• the latest update of guidelines on the management of abnormal cervical screening tests from the American Society for Colposcopy and Cervical Pathology (ASCCP).

cobas HPV TEST IS POISED FOR FDA APPROVAL AS A PRIMARY SCREEN FOR CERVICAL CANCER

Wright TC Jr, Stoler MH, Behrens CM, Apple R, Derion T, Wright TL. The ATHENA human papillomavirus study: design, methods, and baseline results. Am J Obstet Gynecol. 2012;206(1):46.e1–e11.

An FDA expert panel unanimously approved the cobas (Roche Molecular Diagnostics; Pleasanton, California) HPV DNA test on March 12, 2014. The FDA will decide on potential approval within the coming months. Although the FDA sometimes reaches a different decision from one of its advisory committees when it comes to a final vote on a product or device, most often the FDA concurs with the committee’s judgment. Therefore, approval of the cobas HPV test as a primary screen is likely.

Related article: FDA Advisory Committee recommends HPV test as primary screening tool for cervical cancer  Deborah Reale (News for your Practice, March 2014)

The cobas HPV test yields a pooled result for 12 high-risk HPV types (hrHPV 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68), as well as individual results for types 16 and 18; it also has an internal control for specimen adequacy. HPV 16 and 18 account for roughly 70% of all cases of cervical cancer, and infection with both types are known to place women at high risk for having clinically relevant disease—more so than the other hrHPV types.

COMMITTEE REVIEWED DATA FROM ATHENA IN VOTING FOR APPROVAL
In considering the cobas HPV test, the advisory committee reviewed data from the Addressing the Need for Advanced HPV Diagnostics (ATHENA) trial, a prospective, multicenter, US-based study of 47,208 women aged 21 and older. These women were recruited at the time of undergoing routine screening for cervical cancer; only 2.6% had been vaccinated against HPV. All were screened by liquid-based cytology and an HPV test. Those who had abnormal cytology or a positive test for a high-risk HPV type underwent colposcopy, as did a randomly selected group of women aged 25 or older who tested negative on both tests.

The prevalence of abnormal findings was:

• 7.1% for liquid-based cytology
• 12.6% for pooled high-risk HPV
• 2.8% for HPV 16
• 1.0% for HPV 18.

As expected, cytologic abnormalities and infection with high-risk HPV types declined with increasing age. The adjusted prevalence of cervical intraepithelial neoplasia (CIN) grade 2 or higher in women aged 25 to 34 years was 2.3%; it declined to 1.5% among women older than age 34. Of note, approximately 500,000 US women are given a diagnosis of CIN 2 or CIN 3 each year in the United States.

WHY ATHENA IS IMPORTANT
This US-based trial was designed to assess the medical utility of pooled high-risk HPV DNA in addition to genotyping for HPV 16 and 18 in three populations:

• women aged 21 and older with a cytologic finding of atypical squamous cells of undetermined significance (ASC-US)
• women aged 30 and older with normal cytology
• women aged 25 and older in the overall screening population with any cytologic finding.

Investigators were particularly interested in the use of the HPV test as:

• a triage for women with abnormal cytologic findings
• an adjunct to guide clinical management of women with negative cytology results
• a potential front-line test in the screening of women aged 25 and older.

Related article: Endometrial cancer update: The move toward personalized cancer care  Lindsay M. Kuroki, MD, and David G. Mutch, MD (October 2013)

The participants of the ATHENA trial were representative of women undergoing screening for cervical cancer in the United States—both in terms of demographics and in the distribution of cytologic findings. For example, recent US census data indicate that the female population is 79% white, 13% black, and 16% Hispanic or Latino—figures comparable to the breakdown of race/ethnicity in the ATHENA trial.

The trial was conducted in a baseline phase (published in 2012) and a 3-year follow-up phase (not yet published). The 3-year data were reviewed by the FDA advisory committee during its consideration of the cobas HPV test as a primary screen.

DESPITE PROBABLE APPROVAL, INCREMENTAL CHANGE IS LIKELY
Although a move to the HPV test as the primary screen is a definite paradigm shift for what has been cytology-based screening since the initiation of cervical cancer screening, the changeover from primary cytology to primary HPV testing likely will be slow. It will require education of clinicians as well as patients, and a shift in many internal procedures for pathology laboratories.

The ATHENA trial also leaves some intriguing questions unanswered:

• How do we transition women into the new screening strategy? Many women today still undergo cytology screening with reflex HPV testing, as appropriate, and an increasing number of women aged 30 and older undergo cotesting with both cytology and HPV testing. When should they begin screening in a primary HPV testing setting? And what screening intervals will be recommended? If a woman already has been screened with cytology, how should she transition into and at what interval should she begin primary HPV screening?
• How should we manage women’s care after the first round of primary HPV testing? The ATHENA trial so far only has outcomes data after one round of HPV testing. While some data are available from Europe, we do not know what happens after two or three rounds of screening with primary HPV testing in a large US-based cohort. We clearly will be identifying and treating many women with preinvasive disease from screening after one round of testing, at a rate likely higher than with cytology alone—a good thing. We also likely will be reducing the number of unnecessary colposcopies for cytology that are not related to hrHPV.

What this EVIDENCE means for practice
Screening women using the cobas HPV test as a primary screen will require considerable education of providers and patients to explain how this change will affect how a woman will be managed after being screened for cervical cancer. Though much remains to be determined about this new cervical cancer screening paradigm (eg, logistics, timing, use of secondary tests), it should reduce the number of screening tests and colposcopies necessary to detect clinically relevant disease.

UPDATED ASCCP GUIDELINES EMPHASIZE EQUAL MANAGEMENT FOR EQUAL RISK

Massad LS, Einstein MH, Huh WK, et al; 2012 ASCCP Consensus Guidelines Conference. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis. 2013;17(5 Suppl 1):S1–S27.

In formulating this latest set of guidelines for the management of abnormal cervical cancer screening tests and cancer precursors, the ASCCP led a conference consisting of scientific stakeholders to perform a comprehensive review of the literature. Also, with study investigators at Kaiser Permanente Northern California (KPNC) and the National Cancer Institute, the guidelines panel also modeled and assessed data on risk after abnormal tests from almost 1.4 million women followed over 8 years in the KPNC Medical Care Plan—this cohort has provided us with “big data.”

The sheer size of the Kaiser Permanente population made it possible for the ASCCP-led panel to validate its previous guidelines or to modify them, where needed. It also made risk-based stratification possible for even rare abnormalities and clinical outcomes.

Although findings from the KPNC population may not be fully generalizable to the US population as a whole, they enhance our understanding of the optimal management of abnormal cervical cancer screening tests and cancer precursors. More widely dispersed study cohorts on a similar scale in the United States are unlikely in the near future.

Related article: Update on cervical disease  Mark H. Einstein, MD, MS, and J. Thomas Cox, MD (May 2013)

SEVERAL SIGNIFICANT MODIFICATIONS
Although the ASCCP reaffirmed most elements of its 2006 consensus management guidelines, it did make a number of changes:

• Women who have ASC-US cytology but test HPV-negative now should be followed with cotesting at 3 years rather than 5 years before they return to routine screening.
• Women near age 65 who have a negative finding on ASC-US cytology and HPV testing should not exit screening.
• Women who have ASC-US cytology and test HPV-positive should go to immediate colposcopy, regardless of hrHPV results, including genotyping.
• Women who test positive for HPV 16 or 18 but have negative cytology should undergo immediate colposcopy.
• Women aged 21 to 24 years should be managed as conservatively and minimally invasively as possible, especially when an abnormality is minor.
• Endocervical curettage reported as CIN 1 should be managed as CIN 1, not as a positive endocervical curettage.
• When a cytologic sample is unsatisfactory, sampling usually should be repeated, even when HPV cotesting results are known. However, negative cytology that lacks sufficient endocervical cells or a transformation zone component usually can be managed without frequent follow-up.

Related article: New cervical Ca screening guidelines recommend less frequent assessment  Janelle Yates (News for your Practice; April 2012)

EQUAL MANAGEMENT SHOULD BE PERFORMED FOR ABNORMAL TESTS THAT INDICATE EQUAL RISK
The ASCCP-led management panel unanimously agreed to several basic assumptions in formulating the updated guidelines. For example, they concurred that achieving zero risk for cancer is impossible and that attempts to achieve zero risk (which typically means more frequent testing) may cause harm. They also cited the 2011 American Cancer Society/ASCCP/American Society for Clinical Pathology consensus screening document, which stated: “Optimal prevention strategies should identify those HPV-related abnormalities likely to progress to invasive cancers while avoiding destructive treatment of abnormalities not destined to become cancerous.”¹

The panel also agreed that CIN 3+ is a “reasonable proxy for cancer risk.” When ­calculating risk, the KPNC data were modeled for all combinations of cytology and HPV testing, using CIN 3+ for many of the outcomes, and when outcomes were rare, using CIN 2+. The theme of equal management for equal risk was the rationale behind the management approaches detailed in the TABLE. Risks were deemed to be low and return to normal screening was recommended when the risks were similar to the rate of CIN 3+ 3 years after negative cytology or 5 years after negative cotesting. However, immediate colposcopy was recommended when the 5-year risk of CIN 3+ for the combination of cytology and hrHPV testing, when indicated, exceeded 5%. A 6-month to 12-month return (intermediate risk) is indicated with a risk of CIN3+ of 2% to 5%.

An emphasis on avoiding harms
Abnormal findings at the time of cervical cancer screening can lead to a number of harms for the patient, including anxiety and emotional distress, particularly when colposcopy is necessary, as well as time lost from home and work life. For this reason, the guidelines panel emphasized that colposcopy and other interventions should be avoided when the risk of CIN 3+ is low and when the cervical screening abnormalities are likely to resolve without treatment.

However, women who experience postcoital bleeding, unexplained abnormal vaginal bleeding, pelvic pain, abnormal discharge, or a visible lesion should be managed promptly on an individualized basis.

Long-term effects of HPV vaccination are unknown
Among the areas that remain to be addressed are the unknown effects of widespread prophylactic HPV vaccination over the long term. We also lack full understanding of whether and how HPV vaccination will alter the incidence and management of cytologic and histologic abnormalities. Given the low rates of vaccination against HPV in the United States at present, this will need to be re-evaluated in the future.

What this EVIDENCE means for practice
The updated ASCCP guidelines are inherently complex, but their complexity arises from a large body of high-quality prospective data from a large population of women. Equal risk should result in equal management of cervical screening test abnormalities. Practitioners need not feel obligated to memorize the guidelines, owing to the availability of algorithms for specific findings in specific populations at the ASCCP Web site (www.asccp.org/consensus2012). Apps also are available for the iPhone, iPad, and Android.

WE WANT TO HEAR FROM YOU!
Share your thoughts on this article or on any topic relevant to ObGyns and women’s health practitioners. Tell us which topics you’d like to see covered in future issues, and what challenges you face in daily practice. We will consider publishing your letter and in a future issue. Send your letter to: [email protected] Please include the city and state in which you practice. Stay in touch! Your feedback is important to us!

On April 17, 2014, the US Food and Drug Administration (FDA) issued a Safety Communication discouraging the use of laparoscopic power morcellation in hysterectomy and myomectomy for uterine fibroids.

Based on an FDA analysis of current data, “… it is estimated that 1 in 350 women undergoing hysterectomy or myomectomy for the treatment of fibroids is found to have an unsuspected uterine sarcoma, a type of uterine cancer that includes leiomyosarcoma. If laparoscopic power morcellation is performed in women with unsuspected uterine sarcoma, there is a risk that the procedure will spread the cancerous tissue within the abdomen and pelvis, significantly worsening the patient’s likelihood of long-term survival.”¹

FDA recommendations
The FDA posted the following recommendations for health-care providers¹:

1. Laparoscopic uterine power morcellation should not be used in women with suspected or known uterine cancer
2. All available treatment options should be considered for women with symptomatic uterine fibroids
3. The benefits and risks of all treatments should be discussed thoroughly with each patient
4. If, after a careful benefit-risk evaluation, laparoscopic power morcellation is considered the best therapeutic option for an individual patient, then:

• Inform the patient that her fibroid(s) may contain unexpected cancerous tissue and that laparoscopic power morcellation may spread the cancer, significantly worsening her prognosis
• Some clinicians and medical institutions now advocate using a specimen “bag” during morcellation in an attempt to contain the uterine tissue and minimize the risk of spread in the abdomen and pelvis.

Although many women choose laparoscopic hysterectomy or myomectomy because of the associated benefits, there are other treatments available, including vaginal or abdominal hysterectomy and myomectomy; laparoscopic hysterectomy or myomectomy without morcellation; minilaparotomy; uterine artery embolization; high-intensity focused ultrasound; and drug therapy.

FDA actions
To reduce the risk of inadvertent spread of unsuspected cancer to the abdomen and pelvis, the FDA has instructed manufacturers of power morcellators used during laparoscopic hysterectomy and myomectomy to immediately review labeling for accurate risk information.

A to-be-convened public meeting of the FDA’s Obstetrics and Gynecological Medical Device Advisory Committee will discuss¹:

• the clinical role of laparoscopic power morcellation in the treatment of uterine fibroids
• whether surgical techniques and/or use of accessories, such as morcellation and/or specimen bags, can enhance the safe and effective use of these devices
• if a boxed warning relating the risk of cancer spread should be required for laparoscopic power morcellators.

The FDA will continue to review adverse event reports and peer-reviewed literature, as well as patient information and evidence from health-care providers, gynecologic and surgical professional societies, and medical device manufacturers.

Adverse events should promptly be reported to the FDA by filing a voluntary report through MedWatch, the FDA Safety Information and Adverse Event Reporting program.

Institution reaction
Brigham and Women's Hospital had banned the use of open power morcellation on March 31, 2014, allowing for the use of power morcellators within a containment system. In light of the FDA notice that discourages the use of power morcellators during hysterectomy or myomectomy for the treatment of uterine fibroids, however, Robert L. Barbieri, MD, chair of obstetrics and gynecology at Brigham and Women’s advised surgical staff to "immediately suspend use of power morcellators in all cases until further notice."    

Massachusetts General, which also had placed restrictions on the use of power morcellators prior to the FDA communication, suspended the use of power morcellation.

“I have asked our doctors to stop the procedure immediately until more information is available,’’ Dr. Isaac Schiff, Massachusetts General’s chief of obstetrics and gynecology, told the Boston Globe.     

On April 17, 2014, the US Food and Drug Administration (FDA) issued a Safety Communication discouraging the use of laparoscopic power morcellation in hysterectomy and myomectomy for uterine fibroids.

Based on an FDA analysis of current data, “… it is estimated that 1 in 350 women undergoing hysterectomy or myomectomy for the treatment of fibroids is found to have an unsuspected uterine sarcoma, a type of uterine cancer that includes leiomyosarcoma. If laparoscopic power morcellation is performed in women with unsuspected uterine sarcoma, there is a risk that the procedure will spread the cancerous tissue within the abdomen and pelvis, significantly worsening the patient’s likelihood of long-term survival.”¹

FDA recommendations
The FDA posted the following recommendations for health-care providers¹:

1. Laparoscopic uterine power morcellation should not be used in women with suspected or known uterine cancer
2. All available treatment options should be considered for women with symptomatic uterine fibroids
3. The benefits and risks of all treatments should be discussed thoroughly with each patient
4. If, after a careful benefit-risk evaluation, laparoscopic power morcellation is considered the best therapeutic option for an individual patient, then:

• Inform the patient that her fibroid(s) may contain unexpected cancerous tissue and that laparoscopic power morcellation may spread the cancer, significantly worsening her prognosis
• Some clinicians and medical institutions now advocate using a specimen “bag” during morcellation in an attempt to contain the uterine tissue and minimize the risk of spread in the abdomen and pelvis.

Although many women choose laparoscopic hysterectomy or myomectomy because of the associated benefits, there are other treatments available, including vaginal or abdominal hysterectomy and myomectomy; laparoscopic hysterectomy or myomectomy without morcellation; minilaparotomy; uterine artery embolization; high-intensity focused ultrasound; and drug therapy.

FDA actions
To reduce the risk of inadvertent spread of unsuspected cancer to the abdomen and pelvis, the FDA has instructed manufacturers of power morcellators used during laparoscopic hysterectomy and myomectomy to immediately review labeling for accurate risk information.

A to-be-convened public meeting of the FDA’s Obstetrics and Gynecological Medical Device Advisory Committee will discuss¹:

• the clinical role of laparoscopic power morcellation in the treatment of uterine fibroids
• whether surgical techniques and/or use of accessories, such as morcellation and/or specimen bags, can enhance the safe and effective use of these devices
• if a boxed warning relating the risk of cancer spread should be required for laparoscopic power morcellators.

The FDA will continue to review adverse event reports and peer-reviewed literature, as well as patient information and evidence from health-care providers, gynecologic and surgical professional societies, and medical device manufacturers.

Adverse events should promptly be reported to the FDA by filing a voluntary report through MedWatch, the FDA Safety Information and Adverse Event Reporting program.

Institution reaction
Brigham and Women's Hospital had banned the use of open power morcellation on March 31, 2014, allowing for the use of power morcellators within a containment system. In light of the FDA notice that discourages the use of power morcellators during hysterectomy or myomectomy for the treatment of uterine fibroids, however, Robert L. Barbieri, MD, chair of obstetrics and gynecology at Brigham and Women’s advised surgical staff to "immediately suspend use of power morcellators in all cases until further notice."    

Massachusetts General, which also had placed restrictions on the use of power morcellators prior to the FDA communication, suspended the use of power morcellation.

“I have asked our doctors to stop the procedure immediately until more information is available,’’ Dr. Isaac Schiff, Massachusetts General’s chief of obstetrics and gynecology, told the Boston Globe.     

On April 17, 2014, the US Food and Drug Administration (FDA) issued a Safety Communication discouraging the use of laparoscopic power morcellation in hysterectomy and myomectomy for uterine fibroids.

Based on an FDA analysis of current data, “… it is estimated that 1 in 350 women undergoing hysterectomy or myomectomy for the treatment of fibroids is found to have an unsuspected uterine sarcoma, a type of uterine cancer that includes leiomyosarcoma. If laparoscopic power morcellation is performed in women with unsuspected uterine sarcoma, there is a risk that the procedure will spread the cancerous tissue within the abdomen and pelvis, significantly worsening the patient’s likelihood of long-term survival.”¹

FDA recommendations
The FDA posted the following recommendations for health-care providers¹:

1. Laparoscopic uterine power morcellation should not be used in women with suspected or known uterine cancer
2. All available treatment options should be considered for women with symptomatic uterine fibroids
3. The benefits and risks of all treatments should be discussed thoroughly with each patient
4. If, after a careful benefit-risk evaluation, laparoscopic power morcellation is considered the best therapeutic option for an individual patient, then:

• Inform the patient that her fibroid(s) may contain unexpected cancerous tissue and that laparoscopic power morcellation may spread the cancer, significantly worsening her prognosis
• Some clinicians and medical institutions now advocate using a specimen “bag” during morcellation in an attempt to contain the uterine tissue and minimize the risk of spread in the abdomen and pelvis.

Although many women choose laparoscopic hysterectomy or myomectomy because of the associated benefits, there are other treatments available, including vaginal or abdominal hysterectomy and myomectomy; laparoscopic hysterectomy or myomectomy without morcellation; minilaparotomy; uterine artery embolization; high-intensity focused ultrasound; and drug therapy.

FDA actions
To reduce the risk of inadvertent spread of unsuspected cancer to the abdomen and pelvis, the FDA has instructed manufacturers of power morcellators used during laparoscopic hysterectomy and myomectomy to immediately review labeling for accurate risk information.

A to-be-convened public meeting of the FDA’s Obstetrics and Gynecological Medical Device Advisory Committee will discuss¹:

• the clinical role of laparoscopic power morcellation in the treatment of uterine fibroids
• whether surgical techniques and/or use of accessories, such as morcellation and/or specimen bags, can enhance the safe and effective use of these devices
• if a boxed warning relating the risk of cancer spread should be required for laparoscopic power morcellators.

The FDA will continue to review adverse event reports and peer-reviewed literature, as well as patient information and evidence from health-care providers, gynecologic and surgical professional societies, and medical device manufacturers.

Adverse events should promptly be reported to the FDA by filing a voluntary report through MedWatch, the FDA Safety Information and Adverse Event Reporting program.

Institution reaction
Brigham and Women's Hospital had banned the use of open power morcellation on March 31, 2014, allowing for the use of power morcellators within a containment system. In light of the FDA notice that discourages the use of power morcellators during hysterectomy or myomectomy for the treatment of uterine fibroids, however, Robert L. Barbieri, MD, chair of obstetrics and gynecology at Brigham and Women’s advised surgical staff to "immediately suspend use of power morcellators in all cases until further notice."    

Massachusetts General, which also had placed restrictions on the use of power morcellators prior to the FDA communication, suspended the use of power morcellation.

“I have asked our doctors to stop the procedure immediately until more information is available,’’ Dr. Isaac Schiff, Massachusetts General’s chief of obstetrics and gynecology, told the Boston Globe.     

A new study¹ provides the first evidence of a direct effect of maternal metabolism on fetal brain activity, suggesting that insulin resistance, the precursor to type 2 diabetes, begins its formation prenatally.

DETAILS OF THE STUDY

Dr. Katarzyna Linder from the University Hospital Tübingen in Germany and colleagues included in their study 13 healthy pregnant women with normal, singleton pregnancies of between 27 and 36 weeks. All of the women underwent an oral glucose tolerance test, meaning that after a 5-hour overnight fast, each woman drank a solution containing 75 g glucose. The investigators ascertained blood glucose and plasma insulin levels from blood samples taken at 0, 60, and 120 minutes.

At approximately the same time points, but before they drew each blood sample, the authors obtained a fetal magnetoencephalography (fMEG) measurement in an effort to noninvasively record brain activity in utero. During each measurement, they presented an auditory sequence to the fetus. Most (75%) of the time, the sound presented had a frequency of 500 Hz, but 25% of the time the researchers presented a deviant tone with a frequency of 750 Hz to prevent habituation.

The researchers found that maternal insulin sensitivity significantly correlated with response latency of the fetus at the 60-minute time point, so that the higher the insulin sensitivity of the mother, the shorter the response time of the fetus to the sound. The association remained significant even after the investigators controlled for relative maternal weight gain, gestational age, and the child’s birth weight. No significant correlation existed at baseline or at 120 minutes.

The investigators then split the women into 2 groups: those who were insulin-resistant and those who were insulin-sensitive. They found that the fetuses of the insulin-resistant moms were almost 40% slower to respond to the auditory stimuli than those of the insulin-sensitive moms (mean [SD], 283 [79] ms vs 178 [46] ms; P=.03).

INTERPRETING THE FINDINGS

According to the US Centers for Disease Control and Prevention, almost one-third (30.3%) of US adults between the ages of 20 and 39 years—the primary child-bearing years—are obese,² as are 17% of our children and adolescents—triple the rate of 1 generation previous.³ Furthermore, 25.8 million people in the United States have diabetes, including 1 in every 400 children and adolescents.⁴

Experts know that the children of obese or diabetic mothers are at increased risk for obesity and type 2 diabetes as adults, and that the connection is not purely genetic; environmental and epigenetic (environmental elements that affect genetics) factors also play key roles. The latter is the basis for the fetal or developmental origins hypothesis,⁵ which posits that a pregnant woman’s exposure to certain environmental factors can affect the programming of her unborn child and impact adult health.

The authors of the current study demonstrate that the metabolism of a pregnant woman after a sugar load directly affects the response time and brain activity of her developing fetus. They suggest as a mechanism for the effect that “insulin-resistant mothers have higher glucose levels accompanied by increased insulin levels in the postprandial state. As glucose passes the placenta, these postprandially increased glucose levels induce hyperinsulinaemia in the fetus.” The resulting chronic hyperinsulinemia “might induce insulin resistance in the fetal brain.”

A new study¹ provides the first evidence of a direct effect of maternal metabolism on fetal brain activity, suggesting that insulin resistance, the precursor to type 2 diabetes, begins its formation prenatally.

DETAILS OF THE STUDY

Dr. Katarzyna Linder from the University Hospital Tübingen in Germany and colleagues included in their study 13 healthy pregnant women with normal, singleton pregnancies of between 27 and 36 weeks. All of the women underwent an oral glucose tolerance test, meaning that after a 5-hour overnight fast, each woman drank a solution containing 75 g glucose. The investigators ascertained blood glucose and plasma insulin levels from blood samples taken at 0, 60, and 120 minutes.

At approximately the same time points, but before they drew each blood sample, the authors obtained a fetal magnetoencephalography (fMEG) measurement in an effort to noninvasively record brain activity in utero. During each measurement, they presented an auditory sequence to the fetus. Most (75%) of the time, the sound presented had a frequency of 500 Hz, but 25% of the time the researchers presented a deviant tone with a frequency of 750 Hz to prevent habituation.

The researchers found that maternal insulin sensitivity significantly correlated with response latency of the fetus at the 60-minute time point, so that the higher the insulin sensitivity of the mother, the shorter the response time of the fetus to the sound. The association remained significant even after the investigators controlled for relative maternal weight gain, gestational age, and the child’s birth weight. No significant correlation existed at baseline or at 120 minutes.

The investigators then split the women into 2 groups: those who were insulin-resistant and those who were insulin-sensitive. They found that the fetuses of the insulin-resistant moms were almost 40% slower to respond to the auditory stimuli than those of the insulin-sensitive moms (mean [SD], 283 [79] ms vs 178 [46] ms; P=.03).

INTERPRETING THE FINDINGS

According to the US Centers for Disease Control and Prevention, almost one-third (30.3%) of US adults between the ages of 20 and 39 years—the primary child-bearing years—are obese,² as are 17% of our children and adolescents—triple the rate of 1 generation previous.³ Furthermore, 25.8 million people in the United States have diabetes, including 1 in every 400 children and adolescents.⁴

Experts know that the children of obese or diabetic mothers are at increased risk for obesity and type 2 diabetes as adults, and that the connection is not purely genetic; environmental and epigenetic (environmental elements that affect genetics) factors also play key roles. The latter is the basis for the fetal or developmental origins hypothesis,⁵ which posits that a pregnant woman’s exposure to certain environmental factors can affect the programming of her unborn child and impact adult health.

The authors of the current study demonstrate that the metabolism of a pregnant woman after a sugar load directly affects the response time and brain activity of her developing fetus. They suggest as a mechanism for the effect that “insulin-resistant mothers have higher glucose levels accompanied by increased insulin levels in the postprandial state. As glucose passes the placenta, these postprandially increased glucose levels induce hyperinsulinaemia in the fetus.” The resulting chronic hyperinsulinemia “might induce insulin resistance in the fetal brain.”

A new study¹ provides the first evidence of a direct effect of maternal metabolism on fetal brain activity, suggesting that insulin resistance, the precursor to type 2 diabetes, begins its formation prenatally.

DETAILS OF THE STUDY

Dr. Katarzyna Linder from the University Hospital Tübingen in Germany and colleagues included in their study 13 healthy pregnant women with normal, singleton pregnancies of between 27 and 36 weeks. All of the women underwent an oral glucose tolerance test, meaning that after a 5-hour overnight fast, each woman drank a solution containing 75 g glucose. The investigators ascertained blood glucose and plasma insulin levels from blood samples taken at 0, 60, and 120 minutes.

At approximately the same time points, but before they drew each blood sample, the authors obtained a fetal magnetoencephalography (fMEG) measurement in an effort to noninvasively record brain activity in utero. During each measurement, they presented an auditory sequence to the fetus. Most (75%) of the time, the sound presented had a frequency of 500 Hz, but 25% of the time the researchers presented a deviant tone with a frequency of 750 Hz to prevent habituation.

The researchers found that maternal insulin sensitivity significantly correlated with response latency of the fetus at the 60-minute time point, so that the higher the insulin sensitivity of the mother, the shorter the response time of the fetus to the sound. The association remained significant even after the investigators controlled for relative maternal weight gain, gestational age, and the child’s birth weight. No significant correlation existed at baseline or at 120 minutes.

The investigators then split the women into 2 groups: those who were insulin-resistant and those who were insulin-sensitive. They found that the fetuses of the insulin-resistant moms were almost 40% slower to respond to the auditory stimuli than those of the insulin-sensitive moms (mean [SD], 283 [79] ms vs 178 [46] ms; P=.03).

INTERPRETING THE FINDINGS

According to the US Centers for Disease Control and Prevention, almost one-third (30.3%) of US adults between the ages of 20 and 39 years—the primary child-bearing years—are obese,² as are 17% of our children and adolescents—triple the rate of 1 generation previous.³ Furthermore, 25.8 million people in the United States have diabetes, including 1 in every 400 children and adolescents.⁴

Experts know that the children of obese or diabetic mothers are at increased risk for obesity and type 2 diabetes as adults, and that the connection is not purely genetic; environmental and epigenetic (environmental elements that affect genetics) factors also play key roles. The latter is the basis for the fetal or developmental origins hypothesis,⁵ which posits that a pregnant woman’s exposure to certain environmental factors can affect the programming of her unborn child and impact adult health.

The authors of the current study demonstrate that the metabolism of a pregnant woman after a sugar load directly affects the response time and brain activity of her developing fetus. They suggest as a mechanism for the effect that “insulin-resistant mothers have higher glucose levels accompanied by increased insulin levels in the postprandial state. As glucose passes the placenta, these postprandially increased glucose levels induce hyperinsulinaemia in the fetus.” The resulting chronic hyperinsulinemia “might induce insulin resistance in the fetal brain.”

Experts generally have not considered H influenzae disease to be a substantial contributor to severely adverse fetal outcomes. Yet new research from England and Wales finds that even though pregnant women in their study tended to be younger and healthier than their nonpregnant counterparts, they were far more likely to develop the invasive unencapsulated form of disease and far more likely to present with bacteremia. Not to mention that almost all of their pregnancies resulted in miscarriage, stillbirth, extremely preterm birth, or, at best, the birth of infants with respiratory distress with or without sepsis. 

DETAILS OF THE STUDY

Collins and colleagues queried prospectively general practitioners who cared for women of reproductive age (15 to 44 years) with invasive H influenzae disease during the 4-year period of 2009 to 2012. One hundred percent of those queried responded. The study encompassed more than 45 million woman-years of follow-up.

Of the 171 women who developed the infection (confirmed by positive culture from a normally sterile site), approximately 84% (144) had unencapsulated disease. Not quite half (44% or 75) of the 171 women were pregnant at the time of infection. The overall incidence of confirmed invasive H influenzae disease was low at 0.50 per 100,000 women of reproductive age, but the 75 pregnant women were 17.2 (95% confidence interval [CI], 12.2-24.1; P<.001) times as likely to develop the infection as the 96 nonpregnant women (2.98/100,000 woman-years versus 0.17/100,000 woman-years, respectively). And, despite being previously healthy, almost three times as many pregnant as nonpregnant women presented with bacteremia (90.3% versus 33.3%, respectively).

Of 47 women who developed unencapsulated H influenzae infection during the first 24 weeks of pregnancy, 44 lost the fetus and three had extremely preterm births. Of 28 women who developed the infection during the second half of their pregnancy, two had stillbirths. Eight of the 26 live births were preterm, and 21 of the 26 infants had respiratory distress with or without sepsis at birth. The researchers calculated that the rate of pregnancy loss following invasive H influenzae disease was almost 3 times higher than the average rate of pregnancy loss in England and Wales.

CLINICAL RECOMMENDATIONS

It is generally reported that up to one-quarter of the approximately 26,000 stillbirths occurring yearly in the United States are due to some type of maternal or fetal infection.^2,3 Dr. Morven S. Edwards, in an editorial⁴ appearing in the same issue of JAMA as the study, comments, “Given the magnitude of the burden of perinatal deaths, clarifying the extent that bacterial infections result in stillbirth and preterm delivery could potentially inform interventions to improve child and maternal health globally.”

Experts generally have not considered H influenzae disease to be a substantial contributor to severely adverse fetal outcomes. Yet new research from England and Wales finds that even though pregnant women in their study tended to be younger and healthier than their nonpregnant counterparts, they were far more likely to develop the invasive unencapsulated form of disease and far more likely to present with bacteremia. Not to mention that almost all of their pregnancies resulted in miscarriage, stillbirth, extremely preterm birth, or, at best, the birth of infants with respiratory distress with or without sepsis. 

DETAILS OF THE STUDY

Collins and colleagues queried prospectively general practitioners who cared for women of reproductive age (15 to 44 years) with invasive H influenzae disease during the 4-year period of 2009 to 2012. One hundred percent of those queried responded. The study encompassed more than 45 million woman-years of follow-up.

Of the 171 women who developed the infection (confirmed by positive culture from a normally sterile site), approximately 84% (144) had unencapsulated disease. Not quite half (44% or 75) of the 171 women were pregnant at the time of infection. The overall incidence of confirmed invasive H influenzae disease was low at 0.50 per 100,000 women of reproductive age, but the 75 pregnant women were 17.2 (95% confidence interval [CI], 12.2-24.1; P<.001) times as likely to develop the infection as the 96 nonpregnant women (2.98/100,000 woman-years versus 0.17/100,000 woman-years, respectively). And, despite being previously healthy, almost three times as many pregnant as nonpregnant women presented with bacteremia (90.3% versus 33.3%, respectively).

Of 47 women who developed unencapsulated H influenzae infection during the first 24 weeks of pregnancy, 44 lost the fetus and three had extremely preterm births. Of 28 women who developed the infection during the second half of their pregnancy, two had stillbirths. Eight of the 26 live births were preterm, and 21 of the 26 infants had respiratory distress with or without sepsis at birth. The researchers calculated that the rate of pregnancy loss following invasive H influenzae disease was almost 3 times higher than the average rate of pregnancy loss in England and Wales.

CLINICAL RECOMMENDATIONS

It is generally reported that up to one-quarter of the approximately 26,000 stillbirths occurring yearly in the United States are due to some type of maternal or fetal infection.^2,3 Dr. Morven S. Edwards, in an editorial⁴ appearing in the same issue of JAMA as the study, comments, “Given the magnitude of the burden of perinatal deaths, clarifying the extent that bacterial infections result in stillbirth and preterm delivery could potentially inform interventions to improve child and maternal health globally.”

Experts generally have not considered H influenzae disease to be a substantial contributor to severely adverse fetal outcomes. Yet new research from England and Wales finds that even though pregnant women in their study tended to be younger and healthier than their nonpregnant counterparts, they were far more likely to develop the invasive unencapsulated form of disease and far more likely to present with bacteremia. Not to mention that almost all of their pregnancies resulted in miscarriage, stillbirth, extremely preterm birth, or, at best, the birth of infants with respiratory distress with or without sepsis. 

DETAILS OF THE STUDY

Collins and colleagues queried prospectively general practitioners who cared for women of reproductive age (15 to 44 years) with invasive H influenzae disease during the 4-year period of 2009 to 2012. One hundred percent of those queried responded. The study encompassed more than 45 million woman-years of follow-up.

Of the 171 women who developed the infection (confirmed by positive culture from a normally sterile site), approximately 84% (144) had unencapsulated disease. Not quite half (44% or 75) of the 171 women were pregnant at the time of infection. The overall incidence of confirmed invasive H influenzae disease was low at 0.50 per 100,000 women of reproductive age, but the 75 pregnant women were 17.2 (95% confidence interval [CI], 12.2-24.1; P<.001) times as likely to develop the infection as the 96 nonpregnant women (2.98/100,000 woman-years versus 0.17/100,000 woman-years, respectively). And, despite being previously healthy, almost three times as many pregnant as nonpregnant women presented with bacteremia (90.3% versus 33.3%, respectively).

Of 47 women who developed unencapsulated H influenzae infection during the first 24 weeks of pregnancy, 44 lost the fetus and three had extremely preterm births. Of 28 women who developed the infection during the second half of their pregnancy, two had stillbirths. Eight of the 26 live births were preterm, and 21 of the 26 infants had respiratory distress with or without sepsis at birth. The researchers calculated that the rate of pregnancy loss following invasive H influenzae disease was almost 3 times higher than the average rate of pregnancy loss in England and Wales.

CLINICAL RECOMMENDATIONS

It is generally reported that up to one-quarter of the approximately 26,000 stillbirths occurring yearly in the United States are due to some type of maternal or fetal infection.^2,3 Dr. Morven S. Edwards, in an editorial⁴ appearing in the same issue of JAMA as the study, comments, “Given the magnitude of the burden of perinatal deaths, clarifying the extent that bacterial infections result in stillbirth and preterm delivery could potentially inform interventions to improve child and maternal health globally.”

The use of power morcellation to remove the uterus or uterine tumors during hysterectomy may be riskier than many have thought, especially when morcellation is performed in an “open” fashion (without use of a protective bag) in the peritoneal cavity. That’s the conclusion reached by two top Boston hospitals recently, when Brigham and Women’s and Massachusetts General both banned use of open power morcellation in gynecologic surgery.

Both hospitals assert that, when used outside of a containment system such as a morcellation bag, intraperitoneal open morcellation can spread tumor tissue throughout the peritoneal cavity. Robert L. Barbieri, MD, who is chair of obstetrics and gynecology at Brigham and Women’s Hospital, recently wrote about this concern for OBG Management in his capacity as editor in chief of the journal.

“When used to treat tumors presumed to be fibroids, open power morcellation is associated with an increased risk of dispersing benign myoma tissue and occult malignant leiomyosarcoma tissue throughout the abdominal cavity,” he wrote.¹ “Dispersion of benign myoma tissue may result in the growth of fibroids on the peritoneal surface, omentum, and bowel, causing abdominal and pelvic pain and necessitating reoperation. Dispersion of leiomyosarcoma tissue throughout the abdominal cavity may result in a Stage I cancer being upstaged to a Stage IV malignancy, requiring additional surgery and chemotherapy. In cases in which open power morcellation causes the upstaging of a leiomyosarcoma, the death rate is increased.”¹

Related article: Options for reducing the use of open power morcellation of uterine tumors  Robert L. Barbieri, MD (Editorial, March 2014)

The two Boston hospitals are not the only institutions reconsidering the use of open power morcellation. Temple University Hospital in Philadelphia banned the procedure in late February 2014.

And in December 2013, the Society of Gynecologic Oncology issued a position statement on the issue, which said, “power morcellation or other techniques that cut up the uterus in the abdomen have the potential to disseminate an otherwise contained malignancy throughout the abdominal cavity. For this reason, the Society of Gynecologic Oncology (SGO) asserts that it is generally contraindicated in the presence of documented or highly suspected malignancy, and may be inadvisable in premalignant conditions or risk-reducing surgery.”²

For its part, the AAGL, previously known as the American Association of Gynecologic Laparoscopists, “is reviewing the scientific evidence and best practices reported by our members,” stated an article in its Association News. “We recognize that, in rare cases, the use of power morcellators can lead to the dissemination of an occult malignancy of endometrial or myometrial origin, and also of dissemination of benign morcellated tissues. We encourage our members to fully research and understand the risks of power morcellation and to learn more about when alternative methods of tissue extraction may be appropriate.”³

The most recent committee opinion on choosing a hysterectomy route from the American College of Obstetricians and Gynecologists (ACOG) to touch on the issue states that, “the decision to perform a hysterectomy via [minimally invasive surgery] (with or without morcellation) is based on a patient evaluation, including the patient’s history and general health, tests, and procedures, such as pre-surgery biopsies. The evaluation and diagnostic process also provides an opportunity to identify any cautions or contraindications, such as finding a gynecological cancer.”⁴

FILLING THE TECHNOLOGY GAP
Now that open power morcellation appears to be receding as an option for minimally invasive gynecologic surgeons, what is the best approach?

In its position statement, the SGO recommends that, “Patients being considered for minimally invasive surgery performed by laparoscopic or robotic techniques who might require intracorporeal morcellation should be appropriately evaluated for the possibility of coexisting uterine or cervical malignancy. Other options to intracorporeal morcellation include removing the uterus through a mini-laparotomy or morcellating the uterus inside a laparoscopic bag.”²

K. Anthony Shibley, MD, a Minneapolis-area ObGyn, has developed a novel strategy to prevent tissue dissemination during open power morcellation. His strategy involves utilization of a large bowel isolation bag. For more on this approach, click here.

AAGL is in the process of formulating a policy on the use of open power morcellation. ACOG has not signaled its intent to weigh in on the issue.

Brigham and Women’s Hospital intends to carefully review requests for permission to utilize open power morcellation on a case-by-case basis, provided the surgeon presents all case details and a rationale for exemption from the new rule.

The use of power morcellation to remove the uterus or uterine tumors during hysterectomy may be riskier than many have thought, especially when morcellation is performed in an “open” fashion (without use of a protective bag) in the peritoneal cavity. That’s the conclusion reached by two top Boston hospitals recently, when Brigham and Women’s and Massachusetts General both banned use of open power morcellation in gynecologic surgery.

Both hospitals assert that, when used outside of a containment system such as a morcellation bag, intraperitoneal open morcellation can spread tumor tissue throughout the peritoneal cavity. Robert L. Barbieri, MD, who is chair of obstetrics and gynecology at Brigham and Women’s Hospital, recently wrote about this concern for OBG Management in his capacity as editor in chief of the journal.

“When used to treat tumors presumed to be fibroids, open power morcellation is associated with an increased risk of dispersing benign myoma tissue and occult malignant leiomyosarcoma tissue throughout the abdominal cavity,” he wrote.¹ “Dispersion of benign myoma tissue may result in the growth of fibroids on the peritoneal surface, omentum, and bowel, causing abdominal and pelvic pain and necessitating reoperation. Dispersion of leiomyosarcoma tissue throughout the abdominal cavity may result in a Stage I cancer being upstaged to a Stage IV malignancy, requiring additional surgery and chemotherapy. In cases in which open power morcellation causes the upstaging of a leiomyosarcoma, the death rate is increased.”¹

Related article: Options for reducing the use of open power morcellation of uterine tumors  Robert L. Barbieri, MD (Editorial, March 2014)

The two Boston hospitals are not the only institutions reconsidering the use of open power morcellation. Temple University Hospital in Philadelphia banned the procedure in late February 2014.

And in December 2013, the Society of Gynecologic Oncology issued a position statement on the issue, which said, “power morcellation or other techniques that cut up the uterus in the abdomen have the potential to disseminate an otherwise contained malignancy throughout the abdominal cavity. For this reason, the Society of Gynecologic Oncology (SGO) asserts that it is generally contraindicated in the presence of documented or highly suspected malignancy, and may be inadvisable in premalignant conditions or risk-reducing surgery.”²

For its part, the AAGL, previously known as the American Association of Gynecologic Laparoscopists, “is reviewing the scientific evidence and best practices reported by our members,” stated an article in its Association News. “We recognize that, in rare cases, the use of power morcellators can lead to the dissemination of an occult malignancy of endometrial or myometrial origin, and also of dissemination of benign morcellated tissues. We encourage our members to fully research and understand the risks of power morcellation and to learn more about when alternative methods of tissue extraction may be appropriate.”³

The most recent committee opinion on choosing a hysterectomy route from the American College of Obstetricians and Gynecologists (ACOG) to touch on the issue states that, “the decision to perform a hysterectomy via [minimally invasive surgery] (with or without morcellation) is based on a patient evaluation, including the patient’s history and general health, tests, and procedures, such as pre-surgery biopsies. The evaluation and diagnostic process also provides an opportunity to identify any cautions or contraindications, such as finding a gynecological cancer.”⁴

FILLING THE TECHNOLOGY GAP
Now that open power morcellation appears to be receding as an option for minimally invasive gynecologic surgeons, what is the best approach?

In its position statement, the SGO recommends that, “Patients being considered for minimally invasive surgery performed by laparoscopic or robotic techniques who might require intracorporeal morcellation should be appropriately evaluated for the possibility of coexisting uterine or cervical malignancy. Other options to intracorporeal morcellation include removing the uterus through a mini-laparotomy or morcellating the uterus inside a laparoscopic bag.”²

K. Anthony Shibley, MD, a Minneapolis-area ObGyn, has developed a novel strategy to prevent tissue dissemination during open power morcellation. His strategy involves utilization of a large bowel isolation bag. For more on this approach, click here.

AAGL is in the process of formulating a policy on the use of open power morcellation. ACOG has not signaled its intent to weigh in on the issue.

Brigham and Women’s Hospital intends to carefully review requests for permission to utilize open power morcellation on a case-by-case basis, provided the surgeon presents all case details and a rationale for exemption from the new rule.

The use of power morcellation to remove the uterus or uterine tumors during hysterectomy may be riskier than many have thought, especially when morcellation is performed in an “open” fashion (without use of a protective bag) in the peritoneal cavity. That’s the conclusion reached by two top Boston hospitals recently, when Brigham and Women’s and Massachusetts General both banned use of open power morcellation in gynecologic surgery.

Both hospitals assert that, when used outside of a containment system such as a morcellation bag, intraperitoneal open morcellation can spread tumor tissue throughout the peritoneal cavity. Robert L. Barbieri, MD, who is chair of obstetrics and gynecology at Brigham and Women’s Hospital, recently wrote about this concern for OBG Management in his capacity as editor in chief of the journal.

“When used to treat tumors presumed to be fibroids, open power morcellation is associated with an increased risk of dispersing benign myoma tissue and occult malignant leiomyosarcoma tissue throughout the abdominal cavity,” he wrote.¹ “Dispersion of benign myoma tissue may result in the growth of fibroids on the peritoneal surface, omentum, and bowel, causing abdominal and pelvic pain and necessitating reoperation. Dispersion of leiomyosarcoma tissue throughout the abdominal cavity may result in a Stage I cancer being upstaged to a Stage IV malignancy, requiring additional surgery and chemotherapy. In cases in which open power morcellation causes the upstaging of a leiomyosarcoma, the death rate is increased.”¹

Related article: Options for reducing the use of open power morcellation of uterine tumors  Robert L. Barbieri, MD (Editorial, March 2014)

The two Boston hospitals are not the only institutions reconsidering the use of open power morcellation. Temple University Hospital in Philadelphia banned the procedure in late February 2014.

And in December 2013, the Society of Gynecologic Oncology issued a position statement on the issue, which said, “power morcellation or other techniques that cut up the uterus in the abdomen have the potential to disseminate an otherwise contained malignancy throughout the abdominal cavity. For this reason, the Society of Gynecologic Oncology (SGO) asserts that it is generally contraindicated in the presence of documented or highly suspected malignancy, and may be inadvisable in premalignant conditions or risk-reducing surgery.”²

For its part, the AAGL, previously known as the American Association of Gynecologic Laparoscopists, “is reviewing the scientific evidence and best practices reported by our members,” stated an article in its Association News. “We recognize that, in rare cases, the use of power morcellators can lead to the dissemination of an occult malignancy of endometrial or myometrial origin, and also of dissemination of benign morcellated tissues. We encourage our members to fully research and understand the risks of power morcellation and to learn more about when alternative methods of tissue extraction may be appropriate.”³

The most recent committee opinion on choosing a hysterectomy route from the American College of Obstetricians and Gynecologists (ACOG) to touch on the issue states that, “the decision to perform a hysterectomy via [minimally invasive surgery] (with or without morcellation) is based on a patient evaluation, including the patient’s history and general health, tests, and procedures, such as pre-surgery biopsies. The evaluation and diagnostic process also provides an opportunity to identify any cautions or contraindications, such as finding a gynecological cancer.”⁴

FILLING THE TECHNOLOGY GAP
Now that open power morcellation appears to be receding as an option for minimally invasive gynecologic surgeons, what is the best approach?

In its position statement, the SGO recommends that, “Patients being considered for minimally invasive surgery performed by laparoscopic or robotic techniques who might require intracorporeal morcellation should be appropriately evaluated for the possibility of coexisting uterine or cervical malignancy. Other options to intracorporeal morcellation include removing the uterus through a mini-laparotomy or morcellating the uterus inside a laparoscopic bag.”²

K. Anthony Shibley, MD, a Minneapolis-area ObGyn, has developed a novel strategy to prevent tissue dissemination during open power morcellation. His strategy involves utilization of a large bowel isolation bag. For more on this approach, click here.

AAGL is in the process of formulating a policy on the use of open power morcellation. ACOG has not signaled its intent to weigh in on the issue.

Brigham and Women’s Hospital intends to carefully review requests for permission to utilize open power morcellation on a case-by-case basis, provided the surgeon presents all case details and a rationale for exemption from the new rule.